Sardinian Folk Dance for Individuals with Parkinson's Disease: A Randomized Controlled Pilot Trial.
Among different exercise models proposed for individuals with Parkinson's disease (IwPD), the popularity of traditional forms of dance is increasing. The aim of this study was to evaluate the effects of Sardinian folk dance (Ballu Sardu, BS) on functional performance and motor and nonmotor symptoms in IwPD. Single-blind, randomized controlled pilot trial. Outpatient health clinic. Twenty IwPD (13M, 7F; 67.4 ± 6.1 years) were randomly assigned to BS (n = 10) or usual care (n = 10). The dance program consisted of two sessions/week, 90-min/class, for 12 weeks. Motor and nonmotor symptoms, as well as functional performance, were evaluated using different questionnaires and tests such as the Unified Parkinson's Disease Rating Scale Part-III (UPDRS-III), 6-min walking test (6MWT), Berg Balance Scale (BBS), Timed Up-and-Go (TUG) test, Five Times Sit-to-Stand Test (FTSST), Back Scratch Test (BST), Sit-and-Reach Test (SRT), instrumented gait analysis, Parkinson's Disease Fatigue Scale (PFS-16), Beck Depression Inventory, Starkstein Apathy Scale (SAS), and Montreal Cognitive Assessment (MOCA) scale. Repeated-measures analysis of variance revealed significant Time × Group interactions for UPDRS-III and functional variables such as the 6MWT, BBS, FTSST, TUG (all, p < 0.001), BST (p = 0.04), and gait analysis parameters (stride length, p = 0.031; gait speed, p = 0.049; and gait fatigue index (GFI), p = 0.005). For nonmotor symptoms, significant Time × Group interactions for depression (p < 0.001), apathy (p = 0.016), and MOCA scores (p = 0.012) were observed. Of note, for GFI and SAS, the BS group only showed a trend toward improvement, while the condition of the controls worsened significantly. No between-group differences were observed for SRT and PFS-16. BS is an enjoyable activity, which has been proved to be superior to usual care alone in inducing changes in different motor and nonmotor symptoms associated with PD. Results show that BS can be considered a safe tool for contrasting impairments observed in IwPD due to the intrinsic nature of the neurodegenerative disease.


Antioxidant and antiinflammatory activities of anthocyanins and their aglycon, cyanidin, from tart cherries.
The anthocyanins (1-3) and cyanidin isolated from tart cherries exhibited in vitro antioxidant and antiinflammatory activities comparable to commercial products. The inhibition of lipid peroxidation of anthocyanins 1-3 and their aglycon, cyanidin, were 39, 70, 75, and 57%, respectively, at 2-mM concentrations. The antioxidant activities of 1-3 and cyanidin were comparable to the antioxidant activities of tert-butylhydroquinone and butylated hydroxytoluene and superior to vitamin E at 2-mM concentrations. In the antiinflammatory assay, cyanidin gave IC50 values of 90 and 60 mM, respectively, for prostaglandin H endoperoxide synthase-1 and prostaglandin H endoperoxide synthase-2 enzymes.


Relations Between Resilience, Positive and Negative Emotionality, and Symptoms of Anxiety and Depression.
Although research concerning the effects of traumatic and stressful life events on an individual's mental health has been plentiful in the past several decades, research aimed at understanding the nature of resilience and its role in this process has been less plentiful. The present study examined the relationship between a commonly used measure of resilience, the Connor-Davidson Resilience Scale (CD-RISC), facets of personality, and symptoms of psychopathology-specifically, posttraumatic symptomatology-in a sample of college students. We found that the CD-RISC was most strongly linked with the personality facet of positive emotionality rather than the expected facet of negative emotionality. With regard to psychopathology, the CD-RISC displayed the largest relationship to a measure of anhedonic depression rather than a measure of posttraumatic stress. Lastly, the CD-RISC added little in predicting symptoms of posttraumatic stress above and beyond negative emotionality, a personality facet that has previously shown robust relationships with posttraumatic stress. These results suggest that the CD-RISC is most strongly predictive of positive emotionality and thus may be most useful in predicting resilience for disorders characterized by disruptions in positive affect.


Cationic and anionic redox in lithium-ion based batteries.
Lithium-ion batteries have proven themselves to be indispensable among modern day society. Demands stemming from consumer electronics and renewable energy systems have pushed researchers to strive for new electrochemical technologies. To this end, the advent of anionic redox, that is, the sequential or simultaneous redox of the cation and anion in a transition metal oxide based cathode for a Li-ion battery, has garnered much attention due to the enhanced specific capacities. Unfortunately, the higher energy densities are plagued with problems associated with the irreversibility of anionic redox. Much effort has been placed on finding a suitable composition of transition metal oxide, with some groups identifying the underlying features and relationship for anion redox and cationic redox to occur reversibly. Accordingly, it is timely to review anionic redox in terms of what anionic redox is with emphasis on the mechanism and the evidence underlying its discovery and validation. To follow will be a section defining the nature of the transition metal and oxygen bond accompanied by three subsequent sections bridging the redox spectrum from pure anionic, to a mix of cationic and anionic and pure cationic.


NIR Electrofluorochromic Properties of Aza-Boron-dipyrromethene Dyes.
The photophysical properties of near-infrared (NIR) emissive aza-boron-dipyrromethene (aza-BDP) dyes incorporating nitrofluorene and alkoxy decorations were intensively investigated. Their highly reversible one-electron reduction process showed characteristic electrofluorochromic (EF) properties in the NIR range, depending on the substituents. The nitrofluorene ethynyl-substituted (Type I) dyes showed smaller EF effects than the alkoxy-containing (Type II) dyes because of the difference in their intrinsic fluorescence contrast between the neutral and reduced states (radical anion). In addition, the Type II chromophores showed a larger diffusion coefficient for ion transport, which enhanced the EF contrast and the response time for the fluorescence change at a given step potential. With an optimized condition, the NIR EF ON/OFF ratio reached a value of 6.1 and a long cyclability over 1000 EF cycles between -0.4 V and +0.4 V switching potentials, with approximately 20% loss of the initial ON/OFF switching ratio. The NIR EF switching was visually observed through a visible light cut-off filter, featuring high fluorescence contrast.


Dynamic generation of plasmonic bottle-beams with controlled shape.
We demonstrate the generation of plasmonic bottle-beams based on self-accelerating surface plasmons. These beams are excited from free-space beams through a special binary phase mask. The mask generates two mirror-imaged self-accelerating surface plasmons, which form the plasmonic bottle-beam and a hot-spot at the point of convergence. The shape and area of the bottle-beams, together with the location of the hot-spot, are statically controlled by designing arbitrary convex trajectories for the two counter-accelerating beams and also are dynamically controlled by the illumination beam.


Fine structural characterisation of a Rickettsia-like organism in human platelets from patients with symptoms of ehrlichiosis.
Since 1982, Ehrlichia platys infection has been diagnosed in canines from Venezuela by the use of buffy coat smears. In 1992, ehrlichia-like bodies were observed in platelets from a severely ill girl by light microscopy. The patient was seropositive to E. chaffeensis by the indirect fluorescent antibody test (IFAT). Tetracycline was administered and the patient recovered. More than 400 cases with such intra-platelet organisms have been studied at this laboratory over the past 6 years, and all the patients had a good response to the treatment. To determine whether the organisms in human blood platelets were truly platelet ehrlichiae, IFAT and transmission electron microscopy (TEM) studies were undertaken in four patients. Light microscopic examination of blood samples revealed the dense organism inside platelets, and a great reactivity of the blood cells. Sera from the four patients were seronegative against E. chaffeensis and E. platys antigens. Three of four samples contained the intra-platelet organisms when examined by TEM. Electron microscopy showed platelets with vacuoles containing pleomorphic organisms. These organisms had a thickened membrane, an electron-translucent inner area and an electron-dense granular component in the periphery. An abundant electron-dense material was observed surrounding them. The ultrastructure of such micro-organisms has not been reported previously, Based on the similarity of many of their characteristics with rickettsiae, we suggest that the microorganisms found in the present study might belong to the family Rickettsiaceae.


Topical NSAIDs for chronic musculoskeletal pain in adults.
Use of topical nonsteroidal anti-inflammatory drugs (NSAIDs) to treat chronic musculoskeletal conditions has become widely accepted because they can provide pain relief without associated systemic adverse events. This review is an update of 'Topical NSAIDs for chronic musculoskeletal pain in adults', originally published in Issue 9, 2012. To review the evidence from randomised, double-blind, controlled trials on the efficacy and safety of topically applied NSAIDs for chronic musculoskeletal pain in adults. We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, and our own in-house database; the date of the last search was February 2016. We also searched the references lists of included studies and reviews, and sought unpublished studies by asking personal contacts and searching online clinical trial registers and manufacturers' web sites. We included randomised, double-blind, active or inert carrier (placebo) controlled trials in which treatments were administered to adults with chronic musculoskeletal pain of moderate or severe intensity. Studies had to meet stringent quality criteria and there had to be at least 10 participants in each treatment arm, with application of treatment at least once daily. Two review authors independently assessed studies for inclusion and extracted data. We used numbers of participants achieving each outcome to calculate risk ratio and numbers needed to treat (NNT) or harm (NNH) compared to carrier or other active treatment. We were particularly interested to compare different formulations (gel, cream, plaster) of individual NSAIDs. The primary outcome was 'clinical success', defined as at least a 50% reduction in pain, or an equivalent measure such as a 'very good' or 'excellent' global assessment of treatment, or 'none' or 'slight' pain on rest or movement, measured on a categorical scale. We identified five new studies for this update, which now has information from 10,631 participants in 39 studies, a 38% increase in participants from the earlier review; 33 studies compared a topical NSAID with carrier. All studies examined topical NSAIDs for treatment of osteoarthritis, and for pooled analyses studies were generally of moderate or high methodological quality, although we considered some at risk of bias from short duration and small size.In studies lasting 6 to 12 weeks, topical diclofenac and topical ketoprofen were significantly more effective than carrier for reducing pain; about 60% of participants had much reduced pain. With topical diclofenac, the NNT for clinical success in six trials (2343 participants) was 9.8 (95% confidence interval (CI) 7.1 to 16) (moderate quality evidence). With topical ketoprofen, the NNT for clinical success in four trials (2573 participants) was 6.9 (5.4 to 9.3) (moderate quality evidence). There was too little information for analysis of other individual topical NSAIDs compared with carrier. Few trials compared a topical NSAID to an oral NSAID, but overall they showed similar efficacy (low quality evidence). These efficacy results were almost completely derived from people with knee osteoarthritis.There was an increase in local adverse events (mostly mild skin reactions) with topical diclofenac compared with carrier or oral NSAIDs, but no increase with topical ketoprofen (moderate quality evidence). Reporting of systemic adverse events (such as gastrointestinal upsets) was poor, but where reported there was no difference between topical NSAID and carrier (very low quality evidence). Serious adverse events were infrequent and not different between topical NSAID and carrier (very low quality evidence).Clinical success with carrier occurred commonly - in around half the participants in studies lasting 6 to 12 weeks. Both direct and indirect comparison of clinical success with oral placebo indicates that response rates with carrier (topical placebo) are about twice those seen with oral placebo.A substantial amount of data from completed, unpublished studies was unavailable (up to 6000 participants). To the best of our knowledge, much of this probably relates to formulations that have never been marketed. Topical diclofenac and topical ketoprofen can provide good levels of pain relief beyond carrier in osteoarthritis for a minority of people, but there is no evidence for other chronic painful conditions. There is emerging evidence that at least some of the substantial placebo effects seen in longer duration studies derive from effects imparted by the NSAID carrier itself, and that NSAIDs add to that.


Achilles' Heel-The Significance of Maintaining Microenvironmental Homeostasis in the Nucleus Pulposus for Intervertebral Discs.
The dysregulation of intracellular and extracellular environments as well as the aberrant expression of ion channels on the cell membrane are intricately linked to a diverse array of degenerative disorders, including intervertebral disc degeneration. This condition is a significant contributor to low back pain, which poses a substantial burden on both personal quality of life and societal economics. Changes in the number and function of ion channels can disrupt the water and ion balance both inside and outside cells, thereby impacting the physiological functions of tissues and organs. Therefore, maintaining ion homeostasis and stable expression of ion channels within the cellular microenvironment may prove beneficial in the treatment of disc degeneration. Aquaporin (AQP), calcium ion channels, and acid-sensitive ion channels (ASIC) play crucial roles in regulating water, calcium ions, and hydrogen ions levels. These channels have significant effects on physiological and pathological processes such as cellular aging, inflammatory response, stromal decomposition, endoplasmic reticulum stress, and accumulation of cell metabolites. Additionally, Piezo 1, transient receptor potential vanilloid type 4 (TRPV4), tension response enhancer binding protein (TonEBP), potassium ions, zinc ions, and tungsten all play a role in the process of intervertebral disc degeneration. This review endeavors to elucidate alterations in the microenvironment of the nucleus pulposus during intervertebral disc degeneration (IVDD), with a view to offer novel insights and approaches for exploring therapeutic interventions against disc degeneration.


Clonal origin of emerging populations of Ehrlichia ruminantium in Burkina Faso.
Cowdriosis or heartwater is a major tick-borne disease on ruminants in Africa and the Caribbean. The causative agent is Ehrlichia ruminantium, an intracellular bacterium. Development of vaccines against heartwater has been hampered the limited efficiency of vaccine in the field, thought to be a consequence of the high genetic diversity of strains circulating in a same area. A sampling scheme was set to collect ticks over 2 years in a delimited area and well identified flock. Prevalence was low at about 3%. A set of 37 strains was considered for MLST analysis along with two reference strains, i.e. ERGA and ERWO, for which full-length genome was available, using a previously described scheme based on the genes gltA, groEL, lepA, lipA, lipB, secY, sodB and sucA. Two populations were identified both with limited genetic variability but with differing evolutionary patterns. Population 1 is in genomic stasis, in agreement with the paradigm for intracellular bacteria. The two reference strains, one from the Caribbean separated from West African strains three centuries ago and another one isolated in South Africa, belong to Population 1. Population 2 is on expansion following a recent clonal emergence from Population 1. The founder strain was identified as strain 395. Strain 623 displays a particularly high rate of mutations in groEL. Owing to the chaperone function of GroEL, this might indicate another clonal emergence under way. This work brings further insight in the genomic plasticity of E. ruminantium and its impact on vaccine strategy.


Chikungunya on the move.
In December 2013, chikungunya virus (CHIKV) transmission was reported for the first time in the Americas. Since then it has spread quickly, with more than 1 million suspected and confirmed cases being reported in one year, where previously there were only sporadic travel-related cases. Transmission patterns suggest that the epidemic in the southern hemisphere is only beginning and that chikungunya will not go away anytime soon.


Crystal structure of an invertebrate caspase.
Caspases play an essential role in the execution of apoptosis. These cysteine proteases are highly conserved among metazoans and are translated as inactive zymogens, which are activated by proteolytic cleavages to generate the large and small subunits and remove the N-terminal prodomain. The 2.3 A resolution crystal structure of active Sf-caspase-1, the principal effector caspase of the insect Spodoptera frugiperda, is presented here. The structure represents the first nonhuman caspase to be resolved. The structure of the cleaved and active protease was determined with the tetrapeptide inhibitor N-acetyl-Asp-Glu-Val-Asp-chloromethylketone covalently bonded to the active site cysteine. As expected, the overall fold of Sf-caspase-1 is exceedingly similar to that of the five active caspases from humans solved to date. The overall structure and active site arrangement of Sf-caspase-1 is most comparable with that of the human effector caspases, with which it shares highest sequence homology. The most prominent structural difference with Sf-caspase-1 is the position of the N-terminal region of the large subunit. Unlike the N terminus of human caspases, the N terminus of Sf-caspase-1 originates from the active site side where it interacts with active site loop L2 and then extends to the backside of the heterodimer. This unusual structural arrangement raises the possibility that the N-terminal prodomain plays a regulatory role during effector caspase activation or enzyme activity in insects.


Interactions of CBL with BCR-ABL and CRKL in BCR-ABL-transformed myeloid cells.
The Philadelphia chromosome, detected in virtually all cases of chronic myelogenous leukemia (CML), is formed by a reciprocal translocation between chromosomes 9 and 22 that fuses BCR-encoded sequences upstream of exon 2 of c-ABL. The BCR-ABL fusion creates a gene whose protein product, p210BCR-ABL, has been implicated as the cause of the disease. Although ABL kinase activity has been shown to be required for the transforming abilities of BCR-ABL and numerous substrates of the BCR-ABL tyrosine kinase have been identified, the requirement of most of these substrates for the transforming function of BCR-ABL is unknown. In this study we mapped a direct binding site of the c-CBL proto-oncogene to the SH2 domain of BCR-ABL. This interaction only occurs under conditions where c-CBL is tyrosine-phosphorylated. Despite the direct interaction of c-CBL with the SH2 domain of BCR-ABL, deletion of the SH2 domain of BCR-ABL did not result in an alteration in the complex formation of BCR-ABL and c-CBL, suggesting that another site of direct interaction between c-CBL and BCR-ABL exists or that another protein mediates an indirect interaction of c-CBL and BCR-ABL. Since CRKL, an SH2, SH3 domain-containing adapter protein is known to bind directly to BCR-ABL and also binds to tyrosine-phosphorylated c-CBL, the ability of CRKL to mediate a complex between c-CBL and BCR-ABL was examined.


Responses to multiple-nutrient starvation in marine Vibrio sp. strain CCUG 15956.
The response of marine Vibrio sp. strain S14 (CCUG 15956) to long-term (48-h) multiple-nutrient starvation (i.e., starvation for glucose, amino acids, ammonium, and phosphate simultaneously) can be described as a three-phase process. The first phase, defined as the stringent control phase, encompasses an accumulation of guanosine 5'-diphosphate 3'-diphosphate (ppGpp) and decreases in RNA and protein synthesis during the first 40 min. In the second phase, there is a temporary increase in the rates of RNA and protein synthesis between 1 and 3 h paralleling a decrease in the ppGpp pool. The third phase includes gradual decline in macromolecular synthesis after 3 h. Using two-dimensional gel electrophoresis of pulse-labeled proteins, a total of 66 proteins were identified as starvation inducible (Sti), temporally expressed throughout the three phases of starvation. The inhibition of protein synthesis during the first phase of starvation partly disrupted the subsequent temporally ordered synthesis of starvation proteins and prevented the expression of some late starvation proteins. It was also found that the early temporal class of starvation proteins, which included the majority of the Sti proteins, was the most essential for long-term survival. Vibrio sp. strain S14 cultures prestarved (1 h) for glucose, amino acids, ammonium, or phosphate as well as cultures exposed (1 h) to CdCl2 exhibited enhanced survival during the subsequent multiple-nutrient starvation in the presence of chloramphenicol or rifampin, while heat or the addition of cyclic AMP or nalidixic acid prior to starvation had no effect. It was demonstrated that amino acid starvation and CdCl2 exposure, which induced the stringent response, were the most effective in conferring enhanced survival. A few Sti proteins were common to all starvation conditions. In addition, the total number of proteins induced by multiple-nutrient starvation significantly exceeded the sum of those induced by starvation for each of the individual nutrients.


RILP regulates vacuolar ATPase through interaction with the V1G1 subunit.
Rab-interacting lysosomal protein (RILP) is a downstream effector of the Rab7 GTPase. GTP-bound Rab7 recruits RILP to endosomal membranes and, together, they control late endocytic traffic, phagosome and autophagosome maturation and are responsible for signaling receptor degradation. We have identified, using different approaches, the V1G1 (officially known as ATP6V1G1) subunit of the vacuolar ATPase (V-ATPase) as a RILP-interacting protein. V1G1 is a component of the peripheral stalk and is fundamental for correct V-ATPase assembly. We show here that RILP regulates the recruitment of V1G1 to late endosomal and lysosomal membranes but also controls V1G1 stability. Indeed, we demonstrate that V1G1 can be ubiquitylated and that RILP is responsible for proteasomal degradation of V1G1. Furthermore, we demonstrate that alterations in V1G1 expression levels impair V-ATPase activity. Thus, our data demonstrate for the first time that RILP regulates the activity of the V-ATPase through its interaction with V1G1. Given the importance of V-ATPase in several cellular processes and human diseases, these data suggest that modulation of RILP activity could be used to control V-ATPase function.


Is tissue-type plasminogen activator a neuromodulator?
In the last few years, it has been evidenced that serine proteases play key roles in the mammalian brain, both in physiological and pathological conditions. It has been well established that among these serine proteases, the tissue-type plasminogen activator (t-PA) is critically involved in development, plasticity, and pathology of the nervous system. However, its mechanism of action remains to be further investigated. By using pharmacological and immunological approaches, we have evidenced in the present work that t-PA should be considered as a neuromodulator. Indeed, we have observed that: (i). neuronal depolarization induces a release of t-PA; (ii). this release of t-PA is sensitive to exocytosis inhibition and calcium chelation; (iii). released t-PA modulates NMDA receptor signaling and (iv). astrocytes are able to recapture extracellular t-PA through a low-density lipoprotein (LDL) receptor-related protein (LRP)-dependent mechanism.


Effect of cement incorporation on the leaching characteristics of elements from fly ash and slag treated soils.
Inclusion of cement in fly ash and slag mixed soils could potentially alter the leaching behavior of elements. This study investigated the leaching characteristics of calcium (Ca), magnesium (Mg), sulfur (S), manganese (Mn), barium (Ba) and chromium (Cr) from cement activated soil-fly ash, soil-slag mixtures and soil, fly ash, steel slag and cement alone. Batch water leach tests, acid neutralization capacity and pH-dependent leach tests were performed. Test results indicated that, effluent concentrations of Ca and Ba increased, while Mg concentrations decreased with cement additions. No consistent trend was observed between S concentrations and cement content. The leaching of Cr and Mn remained unaffected by cement incorporation. Results of this study showed that the solution pH had the greatest influence on the leaching behaviors of the elements. Ca, Mg, S and Mn followed cationic leaching patterns, whereas Ba showed both cationic and amphoteric leaching patterns. The highest concentrations of Cr were observed at extreme acidic conditions, followed by a concentration plateau at the pH range of 5.5-10, and subsequent decrease and increase in concentrations at pH of 11.5 and 13, respectively. Geochemical modeling results suggested that except for Cr, the leaching mechanisms of the elements were controlled by their sulfate and (hydr)oxide minerals. The leaching of Cr was possibly controlled by BaCrO4 and CaCrO4. It was observed that the presence of carbonate minerals did not play a significant role on the leaching mechanisms of the elements, when cement was used as an activator.


Mathematical modelling of cancer invasion: implications of cell adhesion variability for tumour infiltrative growth patterns.
Cancer invasion, recognised as one of the hallmarks of cancer, is a complex, multiscale phenomenon involving many inter-related genetic, biochemical, cellular and tissue processes at different spatial and temporal scales. Central to invasion is the ability of cancer cells to alter and degrade an extracellular matrix. Combined with abnormal excessive proliferation and migration which is enabled and enhanced by altered cell-cell and cell-matrix adhesion, the cancerous mass can invade the neighbouring tissue. Along with tumour-induced angiogenesis, invasion is a key component of metastatic spread, ultimately leading to the formation of secondary tumours in other parts of the host body. In this paper we explore the spatio-temporal dynamics of a model of cancer invasion, where cell-cell and cell-matrix adhesion is accounted for through non-local interaction terms in a system of partial integro-differential equations. The change of adhesion properties during cancer growth and development is investigated here through time-dependent adhesion characteristics within the cell population as well as those between the cells and the components of the extracellular matrix. Our computational simulation results demonstrate a range of heterogeneous dynamics which are qualitatively similar to the invasive growth patterns observed in a number of different types of cancer, such as tumour infiltrative growth patterns (INF).


Conducting Real-world Evidence Studies on the Clinical Outcomes of Diabetes Treatments.
Real-world evidence (RWE), the understanding of treatment effectiveness in clinical practice generated from longitudinal patient-level data from the routine operation of the healthcare system, is thought to complement evidence on the efficacy of medications from randomized controlled trials (RCTs). RWE studies follow a structured approach. (1) A design layer decides on the study design, which is driven by the study question and refined by a medically informed target population, patient-informed outcomes, and biologically informed effect windows. Imagining the randomized trial we would ideally perform before designing an RWE study in its likeness reduces bias; the new-user active comparator cohort design has proven useful in many RWE studies of diabetes treatments. (2) A measurement layer transforms the longitudinal patient-level data stream into variables that identify the study population, the pre-exposure patient characteristics, the treatment, and the treatment-emergent outcomes. Working with secondary data increases the measurement complexity compared to primary data collection that we find in most RCTs. (3) An analysis layer focuses on the causal treatment effect estimation. Propensity score analyses have gained in popularity to minimize confounding in healthcare database analyses. Well-understood investigator errors, like immortal time bias, adjustment for causal intermediates, or reverse causation, should be avoided. To increase reproducibility of RWE findings, studies require full implementation transparency. This article integrates state-of-the-art knowledge on how to conduct and review RWE studies on diabetes treatments to maximize study validity and ultimately increased confidence in RWE-based decision making.


An EM approach to MAP solution of segmenting tissue mixtures: a numerical analysis.
This work presents an iterative expectation-maximization (EM) approach to the maximum a posteriori (MAP) solution of segmenting tissue mixtures inside each image voxel. Each tissue type is assumed to follow a normal distribution across the field-of-view (FOV). Furthermore, all tissue types are assumed to be independent from each other. Under these assumptions, the summation of all tissue mixtures inside each voxel leads to the image density mean value at that voxel. The summation of all the tissue mixtures' unobservable random processes leads to the observed image density at that voxel, and the observed image density value also follows a normal distribution (image data are observed to follow a normal distribution in many applications). By modeling the underlying tissue distributions as a Markov random field across the FOV, the conditional expectation of the posteriori distribution of the tissue mixtures inside each voxel is determined, given the observed image data and the current-iteration estimation of the tissue mixtures. Estimation of the tissue mixtures at next iteration is computed by maximizing the conditional expectation. The iterative EM approach to a MAP solution is achieved by a finite number of iterations and reasonable initial estimate. This MAP-EM framework provides a theoretical solution to the partial volume effect, which has been a major cause of quantitative imprecision in medical image processing. Numerical analysis demonstrated its potential to estimate tissue mixtures accurately and efficiently.


Development and Utility of Tools to Identify Preventable Perinatal Deaths: Results from a Community-based Interventional Study in Two Districts of Karnataka State, India.
The presently used perinatal death certificate devised by the World Health Organization is incomplete and does not help in identifying "preventability." To develop tools that can help identify (1) preventable perinatal death and (2) preventable and/or avoidable cause for perinatal deaths. As a prerequisite for conduct of a community-based interventional study in two different districts of Karnataka state, two information tools, Perinatal death reporting form (PeNDReF) and perinatal death audit report (PeNDAR), were designed. The process involved series of preparatory and review meetings, before and after the field work to list facilities available, categorize facilities, identify causality, assess risk factors, and assert preventability of a perinatal death. The process was repeated over a period of 6 months and the information tools, PeNDReF and PeNDAR, were finalized. Doctors and paramedical personnel of both the districts were trained to fill the tools, which were analyzed to ascertain contributing risk factors and identify preventable perinatal death. The use of PeNDAR led to identification of 5.7% of perinatal deaths as "preventable" and 19% as "possibly preventable." The use of PeNDReF helped in the identification of risk factors (maternal anemia 49.6%, age of marriage <20 years 18.7%, and maternal weight <50 kg 9.1%), avoidable/preventable factors related to quality of care, transport, and referral. These tools are useful for identifying "preventable" perinatal deaths and avoidable/preventable factors.


Wavelength division multiplexed light source monolithically integrated on a silicon photonics platform.
We demonstrate monolithic integration of a wavelength division multiplexed light source for silicon photonics by a cascade of erbium-doped aluminum oxide (Al2O3:Er3+) distributed feedback (DFB) lasers. Four DFB lasers with uniformly spaced emission wavelengths are cascaded in a series to simultaneously operate with no additional tuning required. A total output power of -10.9 dBm is obtained from the four DFBs with an average side mode suppression ratio of 38.1±2.5 dB. We characterize the temperature-dependent wavelength shift of the cascaded DFBs and observe a uniform dλ/dT of 0.02 nm/°C across all four lasers.


Cervical degenerative disease: systematic review of economic analyses.
Systematic review. To perform an evidence-based synthesis of the literature assessing the cost-effectiveness of surgery for patients with symptomatic cervical degenerative disc disease (DDD). Cervical DDD is a common cause of clinical syndromes such as neck pain, cervical radiculopathy, and myelopathy. The appropriate surgical intervention(s) for a given problem is controversial, especially with regard to quality-of-life outcomes, complications, and costs. Although there have been many studies comparing outcomes and complications, relatively few have compared costs and, more importantly, cost-effectiveness of the interventions. We conducted a systematic search in PubMed/MEDLINE, EMBASE, the Cochrane Collaboration Library, the Cost-Effectiveness Analysis registry database, and the National Health Service Economic Evaluation Database for full economic evaluations published through January 16, 2014. Identification of full economic evaluations that were explicitly designed to evaluate and synthesize the costs and consequences of surgical procedures or surgical intervention with nonsurgical management in patients with cervical DDD were considered for inclusion, based on 4 key questions. Five studies were included, each specific to 1 or more of our focus questions. Two studies suggested that cervical disc replacement may be more cost-effective compared with anterior cervical discectomy and fusion. Two studies comparing anterior with posterior surgical procedures for cervical spondylotic myelopathy suggested that anterior surgery was more cost-effective than posterior surgery. One study suggested that posterior cervical foraminotomy had a greater net economic benefit than anterior cervical discectomy and fusion in a military population with unilateral cervical radiculopathy. No studies assessed the cost-effectiveness of surgical intervention compared with nonoperative treatment of cervical myelopathy or radiculopathy, although it is acknowledged that existing studies demonstrate the cost-effectiveness of surgical intervention for these 2 clinical entities. A paucity of high-quality economic literature exists regarding cost-effectiveness of surgical intervention for cervical DDD. Future research is necessary to validate the findings of the few studies that do exist to guide decisions for surgery by the physician and patient with respect to cost-effectiveness. 2.


Neuropsin promotes oligodendrocyte death, demyelination and axonal degeneration after spinal cord injury.
Previous studies indicated that the expression of neuropsin, a serine protease, is induced in mature oligodendrocytes after injury to the CNS. The pathophysiology of spinal cord injury (SCI) involves primary and secondary mechanisms, the latter contributing further to permanent losses of function. To explore the role of neuropsin after SCI, histochemical and behavioral analyses were performed in wild-type (WT) and neuropsin-deficient (neuropsin(-/-)) mice using a crush injury model, a well-characterized and consistently reproducible model of SCI. In situ hybridization revealed that neuropsin mRNA expression was induced in the spinal cord white matter from WT mice after crush SCI, peaking at day 4. Neuropsin(-/-) mice showed attenuated demyelination, oligodendrocyte death, and axonal damage after SCI. Although axonal degeneration in the corticospinal tract was obvious caudal to the lesion site in both strains of mice after SCI, the number of surviving nerve fibers caudal to the lesion was significantly larger in neuropsin(-/-) mice than WT mice. Behavioral analysis revealed that the recovery at days 10-42 was significantly improved in neuropsin(-/-) mice compared with WT mice in spite of the severe initial hindlimb impairments due to SCI in both strains. These observations suggest that neuropsin is involved in the secondary phase of the pathogenesis of SCI mediated by demyelination, oligodendrocyte death, and axonal degeneration.


Solid organ donation from the emergency department - missed donor opportunities.
A significant gap exists between people awaiting solid organ transplantation and solid organ donors. The purpose of this study was to determine whether there were missed donors in the emergency department (ED). We performed a health records and organ donation database review of all patients dying in a large tertiary ED from November 1, 2014 to October 31, 2017 at two campuses with 160,000 visits per year. Demographic and donor suitability data were collected. The primary outcome was missed potential solid organ donors. Missed potential donors were intubated, had a pulse, and had no donation contraindications. The secondary outcome was cases where no notification was made to the organ donation organization at all. There were 605 deaths in the ED. Patients had a mean age of 71.1 years, 58.3% were male, and 12.4% died of a traumatic cause. There were 10 missed potential donors. Missed potential donors had a mean age of 67.4 years, 70.0% were male, and 20.0% died from trauma. In all 10 cases, patients had withdrawal of life-sustaining therapy for medical futility, and referral for donation occurred after death. Missed ED donors could have increased hospital-wide donation up to 10.6%. No notification was made in 12 (2.0%) cases; however, none of these would have been successful solid organ donors. The ED is a source of missed organ donors. All potential donors were missed due to referral after withdrawal of life-sustaining therapy. ED physicians should consider the possibility of solid organ donation prior to the withdrawal of life-sustaining therapy.


When low-income mothers go to work: implications for children.
When mothers who have depended on welfare become employed, the change affects not only welfare budgets and the women themselves, but the daily lives of the children who make up two-thirds of the welfare population. This article is the first of a set of three that consider what we know--and do not know--about the likely effects that a mother's moving from welfare to work will have on her children. This article gives an overview of research studies conducted from the late 1960s to the present that consider how maternal employment affects children in low-income families. The efforts of these families to juggle working and child rearing have received far less attention than those of middle-class or professional families. Most studies that do focus on low-income groups indicate that children are seldom harmed when their mothers work, and many have improved outcomes, especially in terms of cognitive development. The authors caution, however, that all the working mothers studied thus far entered employment voluntarily, so their experiences may be more favorable than the experiences of families who may be forced off welfare and into jobs. Child outcome research that focuses directly on the families who will be affected by welfare reform is currently unavailable. The two subsequent articles (by Parcel and Menaghan and by Moore and Driscoll) continue with the themes raised in this overview and examine in depth specific questions policymakers should ask as they anticipate the effects that moving mothers into low-wage jobs may have on the development of children: How does a parent's going to work outside the home affect family life? And how do children who were once supported by public assistance fare after their mothers become employed?


Electrical storm: Incidence, Prognosis and Therapy.
Implantable defibrillators are lifesavers and have improved mortality rates in patients at risk of sudden death, both in primary and secondary prevention. However, they are unable to modify the myocardial substrate, which remains susceptible to life-threatening ventricular arrhythmias. Electrical storm is a clinical entity characterized the recurrence of hemodynamically unstable ventricular tachycardia and/or ventricular fibrillation, twice or more in 24 hours, requiring electrical cardioversion or defibrillation. With the arrival of the implantable cardioverter-defibrillator, this definition was broadened, and electrical storm is now defined as the occurrence of three or more distinct episodes of ventricular tachycardia or ventricular fibrillation in 24 hours, requiring the intervention of the defibrillator (anti-tachycardia pacing or shock). Clinical presentation can be very dramatic, with multiple defibrillator shocks and hemodynamic instability. Managing its acute presentation is a challenge, and mortality is high both in the acute phase and in the long term. In large clinical trials involving patients implanted with a defibrillator both for primary and secondary prevention, electrical storm appears to be a harbinger of cardiac death, with notably high mortality soon after the event. In most cases, the storm can be interrupted by medical therapy, though transcatheter radiofrequency ablation of ventricular arrhythmias may be an effective treatment for refractory cases.This narrative literature review outlines the main clinical characteristics of electrical storm and emphasises critical points in approaching and managing this peculiar clinical entity. Finally focus is given to studies that consider transcatheter ablation therapy in cases refractory to medical treatment.


Increasing metformin concentrations and its excretion in both rat and porcine ex vivo normothermic kidney perfusion model.
Metformin can accumulate and cause lactic acidosis in patients with renal insufficiency. Metformin is known to inhibit mitochondria, while renal secretion of the drug by proximal tubules indirectly requires energy. We investigated whether addition of metformin before or during ex vivo isolated normothermic machine perfusion (NMP) of porcine and rat kidneys affects its elimination. First, Lewis rats were pretreated with metformin or saline the day before nephrectomy. Subsequently, NMP of the kidney was performed for 90 min. Metformin was added to the perfusion fluid in one of three different concentrations (none, 30 mg/L or 300 mg/L). Second, metformin was added in increasing doses to the perfusion fluid during 4 hours of NMP of porcine kidneys. Metformin concentration was determined in the perfusion fluid and urine by liquid chromatography-tandem mass spectrometry. Metformin clearance was approximately 4-5 times higher than creatinine clearance in both models, underscoring secretion of the drug. Metformin clearance at the end of NMP in rat kidneys perfused with 30 mg/L was lower than in metformin pretreated rats without the addition of metformin during perfusion (both p≤0.05), but kidneys perfused with 300 mg/L trended toward lower metformin clearance (p=0.06). Creatinine clearance was not different between treatment groups. During NMP of porcine kidneys, metformin clearance peaked at 90 min of NMP (18.2±13.7 mL/min/100 g). Thereafter, metformin clearance declined, while creatinine clearance remained stable. This observation can be explained by saturation of metformin transporters with a Michaelis-Menten constant (95% CI) of 23.0 (10.0 to 52.3) mg/L. Metformin was secreted during NMP of both rat and porcine kidneys. Excretion of metformin decreased under increasing concentrations of metformin, which might be explained by saturation of metformin transporters rather than a self-inhibitory effect. It remains unknown whether a self-inhibitory effect contributes to metformin accumulation in humans with longer exposure times.


Predissociation dynamics of lithium iodide.
The predissociation dynamics of lithium iodide (LiI) in the first excited A-state is investigated for molecules in the gas phase and embedded in helium nanodroplets, using femtosecond pump-probe photoionization spectroscopy. In the gas phase, the transient Li(+) and LiI(+) ion signals feature damped oscillations due to the excitation and decay of a vibrational wave packet. Based on high-level ab initio calculations of the electronic structure of LiI and simulations of the wave packet dynamics, the exponential signal decay is found to result from predissociation predominantly at the lowest avoided X-A potential curve crossing, for which we infer a coupling constant VXA = 650(20) cm(-1). The lack of a pump-probe delay dependence for the case of LiI embedded in helium nanodroplets indicates fast droplet-induced relaxation of the vibrational excitation.


ANNIVERSARY REVIEW: Octreotide, 40 years later.
Octreotide remains 40 years after its development a drug, which is commonly used in the treatment of acromegaly and GEP-NETs. Very little innovation that competes with this drug occurred over this period. This review discusses several aspects of 40 years of clinical use of octreotide, including the application of radiolabeled forms of the peptide.


Oxytocin induces intracellular Ca2+ release in cardiac fibroblasts from neonatal rats.
Pituitary neuropeptide oxytocin is increasingly recognised as a cardiovascular hormone, in addition to its many regulatory roles in other organ systems. Studies in atrial and ventricular myocytes from the neonatal and adult rats have identified synthesis of oxytocin and the expression of oxytocin receptors in these cells. In cardiac fibroblasts, the most populous non-myocyte cell type in mammalian heart, the oxytocin receptors have not been described before. In the present study, we have investigated the direct effects of oxytocin on intracellular Ca2+ dynamics in ventricular myocytes and fibroblasts from new born rats. In myocytes, oxytocin increased the frequency of spontaneous Ca2+ transients and decreased their amplitude. Our data suggest that oxytocin receptors are also present and functional in the majority of cardiac fibroblasts. We used selective oxytocin receptor inhibitor L-371,257 and a number of intracellular Ca 2+ release blockers to investigate the mechanism of oxytocin induced Ca2+ signalling in cardiac fibroblasts. Our findings suggest that oxytocin induces Ca2+ signals in cardiac fibroblasts by triggering endoplasmic reticulum Ca2+ release via inositol trisphosphate activated receptors. The functional significance of the oxytocin induced Ca2+ signalling in cardiac fibroblasts, especially for their activation into secretory active myofibroblasts, remains to be investigated.


[Development of combat medical robots in the US Armed Forces].
The current article is dedicated to the problem of scientific research organization in the field of combat medical robots development in the US Armed Forces. The role of the Telemedicine and Advanced Technology Research Center is singled out. The project A Robotic System for Wounded Patient Extraction and Evacuation from Hostile Environments is described in more detail. It is noted the high cost of such technical systems development and operation.


Recognition of base pairs by polar peptides in double stranded DNA.
The resonance Raman spectrum of native DNA has been obtained using excitation at 257 nm. In a first part, the spectral lines are assigned to the different nucleotide bases which provide the resonance effect. In a second part, the interactions of DNA with basic peptides (Arginine Methylester, Lysine Methylester, Arginyl-Arginine) are investigated using excitation at 300 nm and 257 nm, which give complementary information about the DNA. Both Arginine Methylester and Arginyl-arginine recognize the A-T base pairs, the first one in the large groove, the second one in the narrow groove of DNA. The DNA-Lysine Methylester interaction is very likely not specific but can take place in the large groove of DNA.


Exploring graphene-based materials' genotoxicity: inputs of a screening method.
Graphene-based materials (GBMs) are promising nanomaterials, and several innovations depend on their use. However, the assessment of their potential hazard must be carefully explored before entering any market. GBMs are indeed well-known to induce various biological impacts, including oxidative stress, which can potentially lead to DNA damage. Genotoxicity is a major endpoint for hazard assessment and has been explored for GBMs, but the available literature shows conflicting results. In this study, we assessed the genotoxicity of 13 various GBMs, one carbon black and one amorphous silica through a DNA damage response assay (using a human respiratory cell model, BEAS-2B). Concurrently, oxidative stress was assessed through a ROS production quantification (DCFH-DA assay using a murine macrophage model, RAW 264.7). We also performed a full physicochemical characterization of our samples to explore potential structure-activity relationships involving genotoxicity. We observed that surface oxidation appears linked to genotoxicity response and were able to distinguish several groups within our studied GBMs showing different genotoxicity results. Our findings highlight the necessity to individually consider each nanoform of GBMs since the tested samples showed various results and modes of action. We propose this study as a genotoxicity assessment using a high-throughput screening method and suggest few hypotheses concerning the genotoxicity mode of action of GBMs.


Effects of two herbicidal wastewaters on Chlorella sp. and Phaeodactylum tricornutum.
The effects on Chlorella sp. and Phaeodactylum tricornutum of two industrial wastewaters known to contain the herbicide residues of Trifluralin and Propanil have been determined by monitoring the number of cells, the chlorophyll fluorescence and the carbon dioxide assimilation simultaneously for a period of 14 days. The growth of the diatom, Phaeodactylum tricornutum, was inhibited by concentrations of herbicidal waste of the order of 0.1-0.5%, apparently because the rate of reproduction was reduced. Chlorella sp. cells, on the other hand, whilst dramatically inhibited by 1% concentrations of herbicidal waste, were able to recover over a period of 14 days. If discharged at concentrations below 0.01%, the industrial wastes appeared not to affect phytoplankton.


Studies on an insulin-stimulated insulin receptor serine kinase activity: separation of the kinase activity from the insulin receptor and its reconstitution back to the insulin receptor.
In cells insulin stimulates autophosphorylation of the insulin receptor on tyrosine and its phosphorylation on serine and threonine by poorly characterized kinases. Recently we have achieved co-purification of the insulin receptor with insulin-stimulated insulin receptor serine kinase activity. We now show that the co-purified serine kinase activity can be removed by NaCl washing and reconstituted by adding back the NaCl eluate. Reconstitution enabled higher serine phosphorylation than achieved with the co-purified preparation. Myelin basic protein was discovered to be a potent substrate for insulin-stimulated serine phosphorylation by the co-purified preparation, with the activity responsible having similar properties to the serine kinase activity towards the receptor. Myelin basic protein was also phosphorylated on serine by the NaCl eluate. Myelin basic protein phosphorylated by the co-purified preparation or the NaCl eluate gave the same set of phosphoserine peptides. The major myelin basic protein serine kinase activity in the NaCl eluate co-purified exactly on Mono Q with the activity that restored insulin-stimulated insulin receptor serine phosphorylation. These results provide strong evidence for the true separation of the serine kinase from the insulin receptor and the distinctiveness of the serine kinase activity from the insulin receptor tyrosine kinase and mitogen-activated protein kinases. The procedures developed for the isolation of the serine kinase and the establishment of an effective in vitro substrate should allow purification of the kinase. The protocols also provide flexible systems for identifying the functions of the insulin-stimulated serine phosphorylations and the respective kinase(s).


Quantitative detection of Moraxella catarrhalis in nasopharyngeal secretions by real-time PCR.
The recognition of Moraxella catarrhalis as an important cause of respiratory tract infections has been protracted, mainly because it is a frequent commensal organism of the upper respiratory tract and the diagnostic sensitivity of blood or pleural fluid culture is low. Given that the amount of M. catarrhalis bacteria in the upper respiratory tract may change during infection, quantification of these bacteria in nasopharyngeal secretions (NPSs) by real-time PCR may offer a suitable diagnostic approach. Using primers and a fluorescent probe specific for the copB outer membrane protein gene, we detected DNA from serial dilutions of M. catarrhalis cells corresponding to 1 to 10(6) cells. Importantly, there was no difference in the amplification efficiency when the same DNA was mixed with DNA from NPSs devoid of M. catarrhalis. The specificity of the reaction was further confirmed by the lack of amplification of DNAs from other Moraxella species, nontypeable Haemophilus influenzae, H. influenzae type b, Streptococcus pneumoniae, Streptococcus oralis, Streptococcus pyogenes, Bordetella pertussis, Corynebacterium diphtheriae, and various Neisseria species. The assay applied to NPSs from 184 patients with respiratory tract infections performed with a sensitivity of 100% and a specificity of up to 98% compared to the culture results. The numbers of M. catarrhalis organisms detected by real-time PCR correlated with the numbers detected by semiquantitative culture. This real-time PCR assay targeting the copB outer membrane protein gene provided a sensitive and reliable means for the rapid detection and quantification of M. catarrhalis in NPSs; may serve as a tool to study changes in the amounts of M. catarrhalis during lower respiratory tract infections or following vaccination against S. pneumoniae, H. influenzae, or N. meningitidis; and may be applied to other clinical samples.


Dermatomyositis: diagnosis, evaluation and management.
Dermatomyositis (DM) is a condition primarily of the skin and muscles, but other systemic features may occur. DM in adults is associated with malignancy and thus a careful evaluation of each patient should be part of their initial and follow-up assessments. Patients should also be evaluated for the presence of esophageal, pulmonary and cardiac disease. Corticosteroids, immunosuppressives, biologic agents and/or immune globulin are effective therapies for the myopathy of DM, whereas the skin disease is best managed with sunprotection, topical corticosteroids, antimalarials, methotrexate and/or immune globulin. The prognosis is good except for patients with malignancy, those with severe weakness and those with cardiopulmonary dysfunction. However, many patients are left with residual weakness even after control of the disease.


Phonological Measures for Bilingual Spanish-English-Speaking Preschoolers: The Language Combination Effect.
Purpose The purpose of this study was to examine the diagnostic accuracy of traditional measures of phonological ability developed for monolingual English-speaking children with their bilingual peers in both English and Spanish. We predicted that a composite measure, derived from a combination of English and Spanish phonological measures, would result in higher diagnostic accuracy than examining the individual phonological measures of bilingual children separately by language. Method Sixty-six children, ages 3;3-6;3 (years;months), participated in this study: 29 typically developing bilingual Spanish-English-speaking children (x = 5;3), five bilingual Spanish-English-speaking children with speech sound disorders (x = 4;6), 26 typically developing monolingual English-speaking children (x = 4;8), and six monolingual English-speaking children with speech sound disorders (x = 4;9). Children were recorded producing single words using the Assessments of English and Spanish Phonology, and productions were phonetically transcribed and analyzed using the Logical International Phonetics Program. Overall consonants correct-revised; accuracy of early-, middle-, and late-developing sounds; and percent occurrence of phonological error patterns in both English and Spanish were calculated. Receiver operating characteristic curves and support vector machine models were applied to observe diagnostic accuracy, separately and combined, for each speaker group and each language. Results Findings indicated the combination of measures improved diagnostic accuracy within both the English and Spanish of bilingual children and significantly increased accuracy when measures from both languages of bilingual children were combined. Combining measures for the productions of monolingual English-speaking children did not increase diagnostic accuracy. Conclusion To prevent misdiagnosis of speech sound disorders in bilingual preschoolers, the composite phonological abilities of bilingual children need to be assessed across both gross and discrete measures of phonological ability. Supplemental Material https://doi.org/10.23641/asha.16632604.


Effectiveness and safety of in vitro maturation of oocytes versus in vitro fertilisation in women with high antral follicle count: study protocol for a randomised controlled trial.
In vitro maturation (IVM) is a potential alternative to conventional in vitro fertilisation (IVF) to avoid ovarian hyperstimulation syndrome (OHSS). This is particularly relevant in women with a high antral follicle count (AFC) and/or polycystic ovary syndrome (PCOS), who are at increased risk for OHSS. However, no randomised controlled trials of IVM versus IVF in women with high AFC have reported both pregnancy and OHSS rates. The aim of this study is to compare the effectiveness and safety of one IVM cycle and one IVF with segmentation cycle within women with PCOS or high AFC-related subfertility. This randomised controlled trial will be conducted at a specialist IVF centre in Vietnam. Eligible subfertile women with PCOS and/or high AFC will be randomised to undergo either IVM or IVF. The primary outcome is live birth after the first embryo transfer of the started treatment cycle. Cycles in which no embryo is available for transfer will be considered as failures. The study has a non-inferiority design, with a maximal acceptable between-group difference of 5%. Rates of OHSS will also be reported. Ethical approval was obtained from the participating centre, and informed patient consent was obtained before study enrolment. Results of the study will be submitted for publication in a peer-reviewed journal. NCT03405701; Pre-results.


Insulator-to-conducting transition in dense fluid helium.
By combining diamond-anvil-cell and laser-driven shock wave techniques, we produced dense He samples up to 1.5 g/cm(3) at temperatures reaching 60 kK. Optical measurements of reflectivity and temperature show that electronic conduction in He at these conditions is temperature-activated (semiconducting). A fit to the data suggests that the mobility gap closes with increasing density, and that hot dense He becomes metallic above approximately 1.9 g/cm(3). These data provide a benchmark to test models that describe He ionization at conditions found in astrophysical objects, such as cold white dwarf atmospheres.


Collaboration, user involvement and education: a systematic review of the literature and report of an educational initiative.
Collaboration is advocated widely through government policy as part of enormous change within the Health Service (Department of Health 1998, 2000b). Directives from policy regarding collaboration impact onto organizations, professions and individuals including users of the service. A literature review suggests that there would appear to be limited anecdotal, discursive or rigorous evidence available on collaboration at all levels including involving users. However, literature does demonstrate a mounting body of evidence that collaboration with users is being promoted as a way of working. This paper reviews the literature around collaboration and user involvement in the context of cancer care. Findings suggest that there is confusion of terminology around collaboration and user involvement. Benefits of and barriers to user involvement are identified and these are explored in the context of caring for the patient with cancer. An evaluation of a team-based educational initiative designed to help health-care professionals working within the cancer arena to explore ways to collaborate with users is presented. Findings suggest that education may be one way to develop collaboration between health-care professionals and service users.


Design, synthesis and evaluation of enzyme-responsive fluorogenic probes based on pyridine-flanked diketopyrrolopyrrole dyes.
The ever-growing demand for fluorogenic dyes usable in the rapid construction of analyte-responsive fluorescent probes, has recently contributed to a revival of interest in the chemistry of diketopyrrolopyrrole (DPP) pigments. In this context, we have explored the potential of symmetrical and unsymmetrical DPP derivatives bearing two or one 4-pyridyl substituents acting as optically tunable group(s). The unique fluorogenic behavior of these molecules, closely linked to N-substitution/charge state of their pyridine unit (i.e., neutral pyridine or cationic pyridinium), has been used to design DPP-based fluorescent probes for detection of hypoxia-related redox enzymes and penicillin G acylase (PGA). In this paper, we describe synthesis, spectral characterization and bioanalytical validations of these probes. Dramatic differences in terms of aqueous stability and enzymatic fluorescence activation were observed. This systematic study enables to delineate the scope of application of pyridine-flanked DPP fluorophores in the field of enzyme biosensing.


Mainly on the Plane: Deep Subsurface Bacterial Proteins Bind and Alter Clathrate Structure.
Gas clathrates are both a resource and a hindrance. They store massive quantities of natural gas but also can clog natural gas pipelines, with disastrous consequences. Eco-friendly technologies for controlling and modulating gas clathrate growth are needed. Type I Antifreeze Proteins (AFPs) from cold-water fish have been shown to bind to gas clathrates via repeating motifs of threonine and alanine. We tested whether proteins encoded in the genomes of bacteria native to natural gas clathrates bind to and alter clathrate morphology. We identified putative clathrate-binding proteins (CBPs) with multiple threonine/alanine motifs in a putative operon (cbp) in metagenomes from natural clathrate deposits. We recombinantly expressed and purified five CbpA proteins, four of which were stable, and experimentally confirmed that CbpAs bound to tetrahydrofuran (THF) clathrate, a low-pressure analogue for structure II gas clathrate. When grown in the presence of CbpAs, the THF clathrate was polycrystalline and platelike instead of forming single, octahedral crystals. Two CbpAs yielded branching clathrate crystals, similar to the effect of Type I AFP, while the other two produced hexagonal crystals parallel to the [1 1 1] plane, suggesting two distinct binding modes. Bacterial CBPs may find future utility in industry, such as maintaining a platelike structure during gas clathrate transportation.


Complete sequences of a novel blaNDM-1-harbouring plasmid from Providencia rettgeri and an FII-type plasmid from Klebsiella pneumoniae identified in Canada.
Emergence of plasmids harbouring bla(NDM-1) is a major public health concern due to their association with multidrug resistance and their potential mobility. PCR was used to detect bla(NDM-1) from clinical isolates of Providencia rettgeri (PR) and Klebsiella pneumoniae (KP). Antimicrobial susceptibilities were determined using Vitek 2. The complete DNA sequence of two bla(NDM-1) plasmids (pPrY2001 and pKp11-42) was obtained using a 454-Genome Sequencer FLX. Contig assembly and gap closures were confirmed by PCR-based sequencing. Comparative analysis was done using BLASTn and BLASTp algorithms. Both clinical isolates were resistant to all β-lactams, carbapenems, aminoglycosides, ciprofloxacin and trimethoprim/sulfamethoxazole, and susceptible to tigecycline. Plasmid pPrY2001 (113 295 bp) was isolated from PR. It did not show significant homology to any known plasmid backbone and contained a truncated repA and novel repB. Two bla(NDM-1)-harbouring plasmids from Acinetobacter lwoffii (JQ001791 and JQ060896) shared 100% similarity to a 15 kb region that contained bla(NDM-1). pPrY2001 also contained a type II toxin/antitoxin system. pKp11-42 (146 695 bp) was isolated from KP. It contained multiple repA genes. The plasmid backbone had the highest homology to the IncFIIk plasmid type (51% coverage, 100% nucleotide identity). The bla(NDM-1) region was unique in that it was flanked upstream by IS3000 and downstream by a novel transposon designated Tn6229. pKp11-42 also contained a number of mutagenesis and plasmid stability proteins. pPrY2001 differed from all known plasmids due to its novel backbone and repB. pKp11-42 was similar to IncFIIk plasmids and contained a number of genes that aid in plasmid persistence.


Chlamydia pneumoniae and the risk of first ischemic stroke : The Northern Manhattan Stroke Study.
Serological evidence of infection with Chlamydia pneumoniae has been associated with cardiovascular disease in multiple epidemiological studies. The data on its association with ischemic stroke are limited. We sought to determine whether chronic C pneumoniae infection is associated with ischemic stroke in a multi-ethnic population. The Northern Manhattan Stroke Study contains a population-based, case-control study component. Cases had first ischemic stroke and matched control subjects were derived through random digit dialing. Titers of IgG, IgA, and IgM antibodies specific for C pneumoniae were measured with the use of microimmunofluorescence, and titers >/=1:16 were considered positive. Conditional logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (95% CIs) after adjustment for medical, behavioral, and socioeconomic factors. Eighty-nine cases and 89 control subjects were selected. Mean age among cases was 68.5+/-12.8 years; 53% were women and 15% of the subjects were white, 28% were black, and 54% were Hispanic. Elevated C pneumoniae IgA titers were significantly associated with risk of ischemic stroke after adjusting for other stroke risk factors (adjusted OR 4. 51, 95% CI 1.44 to 14.06). IgG titers were less strongly associated with stroke risk (adjusted OR 2.59, 95% CI 0.87 to 7.75). The association of IgA with stroke risk was detected in both younger and older groups, in men and women, and in whites, blacks, and Hispanics. There was also a significant continuous increase in risk associated with the log-transformation of the titer for IgA (adjusted OR 1.32, 95% CI 1.05 to 1.66) but not IgG. Serological evidence of chronic infection with C pneumoniae is associated with risk of ischemic stroke in an urban, multi-ethnic population. IgA titers may be a better marker of this risk than are IgG titers. This association is independent of other vascular disease risk factors. Further prospective epidemiological studies of the effect of this infection on stroke risk are warranted.


The role of age, sex and steroid sex hormones in radiation cataractogenesis.
It is critical to identify and gain a better understanding of the factors that enhance or reduce the risk of cataractogenesis, to minimize the possibility of occurrence after deliberate (e.g., radiation therapy, interplanetary travel) or unintentional exposure to ionizing radiation. Both gender and age at the time of exposure have been established as key determinants of cataractogenesis induced by sparsely ionizing (low-LET) and densely ionizing (high-LET) radiation. However, animal data from several older studies are often conflicting and somewhat difficult to interpret, in that the experiments suffered from small group sizes, limited dose ranges or short periods of observation, and human data are sparse or statistical significance is sometimes limited. Steroid sex hormones (SSH) may underlie age and gender-based differences in the progression and prevalence of cataracts that otherwise occur spontaneously in humans and animal models, and may also underlie age and sex-related differences in radiation cataractogenesis. Here, we review data that have aided in our understanding of the role of age, sex and steroid sex hormones in radiation cataractogenesis.


Benzodiazepine prescribing in a family medicine center.
We monitored benzodiazepine prescribing in a family medicine center for two years. A total of 1,886 prescriptions were written for four benzodiazepines in the following order of frequency: diazepam, chlordiazepoxide, oxazepam, clorazepate. The most frequent diagnostic indications were anxiety neurosis, hysterical neurosis, and vertebral column disorders. Most benzodiazepine recipients were women, but for alcohol abuse more prescriptions were written for men. More than half of the patients were between the ages of 25 and 44 years. Although daily doses were reduced for elderly patients, the course of therapy was often longer. Female physicians wrote fewer prescriptions for men than for women. More prescriptions for benzodiazepines were written during the summer months than during the rest of the year, and more were written on weekdays than on the weekend. Benzodiazepine recipients were given more prescriptions for other drugs than were the rest of the patients in the practice.


Complementation of HYPONASTIC LEAVES1 by double-strand RNA-binding domains of DICER-LIKE1 in nuclear dicing bodies.
MicroRNAs (miRNAs) are a class of small regulatory RNAs that are found in almost all of the eukaryotes. Arabidopsis (Arabidopsis thaliana) miRNAs are processed from primary miRNAs (pri-miRNAs), mainly by the ribonuclease III-like enzyme DICER-LIKE1 (DCL1) and its specific partner, HYPONASTIC LEAVES1 (HYL1), a double-strand RNA-binding protein, both of which contain two double-strand RNA-binding domains (dsRBDs). These dsRBDs are essential for miRNA processing, but the functions of them are not clear. Here, we report that the two dsRBDs of DCL1 (DCL1-D1D2), and to some extent the second dsRBD (DCL1-D2), complement the hyl1 mutant, but not the first dsRBD of DCL1 (DCL1-D1). DCL1-D1 is diffusely distributed throughout the nucleoplasm, whereas DCL1-D2 and DCL1-D1D2 concentrate in nuclear dicing bodies in which DCL1 and HYL1 colocalize. We show further that protein-protein interaction is mainly mediated by DCL1-D2, while DCL1-D1 plays a major role in binding of pri-miRNAs. These results suggest parallel roles between C-terminal dsRBDs of DCL1 and N-terminal dsRBDs of HYL1 and support a model in which Arabidopsis pri-miRNAs are recruited to dicing bodies through functionally divergent dsRBDs of microprocessor for accurate processing of plant pri-miRNAs.


Serum antioxidant activity in uremic patients.
Serum antioxidant activity (AOA) was examined in 35 healthy subjects and 111 patients with chronic renal failure (CRF), consisting of 13 patients in the predialysis stage, 11 requiring the start of regular dialysis therapy (RDT) and 87 undergoing RDT. Serum AOA was determined by assaying serum activity to inhibit malondialdehyde (MDA) generation. AOA levels were significantly lower in CRF patients, and the lowest levels were noticed in patients with uremic symptoms requiring the start of RDT. These levels were restored to a subnormal level during RDT. Defective serum AOA appears to be an endogenous metabolic consequence in uremia. Sera with low AOA tended to show high MDA levels, indicating that patients with low serum AOA were susceptible to cellular injury by lipid peroxidation. It is proposed that defective serum AOA may contribute to a certain uremic toxicity through peroxidative cell damage.


Tuberous sclerosis complex: review based on new diagnostic criteria.
Tuberous sclerosis complex is a multisystemic, autosomal dominant genetic disorder with complete penetrance, that can evolve with hamartomas in multiple organs, such as skin, central nervous system, kidney and lung. Due to the wide phenotypic variability, the disease is often not recognized. Tuberous sclerosis complex affects one in 10,000 newborns and most patients are diagnosed during the first 15 months of life. The diagnostic criteria for tuberous sclerosis were reviewed in 2012, at the second International Tuberous Sclerosis Complex Consensus Conference. The diagnosis is based on genetic criteria, by the identification of inactivating pathogenic mutation of tumor suppressor genes TSC1 and TSC2, and clinical criteria, including cutaneous, renal, pulmonary, cardiac and neurological manifestations. The treatment of tuberous sclerosis complex consists, mainly, in management of the symptoms caused by hamartomas and in prevention of organ failure. Multidisciplinary approach is recommended, in order to obtain better clinical outcomes.


[The motivation to use complementary medicine healing methods. Study of a general internal medicine and orthopedic patient sample].
436 patients from two different clinics of internal medicine and one orthopaedic unit were asked to fill a questionnaire on their attitude towards and use of alternative medicine. Of the 272 questionnaires returned, 235 could be used for analysis. 42.6% of all analysed persons confirmed use of alternative medicine. About half of them were motivated to do so by their nursing staff. Homeopathy was by far the most frequently used method. Persons who used alternative medicine were characterised by a distinct environmental awareness and regular sports activity. They had also often had positive experience of alternative methods in childhood. On the other hand, age, sex, education, duration of the treated disease and success of conventional therapy did not correlate significantly with the use of alternative medicine. An essential motive for the need to seek help by alternative therapists was the opinion that conventional forms of treatment would concentrate too much on the purely physical side of a health problem. All in all, users of alternative medicine did not seek confrontation with conventional medicine but rather sought a real complement to conventional forms of treatment.


Maternal mortality in the developed world: lessons from the UK confidential enquiry.
The UK confidential maternal mortality enquiry shows that not only has maternal mortality decreased since 1952, the year of the first enquiry, but also the pattern of maternal mortality has changed markedly. Major surgical causes of death, such as post-partum haemorrhage and ruptured uterus, are no longer as important as medical causes such as heart disease. The 'Top Ten' recommendations in the current report for the years 2003-2005 emphasise the need for health care practitioners to be aware of the risks that medical conditions, both pre-existing and those arising de novo in pregnancy, impose on the expectant and newly delivered mother. Training and further education programmes should emphasise the importance of medical problems in pregnancy without omitting the knowledge and skills in basic obstetrics that have made such an impact on maternal mortality in the past.


Guidelines for designing BJT amplifiers with low 1/f AM and PM noise.
In this paper we discuss guidelines for designing linear bipolar junction transistor amplifiers with low 1/f amplitude modulation (AM) and phase modulation (PM) noise. These guidelines are derived from a new theory that relates AM and PM noise to transconductance fluctuations, junction capacitance fluctuations, and circuit architecture. We analyze the noise equations of each process for a common emitter (CE) amplifier and use the results to suggest amplifier designs that minimize the 1/f noise while providing other required attributes such as high gain. Although we use a CE amplifier as an example, the procedure applies to other configurations as well. Experimental noise results for several amplifier configurations are presented.


The spatial distribution mechanism of PM2.5 and NO2 on the eastern coast of China.
The spatial distribution characteristics of multi-air pollutants and their impacts are difficult to quantify effectively. As PM2.5 and NO2 are the main air pollutants, it is of great significance to explore the spatial causes of their pollution and their interaction mechanism. This study used machine learning (LightGBM) and hot spot analysis to map the spatial distribution of PM2.5 and NO2 in Southwest Fujian (SWFJ) in 2018 and their key pollution areas. Then, the factors and interactive detection of geographical detectors were used to conduct a detailed analysis of the quantitative impact of potential factors such as human activities, terrain, air pollutants, and meteorology on PM2.5 and NO2 pollution. From this we can learn that 1. LightGBM has good stability for drawing the spatial distribution of PM2.5 and NO2. 2. The spatial mechanism of PM2.5 and NO2 can be effectively interpreted from a massive data and macro perspective. 3. A large amount of evidence shows that potential factors such as human activities, topography, air pollutants and meteorology have direct or indirect effects on PM2.5 and NO2 pollution in the SWFJ area. This includes the direct impact of local road traffic emissions on the distribution of PM2.5 and NO2 pollution, the digestion of both by vegetation, the mutual transformation of atmospheric pollutants themselves, and the impact of meteorological conditions. This study not only confirms the effectiveness of machine learning combined with geographical detectors to promote the study of regional air pollution mechanisms, but also confirms the feasibility of exploring the spatial distribution mechanisms of various air pollutants. Therefore, this study is of great significance for explaining the spatial distribution of PM2.5 and NO2, and can also provide reference for policy formulation to reduce regional PM2.5 and NO2 concentrations.


Rapid diagnosis of bacterial meningitis by nanopore 16S amplicon sequencing: A pilot study.
Early administration of antibiotics is crucial in the management of bacterial meningitis. Rapid pathogen identification helps to make a definite diagnosis of bacterial meningitis and enables tailored antibiotic treatment. We investigated if the 16S amplicon sequencing performed by MinION, a nanopore sequencer, was capable of rapid pathogen identification in bacterial meningitis. Six retrospective cases of confirmed bacterial meningitis and two prospective cases were included. The initial cerebrospinal fluid (CSF) samples of these patients were used for the experiments. DNA was extracted from the CSF, and PCR was performed on the 16S ribosomal DNA (16S rDNA). Sequencing libraries were prepared using the PCR products, and MinION sequencing was performed for up to 3 h. The reads were aligned to the bacterial database, and the results were compared to the conventional culture studies. Pathogenic bacteria were successfully detected from the CSF by 16S sequencing in all retrospective cases. 16S amplicon sequencing was more sensitive than conventional diagnostic tests and worked properly even in antibiotics-treated samples. MinION sequencing significantly reduced the turnaround time, and even 10 min of sequencing was sufficient for pathogen detection in certain cases. Protocol adjustment could further increase the sensitivity and reduce the turnaround time for MinION sequencing. Finally, the prospective application of MinION 16S sequencing was successful. Nanopore 16S amplicon sequencing is capable of rapid bacterial identification from the CSF of the bacterial meningitis patients. It may have many advantages over conventional diagnostic tests and should therefore be applied in a larger number of patients in the future.


Genetic approaches to adoptive cellular therapy of malignancy.
The rapid strides made in recombinant gene technology have been the impetus for equally dramatic developments in our understanding of various aspects of cancer biology. These areas include genetic events leading to carcinogenesis, growth factors, cellular proliferation, differentiation, apoptosis, and metastasis. Novel therapeutic approaches that take advantage of this new knowledge involve biological alteration of the host target cell at a genetic level. Many of these approaches are discussed in greater detail in other sections of this issue. This article focuses on genetic approaches to the adoptive immunotherapy of malignancy. This form of cellular therapy refers to the infusion of tumor reactive immune cells to mediate regression of established tumor. This review is divided into several areas, each one involving different methods of genetic manipulation to generate immune cells for subsequent adoptive transfer and include: (1) the use of gene-modified tumors to serve as immunogens to generate antitumor T cells, (2) genetic manipulation of effector cells to enhance antitumor reactivity; and (3) genetic construction of immunocompetent effector cells from naive cells.


Biomolecular detection employing the Interferometric Reflectance Imaging Sensor (IRIS).
The sensitive measurement of biomolecular interactions has use in many fields and industries such as basic biology and microbiology, environmental/agricultural/biodefense monitoring, nanobiotechnology, and more. For diagnostic applications, monitoring (detecting) the presence, absence, or abnormal expression of targeted proteomic or genomic biomarkers found in patient samples can be used to determine treatment approaches or therapy efficacy. In the research arena, information on molecular affinities and specificities are useful for fully characterizing the systems under investigation. Many of the current systems employed to determine molecular concentrations or affinities rely on the use of labels. Examples of these systems include immunoassays such as the enzyme-linked immunosorbent assay (ELISA), polymerase chain reaction (PCR) techniques, gel electrophoresis assays, and mass spectrometry (MS). Generally, these labels are fluorescent, radiological, or colorimetric in nature and are directly or indirectly attached to the molecular target of interest. Though the use of labels is widely accepted and has some benefits, there are drawbacks which are stimulating the development of new label-free methods for measuring these interactions. These drawbacks include practical facets such as increased assay cost, reagent lifespan and usability, storage and safety concerns, wasted time and effort in labelling, and variability among the different reagents due to the labelling processes or labels themselves. On a scientific research basis, the use of these labels can also introduce difficulties such as concerns with effects on protein functionality/structure due to the presence of the attached labels and the inability to directly measure the interactions in real time. Presented here is the use of a new label-free optical biosensor that is amenable to microarray studies, termed the Interferometric Reflectance Imaging Sensor (IRIS), for detecting proteins, DNA, antigenic material, whole pathogens (virions) and other biological material. The IRIS system has been demonstrated to have high sensitivity, precision, and reproducibility for different biomolecular interactions [1-3]. Benefits include multiplex imaging capacity, real time and endpoint measurement capabilities, and other high-throughput attributes such as reduced reagent consumption and a reduction in assay times. Additionally, the IRIS platform is simple to use, requires inexpensive equipment, and utilizes silicon-based solid phase assay components making it compatible with many contemporary surface chemistry approaches. Here, we present the use of the IRIS system from preparation of probe arrays to incubation and measurement of target binding to analysis of the results in an endpoint format. The model system will be the capture of target antibodies which are specific for human serum albumin (HSA) on HSA-spotted substrates.


Signalling-competent truncated forms of ErbB2 in breast cancer cells: differential regulation by protein kinase C and phosphatidylinositol 3-kinase.
Alterations that affect the ectodomain of receptor tyrosine kinases are often associated with constitutive activation of the enzymic activity of the mutant cell-associated receptor. Since the ectodomain of the ErbB2 receptor tyrosine kinase has been detected as a soluble fragment in the culture supernatant of cells and serum from patients with advanced breast cancer, the possible presence of cell-associated truncated forms of ErbB2 in cancer cells was investigated. Several cell-bound N-terminal truncated forms of ErbB2 were identified in breast cancer cells overexpressing this receptor. The presence of the truncated fragments was independent of lysosomal/proteasomal activity, indicating that classical receptor tyrosine kinase degradation systems were not involved in the N-terminal cleavages. The presence of these truncated forms of ErbB2 was up-regulated by protein kinase C and neuregulin; and down-regulated by phosphatidylinositol 3-kinase, and monoclonal antibodies that target the ectodomain of ErbB2, indicating that N-terminal cleavages of ErbB2 were regulated by multiple mechanisms. The truncated fragments were tyrosine-phosphorylated under resting conditions, and associated with the signalling intermediates Shc and Grb2. It is therefore likely that these truncated forms may be endowed with constitutive activity that allows them to permanently signal.


Discrimination and Health among Lesbian, Gay, Bisexual and Trans People in Puerto Rico.
To identify the experiences of discrimination among and the perceived priorities for the health of lesbian, gay, bisexual, and trans (LGBT) people in Puerto Rico (PR). Data were collected during the 2013 LGBT Pride Parade in San Juan, using a brief self-administered survey that included questions on sociodemographic characteristics, the disclosure of sexual orientation/gender identity, experiences of discrimination, experiences while receiving social and health services, and perceived healthcare priorities and needs. Most participants reported that they had disclosed their sexual orientation to at least one person. Discrimination due to sexual orientation/gender identity was most frequently reported to have occurred in school settings. At least 25% of the sample reported regular or negative experiences based on sexual orientation/gender identity when receiving government services and when looking for support from relatives. HIV/AIDS, mental health, and sexual health were identified as healthcare priorities. In bivariate analyses, mental health services and aging were the priorities most frequently reported among older participants. HIV/AIDS was the main priority only for gay men; sexual health was the main priority for bisexuals; and mental health was the main priority for lesbians. Most participants reported that their preferred modalities for health service provision were support groups and health education. The experiences of discrimination among LGBT people in PR were consistent across age groups and sexual orientation/gender identity. Policies and interventions to address discrimination in different settings are necessary. The findings also suggest the need to prioritize HIV services among gay men and to address mental and sexual health needs among lesbian and bisexual people.


Trinucleotide insertions, deletions, and point mutations in glucose transporters confer K+ uptake in Saccharomyces cerevisiae.
Deletion of TRK1 and TRK2 abolishes high-affinity K+ uptake in Saccharomyces cerevisiae, resulting in the inability to grow on typical synthetic growth medium unless it is supplemented with very high concentrations of potassium. Selection for spontaneous suppressors that restored growth of trk1delta trk2delta cells on K+-limiting medium led to the isolation of cells with unusual gain-of-function mutations in the glucose transporter genes HXT1 and HXT3 and the glucose/galactose transporter gene GAL2. 86Rb uptake assays demonstrated that the suppressor mutations conferred increased uptake of the ion. In addition to K+, the mutant hexose transporters also conferred permeation of other cations, including Na+. Because the selection strategy required such gain of function, mutations that disrupted transporter maturation or localization to the plasma membrane were avoided. Thus, the importance of specific sites in glucose transport could be independently assessed by testing for the ability of the mutant transporter to restore glucose-dependent growth to cells containing null alleles of all of the known functional glucose transporter genes. Twelve sites, most of which are conserved among eukaryotic hexose transporters, were revealed to be essential for glucose transport. Four of these have previously been shown to be essential for glucose transport by animal or plant transporters. Eight represented sites not previously known to be crucial for glucose uptake. Each suppressor mutant harbored a single mutation that altered an amino acid(s) within or immediately adjacent to a putative transmembrane domain of the transporter. Seven of 38 independent suppressor mutations consisted of in-frame insertions or deletions. The nature of the insertions and deletions revealed a striking DNA template dependency: each insertion generated a trinucleotide repeat, and each deletion involved the removal of a repeated nucleotide sequence.


Consanguineous marriage and its clinical consequences in migrants to Australia.
Marriage between close biological relatives is strongly favoured in many countries in Asia and Africa. Although substantial numbers of migrants from these regions are now living in Australia, little information is available either on the prevalence of consanguineous unions among migrants or on their clinical outcome. Data are presented on a range of generally rare autosomal recessive genetic disorders diagnosed in the children of parents of Eastern Mediterranean origin who attended Westmead Hospital, Sydney for genetic counselling during the period 1990 to 1994. The effects of parental consanguinity are assessed both in terms of the specific recessive disorders detected, and the perceived role of consanguineous marriage in the communities investigated.


Pediatric periodic limb movement disorder: sleep symptom and polysomnographic correlates compared to obstructive sleep apnea.
Although periodic limb movements in sleep (PLMS) have been described in multiple pediatric publications, periodic limb movement disorder (PLMD) has not. The aims of this study were to describe the prevalence, sleep-related correlates, and polysomnographic correlates of PLMD in a large pediatric case series, and compare these to pediatric obstructive sleep apnea (OSA). All PLMD cases (defined by International Classification of Sleep Disorders, 2nd edition criteria + respiratory disturbance index [RDI] < 3) and OSA cases (defined by RDI ≥ 3 + PLMS < 5), from a single pediatric sleep practice, over a 2-year time span, were included. Chart, questionnaire, and polysomnographic data were compiled. Of 468 referred children, 66 PLMD cases were identified (14%). The PLMD cases, mean age 8.1 years (range 1-17), were clinically characterized by frequent sleep onset and maintenance problems, difficulty awakening, restless sleep, leg pain/discomfort at night, and parasomnias. Compared to 90 OSA children, those with PLMD had a history of significantly more sleep onset and maintenance problems, leg pain/discomfort at night, parasomnias, getting out of bed at night, and family history of restless legs syndrome. Polysomnographically, PLMD cases had more awakenings, stage 1 sleep, stage shifts, and spontaneous arousals. These data indicate that pediatric PLMD has important clinical and polysomnographic correlates. In addition, PLMD has many characteristics that are different from pediatric OSA, suggesting that PLMD is a distinct pediatric sleep disorder, of which clinicians should be aware.


Outcomes After Surgical Treatment of Adolescent Intra-articular Distal Humerus Fractures.
To determine the radiographic and clinical outcomes of the surgical management of adolescent intra-articular distal humerus fractures. We performed a retrospective review of the clinical and radiographic outcomes of 31 consecutive adolescent patients surgically treated for acute distal humerus intra-articular fractures. Nine patients returned for objective measures of range of motion, strength testing, and completion of validated outcome scores including the Mayo Elbow Performance Score (MEPS); The Disabilities of the Arm, Shoulder, and Hand Score (DASH); and the SF-36. The average age at the time of injury was 13.5 years (range, 12 to 16 y) with a mean follow-up of 1.22 years (range, 9 d to 5.5 y). Multiple surgical approaches were performed. Overall, the active range of motion for our patients was 10.7 to 133.9 degrees with a mean arc of 123.4 degrees. AO classification type C2 and C3 injuries lost significantly more motion than other fracture patterns. Twelve patients sustained perioperative nerve palsies that resolved by final follow-up; seven of these nerve injuries were iatrogenic and sustained during a Bryan-Morrey tricepital slide approach. Eight patients required implant removal; 7 of these patients had prominent olecranon screws after an olecranon osteotomy. Including postoperative neuropathies, there were 20 complications in 15 patients. Thirteen complications in 9 patients required a return to the operating room. Of the 9 patients who returned for objective testing, there was no statistically significant loss of range of motion or strength of the injured extremity when compared with the uninjured limb. The MEPS revealed 6 excellent, 1 good, and 2 fair results. The average DASH score was 5.1 (range, 0 to 19.1) and the physical (average 55.7; range, 47.4 to 59.0) and mental components (average 54.2; range, 29.8 to 63.4) of the SF-36 were comparable. After surgical intervention for an adolescent intra-articular distal humerus fracture, one can expect no significant loss of motion or strength. The reported outcomes are not all excellent. The peri-operative complication rates are high and may be related to surgical approach and fracture pattern. Level IV.


Novel mutations of cathepsin C gene in two Chinese patients with Papillon-Lefèvre syndrome.
Papillon-Lefèvre syndrome (PLS) is an inherited human disease characterized by early-onset periodontitis and palmoplantar hyperkeratosis. Mutations of the lysosomal protease cathepsin C (CTSC) gene have been shown to be the genetic cause of Papillon-Lefèvre syndrome. There are several case reports in China, while there has been no study on the genetic analysis of PLS. We studied two Chinese patients carrying Papillon-Lefèvre syndrome and showing premature tooth loss and palmoplantar hyperkeratosis. Mutation screening and sequence analysis of the CTSC gene revealed a compound heterozygous mutation (c.415 G>A and c.778 T>C) in one patient, and two novel compound heterozygous mutations (c.851G>A and c.112delCCTG) in the other patient. Our novel discovery indicates that the phenotypes observed in these two patients are due to the CTSC gene mutation.


An Information Ontology for the Process Algebra Model of Non-Relativistic Quantum Mechanics.
The process algebra model has been suggested as an alternative mathematical framework for non-relativistic quantum mechanics (NRQM). It appears to reproduce the wave functions of non-relativistic quantum mechanics to a high degree of accuracy. It posits a fundamental level of finite, discrete events upon which the usual entities of NRQM supervene. It has been suggested that the process algebra model provides a true completion of NRQM, free of divergences and paradoxes, with causally local information propagation, contextuality, and realism. Arguments in support of these claims have been mathematical. Missing has been an ontology of this fundamental level from which the formalism naturally emerges. In this paper, it is argued that information and information flow provides this ontology. Higher level constructs such as energy, momentum, mass, spacetime, are all emergent from this fundamental level.