Brief report: concurrent validity of autism symptom severity measures.
The autism spectrum disorder (ASD) diagnostic classifications, according to the DSM-5, include a severity rating. Several screening and/or diagnostic measures, such as the autism diagnostic and observation schedule (ADOS), Childhood Autism Rating Scale (CARS) and social responsiveness scale (SRS) (teacher and parent versions), include an assessment of symptom severity. The purpose of this study was to examine whether symptom severity and/or diagnostic status of preschool-aged children with ASD (N = 201) were similarly categorized on these measures. For half of the sample, children were similarly classified across the four measures, and scores on most measures were correlated, with the exception of the ADOS and SRS-P. While the ADOS, CARS, and SRS are reliable and valid measures, there is some disagreement between measures with regard to child classification and the categorization of autism symptom severity.


Tobacco smoking induces cardiovascular mitochondrial oxidative stress, promotes endothelial dysfunction, and enhances hypertension.
Tobacco smoking is a major risk factor for cardiovascular disease and hypertension. It is associated with the oxidative stress and induces metabolic reprogramming, altering mitochondrial function. We hypothesized that cigarette smoke induces cardiovascular mitochondrial oxidative stress, which contributes to endothelial dysfunction and hypertension. To test this hypothesis, we studied whether the scavenging of mitochondrial H2O2 in transgenic mice expressing mitochondria-targeted catalase (mCAT) attenuates the development of cigarette smoke/angiotensin II-induced mitochondrial oxidative stress and hypertension compared with wild-type mice. Two weeks of exposure of wild-type mice with cigarette smoke increased systolic blood pressure by 17 mmHg, which was similar to the effect of a subpresssor dose of angiotensin II (0.2 mg·kg-1·day-1), leading to a moderate increase to the prehypertensive level. Cigarette smoke exposure and a low dose of angiotensin II cooperatively induced severe hypertension in wild-type mice, but the scavenging of mitochondrial H2O2 in mCAT mice completely prevented the development of hypertension. Cigarette smoke and angiotensin II cooperatively induced oxidation of cardiolipin (a specific biomarker of mitochondrial oxidative stress) in wild-type mice, which was abolished in mCAT mice. Cigarette smoke and angiotensin II impaired endothelium-dependent relaxation and induced superoxide overproduction, which was diminished in mCAT mice. To mimic the tobacco smoke exposure, we used cigarette smoke condensate, which induced mitochondrial superoxide overproduction and reduced endothelial nitric oxide (a hallmark of endothelial dysfunction in hypertension). Western blot experiments indicated that tobacco smoke and angiotensin II reduce the mitochondrial deacetylase sirtuin-3 level and cause hyperacetylation of a key mitochondrial antioxidant, SOD2, which promotes mitochondrial oxidative stress. NEW & NOTEWORTHY This work demonstrates tobacco smoking-induced mitochondrial oxidative stress, which contributes to endothelial dysfunction and development of hypertension. We suggest that the targeting of mitochondrial oxidative stress can be beneficial for treatment of pathological conditions associated with tobacco smoking, such as endothelial dysfunction, hypertension, and cardiovascular diseases.


Study protocol of SWEPIS a Swedish multicentre register based randomised controlled trial to compare induction of labour at 41 completed gestational weeks versus expectant management and induction at 42 completed gestational weeks.
Observational data shows that postterm pregnancy (≥42 gestational weeks, GW) and late term pregnancy (≥41 GW), as compared to term pregnancy, is associated with an increased risk for adverse outcome for the mother and infant. Standard care in many countries is induction of labour at 42 GW. There is insufficient scientific support that induction of labour at 41 GW, as compared with expectant management and induction at 42 GW will reduce perinatal mortality and morbidity without an increase in operative deliveries, negative delivery experiences or higher costs. Large randomised studies are needed since important outcomes; such as perinatal mortality and hypoxic ischaemic encephalopathy are rare events. A total of 10 038 healthy women ≥18 years old with a normal live singleton pregnancy in cephalic presentation at 41 GW estimated with a first or second trimester ultrasound, who is able to understand oral and written information will be randomised to labour induction at 41 GW (early induction) or expectant management and induction at 42 GW (late induction). Women will be recruited at university clinics and county hospitals in Sweden comprising more than 65 000 deliveries per year. Primary outcome will be a composite of stillbirth, neonatal mortality and severe neonatal morbidity. Secondary outcomes will be other adverse neonatal and maternal outcomes, mode of delivery, women's experience, cost effectiveness and infant morbidity up to 3 months of age. Data on background variables, obstetric and neonatal outcomes will be obtained from the Swedish Pregnancy Register and the Swedish Neonatal Quality Register. Data on women's experiences will be collected by questionnaires after randomisation and 3 months after delivery. Primary analysis will be intention to treat. The statistician will be blinded to group and intervention. It is important to investigate if an intervention at 41 GW is superior to standard care in order to reduce death and lifelong disability for the children. The pregnant population, >41 GW, constitutes 15-20% of all pregnancies and the results of the study will thus have a great impact. The use of registries for randomisation and collection of outcome data represents a unique and new study design. The study was registered in Current Controlled Trials, ISRCTN26113652 the 30(th) of March 2015 (DOI 10.1186/ISRCTN26113652 ).


A coupled recreational anglers' decision and fish population dynamics model.
The effective management of fish populations requires understanding of both the biology of the species being managed and the behavior of the humans who harvest those species. For many marine fisheries, recreational harvests represent a significant portion of the total fishing mortality. For such fisheries, therefore, a model that captures the dynamics of angler choices and the fish population would be a valuable tool for fisheries management. In this study, we provide such a model, focusing on red drum and spotted seatrout, which are the two of the main recreational fishing targets in the Gulf of Mexico. The biological models are in the form of vector autoregressive models. The anglers' decision model takes the discrete choice approach, in which anglers first decide whether to go fishing and then determine the location to fish based on the distance and expected catch of two species of fish if they decide to go fishing. The coupled model predicts that, under the level of fluctuation in the abundance of the two species experienced in the past 35 years, the number of trips that might be taken by anglers fluctuates moderately. This fluctuation is magnified as the cost of travel decreases because the anglers can travel long distance to seek better fishing conditions. On the other hand, as the cost of travel increases, their preference to fish in nearby areas increases regardless of the expected catch in other locations and variation in the trips taken declines. The model demonstrates the importance of incorporating anglers' decision processes in understanding the changes in a fishing effort level. Although the model in this study still has a room for further improvement, it can be used for more effective management of fish and potentially other populations.


'But is it a question worth asking?' A reflective case study describing how public involvement can lead to researchers' ideas being abandoned.
It is good practice for the public to be involved in developing research ideas into grant applications. Some positive accounts of this process have been published, but little is known about when their reactions are negative and when researchers' ideas are abandoned. To present a case study account of when an academic-led idea for funding was not supported by stroke survivors and carers who were asked to contribute to its development, together with a reflection on the implications of the case from all the stakeholders involved. A reflective case study of a research idea, developed by an academic researcher, on which stakeholders were consulted. University researchers, clinicians, public involvement managers, and stroke survivors and carers from the NIHR's Stroke Research Network. Although the idea met with the approval of health professionals, who were keen to develop it into a funding bid, the stroke survivors and carers did not think the idea worth pursuing. This lack of patient and carer support led to the idea being abandoned. Reflecting on this, those involved in the consultation believed that the savings accrued from abandoning the idea, in terms of ensuring that public money is not wasted, should be seen as an important benefit of public involvement in the research process. Little is known about the role of the public in the abandonment of research ideas. We recommend that further research is undertaken into this important contribution that patients and the public can make to health research.


Chronic disease and hospitalisation for pandemic (H1N1) 2009 influenza in Indigenous and non-Indigenous Western Australians.
Indigenous and non-indigenous Western Australians with pandemic (H1N1) 2009 influenza (pH1N1) infection were compared for risk factors, influenza vaccination history, symptoms, use of antiviral medications, and hospitalisation. Data were collected systematically on 856 notified cases with laboratory confirmed pH1N1 infection during the first 10 weeks of pH1N1 virus transmission in Western Australia in 2009. Indigenous people with pH1N1 were approximately 3 times more likely to be hospitalised and were more likely to have a range of underlying medical conditions and be smokers, compared with non-Indigenous cases. Age (P < 0.001) and the presence of two or more co-morbidities (P < 0.001) were independent predictors of hospitalisation, while Indigenous status was not, indicating that higher pH1N1 hospitalisation rates in Indigenous Australians during the 2009 winter season were attributable to the higher prevalence of underlying chronic disease. These results underscore the need to ensure that influenza vaccination is delivered as widely as possible among those with chronic health conditions.


Factors affecting the achievement of fertility intentions in urban Nigeria: analysis of longitudinal data.
Maternal mortality ratio in Nigeria is among the highest in the world with an estimated 160 women dying every day of complications related to pregnancy and childbirth. In addition to appropriate management of complications related to pregnancy and childbirth, preventing unwanted pregnancies is an effective way to reduce maternal deaths. Identifying potentially modifiable factors associated with the achievement of fertility intentions is critical for developing behavior change interventions that will contribute to reducing maternal mortality. The data analyzed came from a longitudinal design with data collected in 2010/2011 and 2014 from the same group of women of reproductive age in six Nigerian cities. The data were collected as part of efforts to evaluate the effects of the Nigerian Urban Reproductive Health Initiative (NURHI). A total of 10,672 women were interviewed at the two points in time but the analyses in this manuscript were limited to 1921 in-union women who reported that they desired no more children at baseline in 2010/2011. The principal analytic method was multivariable regression adjusted for clustering at the enumeration area level. The analysis controlled for socio-demographic and household variables, ideational characteristics, and contraceptive use at baseline. About two thirds of the women who desired no more children at baseline have neither had any children nor were pregnant at endline. The strongest predictors of the achievement of fertility intentions include parity, age, religion, residence, spousal communication about family size, perceived severity of another pregnancy, and spousal agreement about family size. A comprehensive strategy to help women avoid unwanted pregnancies should include efforts to increase women's understanding about effective ways to prevent unplanned pregnancies and strengthen self-efficacy for contraceptive use. Promoting spousal communication about reproductive issues, engaging men, promoting smaller family sizes and changing pronatalist attitudes should also be part of such a strategy.


High in vivo production of a model monoclonal antibody on adenoviral gene transfer.
The therapeutic potential of monoclonal antibodies (MAbs) for treating a variety of severe or life-threatening diseases is high. Although intravenous infusion appears to be the simplest and most obvious mode of administration, it is not applicable in many long-term treatments. It might, however, be advantageously replaced by gene/cell therapies, rendering treatments cost-effective and eliminating the short- and long-term side effects associated with injection of massive doses of antibodies. Grafting of ex vivo genetically modified cells of various types has already been used for in vivo production and systemic delivery of MAbs in mice. However, although sustained for long periods of time, serum levels of ectopic MAbs were low. We show here that in vivo administration to mice of a first-generation adenoviral vector expressing a model MAb also permits achievement of the same goal, but with 100 to 200 times better efficiency that in any other case of gene transfer described thus far. We also investigated for possible anti-idiotypic response against the ectopic MAb. None was detected in the animals expressing the lowest levels of ectopic MAb production; a response was detected among the highest producers. In the latter case, however, the response was low and could not exert any significant neutralizing activity. In conclusion, our work indicates that high levels of circulating ectopic MAb can be obtained on direct in vivo gene transfer without inducing an anti-idiotypic response sufficiently robust to exert a neutralizing effect. This observation is encouraging in the perspective of clinical applications of this technology.


Fluorescently-tagged human eIF3 for single-molecule spectroscopy.
Human translation initiation relies on the combined activities of numerous ribosome-associated eukaryotic initiation factors (eIFs). The largest factor, eIF3, is an ∼800 kDa multiprotein complex that orchestrates a network of interactions with the small 40S ribosomal subunit, other eIFs, and mRNA, while participating in nearly every step of initiation. How these interactions take place during the time course of translation initiation remains unclear. Here, we describe a method for the expression and affinity purification of a fluorescently-tagged eIF3 from human cells. The tagged eIF3 dodecamer is structurally intact, functions in cell-based assays, and interacts with the HCV IRES mRNA and the 40S-IRES complex in vitro. By tracking the binding of single eIF3 molecules to the HCV IRES RNA with a zero-mode waveguides-based instrument, we show that eIF3 samples both wild-type IRES and an IRES that lacks the eIF3-binding region, and that the high-affinity eIF3-IRES interaction is largely determined by slow dissociation kinetics. The application of single-molecule methods to more complex systems involving eIF3 may unveil dynamics underlying mRNA selection and ribosome loading during human translation initiation.


PM2.5 speciation trends network: evaluation of whole-system uncertainties using data from sites with collocated samplers.
The objectives of this paper are to contrast the relative variability of replicate laboratory measurements of selected chemical components of fine particulate matter (PM) with total variability from collocated measurements and to compare the magnitudes of the uncertainties determined from collocated sampler data with those currently being provided to U.S. Environmental Protection Agency (EPA)'s Air Quality System (AQS) database by RTI International (RTI). Pointwise uncertainty values are needed for modeling and data analysis and should include all the random errors affecting each data point. Total uncertainty can be decomposed into two primary components: analytical measurement uncertainty and sampling uncertainty. Analytical measurement uncertainties are relatively easy to calculate from routine quality control (QC) data. Sampling uncertainties, on the other hand, are comparatively difficult to measure. In this paper, the authors describe data from collocated samplers to provide a snapshot of whole-system uncertainty for several important chemical species. The components of uncertainty were evaluated for key species from each of the analytical methods employed by the PM2.5 Speciation Trends Network (STN) program: gravimetry, ion chromatography (IC), X-ray fluorescence (XRF), and thermal-optical analysis for organic carbon and elemental carbon. The results show that the laboratory measurement uncertainties are typically very small compared with uncertainties calculated from the differences between samples collected from collocated samplers. These differences are attributable to the "field" components uncertainty, which may include contamination and/or losses during shipping, handling, and sampling, as well as other distortions of the concentration level due to flow and sample volume variations. Uncertainties calculated from the collocation results were found to be generally similar to the uncertainties currently being loaded into EPA's AQS system, with some exceptions described below.


Adsorption according to the Langmuir-Freundlich model is the detection mechanism of the antigen p53 for early diagnosis of cancer.
Biosensors for early detection of cancer biomarkers normally depend on specific interactions between such biomarkers and immobilized biomolecules in the sensing units. Though these interactions are expected to yield specific, irreversible adsorption, the underlying mechanism appears not to have been studied in detail. In this paper, we show that adsorption explained with the Langmuir-Freundlich model is responsible for detection of the antigen p53 associated with various types of cancers. Irreversible adsorption was proven between anti-p53 antibodies immobilized on the biosensors and the antigen p53, with the adequacy of the Langmuir-Freundlich model being confirmed with three independent experimental methods, viz. polarization-modulated infrared reflection absorption spectroscopy (PM-IRRAS), nanogravimetry using a quartz crystal microbalance and electrochemical impedance spectroscopy. The method based on this irreversible adsorption was sufficiently sensitive (limit of detection of 1.4 pg mL(-1)) for early diagnosis of Hodgkin lymphoma, pancreatic and colon carcinomas, and bladder, ovarian and lung cancers, and could distinguish between MCF7 cells containing the antigen p53 from Saos-2 cells that do not contain it.


Stability studies of chitosan-DNA-FAP-B nanoparticles for gene delivery to lung epithelial cells.
A successful gene delivery system requires efficiency and stability during storage. Stability studies are imperative for nanomedicines containing biotechnological products such as plasmids and targeting peptides. Chitosan-DNA-FAP-B nanoparticles are novel non-viral vectors for specific gene delivery to the lung epithelial cells. In this study, the storage stability of chitosan-DNA-FAP-B nanoparticles at -20, 5 and 24 °C was examined. Size, zeta potential and transfection efficiency of these nano-particles in storage were also evaluated. Stability studies showed that chitosan-DNA-FAP-B nanoparticles were stable after 1 month when stored at -20 °C and retained their initial size, zeta potential and transfection efficiency. However, their stability was not desirable at 5 and 24 °C. Based on these results, it can be concluded that chitosan-DNA-FAP-B nanoparticles can be a promising candidate for gene delivery to lung epithelial cells with good storage stability at -20 °C during 1 month.


Distal spinal nerve development and divergence of avian groups.
The avian transition from long to short, distally fused tails during the Mesozoic ushered in the Pygostylian group, which includes modern birds. The avian tail embodies a bipartite anatomy, with the proximal separate caudal vertebrae region, and the distal pygostyle, formed by vertebral fusion. This study investigates developmental features of the two tail domains in different bird groups, and analyzes them in reference to evolutionary origins. We first defined the early developmental boundary between the two tail halves in the chicken, then followed major developmental structures from early embryo to post-hatching stages. Differences between regions were observed in sclerotome anterior/posterior polarity and peripheral nervous system development, and these were consistent in other neognathous birds. However, in the paleognathous emu, the neognathous pattern was not observed, such that spinal nerve development extends through the pygostyle region. Disparities between the neognaths and paleognaths studied were also reflected in the morphology of their pygostyles. The ancestral long-tailed spinal nerve configuration was hypothesized from brown anole and alligator, which unexpectedly more resembles the neognathous birds. This study shows that tail anatomy is not universal in avians, and suggests several possible scenarios regarding bird evolution, including an independent paleognathous long-tailed ancestor.


Experimental manipulation of the Trier Social Stress Test-Modified (TSST-M) to vary arousal across development.
Reliable laboratory protocols manipulating the intensity of biobehavioral arousal for children are uncommon, and those available have minimal converging evidence of their efficacy in manipulating arousal across multiple biological systems. This report presents two studies of the efficacy of the modified Trier Social Stress Test (TSST-M). In Study 1, sixty-three 7-15-year olds, and 19 young adults (18-25 yrs) completed the TSST-M. Comparable reactivity across age groups was observed for salivary cortisol, salivary alpha-amylase (sAA), pre-ejection period (PEP) and respiratory sinus arrhythmia (RSA), whereas self-reported stress was higher in adults compared to children. In Study 2, eighty-four 7-8-year olds and eighty-six 12-15-year olds were randomly assigned to a standard or low-stress TSST-M condition. Cortisol and self-reported stress responses were higher in the standard compared to the low-stress condition. In contrast, sAA and PEP were higher in the low-stress condition and RSA responses were comparable between the two TSST-M conditions. In addition, age group differences emerged in Study 2, though never in conjunction with the TSST-M manipulation. To test, refine, and advance theory about the implications of stress for child development, laboratory tasks that manipulate and enable assessment of biobehavioral arousal in children are needed.


Rapid maxillary expansion and surgically assisted rapid maxillary expansion effects on nasal volume.
The purpose of this study was to compare the effects of rapid maxillary expansion (RME) and surgically assisted rapid maxillary expansion (SARME) on nasal volume using acoustic rhinometric methods. Two groups of subjects were used in the study. Group 1 consisted of 10 subjects (mean age 12.30 +/- 0.82 years) who were treated with RME, and group 2 consisted of 10 subjects (mean age 18.70 +/- 2.54 years) who were treated by SARME. In both groups, all cases had a maxillary width deficiency with bilateral crossbites. Nasal volume records were taken by the same otorhinolaryngologist with an AR device. AR recordings were performed for each patient with and without the use of a decongestant. The first record was taken before expansion, and the second record was taken at the end of retention. The data for both groups were evaluated using Wilcoxon signed rank test and Mann-Whitney U-test. The nasal volume showed a significant increase in both the RME and the SARME groups (P < .05). The measurement with the use of decongestant was similar to that without use of decongestant on the both groups (P < .05), but the different increments in nasal volume between the RME and the SARME groups were not statistically significant. Although the mean ages between the RME and the SARME groups were different, the increase in nasal volume was similar in both groups.


Determination of the shell growth direction during the formation of silica microcapsules by confocal fluorescence microscopy.
A novel procedure was developed to determine the direction of silica growth during the formation of a silica shell around aqueous microdroplets in water-in-oil Pickering emulsions. Two fluorescently labeled silica precursors were added consecutively and the resulting microcapsules were visualized via confocal fluorescence microscopy, allowing the conclusion that the locus of reaction moves in the positive radial direction, i.e. from the inside to the outside. A consequence of the growth direction is that water has to diffuse through the shell to participate in the reaction on the outer surface of the shell.


Anatomic Double-Bundle Posterior Cruciate Ligament Reconstruction.
The posterior cruciate ligament (PCL) is the main posterior stabilizer of the knee. It is composed of 2 bundles, the larger anterolateral bundle (ALB) and the smaller posteromedial bundle (PMB). The 2 bundles were historically believed to function independently, with the ALB predominantly being an important stabilizer in flexion and the PMB being a stabilizer mainly in extension. However, a recent biomechanical study1 noted a codominant relationship between these 2 bundles. The anatomic single-bundle PCL reconstruction, focusing on reconstruction of the larger ALB, is the most commonly performed procedure. Because of the residual posterior and rotational tibial instability after a single-bundle reconstruction and the inability to restore the normal knee kinematics, an anatomic double-bundle PCL reconstruction has been proposed in an effort to recreate both bundles using the native footprint, thereby restoring the normal knee kinematics. The anatomic double-bundle PCL reconstruction has demonstrated improved subjective and objective patient outcomes with a low complication rate. Indications for PCL reconstruction are isolated symptomatic acute grade-III PCL tears, combined multiligament lesions, or acute grade-III PCL tears combined with repairable meniscal body or root tears. For chronic PCL tears, indications include functional limitations due to the PCL tear (e.g., difficulty with deceleration, incline descent, or stairs) and comparative PCL stress radiographic laxity of >8 mm in a symptomatic patient. The steps of this procedure include (1) correct patient positioning to allow for good accessibility of both sides of the joint; (2) graft preparation (Achilles tendon [ALB] and tibialis anterior [PMB] allografts are used); (3) creation of femoral tunnels (11 mm for the ALB adjacent to the cartilage and 7 mm for the PMB with a 2-mm bone bridge); (4) tibial tunnel creation (12-mm diameter, 7 mm anterior to the so-called champagne-glass drop-off); (5) graft fixation and tibial graft passage (a metal screw for the ALB and a bioabsorbable screw for the PMB, with the screws away from the bone bridge to avoid bone bridge breakage); and (6) tibial fixation (the grafts are independently fixed with the knee at 90° of flexion (ALB) and extension (PMB) with screws and washers on the medial side of the tibia. Three prospective randomized studies18,19,23 suggested that, while clinical outcomes are similar between both isolated transtibial reconstruction techniques, the objective measures of postoperative side-to-side posterior translation and objective International Knee Documentation Committee scores were significantly improved with double-bundle compared with single-bundle PCL reconstructions.


Influence of Viscose Fibre Geometry on the Structure-Property Relationships of High-Density Polyethylene Composites.
This study investigated the influence of viscose fibre (VF) geometry on the microstructures and resulting properties of high-density polyethylene (HDPE) composites. Seven types of viscose fibres varying in cross-section shape, linear density, and length were pelletised, compounded into HDPE with a twin-screw extruder, and injection moulded. The microstructures of the composites were characterised by investigating their cross-sections and by extracting the fibres and measuring their lengths using optical microscopy (OM). The mechanical and thermal properties of the composites were characterised using differential scanning calorimetry (DSC), tensile tests, Charpy impact tests, and dynamic mechanical analysis (DMA). The composites prepared using cylindrical fibres with a linear density of 1.7 dtex exhibited the best fibre dispersion, highest orientation, and lowest fibre-fibre contact area. The decrease in the linear density of the cylindrical fibres resulted in increasingly worse dispersion and orientation, while composites containing non-cylindrical fibres exhibited a comparably larger fibre-fibre contact area. The initial fibre length of about 3 to 10 mm decreased to the mean values of 0.29 mm to 0.41 mm during processing, depending on the initial geometry. In general, cylindrical fibres exhibited a superior reinforcing effect in comparison to non-cylindrical fibres. The composites containing cylindrical fibres with a linear density of 1.7 dtex and a length of 5 mm exhibited the best reinforcing effect with an increase in tensile modulus and strength of 323% and 141%, respectively.


The unfolded protein response and endoplasmic reticulum protein targeting machineries converge on the stress sensor IRE1.
The protein folding capacity of the endoplasmic reticulum (ER) is tightly regulated by a network of signaling pathways, known as the unfolded protein response (UPR). UPR sensors monitor the ER folding status to adjust ER folding capacity according to need. To understand how the UPR sensor IRE1 maintains ER homeostasis, we identified zero-length crosslinks of RNA to IRE1 with single nucleotide precision in vivo. We found that IRE1 specifically crosslinks to a subset of ER-targeted mRNAs, SRP RNA, ribosomal and transfer RNAs. Crosslink sites cluster in a discrete region of the ribosome surface spanning from the A-site to the polypeptide exit tunnel. Moreover, IRE1 binds to purified 80S ribosomes with high affinity, indicating association with ER-bound ribosomes. Our results suggest that the ER protein translocation and targeting machineries work together with the UPR to tune the ER's protein folding load.


The impact of concordant and discordant conditions on the quality of care for hyperlipidemia.
Physician treatment of cardiovascular risk factors may be affected by specific types of patient comorbidities. To examine the relationship between discordant comorbidities and LDL-cholesterol management in hypertensive patients not previously treated with lipid-lowering therapy; to determine whether the presence of cardiovascular (concordant) conditions mediates this relationship. We performed a retrospective cohort study of 1,935 hypertensive primary care patients (men >45 years of age, women >55 years of age) with documented elevated low-density lipoprotein (LDL) cholesterol and no lipid-lowering therapy at baseline. The outcome was guideline-consistent hyperlipidemia management defined as optimal value on repeat LDL cholesterol testing or initiation of lipid-lowering therapy. Using generalized estimating equations (GEE), we examined the association of concordant and discordant comorbidities with guideline-consistent hyperlipidemia management over a 2-year follow-up period, adjusting for patient characteristics. Guideline-consistent hyperlipidemia management was achieved in 1,236 patients (64%). In the fully adjusted model, each additional discordant condition resulted in a 19% lower adjusted odds ratio of guideline-consistent hyperlipidemia management (p < 0.001) when compared with no discordant conditions. The dampening effect of discordant conditions on guideline-consistent management persisted even in the presence of concordant conditions, but each additional concordant condition was associated with a 37% increase in the adjusted odds of guideline-consistent hyperlipidemia management (p < 0.001). In this cohort of hypertensive primary care patients, the number of conditions discordant with cardiovascular risk was strongly negatively associated with guideline-consistent hyperlipidemia management even in patients at the highest risk for cardiovascular events and cardiac death.


Calcium balance in uremia: longitudinal study of long-term survivors.
Twelve male patients surviving uremia of 9-15 years duration were studied sequentially over a mean period of 9.2 years. Radiographs, bone biopsies, bone mineral mass (BMM) measured by photon absorptiometry, and total body calcium (TBC) determined by in vivo neutron activation analysis (NAA) were used. Pathologic fractures correlated with TBC corrected for height: 4 of 5 patients without fractures had TBC above 80% predicted, whereas 5 of 7 patients with fractures fell below this value. Unlike previous studies, negative calcium balance was seen in 3 patients with prolonged hyperparathyroidism. Though soft tissue calcification occurred in 6 patients, only 1 with massive shoulder calcification had an increase in TBC; this drawback of NAA has been previously overemphasized. Moreover, radial BMM also increased in 2 patients due to soft tissue calcification. When viewed at a single point in time, nearly all patients fell within the wide normal limits of BMM vs TBC. However, 6 patients with variable bone histology studied sequentially over a mean of 8.5 years showed significant preferential loss of radial bone mass compared to TBC. Aluminium retention did not influence calcium balance in these subjects.


Monitoring and assessment in maternal and child health: recommendations for action at the state level.
Recent administration-sponsored changes in federal health policy and funding may harbor adverse effects for the health of mothers and children, and for the capabilities of state-level programs to serve them appropriately. Careful monitoring is required to assess the nature, extent, and impact of those changes. This paper examines several monitoring efforts in maternal and child health and recommends additional action at the state level to meet urgent information requirements.


Form of aluminium for uptake and translocation in buckwheat (Fagopyrum esculentum Moench).
The forms of Al for uptake by the roots and translocation from the root to the shoot were investigated in a buckwheat (Fagopyrum esculentum Moench, cv. Jianxi) that accumulates Al in its leaves. The Al concentration in the xylem sap was 15-fold higher in the plants exposed to AlCl3 than in those exposed to an Al-oxalate (1:3) complex, suggesting that the roots take up Al in the ionic form. The Al concentration in the xylem sap was 4-fold higher than that in the external solution after a 1-h exposure to AICl3 solution and 10-fold higher after a 2-h exposure. The Al concentration in the xylem sap increased with increasing Al concentration in the external solution. The Al uptake was not affected by a respiratory inhibitor, hydroxylamine, but significantly inhibited by the addition of La. These results suggest that Al uptake by the root is a passive process, and La3+ competes for the binding sites for Al3+ on the plasma membrane. The form of Al in the xylem sap was identified by 27Al-nuclear magnetic resonance analysis. The chemical shift of 27Al in the xylem sap was around 10.9 ppm, which is consistent with that of the Al-citrate complex. Furthermore, the dominant organic acid in the xylem sap was citric acid, indicating that Al was translocated in the form of Al-citrate complex. Because Al is present as Al-oxalate (1:3) in the root, the present data show that ligand exchange from oxalate to citrate occurs before Al is released to xylem.


Specialized vascularization of the primate visual cortex.
We have analyzed blood vessel distribution in the primary and secondary visual cortices of the squirrel monkey in relation to cortical modules, laminae, and cytoarchitectonic areas. Measurements of microvessel length in tangential sections through the primary visual cortex showed that blobs are more richly vascularized than intervening cortical regions. Thus, the mean total length of microvessel profiles per unit was 42% greater within these cortical modules than within adjacent (interblob) areas. Total microvessel length per unit area in another class of module, the stripes in the secondary visual cortex, was 27% greater than in interstripe regions. Microvessel distribution also varied systematically from layer to layer in the primary visual cortex, being greatest in lamina IVc. Finally, the overall microvessel length per unit area in sections of the primary visual cortex was 26% greater than that in the secondary visual cortex. These observations indicate that the modular, laminar, and regional organization of the primate visual cortex is reflected in the underlying distribution of cortical microvessels. These vascular patterns should be discernable in living animals with vascular contrast agents and appropriate imaging techniques.


Gating pore currents in DIIS4 mutations of NaV1.4 associated with periodic paralysis: saturation of ion flux and implications for disease pathogenesis.
S4 voltage-sensor mutations in CaV1.1 and NaV1.4 channels cause the human muscle disorder hypokalemic periodic paralysis (HypoPP). The mechanism whereby these mutations predispose affected sarcolemma to attacks of sustained depolarization and loss of excitability is poorly understood. Recently, three HypoPP mutations in the domain II S4 segment of NaV1.4 were shown to create accessory ionic permeation pathways, presumably extending through the aqueous gating pore in which the S4 segment resides. However, there are several disparities between reported gating pore currents from different investigators, including differences in ionic selectivity and estimates of current amplitude, which in turn have important implications for the pathological relevance of these aberrant currents. To clarify the features of gating pore currents arising from different DIIS4 mutants, we recorded gating pore currents created by HypoPP missense mutations at position R666 in the rat isoform of Nav1.4 (the second arginine from the outside, at R672 in human NaV1.4). Extensive measurements were made for the index mutation, R666G, which created a gating pore that was permeable to K(+) and Na(+). This current had a markedly shallow slope conductance at hyperpolarized voltages and robust inward rectification, even when the ionic gradient strongly favored outward ionic flow. These characteristics were accounted for by a barrier model incorporating a voltage-gated permeation pathway with a single cation binding site oriented near the external surface of the electrical field. The amplitude of the R666G gating pore current was similar to the amplitude of a previously described proton-selective current flowing through the gating pore in rNaV1.4-R663H mutant channels. Currents with similar amplitude and cation selectivity were also observed in R666S and R666C mutant channels, while a proton-selective current was observed in R666H mutant channels. These results add support to the notion that HypoPP mutations share a common biophysical profile comprised of a low-amplitude inward current at the resting potential that may contribute to the pathological depolarization during attacks of weakness.


Salmonella enterica serotypes and antibiotic susceptibility in New Zealand, 2002-2007.
We analysed the serotypes and antibiotic susceptibility of 1560 human and 1505 non-human Salmonella isolated in New Zealand (NZ) between 2002 and 2007. The most common serotypes in humans were Salmonella enterica serovar Typhimurium, S. Enteritidis, S. Brandenburg and S. Infantis. Over the 6-year period human cases due to S. Agona and S. Enteritidis increased and cases due to S. Typhimurium decreased. The most common serotypes from non-human sources were S. Typhimurium, S. Brandenberg, S. Hindmarsh and S. Infantis, and there were no significant changes over time. More isolates were non-susceptible to streptomycin than to any other antibiotic. Almost all isolates were susceptible to ciprofloxacin and gentamicin. There were significant trends of increasing non-susceptibility to streptomycin and sulfonamides in isolates from human and non-human sources, while ampicillin, tetracycline and multidrug non-susceptibility also increased in human isolates. Despite these increases, rates of antibiotic non-susceptibility in Salmonella in NZ are still lower than in many international settings.


Similar effect of cueing conditions on attentional and saccadic temporal dynamics.
Spatial attention permits to allocate more processing resources to a restricted portion of the visual space. The influential premotor theory states that the allocation of spatial attention relies on the same processes as those responsible for programming saccadic eye movements. Accordingly, several studies have already demonstrated a close spatial correspondence between attention and saccades. However, the question of the temporal coupling between attention displacements and saccades remains unclear. To address this issue, we compared the saccadic latencies to the temporal dynamics of attentional shifts under various cueing conditions known to affect attentional timing. In Experiment 1, we evaluated the effect of peripheral and central cues, and in Experiment 2, we assessed the influence of peripheral cues of different salience levels. We found that the different cue types had a similar effect on saccade latencies and on the dynamics of attentional shifts, either overt or covert. Moreover, even within a given cueing condition, attentional shift times were strongly correlated with saccadic latencies. These results indicate that, in agreement with the premotor theory, both spatial attention and saccades rely on a common process and that the allocation of spatial attention is tightly time-locked to saccade execution.


Induction of tolerance to experimental anti-phospholipid syndrome (APS) by syngeneic bone marrow cell transplantation.
Previously, we have shown the ability to induce experimental autoimmune conditions (e.g. SLE, APLS, Wegener's granulomatosis) following active immunization with the pathogenic autoantibody emulsified in adjuvant. The mice first develop anti-autoantibodies (Ab2: anti-id) and eventually generate anti-anti-autoantibodies (Ab3: anti-anti-id) which carry the same antigen binding characteristic as the autoantibody (Ab1). The appearance of the specific autoantibodies in mice sera was associated with the emergence of the compatible laboratory and with the clinical findings characteristic to the respective autoimmune disease. The effects of syngeneic bone marrow transplantation (BMT) on experimental anti-phospholipid syndrome (APS) were investigated. BALB/c mice were immunized with anti-cardiolipin monoclonal antibody (MoAb) named CAM and developed elevated serum titres of anti-phospholipid Abs accompanied by prolonged activated partial thromboplastin time, thrombocytopenia and a high percentage of fetal resorptions. These mice were then lethally irradiated and transfused with bone marrow (BM) cells (T cell depleted) from syngeneic naive mice. The titres of antiphospholipid antibodies were reduced in the recipients. The decrease in titre of autoantibodies was found to be related to depletion of antibody forming cells in vivo, associated with reduced proliferative response of lymph node cells to anti-cardiolipin MoAbs. The recipients showed improvement in clinical parameters following syngeneic BMT. The same recipients developed specific unresponsiveness to a second challenge with the anticardiolipin MoAb (CAM), but developed experimental systemic lupus erythematosus upon immunization with a monoclonal anti-DNA antibody. We conclude that acute myeloablative immunosuppression combined with syngeneic bone marrow transplantation may induce a state of tolerance to the pathogenic autoantibodies in mice with experimental APLS. Our results suggest that a similar approach may be useful in treating life-threatening autoimmune syndromes (e.g. catastrophic APLS) in clinical practice.


Differential cutaneous wound healing in thermally injured MRL/MPJ mice.
Adult wound repair occurs with an initial inflammatory response, reepithelialization, and the formation of a permanent scar. MRL/MpJ mice following ear-hole punch biopsies display accelerated healing and tissue regeneration. In this study, we characterized the healing responses in both MRL/MpJ and BALB/c mice following a 15% total body surface area full-thickness cutaneous burn injury. Macroscopic and histological observations show that delayed wound closure in MRL/MpJ mice is accompanied by an increase in edema, reduced neutrophil infiltration, and more prominent eschar. In vivo bromodeoxyuridine labeling showed no defect in keratinocyte proliferation and migration (reepithelialization). In comparison with BALB/c mice, MRL/MpJ wounds had greater collagen deposition, less granulation tissue formation, and contained fewer alpha-smooth muscle actin-positive myofibroblasts. An observed reduction in dermal neutrophil infiltration and myofibroblast development correlated with enhanced angiogenesis. Overall, BALB/c wounds contracted sooner and to a larger degree, resulting in a significant decrease in scar formation. Interestingly, MRL/MpJ mice showed overt abnormalities in hair follicle proliferation, morphogenesis, and subsequent hair regrowth postburn injury. No substantial evidence of tissue regeneration was observed in either BALB/c or MRL/MpJ wounds. Our results convincingly demonstrate that MRL/MpJ skin burn wounds heal with scar formation with delays in two critical wound healing events: wound closure, and myofibroblast development.


Assessing pig body language: agreement and consistency between pig farmers, veterinarians, and animal activists.
This study investigates the interobserver and intraobserver reliability of qualitative behavior assessments (QBA) of individual pigs by 3 observer groups selected for their diverging backgrounds, experience, and views of pigs. Qualitative behavior assessment is a "whole animal" assessment approach that characterizes the demeanor of an animal as an expressive body language, using descriptors such as relaxed, anxious, or content. This paper addresses the concern that use of such descriptors in animal science may be prone to distortion by observer-related bias. Using a free-choice profiling methodology, 12 pig farmers, 10 large animal veterinarians, and 10 animal protectionists were instructed to describe and score the behavioral expressions of 10 individual pigs (sus scrofa) in 2 repeat sets of 10 video clips, showing these pigs in interaction with a human female. They were also asked to fill in a questionnaire gauging their experiences with and views on pigs. Pig scores were analyzed with generalized procrustes analysis and effect of treatment on these scores with ANOVA. Questionnaire scores were analyzed with a χ(2) test or ANOVA. Observers achieved consensus both within and among observer groups (P < 0.001), identifying 2 main dimensions of pig expression (dim1: playful/confident-cautious/timid; dim2: aggressive/nervous-relaxed/bored), on which pig scores for different observer groups were highly correlated (pearson r > 0.90). The 3 groups also repeated their assessments of individual pigs with high precision (r > 0.85). Animal protectionists used a wider quantitative range in scoring individual pigs on dimension 2 than the other groups (P < 0.001); however, this difference did not distort the strong overall consistency of characterizations by observers of individual pigs. Questionnaire results indicated observer groups to differ in various ways, such as daily and lifetime contact with pigs (P < 0.001), some aspects of affection and empathy for pigs (P < 0.05), and confidence in the validity of personal QBA descriptors (P < 0.02). The main finding of this study is that despite such differences in background and outlook, the 3 observer groups showed high interobserver and intraobserver reliability in their characterizations of pig body language. This supports the empirical nature of QBA in context of the wider anthropomorphism debate.


The development of lesions in the glomerular basement membrane and mesangium after transplantation of normal kidneys to diabetic patients.
Renal allograft biopsies at the time of transplantation (baseline) and 2 yr later were obtained in 6 type I diabetic and 12 nondiabetic patients and studied for glomerular basement membrane (GBM) and mesangial changes. Diabetic patients had significantly greater GBM thickness compared with nondiabetics at 2 yr (P = 0.05, rank sum test), and the increase in GBM thickness comparing baseline and 2-yr biopsies was greater in the diabetic compared with nondiabetic patients (P = 0.005, rank sum test). Similarly, diabetic patients developed significant mesangial thickening by light microscopy while no changes were observed in nondiabetic patients (P = 0.001). Electron microscopic morphometric analysis of the percentage of total mesangium was not different on comparing diabetic and nondiabetic patients at 2 yr. There was an increase in the matrix component of the mesangium in the diabetics at this time, although this did not reach statistical significance (P = 0.06). In addition, the surface density of the peripheral glomerular capillary wall, presumably reflecting mesangial expansion, was decreased in the diabetic and unchanged in the nondiabetic patients (P = 0.005). These studies document, for the first time, the development of GBM and mesangial lesions of diabetic nephropathy in normal living related donor and cadaver kidneys transplanted into diabetic patients and support the hypothesis that these lesions are secondary to the diabetic state.


Radiomic MRI signature reveals three distinct subtypes of glioblastoma with different clinical and molecular characteristics, offering prognostic value beyond IDH1.
The remarkable heterogeneity of glioblastoma, across patients and over time, is one of the main challenges in precision diagnostics and treatment planning. Non-invasive in vivo characterization of this heterogeneity using imaging could assist in understanding disease subtypes, as well as in risk-stratification and treatment planning of glioblastoma. The current study leveraged advanced imaging analytics and radiomic approaches applied to multi-parametric MRI of de novo glioblastoma patients (n = 208 discovery, n = 53 replication), and discovered three distinct and reproducible imaging subtypes of glioblastoma, with differential clinical outcome and underlying molecular characteristics, including isocitrate dehydrogenase-1 (IDH1), O6-methylguanine-DNA methyltransferase, epidermal growth factor receptor variant III (EGFRvIII), and transcriptomic subtype composition. The subtypes provided risk-stratification substantially beyond that provided by WHO classifications. Within IDH1-wildtype tumors, our subtypes revealed different survival (p < 0.001), thereby highlighting the synergistic consideration of molecular and imaging measures for prognostication. Moreover, the imaging characteristics suggest that subtype-specific treatment of peritumoral infiltrated brain tissue might be more effective than current uniform standard-of-care. Finally, our analysis found subtype-specific radiogenomic signatures of EGFRvIII-mutated tumors. The identified subtypes and their clinical and molecular correlates provide an in vivo portrait of phenotypic heterogeneity in glioblastoma, which points to the need for precision diagnostics and personalized treatment.


Smurf2 as a novel mitotic regulator: From the spindle assembly checkpoint to tumorigenesis.
The execution of the mitotic program with high fidelity is dependent upon precise spatiotemporal regulation of posttranslational protein modifications. For example, the timely polyubiquitination of critical mitotic regulators by Anaphase Promoting Complex/Cyclosome (APC/C) is essential for the metaphase to anaphase transition and mitotic exit. The spindle assembly checkpoint prevents unscheduled activity of APC/C-Cdc20 in early mitosis, allowing bipolar attachment of kinetochores to mitotic spindle and facilitating equal segregation of sister chromatids. The critical effector of the spindle checkpoint, Mitotic arrest deficient 2 (Mad2), is recruited to unattached kinetochores forming a complex with other regulatory proteins to efficiently and cooperatively inhibit APC/C-Cdc20. A weakened and/or dysfunctional spindle checkpoint has been linked to the development of genomic instability in both cell culture and animal models, and evidence suggests that aberrant regulation of the spindle checkpoint plays a critical role in human carcinogenesis. Recent studies have illuminated a network of both degradative and non-degradative ubiquitination events that regulate the metaphase to anaphase transition and mitotic exit. Within this context, our recent work showed that the HECT (Homologous to E6-AP C-terminus)-family E3 ligase Smurf2 (Smad specific ubiquitin regulatory factor 2), known as a negative regulator of transforming growth factor-beta (TGF-beta) signaling, is required for a functional spindle checkpoint by promoting the functional localization and stability of Mad2. Here we discuss putative models explaining the role of Smurf2 as a new regulator in the spindle checkpoint. The dynamic mitotic localization of Smurf2 to the centrosome and other critical mitotic structures provides implications about mitotic checkpoint control dependent on various ubiquitination events. Finally, deregulated Smurf2 activity may contribute to carcinogenesis by perturbed mitotic control.


Crystal structure of recombinant triosephosphate isomerase from Bacillus stearothermophilus. An analysis of potential thermostability factors in six isomerases with known three-dimensional structures points to the importance of hydrophobic interactions.
The structure of the thermostable triosephosphate isomerase (TIM) from Bacillus stearothermophilus complexed with the competitive inhibitor 2-phosphoglycolate was determined by X-ray crystallography to a resolution of 2.8 A. The structure was solved by molecular replacement using XPLOR. Twofold averaging and solvent flattening was applied to improve the quality of the map. Active sites in both the subunits are occupied by the inhibitor and the flexible loop adopts the "closed" conformation in either subunit. The crystallographic R-factor is 17.6% with good geometry. The two subunits have an RMS deviation of 0.29 A for 248 C alpha atoms and have average temperature factors of 18.9 and 15.9 A2, respectively. In both subunits, the active site Lys 10 adopts an unusual phi, psi combination. A comparison between the six known thermophilic and mesophilic TIM structures was conducted in order to understand the higher stability of B. stearothermophilus TIM. Although the ratio Arg/(Arg+Lys) is higher in B. stearothermophilus TIM, the structure comparisons do not directly correlate this higher ratio to the better stability of the B. stearothermophilus enzyme. A higher number of prolines contributes to the higher stability of B. stearothermophilus TIM. Analysis of the known TIM sequences points out that the replacement of a structurally crucial asparagine by a histidine at the interface of monomers, thus avoiding the risk of deamidation and thereby introducing a negative charge at the interface, may be one of the factors for adaptability at higher temperatures in the TIM family. Analysis of buried cavities and the areas lining these cavities also contributes to the greater thermal stability of the B. stearothermophilus enzyme. However, the most outstanding result of the structure comparisons appears to point to the hydrophobic stabilization of dimer formation by burying the largest amount of hydrophobic surface area in B. stearothermophilus TIM compared to all five other known TIM structures.


Acupuncture-Related Quality of Life Changes Using PROMIS Computer Adaptive Tests in a Pragmatic Trial with Oncology and General Integrative Medicine Patients: The Role of Baseline Acupuncture Expectations.
Acupuncture has been shown to alleviate symptoms and increase general well-being in different medical patient samples. A major challenge in acupuncture clinical research is the availability of comparable and standardized patient-reported outcome measurement (PRO) tools. This study used a pragmatic design to examine longitudinal changes in quality of life (QOL) in a medical patient sample following acupuncture using PROs from the National Institutes of Health's Patient Reported Outcomes Measurement Information System (PROMIS) initiative. It also examined the role of acupuncture expectancies, as well as patient and provider perceptions of acupuncture benefit. Following informed consent, patients completed baseline QOL measures (T1) prior to their first acupuncture session. Subsequent assessments (up to 20) were completed immediately following ensuing acupuncture sessions. Patients completed assessments either on a touch-screen computer at the clinic or from their home computer. Compared with acupuncture-naïve participants, those who received prior acupuncture treatment reported significantly higher anxiety, fatigue, sleep disturbance, and lower positive affect at baseline. By the second assessment, however, these differences became nonexistent. Participants who held greater baseline acupuncture expectations (e.g., their situation would improve a lot, they would have improved coping skills, their symptoms would disappear, their energy would increase) reported significantly higher fatigue, pain interference, and problems with physical functioning. Between T1 and T2, all participants reported significant improvements in anxiety, depression, and fatigue. Exploratory longitudinal models demonstrated significant linear improvements over time in anxiety (p = 0.006), depression (p = 0.007), pain interference (p < 0.001), and sleep disturbance (p = 0.004). No linear reduction over time was found with fatigue (p = 0.587), physical function (p = 0.654), or positive affect (p = 0.247). Overall, PROMIS computer adaptive tests were able to assess domains of QOL briefly. Although pretreatment acupuncture expectations highlighted subgroup differences in outcomes at baseline, linear-growth models demonstrated the positive effects of acupuncture over time on anxiety, depression, pain interference, and sleep disturbance.


Comparative transcriptome profiling of virulent and non-virulent Trypanosoma cruzi underlines the role of surface proteins during infection.
Trypanosoma cruzi, the protozoan that causes Chagas disease, has a complex life cycle involving several morphologically and biochemically distinct stages that establish intricate interactions with various insect and mammalian hosts. It has also a heterogeneous population structure comprising strains with distinct properties such as virulence, sensitivity to drugs, antigenic profile and tissue tropism. We present a comparative transcriptome analysis of two cloned T. cruzi strains that display contrasting virulence phenotypes in animal models of infection: CL Brener is a virulent clone and CL-14 is a clone that is neither infective nor pathogenic in in vivo models of infection. Gene expression analysis of trypomastigotes and intracellular amastigotes harvested at 60 and 96 hours post-infection (hpi) of human fibroblasts revealed large differences that reflect the parasite's adaptation to distinct environments during the infection of mammalian cells, including changes in energy sources, oxidative stress responses, cell cycle control and cell surface components. While extensive transcriptome remodeling was observed when trypomastigotes of both strains were compared to 60 hpi amastigotes, differences in gene expression were much less pronounced when 96 hpi amastigotes and trypomastigotes of CL Brener were compared. In contrast, the differentiation of the avirulent CL-14 from 96 hpi amastigotes to extracellular trypomastigotes was associated with considerable changes in gene expression, particularly in gene families encoding surface proteins such as trans-sialidases, mucins and the mucin associated surface proteins (MASPs). Thus, our comparative transcriptome analysis indicates that the avirulent phenotype of CL-14 may be due, at least in part, to a reduced or delayed expression of genes encoding surface proteins that are associated with the transition of amastigotes to trypomastigotes, an essential step in the establishment of the infection in the mammalian host. Confirming the role of members of the trans-sialidase family of surface proteins for parasite differentiation, transfected CL-14 constitutively expressing a trans-sialidase gene displayed faster kinetics of trypomastigote release in the supernatant of infected cells compared to wild type CL-14.


MOSBIE: a tool for comparison and analysis of rule-based biochemical models.
Mechanistic models that describe the dynamical behaviors of biochemical systems are common in computational systems biology, especially in the realm of cellular signaling. The development of families of such models, either by a single research group or by different groups working within the same area, presents significant challenges that range from identifying structural similarities and differences between models to understanding how these differences affect system dynamics. We present the development and features of an interactive model exploration system, MOSBIE, which provides utilities for identifying similarities and differences between models within a family. Models are clustered using a custom similarity metric, and a visual interface is provided that allows a researcher to interactively compare the structures of pairs of models as well as view simulation results. We illustrate the usefulness of MOSBIE via two case studies in the cell signaling domain. We also present feedback provided by domain experts and discuss the benefits, as well as the limitations, of the approach.


When has service provision for transient ischaemic attack improved enough? A discrete event simulation economic modelling study.
The aim of this study was to examine the impact of transient ischaemic attack (TIA) service modification in two hospitals on costs and clinical outcomes. Discrete event simulation model using data from routine electronic health records from 2011. Patients with suspected TIA were followed from symptom onset to presentation, referral to specialist clinics, treatment and subsequent stroke. Included existing versus previous (less same day clinics) and hypothetical service reconfiguration (7-day service with less availability of clinics per day). The primary outcome of the model was the prevalence of major stroke after TIA. Secondary outcomes included service costs (including those of treating subsequent stroke) and time to treatment and attainment of national targets for service provision (proportion of high-risk patients (according to ABCD2 score) seen within 24 hours). The estimated costs of previous service provision for 490 patients (aged 74±12 years, 48.9% female and 23.6% high risk) per year at each site were £340 000 and £368 000, respectively. This resulted in 31% of high-risk patients seen within 24 hours of referral (47/150) with a median time from referral to clinic attendance/treatment of 1.15 days (IQR 0.93-2.88). The costs associated with the existing and hypothetical services decreased by £5000 at one site and increased £21 000 at the other site. Target attainment was improved to 79% (118/150). However, the median time to clinic attendance was only reduced to 0.85 days (IQR 0.17-0.99) and thus no appreciable impact on the modelled incidence of major stroke was observed (10.7 per year, 99% CI 10.5 to 10.9 (previous service) vs 10.6 per year, 99% CI 10.4 to 10.8 (existing service)). Reconfiguration of services for TIA is effective at increasing target attainment, but in services which are already working efficiently (treating patients within 1-2 days), it has little estimated impact on clinical outcomes and increased investment may not be worthwhile.


Clinical manifestations of strongyloidiasis in southern Taiwan.
The diagnosis and management of strongyloidiasis present a continuous challenge in developing countries including Taiwan. In this study, the clinical characteristics and microbiological findings of 27 patients with Strongyloides stercoralis infection were retrospectively analyzed. Intestinal infection was identified in 17 patients and hyperinfection syndrome or disseminated disease in 10 (including 2 autopsy cases). The most frequent clinical findings were diarrhea (74%), fever (70%), abdominal pain (59%), cough (37%), dyspnea (33%), and constipation (26%). The common initial laboratory abnormalities were leukocytosis (81%), anemia (67%), liver function impairment (52%), and eosinophilia (44%). Most of the 27 patients had comorbid conditions, including malnutrition in 20 (74%), corticosteroid dependence in 15 (55%), chronic obstructive pulmonary disease in 9 (33%), chronic liver disease or cirrhosis in 8 (30%), and peptic ulcer disease in 7 (26%). There was no difference in the time interval from symptom onset to diagnosis between the intestinal infection group and the hyperinfection/disseminated group (22 +/- 15 vs 17 +/- 9 days). Larvae of S. stercoralis were identified in the stool of 24 patients, in the sputum smear of 5, in the gastric biopsy of one, and on histology of autopsy specimens in 2. Twenty-six patients received antiparasitic drug therapy of variable duration (mebendazole in 24, albendazole in 2, combined therapy in one). The overall cure rate was 52% (14/27). Relapse occurred in 4 patients. The overall mortality was 26% (7/27). There was a high mortality (up to 50%) in the hyperinfection/disseminated disease group. In conclusion, diagnosis of strongyloidiasis is often delayed and overlooked because of nonspecific symptoms. Physicians in endemic regions should include strongyloidiasis in the differential diagnosis when patients present with gastrointestinal and/or pulmonary symptoms with peripheral eosinophilia.


The meaning of fatigue for women with multiple sclerosis.
This paper reports the findings of a study that aimed to elucidate the meaning of fatigue for women with multiple sclerosis (MS). Living with chronic illness can involve giving up usual activities. MS is a chronic autoimmune disease of the central nervous system. Fatigue is a common experience among people with MS; however, little is known about the meaning of fatigue experienced by women with this condition. Ten women with MS were interviewed about their experience of fatigue. A phenomenological hermeneutic method influenced by Ricoeur was used to interpret the transcribed interviews. The findings were presented in two major themes with five subthemes; experiencing the body as a barrier and experiencing a different absence. Fatigue seemed to give rise to an experience of being absent and divided into two parts. This also led to a feeling of not being able to participate in the surrounding world. The feeling of being an outsider and lacking the ability as a healthy person is interpreted as a form of suffering. Although the fatigue had a great impact on the women's daily life, the women still hoped for some relief. Fatigue seemed to imply that instead of working as an implement to manage in the world the body has become an enemy of survival. This study highlights the importance for nurses of understanding how women with MS experience fatigue, which is a prerequisite for communication based on a shared understanding. This awareness would enhance nurses' opportunities to alleviate suffering. More research is needed to investigate what kinds of interventions can help these women to manage their everyday lives and to maintain a sense of normality despite their fatigue and illness. Such interventions should be subject to empirical evaluation research.


Reliability and validity of Azeri Turkish version of geriatric depression scale.
Background: In older adults, depression symptoms may be masked by physical complaints and be even attributed to the natural aging process, which may be resulted in improper diagnosis. Native-language scales can be highly effective in the detection of depressive disorders. In this study we attempted to assess the reliability and validity of the Azeri Turkish version of the geriatric depression scale (GDS). Methods: In this psychometric study, the GDS and the Structured Clinical Interview for DSM IV(SCID) questionnaires were administered to a sample of 387 older adults (60 years and older)from the member households of Tabriz health centers. The English version of GDS was translated into Azeri Turkish. Translation-back translation process was conducted. The receiver operating characteristics (ROC) curve, as well as sensitivity and specificity, were used to determine the validity of the questionnaire, and the test-retest method was used to calculate reliability. Results: The mean age of participants was 69.30. The area under the ROC curve for the scores higher than five was 0.832 and for the scores equal to ten and above was 0.871. The sensitivity and specificity for the scores higher than five were 90.9% and 73.4%, respectively. The reliability of this scale was confirmed based on intraclass coefficient (ICC) = 0.79. Conclusion : The Azeri Turkish version of GDS was found with appropriate levels of validity and reliability.


Three rules for bone adaptation to mechanical stimuli.
The primary mechanical function of bones is to provide rigid levers for muscles to pull against, and to remain as light as possible to allow efficient locomotion. To accomplish this bones must adapt their shape and architecture to make efficient use of material. Bone adaptation during skeletal growth and development continuously adjusts skeletal mass and architecture to changing mechanical environments. There are three fundamental rules that govern bone adaptation: (1) It is driven by dynamic, rather than static, loading. (2) Only a short duration of mechanical loading is necessary to initiate an adaptive response. (3) Bone cells accommodate to a customary mechanical loading environment, making them less responsive to routine loading signals. From these rules, several mathematical equations can be derived that provide simple parametric models for bone adaptation.


Prolongation of ovarian lifespan into advanced chronological age by Bax-deficiency.
Female mammals are endowed with a finite number of oocytes at birth, each enclosed by a single layer of somatic (granulosa) cells in a primordial follicle. The fate of most follicles is atretic degeneration, a process that culminates in near exhaustion of the oocyte reserve at approximately the fifth decade of life in women, leading to menopause. Apoptosis has a fundamental role in follicular atresia, and recent studies have shown that Bax, which is expressed in both granulosa cells and oocytes, may be central to ovarian cell death. Here we show that young adult female Bax-/- mice possess threefold more primordial follicles in their ovarian reserve than their wild-type sisters, and this surfeit of follicles is maintained in advanced chronological age, such that 20-22-month-old female Bax-/- mice possess hundreds of follicles at all developmental stages and exhibit ovarian steroid-driven uterine hypertrophy. These observations contrast with the ovarian and uterine atrophy seen in aged wild-type female mice. Aged female Bax-/- mice fail to become pregnant when housed with young adult males; however, metaphase II oocytes can be retrieved from, and corpora lutea form in, ovaries of aged Bax-/- females following superovulation with exogenous gonadotropins, and some oocytes are competent for in vitro fertilization and early embryogenesis. Therefore, ovarian lifespan can be extended by selectively disrupting Bax function, but other aspects of normal reproductive performance remain defective in aged Bax-/- female mice.


Effectiveness of Intermittent Pneumatic Compression Devices for Venous Thromboembolism Prophylaxis in High-Risk Surgical Patients: A Systematic Review.
Thromboprophylaxis regimens include pharmacologic and mechanical options such as intermittent pneumatic compression devices (IPCDs). There are a wide variety of IPCDs available, but it is uncertain if they vary in effectiveness or ease of use. This is a systematic review of the comparative effectiveness of IPCDs for selected outcomes (mortality, venous thromboembolism [VTE], symptomatic or asymptomatic deep vein thrombosis, major bleeding, ease of use, and adherence) in postoperative surgical patients. We searched MEDLINE (via PubMed), Embase, CINAHL, and Cochrane CENTRAL from January 1, 1995, to October 30, 2014, for randomized controlled trials, as well as relevant observational studies on ease of use and adherence. We identified 14 eligible randomized controlled trials (2633 subjects) and 3 eligible observational studies (1724 subjects); most were conducted in joint arthroplasty patients. Intermittent pneumatic compression devices were comparable to anticoagulation for major clinical outcomes (VTE: risk ratio, 1.39; 95% confidence interval, 0.73-2.64). Limited data suggest that concurrent use of anticoagulation with IPCD may lower VTE risk compared with anticoagulation alone, and that IPCD compared with anticoagulation may lower major bleeding risk. Subgroup analyses did not show significant differences by device location, mode of inflation, or risk of bias elements. There were no consistent associations between IPCDs and ease of use or adherence. Intermittent pneumatic compression devices are appropriate for VTE thromboprophylaxis when used in accordance with current clinical guidelines. The current evidence base to guide selection of a specific device or type of device is limited.


Searching the Mouse Genome Informatics (MGI) Resources for Information on Mouse Biology from Genotype to Phenotype.
The Mouse Genome Informatics (MGI) resource provides the research community with access to information on the genetics, genomics, and biology of the laboratory mouse. Core data in MGI include gene characterization and function, phenotype and disease model descriptions, DNA and protein sequence data, gene expression data, vertebrate homologies, SNPs, mapping data, and links to other bioinformatics databases. Semantic integration is supported through the use of standardized nomenclature, and through the use of controlled vocabularies such as the mouse Anatomical Dictionary, the Mammalian Phenotype Ontology, and the Gene Ontologies. MGI extracts and organizes data from primary literature. MGI data are shared with and widely displayed from other bioinformatics resources. The database is updated weekly with curated annotations, and regularly adds new datasets and features. This unit provides a guide to using the MGI bioinformatics resource. © 2016 by John Wiley & Sons, Inc.


Applying the intention-to-treat principle in practice: Guidance on handling randomisation errors.
The intention-to-treat principle states that all randomised participants should be analysed in their randomised group. The implications of this principle are widely discussed in relation to the analysis, but have received limited attention in the context of handling errors that occur during the randomisation process. The aims of this article are to (1) demonstrate the potential pitfalls of attempting to correct randomisation errors and (2) provide guidance on handling common randomisation errors when they are discovered that maintains the goals of the intention-to-treat principle. The potential pitfalls of attempting to correct randomisation errors are demonstrated and guidance on handling common errors is provided, using examples from our own experiences. We illustrate the problems that can occur when attempts are made to correct randomisation errors and argue that documenting, rather than correcting these errors, is most consistent with the intention-to-treat principle. When a participant is randomised using incorrect baseline information, we recommend accepting the randomisation but recording the correct baseline data. If ineligible participants are inadvertently randomised, we advocate keeping them in the trial and collecting all relevant data but seeking clinical input to determine their appropriate course of management, unless they can be excluded in an objective and unbiased manner. When multiple randomisations are performed in error for the same participant, we suggest retaining the initial randomisation and either disregarding the second randomisation if only one set of data will be obtained for the participant, or retaining the second randomisation otherwise. When participants are issued the incorrect treatment at the time of randomisation, we propose documenting the treatment received and seeking clinical input regarding the ongoing treatment of the participant. Randomisation errors are almost inevitable and should be reported in trial publications. The intention-to-treat principle is useful for guiding responses to randomisation errors when they are discovered.


Cloning and identity.
Critics of human cloning allege that the results of the process are likely to suffer from compromised identities making it near impossible for them to live worthwhile lives. This paper uses the account of the metaphysics of personal identity offered by Derek Parfit to investigate and support the claim of identity-compromise. The cloned person may, under certain circumstances, be seen as surviving, to some degree, in the clone. However, I argue that rather than warranting concern, the potential for survival by cloning ought to help protect against the misuse of the technology.


Grid computing in image analysis.
Diagnostic surgical pathology or tissue–based diagnosis still remains the most reliable and specific diagnostic medical procedure. The development of whole slide scanners permits the creation of virtual slides and to work on so-called virtual microscopes. In addition to interactive work on virtual slides approaches have been reported that introduce automated virtual microscopy, which is composed of several tools focusing on quite different tasks. These include evaluation of image quality and image standardization, analysis of potential useful thresholds for object detection and identification (segmentation), dynamic segmentation procedures, adjustable magnification to optimize feature extraction, and texture analysis including image transformation and evaluation of elementary primitives. Grid technology seems to possess all features to efficiently target and control the specific tasks of image information and detection in order to obtain a detailed and accurate diagnosis. Grid technology is based upon so-called nodes that are linked together and share certain communication rules in using open standards. Their number and functionality can vary according to the needs of a specific user at a given point in time. When implementing automated virtual microscopy with Grid technology, all of the five different Grid functions have to be taken into account, namely 1) computation services, 2) data services, 3) application services, 4) information services, and 5) knowledge services. Although all mandatory tools of automated virtual microscopy can be implemented in a closed or standardized open system, Grid technology offers a new dimension to acquire, detect, classify, and distribute medical image information, and to assure quality in tissue–based diagnosis.


Extracellular matrix proteins and chemoradiotherapy: alpha5beta1 integrin as a predictive marker in rectal cancer.
To investigate the effects of extracellular matrix (ECM) protein expression on the rates of apoptosis and proliferation in rectal cancers and subsequent response to chemoradiotherapy (CRT). The expression of fibronectin, collagen IV, laminin and the fibronectin receptor (FnR, alpha5beta1 integrin) were analysed in 32 pre-treatment rectal cancer biopsies by immunohistochemistry. ECM expression was correlated with tumour mitotic index (MI), apoptotic index (AI) and histopathological response to CRT. 18/32 cancers showed a poor response and 14/32 a good response (5/14 with complete pathological response) to CRT. Moderate to strong staining was seen in 22/32 cancers for fibronectin, 5/32 for collagen IV and 18/32 for laminin. Tumour FnR was related to stromal fibronectin content, and was significantly associated with CRT response; good responders having higher FnR expression compared to poor responders. No association was found between FnR expression and either MI or AI in pre-treatment biopsies, nor between MI or AI and CRT response. Tumour FnR expression is independent of MI and AI, and may serve as a useful marker for CRT response in rectal cancer.


Vaccine-Preventable Disease-Associated Hospitalisations Among Migrant and Non-migrant Children in New Zealand.
Migrants may experience a higher burden of vaccine-preventable disease (VPD)-associated hospitalisations compared to the host population. A retrospective cohort study from 2006 to 2015 was conducted that linked de-identified data from government sources using Statistic NZ's Integrated Data Infrastructure. VPD-related hospitalisations were compared between three cohorts of children from birth to 5 years old: foreign-born children who migrated to NZ, children born in NZ of recent migrant mothers, and a comparator group of children born in NZ without a recent migration background. VPD-related hospitalisation rates were higher among NZ-born non-migrant children compared to NZ-born migrant and foreign-born children for all of the diseases of interest. For instance, 5.21% of NZ-born non-migrant children were hospitalised at least once due to all-cause gastroenteritis compared to 4.47% of NZ-born migrant children and only 1.13% of foreign-born migrant children. The overall hospitalisation rate for NZ-born non-migrant children was 3495 hospitalisations per 100,000 person years. Among children with migrant backgrounds, higher hospitalisation rates were noted among those of Pacific ethnicity and those with refugee backgrounds. Those arriving on Pacific visa schemes were hospitalised at rates ranging from 2644/100,000 person years among foreign-born migrant children and 4839/100,000 person years among NZ-born migrant children. Foreign-born quota refugee children and NZ-born children of quota refugee mothers were hospitalised at a rate of 4000-5000/100,000 person years. It is important to disaggregate migrant data to improve our understanding of migrant health. Children need to be age-appropriately vaccinated, and other individual and environmental factors addressed, to reduce the risk of infectious diseases.


Delivery of preventive health services to Indigenous adults: response to a systems-oriented primary care quality improvement intervention.
To describe changes in delivery of preventive services among adults in Aboriginal communities that occurred in association with a systems-oriented intervention. A quality improvement intervention with a 2-year follow-up was undertaken at 12 Aboriginal community health centres in the Northern Territory between January 2002 and December 2005. The study involved 360 well adults aged 16-49 years who had no known diagnosis of chronic disease. Two annual cycles of assessment, feedback workshops, action planning, and implementation of system changes. Assessment included a structured review of health service systems and an audit of clinical records. Adherence to guideline-scheduled preventive services including taking basic measurements, laboratory investigations, lifestyle counselling and pneumococcal vaccination. Of 12 preventive services measured, delivery of four services showed improvement over the study period: counselling on diet increased from 3% to 8% (P = 0.018); counselling on physical activity from 2% to 8% (P = 0.006); counselling on smoking from 2% to 11% (P = 0.003); and counselling on alcohol from 2% to 10% (P = 0.007). There was no improvement in important measures such as monitoring of waist circumference, blood pressure and blood glucose level, and delivery of pneumococcal vaccination. Our systems-oriented intervention was associated with some improvement in counselling activities, but no significant improvement in delivery of other preventive services. The main reason may be that implementation focused more on chronic illness management than preventive services for generally well adults.


Unconjugated morphine in blood by radioimmunoassay and gas chromatography/mass spectrometry.
Morphine, the active metabolite of heroin, is rapidly inactivated by glucuronidation at the 3 carbon. Unconjugated (pharmacologically active) morphine was measured in postmortem blood by radioimmunoassay using an antibody-coated tube kit. The kit shows less than 0.2% cross-reactivity with codeine and morphine-glucuronide. Unconjugated morphine concentrations were confirmed by gas chromatography/mass spectrometry (GC/MS) using deuterated morphine as the internal standard. The blood was precipitated with 10% trichloroacetic acid (TCA) and concentrated hydrochloric acid (HCl), centrifuged, and decanted. The supernatant was then either diluted (unhydrolyzed) or heated to 100 degrees C, 30 min (hydrolyzed), followed by a wash with 4:1 chloroform:isopropranol. The upper aqueous layer was then saturated with sodium bicarbonate (NaHCO3) and extracted with 4:1 chloroform:isopropranol. The organic layer was evaporated, derivatized with trifluoroacetic anhydride (TFA), and analyzed by selected ion monitoring (SIM) GC/MS. Comparison of the results for unconjugated morphine by radioimmunoassay and unhydrolyzed morphine by GC/MS gave a correlation coefficient of r = 0.98, n = 100. Unconjugated morphine ranged from 0 to 100% of total morphine with a mean of 42%, n = 200, for heroin or morphine involved deaths. Review of 56 putative rapid deaths gave a mean of 68% unconjugated morphine with a range of 26 to 100%. The ratio of unconjugated to total morphine was found to be stable in postmortem blood after more than a year of storage at room temperature, within the precision of the method.


Far cortical locking can reduce stiffness of locked plating constructs while retaining construct strength.
Several strategies to reduce construct stiffness have been proposed to promote secondary bone healing following fracture fixation with locked bridge plating constructs. However, stiffness reduction is typically gained at the cost of construct strength. In the present study, we tested whether a novel strategy for stiffness reduction, termed far cortical locking, can significantly reduce the stiffness of a locked plating construct while retaining its strength. Locked plating constructs and far cortical locking constructs were tested in a diaphyseal bridge plating model of the non-osteoporotic femoral diaphysis to determine construct stiffness in axial compression, torsion, and bending. Subsequently, constructs were dynamically loaded until failure in each loading mode to determine construct strength and failure modes. Finally, failure tests were repeated in a validated model of the osteoporotic femoral diaphysis to determine construct strength and failure modes in a worst-case scenario of bridge plating in osteoporotic bone. Compared with the locked plating constructs, the initial stiffness of far cortical locking constructs was 88% lower in axial compression (p < 0.001), 58% lower in torsion (p < 0.001), and 29% lower in bending (p < 0.001). Compared with the locked plating constructs, the strength of far cortical locking constructs was 7% lower (p = 0.005) and 16% lower (p < 0.001) under axial compression in the non-osteoporotic and osteoporotic diaphysis, respectively. However, far cortical locking constructs were 54% stronger (p < 0.001) and 9% stronger (p = 0.04) under torsion and 21% stronger (p < 0.001) and 20% stronger (p = 0.02) under bending than locked plating constructs in the non-osteoporotic and osteoporotic diaphysis, respectively. Within the initial stiffness range, far cortical locking constructs generated nearly parallel interfragmentary motion. Locked plating constructs generated significantly less motion at the near cortex adjacent to the plate than at the far cortex (p < 0.01). Far cortical locking significantly reduces the axial stiffness of a locked plating construct. This gain in flexibility causes only a modest reduction in axial strength and increased torsional and bending strength.


Does removal of tracheostomy affect dysphagia? A kinematic analysis.
Tracheostomy tubes are thought to increase the incidence of aspiration and several mechanisms that might cause this have been suggested. Some studies reported alterations in laryngeal elevation during swallowing, which they attributed to an anchoring effect of the tracheostomy tube resulting in dysphagia. The purpose of the present study was to kinematically investigate the effect of tracheostomy on the swallowing process in dysphagic patients. Thirteen patients (7 males, 6 females; mean age = 61.4 years) were prospectively enrolled between August 2008 and December 2009. The inclusion criteria for a patient who had undergone tracheostomy were an ability to tolerate tube plugging for 48 h and the capacity to expectorate without assistance. All patients underwent two videofluoroscopic swallow studies (VFSS), before and after decannulation. We measured 21 time interval variables during swallowing in the pharyngeal phase and the extent of laryngeal elevation. No patient exhibited any change in swallowing function status [Penetration - Aspiration Scale (PAS) (median value = 1)] in the interval between the two VFSS tests. Upon kinematic analysis, no significant difference in any variable pertaining to laryngeal elevation or pharyngeal constriction was found when pre- and post-decannulation VFSS test data were compared (p > 0.05). The present study thus showed that removal of a tracheostomy tube does not affect the kinematics of swallowing. Our results support previous findings that indicated no relationship between tracheostomy tube placement and dysphagia.


MR of the brain in mitochondrial myopathy.
To determine the spectrum of MR findings in patients with mitochondrial myopathy and correlate them with central nervous system symptoms and signs. We performed a prospective evaluation of the MR findings of eight patients with mitochondrial myopathy (three with Kearns-Sayre syndrome and five with chronic progressive external ophthalmoplegia), six of whom had central nervous system symptoms or signs (ataxia, sensorineural hearing loss, or cognitive dysfunction). All six patients with neurologic symptoms or signs had multiple abnormal MR findings, whereas patients without neurologic symptoms had either normal MR findings (one patient) or the solitary finding of cortical atrophy (one patient). Abnormal MR findings consisted of cerebral cortical atrophy (seven patients), cerebellar atrophy (six patients), and hyperintense signal abnormalities on T2-weighted images within the cerebral white matter (three patients), cerebellar white matter (one patient), basal ganglia (three patients), brain stem (one patient), and thalamus (one patient). In two patients, the cerebral white matter signal abnormalities were primarily peripheral and involved the arcuate fibers. All patients with ataxia had abnormal cerebellar findings on MR imaging, but there was poor correlation between other neurologic features and MR findings. Cerebral and cerebellar atrophy are the most common MR findings in Kearns-Sayre syndrome and chronic progressive external ophthalmoplegia. White matter and deep gray nuclei abnormalities, presumed to result from the diffuse spongiform encephalopathy reported in these patients, can also be seen. Patients with abnormal neurologic findings typically have multiple abnormalities on MR imaging, which frequently do not correlate with specific symptoms.


Evaluating maternity care: a core set of outcome measures.
Comparing the relative effectiveness of interventions on specific outcomes across trials can be problematic due to differences in the choice and definitions of outcome measures used by researchers. We sought to identify a minimum set of outcome measures for evaluating models of maternity care from the perspective of key stakeholders. A 3-round, electronic Delphi survey design was used. Setting was multinational, comprising a range of key stakeholders. Participants consisted of a single heterogeneous panel of maternity service users, midwives, obstetricians, pediatricians/neonatologists, family physicians/general practitioners, policy-makers, service practitioners, and researchers of maternity care. Members of the panel self-assessed their expertise in evaluating models of maternity care. A total of 320 people from 28 countries expressed willingness to take part in this survey. Round 1 was completed by 218 (68.1%) participants, of whom 173 (79.4%) completed round 2 and 152 (87.9%) of these completed round 3. Fifty outcomes were identified, with both a mean value greater than the overall group mean for all outcomes combined (x=4.18) and rated 4 or more on a 5-point Likert-type scale for importance of inclusion in a minimum data set of outcome measures by at least 70 percent of respondents. Three outcomes were collapsed into a single outcome so that the final minimum set includes 48 outcomes. Given the inconsistencies in the choice of outcome measures routinely collected and reported in randomized evaluations of maternity care, it is hoped that use of the data set will increase the potential for national and international comparisons of models for maternity care. Although not intended to be prescriptive or to inhibit the collection of other outcomes, we hope that the core set will make it easier to assess the care of women and their babies during pregnancy and childbirth.


Aortic prosthetic valve design and size: relation to Doppler echocardiographic findings and pressure recovery- an in vitro study.
The extent to which Doppler echocardiography information can be used in the assessment of prosthesis hemodynamic performance is still controversial. The goals of our study were to assess the importance of valve design and size both on Doppler echocardiography findings and on pressure recovery in a fluid mechanics model. We performed Doppler and catheter measurements in the different orifices of the bileaflet St Jude (central and side orifices), the monoleaflet Omnicarbon (major and minor orifices), and the stented Biocor porcine prosthesis. Net pressure gradients were predicted from Doppler flow velocities, assuming either independence or dependence of valve size. The peak Doppler estimated gradients (mean +/- SD for sizes 21 to 27) were 21 +/- 10.3 mm Hg for St Jude, 18 +/- 9.3 mm Hg for Omnicarbon, and 37 +/- 14.5 mm Hg for Biocor (P <.05 for St Jude and Omnicarbon vs Biocor). The pressure recovery (proportion of peak catheter pressure) was 53% +/- 8.6% for central-St Jude, 29% +/- 8. 9% for side-St Jude, 20% +/- 5.6% for major-Omnicarbon, 23% +/- 7.4% for minor-Omnicarbon, and 18% +/- 3.6% for Biocor (P <.05 for central-St Jude and side-St Jude vs Omnicarbon and Biocor). Valve sizes (x) significantly influenced pressure recovery (y in percentage) (central-St Jude: y = 3.7x - 35.9, r = 0.88, P =.0001; major-Omnicarbon: y = 2.1x - 30.3, r = 0.85, P =.0001). By assuming dependence of valve size, Doppler was able to predict net pressure gradients in St Jude with a mean difference between net catheter and Doppler-predicted gradient of -3.8 +/- 2.5 mm Hg. In conclusion, prosthetic valve design and size influence the degree of pressure recovery, making Doppler gradients potentially misleading in both the assessment of hemodynamic performance and the comparison of one design with another. The preliminary results indicate that net gradient can be predicted from Doppler gradients.