Role of metformin accumulation in metformin-associated lactic acidosis.
To investigate the role of metformin accumulation in the pathophysiology of metformin-associated lactic acidosis. We used high-performance liquid chromatography to measure plasma metformin concentrations in 14 patients who experienced lactic acidosis (pH < 7.35 and lactate concentration 5 > mmol/l) while receiving chronic metformin treatment. Their treatment was generally based on alkalinization and dialysis therapy. Clinical shock and/or evidence of tissue hypoxia was found in all patients with the exception of one who had a nonsteroidal anti-inflammatory drug-induced anuria. Ten patients had significant metformin accumulation (plasma metformin concentrations 4.1-84.9 mg/l, normal value 0.6 +/- 0.5 mg/l before drug intake), generally because of failure to withdraw metformin despite intercurrent pathological conditions affecting its renal elimination (serum creatinine concentrations ranging from 269 to 1,091 mumol/l). There was no metformin accumulation (plasma metformin 0.03-0.7 mg/l) in the four other patients, who had less severe renal failure (serum creatinine 140-349 mumol/l). The severity of the patient's general condition did not predict early hospital mortality (death before discharge from the intensive care unit) even in patients in shock. Whereas it was high in those without metformin accumulation (only 1 of 4 patients recovered), early hospital mortality was low in the 10 patients with metformin accumulation and was not related to its extent (3 patients died with end-stage hepatic failure or cardiac failure). Correlation studies showed a positive correlation between serum creatinine and plasma metformin and between plasma metformin and arterial lactate but, for the latter correlation, only in patients with metformin accumulation. Metformin-associated lactic acidosis is not necessarily due to metformin accumulation; true type B (aerobic) lactic acidosis, i.e., without an apparent associated hypoxic factor, seems exceptional. Neither the severity of the clinical picture nor the degree of metformin accumulation predicted survival; rather, the prognosis was dependent upon the severity of the associated pathological conditions.


Determination of human caucasian mitochondrial DNA haplogroups by means of a hierarchical approach.
In this paper we propose a hierarchical approach that allows the screening of mitochondrial DNA (mtDNA) haplogroups in populations that have essentially West Eurasian mtDNA backgrounds but that could have some non-West Eurasian contributions. To develop and validate this scheme, we used data on 18 coding region polymorphisms (17 analyzed by RFLP analysis and 1 by sequencing) and sequences of hypervariable segment I (HVSI) of the mtDNA control region from the Azores Islands (Portugal) population. The proposed scheme allows the characterization of almost all West Eurasian and African major clusters by means of RFLPs. Furthermore, the scheme includes information on situations in which sequencing is pertinent to defining a particular haplogroup. The validity of the scheme is ensured by (1) using relatively stable polymorphic positions, (2) screening more than one position to define a specific haplogroup, and (3) typing confirmatory positions. Dubious samples can be resolved by sequencing. The robustness of this approach was assessed by sequencing all samples for HVSI, taking advantage of the previously established relationships between RFLPs and control region sequence polymorphisms. The use of this hierarchical approach avoids the screening of unnecessary control region polymorphisms and therefore results in a more rapid and cost-efficient screening than one in which all polymorphic positions are analyzed. Even if this approach leads to a lower level of phylogeographic resolution than the sequencing of all samples, it allows us to define population movements on a continental level and can be applied, unlike sequencing all samples, with a low cost in any laboratory.


Error negativity does not reflect conflict: a reappraisal of conflict monitoring and anterior cingulate cortex activity.
Our ability to detect and correct errors is essential for our adaptive behavior. The conflict-loop theory states that the anterior cingulate cortex (ACC) plays a key role in detecting the need to increase control through conflict monitoring. Such monitoring is assumed to manifest itself in an electroencephalographic (EEG) component, the "error negativity" (Ne or "error-related negativity" [ERN]). We have directly tested the hypothesis that the ACC monitors conflict through simulation and experimental studies. Both the simulated and EEG traces were sorted, on a trial-by-trial basis, as a function of the degree of conflict, measured as the temporal overlap between incorrect and correct response activations. The simulations clearly show that conflict increases as temporal overlap between response activation increases, whereas the experimental results demonstrate that the amplitude of the Ne decreases as temporal overlap increases, suggesting that the ACC does not monitor conflict. At a functional level, the results show that the duration of the Ne depends on the time needed to correct (partial) errors, revealing an "on-line" modulation of control on a very short time scale.


Analytical method for band structure calculation of photonic crystal fibers filled with liquid crystal.
An analytical method for band structure calculations of photonic crystal fibers with liquid crystal infiltrations is presented. The scalar eigenvalue equation is extended to treat both isotropic and anisotropic materials by introducing a coefficient to describe the index contrast between the extraordinary and ordinary refractive index of the liquid crystal. The simple model provides a fast insight into bandgap formation in photonic crystal fibers filled with anisotropic material such as liquid crystal, which would be useful to aid the design based on such fibers.


Diagnostic Accuracy Of The Electrocardiographic Decision Support - Myocardial Ischaemia (EDS-MI) Algorithm In Detection Of Acute Coronary Occlusion.
Electrocardiographic Decision Support - Myocardial Ischaemia (EDS-MI) is a graphical decision support for detection and localization of acute transmural ischaemia. A recent study indicated that EDS-MI performs well for detection of acute transmural ischaemia. However, its performance has not been tested in patients with non-ischaemic ST-deviation. We aimed to optimize the diagnostic accuracy of EDS-MI in patients with verified acute coronary occlusion as well as patients with non-ischaemic ST deviation and compare its performance with STEMI criteria. We studied 135 patients with non-ischaemic ST deviation (perimyocarditis, left ventricular hypertrophy, takotsubo cardiomyopathy and early repolarization) and 117 patients with acute coronary occlusion. In 63 ischaemic patients, the extent and location of the ischaemic area (myocardium at risk) was assessed by both cardiovascular magnetic resonance imaging and EDS-MI. Sensitivity and specificity of ST elevation myocardial infarction criteria were 85% (95% confidence interval (CI) 77, 90) and 44% (95% CI 36, 53) respectively. Using EDS-MI, sensitivity and specificity increased to 92% (95% CI 85, 95) and 81% (95% CI 74, 87) respectively (p=0.035 and p<0.001). Agreement was strong (83%) between cardiovascular magnetic resonance imaging and EDS-MI in localization of ischaemia. Mean myocardium at risk was 32% (± 10) by cardiovascular magnetic resonance imaging and 33% (± 11) by EDS-MI when the estimated infarcted area according to Selvester QRS scoring was included in myocardium at risk estimation. In conclusion, EDS-MI increases diagnostic accuracy and may serve as an automatic decision support in the early management of patients with suspected acute coronary syndrome. The added clinical benefit in a non-selected clinical chest pain population needs to be assessed.


A chronic toxicity test for the tropical marine snail Nassarius dorsatus to assess the toxicity of copper, aluminium, gallium, and molybdenum.
Chronic toxicity test methods for assessing the toxicity of contaminants to tropical marine organisms are generally lacking. A 96-h chronic growth rate toxicity test was developed for the larval stage of the tropical dogwhelk, Nassarius dorsatus. Growth rates of N. dorsatus larvae were assessed following exposures to copper (Cu), aluminium (Al), gallium (Ga), and molybdenum (Mo). Exposure to Cu at 28 °C validated the sensitivity of the test method, with 10% (EC10) and 50% (EC50) effect concentrations of 4.2 μg/L and 7.3 μg/L Cu, respectively. The EC10 and EC50 values for Al (<0.45-μm filtered fraction) at 28 °C were 115 μg/L and 185 μg/L, respectively. The toxicity of Cu and Al was also assessed at 24 °C and 31 °C, representing average year-round water temperatures for subtropical and tropical Australian coastal environments. At 24 °C, the growth rate of control larvae was reduced by 52% compared with the growth rate at 28 °C and there was an increase in sensitivity to Cu (EC50 = 4.7 μg/L) but a similar sensitivity to Al (EC50 = 180 μg/L). At 31 °C the control growth rate increased by 35% from that measured at 28 °C and there was reduced sensitivity to both Cu and Al (EC50s = 8.5 μg/L and 642 μg/L, respectively). There was minimal toxicity resulting from Ga (EC50 = 4560 μg/L) and Mo (no effect at ≤7000 μg/L Mo). Environ Toxicol Chem 2016;35:1788-1795. © 2015 SETAC.


Influence of the intertropical convergence zone on the East Asian monsoon.
The Asian-Australian monsoon is an important component of the Earth's climate system that influences the societal and economic activity of roughly half the world's population. The past strength of the rain-bearing East Asian summer monsoon can be reconstructed with archives such as cave deposits, but the winter monsoon has no such signature in the hydrological cycle and has thus proved difficult to reconstruct. Here we present high-resolution records of the magnetic properties and the titanium content of the sediments of Lake Huguang Maar in coastal southeast China over the past 16,000 years, which we use as proxies for the strength of the winter monsoon winds. We find evidence for stronger winter monsoon winds before the Bølling-Allerød warming, during the Younger Dryas episode and during the middle and late Holocene, when cave stalagmites suggest weaker summer monsoons. We conclude that this anticorrelation is best explained by migrations in the intertropical convergence zone. Similar migrations of the intertropical convergence zone have been observed in Central America for the period ad 700 to 900 (refs 4-6), suggesting global climatic changes at that time. From the coincidence in timing, we suggest that these migrations in the tropical rain belt could have contributed to the declines of both the Tang dynasty in China and the Classic Maya in Central America.


Incidence and prevalence of primary care antidepressant prescribing in children and young people in England, 1998-2017: A population-based cohort study.
The use of antidepressants in children and adolescents remains controversial. We examined trends over time and variation in antidepressant prescribing in children and young people in England and whether the drugs prescribed reflected UK licensing and guidelines. QResearch is a primary care database containing anonymised healthcare records of over 32 million patients from more than 1,500 general practices across the UK. All eligible children and young people aged 5-17 years in 1998-2017 from QResearch were included. Incidence and prevalence rates of antidepressant prescriptions in each year were calculated overall, for 4 antidepressant classes (selective serotonin reuptake inhibitors [SSRIs], tricyclic and related antidepressants [TCAs], serotonin and norepinephrine reuptake inhibitors [SNRIs], and other antidepressants), and for individual drugs. Adjusted trends over time and differences by social deprivation, region, and ethnicity were examined using Poisson regression, taking clustering within general practitioner (GP) practices into account using multilevel modelling. Of the 4.3 million children and young people in the cohort, 49,434 (1.1%) were prescribed antidepressants for the first time during 20 million years of follow-up. Males made up 52.0% of the cohorts, but only 34.1% of those who were first prescribed an antidepressant in the study period. The largest proportion of the cohort was from London (24.4%), and whilst ethnicity information was missing for 39.5% of the cohort, of those with known ethnicity, 75.3% were White. Overall, SSRIs (62.6%) were the most commonly prescribed first antidepressant, followed by TCAs (35.7%). Incident antidepressant prescribing decreased in 5- to 11-year-olds from a peak of 0.9 in females and 1.6 in males in 1999 to less than 0.2 per 1,000 for both sexes in 2017, but incidence rates more than doubled in 12- to 17-year-olds between 2005 and 2017 to 9.7 (females) and 4.2 (males) per 1,000 person-years. The lowest prescription incidence rates were in London, and the highest were in the South East of England (excluding London) for all sex and age groups. Those living in more deprived areas were more likely to be prescribed antidepressants after adjusting for region. The strongest trend was seen in 12- to 17-year-old females (adjusted incidence rate ratio [aIRR] 1.12, 95% confidence interval [95% CI] 1.11-1.13, p < 0.001, per deprivation quintile increase). Prescribing rates were highest in White and lowest in Black adolescents (aIRR 0.32, 95% CI 0.29-0.36, p < 0.001 [females]; aIRR 0.32, 95% CI 0.27-0.38, p < 0.001 [males]). The 5 most commonly prescribed antidepressants were either licensed in the UK for use in children and young people (CYP) or included in national guidelines. Limitations of the study are that, because we did not have access to secondary care prescribing information, we may be underestimating the prevalence and misidentifying the first antidepressant prescription. We could not assess whether antidepressants were dispensed or taken. Our analysis provides evidence of a continuing rise of antidepressant prescribing in adolescents aged 12-17 years since 2005, driven by SSRI prescriptions, but a decrease in children aged 5-11 years. The variation in prescribing by deprivation, region, and ethnicity could represent inequities. Future research should examine whether prescribing trends and variation are due to true differences in need and risk factors, access to diagnosis or treatment, prescribing behaviour, or young people's help-seeking behaviour.


Kidney transplantation: analysis of 200 cases.
The first 200 renal allograft operations performed at Addenbrooke's Hospital, Cambridge, have been analysed. At the time of writing the fractional graft survivals at one, two, and three years were 53%, 49%, and 39% respectively, and these showed no observable change through the seven years of the programme. On the other hand, the survival of patients undergoing renal transplantation steadily improved, the most recent survival rates at one, two, and three years being 83%, 78%, and 67%, whereas the overall rates were 74%, 66%, and 54% respectively. The survival of second allografts was similar to that of first allografts. Ninety per cent. of the patients whose allografts functioned for a year or more returned to active and gainful employment. The return of children to school and of housewives to running a household was similarly gratifying. We conclude on both social and economic grounds that renal transplantation is fully justified as a therapeutic procedure.


Calibrating optical tweezers with Bayesian inference.
We present a new method for calibrating an optical-tweezer setup that does not depend on input parameters and is less affected by systematic errors like drift of the setup. It is based on an inference approach that uses Bayesian probability to infer the diffusion coefficient and the potential felt by a bead trapped in an optical or magnetic trap. It exploits a much larger amount of the information stored in the recorded bead trajectory than standard calibration approaches. We demonstrate that this method outperforms the equipartition method and the power-spectrum method in input information required (bead radius and trajectory length) and in output accuracy.


Heterogeneous cardiac sympathetic denervation and decreased myocardial nerve growth factor in streptozotocin-induced diabetic rats: implications for cardiac sympathetic dysinnervation complicating diabetes.
Heterogeneous myocardial sympathetic denervation complicating diabetes has been invoked as a factor contributing to sudden unexplained cardiac death. In subjects with diabetic autonomic neuropathy (DAN), distal left ventricular (LV) denervation contrasts with preservation of islands of proximal innervation, which exhibit impaired vascular responsiveness. The aims of this study were to determine whether this heterogeneous pattern of myocardial sympathetic denervation occurs in a rat model of diabetes and to explore a potential association with regional fluctuations in myocardial nerve growth factor (NGF) protein. Myocardial sympathetic denervation was characterized scintigraphically using the sympathetic neurotransmitter analog C-11 hydroxyephedrine ([11C]HED) and compared with regional changes in myocardial NGF protein abundance and norepinephrine content after 6 and 9 months in nondiabetic (ND) and streptozotocin-induced diabetic (STZ-D) rats. In ND rats, no difference in [11C]HED retention or norepinephrine content was detected in the proximal versus distal myocardium. After 6 months, compared with ND rats, myocardial [11C]HED retention had declined in the proximal segments of STZ-D rats by only 9% (NS) compared with a 33% decrease in the distal myocardium (P < 0.05). Myocardial norepinephrine content was similar in both ND and STZ-D rats. At 6 months, LV myocardial NGF protein content in STZ-D rats decreased by 52% in the proximal myocardial segments (P < 0.01 vs. ND rats) and by 82% distally (P < 0.01 vs. ND rats, P < 0.05 vs. proximal segments). By 9 months, [11C]HED retention had declined in both the proximal and distal myocardial segments of the STZ-D rats by 42% (P < 0.01 vs. ND rats), and LV norepinephrine content and NGF protein were decreased in parallel. Therefore, 6 months of STZ-induced diabetes results in heterogeneous cardiac sympathetic denervation in the rat, with maximal denervation occurring distally, and is associated with a proximal-to-distal gradient of LV NGF protein depletion. It is tempting to speculate that regional fluctuations of NGF protein in the diabetic myocardium contribute to heterogeneous cardiac sympathetic denervation complicating diabetes.


Anterior parietal cortical response to tactile and skin-heating stimuli applied to the same skin site.
1. The response of anterior parietal cortex to skin stimuli was evaluated with optical intrinsic signal imaging and extracellular microelectrode recording methods in anesthetized squirrel monkeys. 2. Nonnoxious mechanical stimulation (vibrotactile or skin tapping) of the contralateral radial interdigital pad was accompanied by a decrease in reflectance (at 833 nm) in sectors of cytoarchitectonic areas 3b and 1. This intrinsic signal was in register with regions shown by previous receptive field mapping studies to receive low-threshold mechanoreceptor input from the radial interdigital pad. 3. A skin-heating stimulus applied to the contralateral radial interdigital pad with a stationary probe/thermode evoked no discernable intrinsic signal in areas 3b and 1, but evoked a signal within a circumscribed part of area 3a. The region of area 3a responsive to skin heating with the stationary probe/thermode was adjacent to the areas 3b and 1 regions that developed an intrinsic signal in response to vibrotactile stimulation of the same skin site. Skin heating with a stationary probe/thermode also evoked intrinsic signal in regions of areas 4 and 2 neighboring the area 3b/1 regions activated by vibrotactile stimulation of the contralateral radial interdigital pad. 4. The intrinsic signal evoked in area 3a by a series of heating stimuli to the contralateral radial interdigital pad (applied with a stationary probe/thermode) increased progressively in magnitude with repeated stimulation (exhibited slow temporal summation) and remained above prestimulus levels for a prolonged period after termination of repetitive stimulation. 5. Brief mechanical stimuli ("taps") applied to the contralateral radial interdigital pad with a probe/thermode maintained either at 37 degrees C or at 52 degrees C were accompanied by the development of an intrinsic signal in both area 3a and areas 3b/1. For the 52 degrees C stimulus, the area 3a intrinsic signal was larger and the intrinsic signal in areas 3b/1 smaller than the corresponding signals evoked by the 37 degrees C stimulus. 6. Spike discharge activity was recorded from area 3a neurons during a repetitive heating stimulus applied with a stationary probe/ thermode to the contralateral radial interdigital pad. Like the area 3a intrinsic signal elicited by repetitive heating of the same skin site, the area 3a neuron spike discharge activity also exhibited slow temporal summation and poststimulus response persistence. 7. The experimental findings suggest 1) a leading role for area 3a in the anterior parietal cortical processing of skin-heating stimuli, and 2) the presence of inhibitory interactions between the anterior parietal responses to painful and vibrotactile stimuli consistent with those demonstrated in recent cortical imaging and psychophysical studies of human subjects.


The impact of military service on the mental health of older UK veterans: A qualitative study.
There may be ongoing psychological problems associated with military service later in life; yet as the elderly in the general population also suffer from mental health problems, whether such issues can be attributed to military service or are a feature of ageing remains unclear. This study aimed to explore veteran and nonveteran perceptions of the impact of their occupation on their psychological well-being later in life. Twenty-five veterans (≥65 y); 25 nonveterans (≥65 y); 10 veterans with diagnoses of mental health issues (≥65 y); and a close companion of all participants (≥18 y, spouse, child, and close friend) were recruited. Using a qualitative approach, participants completed semistructured qualitative interviews with measures of psychological adjustment used to describe the sample. Veterans were found to experience higher levels of workplace stress and trauma exposure compared with nonveterans. When such challenges were positively appraised, veterans described increased confidence and resilience. Social support in response to occupational stress was central to veteran and nonveteran well-being, especially for those with mental health problems. Nonetheless, providing support was challenging for close companions, with many feeling overwhelmed and requiring additional guidance from the veteran's clinical care team. The findings delineate the impact of occupation on the well-being of older veterans and nonveterans. The results illustrated the psychological support needs and formal guidance desired by veterans, nonveterans, and their families, which could ultimately improve coping of both the individual and family.


Practical considerations for noise power spectra estimation for clinical CT scanners.
Local noise power spectra (NPS) have been commonly calculated to represent the noise properties of CT imaging systems, but their properties are significantly affected by the utilized calculation schemes. In this study, the effects of varied calculation parameters on the local NPS were analyzed, and practical suggestions were provided regarding the estimation of local NPS for clinical CT scanners. The uniformity module of a Catphan phantom was scanned with a Philips Brilliance 64 slice CT simulator with varied scanning protocols. Images were reconstructed using FBP and iDose4 iterative reconstruction with noise reduction levels 1, 3, and 6. Local NPS were calculated and compared for varied region of interest (ROI) locations and sizes, image background removal methods, and window functions. Additionally, with a predetermined NPS as a ground truth, local NPS calculation accuracy was compared for computer simulated ROIs, varying the aforementioned parameters in addition to ROI number. An analysis of the effects of these varied calculation parameters on the magnitude and shape of the NPS was conducted. The local NPS varied depending on calculation parameters, particularly at low spatial frequencies below ~ 0.15 mm-1. For the simulation study, NPS calculation error decreased exponentially as ROI number increased. For the Catphan study the NPS magnitude varied as a function of ROI location, which was better observed when using smaller ROI sizes. The image subtraction method for background removal was the most effective at reducing low-frequency background noise, and produced similar results no matter which ROI size or window function was used. The PCA background removal method with a Hann window function produced the closest match to image subtraction, with an average percent difference of 17.5%. Image noise should be analyzed locally by calculating the NPS for small ROI sizes. A minimum ROI size is recommended based on the chosen radial bin size and image pixel dimensions. As the ROI size decreases, the NPS becomes more dependent on the choice of background removal method and window function. The image subtraction method is most accurate, but other methods can achieve similar accuracy if certain window functions are applied. All dependencies should be analyzed and taken into account when considering the interpretation of the NPS for task-based image quality assessment.


Managing the Earth's Biggest Mass Gathering Event and WASH Conditions: Maha Kumbh Mela (India).
Mass gatherings including a large number of people makes the planning and management of the event a difficult task. Kumbh Mela is one such, internationally famous religious mass gathering. It creates the substantial challenge of creating a temporary city in which millions of people can stay for a defined period of time. The arrangements need to allow this very large number of people to reside with proper human waste disposal, medical services, adequate supplies of food and clean water, transportation etc. We report a case study of Maha Kumbh, 2013 which focuses on the management and planning that went into the preparation of Kumbh Mela and understanding its water, sanitation and hygiene conditions. It was an observational cross-sectional study, the field work was done for 13 days, from 21 January to 2 February 2013. Our findings suggest that the Mela committee and all other agencies involved in Mela management proved to be successful in supervising the event and making it convenient, efficient and safe. Health care services and water sanitation and hygiene conditions were found to be satisfactory. BhuleBhatke Kendra (Center for helping people who got separated from their families) had the major task of finding missing people and helping them to meet their families. Some of the shortfalls identified were that drainage was a major problem and some fire incidents were reported. Therefore, improvement in drainage facilities and reduction in fire incidents are essential to making Mela cleaner and safer. The number of persons per toilet was high and there were no separate toilets for males and females. Special facilities and separate toilets for men and women will improve their stay in Mela. Inculcation of modern methods and technologies are likely to help in supporting crowd management and improving water, sanitation and hygiene conditions in the continuously expanding KumbhMela, in the coming years.


A new paradigm in the treatment of the cardiovascular disease continuum: focus on prevention.
The cardiovascular disease continuum (CVDC) is a sequence of cardiovascular events, which begins from a cluster of cardiovascular risk factors consisting of diabetes mellitus, dyslipidemia, hypertension, smoking and visceral obesity. If these factors are not intervened with early, they will, inexorably, progress to atherosclerosis, coronary artery disease, myocardial infarction, left ventricular hypertrophy, left ventricular dilatation leading to left ventricular diastolic or systolic dysfunction and eventually end stage heart failure and death. For this concise review, a Medline search of the English language literature between the years 2000 and 2009 was conducted and 33 pertinent publications were selected. Based on the evidence contained in these publications, it is possible that early intervention and treatment of the various cardiovascular risk factors, which initiate and perpetuate the CVDC, could prevent it or arrest its further progress. Therefore, this concise review will emphasize the early detection and treatment of the various cardiovascular risk factors, which initiate and perpetuate the CVDC.


Fast and Memory-Efficient Topological Denoising of 2D and 3D Scalar Fields.
Data acquisition, numerical inaccuracies, and sampling often introduce noise in measurements and simulations. Removing this noise is often necessary for efficient analysis and visualization of this data, yet many denoising techniques change the minima and maxima of a scalar field. For example, the extrema can appear or disappear, spatially move, and change their value. This can lead to wrong interpretations of the data, e.g., when the maximum temperature over an area is falsely reported being a few degrees cooler because the denoising method is unaware of these features. Recently, a topological denoising technique based on a global energy optimization was proposed, which allows the topology-controlled denoising of 2D scalar fields. While this method preserves the minima and maxima, it is constrained by the size of the data. We extend this work to large 2D data and medium-sized 3D data by introducing a novel domain decomposition approach. It allows processing small patches of the domain independently while still avoiding the introduction of new critical points. Furthermore, we propose an iterative refinement of the solution, which decreases the optimization energy compared to the previous approach and therefore gives smoother results that are closer to the input. We illustrate our technique on synthetic and real-world 2D and 3D data sets that highlight potential applications.


Exhaustive reanalysis of barcode sequences from public repositories highlights ongoing misidentifications and impacts taxa diversity and distribution.
Accurate species identification often relies on public repositories to compare the barcode sequences of the investigated individual(s) with taxonomically assigned sequences. However, the accuracy of identifications in public repositories is often questionable, and the names originally given are rarely updated. For instance, species of the Sea Lettuce (Ulva spp.; Ulvophyceae, Ulvales, Ulvaceae) are frequently misidentified in public repositories, including herbaria and gene banks, making species identification based on traditional barcoding unreliable. We DNA barcoded 295 individual distromatic foliose strains of Ulva from the North-East Atlantic for three loci (rbcL, tufA, ITS1). Seven distinct species were found, and we compared our results with all worldwide Ulva spp. sequences present in the NCBI database for the three barcodes rbcL, tufA and the ITS1. Our results demonstrate a large degree of species misidentification, where we estimate that 24%-32% of the entries pertaining to foliose species are misannotated and provide an exhaustive list of NCBI sequences reannotations. An analysis of the global distribution of registered samples from foliose species also indicates possible geographical isolation for some species, and the absence of U. lactuca from Northern Europe. We extended our analytical framework to three other genera, Fucus, Porphyra and Pyropia and also identified erroneously labelled accessions and possibly new synonymies, albeit less than for Ulva spp. Altogether, exhaustive taxonomic clarification by aggregation of a library of barcode sequences highlights misannotations and delivers an improved representation of species diversity and distribution.


Folding kinetics of the SH3 domain of PI3 kinase by real-time NMR combined with optical spectroscopy.
The refolding kinetics of the chemically denatured SH3 domain of phosphatidylinositol 3'-kinase (PI3-SH3) have been monitored by real-time one-dimensional 1H NMR coupled with a variety of other biophysical techniques. These experiments indicate that the refolding kinetics of PI3-SH3 are biphasic. The slow phase (27 (+/- 8)% amplitude) is due to a population of substantially unfolded molecules with an incorrectly configured cis proline residue. The fast phase (73 (+/- 8)% amplitude) corresponds to the folding of protein molecules with proline residues in a trans configuration in the unfolded state. NMR experiments indicate that the first species populated after the initiation of folding exhibit poor chemical shift dispersion and have spectra very similar to that of the denatured protein in 8 M guanidine hydrochloride. Linear combinations of the first spectrum and of the spectrum of the native protein accurately reconstruct all of the spectra acquired during refolding. Consistent with this, native side-chain and backbone H alpha atom packing (NMR), secondary structure (far-UV circular dichroism), burial of aromatic residues (near-UV circular dichroism), intrinsic fluorescence and peptide binding activity are all recovered with effectively identical kinetics. Equilibrium unfolding and folding/unfolding kinetics yield, within experimental error, identical values for the free energy of unfolding (delta Gu-H2O = 3.38 kcal mol-1) and for the slope of the free energy of unfolding versus denaturant concentration (meq = 2.33 kcal mol-1 M-1). Together, these data provide strong evidence that PI3-SH3 folds without significant population of kinetic well-structured intermediates. That PI3-SH3 folds slowly (time constant 2.8 seconds in H2O at 20 degrees C) indicates that slow refolding is not always a consequence of kinetic traps but may be observed even when a protein appears to fold via a simple, two-state mechanism.


Reading skills in hyperlexia: a developmental perspective.
Hyperlexia is characterized by advanced word-recognition skills in individuals who otherwise have pronounced cognitive, social, and linguistic handicaps. Language, word recognition, and reading-comprehension skills are reviewed to clarify the nature and core deficits associated with the disorder. It is concluded that hyperlexia should be viewed as part of the normal variation in reading skills, which are themselves associated with individual differences in phonological, orthographic, and semantic processing, short-term memory, and print exposure. A compulsive preoccupation with reading may also be crucial to the development of a hyperlexic reading profile. A theoretical framework, based on recent connectionist models of reading development, is described. This perspective provides a satisfactory account for how individual differences in a number of different skills can lead to a variety of manifestations of reading behavior, including hyperlexia.


Unique molecular signatures of microRNAs in ocular fluids and plasma in diabetic retinopathy.
The main objective of this pilot study was to identify circulatory microRNAs in aqueous or plasma that were reflecting changes in vitreous of diabetic retinopathy patients. Aqueous, vitreous and plasma samples were collected from a total of 27 patients undergoing vitreoretinal surgery: 11 controls (macular pucker or macular hole patients) and 16 with diabetes mellitus(DM): DM-Type I with proliferative diabetic retinopathy(PDR) (DMI-PDR), DM Type II with PDR(DMII-PDR) and DM Type II with nonproliferative DR(DMII-NPDR). MicroRNAs were isolated using Qiagen microRNeasy kit, quantified on BioAnalyzer, and profiled on Affymetrix GeneChip miRNA 3.0 microarrays. Data were analyzed using Expression Console, Transcriptome Analysis Console, and Ingenuity Pathway Analysis. The comparison analysis of circulatory microRNAs showed that out of a total of 847 human microRNA probes on the microarrays, common microRNAs present both in aqueous and vitreous were identified, and a large number of unique microRNA, dependent on the DM type and severity of retinopathy. Most of the dysregulated microRNAs in aqueous and vitreous of DM patients were upregulated, while in plasma, they were downregulated. Dysregulation of miRNAs in aqueous did not appear to be a good representative of the miRNA abundance in vitreous, or plasma, although a few potential candidates for common biomarkers stood out: let-7b, miR-320b, miR-762 and miR-4488. Additionally, each of the DR subtypes showed miRNAs that were uniquely dysregulated in each fluid (i.e. aqueous: for DMII-NPDR was miR-455-3p; for DMII-PDR was miR-296, and for DMI-PDR it was miR-3202). Pathway analysis identified TGF-beta and VEGF pathways affected. The comparative profiling of circulatory miRNAs showed that a small number of them displayed differential presence in diabetic retinopathy vs. controls. A pattern is emerging of unique molecular microRNA signatures in bodily fluids of DR subtypes, offering promise for the use of ocular fluids and plasma for diagnostic and therapeutic purposes.


Pedigree analysis and exclusion of alpha-tocopherol transfer protein (TTPA) as a candidate gene for neuroaxonal dystrophy in the American Quarter Horse.
Equine neuroaxonal dystrophy/equine degenerative myeloencephalopathy (NAD/EDM) is a neurodegenerative disorder affecting young horses of various breeds that resembles ataxia with vitamin E deficiency in humans, an inherited disorder caused by mutations in the alpha-tocopherol transfer protein gene (TTPA). To evaluate variants found upon sequencing TTPA in the horse, the mode of inheritance for NAD/EDM had to be established. NAD/EDM in the American Quarter Horse (QH) is caused by a mutation in TTPA. 88 clinically phenotyped (35 affected [ataxia score ≥2], 53 unaffected) QHs with a diagnosis of NAD/EDM with 6 affected and 4 unaffected cases confirmed at postmortem examination. Pedigrees and genotypes across 54,000 single nucleotide polymorphism (SNP) markers were assessed to determine heritability and mode of inheritance of NAD/EDM. TTPA sequence of exon/intron boundaries was evaluated in 2 affected and 2 control horses. An association analysis was performed by 71 SNPs surrounding TTPA and 8 SNPs within TTPA that were discovered by sequencing. RT-PCR for TTPA was performed on mRNA from the liver of 4 affected and 4 control horses. Equine NAD/EDM appears to be inherited as a polygenic trait and, within this family of QHs, demonstrates high heritability. Sequencing of TTPA identified 12 variants. No significant association was found using the 79 available variants in and surrounding TTPA. RT-PCR yielded PCR products of equivalent sizes between affected cases and controls. NAD/EDM demonstrates heritability in this family of QHs. Variants in TTPA are not responsible for NAD/EDM in this study population.


Normal and malignant epithelial cells with stem-like properties have an extended G2 cell cycle phase that is associated with apoptotic resistance.
Subsets of cells with stem-like properties have been previously isolated from human epithelial cancers and their resistance to apoptosis-inducing stimuli has been related to carcinoma recurrence and treatment failure. The aim of this study was to investigate the mechanisms of resistance to apoptosis-inducing agents of cells with stem-like properties in both normal and malignant human epithelia. Cells isolated from fresh human head and neck carcinomas (n = 11), cell lines derived from head and neck, prostate and breast human carcinomas (n = 7), and from normal human oral mucosa (n = 5), were exposed to various apoptosis-inducing stimuli (UV, Tumour Necrosis Factor, Cisplatin, Etoposide, and Neocarzinostatin). Flow cytometry for CD44 and epithelial-specific antigen (ESA) expression, colony morphology, tumour sphere formation and rapid adherence assays were used to identify the subset of cells with stem-like properties. Apoptosis, cell cycle and expression of various cell cycle checkpoint proteins were assessed (Western Blot, qPCR). The role of G2-checkpoint regulators Chk1 and Chk2 was investigated by use of debromohymenialdisine (DBH) and siRNA. In both cancer biopsies and carcinoma cell lines a subset of CD44(high) cells showed increased clonogenicity, a significantly lower rate of apoptosis, and a significantly higher proportion of cells in the G2-phase of the cell cycle. An inverse correlation between the percentage of cells in G2-phase and the rate of apoptosis was found. Pulse-chase with iododeoxyuridine (IdU) demonstrated that CD44(high) carcinoma cells spent longer time in G2, even in un-treated controls. These cells expressed higher levels of G2 checkpoint proteins, and their release from G2 with BDH or Chk1 siRNA increased their rate of apoptosis. Low passage cultures of normal keratinocytes were also found to contain a subset of CD44(high) cells showing increased clonogenicity, and a similar pattern of G2-block associated with apoptotic resistance. These data indicate that both normal and malignant human epithelial cells with stem-like properties show greater resistance to apoptosis associated with extended G2 cell cycle phase, and that this property is not a consequence of neoplastic transformation. Targeting G2 checkpoint proteins releases these cells from the G2-block and makes them more prone to apoptosis, implying an opportunity for improved therapeutic approaches.


Maternal exposure to a continuous 900-MHz electromagnetic field provokes neuronal loss and pathological changes in cerebellum of 32-day-old female rat offspring.
Large numbers of people are unknowingly exposed to electromagnetic fields (EMF) from wireless devices. Evidence exists for altered cerebellar development in association with prenatal exposure to EMF. However, insufficient information is still available regarding the effects of exposure to 900 megahertz (MHz) EMF during the prenatal period on subsequent postnatal cerebellar development. This study was planned to investigate the 32-day-old female rat pup cerebellum following exposure to 900MHz EMF during the prenatal period using stereological and histopathological evaluation methods. Pregnant rats were divided into control, sham and EMF groups. Pregnant EMF group (PEMFG) rats were exposed to 900MHz EMF for 1h inside an EMF cage during days 13-21 of pregnancy. Pregnant sham group (PSG) rats were also placed inside the EMF cage during days 13-21 of pregnancy for 1h, but were not exposed to any EMF. No procedure was performed on the pregnant control group (PCG) rats. Newborn control group (CG) rats were obtained from the PCG mothers, newborn sham group (SG) rats from the PSG and newborn EMF group (EMFG) rats from the PEMFG rats. The cerebellums of the newborn female rats were extracted on postnatal day 32. The number of Purkinje cells was estimated stereologically, and histopathological evaluations were also performed on cerebellar sections. Total Purkinje cell numbers calculated using stereological analysis were significantly lower in EMFG compared to CG (p<0.05) and SG (p<0.05). Additionally, some pathological changes such as pyknotic neurons with dark cytoplasm were observed in EMFG sections under light microscopy. In conclusion, our study results show that prenatal exposure to EMF affects the development of Purkinje cells in the female rat cerebellum and that the consequences of this pathological effect persist after the postnatal period.


Peritoneal dialysis-associated peritonitis in Scotland (1999-2002).
Peritonitis is a major complication of peritoneal dialysis (PD). We have performed a national study of all patients on PD in Scotland over a 3.5 year period examining the causes of technique failure, rates of peritonitis, causative organisms, clinical outcomes and differences between automated peritoneal dialysis (APD) and continuous ambulatory peritoneal dialysis (CAPD). All 10 adult renal units in Scotland participated in the study and the data include all 1205 patients who were on PD in Scotland from January 1999 to June 2002. The data were collected prospectively by the PD nurses and reported to the Scottish Renal Registry every 6 months. Refractory or recurrent peritonitis was the cause of technique failure in 167 patients (42.6% of all cases of technique failure). There were 928 cases of peritonitis in 1487 patient-years, which equates to an overall peritonitis rate of one episode every 19.2 months. The peritonitis rates for APD and CAPD were similar at one episode every 20.3 months and one episode every 18.6 months, respectively. These results include 88 cases of peritonitis due to relapse or re-infection. There was a statistically significant difference (P = 0.012) in peritonitis rates between units using nasal mupiricin (one episode every 21.9 months) and those that did not (one episode every 18.3 months). Coagulase-negative Staphylococcus was the most common cause of peritonitis (29%), although this rate is lower than in historic studies. The overall initial cure rate was 75%. The initial cure rate for APD was 77.2% and for CAPD was 73.7%. No causative organism was isolated in 17% of cases. PD-associated peritonitis is the leading cause of technique failure in Scotland. We validate previous studies showing a decrease in the proportion of peritonitis episodes that are caused by coagulase-negative staphylococci. APD peritonitis rates are not significantly better than CAPD peritonitis rates in Scotland, and the initial cure rates for APD and CAPD are similar.


Extension of longevity and reduction of inflammation is ovarian-dependent, but germ cell-independent in post-reproductive female mice.
Cardiovascular disease, rare in premenopausal women, increases sharply at menopause and is typically accompanied by chronic inflammation. Previous work in our laboratory demonstrated that replacing senescent ovaries in post-reproductive mice with young, actively cycling ovaries restored many health benefits, including decreased cardiomyopathy and restoration of immune function. Our objective here was to determine if depletion of germ cells from young transplanted ovaries would alter the ovarian-dependent extension of life and health span. Sixty-day-old germ cell-depleted and germ cell-containing ovaries were transplanted to post-reproductive, 17-month-old mice. Mean life span for female CBA/J mice is approximately 644 days. Mice that received germ cell-containing ovaries lived 798 days (maximum = 815 days). Mice that received germ cell-depleted ovaries lived 880 days (maximum = 1046 days), 29% further past the time of surgery than mice that received germ cell-containing ovaries. The severity of inflammation was reduced in all mice that received young ovaries, whether germ cell-containing or germ cell-depleted. Aging-associated inflammatory cytokine changes were reversed in post-reproductive mice by 4 months of new-ovary exposure. In summary, germ cell depletion enhanced the longevity-extending effects of the young, transplanted ovaries and, as with germ cell-containing ovaries, decreased the severity of inflammation, but did so independent of germ cells. Based on these observations, we propose that gonadal somatic cells are programed to preserve the somatic health of the organism with the intent of facilitating future germline transmission. As reproductive potential decreases or is lost, the incentive to preserve the somatic health of the organism is lost as well.


Patient Profiles of Criminal Behavior in the Context of Traumatic Brain Injury.
Traumatic brain injury (TBI) can lead to significant post-traumatic disturbances in mood and behavior, with the frontal lobes playing a key role in emotional and behavioral regulation. Injury to the frontal lobe can result in disinhibition and aggression which can result in police intervention and/or incarceration. We highlight four adult cases with a history of severe TBI with frontal lobe injuries and the presence of post-TBI criminal behaviors. There is evidence to support an anatomical basis for aggressive behaviors, yet there are other risk factors to be considered. Behaviors must be investigated thoroughly by obtaining adequate pre- and post-TBI psychiatric and psychosocial histories. By having a comprehensive understanding of aggression while appreciating the complex relationship between TBI, aggression, and premorbid risk factors, clinicians can more adequately treat patients with TBI, with the aim of potentially preventing criminal behaviors and recidivism.


Discrete dipole approximation for the study of radiation dynamics in a magnetodielectric environment.
We develop a general computational approach, based on the discrete dipole approximation, for the study of radiation dynamics near or inside an object with arbitrary linear dielectric permittivity, and magnetic permeability tensors. Our method can account for dispersion and losses and provides insight on the role of local-field corrections in discrete magnetodielectric structures. We illustrate our method in the case of a source inside a magneto-dielectric, isotropic sphere for which the spontaneous emission rate of a source can be computed analytically. We show that our approach is in excellent agreement with the exact result, providing an approach capable of handling both the electric and magnetic response of advanced metamaterials.


Dual-Task Performance in Hearing-Impaired Older Adults-Study Protocol for a Cross-Sectional Mobile Brain/Body Imaging Study.
Background: Hearing impairments are associated with reduced walking performance under Dual-task (DT) conditions. Little is known about the neural representation of DT performance while walking in this target group compared to healthy controls or younger adults. Therefore, utilizing the Mobile Brain/Body Imaging approach (MoBI), we aim at gaining deeper insights into the brain dynamics underlying the interaction of cognitive and motor processes during different DT conditions (visual and auditory) controlling for age and the potential performance decrements of older adults with hearing impairments. Methods: The cross-sectional study integrates a multifactorial mixed-measure design. Between-subject factors grouping the sample will be age (younger vs. older adults) and hearing impairment (mild vs. not hearing impaired). The within-subject factors will be the task complexity (single- vs. DT) and cognitive task modality (visual vs. auditory). Stimuli of the cognitive task will vary according to the stimulus modality (visual vs. auditory), presentation side (left vs. right), and presentation-response compatibility (ipsilateral vs. contralateral). Analyses of DT costs and underlying neuronal correlates focus either on gait or cognitive performance. Based on an a priori sample size calculation 96 (48 healthy and 48 mildly hearing impaired) community-dwelling older adults (50-70 years) and 48 younger adults (20-30 years) will be recruited. Gait parameters of speed and rhythm will be captured. EEG activity will be recorded using 64 active electrodes. Discussion: The study evaluates cognitive-motor interference (CMI) in groups of young and older adults as well as older adults with hearing impairment. The underlying processes of the interaction between motor and cognitive tasks will be identified at a behavioral and neurophysiological level comparing an auditory or a visual secondary task. We assume that performance differences are linked to different cognitive-motor processes, i.e., stimulus input, resource allocation, and movement execution. Moreover, for the different DT conditions (auditory vs. visual) we assume performance decrements within the auditory condition, especially for older, hearing-impaired adults. Findings will provide evidence of general mechanisms of CMI (ST vs. DT walking) as well as task-specific effects in dual-task performance while over ground walking.


Short-wave infrared light imaging measures tissue moisture and distinguishes superficial from deep burns.
Existing clinical approaches and tools to measure burn tissue destruction are limited resulting in misdiagnosis of injury depth in over 40% of cases. Thus, our objective in this study was to characterize the ability of short-wave infrared (SWIR) imaging to detect moisture levels as a surrogate for tissue viability with resolution to differentiate between burns of various depths. To accomplish our aim, we constructed an imaging system consisting of a broad-band Tungsten light source; 1,200-, 1,650-, 1,940-, and 2,250-nm wavelength filters; and a specialized SWIR camera. We initially used agar slabs to provide a baseline spectrum for SWIR light imaging and demonstrated the differential absorbance at the multiple wavelengths, with 1,940 nm being the highest absorbed wavelength. These spectral bands were then demonstrated to detect levels of moisture in inorganic and in vivo mice models. The multiwavelength SWIR imaging approach was used to diagnose depth of burns using an in vivo porcine burn model. Healthy and injured skin regions were imaged 72 hours after short (20 seconds) and long (60 seconds) burn application, and biopsies were extracted from those regions for histologic analysis. Burn depth analysis based on collagen coagulation histology confirmed the formation of superficial and deep burns. SWIR multispectral reflectance imaging showed enhanced intensity levels in long burned regions, which correlated with histology and distinguished between superficial and deep burns. This SWIR imaging method represents a novel, real-time method to objectively distinguishing superficial from deep burns.


Report of the 2019 NIST-FDA workshop on standards for next generation sequencing detection of viral adventitious agents in biologics and biomanufacturing.
Adventitious virus testing assures product safety by demonstrating the absence of viruses that could be unintentionally introduced during the manufacturing process. The capabilities of next-generation sequencing (NGS) for broad virus detection in biologics have been demonstrated by the detection of known and novel viruses that were previously missed using the recommended routine assays for adventitious agent testing. A meeting was co-organized by the National Institute of Standards and Technology and the U.S. Food and Drug Administration on September 18-19, 2019 in Gaithersburg, Maryland, USA, to facilitate standardization of NGS technologies for applications of adventitious virus testing in biologics. The goal was to assess the currently used standards for virus detection by NGS and their public availability, and to identify additional needs for different types of reference materials and standards (natural and synthetic). The meeting focused on the NGS processes from sample preparation through sequencing but did not thoroughly cover bioinformatics, since this was considered to be the topic of a separate meeting.


Emerging concepts in acute mountain sickness and high-altitude cerebral edema: from the molecular to the morphological.
Acute mountain sickness (AMS) is a neurological disorder that typically affects mountaineers who ascend to high altitude. The symptoms have traditionally been ascribed to intracranial hypertension caused by extracellular vasogenic edematous brain swelling subsequent to mechanical disruption of the blood-brain barrier in hypoxia. However, recent diffusion-weighted magnetic resonance imaging studies have identified mild astrocytic swelling caused by a net redistribution of fluid from the "hypoxia-primed" extracellular space to the intracellular space without any evidence for further barrier disruption or additional increment in brain edema, swelling or pressure. These findings and the observation of minor vasogenic edema present in individuals with and without AMS suggest that the symptoms are not explained by cerebral edema. This has led to a re-evaluation of the relevant pathogenic events with a specific focus on free radicals and their interaction with the trigeminovascular system.


A comprehensive small interfering RNA screen identifies signaling pathways required for gephyrin clustering.
The postsynaptic scaffold protein gephyrin is clustered at inhibitory synapses and serves for the stabilization of GABA(A) receptors. Here, a comprehensive kinome-wide siRNA screen in a human HeLa cell-based model for gephyrin clustering was used to identify candidate protein kinases implicated in the stabilization of gephyrin clusters. As a result, 12 hits were identified including FGFR1 (FGF receptor 1), TrkB, and TrkC as well as components of the MAPK and mammalian target of rapamycin (mTOR) pathways. For confirmation, the impact of these hits on gephyrin clustering was analyzed in rat primary hippocampal neurons. We found that brain-derived neurotrophic factor (BDNF) acts on gephyrin clustering through MAPK signaling, and this process may be controlled by the MAPK signaling antagonist sprouty2. BDNF signaling through phosphatidylinositol 3-kinase (PI3K)-Akt also activates mTOR and represses GSK3β, which was previously shown to reduce gephyrin clustering. Gephyrin is associated with inactive mTOR and becomes released upon BDNF-dependent mTOR activation. In primary neurons, a reduction in the number of gephyrin clusters due to manipulation of the BDNF-mTOR signaling is associated with reduced GABA(A) receptor clustering, suggesting functional impairment of GABA signaling. Accordingly, application of the mTOR antagonist rapamycin leads to disinhibition of neuronal networks as measured on microelectrode arrays. In conclusion, we provide evidence that BDNF regulates gephyrin clustering via MAPK as well as PI3K-Akt-mTOR signaling.


Reconciling the professional and student identities of clinical psychology trainees.
The study explored the ways in which qualified and trainee clinical psychologists perceived professional behaviour, as illustrated in a series of short vignettes, in student and clinical practice contexts. Comparisons were made to identify the extent to which ideas of professionalism differed across different learning contexts and between qualified and unqualified staff, with the aim of adding to the literature on which factors influence the development of professional identity in health professionals. An online questionnaire depicting a range of potentially unprofessional behaviours was completed by 265 clinical psychology trainees and 106 qualified clinical psychologists. The data were analysed using a general linear model with simultaneous entry in which rater (trainee vs qualified clinical psychologist), setting (student vs placement) and their interaction predicted acceptability ratings. We found that, in general, trainees and qualified staff agreed on those behaviours that were potentially unprofessional, although where significant differences were found, these were due to trainees rating the same behaviours as more professionally acceptable than qualified clinical psychologists. Despite trainees identifying a range of behaviours as professionally unacceptable, some percentage reported having engaged in a similar behaviour in the past. Irrespective of the status of the rater, the same behaviours tended to be viewed as more professionally unacceptable when in a placement (clinical) setting than in a student (university) setting. Generally, no support was found for a rater by setting interaction. The study suggests that trainee clinical psychologists are generally successful at identifying professional norms, although they do not always act in accordance with these. Conflicting student and professional norms may result in trainees viewing some potentially unprofessional behaviour as less severe than qualified staff. Health professional educators should be aware of this fact and take steps to shape trainee norms to be consistent with that of the professional group.


High non-protective, long-lasting antibody levels in malaria are associated with haplotype shifting in MHC-peptide-TCR complex formation: a new mechanism for immune evasion.
An effective malarial vaccine must contain multiple immunogenic, protection-inducing epitopes able to block and destroy the P. falciparum malaria parasite, the most lethal form of this disease in the world. Our strategy has consisted in using conserved peptides blocking parasite binding to red blood cells; however, these peptides are non-immunogenic and non-protection-inducing. Modifying their critical residues can make them immunogenic. Such peptides induced antibody titers (determined by immunofluorescence antibody test, IFA) and made the latter reactive (determined by Western blot) and protection inducing against experimental challenge with a highly infective Aotus monkey adapted P. falciparum strain. Modified peptides also induce highly non-protective long-lasting antibody levels. Modifications performed might allow them to bind specifically to different HLA-DRbeta purified molecules. These immunological and biological activities are associated with modifications in their three-dimensional structure as determined by (1)H-NMR. It was found that modified, high non-protective long-lasting antibody level peptides bound to HLA-DR molecules from a different haplotype (to which immunogenic, protection-inducers bind) and had 4.6 +/- 1.4 A shorter distances between residues fitting into these molecules' Pocket 1 to Pocket 9, suggesting fitting into an inappropriate HLA-DR molecule. A multi-component, subunit-based, malarial vaccine is therefore feasible if modified peptides are suitably modified for an appropriate fit into the correct HLA-DRbeta1* molecule in order to form a proper MHC-II-peptide-TCR complex.


Continuous infusion high-dose cytosine arabinoside in refractory childhood leukemia.
Ten pediatric patients with refractory leukemia received continuous infusion high-dose cytosine arabinoside (ara-C) according to one of two escalating dosage schedules: (1) a 500-mg/m2 rapid infusion loading dose followed by 3.5 g/m2 per day continuous infusion daily for four consecutive days, or (2) a 600-mg/m2 rapid infusion loading dose followed by 5.0 g/m2 per day continuous infusion daily for four consecutive days. Major toxicity at the lower dosage level was grade IV hematopoietic aplasia of three weeks' duration. At the higher dosage level, there was a prohibitive toxicity in multiple organ systems including transient noncardiogenic pulmonary edema, fungal infections, peritonitis, severe diarrhea, transaminase elevations, and one treatment-related death due to acute renal failure. In contrast to other methods of administration of high-dose ara-C, no CNS toxicity occurred. Oncolytic responses were seen in all patients and two achieved brief, partial remissions. Steady-state plasma ara-C concentrations were 13 to 40 mumol/L at the 3.5-g/m2 dosage level and 10 to 225 mumol/L at the 5-g/m2 dosage level; CSF concentrations at both dosages ranged from 2 to 5 mumol/L. Intracellular levels and ratios of 1-beta-D-arabinofuranosylcytidine-5' triphosphate and endogenous deoxycytidine 5' triphosphate in marrow blasts varied widely at steady state during infusion. No positive correlation existed between steady-state plasma ara-C levels, toxicity, oncolytic effect, or intracellular nucleotide concentration.


Y4 receptors and pancreatic polypeptide regulate food intake via hypothalamic orexin and brain-derived neurotropic factor dependent pathways.
Gut-derived peptides are known to regulate food intake by activating specific receptors in the brain, but the target nuclei and neurons influenced are largely unknown. Here we show that peripherally administered pancreatic polypeptide (PP) stimulates neurons in key nuclei of the hypothalamus critical for appetite and satiety regulation. In the lateral hypothalamic area (LHA), also known as the feeding center, neurons expressing the orexigenic neuropeptide orexin co-localize with the early neuronal activation marker c-Fos upon i.p. injection of PP into mice. In the ventromedial hypothalamus (VMH), also known as the satiety center, neurons activated by PP, as indicated by induction of c-Fos immunoreactivity, express the anorexigenic brain-derived neurotrophic factor (BDNF). Activation of neurons in the LHA and VMH in response to PP occurs via a Y4 receptor-dependent process as it is not seen in Y4 receptor knockout mice. We further demonstrate that in response to i.p. PP, orexin mRNA expression in the LHA is down-regulated, with Y4 receptors being critical for this effect as it is not seen in Y4 receptor knockout mice, whereas BDNF mRNA expression is up-regulated in the VMH in response to i.p. PP in the fasted, but not in the non-fasted state. Taken together these data suggest that PP can regulate food intake by suppressing orexigenic pathways by down-regulation of orexin and simultaneously increasing anorexigenic pathways by up-regulating BDNF.


Gene set enrichment analysis unveils the mechanism for the phosphodiesterase 4B control of glucocorticoid response in B-cell lymphoma.
Resistance to glucocorticoid (GC) is a significant problem in the clinical management of lymphoid malignancies. Addressing this issue via a mechanistic understanding of relevant signaling pathways is more likely to yield positive outcomes. We used gene set enrichment analysis (GSEA), multiple genetic models of gain and loss of function in B-cell lymphoma cell lines, in vitro and in vivo, and primary patient samples to characterize a novel relationship between the cyclic AMP/phosphodiesterase 4B (cAMP/PDE4B), AKT/mTOR activities, and GC responses. Starting from the GSEA, we found that overexpression of the PDE4B in diffuse large B-cell lymphoma (DLBCL) impinge on the same genes/pathways that are abnormally active in GC-resistant tumors. We used genetically modified cell lines to show that PDE4B modulates cAMP inhibitory activities toward the AKT/mTOR pathway and defines GC resistance in DLBCL. In agreement with these data, pharmacologic inhibition of PDE4 in a xenograft model of human lymphoma unleashed cAMP effects, inhibited AKT, and restored GC sensitivity. Finally, we used primary DLBCL samples to confirm the clinical relevance and biomarker potential of AKT/mTOR regulation by PDE4B. Together, these data mechanistically elucidated how cAMP modulates GC responses in lymphocytes, defined AKT as the principal transducer of the growth inhibitory effects of cAMP in B cells, and allowed the formulation of genomics-guided clinical trials that test the ability of PDE4 inhibitors to restore GC sensitivity and improve the outcome of patients with B-cell malignancies.


Modification to the AOAC Sporicidal Activity of Disinfectants Test (Method 966.04): collaborative study.
In an effort to improve AOAC Method 966.04, the Sporicidal Activity of Disinfectants Test, selected modifications to the procedure were evaluated in a collaborative study. Method 966.04 is used to generate efficacy data to support the product registration of sporicides and sterilants. The method is a carrier-based test that provides a qualitative measure of product efficacy against spores of Bacillus subtilis and Clostridium sporogenes. The use of garden soil extract and the lack of standard procedures for the enumeration of spores and neutralization of the test chemicals have been considered problematic for many years. The proposed modifications were limited to the B. subtilis and hard surface carrier (porcelain penicylinder) components of the method. The study included the evaluation of a replacement for soil extract nutrient broth and an establishment of a minimum spore titer per carrier, both considered crucial for the improvement and utilization of the method. Additionally, an alternative hard surface material and a neutralization confirmation procedure were evaluated. To determine the equivalence of the proposed alternatives to the standard method, 3 medium/carrier combinations, (1) soil extract nutrient broth/porcelain carrier (current method), (2) nutrient agar amended with 5 microg/mL manganese sulfate/porcelain carrier, and (3) nutrient agar amended with 5 microg/mL manganese sulfate/stainless steel carrier were analyzed for carrier counts, HCI resistance, efficacy, quantitative efficacy, and spore wash-off. The test chemicals used in the study represent 3 chemical classes and are commercially available antimicrobial liquid products: sodium hypochlorite (bleach), glutaraldehyde, and a combination of peracetic acid and hydrogen peroxide. Four laboratories participated in the study. The results of the spore titer per carrier, HCI resistance, efficacy, and wash-off studies demonstrate that amended nutrient agar in conjunction with the porcelain is comparable to the current method, soil extract nutrient broth/porcelain. The nutrient agar method is simple, inexpensive, reproducible, and provides an ample supply of high quality spores. Due to the current use of porcelain carriers for testing C. sporogenes, it is advisable to retain the use of porcelain carriers until stainless steel can be evaluated as a replacement carrier material for Clostridium. The evaluation of stainless steel for Clostridium has been initiated by the Study Director. Study Director recommendations for First Action revisions are provided in a modified method.


Impact of tissue heterogeneity correction on Gamma Knife stereotactic radiosurgery of acoustic neuromas.
Treatment planning systems (TPS) for Gamma Knife stereotactic radiosurgery (GK-SRS) include TMR10 algorithms, which assumes tissue homogeneity equivalent to water, and collapsed-cone convolutional (CCC) algorithms, which accounts for tissue inhomogeneity. This study investigated dosimetric differences between TMR10 and CCC TPS for acoustic neuromas (ANs) treated with GK-SRS. A retrospective review of 56 AN treated with GK-SRS was performed. All patients underwent MRI and CT imaging during their initial treatment and were planned using TMR10. Each plan was recalculated with CCC using electron density extracted from CT. Parameters of interest included Dmax, Dmin, D50%, cochlea Dmax, mean cochlea dose, target size, and laterality (>20 mm from central axis). Median target volume of patients was 1.5 cc (0.3 cc-2.8 cc) with median dose of 12 Gy prescribed to the 50% isodose line. Compared to CCC algorithms, the TMR10 calculated dose was higher: Dmax was higher by an average 6.2% (p < 0.001), Dmin was higher by an average 3.1% (p < 0.032), D50% was higher by an average of 11.3%. For lateralized targets, calculated Dmax and D50% were higher by 7.1% (p < 0.001) and 10.6% (p < 0.001), respectively. For targets <1 cc, Dmax and D50% were higher by 8.9% (p ≤ 0.009) and 12.1% (p ≤ 0.001), respectively. Cochlea Dmax was higher, by an average of 20.1% (p < 0.001). There was a statistically significant dosimetric differences observed between TMR10 and CCC algorithms for AN GK-SRS, particularly in small and lateralized ANs. It may be important to note these differences when relating GK-SRS with standard heterogeneity-corrected SRS regimens.


Incidence, classification, and treatment of angiographically occult intracranial aneurysms found during microsurgical aneurysm clipping of known aneurysms.
During the microsurgical clipping of known aneurysms, angiographically occult (AO) aneurysms are sometimes found and treated simultaneously to prevent their growth and protect the patient from future rupture or reoperation. The authors analyzed the incidence, treatment, and outcomes associated with AO aneurysms to determine whether limited surgical exploration around the known aneurysm was safe and justified given the known limitations of diagnostic angiography. An AO aneurysm was defined as a saccular aneurysm detected using the operative microscope during dissection of a known aneurysm, and not detected on preoperative catheter angiography. A prospective database was retrospectively reviewed to identify patients with AO aneurysms treated microsurgically over a 20-year period. One hundred fifteen AO aneurysms (4.0%) were identified during 2867 distinct craniotomies for aneurysm clipping. The most common locations for AO aneurysms were the middle cerebral artery (60 aneurysms, 54.1%) and the anterior cerebral artery (20 aneurysms, 18.0%). Fifty-six AO aneurysms (50.5%) were located on the same artery as the known saccular aneurysm. Most AO aneurysms (95.5%) were clipped and there was no attributed morbidity. The most common causes of failed angiographic detection were superimposition of a large aneurysm (type 1, 30.6%), a small aneurysm (type 2, 18.9%), or an adjacent normal artery (type 3, 36.9%). Multivariate analysis identified multiple known aneurysms (odds ratio [OR] 3.45, 95% confidence interval [CI] 2.16-5.49, p < 0.0001) and young age (OR 0.981, 95% CI 0.965-0.997, p = 0.0226) as independent predictors of AO aneurysms. Meticulous inspection of common aneurysm sites within the surgical field will identify AO aneurysms during microsurgical dissection of another known aneurysm. Simultaneous identification and treatment of these additional undiagnosed aneurysms can spare patients later rupture or reoperation, particularly in those with multiple known aneurysms and a history of subarachnoid hemorrhage. Limited microsurgical exploration around a known aneurysm can be performed safely without additional morbidity.


Migration of transfused granulocytes in leukopenic dogs.
Although granulocyte transfusion therapy has been shown to be effective in infected granulocytopenic animals and humans, the relative effectiveness of granulocytes (PMN) harvested by continuous flow centrifugation (CFC) or by continuous flow filtration leukapheresis (FL) remains uncertain. Studies in vitro of morphology and granulocyte functions have suggested cells collected by FL may be damaged. To compare the function in vivo of granulocytes collected by different methods, dogs were made granulocytopenic with cyclophosphamide (CYT) and then transfused with granulocytes collected by CFC or FL. The local neutrophil mobilization (LNM) through a standard skin abrasion into a chamber containing a strong chemoattractant, autologous serum, was measured. Greater LNM was found after transfusions of CFC PMN than after transfusions of the same number of FL PMN (p less than 0.0003). This difference persisted even when the dose of FL PMNs was four times greater than that of CFC mn and when the FL donor was pretreated with steroids (p less than 0.001). These results suggest that during filtration leukapheresis, granulocytes are functionally altered and that their function in vivo may be compromised.


The effect of hematocrit on solid-phase microextraction.
Solid-phase microextraction (SPME) is an approach to sample preparation that has demonstrated its appropriateness for isolating/enriching analytes present in complex biofluids with minimum sample pre-treatment. Several prior in vitro and in vivo studies have used SPME to monitor the concentrations of various drugs and metabolites in blood samples. In this work, we present the results of an investigation into how various levels of hematocrit (Hct) affect SPME recoveries. The matrices for this study consisted of whole blood samples that had been adjusted at three different Hct levels (20%, 45%, and 70%), and the selected model compounds were drugs with different physicochemical characteristics (log P range from 0.33 to 6.36). In addition, two experimental setups were employed to conduct the extractions: hydrophilic lipophilic balanced (HLB) coated SPME devices (HLB-D) at 1500 rpm (vortex agitation), and mixed mode SPME fibres (MM-F) at 400 rpm (orbital shaking agitation). Our results demonstrated that the Hct effect in SPME is dependent on the analytes of interest, and that different outcomes can be attained by altering experimental conditions, such as coating type, convection, and extraction time. Interestingly, a target compound's relative affinity for the matrix components and for the coating material proved to be one of the main factors that determine the final effect that different erythrocyte levels have on SPME recoveries. Finally, although the Hct content affects each analyte differently and the final Hct effect depends on the experimental parameters, matrix variability can be corrected by using appropriate internal standards, thereby resulting in correct quantification.


[A recent trial of chemo-radiation with S-1 against gastric cancer].
A recent development of novel anticancer agents like S-1, CPT-11 or taxanes has improved a therapeutic outcome for advanced gastric cancer, while conventional anticancer agents showed less anticancer effect against gastric cancer. The present main drug in Japan is S-1, which is easily used for outpatient with a high efficacy rate and low toxicity, also shows better effect in combination with other anticancer drugs than S-1 alone. In the present article, we demonstrated significant meaning of additional radiation therapy with anticancer drugs like S-1. With novel anticancer drugs like S-1, we will expose a clinical advantage and appropriateness for chemo-radiation therapy against gastric cancer discussed in the present references according to chemo-radiation therapy. Although chemo-radiation therapy has been recognized as one of the standard therapies for gastric cancer in Western countries, radiation therapy was selected in Japan for palliation therapy of recurrent disease or a terminal cancer to improve patients' QOL. On the other hand, we demonstrated in our trial of chemo-radiation therapy with S-1/low-dose CDDP/radiation (TSLDR), which was applied to initial treatment against highly advanced Stage IV gastric cancer and revealed the usefulness of the regimen in anticancer effect and toxicity. In addition, chemo-radiation therapy including novel anticancer agents like S-1 will be discussed based on various kinds of view points, expecting a better clinical outcome of multimodal therapies against advanced gastric cancer.


Dynamic modulation of visual and electrosensory gains for locomotor control.
Animal nervous systems resolve sensory conflict for the control of movement. For example, the glass knifefish, Eigenmannia virescens, relies on visual and electrosensory feedback as it swims to maintain position within a moving refuge. To study how signals from these two parallel sensory streams are used in refuge tracking, we constructed a novel augmented reality apparatus that enables the independent manipulation of visual and electrosensory cues to freely swimming fish (n = 5). We evaluated the linearity of multisensory integration, the change to the relative perceptual weights given to vision and electrosense in relation to sensory salience, and the effect of the magnitude of sensory conflict on sensorimotor gain. First, we found that tracking behaviour obeys superposition of the sensory inputs, suggesting linear sensorimotor integration. In addition, fish rely more on vision when electrosensory salience is reduced, suggesting that fish dynamically alter sensorimotor gains in a manner consistent with Bayesian integration. However, the magnitude of sensory conflict did not significantly affect sensorimotor gain. These studies lay the theoretical and experimental groundwork for future work investigating multisensory control of locomotion.


The Effect of Nucleic Acid Extraction Platforms and Sample Storage on the Integrity of Viral RNA for Use in Whole Genome Sequencing.
Extraction of viral RNA and the storage of sample material are extremely important factors in the detection and whole genome sequencing (WGS) of viral pathogens. Although PCR-based detection methods focus on small amplicons, viral WGS applications require RNA of high quality and integrity for adequate sequence coverage and depth. This study examined the fitness of one manual and four automated RNA extraction platforms commonly used in diagnostic laboratories for use in metagenomic sequencing, how the practice of storing sample material in Qiagen buffer AVL before extraction affected the integrity of viral RNA and its suitability for use in amplicon-based WGS methods, and how the addition of Triton X-100 to buffer AVL affected the capability of the extraction platforms and the integrity of viral RNA in stored samples. This study found that the EZ1 platform gave the best performance of the automated platforms and gave comparable results to the frequently used manual Qiagen extraction protocol when extracted viral RNA was used in metagenomics sequencing. To maintain high levels of viral RNA integrity suitable for amplicon-based WGS, nucleic acid should be extracted from samples immediately, because even short storage periods in buffer AVL have a severe effect on integrity, and the addition of Triton X-100 had little effect on the quality of viral material for WGS.


Genomic expression programs in the response of yeast cells to environmental changes.
We explored genomic expression patterns in the yeast Saccharomyces cerevisiae responding to diverse environmental transitions. DNA microarrays were used to measure changes in transcript levels over time for almost every yeast gene, as cells responded to temperature shocks, hydrogen peroxide, the superoxide-generating drug menadione, the sulfhydryl-oxidizing agent diamide, the disulfide-reducing agent dithiothreitol, hyper- and hypo-osmotic shock, amino acid starvation, nitrogen source depletion, and progression into stationary phase. A large set of genes (approximately 900) showed a similar drastic response to almost all of these environmental changes. Additional features of the genomic responses were specialized for specific conditions. Promoter analysis and subsequent characterization of the responses of mutant strains implicated the transcription factors Yap1p, as well as Msn2p and Msn4p, in mediating specific features of the transcriptional response, while the identification of novel sequence elements provided clues to novel regulators. Physiological themes in the genomic responses to specific environmental stresses provided insights into the effects of those stresses on the cell.


Dysregulated relationship of inflammation and oxidative stress in major depression.
Chronic inflammation and oxidative stress have been implicated in the pathophysiology of Major Depressive Disorder (MDD), as well as in a number of chronic medical conditions. The aim of this study was to examine the relationship between peripheral inflammatory and oxidative stress markers in un-medicated subjects with MDD compared to non-depressed healthy controls and compared to subjects with MDD after antidepressant treatment. We examined the relationships between IL-6, IL-10, and the IL-6/IL-10 inflammatory ratio vs. F2-isoprostanes (F2-IsoP), a marker of oxidative stress, in un-medicated MDD patients (n=20) before and after 8 weeks of open-label sertraline treatment (n=17), compared to healthy non-depressed controls (n=20). Among the un-medicated MDD subjects, F2-IsoP concentrations were positively correlated with IL-6 concentrations (p<0.05) and were negatively correlated with IL-10 concentrations (p<0.01). Accordingly, F2-IsoP concentrations were positively correlated with the ratio of IL-6/IL-10 (p<0.01). In contrast, in the control group, there were no significant correlations between F2-IsoPs and either cytokine or their ratio. After MDD subjects were treated with sertraline for 8 weeks, F2-IsoPs were no longer significantly correlated with IL-6, IL-10 or the IL-6/IL-10 ratio. These data suggest oxidative stress and inflammatory processes are positively associated in untreated MDD. Our findings are consistent with the hypothesis that the homeostatic buffering mechanisms regulating oxidation and inflammation in healthy individuals become dysregulated in untreated MDD, and may be improved with antidepressant treatment. These findings may help explain the increased risk of comorbid medical illnesses in MDD.


Food analysis on microfluidic devices using ultrasensitive carbon nanotubes detectors.
Microfluidic devices using carbon nanotube (CNT) materials (single-walled and two multiwalled (MWCNT)) for the analysis of selected analyte groups of significance in foods such as dietary antioxidants, water-soluble vitamins, vanilla flavors, and isoflavones involved in representative food samples have been explored for the first time. Ultrafast separations resulted in well-defined and resolved peaks with enhanced voltammetric current in comparison with those obtained from unmodified screen-printed electrodes, turning MWCNT into an ideal material for electrochemical sensing in food analysis. Resolution was improved by a factor of 2, and sensitivity was dramatically enhanced with amplification factors toward calibration slopes from 4- to 16-fold. In both qualitative and quantitative domains, this impressive performance of CNTs integrated on microfluidics allowed solving specific challenges in food environments such as the direct detection of analytes in complex natural samples and unambiguous analytes in the control of fraud, which was not possible on nonmodified surfaces, avoiding the integration of complex preconcentration steps on these microdevices. The use of these unique materials in microfluidics for food analysis has opened new expectations in "lab-on-a-chip" domains.


Identification of pro-inflammatory cytokines associated with muscle invasive bladder cancer; the roles of IL-5, IL-20, and IL-28A.
We used gene expression profiling to identify inflammatory cytokines that correlate with bladder cancer development. Gene expression profiles of the tissue samples were investigated using cDNA microarrays that contained 103 non-muscle invasive bladder cancers (NMIBC), 62 muscle invasive bladder cancers (MIBC), 58 samples of histologically normal-looking surrounding tissues, and 10 normal, healthy subjects who served as the control cohort for comparison. We grouped the data-sets according to biological characterizations and focused on immune response genes with at least 2-fold differential expression in MIBC vs. controls. The experimental data-set identified 36 immune-related genes that were significantly altered in MIBC samples. In addition, 10 genes were up-regulated and 26 genes were down-regulated in MIBC samples compared with the normal tissues. Among the 10 up-regulated molecules examined, the capacity for both wound-healing migration and invasion was enhanced in response to IL-5, IL-20, and IL-28A in bladder cancer cell lines (253J and EJ cells), compared with untreated cells. The expression levels of IL-5, IL-20, and IL-28A were increased in patients with MIBC. All 3 cytokines and their receptors were produced in bladder cancer cell lines, as determined by real-time PCR, immunoblot analysis and confocal immunofluorescence. Up-regulation of MMP-2 and MMP-9 was found after IL-5, IL-20, and IL-28A stimulation in both cell types. Moreover, an EMSA assay showed that treatment with IL-5, IL-20, and IL-28A induced activation of the transcription factors NF-κB and AP-1 that regulate the MMP-9 promoter. Finally, activation of MAPK and Jak-Stat signaling was observed after the addition of IL-5, IL-20, and IL-28A to bladder cancer cells. This study suggests the presence of specific inflammatory cytokine (IL-5, IL-20, and IL-28A)-mediated association in bladder cancer development. All 3 cytokines may be important new molecular targets for the modulation of migration and invasion in bladder cancer.


Innovative technologies and social inequalities in health: A scoping review of the literature.
The aim of this study was to systematically review the range, nature, and extent of current research activity exploring the influence of innovative health-related technologies on social inequalities in health, with specific focus on a deeper understanding of the variables used to measure this connection and the pathways leading to the (re)production of inequalities. A review process was conducted, based on scoping review techniques, searching literature published from January 1, 1996 to November 25, 2016 using MEDLINE, Scopus, and ISI web of science. Search, sorting, and data extraction processes were conducted by a team of researchers and experts using a dynamic, reflexive examination process. Of 4139 studies collected from the search process, a total of 33 were included in the final analysis. Results of this study include the classification of technologies based on how these technologies are accessed and used by end users. In addition to the factors and mechanisms that influence unequal access to technologies, the results of this study highlight the importance of variations in use that importantly shape social inequalities in health. Additionally, focus on health care services technologies must be accompanied by investigating emerging technologies influencing healthy lifestyle, genomics, and personalized devices in health. Findings also suggest that choosing one measure of social position over another has important implications for the interpretation of research results. Furthermore, understanding the pathways through which various innovative health technologies reduce or (re)produce social inequalities in health is context dependent. In order to better understand social inequalities in health, these contextual variations draw attention to the need for critical distinctions between technologies based on how these various technologies are accessed and used. The results of this study provide a comprehensive starting point for future research to further investigate how innovative technologies may influence the unequal distribution of health as a human right.


Lack of correlation between residual radiation-induced DNA damage, in keratinocytes assayed directly from skin, and late radiotherapy reactions in breast cancer patients.
To study the relationship between the severity of late reactions to radiotherapy in breast cancer patients, and the extent of residual radiation-induced DNA damage, using a rapid assay of keratinocytes obtained directly from skin biopsies. A review was made of 32 patients with breast cancer, treated uniformly by radiotherapy between 1983 and 1988, following breast-conserving surgery. Their late radiotherapy reactions were scored (9-14 years post-radiotherapy) using a modified LENT SOMA scale, and a 5-mm buttock skin punch biopsy was obtained. Intact skin was irradiated at room temperature, and after allowing 24 h for repair, the tissue was disaggregated and the cells processed for pulsed field gel electrophoresis (PFGE). Residual DNA damage was expressed as the fraction of DNA released (FDR) following 150 Gy. Studies using flow cytometry on disaggregated breast skin showed that over 90% of the cells were keratinocytes. The PFGE assay was robust with low background FDRs in unirradiated skin samples (mean 3.2%) and a wide range of FDRs following irradiation from 11.5% to 26.6%. No correlation was found between the FDR at 150 Gy (FDR 150) and any of the late reaction scores or retrospective acute reaction scores. There was, however, a borderline significant correlation for family history and FDR 150 (p = 0.059). Rapid measurement of residual DNA damage in irradiated differentiated keratinocytes, the predominant cell population in skin biopsies, showed no correlation with the severity of symptomatic early or documented late reactions in a retrospectively studied group of 32 breast cancer patients.


Urine uric acid and urine creatine ratio in acute renal failure.
The urine uric acid (UUA) and urine creatinine (UC) concentration ratio was studied in 23 patients with acute renal failure. The ratio was higher than 1 in 12 patients and lower than 1 in 11. The clinical characteristics of the first group of patients included the association of infectious disease with high fever, hyperbilirubinemia, nonoliguric renal failure, less reduction of creatinine clearance, and higher urinary excretion of uric acid when compared with the second group. Jaundice and perhaps overproduction of uric acid due to hypercatabolism are believed to be responsible for the high uric acid excretion and the high UUA-UC ratio.


INFLUENCE OF LIMB DOMINANCE AND SHOULDER INJURY ON STRENGTH AND EXPLOSIVE FORCE IN US MARINES.
The specialized roles of many military personnel require specific skills and high physical demands, placing unique stresses on the shoulders and increasing risk of injury. As normal dominant/nondominant shoulder asymmetries have been established in military personnel, bilateral strength comparisons must be understood in context of daily physical demands to monitor patients' progress or readiness to return to duty. This study aims to assess bilateral differences in strength and explosive force in United States Marines with a history of dominant or nondominant shoulder pathology. Cross-Sectional. A total of 52 full-duty, male US Marines with a shoulder injury within the prior year participated. Bilateral isokinetic shoulder internal (IR) and external (ER) rotation strength, and peak force (Peak Force) and average rate of force production (Avg Rate) during an explosive push-up were collected. Dominant versus nondominant side data were independently examined within each group (DOM: dominant injury, NOND: nondominant injury). Comparison between DOM and NOND, as well as previously published CON (no history of shoulder injury) was also completed. NOND (n = 26) demonstrated significantly less IR (p < 0.001) and ER (p = 0.003) strength and Peak Force (p = 0.001) and Avg Rate (p = 0.047) on the injured side, while DOM (n = 26) demonstrated no bilateral differences in strength or push-up performance. Comparison between the three groups showed that NOND demonstrated significantly less ER strength than CON (p = 0.022). Military personnel demonstrate asymmetric strength patterns likely due to increased demand of the dominant shoulder. US Marines with a history of injury to the nondominant shoulder performed differently than those with a dominant side injury, presenting with both strength and push-up asymmetries. They also demonstrated significant ER strength deficits compared to CON. Common clinical practice and previous literature often compare injured and uninjured limbs or injured individuals to healthy controls, but further distinction of dominant or nondominant side may provide more accurate information needed to develop targeted treatment strategies. Recognizing unique occupational demands and how patients may present differently with dominant versus nondominant side shoulder injuries are important considerations for ensuring accurate assessment and effective individualized rehabilitation. 3.


Molecular manipulation of microstructures: biomaterials, ceramics, and semiconductors.
Organic molecules can alter inorganic microstructures, offering a very powerful tool for the design of novel materials. In biological systems, this tool is often used to create microstructures in which the organic manipulators are a minority component. Three groups of materials-biomaterials, ceramics, and semiconductors-have been selected to illustrate this concept as used by nature and by synthetic laboratories exploring its potential in materials technology. In some of nature's biomaterials, macromolecules such as proteins, glycoproteins, and polysaccharides are used to control nucleation and growth of mineral phases and thus manipulate microstructure and physical properties. This concept has been used synthetically to generate apatite-based materials that can function as artificial bone in humans. Synthetic polymers and surfactants can also drastically change the morphology of ceramic particles, impart new functional properties, and provide new processing methods for the formation of useful objects. Interesting opportunities also exist in creating semiconducting materials in which molecular manipulators connect quantum dots or template cavities, which change their electronic properties and functionality.


Effectiveness of peers in delivering programs or motivating older people to increase their participation in physical activity: Systematic review and meta-analysis.
The objective of this systematic review and meta-analysis was to evaluate the effectiveness of peers to deliver programs or encourage older people to be physically active and improve physical outcomes. Peer reviewed articles published in English between January 1976 and June 2016, retrieved from six databases according to the predefined inclusion criteria were included. Where possible results were pooled and meta-analyses conducted. Eighteen articles were included in the review, a total of 3,492 intervention participants, average age 66.5 years and 67.1% were female. Overall, study quality was medium to high. Interventions mainly included resistance, flexibility and cardiovascular training, however there was one aquatic exercise group. Eight studies were delivered by peers and five utilised peer support, which included advice and being positive but was not directly linked to an exercise intervention. While 16 of the 18 studies reported improvement in levels of physical activity and/or noted physical benefits by peer involvement, the meta-analyses findings supported the control groups for the six-minute-walk-test and the timed-up-and-go test. Findings from this review suggest exercise programs involving peers can promote and maintain adherence to exercise programs. However, results were inconclusive as to whether peers have a positive effect on improving older people's physical function.


Crystal and solution structures of the helicase-binding domain of Escherichia coli primase.
During bacterial DNA replication, the DnaG primase interacts with the hexameric DnaB helicase to synthesize RNA primers for extension by DNA polymerase. In Escherichia coli, this occurs by transient interaction of primase with the helicase. Here we demonstrate directly by surface plasmon resonance that the C-terminal domain of primase is responsible for interaction with DnaB6. Determination of the 2.8-angstroms crystal structure of the C-terminal domain of primase revealed an asymmetric dimer. The monomers have an N-terminal helix bundle similar to the N-terminal domain of DnaB, followed by a long helix that connects to a C-terminal helix hairpin. The connecting helix is interrupted differently in the two monomers. Solution studies using NMR showed that an equilibrium exists between a monomeric species with an intact, extended but naked, connecting helix and a dimer in which this helix is interrupted in the same way as in one of the crystal conformers. The other conformer is not significantly populated in solution, and its presence in the crystal is due largely to crystal packing forces. It is proposed that the connecting helix contributes necessary structural flexibility in the primase-helicase complex at replication forks.