Measurement of total ultrasonic power using thermal expansion and change in buoyancy of an absorbing target.
The Radiation Force Balance (RFB) technique is well established and most widely used for the measurement of total ultrasonic power radiated by ultrasonic transducer. The technique is used as a primary standard for calibration of ultrasonic transducers with relatively fair uncertainty in the low power (below 1 W) regime. In this technique, uncertainty comparatively increases in the range of few watts wherein the effects such as thermal heating of the target, cavitations, and acoustic streaming dominate. In addition, error in the measurement of ultrasonic power is also caused due to movement of absorber at relatively high radiated force which occurs at high power level. In this article a new technique is proposed which does not measure the balance output during transducer energized state as done in RFB. It utilizes the change in buoyancy of the absorbing target due to local thermal heating. The linear thermal expansion of the target changes the apparent mass in water due to buoyancy change. This forms the basis for the measurement of ultrasonic power particularly in watts range. The proposed method comparatively reduces uncertainty caused by various ultrasonic effects that occur at high power such as overshoot due to momentum of target at higher radiated force. The functionality of the technique has been tested and compared with the existing internationally recommended RFB technique.


Antibiotic Prophylaxis, Immunoglobulin Substitution and Supportive Measures Prevent Infections in MECP2 Duplication Syndrome.
Respiratory infections are the main cause of early death in patients with MECP2 duplication syndrome. We report on a 20-year-old patient with MECP2 duplication syndrome, IgG2/IgG4/IgA/IgM deficiency and polysaccharide-specific antibody deficiency, who had 46 episodes of pneumonia in his first 13 8/12 years of life. Immunoglobulin substitution, daily antibiotic prophylaxis with two agents and supportive measures reduced occurrence of pneumonia to four episodes in the following 6 2/12 years of life.


Antihypertensive drug prescribing and persistence among new elderly users: implications for persistence improvement interventions.
The objective of this study was to examine persistence rates and factors influencing persistence for new elderly users of antihypertensive drugs. We conducted a population-based cohort study in Ontario of adults aged 66 years or older to identify new users of antihypertensive medications between 1999 and 2010. Two-year therapy and class persistence were defined as persistence on any antihypertensive medication and persistence only on the same antihypertensive medication class, respectively. From 1999-2010, the prevalence of antihypertensive drug use increased from 47.8%-60.5% (P < 0.0001). Persistence was evaluated in 420,148 new users of antihypertensive drugs. After 2 years, therapy persistence was 58.9% and varied according to initial class prescribed, from 52.3% for diuretics to 64.1% for angiotensin-converting enzyme inhibitors. Class persistence ranged from 25.3% for diuretics to 35.8% for angiotensin II receptor blockers. Therapy persistence rates were greater in new users from more recent years (adjusted odds ratio [aOR], 1.24; 95% confidence interval [CI], 1.21-1.27). Subgroups that demonstrated poorer persistence included patients older than 75 years (aOR, 0.95; 95% CI, 0.94-0.96), those with lowest neighbourhood income quintile (aOR, 0.81; 95% CI, 0.80-0.83 compared with the highest quintile), those from urban vs rural areas (aOR, 0.83; 95% CI, 0.81-0.84), and those who started on diuretics as initial monotherapy compared with all other drug classes. Although 2-year therapy and class persistence were low for new users of antihypertensive drugs, improvements have occurred over the past decade. Our data highlight subgroups to target for future persistence improvement interventions.


Sweat rate and fluid intake in young elite basketball players on the FIBA Europe U20 Championship.
Previous investigations in many sports indicated that continued exercise, especially in hot environments, can cause high sweat rate and huge water and electrolyte losses, thus impairing the performance of athletes. Most these studies were conducted during training sessions, but rarely during an official competition. Therefore, the aim of our study was to determine pre- and post-competition hydration, fluid intake and sweat loss of young elite basketball players during the FIBA Europe U20 Championship. The study included 96 basketball male players, (19 ± 0.79 years) of eight national teams. Ambient temperature was 30 ± 2°C, humidity 55 ± 4% and the mean playing time in game 18.8 ± 10.5 min. The following parameters related to hydration status were measured: fluid intake, urine output, sweat rate, percent of dehydration, urine parameters (specific gravity, color and osmolarity), body mass and body surface area. We found that the mean fluid intake was 1.79 ± 0.8 L/h, sweat rate 2.7 ± 0.9 L/h, urine output 55 ± 61 mL and the percentage of dehydration 0.99 ± 0.7%. According to urine osmolarity more than 75% of players were dehydrated before the game and the process continued during the game. The difference in body mass (0.9 ± 0.7 kg) before and after the game was statistically significant. There were statistically significant correlations between the sweat rate and fluid intake, urine osmolarity, body mass loss, body surface area and percentage of dehydration. Fluid intake correlated with the percentage of dehydration, body mass loss, urine specific gravity and urine color. The sweat rate, which varied between the teams, was the highest for centers when this parameter was calculated on the effective time in game. Most of the athletes start competition dehydrated, fail to compensate sweat loss during the game and continue to be dehydrated, regardless what kind of drink was used. These results suggest that hydration strategies must be carefully taken into account, not only by the players, but also by the coaches and the team doctors.


Light-induced piston nanoengines: ultrafast shuttling of a styryl dye inside cucurbit[7]uril.
The combination of photoactive styryl(pyridinium) dyes and cucurbit[7]uril (CB[7]) in an integrated supramolecular system allowed us to design a novel high speed molecular machine based on the fully reversible shuttling motion of the dye inside the CB[7] host cavity. The driving force of this movement is the electrostatic potential change after the occurrence of intramolecular charge transfer in the excited state of the dye molecule that can be externally controlled by light. Steady-state and time-resolved optical spectroscopy as well as DFT calculations provided an unambiguous evidence for the ultrafast piston-like movement of the system between two states. The shuttling process occurs in the picosecond timescale and its bistability depends on the strength of the dye donor fragment.


The Impact of DNMT3A Status on NPM1 MRD Predictive Value and Survival in Elderly AML Patients Treated Intensively.
Minimal residual disease (MRD) is now a powerful surrogate marker to assess the response to chemotherapy in acute myeloid leukemia (AML). DNMT3A mutation has been associated with adverse outcomes. In this study, we aimed to investigate the impact of DNMT3A status on NPM1 MRD predictive value for survival in a retrospective cohort of AML patients aged over 60 years old treated intensively. A total of 138 patients treated for NPM1-mutated AML in two French institutions were analyzed retrospectively. DNMT3A status did not influence the probability of having a ≥ 4log MRD1 reduction after induction. Only 20.4% of FLT3-ITD patients reached ≥ 4log MRD1 reduction compared to 47.5% in FLT3wt cases. A 4log reduction of NPM1 MRD was associated with a better outcome, even in FLT3-ITD mutated patients, independent of the allelic ratio. DNMT3A negative patients who reached a 4log reduction had a superior outcome to those who did not (HR = 0.23; p < 0.001). However, postinduction NPM1 MRD1 reduction was not predictive of OS and LFS in DNMT3Amut patients. These results confirm that post-induction NPM1 MRD1 is a reliable tool to assess disease outcome in elderly AML patients. However, the presence of DNMT3A also identifies a subgroup of patients at high risk of relapse.


Successful removal of Chlamydia pneumoniae from plateletpheresis products collected using automated leukoreduction hemapheresis techniques.
Chlamydia pneumoniae (Cp) is an obligate intracellular pathogen associated with a variety of maladies. Best known for its involvement in community-acquired pneumonia outbreaks; the potential role of Cp in diverse illnesses is a topic of increasing interest and investigation. Previous studies suggested that white blood cells from normal blood donors harboring this agent may be eliminated through leukoreduction by filtration. Here we examine the ability and efficacy of apheresis-related leukoreduction for its effect on the carriage and potential infectivity of these organisms in the preparation of platelet products. Matched pre-apheresis peripheral blood (PB) samples and product samples obtained from healthy plateletpheresis donors were analyzed for the presence and potential infectivity of Cp organisms by direct smear inspection and tissue culture techniques. Antibody seroreactivity directed towards the organism was assessed using a solid phase immunoassay. Forty-eight percent of the donor blood samples exhibited elevated anti-Cp antibody titers (> or =200). Specimens from 31 (27%) and 34 (30%) of 115 plateletpheresis donors were positive for the presence of Cp organisms in their pre-apheresis PB samples when analyzed by direct smear examination and culture, respectively. Examination of the 115 post-leukodepleted plateletpheresis product samples revealed only two (1.7%) and one (0.009%) product(s) to be smear-positive and culture-positive, respectively. Certain plateletpheresis donors may harbor infectious Cp organisms in circulating WBC. Collections from such donors of apheresis platelet products using standard apheresis leukoreduction strategies appear successful in markedly decreasing or eliminating the organisms found in the final products.


Crystallization and preliminary X-ray analysis of the small component of 4-hydroxyphenylacetate 3-monooxygenase (HpaC) and its cofactor complex from Thermus thermophilus HB8.
The small component of 4-hydroxyphenylacetate 3-monooxygenase (HpaC) is an NADH oxidoreductase containing a flavin molecule as a cofactor. HpaC reduces a flavin molecule and reduced flavin is subsequently supplied to the large component of 4-hydroxyphenylacetate 3-monooxygenase (HpaB). The HpaC protein from Thermus thermophilus HB8 has been overexpressed in Escherichia coli and crystallized. During purification, the eluted HpaC protein solutions were separated into colourless and yellow-coloured fractions (i.e. apo-HpaC and HpaC-flavin complex, respectively). Crystals of apo-HpaC grown in 5%(v/v) isopropyl alcohol, 0.1 M HEPES-NaOH pH 7.0, 40%(w/v) polyethylene glycol (PEG) 4000 and 10%(v/v) glycerol diffracted X-rays to a resolution of 1.85 A, whereas crystals of the HpaC-flavin complex grown in 20%(w/v) PEG 1000, 10%(w/v) PEG 8000 and 10%(v/v) glycerol diffracted X-rays to a resolution of 1.3 A. Both crystals belong to the monoclinic system, space group P2(1), with similar unit-cell parameters. Selenomethionyl protein crystals of the HpaC-flavin complex grown under similar conditions to the native crystals diffracted X-rays to a resolution of 1.8 A. They also belong to the monoclinic space group P2(1), but are not isomorphous to crystals of the HpaC-flavin complex of the native protein. MAD data for structure determination were successfully collected using these crystals.


Transforming growth factor beta1 gene polymorphism in patients with systemic sclerosis.
To determine whether transforming growth factor beta1 (TGFbeta1) gene DNA polymorphism is associated with pathogenesis in the fibrosis of patients with systemic sclerosis (SSc). Eighty-seven Japanese patients with SSc including 30 with diffuse type and 57 with limited type together with 110 unrelated controls were investigated. Pulmonary fibrosis was determined in 34 SSc patients using high-resolution chest computed tomography. TGFbeta1 genetic polymorphisms were analyzed in 2 loci; T869C (Leu10Pro) in codon 10 at exon 1, and C-509T in the promoter region using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Neither the genotype of T/C polymorphism in T869C nor C/T polymorphism in C-509T revealed any difference in distribution between SSc and controls. In the group of SSc patients with pulmonary fibrosis, a weak but significantly high frequency (p = 0.05) of TC+CC (the presence of C allele) in T869C, and CT+TT (the presence of T allele) in C-509T was found. Compared with controls, the pulmonary fibrosis group showed no difference in the highly frequent alleles. Our results suggest that TGFbeta1 polymorphisms do not play a role in the pathogenesis of SSc, even though there remains the possibility of a risk factor for genetic susceptibility to pulmonary fibrosis.


Violation of the craniocentricity principle for vestibularly evoked balance responses under conditions of anisotropic stability.
The balance response direction to electrically evoked vestibular perturbation is closely tied to head orientation. Such craniocentric response organization is expected of a simple error correction process. Here we ask whether this is maintained when the body is made more stable, but with the stability being greater in one direction than another. Since it is known that vestibularly evoked balance responses become smaller as body stability increases, the following two outcomes are possible: (1) response magnitude is attenuated, but with craniocentricity maintained; and (2) anisotropy of stability is considered such that components of the response are differentially attenuated, which would violate a craniocentric organizing principle. We tested these alternatives by measuring the direction of balance responses to electrical vestibular stimulation across a range of head orientations and stance widths in healthy humans. With feet together, the response was highly craniocentric. However, when stance width was increased so that the body was more stable in the frontal plane, response direction became biased toward the sagittal direction. This resulted in a nonlinear relationship between head orientation and response direction. While stance width changes the mechanical state of the body, the effect was also present when lateral light touch was used to produce anisotropy in stability, demonstrating that a significantly altered mechanical state was not crucial. We conclude that the balance system does not simply act according to the direction of vestibular input. Instead, it appears to assign greater relevance to components of vestibular input acting in the plane of lesser body stability than the plane of greater body stability, and acts accordingly.


Fecal calprotectin and need of multiple microbiota trasplantation infusions in Clostridium difficile infection.
Fecal microbiota transplantation (FMT) has proven to be very effective in recurrent Clostridium difficile infection (CDI) when compared with standard antibiotic therapy. However, given the lack of validated criteria, decision regarding number and timing of infusions is currently based on the clinician's experience, severity of infection, and clinical response. We performed a longitudinal assessment of fecal calprotectin concentration (FCC) in CDI patients undergoing FMT. FCCs were correlated with the need for multiple infusions and with the clinical status of the patient. Fecal calprotectin concentration measurement was performed just before first procedure (T0 ) and 2 (T1 ) and 5 (T2 ) days later. The need for reinfusion was accounted for in the 8 weeks following procedure, and clinical status was evaluated at the end of the given period. Both outcomes were correlated with measured FCCs. A total of 28 CDI patients undergoing FMT were enrolled. Median FCCs at T0 were significantly higher in patients who needed repeat FMT, 540 μg/g versus patients who underwent single FMT, 290 μg/g (P < 0.05). Differences were not significant for FCC at T1 and T2 . Regarding correlation with clinical outcome, median FCC at T0 was found to be lower in responders compared with non-responders with a trend towards statistical significance (P = 0.07). Correlation at T1 and T2 was not significant. The use of an easily obtainable parameter such as fecal calprotectin could possibly optimize overall management of FMT procedural framework potentially being able to immediately identify patients who may benefit from repeat infusions.


[Youth friendly health services: how to promote quality health care for adolescents].
Many young people have difficulties requesting medical or psychosocial support, although some badly need it. This difficulty is related to the fact that, as part of their search for autonomy, young people prefer to solve their problems by themselves. To improve the quality of care, the World Health Organization, UNICEF and allied organizations have developed the concept of "Youth friendly health services". This concept includes policies and strategies to improve the accessibility and flexibility, staff's competence and communication skills, etc. Such an approach should not be limited to specialized centers for adolescent health. It should be adopted by all health care institutions dealing with young people.


Atherosclerosis and sudden death.
The prevalence of complicated and calcified lesions and coronary stenosis, the mean heart weight, and the extent of atherosclerosis in the aorta and coronary arteries were greater in the "sudden heart death" group than in the high atherosclerosis group. In the "other sudden death" group, which included sudden deaths without myocardial infarction or coronary occlusion, all the above variables, except heart weight, were found to be lower than in the low atherosclerosis group and were close to those in the standardized average atherosclerosis group. The mean heart weight in the "other sudden death" group was lower than in the "sudden heart death" group but significantly higher than in the three reference atherosclerosis groups.


Conditional association.
Estimating conditional dependence between two random variables given the knowledge of a third random variable is essential in neuroscientific applications to understand the causal architecture of a distributed network. However, existing methods of assessing conditional dependence, such as the conditional mutual information, are computationally expensive, involve free parameters, and are difficult to understand in the context of realizations. In this letter, we discuss a novel approach to this problem and develop a computationally simple and parameter-free estimator. The difference between the proposed approach and the existing ones is that the former expresses conditional dependence in terms of a finite set of realizations, whereas the latter use random variables, which are not available in practice. We call this approach conditional association, since it is based on a generalization of the concept of association to arbitrary metric spaces. We also discuss a novel and computationally efficient approach of generating surrogate data for evaluating the significance of the acquired association value.


HaloTag mediated artificial cellulosome assembly on a rolling circle amplification DNA template for efficient cellulose hydrolysis.
We report here the generation of four-component artificial cellulosomes onto a DNA scaffold using the self-labeling HaloTag for DNA conjugation. The resulting structures exhibited significantly improved cellulosome assembly as well as cellulose hydrolysis over compatible structures generated using protein scaffolds. Cellulose hydrolysis was further enhanced by 2-fold using the more complex cellulosome structures assembled onto DNA templates generated by rolling circle amplification (RCA). The flexibility to insert additional hybridization sites in a multiplexing manner using RCA should enable the assembly of a larger array of cellulases to better mimic the enzyme diversity of naturally occurring cellulosomes.


Convergence of the simultaneous algebraic reconstruction technique (SART).
Computed tomography (CT) has been extensively studied for years and widely used in the modern society. Although the filtered back-projection algorithm is the method of choice by manufacturers, efforts are being made to revisit iterative methods due to their unique advantages, such as superior performance with incomplete noisy data. In 1984, the simultaneous algebraic reconstruction technique (SART) was developed as a major refinement of the algebraic reconstruction technique (ART). However, the convergence of the SART has never been established since then. In this paper, the convergence is proved under the condition that coefficients of the linear imaging system are nonnegative. It is shown that from any initial guess the sequence generated by the SART converges to a weighted least square solution.


Electroporation of adherent cells with low sample volumes on a microscope stage.
The labeling of specific molecules and their artificial control in living cells are powerful techniques for investigating intracellular molecular dynamics. To use these techniques, molecular compounds (hereinafter described simply as 'samples') need to be loaded into cells. Electroporation techniques are exploited to load membrane-impermeant samples into cells. Here, we developed a new electroporator with four special characteristics. (1) Electric pulses are applied to the adherent cells directly, without removing them from the substratum. (2) Samples can be loaded into the adherent cells while observing them on the stage of an inverted microscope. (3) Only 2 μl of sample solution is sufficient. (4) The device is very easy to use, as the cuvette, which is connected to the tip of a commercially available auto-pipette, is manipulated by hand. Using our device, we loaded a fluorescent probe of actin filaments, Alexa Fluor 546 phalloidin, into migrating keratocytes. The level of this probe in the cells could be easily adjusted by changing its concentration in the electroporation medium. Samples could be loaded into keratocytes, neutrophil-like HL-60 cells and Dictyostelium cells on a coverslip, and keratocytes on an elastic silicone substratum. The new device should be useful for a wide range of adherent cells and allow electroporation for cells on various types of the substrata.


Susceptibility to Toxoplasma gondii proliferation in BeWo human trophoblast cells is dose-dependent of macrophage migration inhibitory factor (MIF), via ERK1/2 phosphorylation and prostaglandin E2 production.
Macrophage migration inhibitory factor (MIF) participates in the immune response to Toxoplasma gondii, triggers ERK1/2 and prostaglandin E2 (PGE2) activation, but there is limited information on these mechanisms in human trophoblast. The present study aimed to verify the role of MIF in the ERK1/2 phosphorylation and PGE2 production, as well as its effect on the susceptibility to T. gondii in BeWo cells. BeWo cells were treated with increasing concentrations of recombinant MIF (rMIF) and/or T. gondii-soluble tachyzoite antigen (STAg) and analyzed for ERK1/2 phosphorylation and PGE2 production by Western blotting and ELISA, respectively. Cells were also treated with increasing concentrations of rMIF, rPGE2, or ERK1/2 inhibitor and tested for T. gondii proliferation. The supernatants of cells treated with rPGE2 were assayed for cytokine production by ELISA or CBA. ERK1/2 phosphorylation and PGE2 production increased when the cells were treated with low MIF concentrations while the parasitism control occurred only at high MIF concentrations. STAg was unable to change ERK1/2 phosphorylation or PGE2 release. BeWo cells demonstrated increased T. gondii proliferation and reduced production of pro-inflammatory cytokines when treated with PGE2, while PD98059 diminished the parasite proliferation. The intracellular mechanisms triggered by MIF are dose-dependent in BeWo cells, and PGE2 is an important factor for the persistence of T. gondii at the maternal fetal interface. MIF was unable to control T. gondii infection in BeWo cells at low concentrations since ERK1/2 and PGE2 expression were activated, demonstrating a critical effect of these mediators favoring parasite proliferation.


Predictive Performances of Blood-Count-Derived Inflammatory Markers for Liver Fibrosis Severity in Psoriasis Vulgaris.
Psoriasis is an immune-mediated, chronic disorder that significantly alters patients' quality of life and predisposes them to a higher risk of comorbidities, including liver fibrosis. Various non-invasive tests (NITs) have been validated to assess liver fibrosis severity, while blood-count-derived inflammatory markers have been proven to be reliable in reflecting inflammatory status in psoriatic disease. The fibrosis-4 (FIB-4) index became part of the newest guideline for monitoring psoriasis patients undergoing systemic treatment. Patients with psoriasis vulgaris and fulfilling inclusion criteria were enrolled in this study, aiming to assess for the first time in the literature whether such inflammatory markers are useful in predicting liver fibrosis. Based on internationally validated FIB-4 index values, patients were divided into two study groups: a low risk of significant fibrosis (LR-SF) and a high risk of significant fibrosis (HR-SF). Patients from HR-SF were significantly older and had higher values of the monocyte-to-lymphocyte ratio (MLR) (p < 0.001), which further significantly correlated with fibrosis severity (p < 0.001). Platelet-to-lymphocyte ratio (PLR), systemic immune inflammation index (SII), platelet-to-white blood cell ratio (PWR), and aggregate index of systemic inflammations (AISI) significantly correlated negatively with liver fibrosis (p < 0.001). PWR proved to be the most reliable inflammatory predictor of fibrosis severity (AUC = 0.657). MLR, PWR, and AISI were independent inflammatory markers in multivariate analysis (p < 0.001), while the AST to platelet ratio index (APRI) and AST to ALT ratio (AAR) can be used as additional NITs for significant liver fibrosis (p < 0.001). In limited-resources settings, blood-count-derived inflammatory markers such as MLR, PWR, and AISI, respectively, and hepatic indexes APRI and AAR prove to be of particular help in predicting significant liver fibrosis.


Communication and mass vaccination strategies after pertussis outbreak in rural Amish communities-Illinois, 2009-2010.
During January 2010, 2 infants from an Amish community in east-central Illinois were hospitalized with pertussis. The local health department (LDH) intervened to control disease transmission, identify contributing factors, and determine best communications methods to improve vaccination coverage. A retrospective cohort study was conducted using public health surveillance data to determine the extent of the outbreak; the standard Centers for Disease Control and Prevention and Council of State and Territorial Epidemiologists case definition for pertussis was used. The standardized Illinois Department of Public Health pertussis patient interview form was used to collect demographic, symptom, vaccination history, and treatment history information. To control disease transmission, LDH staff worked with the Amish community to promote a vaccination campaign during February 6-April 30, 2010. Forty-seven cases were identified, with onsets during December 2009-March 2010. Median age was 7 (interquartile range 1-12) years. Nineteen (40%) patients were male; 39 (83%) were aged <18 years; 37 (79%) had not received any pertussis-containing vaccine. Presenting symptoms did not differ substantially between vaccinated and unvaccinated patients. Duration of cough was longer among unvaccinated than vaccinated patients (32 vs. 15.5 days, P = .002). Compared with vaccinated patients, proportionately more unvaccinated patients reported secondary household transmission (30% vs. 72%; P = .012). Through enhanced vaccination campaigns, 251 (∼10%) Amish community members were administered 254 pertussis-containing vaccines. Targeted health communication and outreach resulted in a successful vaccine campaign and long-running monthly vaccination clinic. Amish do not universally reject vaccines, and their practices regarding vaccination are not static.


Antifungal activity of amphotericin B cochleates against Candida albicans infection in a mouse model.
Cochleates are lipid-based supramolecular assemblies composed of natural products, negatively charged phospholipid, and a divalent cation. Cochleates can encapsulate amphotericin B (AmB), an important antifungal drug. AmB cochleates (CAMB) have a unique shape and the ability to target AmB to fungi. The minimal inhibitory concentration and the minimum lethal concentration against Candida albicans are similar to that for desoxycholate AmB (DAMB; Fungizone). In vitro, CAMB induced no hemolysis of human red blood cells at concentrations of as high as 500 microg of AmB/ml, and DAMB was highly hemolytic at 10 microg of AmB/ml. CAMB protect ICR mice infected with C. albicans when the agent is administered intraperitoneally at doses of as low as 0.1 mg/kg/day. In a tissue burden study, CAMB, DAMB, and AmBisome (liposomal AmB; LAMB) were effective in the kidneys, but in the spleen CAMB was more potent than DAMB at 1 mg/kg/day and was equivalent to LAMB at 10 mg/kg/day. In summary, CAMB are highly effective in treating murine candidiasis and compare well with AmBisome and AmB.


Targeting the epithelial cells in fibrosis: a new concept for an old disease.
Fibrosis, which affects millions of individuals worldwide, is a leading cause of organ failure. For 40 years myofibroblasts have been recognized to be the key cellular players in fibrosis. Currently, several pharmaceutical targets are under investigation that may contribute to the activation of myofibroblasts. Recent preclinical and clinical evidence suggests that other components in the fibrotic microenvironment can trigger myofibroblast activation, providing new targets for pharmaceutical intervention. Epithelial cells may represent the most promising cellular phenotype that could be exploited in the design of new anti-fibrotic medicines through their paracrine action on myofibroblasts. The present review briefly highlights this hypothesis and discusses some interesting related pharmacological targets.


Pheromone synthesis in a biomicroreactor coated with anti-adsorption polyelectrolyte multilayer.
To prepare a biosynthetic module in an infochemical communication project, we designed a silicon/glass microreactor with anti-adsorption polyelectrolyte multilayer coating and immobilized alcohol acetyl transferase (atf), one of the key biosynthetic enzymes of the pheromone of Spodoptera littoralis, on agarose beads inside. The system reproduces the last step of the biosynthesis in which the precursor diene alcohol (Z,E)-9,11-tetradecadienol is transformed into the major component (Z,E)-9,11-tetradecadienyl acetate. The scope of this study was to analyze and implement a multilayer, anti-adsorption coating based on layer-by-layer deposition of polyethylenimine/dextransulfate sodium salt (PEI/DSS). The multilayers were composed of two PEI with molecular weights 750 and 1.2 kDa at pH 9.2 or 6.0. Growth, morphology, and stability of the layers were analyzed by ellipsometry and atomic force microscopy (AFM). The anti-adsorption functionality of the multilayer inside the microreactor was validated. The activity of His(6)-(atf) was measured by gas chromatography coupled to mass spectrometer (GC-MS).


What are the most effective risk-reduction strategies in sport concussion?
To critically review the evidence to determine the efficacy and effectiveness of protective equipment, rule changes, neck strength and legislation in reducing sport concussion risk. Electronic databases, grey literature and bibliographies were used to search the evidence using Medical Subject Headings and text words. Inclusion/exclusion criteria were used to select articles for the clinical equipment studies. The quality of evidence was assessed using epidemiological criteria regarding internal/external validity (eg, strength of design, sample size/power, bias and confounding). No new valid, conclusive evidence was provided to suggest the use of headgear in rugby, or mouth guards in American football, significantly reduced players' risk of concussion. No evidence was provided to suggest an association between neck strength increases and concussion risk reduction. There was evidence in ice hockey to suggest fair-play rules and eliminating body checking among 11-years-olds to 12-years-olds were effective injury prevention strategies. Evidence is lacking on the effects of legislation on concussion prevention. Equipment self-selection bias was a common limitation, as was the lack of measurement and control for potential confounding variables. Lastly, helmets need to be able to protect from impacts resulting in a head change in velocities of up to 10 and 7 m/s in professional American and Australian football, respectively, as well as reduce head resultant linear and angular acceleration to below 50 g and 1500 rad/s(2), respectively, to optimise their effectiveness. A multifactorial approach is needed for concussion prevention. Future well-designed and sport-specific prospective analytical studies of sufficient power are warranted.


Chicken egg yolk anti-asialoGM1 immunoglobulin (IgY): an inexpensive glycohistochemical probe for localization of T-antigen in human colorectal adenocarcinomas.
A egg yolk polyclonal IgY has been prepared by immunization of white leghorn chickens with small unilamellar liposomal asialoGM1. The newly prepared anti-asialoGM1 IgY has been characterized to be specific toward the terminal carbohydrate moiety of asialoGM1, and has no cross reactivity to its sialylated counterpart (ganglioside, GM1) as evidenced by immunochromatographic studies. General glycohistochemical methods along with antigen specific lectin and immunohistochemical staining using anti-asialoGM1 IgY were used to study the expression of Thomsen-Friedenreich (T-) disaccharide antigen in human colorectal adenocarcinoma tissues. The expression of T-antigen in colon cancer tissue was detected by two T-disaccharide specific probes, chicken anti-T-yolk antibody (IgY) and Artocarpus integrifolia lectin (AIL) and was found to be more pronounced in both the secreted mucin as well as the cytoplasmic mucin deposits. These immunochemical detection methods for T-antigen showed a weaker correlation with other glycostaining methods using, alcian-blue/periodic acid-Schiff (AB-PAS) and high iron diamine (HID). However, a general enzymatic staining for galactose and galactosamine containing glycoconjugates, by galactose oxidase-Schiff method, showed a good correlation with T-antigen detection. While the T-beta specific anti-asialoGM1 could localize T-antigen in 11 of 13 (84%) human colorectal adenocarcinoma tissue sections tested, the T-alpha specific AIL could localize the T-antigen in only 6 of the tissues (46%). These observations confirm previously reported findings, of the prevalence of T-beta conformation in colon cancer, that binds significantly more with the anti-asialoGM1 IgY than with the T-alpha specific AIL. Hence, both anti-T IgY and the AIL immunohistochemical probes may have useful diagnostic value because of the ease of preparation and cost effectiveness, but the T-beta specific anti-asialoGM1 probe (IgY) would have a better prognostic value in colon adenocarcinomas.


Lymphangiogenesis and Anti-lymphangiogenesis in Cutaneous Melanoma.
Cutaneous malignant melanoma is an aggressive tumor characterized by early lymph node metastasis and bad prognosis. Although the spread of tumor cells in the regional lymph nodes is very important in the staging, prognosis and therapeutic strategy of malignant melanoma, the mechanism(s) of initial lymphatic vessels invasion is are) not completely understood. In the present review, we analyze the main factors involved in melanoma-associated lymphangiogenesis, based on existing available evidence. Currently, there are no anti-lymphangiogenic drugs approved for clinical trials. On the other hand, inhibition of lymph node metastasis has been demonstrated in experimental models by inhibiting tumor-associated lymphangiogenesis.


Morphological and molecular characterization of Paratylenchus beltsvillensis n. sp. (Tylenchida: Paratylenchidae) from the rhizosphere of pine tree (Pinus virginiana Mill) in Maryland, USA.
The pin nematode, Paratylechus beltsvillensis n. sp. collected from rhizosphere soil of a Virginia pine tree (Pinus virginiana Mill) growing in Little Paint Branch Park, Beltsville, Prince George's County, Maryland, USA, is described and illustrated along with light and scanning electron photomicrographs. Females, males, and juveniles of this new species were recovered from soil samples using the sugar centrifugal flotation and Baermann funnel extraction methods. Morphologically, females are short, body length ranging from 245 to 267 μm, stylet from 70 to 75 μm long with anchor shaped knobs, vulva located at 70-73% and small vulval flap, spermatheca large, and ovoid filled with sperms. Lateral field with three incisures, of which the outer two are prominent. Tail slender, having a rounded tail terminus. Males without stylet and have a degenerated pharynx, spicules = 17-20 µm and gubernaculum = 5.0-5.5 µm. Both morphological observations and molecular analysis of ITS and partial 28S ribosomal RNA gene sequences indicated that the specimens collected from the soil at Beltsville Park from rhizosphere soil samples from Virginia pine represents a new pin nematode species.


When you smile, the world smiles at you: ERP evidence for self-expression effects on face processing.
Current models of emotion simulation propose that intentionally posing a facial expression can change one's subjective feelings, which in turn influences the processing of visual input. However, the underlying neural mechanism whereby one's facial emotion modulates the visual cortical responses to other's facial expressions remains unknown. To understand how one's facial expression affects visual processing, we measured participants' visual evoked potentials (VEPs) during a facial emotion judgment task of positive and neutral faces. To control for the effects of facial muscles on VEPs, we asked participants to smile (adopting an expression of happiness), to purse their lips (incompatible with smiling) or to pose with a neutral face, in separate blocks. Results showed that the smiling expression modulates face-specific visual processing components (N170/vertex positive potential) to watching other facial expressions. Specifically, when making a happy expression, neutral faces are processed similarly to happy faces. When making a neutral expression or pursing the lips, however, responses to neutral and happy face are significantly different. This effect was source localized within multisensory associative areas, angular gyrus, associative visual cortex and somatosensory cortex. We provide novel evidence that one's own emotional expression acts as a top-down influence modulating low-level neural encoding during facial perception.


ALK Rearrangement Adenocarcinoma with Histological Transformation to Squamous Cell Carcinoma Resistant to Alectinib and Ceritinib.
Specific tyrosine-kinase inhibitors (TKIs) are widely used for the treatment of non-small-cell lung cancers with anaplastic lymphoma kinase (ALK) translocations. However, most treated patients eventually develop resistance to the TKIs. The histological transformation into small cell carcinoma is well known to be the underlying mechanism for acquired resistance; however, transformation to squamous cell carcinoma is extremely rare. We, herein, report a case of ALK rearrangement-positive adenocarcinoma that transformed to squamous cell carcinoma after administration of alectinib, and was found to be resistant to ceritinib.


N-trimethyl chitosan chloride-coated liposomes for the oral delivery of curcumin.
The aims of this study were to design the formulation of curcumin (CUR) liposomes coated with N-trimethyl chitosan chloride (TMC) and to evaluate in vitro release characteristics and in vivo pharmacokinetics and bioavailability of TMC-coated CUR liposomes in rats. The structure of synthesized TMC was examined by infrared spectroscopy, with the presence of trimethyl groups, and by proton nuclear magnetic resonance spectroscopy, indicating the high degree of substitution quaternization (65.6%). Liposomes, composed of soybean phosphotidylcholine, cholestrol, and D-α-tocopheryl polyethylene glycol 1000 succinate, were prepared by a thin-film dispersion method. Characteristics of the CUR liposomes, including entrapment efficiency (86.67%), drug-loading efficiency (2.33%), morphology, particle size (221.4 nm for uncoated liposomes and 657.7 nm for TMC-coated liposomes), and zeta potential (-9.63 mV for uncoated liposomes and +15.64 mV for TMC-coated liposomes) were investigated. Uncoated CUR liposomes and TMC-coated CUR liposomes showed a similar in vitro release profile. Nearly 50% of CUR was released from liposomes, whereas 80% of CUR was released from CUR propylene glycol solution. CUR incorporated into TMC-coated liposomes exhibited different pharmacokinetic parameters and enhanced bioavailability (C(max) = 46.13 μg/L, t(1/2) = 12.05 hours, AUC = 416.58 μg/L·h), compared with CUR encapsulated by uncoated liposomes (C(max) = 32.12 μg/L, t(1/2) = 9.79 hours, AUC = 263.77 μg/L·h) and CUR suspension (C(max) = 35.46 μg/L, t(1/2) = 3.85 hours, AUC = 244.77 μg/L·h). In conclusion, oral delivery of coated CUR liposomes is a promising strategy for poorly water-soluble CUR.


The progression of regional atrophy in premanifest and early Huntington's disease: a longitudinal voxel-based morphometry study.
Unbiased longitudinal studies are needed to understand the distributed neurodegenerative changes of Huntington's disease (HD). They may also provide tools for assessing disease-modifying interventions. The authors investigated the progression of regional atrophy in premanifest and early HD compared with controls. Nine controls, 17 premanifest and 21 early HD subjects underwent volumetric MRI at baseline and 2 years. Premanifest subjects were on average 18.1 years before predicted motor onset. Non-linear registration was used to model within-subject change over the scanning interval, and statistical parametric mapping was used to examine group differences and associations with clinical variables. In early HD, increased grey-matter (GM) atrophy rates were evident throughout the subcortical GM and over selective cortical regions compared with controls. This group also demonstrated strikingly widespread increases in white-matter (WM) atrophy rates. The authors observed no significant differences between premanifest HD and controls. Longer CAG was associated with higher atrophy rates over large WM areas including brainstem and internal capsule and over small GM regions including thalamus and occipital cortex. Worse baseline motor score was associated with regionally increased rates in the thalamus, internal capsule and occipital lobe. Sample-size calculations indicate that 19 and 24 early HD subjects per treatment arm would need to complete a 2-year trial in order to detect a 50% reduction in WM and GM atrophy rates respectively. Degeneration of structural connectivity may play an important role in early HD symptoms. Assessment of WM and GM changes will be important in understanding the complexity of HD and its treatment.


Energy shedding during nonlinear self-focusing of optical beams.
Self-focusing of intense laser beams and pulses of light in real nonlinear media is in general accompanied by material losses that require corrections to the conservative Nonlinear Schrödinger equations describing their propagation. Here we examine loss mechanisms that exist even in lossless media and are caused by shedding of energy away from the self-trapping beam making it to relax to an exact solution of lower energy. Using the conservative NLS equations with absorbing boundary conditions we show that energy shedding not only occurs during the initial reshaping process but also during oscillatory propagation induced by saturation of the nonlinear effect. For pulsed input we also show that, depending on the sign and magnitude of dispersion, pulse splitting, energy shedding, collapse or stable self-focusing may result.


Diagnostic and analytical applications of protein microarrays.
DNA microarrays have changed the field of biomedical sciences over the past 10 years. For several reasons, antibody and other protein microarrays have not developed at the same rate. However, protein and antibody arrays have emerged as a powerful tool to complement DNA microarrays during the past 5 years. A genome-scale protein microarray has been demonstrated for identifying protein-protein interactions as well as for rapid identification of protein binding to a particular drug. Furthermore, protein microarrays have been shown as an efficient tool in cancer profiling, detection of bacteria and toxins, identification of allergen reactivity and autoantibodies. They have also demonstrated the ability to measure the absolute concentration of small molecules. Besides their capacity for parallel diagnostics, microarrays can be more sensitive than traditional methods such as enzyme-linked immunosorbent assay, mass spectrometry or high-performance liquid chromatography-based assays. However, for protein and antibody arrays to be successfully introduced into diagnostics, the biochemistry of immunomicroarrays must be better characterized and simplified, they must be validated in a clinical setting and be amenable to automation or integrated into easy-to-use systems, such as micrototal analysis systems or point-of-care devices.


Effect of different-sized bulking agents on nitrification process during food waste digestate composting.
Food waste digestate (FWD) disposal is a serious bottleneck in anaerobic digestion plants to achieve a circular bioeconomy. FWD could be recycled into nitrogen-rich compost; however, the co-composting process optimisation along with bulking agents is required to reduce nitrogen loss and unwanted gaseous emissions. In the present study, two different-sized bulking agents, namely, wood shaving (WS) and fine sawdust (FS), were used to investigate their impact on FWD composting performance along with the nitrogen dynamics. The mixing of FWD with different bulking agents altered the physiochemical characteristics of composting matrix and the effective composting performance was observed through reduced ammonium nitrogen and increased seed germination index during 28 days of composting. The carbon loss of 19-22% through CO2 emission indicated similar carbon mineralisation with both types of sawdust; however, the nitrogen transformation pathways were different. Only WS treatment demonstrated the nitrification process, whereas the nitrogen loss was higher with FS. A total nitrogen loss of ∼15% was observed in treatments with FS, whereas WS treatments displayed a nitrogen loss of 12%. The outcome of the present study could significantly contribute to the practical aspect of the FWD composting operation with the promotion of the bio-recycling economy.


Formic acid as a hydrogen storage material - development of homogeneous catalysts for selective hydrogen release.
Formic acid (FA, HCO2H) receives considerable attention as a hydrogen storage material. In this respect, hydrogenation of CO2 to FA and dehydrogenation of FA are crucial reaction steps. In the past decade, for both reactions, several molecularly defined and nanostructured catalysts have been developed and intensively studied. From 2010 onwards, this review covers recent advancements in this area using homogeneous catalysts. In addition to the development of catalysts for H2 generation, reversible H2 storage including continuous H2 production from formic acid is highlighted. Special focus is put on recent progress in non-noble metal catalysts.


Personality differences affect brainstem autonomic responses to visceral pain.
Brainstem autonomic nuclei integrate interoceptive inputs including pain, with descending modulation, to produce homeostatic and defence outputs. Cardiac Vagal Control is especially implicated in psychophysiological processes for both health and disease and is indexed non-invasively by heart rate variability. The study aim was to determine the nature of psychophysiological response profiles for visceral pain. Nineteen healthy subjects had electrocardiographic recordings at rest and during 10 painful oesophageal balloon distensions. Cardiac Vagal Control originating from nucleus ambiguus (CVC(NA)) was determined by polynomial filter application to the electrocardiogram inter-beat interval series. Heart rate and 'Cardiac Sympathetic Index (CSI)' were also determined. Psychological state and trait, including neuroticism and extroversion, were assessed. Subjects who increased CVC(NA) to pain were more neurotic, anxious and sensory sensitive than those who decreased CVC(NA.) Cluster analysis identified two psychophysiological groups: Group 1 (n = 11) demonstrated lower baseline CVC(NA) (P = 0.0001), higher heart rate (P = 0.02) and CSI (P = 0.015), pain tolerance at lower balloon volumes (P = 0.04), but attenuated heart rate response to pain (P = 0.01). Group 2 (n = 8) had the converse profile. Neuroticism scores were higher (P = 0.0004) and extroversion lower (P = 0.01) for group 1 than group 2. Two distinct psychophysiological response profiles to visceral pain exist that are influenced by personality. These may reflect different psychobiological bases for active and passive defence repertoires. Prevalence and clinical relevance of these endophenotypes as vulnerability factors for pain and emotion disorders warrant further exploration.


MDS 3.0: brief interview for mental status.
To test the feasibility and validity of the Brief Interview for Mental Status (BIMS) as a performance-based cognitive screener that could be easily completed by nursing home staff. The current study examines the performance of the BIMS as part of the national testing of the Minimum Data Set 3.0 (MDS 3.0) for Nursing Homes. The BIMS was tested as part of the national MDS 3.0 evaluation study among 3822 residents scheduled for MDS 2.0 assessments. Residents were from 71 community nursing homes (NHs) in eight states. Residents were randomly included in a feasibility sample (n = 3258) and a validation sample (n = 418). Cognition was assessed with three instruments: the Brief Interview for Mental Status (BIMS), the MDS 2.0 Cognitive Performance Scale (CPS), and the Modified Mini-Mental State Examination (3MS). Trained research nurses administered the 3MS and BIMS to all subjects in the validation study. The CPS score was determined based on the MDS 2.0 completed by nursing home staff who had undergone additional training on cognitive testing. Standard cutoff scores on the 100-point 3MS were used as the gold standard for any cognitive impairment (<78) and for severe impairment (<48). Staff impressions were obtained from anonymous surveys. The BIMS was attempted and completed in 90% of the 3258 residents in the feasiblity sample. BIMS scores covered the full instrument range (0-15). In the validation sample, correlation with the criterion measure (3MS) was higher for BIMS (0.906, P < .0001) than for CPS (-0.739, P < .0001); P < .01 for difference. For identifying any impairment, a BIMS score of 12 had sensitivity = 0.83 and specificity = 0.91; for severe impairment, a BIMS score of 7 had sensitivity = 0.83 and specificity = 0.92. The area under the receiver operator characteristics curve, a measure of test accuracy, was higher for BIMS than for CPS for identifying any impairment (AUC = 0.930 and 0.824, respectively) and for identifying severe impairment (AUC = 0.960 and 0.857, respectively). Eighty-eight percent of survey respondents reported that the BIMS provided new insight into residents' cognitive abilities. The average time for completing the BIMS was 3.2 minutes. The BIMS, a short performance-based cognitive screener expressly designed to facilitate cognitive screening in MDS assessments, was completed in the majority of NH residents scheduled for MDS assessments in a large sample of NHs, demonstrating its feasibility. Compared with MDS 2.0 observational items, the BIMS performance-based assessment approach was more highly correlated with a criterion cognitive screening test and demonstrated greater accuracy. The majority of surveyed staff reported improved assessments with the new approach.


Effectiveness of Social Media Interventions for People With Schizophrenia: A Systematic Review and Meta-Analysis.
Recent studies have shown that people with serious mental disorders spend time online for the purposes of disclosure, information gathering, or gaming. However, coherent information on the effects of social media on treatment for people with schizophrenia is still lacking. Our aim was to determine the effects of social media interventions for supporting mental health and well-being among people with schizophrenia. A systematic review and meta-analysis were undertaken to determine the effects of social media interventions for supporting mental health and well-being among people with schizophrenia. Ten databases were searched, while search parameters included English-only manuscripts published prior to June 25, 2015. Study appraisals were made independently by 2 reviewers, and qualitative and quantitative syntheses of data were conducted. Out of 1043 identified records, only two randomized studies of moderate quality (three records, total N=331, duration 12 months) met the inclusion criteria. Participants were people with schizophrenia spectrum or an affective disorder. Social media was used as part of Web-based psychoeducation, or as online peer support (listserv and bulletin board). Outcome measures included perceived stress, social support, and disease-related distress. At 3 months, participants with schizophrenia in the intervention group reported lower perceived stress levels (P=.04) and showed a trend for a higher perceived level of social support (P=.06). However, those who reported more positive experiences with the peer support group also reported higher levels of psychological distress (P=.01). Despite using comprehensive searches from 10 databases, we found only two studies, whereas numerous reports have been published citing the benefits of social media in mental health. Findings suggest the effects of social media interventions are largely unknown. More research is needed to understand the effects of social media, for users with and without mental illness, in order to determine the impact on mental well-being ofsocial media use as well as its risks.


Infectious disease and perinatal morbidity.
Excess perinatal morbidity and mortality continue to be major problems in developed and developing nations. Most perinatal deaths occur in infants born weighing less than 2500 g. Large expenditures of time, equipment, and personnel have led to striking reductions in neonatal mortality. However, rates of prematurity have not declined. Exploration of proven causes of prematurity and low birth weight suggests a role for infection that has hitherto not received sufficient attention. Women with symptomatic pyelonephritis, even when treated promptly, experience an excess of prematurity and perinatal death, and their children have lowered intelligence scores and neurologic scores. Women with asymptomatic bacteriuria experience higher rates of low birth weight and perinatal mortality, as well as symptomatic pyelonephritis, and these are preventable by screening and treatment during pregnancy. Recent evidence also suggests that genital mycoplasmas (Ureaplasma urealyticum and Mycoplasma hominis) are a cause of prematurity and that treatment of women colonized with these organisms results in significant reduction in prematurity rates.


Fracturing highly disordered materials.
We investigate the role of disorder on the fracturing process of heterogeneous materials by means of a two-dimensional fuse network model. Our results in the extreme disorder limit reveal that the backbone of the fracture at collapse, namely, the subset of the largest fracture that effectively halts the global current, has a fractal dimension of 1.22 ± 0.01. This exponent value is compatible with the universality class of several other physical models, including optimal paths under strong disorder, disordered polymers, watersheds and optimal path cracks on uncorrelated substrates, hulls of explosive percolation clusters, and strands of invasion percolation fronts. Moreover, we find that the fractal dimension of the largest fracture under extreme disorder, d(f) = 1.86 ± 0.01, is outside the statistical error bar of standard percolation. This discrepancy is due to the appearance of trapped regions or cavities of all sizes that remain intact till the entire collapse of the fuse network, but are always accessible in the case of standard percolation. Finally, we quantify the role of disorder on the structure of the largest cluster, as well as on the backbone of the fracture, in terms of a distinctive transition from weak to strong disorder characterized by a new crossover exponent.


Population-based study of contralateral prophylactic mastectomy and survival outcomes of breast cancer patients.
Despite increased demand for contralateral prophylactic mastectomy (CPM), the survival benefit of this procedure remains uncertain. We used the Surveillance, Epidemiology, and End Results database to identify 107 106 women with breast cancer who had undergone mastectomy for treatment between 1998 and 2003 and a subset of 8902 women who also underwent CPM during the same period. Associations between predictor variables and the likelihood of undergoing CPM were evaluated by use of chi(2) analyses. Risk-stratified (estrogen receptor [ER] status, stage, and age) adjusted survival analyses were performed by using Cox regression. Statistical tests were two-sided. In a univariate analysis, CPM was associated with improved disease-specific survival (hazard ratio [HR] of death = 0.63, 95% confidence interval [CI] = 0.57 to 0.69; P < .001). Risk-stratified analysis showed that this association was because of a reduction in breast cancer-specific mortality in women aged 18-49 years with stages I-II ER-negative cancer (HR of death = 0.68, 95% CI = 0.53 to 0.88; P = .004). Five year-adjusted breast cancer survival for this group was improved with CPM vs without (88.5% vs 83.7%, difference = 4.8%). Although rates of contralateral breast cancer among young women with stages I-II disease undergoing CPM were independent of ER status, women with ER-positive tumors in the absence of prophylactic mastectomy also had a lower overall risk for contralateral breast cancer than women with ER-negative tumors (0.46% vs 0.90%, difference = 0.44%; P < .001). CPM is associated with a small improvement in 5-year breast cancer-specific survival mainly in young women with early-stage ER-negative breast cancer. This effect is related to a higher baseline risk of contralateral breast cancer.


Characterisation of a collagen membrane for its potential use in cardiovascular tissue engineering applications.
In this study, Biomend, a collagen membrane conventionally used in the regeneration of periodontal tissue, is investigated for its possible use in the field of cardiovascular tissue engineering. A key requirement of most potential tissue engineering scaffolds is that degradation occurs in tandem with tissue regeneration and extra cellular matrix remodelling. To this end, it is crucial to understand the degradation mechanics and mechanisms of the material and to investigate the practicability of using Biomend as a possible scaffold material. With this in mind, methodologies for the initial characterisation of the scaffold material were determined. The mechanical properties of Biomend samples, subjected to various degrees of hydration and enzymatic degradation, were examined primarily through tensile testing experiments. The effects of enzymatic degradation were monitored quantitatively, by observing weight loss, and visually, by studying micrographs. Cell adhesion and viability were of primary concern. Confocal laser scanning microscopy was employed to illustrate endothelialisation on the surface of this collagen membrane. Fluorescence microscopy was used to visualise cell viability on the membrane surface. These images, coupled with assays to measure cell activity, suggest that Biomend is not a suitable substrate to allow endothelialisation. In summary, this collagen membrane has suitable mechanical properties with the potential to control its degradation rate. However, since poor endothelial cell viability was observed on the membrane, it may not be suitable for use in cardiovascular tissue engineering applications.


Pharmacological treatments for acute respiratory distress syndrome.
Studies of the pharmacologic management of acute respiratory distress syndrome (ARDS) have yielded conflicting results. The purpose of this review is to discuss recent pharmacologic trials in ARDS, using the conceptual framework of ARDS as a heterogeneous disease. Whereas most drug trials in ARDS have been negative, some studies suggest that targeting therapies at subgroups of patients may be successful. Proposed subgroups include early versus late-phase ARDS, direct versus indirect lung injury, and patients with altered coagulation. Corticosteroids have beneficial short-term effects when given at low or moderate doses sooner than 2 weeks but appear to be harmful if initiated later and are of unclear benefit if lung protective ventilation is also used. Surfactant may be helpful in patients with direct lung injury. Anticoagulants and vasodilators may have a greater chance for success in the subset of patients with vascular disease and a high dead-space fraction may identify such a population. ARDS is a heterogeneous syndrome. Failure to target subgroups more likely to benefit from specific therapies may be one explanation for largely disappointing trial results so far.


Acute infectious hepatitis in hospitalised children: a British Paediatric Surveillance Unit study.
Hepatitis remains a key public health priority globally. Most childhood cases are caused by viruses, especially hepatitis A virus (HAV) and hepatitis B virus (HBV). This study aimed to estimate the burden of acute infectious hepatitis in hospitalised children and to describe their clinical characteristics and outcomes. Paediatricians in the UK and Ireland reported cases in children aged 1 month to 14 years diagnosed between January 2014 and January 2015 (inclusive) through the British Paediatric Surveillance Unit (BPSU) and completed a detailed questionnaire. Additional HAV and HBV cases in England and Wales were identified through a national electronic database, LabBase2. All confirmed cases were followed up at 6 months with a second questionnaire. The BPSU survey identified 69 children (annual incidence, 0.52/100 000), including 27 HAV (39%), three HBV (4%), 16 other viruses (23%) and 23 with no aetiology identified (33%). LabBase2 identified an additional 10 HAV and 2 HBV cases in England. Of the 37 hospitalised HAV cases, 70% had travelled abroad, but only 8% had been vaccinated. Similarly, three of the five children with acute HBV had not been immunised, despite being a household contact of a known infectious individual. All patients with HAV recovered uneventfully. In contrast, three children with acute HBV developed liver failure and two required liver transplantation. Acute infectious hepatitis is a rare cause of hospital admission. Most children recovered without complications, but those with acute HBV had severe presentations. At least three of the five HBV cases could have been prevented through appopriate vaccination of household contacts.


Short-term functional adaptation of aquaporin-1 surface expression in the proximal tubule, a component of glomerulotubular balance.
Transepithelial water flow across the renal proximal tubule is mediated predominantly by aquaporin-1 (AQP1). Along this nephron segment, luminal delivery and transepithelial reabsorption are directly coupled, a phenomenon called glomerulotubular balance. We hypothesized that the surface expression of AQP1 is regulated by fluid shear stress, contributing to this effect. Consistent with this finding, we found that the abundance of AQP1 in brush border apical and basolateral membranes was augmented >2-fold by increasing luminal perfusion rates in isolated, microperfused proximal tubules for 15 minutes. Mouse kidneys with diminished endocytosis caused by a conditional deletion of megalin or the chloride channel ClC-5 had constitutively enhanced AQP1 abundance in the proximal tubule brush border membrane. In AQP1-transfected, cultured proximal tubule cells, fluid shear stress or the addition of cyclic nucleotides enhanced AQP1 surface expression and concomitantly diminished its ubiquitination. These effects were also associated with an elevated osmotic water permeability. In sum, we have shown that luminal surface expression of AQP1 in the proximal tubule brush border membrane is regulated in response to flow. Cellular trafficking, endocytosis, an intact endosomal compartment, and controlled protein stability are the likely prerequisites for AQP1 activation by enhanced tubular fluid shear stress, serving to maintain glomerulotubular balance.


Seeing you through London 2012: eye care at the Olympics.
Provision of eye care services for competitors and their support teams has become an integral part of the modern Olympic Games. To describe the organisation of the eye clinic at London 2012 over a 4-week period and provide outline audit data. The clinic employed multidisciplinary eye care professionals and utilised state-of-the-art instrumentation to provide the highest level of eye care. A total of 1406 patients from 154 countries attended the clinic over the Olympic Games, of which, 276 were competitors. All individuals received a comprehensive refractive and ocular health examination. Minor ocular injuries, glaucoma, diabetic retinopathy and macular degeneration were among the conditions detected and managed. Most patients attended the clinic to have their refractive status checked: 973 spectacles and 50 pairs of contact lenses were dispensed. It is hoped that this account of the provision of eye care at London 2012 will assist with the planning of this service at future events.


Modular revision stems in total hip arthroplasty.
Many different clinical circumstances are seen in revision total hip arthroplasty. Modular stems provide significant flexibility in choices to ensure distal and/or proximal unitary construct of implant and host bone. There are two basic types of modular stems. Designs that incorporate a metaphyseal sleeve taper fit with a splined, slotted distal body of varying lengths and neck offsets and also provide infinite choices for version of the components. Designs incorporate a distal stem with various proximal stems and Morse tapers. These designs also may vary the distal stem configuration from extensively porous-coated, to tapered and with corundum, to splined and slotted. Although there have been no clinical studies that document improved outcomes with modular stems over one-piece stems, the intraoperative flexibility provided by choices of diameter, stem length, fixation type, and proximal stem size and orientation enable establishment of a stable hip center. I will review the clinical indications for modular stems, outline their advantages, discuss the applicable operative techniques, the reported results, and the limitations of the current literature.


A new mutation in the SQLE gene of Trichophyton mentagrophytes associated to terbinafine resistance in a couple with disseminated tinea corporis.
Trichophyton is the most common dermatophyte genus responsible for tinea corporis and topical treatment with terbinafine is effective for limited disease but extensive disease required systemic therapy. Failure of terbinafine therapy in patients infected with T. rubrum or T. mentagrophytes is associated with mutations in the gene encoding squalene epoxidase, the terbinafine target. We report two cases of tinea corporis resistant to systemic terbinafine in a 60-year-old man and his wife, a 51 year-old-woman. Both patients had multiple diffuse erythematous annular scaly plaques and T. mentagrophytes was isolated in culture. Systemic treatment with terbinafine in combination with topical terbinafine and then topical ketoconazole failed to improve the disease after 8 weeks. The broth microdilution tests performed to evaluate the antifungal sensitivity of the T. mentagrophytes isolate revealed a high MIC for terbinafine but a low MIC for posaconazole and itraconazole. An A1223T point mutation leading to a Q408L substitution was identified by DNA sequencing the SQLE gene of the isolate. Itraconazole 200mg daily was then introduced but stopped because of elevated liver transaminases in the man. Finally, complete healing was achieved only six months later for both patients and required a 3 and 2-week regimen of itraconazole with topical eberconazole in the man and woman respectively. We believe that a close monitoring and antifungal susceptibility tests should now be done more systematically in dermatophytic infections that do not respond to conventional treatment as terbinafine resistant strains are likely to spread worlwide.


Successful treatment of metastatic congenital intraocular medulloepithelioma with neoadjuvant chemotherapy, enucleation and superficial parotidectomy.
To report a case of metastatic intraocular medulloepithelioma successfully treated with neoadjuvant chemotherapy, superficial parotidectomy, and enucleation. A 5-year-old male with history of cataract surgery, glaucoma drainage device, endocyclophotocoagulation, scleral patch grafting, and chronic posterior "inflammation" in a blind left eye presented with a rapidly enlarging painful mass under the left upper eyelid. Biopsy of the conjunctival mass and fine needle aspiration of an enlarged preauricular lymph node revealed medulloepithelioma, which was also seen in the left parotid gland on positron emission tomography (PET) scan. The patient's father refused exenteration, so the patient received 3 cycles of vincristine, cisplatin, cyclophosphamide, and etoposide per a retinoblastoma protocol. Repeat magnetic resonance imaging (MRI) showed regression of ocular extension, and an enucleation was performed, histologically confirming the diagnosis of malignant, non-teratoid medulloepithelioma. The child later underwent superficial parotidectomy and received an additional round of chemotherapy. There has been no evidence of recurrence for 9 years. There is no standard treatment for metastatic intraocular medulloepithelioma. The neoadjuvant chemotherapy regimen used in our patient led to regression of the extrascleral extension of the tumor, allowing for enucleation rather than a more disfiguring exenteration, as well as likely improving his prognosis. We believe that it is reasonable to consider neoadjuvant chemotherapy for patients with extrascleral and/or metastatic medulloepithelioma.


Assessment of quality of life and physical activity in patients with oligoarticular juvenile idiopathic arthritis in remission.
The purpose of this study was to evaluate physical activity (PA) and health-related quality of life (HRQOL) in children with oligoarticular juvenile idiopathic arthritis (JIA) in remission in comparison with healthy peers and to determine the disease-related factors affecting PA levels. This study was conducted with 50 oligoarticular JIA patients in remission and 50 healthy peers between 9 and 14 years. Demographic and clinical characteristics, laboratory parameters, and treatments were noted from electronic medical records. HRQOL was assessed with the Pediatric Quality of Life Inventory (PedsQL). PA was evaluated with the Physical Activity Questionnaire for Children (PAQ-C). Oligoarticular JIA patients had significantly lower self-reported median PedsQL scores in the domains of school functioning and social functioning compared to the control group (67.5 (10) vs. 75 (25), p = 0.001 and 70 (15) vs. 85 (26.3), p < 0.001, respectively). The median PAQ-C score was 2.6 (1.1) in patients with JIA and 3 (0.9) in their healthy peers (p = 0.02). The PAQ-C score was 2.8 (1.2) in patients < 8 years at the disease onset and 2.3 (1) in those aged ≥ 8 years (p = 0.022). There was no significant difference in the number of affected joints, type of affected joint, MTX and biologic agent treatment, and remission with or without drugs with the total score of the PedsQL and PAQ-C. All PedsQL domains were positively correlated with the PAQ-C. Conclusion: Oligoarticular JIA patients demonstrated lower PA and HRQOL scores compared to healthy controls despite favorable disease control. What is Known: • Oligoarticular JIA has fewer functional limitations and disabilities compared to other JIA subtypes. • As JIA can affect all aspects of a child's life, there is a need to improve the quality of life related to the disease. What is New: • It should be considered that patients with oligoarticular JIA may show lower PA and HRQOL scores compared to healthy controls despite favorable disease control. • Since there may be a relationship between PA and HRQOL, factors that may affect PA should be investigated to provide a holistic approach to JIA treatment.


Protein-protein interactions in reversibly assembled nanopatterns.
We describe herein a platform to study protein-protein interactions and to form functional protein complexes in nanoscopic surface domains. For this purpose, we employed multivalent chelator (MCh) templates, which were fabricated in a stepwise procedure combining dip-pen nanolithography (DPN) and molecular recognition-directed assembly. First, we demonstrated that an atomic force microscope (AFM) tip inked with an oligo(ethylene glycol) (OEG) disulfide compound bearing terminal biotin groups can be used to generate biotin patterns on gold achieving line widths below 100 nm, a generic platform for fabrication of functional nanostructures via the highly specific biotin-streptavidin recognition. Subsequently, we converted such biotin/streptavidin patterns into functional MCh patterns for reversible assembly of histidine-tagged (His-tagged) proteins via the attachment of a tris-nitriloacetic acid (trisNTA) biotin derivative. Fluorescence microscopy confirmed reversible immobilization of the receptor subunit ifnar2-His10 and its interaction with interferon-alpha2 labeled with fluorescent quantum dots in a 7 x 7 dot array consisting of trisNTA spots with a diameter of approximately 230 nm. Moreover, we carried out characterization of the specificity, stability, and reversibility as well as quantitative real-time analysis of protein-protein interactions at the fabricated nanopatterns by imaging surface plasmon resonance. Our work offers a route for construction and analysis of functional protein-based nanoarchitectures.


Cardiovascular Drug Interactions With Nirmatrelvir/Ritonavir in Patients With COVID-19: JACC Review Topic of the Week.
Nirmatrelvir-ritonavir (NMVr) is used to treat symptomatic, nonhospitalized patients with coronavirus disease-2019 (COVID-19) who are at high risk of progression to severe disease. Patients with cardiovascular risk factors and cardiovascular disease are at a high risk of developing adverse events from COVID-19 and as a result have a higher likelihood of receiving NMVr. Ritonavir, the pharmaceutical enhancer used in NMVr, is an inhibitor of the enzymes of CYP450 pathway, particularly CYP3A4 and to a lesser degree CYP2D6, and affects the P-glycoprotein pump. Co-administration of NMVr with medications commonly used to manage cardiovascular conditions can potentially cause significant drug-drug interactions and may lead to severe adverse effects. It is crucial to be aware of such interactions and take appropriate measures to avoid them. In this review, we discuss potential drug-drug interactions between NMVr and commonly used cardiovascular medications based on their pharmacokinetics and pharmacodynamic properties.


Expression of transforming growth factor-beta in cultured normal human lens epithelia cells.
In order to investigate whether cultured normal human lens epithelial cells (LEC) express transforming growth factor beta (TGF-beta), reverse transcriptase polymerase chain reaction (RT-PCR) and immunohistochemical methods were used for detection of TGF-beta mRNA and protein in cultured normal human LEC. The results showed that a single RT-PCR amplified product about 310bp was obtained, and the sequence was homologous to the known sequence. TGF-beta immunostain was positive in the plasma of LEC. It was suggested that normal human LEC could produce TGF-beta, and LEC could be affected by TGF-beta through autocrine action.


Documentation of hospice care plan development and team meetings.
The interdisciplinary team meeting documentation system as described in this article meets the documentation requirements specified by JCAH and Medicare. The goal of the system is to provide necessary documentation in a format that is easy to use. Because of the generic content and format of this system, hospices in any setting or from any provider can adapt the forms to their particular needs. Delaware Hospice has shared this documentation system together with the interdisciplinary care plan form with numerous hospices who have also found them practical and instrumental in providing high-quality patient care.


Molecular profiling of extracellular vesicles via charge-based capture using oxide nanowire microfluidics.
Extracellular vesicles (EVs) have shown promising features as biomarkers for early cancer diagnoses. The outer layer of cancer cell-derived EVs consists of organotropic metastasis-induced membrane proteins and specifically enriched proteoglycans, and these molecular compositions determine EV surface charge. Although many efforts have been devoted to investigating the correlation between EV subsets obtained through density-, size-, and immunoaffinity-based captures and expressed membrane proteins, understanding the correlation between EV subsets obtained through surface charge-based capture and expressed membrane proteins is lacking. Here, we propose a methodology to profile membrane proteins of EV subsets obtained through surface charge-based capture. Nanowire-induced charge-based capture of EVs and in-situ profiling of EV membrane proteins are the two key methodology points. The oxide nanowires allowed EVs to be obtained through surface charge-based capture due to the diverse isoelectric points of the oxides and the large surface-to-volume ratios of the nanowire structures. And, with the ZnO nanowire device, whose use does not require any purification and concentration processes, we demonstrated the correlation between negatively-charged EV subsets and expressed membrane proteins derived from each cell. Furthermore, we determined that a colon cancer related membrane protein was overexpressed on negatively charged surface EVs derived from colon cancer cells.


Anti-Quorum-Sensing Potential of Ethanolic Extracts of Aromatic Plants from the Flora of Cyprus.
Quorum sensing (QS) is a form of intra- and inter-species communication system employed by bacteria to regulate their collective behavior in a cell population-dependent manner. QS has been implicated in the virulence of several pathogenic bacteria. This work aimed to investigate the anti-QS potential of ethanolic extracts of eight aromatic plants of Cyprus, namely, Origanum vulgare subsp. hirtum, Rosmarinus officinalis, Salvia officinalis, Lavendula spp., Calendula officinalis, Melissa officinalis, Sideritis cypria, and Aloysia citriodora. We initially assessed the effects of the extracts on autoinducer 2 (AI-2) signaling activity, using Vibrio harveyi BB170 as a reported strain. We subsequently assessed the effect of the ethanolic extracts on QS-related processes, including biofilm formation and the swarming and swimming motilities of Escherichia coli MG1655. Of the tested ethanolic extracts, those of Origanum vulgare subsp. hirtum, Rosmarinus officinalis, and Salvia officinalis were the most potent AI-2 signaling inhibitors, while the extracts from the other plants exhibited low to moderate inhibitory activity. These three ethanolic extracts also inhibited the biofilm formation (>60%) of E. coli MG1655, as well as its swimming and swarming motilities, in a concentration-dependent manner. These extracts may be considered true anti-QS inhibitors because they disrupt QS-related activities of E. coli MG1655 without affecting bacterial growth. The results suggest that plants from the unexplored flora of Cyprus could serve as a source for identifying novel anti-QS inhibitors to treat infectious diseases caused by pathogens that are resistant to antibiotics.


Maternal glucose levels during pregnancy and childhood adiposity in the Hyperglycemia and Adverse Pregnancy Outcome Follow-up Study.
Maternal type 2 diabetes during pregnancy and gestational diabetes are associated with childhood adiposity; however, associations of lower maternal glucose levels during pregnancy with childhood adiposity, independent of maternal BMI, remain less clear. The objective was to examine associations of maternal glucose levels during pregnancy with childhood adiposity in the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) cohort. The HAPO Study was an observational epidemiological international multi-ethnic investigation that established strong associations of glucose levels during pregnancy with multiple adverse perinatal outcomes. The HAPO Follow-up Study (HAPO FUS) included 4832 children from ten HAPO centres whose mothers had a 75 g OGTT at ~28 weeks gestation 10-14 years earlier, with glucose values blinded to participants and clinical caregivers. The primary outcome was child adiposity, including: (1) being overweight/obese according to sex- and age-specific cut-offs based on the International Obesity Task Force (IOTF) criteria; (2) IOTF-defined obesity only; and (3) measurements >85th percentile for sum of skinfolds, waist circumference and per cent body fat. Primary predictors were maternal OGTT and HbA1c values during pregnancy. Fully adjusted models that included maternal BMI at pregnancy OGTT indicated positive associations between maternal glucose predictors and child adiposity outcomes. For one SD difference in pregnancy glucose and HbA1c measures, ORs for each child adiposity outcome were in the range of 1.05-1.16 for maternal fasting glucose, 1.11-1.19 for 1 h glucose, 1.09-1.21 for 2 h glucose and 1.12-1.21 for HbA1c. Associations were significant, except for associations of maternal fasting glucose with offspring being overweight/obese or having waist circumference >85th percentile. Linearity was confirmed in all adjusted models. Exploratory sex-specific analyses indicated generally consistent associations for boys and girls. Exposure to higher levels of glucose in utero is independently associated with childhood adiposity, including being overweight/obese, obesity, skinfold thickness, per cent body fat and waist circumference. Glucose levels less than those diagnostic of diabetes are associated with greater childhood adiposity; this may have implications for long-term metabolic health.


Collateral score complements clot location in predicting the outcome of intravenous thrombolysis.
Collateral circulation is an important determinant of stroke outcome. We studied the impact of leptomeningeal collateral circulation with respect to the location of the thrombus in predicting the clinical outcome of patients treated with intravenous thrombolytic therapy (<3 hours) in a retrospective cohort. Anterior circulation thrombus was detected with CT angiography in 105 patients. Baseline clinical and imaging information was collected, and the site of the occlusion was recorded. Collaterals were assessed by using a 5-grade collateral score and were entered into logistic regression analysis to predict favorable clinical outcome (3-month modified Rankin Scale score of 0-2). Two-thirds of patients with a proximal occlusion displayed poor collateral filling (collateral score 0-1), whereas in more distal clot locations, approximately one-third had poor collaterals. Only 36% of patients with a proximal occlusion and good collaterals experienced favorable clinical outcome. In multivariate analysis, both clot location and collateral score were highly significant (P = .003 and P = .001) and independent predictors of favorable clinical outcome. Good collateral status increased the odds of favorable clinical outcome about 9-fold (OR = 9.3; 95% CI, 2.4-35.8). After dichotomization, a distal clot location had a larger odds ratio (OR = 13.3; 95% CI, 3.0-60.0) compared with the odds ratio of good collaterals (OR = 5.9; 95% CI, 1.8-19.0). A proximal occlusion in the anterior circulation is associated with poorer collateral status compared with a more distal occlusion. Both the clot location and collateral score are important and independent predictors of favorable clinical outcome of hyperacute stroke treated with intravenous thrombolysis. The location of the clot is a stronger determinant of the outcome than the collateral score.


Revisiting the pathogenesis of ovarian cancer: the central role of the fallopian tube.
Among all gynecological malignancies, ovarian cancer is associated with the highest rate of mortality. Recent findings now propose a pivotal role for the fallopian tube during ovarian cancer pathogenesis. Until recently, ovarian cancer was thought to derive from the ovarian surface epithelium. Nevertheless, attempts to define a precursor lesion from this tissue failed. Instead, prophylactic surgery performed on BRCA mutation carriers and subsequent histological analyses revealed a characteristic pre-neoplastic alteration at the fimbriated end of the fallopian tubes, the so-called serous tubal intraepithelial carcinoma (STIC). By morphology and molecular genetics, STIC was found to resemble serous ovarian cancer. As STIC can also be detected in >60 % of BRCA-unrelated serous ovarian carcinomas, it is now considered to be the precursor of the most common ovarian cancer subtype. Based on this hypothesis, a salpingectomy, i.e., the removal of the post-reproductive fallopian tubes may remove the actual site of tumorigenesis and thereby prevent spreading over the ovarian surface and throughout the peritoneum. Consequently, prophylactic salpingectomy might protect against serous ovarian cancer. Moreover, the procedure interrupts the connection between the uterine cavity and the lesser pelvis. Hence, it prevents the ascension of exfoliated endometrial cells which will likely reduce the incidence of endometrioid and clear cell ovarian cancers. Increasing evidence suggests that serous ovarian cancer originates from the fimbriated distal end of the fallopian tube, whereas the ovary gets only involved at a later stage. Given the lack of suitable screening or early detection strategies for ovarian cancer, post-reproductive salpingectomy deserves serious consideration as a prophylactic intervention that will likely confer significant protection against an often deadly disease.


Windscapes and olfactory foraging in a large carnivore.
The theoretical optimal olfactory search strategy is to move cross-wind. Empirical evidence supporting wind-associated directionality among carnivores, however, is sparse. We examined satellite-linked telemetry movement data of adult female polar bears (Ursus maritimus) from Hudson Bay, Canada, in relation to modelled winds, in an effort to understand olfactory search for prey. In our results, the predicted cross-wind movement occurred most frequently at night during winter, the time when most hunting occurs, while downwind movement dominated during fast winds, which impede olfaction. Migration during sea ice freeze-up and break-up was also correlated with wind. A lack of orientation during summer, a period with few food resources, likely reflected reduced cross-wind search. Our findings represent the first quantitative description of anemotaxis, orientation to wind, for cross-wind search in a large carnivore. The methods are widely applicable to olfactory predators and their prey. We suggest windscapes be included as a habitat feature in habitat selection models for olfactory animals when evaluating what is considered available habitat.


Manual wheelchair propulsion: effects of power output on physiology and technique.
Eight wheelchair sportsmen conducted eight wheelchair exercise tests on a treadmill. Two workload strategies were followed: strategy 1--increments in speed at a constant slope and strategy 2--increments in slope at constant velocity. Thus, data on cardio-respiratory and propulsion technique parameters were obtained on two identical series of 16 speed and slope combinations. Between each two identical speed and slope combinations of strategies 1 and 2, a different workload history is apparent. A four-factor analysis of variance with repeated measures on the factors "strategy" (workload history), "speed," and "slope" was applied (P less than 0.05). No "strategy" effect was seen in the cardio-respiratory parameters (gross mechanical efficiency, ventilation, oxygen consumption, and heart rate), work/cycle, and cycle time. Thus, within the experimental set-up, workload history did not affect the parameters studied and 3-min workload periods appeared sufficiently long for experienced wheelchair users to adapt to the requirements of a given speed and slope combination. Significant effects were found on "speed," "slope," and their interaction in all parameters tested. Moreover, a comparison of two equal levels of power output, but different speed and slope, led to a significantly higher efficiency, cycle time, and work per cycle for the "low speed and high slope" combination. Push time and recovery time appeared highly dependent on speed and slope, respectively. The findings indicate that propulsion technique and cardio-respiratory parameters should not merely be studied in relation to power output, but also with respect to its constituents, speed, and slope/resistance.


Prevention and management of osteoporotic fractures by non-physician health professionals: a systematic literature review to inform EULAR points to consider.
To perform a systematic literature review (SLR) about the effect of non-pharmacological interventions delivered by non-physician health professionals to prevent and manage osteoporotic fractures. Eight clinical questions based on two criteria guided the SLR: (1) adults≥50 years at high risk of osteoporotic fracture and (2) interventions delivered by non-physician health professionals to prevent and manage osteoporotic fractures. Interventions focused on diagnostic procedures to identify risk of falling, therapeutic approaches and implementation strategies. Outcomes included fractures, falls, risk of falling and change in bone mineral density. Systematic reviews and randomised controlled trials were preferentially selected. Data were synthesised using a qualitative descriptive approach. Of 15 917 records, 43 articles were included. Studies were clinically and methodologically diverse. We identified sufficient evidence that structured exercise, incorporating progressive resistance training delivered to people who had undergone hip fracture surgery, and multicomponent exercise, delivered to people at risk of primary fracture, reduced risk of falling. The effectiveness of multidisciplinary fracture liaison services in reducing refracture rate was confirmed. There was insufficient evidence found to support the effectiveness of nutrients and falls prevention programmes in this patient population. Despite study heterogeneity, our SLR showed beneficial effects of some interventions delivered by non-physician health professionals and the positive impact of multidisciplinary team working and patient educational approaches to prevent and manage osteoporotic fractures. These results informed a EULAR taskforce that developed points to consider for non-physician health professionals to prevent and manage osteoporotic fractures.


Serum autoleukocytotoxic activity and the positive cross-match in potential allograft recipients.
To evaluate possible causes of the false-positive cross-match test for clinical renal transplantation, the incidence of serum autoleukocytotoxic activity and its relationship to allogeneic sensitization to HLA antigens (the positive cross-match) were determined in 234 sera from 28 sensitized and eight nonsensitized chronic renal failure patients. Seven sera from four patients had autoleukocytotoxic activity. The autoleukocytotoxic activity was detected only in patients who showed transient allogeneic sensitization at some point. This activity could be adsorbed either by autologous or allogeneic platelets, but adsorption with autologous platelets did not remove the synchronous allogeneic leukocytotoxicity. This autoleukocytotoxic activity appears to coexist with alloreactive antibody, and in such a setting the positive alloreactive cross-match should contraindicate the proposed transplant until adsorption studies prove the false-positiveness of the test.


TLR5 signalling is hyper-responsive in porcine cystic fibrosis airways epithelium.
Excessive lung inflammation and airway epithelium damage are hallmarks of cystic fibrosis (CF) disease. It is unclear whether lung inflammation is related to an intrinsic defect in the immune response or to chronic infection. We aimed to determine whether TLR5-mediated response is defective in the CF airway epithelium. We used a newborn CF pig model to study intrinsic alterations in CF airway epithelium innate immune response. Airway epithelial cells (AECs) were stimulated with flagellin or lipopolysaccharide to determine responses specific for TLR5 and TLR4, respectively. We observed a significant increase in cytokine secretion when CF AECs were stimulated with flagellin compared to wild type (WT) AECs. These results were recapitulated when AECs were treated with an inhibitor of CFTR channel activity. We show that TLR5-signalling is altered in CF lung epithelium at birth. Modulation of TLR5 signalling could contribute to better control the excessive inflammatory response observed in CF lungs.


Advanced glycation end product (AGE) modified proteins in tears of diabetic patients.
High glucose level in diabetic patients may lead to advanced glycation end product (AGE) modified proteins. This study investigated AGE modified proteins in tears and compared their levels in diabetic patients (DM) with non-diabetic controls (CTL). Basal tears were collected from DM with (DR) or without (DNR) retinopathy and CTL. Total AGE modified proteins were detected quantitatively by a dot immunobinding assay. The AGE modified proteins were separated in 1D- and 2D-SDS gels and detected by western-blotting. The individual AGE modified proteins were also compared between groups using densitometry. Compared with the CTL group, tear concentrations of AGE modified proteins were significantly elevated in DR and DNR groups. The concentration of AGE modified proteins in diabetic tears were positively correlated with AGE modified hemoglobin (HbA1c) and postprandial blood glucose level (PBG). Western blotting of AGE modified proteins from 1D-SDS gels showed several bands, the major one at around 60 kDa. The intensities of AGE modified protein bands were higher in DM tears than in CTL tears. Western blotting from 2D-SDS gels showed a strongly stained horizontal strip, which corresponded to the major band in 1D-SDS gels. Most of the other AGE modified protein species were within molecular weight of 30-60 kDa, PI 5.2-7.0. Densitometry analysis demonstrated several AGE modified proteins were elevated in DR or DNR tears. Total and some individual AGE modified proteins were elevated in DM tears. AGE modified proteins in tears may be used as biomarkers to diagnose diabetes and/or diabetic retinopathy.


Renal failure in critically ill patients, beware of applying (central venous) pressure on the kidney.
The central venous pressure (CVP) is traditionally used as a surrogate of intravascular volume. CVP measurements therefore are often applied at the bedside to guide fluid administration in postoperative and critically ill patients. Pursuing high CVP levels has recently been challenged. A high CVP might impede venous return to the heart and disturb microcirculatory blood flow which may cause tissue congestion and organ failure. By imposing an increased "afterload" on the kidney, an elevated CVP will particularly harm kidney hemodynamics and promote acute kidney injury (AKI) even in the absence of volume overload. Maintaining the lowest possible CVP should become routine to prevent and treat AKI, especially when associated with septic shock, cardiac surgery, mechanical ventilation, and intra-abdominal hypertension.