The human sex odds at birth after the atmospheric atomic bomb tests, after Chernobyl, and in the vicinity of nuclear facilities.
Ever since the discovery of the mutagenic properties of ionizing radiation, the possibility of birth sex odds shifts in exposed human populations was considered in the scientific community. Positive evidence, however weak, was obtained after the atomic bombing of Japan. We previously investigated trends in the sex odds before and after the Chernobyl Nuclear Power Plant accident. In a pilot study, combined data from the Czech Republic, Denmark, Finland, Germany, Hungary, Norway, Poland, and Sweden between 1982 and 1992 showed a downward trend in the sex odds and a significant jump in 1987, the year immediately after Chernobyl. Moreover, a significant positive association of the sex odds between 1986 and 1991 with Chernobyl fallout at the district level in Germany was observed. Both of these findings, temporality (effect after exposure) and dose response association, yield evidence of causality. The primary aim of this study was to investigate longer time periods (1950-2007) in all of Europe and in the USA with emphasis on the global atmospheric atomic bomb test fallout and on the Chernobyl accident. To obtain further evidence, we also analyze sex odds data near nuclear facilities in Germany and Switzerland. DATA AND STATISTICAL METHODS: National gender-specific annual live births data for 39 European countries from 1975 to 2007 were compiled using the pertinent internet data bases provided by the World Health Organization, United Nations, Council of Europe, and EUROSTAT. For a synoptic re-analysis of the period 1950 to 1990, published data from the USA and from a predominantly western and less Chernobyl-exposed part of Europe were studied additionally. To assess spatial, temporal, as well as spatial-temporal trends in the sex odds and to investigate possible changes in those trends after the atomic bomb tests, after Chernobyl, and in the vicinity of nuclear facilities, we applied ordinary linear logistic regression. Region-specific and eventually changing spatial-temporal trends were analyzed using dummy variables coding for continents, countries, districts, municipalities, time periods, and appropriate spatial-temporal interactions. The predominantly western European sex odds trend together with the US sex odds trend (1950-1990 each) show a similar behavior. Both trends are consistent with a uniform reduction from 1950 to 1964, an increase from 1964 to 1975 that may be associated with delayed global atomic bomb test fallout released prior to the Partial Test Ban Treaty in 1963 and again a more or less constant decrease from 1975 to 1990. In practically all of Europe, including eastern European countries, from 1975 to 1986, and in the USA from 1975 to 2002, there were highly significant uniform downward trends in the sex odds with a reduction of 0.22% to 0.25% per 10 years. In contrast to the USA, in Europe there was a highly significant jump of the sex odds of 0.20% in the year 1987 following Chernobyl. From 1987 to 2000, the European sex odds trend reversed its sign and went upward, highly significantly so, with 0.42% per 10 years relative to the downward trend before Chernobyl. The global secular trend analyses are corroborated by the analysis of spatial-temporal sex odds trends near nuclear facilities (NF) in Germany and Switzerland. Within 35 km distance from those NF, the sex odds increase significantly in the range of 0.30% to 0.40% during NF operating time. The atmospheric atomic bomb test fallout affected the human sex odds at birth overall, and the Chernobyl fallout had a similar impact in Europe and parts of Asia. The birth sex odds near nuclear facilities are also distorted. The persistently disturbed secular human sex odds trends allow the estimation of the global deficit of births in the range of several millions.


Analyses of muscular mass and function: the impact on bone mineral density and peak muscle mass.
Bone density and bone mass are commonly regarded as the essential parameters to describe fracture risk in osteology. Because fractures primarily depend on bone strength and secondarily on bone mass and density, bone strength should be the main parameter to describe fracture risk. The quantitative description of bone strength has the prerequisite that bone geometry is assessed despite bone density. Thus, volumetric osteodensitometric methods should be preferred, which enable the physician to evaluate parameters primarily associated with bone modeling or remodeling. Modeling describes the adaptation of bone geometry to applied muscular forces in contrast to remodeling representing bone turnover. The adaptation of bone geometry to muscle forces led to the term functional muscle-bone unit, which enables the physician to differentiate between primary and secondary bone diseases. Primary bone diseases are characterized by a defective adaptation of bone to muscle forces in contrast to secondary bone diseases, which are primary diseases of the neuromuscular system. Because muscle forces are essential in the feedback loop of bone adaptation to forces (mechanostat), the assessment of muscle function has become an essential part of osteologic diagnostics in pediatrics. Dynamometric and mechanographic methods have been introduced to properly characterize kinetic aspects of muscle function in children and adolescents. Therefore, emphasis should be put on the assessment of muscle function despite the evaluation of osteodensitometric parameters in pediatric osteology.


Surface plasmon-waveguide hybrid polymer light-emitting devices using hexagonal Ag dots.
We investigated surface plasmon-waveguide hybrid resonances for enhancement of light emission in polymer light-emitting diodes (PLEDs). Hybrid waveguide-plasmon resonances in the visible range for waveguide mode and near IR range for surface plasmons were observed by incorporation of hexagonal Ag dot arrays. Considerable overlap between the emission wavelength of the PLEDs and the waveguide mode by an Ag dot array with a lattice constant of 500 nm was observed. Because of enhanced light extraction by Bragg scattering of waveguide modes, photoluminescence (PL) and electroluminescence (EL) were increased by 70% and 50%, respectively.


Effects of intensive exercise training on immunity in athletes.
A large number of studies have failed to show whether exercise-induced perturbations in immune function are associated with the incidence of infection. "Sports immunology", examining the interaction of physical, psychological and environmental stress on immunity, is emerging as a sub-discipline of sports medicine. A series of studies by our research team has profiled the immune responses of elite swimmers during training. Serum immunoglobulin and IgG subclass levels were lower in swimmers than controls. Suppression of mucosal immune parameters has been associated with the risk of upper respiratory tract infection. Swimmers with a lower pre-season salivary IgA and/or lower pre-exercise salivary IgA level were more likely to contract an URTI during a 7-month training period. In a shorter 12-week study, infected swimmers had a mean salivary IgM concentration that dropped more sharply after a single training session. Significant declines in natural killer cell count and neutrophil oxidative activity were not associated with URTI. Despite systemic and mucosal immunosuppression a cohort of swimmers were also able to mount an antibody response to pneumococcal vaccine equivalent to that of sedentary individuals. Observations of chronic suppression of aspects of host defence and the significant relationship between changes in mucosal immune parameters and URTI, provide a framework for assessment of the immune status of athletes. The underlying causes of upper respiratory tract distress symptoms may be infective, inflammatory or allergic in origin: a differential diagnosis has implications for treatment and management.


The Noise Exposure Structured Interview (NESI): An Instrument for the Comprehensive Estimation of Lifetime Noise Exposure.
Lifetime noise exposure is generally quantified by self-report. The accuracy of retrospective self-report is limited by respondent recall but is also bound to be influenced by reporting procedures. Such procedures are of variable quality in current measures of lifetime noise exposure, and off-the-shelf instruments are not readily available. The Noise Exposure Structured Interview (NESI) represents an attempt to draw together some of the stronger elements of existing procedures and to provide solutions to their outstanding limitations. Reporting is not restricted to prespecified exposure activities and instead encompasses all activities that the respondent has experienced as noisy (defined based on sound level estimated from vocal effort). Changing exposure habits over time are reported by dividing the lifespan into discrete periods in which exposure habits were approximately stable, with life milestones used to aid recall. Exposure duration, sound level, and use of hearing protection are reported for each life period separately. Simple-to-follow methods are provided for the estimation of free-field sound level, the sound level emitted by personal listening devices, and the attenuation provided by hearing protective equipment. An energy-based means of combining the resulting data is supplied, along with a primarily energy-based method for incorporating firearm-noise exposure. Finally, the NESI acknowledges the need of some users to tailor the procedures; this flexibility is afforded, and reasonable modifications are described. Competency needs of new users are addressed through detailed interview instructions (including troubleshooting tips) and a demonstration video. Limited evaluation data are available, and future efforts at evaluation are proposed.


Complete DNA sequence of yeast chromosome XI.
The complete DNA sequence of the yeast Saccharomyces cerevisiae chromosome XI has been determined. In addition to a compact arrangement of potential protein coding sequences, the 666,448-base-pair sequence has revealed general chromosome patterns; in particular, alternating regional variations in average base composition correlate with variations in local gene density along the chromosome. Significant discrepancies with the previously published genetic map demonstrate the need for using independent physical mapping criteria.


Low-dose Bisphenol-A Promotes Epigenetic Changes at Pparγ Promoter in Adipose Precursor Cells.
Exposure to endocrine-disrupting chemicals such as Bisphenol-A (BPA) is associated with an increase in obesity prevalence. Diet is the primary cause of human exposure to this contaminant. BPA promotes obesity by inducing adipocyte dysfunction and altering adipogenesis. Contradictory evidence and unanswered questions are reported in the literature concerning the BPA effects on adipogenesis. To clarify this issue, we tested the effects of prolonged low-dose BPA exposure on different phases of adipogenesis in committed 3T3L1 and uncommitted NIH3T3 preadipocytes. Our findings show that BPA effects on the adipogenesis are mediated by epigenetic mechanisms by reducing peroxisome proliferator-activated receptor gamma (Pparγ) promoter methylation in preadipocytes. Nevertheless, in BPA-exposed 3T3L1, Pparγ expression only transiently increases as lipid accumulation at day 4 of differentiation, without altering the adipogenic potential of the precursor cells. In the absence of differentiation mix, BPA does not make the 3T3L1 an in vitro model of spontaneous adipogenesis and the effects on the Pparγ expression are still limited at day 4 of differentiation. Furthermore, BPA exposure does not commit the NIH3T3 to the adipocyte lineage, although Pparγ overexpression is more evident both in preadipocytes and during the adipocyte differentiation. Interestingly, termination of the BPA exposure restores the Pparγ promoter methylation and inflammatory profile of the 3T3L1 cells. This study shows that BPA induces epigenetic changes in a key adipogenic gene. These modifications are reversible and do not affect preadipocyte commitment and/or differentiation. We identify an alternative transcriptional mechanism by which BPA affects gene expression and demonstrate how the challenge of preventing exposure is fundamental for human health.


A crustacean annotated transcriptome (CAT) database.
Decapods are an order of crustaceans which includes shrimps, crabs, lobsters and crayfish. They occur worldwide and are of great scientific interest as well as being of ecological and economic importance in fisheries and aquaculture. However, our knowledge of their biology mainly comes from the group which is most closely related to crustaceans - insects. Here we produce a de novo transcriptome database, crustacean annotated transcriptome (CAT) database, spanning multiple tissues and the life stages of seven crustaceans. A total of 71 transcriptome assemblies from six decapod species and a stomatopod species, including the coral shrimp Stenopus hispidus, the cherry shrimp Neocaridina davidi, the redclaw crayfish Cherax quadricarinatus, the spiny lobster Panulirus ornatus, the red king crab Paralithodes camtschaticus, the coconut crab Birgus latro, and the zebra mantis shrimp Lysiosquillina maculata, were generated. Differential gene expression analyses within species were generated as a reference and included in a graphical user interface database at http://cat.sls.cuhk.edu.hk/. Users can carry out gene name searches and also access gene sequences based on a sequence query using the BLAST search function. The data generated and deposited in this database offers a valuable resource for the further study of these crustaceans, as well as being of use in aquaculture development.


Main bile duct carcinoma management. Our experience on 38 cases.
Cholangiocarcinoma (CC) is rare malignant tumors arising from cells of the biliary tract. It presents some difficulties to diagnose, and is associated with a high mortality. Traditionally extrahepatic CC is divided into klatskin tumors, intermediate tract and distal or iuxtapapillar tumors according to its location within the biliary tree. CT RM, PET may provide useful diagnostic information in those patients. Surgical resection is the only chance for cure, with results depending on selected patients and careful surgical technique. Liver transplantation could offer long-term survival in selected patients when combined with chemotherapy. Chemotherapy, radiation therapy, and external drainage remain as the only treatment for inoperable patients. The authors report their experience since 1997 inherent to 38 cases of extrahepatic CC, 21 of which were treated by surgery: their outcome has been evaluated. Surprisingly four of them (2 with intermediate tract tumor and 2 with distal tract tumors) are still alive and apparently disease-free after 5 years since surgery. Moreover another one patient with papillar tumor has reached 5 years survival despite has undergone surgery two times. Surgery remains the best chance for long-term survival, and lymph node status is the most important prognostic factor following R0 resection.


Omega-3 fatty acids and sudden arrhythmic death.
Cardiovascular disease is the leading cause of death in developed countries. In Canada, in 1999, cardiovascular disease was responsible for 36% of all deaths. Ischemic heart disease accounts for the greatest percentage of these deaths (20% of all deaths), half of which are due to the acute effects of myocardial infarction. The other half are related to the late manifestations and complications of myocardial infarction. Once coronary arteriosclerosis has reached the point where it results in myocardial infarction, two main complications can ensue, loss of myocardial function and disturbance of cardiac rhythm. Progressive loss of myocardial pump function results in the syndrome of congestive heart failure. Abnormalities of the heart rhythm result in ventricular fibrillation, which is the direct cause of sudden death. Congestive heart failure rates have been easy to track because of the frequent need for hospitalization and we know from analysis of administrative databases that the annual rate of death from heart failure is about 2.5% in Canada. Sudden death, however most often occurs at home and without warning, making it much more difficult to quantitate its impact. However, the most conservative estimates suggest that no less than 25% of deaths in patients with a diagnosis of ischemic heart disease are due to ventricular fibrillation.


Comparison Tests of BioRID II and RID 2 with Regard to Repeatability, Reproducibility and Sensitivity for Assessment of Car Seat Protection Potential in Rear-End Impacts.
The objective of our study was to investigate the properties of the BioRID II and RID2 dummies regarding repeatability and reproducibility as well as their suitability to identify the protection potential of different car seats. For repeatability and reproducibility tests, three BioRID II and three RID 2 dummies at current build levels were seated on a rigid bench seat equipped with a head restraint, and mounted on a HyGe-type sled. The test velocity was prescribed by the proposed ISO-Pulse. For testing the interaction of the dummies with varying car seat geometries and mechanical properties and their ability to assess the protection potential of the seats, three seat types with passive and one seat with an active head restraint system from different car manufacturers were used. The seats were chosen due to their injury protection potential, indicated by accident field data and results of seat evaluation tests. One BioRID II equipped with a T1-load cell and one RID2 were positioned side-by-side on identical seats for each test. The tests were performed at velocities prescribed by the ISO-Pulse (deltav 16km/h / 8 g max.)and a more severe pulse (deltav 24km/h / 13 g max.). The dummy responses were interpreted by applying all currently proposed whiplash injury criteria (e.g. NIC, N(km), NDC, LNL). A comparison of these criteria shows their sensitivity for identification of the respective seat protection potential. This study examines the repeatability, reproducibility, kinematics and sensitivity of these two dummies in sled tests as well as their suitability with regard to the different injury criteria. The RID2 exhibited better repeatability and reproducibility than the BioRID II, because of its simpler mechanical design. The dummies did not give a consistent ranking of the low-speed, rear-end impact protection potentials of the four seat evaluated. More experience is needed to decide which dummy, injury criteria and limits should be used to assess the whiplash protection potential of seat designs.


Borg: an auto-adaptive many-objective evolutionary computing framework.
This study introduces the Borg multi-objective evolutionary algorithm (MOEA) for many-objective, multimodal optimization. The Borg MOEA combines ε-dominance, a measure of convergence speed named ε-progress, randomized restarts, and auto-adaptive multioperator recombination into a unified optimization framework. A comparative study on 33 instances of 18 test problems from the DTLZ, WFG, and CEC 2009 test suites demonstrates Borg meets or exceeds six state of the art MOEAs on the majority of the tested problems. The performance for each test problem is evaluated using a 1,000 point Latin hypercube sampling of each algorithm's feasible parameterization space. The statistical performance of every sampled MOEA parameterization is evaluated using 50 replicate random seed trials. The Borg MOEA is not a single algorithm; instead it represents a class of algorithms whose operators are adaptively selected based on the problem. The adaptive discovery of key operators is of particular importance for benchmarking how variation operators enhance search for complex many-objective problems.


Hexa-functional tumour-seeking nano voyagers and annihilators for synergistic cancer theranostic applications.
In order to meet the unmet medical needs for effective cancer treatment, multifunctional nanocarriers based on iron oxide nanoparticles hold tremendous promise. Here we report a superparamagnetic iron oxide nanoparticles based hexa-functional nanosystem for synergistic cancer theranostic applications by offering active tumour targeting, accumulation and complementary imaging capability by combining magnetic resonance imaging as well as near-infrared fluorescence, magnetophotothermia and chemotherapy. The uniquely designed nanosystem exhibited a paramount increase in the antitumour efficacy through the simultaneous application of multiple thermal effects called magnetophotothermia, which outweighed the therapeutic efficacy of the current thermo-chemo therapies or stand-alone therapies. The active tumour-seeking property with prolonged tumour accumulation and complementary imaging capability with improved sensitivity and resolution also augments the therapeutic efficacy of the proposed nanosystem. Additionally, the work proposes a deep-learning-based tumour cell nuclei detection technique from H&E stained images in anticipation of providing much inspiration for the future of precision histology.


Psoriatic skin inflammation induces a pre-diabetic phenotype via the endocrine actions of skin secretome.
Psoriasis is a chronic inflammatory skin disease that is thought to affect ∼2% of the global population. Psoriasis has been associated with ∼30% increased risk of developing type 2 diabetes (T2D), with numerous studies reporting that psoriasis is an independent risk-factor for T2D, separate from underlying obesity. Separately, studies of skin-specific transgenic mice have reported altered whole-body glucose homeostasis in these models. These studies imply a direct role for skin inflammation and dysfunction in mediating the onset of T2D in psoriasis patients, potentially via the endocrine effects of the skin secretome on key metabolic tissues. We used a combination of in vivo and ex vivo mouse models and ex vivo human imiquimod (IMQ) models to investigate the effects of psoriasis-mediated changes in the skin secretome on whole-body metabolic function. To induce psoriatic skin inflammation, mice were topically administered 75 mg of 5% IMQ cream (or Vaseline control) to a shaved dorsal region for 4 consecutive days. On day 5, mice were fasted for glucose and insulin tolerance testing, or sacrificed in the fed state with blood and tissues collected for analysis. To determine effects of the skin secretome, mouse skin was collected at day 5 from IMQ mice and cultured for 24 h. Conditioned media (CM) was collected and used 1:1 with fresh media to treat mouse explant subcutaneous adipose tissue (sAT) and isolated pancreatic islets. For human CM experiments, human skin was exposed to 5% IMQ cream for 20 min, ex vivo, to induce a psoriatic phenotype, then cultured for 24 h. CM was collected, combined 1:1 with fresh media and used to treat human sAT ex vivo. Markers of tissue inflammation and metabolic function were determined by qPCR. Beta cell function in isolated islets was measured by dynamic insulin secretion. Beta-cell proliferation was determined by measurement of Ki67 immunofluorescence histochemistry and BrDU uptake, whilst islet apoptosis was assessed by caspase 3/7 activity. All data is expressed as mean ± SEM. Topical treatment with IMQ induced a psoriatic-like phenotype in mouse skin, evidenced by thickening, erythema and inflammation of the skin. Topical IMQ treatment induced inflammation and signs of metabolic dysfunction in sub-cutaneous and epidydimal adipose tissue, liver, skeletal muscle and gut tissue. However, consistent with islet compensation and a pre-diabetic phenotype, IMQ mice displayed improved glucose tolerance, increased insulin and c-peptide response to glucose, and increased beta cell proliferation. Treatment of sAT with psoriatic mouse or human skin-CM replicated the in vivo phenotype, leading to increased inflammation and metabolic dysfunction in mouse and human sAT. Treatment of pancreatic islets with psoriatic mouse skin-CM induced increases in beta-proliferation and apoptosis, thus partially replicating the in vivo phenotype. Psoriasis-like skin inflammation induces a pre-diabetic phenotype, characterised by tissue inflammation and markers of metabolic dysfunction, together with islet compensation in mice. The in vivo phenotype is partially replicated by exposure of sAT and pancreatic islets to psoriatic-skin conditioned media. These results support the hypothesis that psoriatic skin inflammation, potentially via the endocrine actions of the skin secretome, may constitute a novel pathophysiological pathway mediating the development of T2D.


Phylogenetic investigation of skin sloughing rates in frogs: relationships with skin characteristics and disease-driven declines.
Amphibian skin is highly variable in structure and function across anurans, and plays an important role in physiological homeostasis and immune defence. For example, skin sloughing has been shown to reduce pathogen loads on the skin, such as the lethal fungus Batrachochytrium dendrobatidis ( Bd), but interspecific variation in sloughing frequency is largely unknown. Using phylogenetic linear mixed models, we assessed the relationship between skin turnover rate, skin morphology, ecological traits and overall evidence of Bd-driven declines. We examined skin sloughing rates in 21 frog species from three continents, as well as structural skin characteristics measured from preserved specimens. We found that sloughing rate varies significantly with phylogenetic group, but was not associated with evidence of Bd-driven declines, or other skin characteristics examined. This is the first comparison of sloughing rate across a wide range of amphibian species, and creates the first database of amphibian sloughing behaviour. Given the strong phylogenetic signal observed in sloughing rate, approximate sloughing rates of related species may be predicted based on phylogenetic position. While not related to available evidence of declines, understanding variation in sloughing rate may help explain differences in the severity of infection in genera with relatively slow skin turnover rates (e.g. Atelopus).


The rice transcription factor IDEF1 is essential for the early response to iron deficiency, and induces vegetative expression of late embryogenesis abundant genes.
Higher plants maintain iron homeostasis by regulating the expression of iron (Fe)-related genes in accordance with Fe availability. The transcription factor IDEF1 regulates the response to Fe deficiency in Oryza sativa (rice) by recognizing CATGC sequences within the Fe deficiency-responsive cis-acting element IDE1. To investigate the function of IDEF1 in detail, we analyzed the response to Fe deficiency in transgenic rice plants exhibiting induced or repressed IDEF1 expression. Fe-deficiency treatment in hydroponic culture revealed that IDEF1 knock-down plants are susceptible to early-stage Fe deficiency, in contrast to IDEF1-induced plants. Time-course expression analyses using quantitative reverse-transcriptase PCR revealed that the IDEF1 expression level was positively correlated with the level of induction of the Fe utilization-related genes OsIRO2, OsYSL15, OsIRT1, OsYSL2, OsNAS1, OsNAS2, OsNAS3 and OsDMAS1, just after the onset of Fe starvation. However, this overall transactivation mediated by IDEF1 became less evident in subsequent stages. Microarray and in-silico analyses revealed that genes positively regulated by IDEF1, especially at the early stage, exhibit over-representation of CATGC and IDE1-like elements within the proximal promoter regions. These results indicate the existence of early and subsequent responses to Fe deficiency, with the former requiring IDEF1 more specifically. Proximal regions of IDEF1-regulated gene promoters also showed enrichment of RY elements (CATGCA), which regulate gene expression during seed maturation. The expression of several genes encoding late embryogenesis abundant proteins, including Osem, was induced in Fe-deficient roots and/or leaves in an IDEF1-dependent manner, suggesting a possible function of seed maturation-related genes in Fe-deficient vegetative organs.


BH3-only Bcl-2 family member Bim is required for apoptosis of autoreactive thymocytes.
During lymphocyte development, the assembly of genes coding for antigen receptors occurs by the combinatorial linking of gene segments. The stochastic nature of this process gives rise to lymphocytes that can recognize self-antigens, thereby having the potential to induce autoimmune disease. Such autoreactive lymphocytes can be silenced by developmental arrest or unresponsiveness (anergy), or can be deleted from the repertoire by cell death. In the thymus, developing T lymphocytes (thymocytes) bearing a T-cell receptor (TCR)-CD3 complex that engages self-antigens are induced to undergo programmed cell death (apoptosis), but the mechanisms ensuring this 'negative selection' are unclear. We now report that thymocytes lacking the pro-apoptotic Bcl-2 family member Bim (also known as Bcl2l11) are refractory to apoptosis induced by TCR-CD3 stimulation. Moreover, in transgenic mice expressing autoreactive TCRs that provoke widespread deletion, Bim deficiency severely impaired thymocyte killing. TCR ligation upregulated Bim expression and promoted interaction of Bim with Bcl-XL, inhibiting its survival function. These findings identify Bim as an essential initiator of apoptosis in thymocyte-negative selection.


Age-Specific Associations of Renal Impairment With Magnetic Resonance Imaging Markers of Cerebral Small Vessel Disease in Transient Ischemic Attack and Stroke.
It has been hypothesized that cerebral small vessel disease (SVD) and chronic renal impairment may be part of a multisystem small-vessel disorder, but their association may simply be as a result of shared risk factors (eg, hypertension) rather than to a systemic susceptibility to premature SVD. However, most previous studies were hospital based, most had inadequate adjustment for hypertension, many were confined to patients with lacunar stroke, and none stratified by age. In a population-based study of transient ischemic attack and ischemic stroke (OXVASC [Oxford Vascular Study]), we evaluated the magnetic resonance imaging markers of cerebral SVD, including lacunes, white matter hyperintensities, cerebral microbleeds, and enlarged perivascular space. We studied the age-specific associations of renal impairment (estimated glomerular filtration rate <60 mL/min per 1.73 m2) and total SVD burden (total SVD score) adjusting for age, sex, vascular risk factors, and premorbid blood pressure (mean blood pressure during 15 years preevent). Of 1080 consecutive patients, 1028 (95.2%) had complete magnetic resonance imaging protocol and creatinine measured at baseline. Renal impairment was associated with total SVD score (odds ratio [OR], 2.16; 95% confidence interval [CI], 1.69-2.75; P<0.001), but only at age <60 years (<60 years: OR, 3.97; 95% CI, 1.69-9.32; P=0.002; 60-79 years: OR, 1.01; 95% CI, 0.72-1.41; P=0.963; ≥80 years: OR, 0.95; 95% CI, 0.59-1.54; P=0.832). The overall association of renal impairment and total SVD score was also attenuated after adjustment for age, sex, history of hypertension, diabetes mellitus, and premorbid average systolic blood pressure (adjusted OR, 0.76; 95% CI, 0.56-1.02; P=0.067), but the independent association of renal impairment and total SVD score at age <60 years was maintained (adjusted OR, 3.11; 95% CI, 1.21-7.98; P=0.018). Associations of renal impairment and SVD were consistent for each SVD marker at age <60 years but were strongest for cerebral microbleeds (OR, 5.84; 95% CI, 1.45-23.53; P=0.013) and moderate-severe periventricular white matter hyperintensities (OR, 6.28; 95% CI, 1.54-25.63; P=0.010). The association of renal impairment and cerebral SVD was attenuated with adjustment for shared risk factors at older ages, but remained at younger ages, consistent with a shared susceptibility to premature disease.


Superior estimation abilities in two autistic spectrum children.
Anecdotal reports of superior estimation abilities in autistic individuals (e.g., Sacks, 1985) have never been confirmed empirically. We present here case studies of 2 children with autistic spectrum diagnoses and report remarkable abilities in estimation for several quantifiable dimensions. K.T. and G.T. were tested at 9 years of age for estimation of rank, numerosity, time, weight, length, surface, distance, and precise enumeration for small numbers. Their performances were compared to those of 6 age- and IQ- matched comparison children. K.T. demonstrated a superior level of performance in estimating rank (e.g., which set has larger numerosity?) but his performance in other tasks was average. G.T. displayed outstanding performance in estimating numerosity, time, weight, surface, length, and distance, with average performance in other tasks. These results show that certain autistic spectrum individuals may develop superior and highly specialized abilities in estimation. We discuss these findings in relation to the role of "veridical mapping" in the development of special ability (Mottron, Dawson, & Soulieres, 2009; Mottron, Dawson, Soulieres, Hubert, & Burack, 2006a). Veridical mapping is the detection of isomorphism within a code, between two codes, or between one code and isomorphic elements of the world. Within this framework, it is proposed that estimation abilities, like absolute pitch, rely on the ability to map a verbal code with a specific magnitude of a psychophysical dimension.


Cancellous bone mechanical properties from normals and patients with hip fractures differ on the structure level, not on the bone hard tissue level.
Osteoporosis is currently defined in terms of low bone mass. However, the source of fragility leading to fracture has not been adequately described. In particular, the contributions of bone tissue properties and architecture to the risk or incidence of fracture are poorly understood. In an earlier experimental study, it was found that the architectural anisotropy of cancellous bone from the femoral heads of fracture patients was significantly increased compared with age- and density-matched control material (Ciarelli et al., J Bone Miner Res 15:32-40; 2000). Using a combination of compression testing and micro-finite element analysis on a subset of cancellous bone specimens from that study, we calculated the hard tissue mechanical properties and the apparent (macroscopic) mechanical properties. The tissue modulus was 10.0 GPa (SD 2.2) for the control group and 10.8 GPa (SD 3.3) for the fracture group (not significant). There were no differences in either the apparent yield strains, percentages of highly strained tissue, or the relationship between apparent yield stress and apparent elastic modulus. Hence, a difference in the tissue yield properties is unlikely. At the apparent level, the fracture group had a significantly decreased transverse stiffness, resulting in increased mechanical anisotropy. These changes suggest that bone in the fracture group was "overadapted" to the primary load axis, at the cost of fragility in the transverse direction. We conclude that individuals with a history of osteoporotic fractures do not have weaker bone tissue. Architectural and mechanical anisotropy alone renders their bone weaker in the nonprimary loading direction.


PRINTO/PRES international website for families of children with rheumatic diseases: www.pediatric-rheumatology.printo.it.
To prepare a website for families and health professionals containing up to date information about paediatric rheumatic diseases (PRD). Firstly, paediatric rheumatology centres and family self help associations were surveyed to characterise current clinical practice of physicians providing care for children with PRD, research activities, and training facilities of each centre. Secondly, international consensus was reached on the content of the website. Finally, the website was developed and the texts translated. The web page contains three main sections: (a) description for families of the characteristics of 15 PRD; (b) list of paediatric rheumatology centres; (c) contact information for family self help associations. A version for 45 countries in 52 languages (with another three in progress) is now available on the web. 291 surveys from 171 centres and 102 family associations were received from 42 countries. The median proportion of time spent in paediatric practice in the centres examined was 100%, with 70% of this time dedicated to paediatric rheumatology. 90% of the centres were willing to perform clinical trials in the future. The PRINTO/PRES website provides a well defined and competent set of information about PRD, with appropriate multiple translated versions and easy web navigational direction.


Clinical Features and Outcomes of Children Admitted to the PICU due to Rotavirus Infection.
In this study, we aimed to evaluate the clinical and laboratory features of the patients with rotavirus (RV) antigen positivity on or following admission to the pediatric intensive care unit (PICU). Patients admitted to the PICU due to community-acquired rotavirus (CA-RV) or hospital-acquired rotavirus (HA-RV)-induced gastroenteritis between January 1, 2013, and December 31, 2019 were evaluated. Thirty-four patients with a mean age of 14.00 ± 19.17 months were enrolled. Fortyfour percent were girls. Twenty (58.8%) patients had a history of chronic diseases. Nine (26.5%) patients had CA-RV and 25 (73.5%) patients had HA-RV infection. RV antigens were simultaneously found in 44.1% (n = 14) of the other patients at the time of diagnosis. In the study sample, 5 patients had hyponatremia, 8 had hypernatremia, 6 had hypokalemia, 4 had hypoalbuminemia, 21 had leukocytosis, 2 had leukopenia and 3 had thrombocytopenia, and 17 had elevatedC-reactive protein (CRP) levels. Three patients had seizures, 1 patient had cardiac arrest, and 2 patients had secondary bacteremia. The mean (SD) PICU length of stay was 6 (6.02) with CA-RV gastroenteritis. All CA-RV patients survived, but 8 of the HA-RV patients succumbed to causes other than RV. RV-related PICU admission is not rare, and occasional severe clinical consequences occur, especially in young children, with both CA-RV and HA-RV gastroenteritis. Appropriate timely intervention and meticulous follow-up improve survival.


The effect of lemon inhalation aromatherapy on nausea and vomiting of pregnancy: a double-blinded, randomized, controlled clinical trial.
Nausea and vomiting of pregnancy are amongst the most common complaints that effects on both the physical and mental conditions of the pregnant women. Due to the increasing tendency of women to use herbal medications during pregnancy, the effect of lemon inhalation aromatherapy on nausea and vomiting of pregnancy was investigated in this study. The aim of this study was to determine the effect of lemon inhalation aromatherapy on nausea and vomiting during pregnancy. This was a randomized clinical trial in which 100 pregnant women with nausea and vomiting who had eligibility criteria were randomly divided into intervention and control groups based on four- and six-random block sampling method. Lemon essential oil and placebo were given to the intervention and control groups, respectively, to inhale it as soon as they felt nausea. The nausea, vomiting, and retch intensity were investigated 24 hours before and during the four days of treatment by means of PUQE-24 (24-hour Pregnancy Unique Quantification of Emesis). There was a statistically significant difference between the two groups in the mean scores of nausea and vomiting on the second and fourth days (P = 0.017 and P = 0.039, respectively). The means of nausea and vomiting intensity in the second and fourth days in the intervention group were significantly lower than the control group. In addition, in intragroup comparison with ANOVA with repeated measures, the nausea and vomiting mean in the five intervals, showed a statistically significant difference in each group (P < 0.001 and P = 0.049, respectively). Lemon scent can be effective in reducing nausea and vomiting of pregnancy.


Adjuvant Therapy for Thymic Carcinoma--A Decade of Experience in a Taiwan National Teaching Hospital.
Thymic carcinomas are rare tumors for which surgical resection is the first treatment of choice. The role of adjuvant treatment after surgery is unknown because of limited available data. The present study evaluated the efficacy of post-surgery adjuvant chemotherapy or radiotherapy in patients with thymic carcinoma. To evaluate the role of adjuvant therapy in patients with thymic carcinoma, we retrospectively reviewed the records of patients with thymic carcinoma who were diagnosed and treated between 2004 and 2014. Among 78 patients with thymic carcinoma, 30 patients received surgical resection. Progression-free survival (PFS) and overall survival (OS) were significantly longer among these patients than among patients who received other treatments (PFS: 88.4 months vs 9.1 months, p<0.001; OS: 134.9 months vs 60.9 months; p = 0.003). Patients with stage III thymic carcinoma who received surgery had a longer OS than patients who did not receive surgery (70.1 months vs 23.9 months; p = 0.017, n = 11). Among 47 patients with stage IV carcinoma, 12 patients who received an extended thymothymectomy had a longer PFS than 35 patients who did not receive surgery (18.9 months vs 8.7 months; p = 0.029). Among 30 patients (with stage I- IV carcinoma) who received primary lesion surgery, 19 patients received an R0 resection and 9 patients of the 19 patients received adjuvant radiotherapy. These patients had longer PFS (50.3 months) than 2 patients who received adjuvant chemotherapy (5.9 months) or 4 patients who received concurrent chemoradiotherapy (7.5 months) after surgery (p = 0.003). Surgical resection should be considered for patients with thymic carcinoma, even for patients with locally advanced or stage IV carcinoma. Adjuvant radiotherapy resulted in a better PFS after R0 resection.


Electromechanical oscillations in bilayer graphene.
Nanoelectromechanical systems constitute a class of devices lying at the interface between fundamental research and technological applications. Realizing nanoelectromechanical devices based on novel materials such as graphene allows studying their mechanical and electromechanical characteristics at the nanoscale and addressing fundamental questions such as electron-phonon interaction and bandgap engineering. In this work, we realize electromechanical devices using single and bilayer graphene and probe the interplay between their mechanical and electrical properties. We show that the deflection of monolayer graphene nanoribbons results in a linear increase in their electrical resistance. Surprisingly, we observe oscillations in the electromechanical response of bilayer graphene. The proposed theoretical model suggests that these oscillations arise from quantum mechanical interference in the transition region induced by sliding of individual graphene layers with respect to each other. Our work shows that bilayer graphene conceals unexpectedly rich and novel physics with promising potential in applications based on nanoelectromechanical systems.


Validity and responsiveness of generic preference-based HRQOL instruments in chronic epilepsy.
Generic, preference-based instruments are recommended for assessing health-related quality of life (HRQOL) in cost-utility analyses (CUA). We aimed to determine which instrument is the most appropriate for CUA of epilepsy care, using established psychometric criteria. We compared validity and responsiveness of EQ5D (using both UK and US preferences), visual analog scale (VAS), Health Utilities Index Mark II (HUI-2) and Mark III (HUI-3) and SF6D in 165 adults evaluated for epilepsy surgery. SF6D had the strongest or next-strongest associations with seizure severity and seizure control. It was not associated with education or IQ. Only SF6D and HUI-3 discriminated between patients with and without seizures 2 years after baseline evaluation. SF6D was most or next-most responsive to being seizure-free for 2 years, in most responsiveness analyses. VAS was also responsive, but showed less evidence of validity. The QOLIE-89, an epilepsy-targeted profile instrument, had stronger evidence for validity and responsiveness than the preference instruments. SF6D has several key psychometric advantages over four other preference instruments in CUAs of epilepsy care. This may reflect better coverage of HRQOL dimensions affected by epilepsy, greater sensitivity at the upper end of the HRQOL continuum, or both. These findings may not generalize to other chronic conditions.


Ablative techniques for the treatment of benign and malignant breast tumours.
Minimally invasive techniques like high intensity focused ultrasound, radiofrequency ablation, cryo-ablation, laser ablation and microwave ablation have been used to treat both breast fibroadenomata and breast cancer as an alternative to surgical excision, potentially reducing the complications, improving cosmesis and reducing hospital stay. This review describes the most common minimally invasive techniques available, their history and some of the studies performed with these techniques in both benign and malignant lesions. In addition we described some of the difficulties of using these minimally invasive techniques such as optimization of anaesthesia, imaging and immobilisation in order to increase the complete histopathological ablation rates.


Consensus guidelines for the promotion and management of continence by primary health care teams: development, implementation and evaluation. NHS Executive Nursing Directorate.
A project was undertaken as part of the NHS Executive Strategy for Major Clinical Guidelines, involving the development of national clinical guidelines for the promotion and management of continence by primary health care teams, through the process of managed consensus based on scientific review. The guidelines were then implemented at one urban general practice. This article outlines the development and implementation of the guidelines and describes the study undertaken to evaluate the impact of implementation on clinical outcomes. The study involved a pre-and post-implementation postal survey of a random sample of 17% of patients aged 18 years and over from the practice (n = 1503). The pre-implementation survey determined the period prevalence of incontinence, related biological data and data on the pre-implementation management of incontinence. Incontinence sufferers were invited to have their condition assessed or reviewed. All sufferers who agreed to be followed-up were sent the post-implementation survey, which identified those patients who had sought help, and ascertained reasons for not seeking help. Data on the management of incontinence post-implementation were also obtained. Clinical outcomes measured pre- and post-implementation were a validated severity index for urinary incontinence, (also adapted for faecal incontinence) and perception of the incontinence as a problem. A 3-month period was allowed between pre- and post-implementation surveys. The study confirmed previous research which showed that few incontinence sufferers respond to invitations to seek help, and that help-seeking behaviour was significantly related to severity of incontinence. The guidelines did not have any positive impact on the clinical outcomes measured, although slight improvements in approaches taken by the primary health care team to the promotion and management of continence were recorded. However, the study was limited by the small sample size and short time scale. Further evaluation of the impact of the guidelines on these outcomes is therefore recommended.


Mapping the spatial and temporal progression of human dental enamel biomineralization using synchrotron X-ray diffraction.
The complex biological, physicochemical process of human dental enamel formation begins in utero and for most teeth takes several years to complete. Lost enamel tissue cannot regenerate, therefore a better understanding of the spatial and temporal progression of mineralization of this tissue is needed in order to design improved in vivo mineral growth processes for regenerative dentistry and allow the possibility to grow a synthetic whole or partial tooth. Human dental enamel samples across a range of developmental stages available through archaeological collections have been used to explore the spatial and temporal progression of enamel biomineralization. Position sensitive synchrotron X-ray diffraction was used to quantify spatial and temporal variations in crystallite organization, lattice parameters and crystallite thickness at three different stages in enamel maturation. In addition X-ray microtomography was used to study mineral content distributions. An inverse correlation was found between the spatial variation in mineral content and the distribution of crystallite organization and thickness as a function of time during enamel maturation. Combined X-ray microtomography and synchrotron X-ray diffraction results show that as enamel matures the mineral content increases and the mineral density distribution becomes more homogeneous. Starting concurrently but proceeding at a slower rate, the enamel crystallites become more oriented and larger; and the crystallite organization becomes spatially more complex and heterogeneous. During the mineralization of human dental enamel, the rate of mineral formation and mineral organization are not identical. Whilst the processes start simultaneously, full mineral content is achieved earlier, and crystallite organization is slower and continues for longer. These findings provide detailed insights into mineral development in human dental enamel which can inform synthetic biomimetic approaches for the benefit of clinical dentistry.


Mitochondrial hyperfusion during oxidative stress is coupled to a dysregulation in calcium handling within a C2C12 cell model.
Atrial Fibrillation is the most common sustained cardiac arrhythmia worldwide harming millions of people every year. Atrial Fibrillation (AF) abruptly induces rapid conduction between atrial myocytes which is associated with oxidative stress and abnormal calcium handling. Unfortunately this new equilibrium promotes perpetuation of the arrhythmia. Recently, in addition to being the major source of oxidative stress within cells, mitochondria have been observed to fuse, forming mitochondrial networks and attach to intracellular calcium stores in response to cellular stress. We sought to identify a potential role for rapid stimulation, oxidative stress and mitochondrial hyperfusion in acute changes to myocyte calcium handling. In addition we hoped to link altered calcium handling to increased sarcoplasmic reticulum (SR)-mitochondrial contacts, the so-called mitochondrial associated membrane (MAM). We selected the C2C12 murine myotube model as it has previously been successfully used to investigate mitochondrial dynamics and has a myofibrillar system similar to atrial myocytes. We observed that rapid stimulation of C2C12 cells resulted in mitochondrial hyperfusion and increased mitochondrial colocalisation with calcium stores. Inhibition of mitochondrial fission by transfection of mutant DRP1K38E resulted in similar effects on mitochondrial fusion, SR colocalisation and altered calcium handling. Interestingly the effects of 'forced fusion' were reversed by co-incubation with the reducing agent N-Acetyl cysteine (NAC). Subsequently we demonstrated that oxidative stress resulted in similar reversible increases in mitochondrial fusion, SR-colocalisation and altered calcium handling. Finally, we believe we have identified that myocyte calcium handling is reliant on baseline levels of reactive oxygen species as co-incubation with NAC both reversed and retarded myocyte response to caffeine induced calcium release and re-uptake. Based on these results we conclude that the coordinate regulation of mitochondrial fusion and MAM contacts may form a point source for stress-induced arrhythmogenesis. We believe that the MAM merits further investigation as a therapeutic target in AF-induced remodelling.


Individual rights advocacy in tobacco control policies: an assessment and recommendation.
Efforts to control environmental tobacco smoke (ETS) could be assisted if the tobacco control movement gave greater emphasis to the issue of individual rights. Benefits that may accrue from the promotion of a clear individual rights perspective in tobacco control include adding coherence to the tobacco control advocacy agenda and winning support from those who may have been concerned about loss of personal freedom, excessive governmental power, use of social coercion, or the rights of smokers. Risks also attend to such a policy. It might inadvertently assist the tobacco industry, stir resistance to ETS limitation efforts, or confuse tobacco control supporters. On balance, though, liabilities are outweighed by the ethical and operational merits in tobacco control of a heightened pro-individual rights stance.


Deliberate self-harm in Oxford University students, 1993-2005: a descriptive and case-control study.
Deliberate self-harm (DSH; intentional self-poisoning or self-injury) is a major problem among young people and has been identified as one of the key mental health problems affecting students. Data on DSH presentations to the general hospital in Oxford by Oxford University students were analysed for the 12-year period from 1993 to 2005. The characteristics of the students with DSH were compared with those of age-matched DSH controls in the Oxford City area. Problems with academic work, relationships with family, partners and friends were most likely to contribute to DSH episodes in students. Many experienced problems with psychiatric disorders and social isolation. The frequency of eating disorders was very high in students, and contributed to DSH significantly more often than in controls. Fewer students than controls self-poisoned in the DSH episode, fewer had personality disorder and fewer had problems with physical health, finance, housing and violence. Alcohol consumption in association with DSH and alcohol-related problems were common in both students and controls. Male students had significantly higher suicide intent than controls. Many students were referred to the university counselling service for follow-up, a resource not available to non-student controls. Comparison of university students following DSH with age-matched controls has shown key differences in psychiatric characteristics, problems contributing to DSH and aftercare offered. These findings may help in the design of targeted self-harm prevention and management strategies for students.


Evidence from household surveys for measuring coverage of newborn care practices.
Aside from breastfeeding, there are little data on use of essential newborn care practices, such as thermal protection and hygienic cord care, in high mortality countries. These practices have not typically been measured in national household surveys, often the main source for coverage data in these settings. The Every Newborn Action Plan proposed early breastfeeding as a tracer for essential newborn care due to data availability and evidence for the benefits of breastfeeding. In the past decade, a few national surveys have added questions on other practices, presenting an opportunity to assess the performance of early breastfeeding initiation as a tracer indicator. We identified twelve national surveys between 2005-2014 that included at least one indicator for immediate newborn care in addition to breastfeeding. Because question wording and reference populations varied, we standardized data to the extent possible to estimate coverage of newborn care practices, accounting for strata and multistage survey design. We assessed early breastfeeding as a tracer by: 1) examining associations with other indicators using Pearson correlations; and 2) stratifying by early breastfeeding to determine differences in coverage of other practices for initiators vs non-initiators in each survey, then pooling across surveys for a meta-analysis, using the inverse standard error as the weight for each observation. Associations between pairs of coverage indicators are generally weak, including those with breastfeeding. The exception is drying and wrapping, which have the strongest association of any two interventions in all five surveys where measured; estimated correlations for this range from 0.47 in Bangladesh's 2007 DHS to 0.83 in Nepal's 2006 DHS. The contrast in coverage for other practices by early breastfeeding is generally small; the greatest absolute difference was 6.7%, between coverage of immediate drying for newborns breastfed early compared to those who were not. Early initiation of breastfeeding is not a high performing tracer indicator for essential newborn care practices measured in previous national surveys. To have informative data on whether newborns are getting life-saving services, standardized questions about specific practices, in addition to breastfeeding initiation, need to be added to surveys.


Global Environmental Engineering for and with Historically Marginalized Communities.
Marginalized communities lack full participation in social, economic, and political life, and they disproportionately bear the burden of environmental and health risks. This special issue of Environmental Engineering Science, the official journal of the Association of Environmental Engineering and Science Professors (AEESP), reports research on the unique environmental challenges faced by historically marginalized communities around the world. The results of community-based participatory research with an Afro-descendant community in Columbia, Native American communities in Alaska, United States, villagers in the Philippines, disadvantaged communities in California, United States, rural communities in Mexico and Costa Rica, homeless encampments in the San Diego River (United States) watershed entrepreneurs in Durban, South Africa, and remote communities in the island nation of Fiji are presented. The research reported in this special issue is transdisciplinary, bringing engineers together with anthropologists, sociologists, economists, and public health experts. In the 13 articles in this special issue, some of the topics covered include inexpensive technologies for water treatment, novel agricultural strategies for reversing biodiversity losses, and strategies for climate change adaptation. In addition, one article covered educational strategies for teaching ethics to prepare students for humanitarian engineering, including topics of poverty, sustainability, social justice, and engineering decisions under uncertainty. Finally, an article presented ways that environmental engineering professors can engage and promote the success of underrepresented minority students and enable faculty engaged in community-based participatory research.


Antioxidant markers based TLC-DPPH differentiation on four commercialized botanical sources of Shankhpushpi (A Medhya Rasayana): A preliminary assessment.
Shankhpushpi is a cognition boosting traditional ayurvedic brain supplement. Convolvulus pluricaulis (Convolvulaceae), Evolvulus alsinoides (Convolvulaceae), Clitoria ternatea (Papilionaceae), and Canscora decussata (Gentianaceae) are botanical claimants of Shankhpushpi. This investigation is to focus the identification of the compound based on biological marker differentiation of four botanical claimants of Shankhpushpi for their antioxidant evaluation on thin layer chromatography (TLC) by 2,2-diphenyl-1-picrylhydrazyl (DPPH) method. A rapid TLC-DPPH method was developed to identify and differentiate four botanical claimants of Shankhpushpi in terms of presence of β-carotene, rutin, scopoletin, chlorogenic acid, and mangiferin. C. pluricaulis shows presence of scopoletin; E. alsinoides shows presence of β-carotene, scopoletin, and chlorogenic acid; C. ternatea shows presence of β-carotene, scopoletin, and rutin; and C. decussata shows presence of β-carotene, scopoletin, and mangiferin. The order, they followed, based on their antioxidant potential is β-carotene < mangiferin < rutin < scopoletin < chlorogenic acid. Antioxidants are attributed for their beneficial role in age-related cognition decline. The proposed method provides an edge in terms of identification and quantification of antioxidant constituents in a multi-component system. This method may also provide application for identification of correct plant sources used in the name of Shankhpushpi in marketed ayurvedic formulation, food supplement, and extracts.


Cell therapies for type 1 diabetes mellitus.
Type 1 diabetes is caused by autoimmune destruction of pancreatic beta-cells and is characterised by absolute insulin insufficiency. The monocellular nature of this disease and endocrine action of insulin make this disease an excellent candidate for cellular therapy. Furthermore, precedent for cellular therapies has been set by successful cadaveric whole pancreas and islet transplantation. In order to expand the supply of cells to meet current and future needs, several novel cell sources have been proposed, including human beta-cells or islets expanded in culture, islet xenografts and pancreatic ductal progenitor cells. Surrogate beta-cells derived from hepatocytes, intestinal K cells or non-endodermal cell types have also been suggested. Stem cells found in bone marrow and umbilical cord blood have been used extensively to repopulate the haematopoietic system and offer the possibility of autologous transplantation. Recent studies have suggested that these stem cells may also have a broader capacity to differentiate, possibly into beta-cells. Stem cells from embryonic sources, such as human embryonic stem and embryonic germ cells, have the ability to proliferate extensively in culture and have an inherent developmental plasticity that may make them a potentially unlimited source of cells that can sense glucose and produce mature insulin. The wide range of proposed cell sources and our increasingly clear picture of pancreatic development suggest that novel cellular therapies might one day compete with non-cellular glucose sensing and insulin delivery devices.


Financial incentives for quality in breast cancer care.
To examine the use of financial incentives related to performance on quality measures reported by oncologists and surgeons associated with a population-based cohort of patients with breast cancer in Los Angeles County, California, and to explore the physician and practice characteristics associated with the use of these incentives among breast cancer care providers. Cross-sectional observational study. Physician self-reported financial arrangements from a survey of 348 medical oncologists, radiation oncologists, and surgeons caring for patients with breast cancer in Los Angeles County (response rate, 76%). Physicians were asked whether they were subject to financial incentives for quality (ie, patient satisfaction surveys and adherence to practice guidelines). We examined the prevalence and correlates of incentives and performed multivariate logistic regression analyses to assess predictors of incentives, controlling for other covariates. Twenty percent of respondents reported incentives based on patient satisfaction, and 15% reported incentives based on guideline adherence. The use of incentives for quality in this cohort of oncologists and surgeons was modest and was primarily associated with staff- or group-model health maintenance organization (HMO) settings. In other settings, important predictors were partial physician ownership interest, large practice size, and capitation. Most cancer care providers in Los Angeles County outside of staff- or group-model HMOs are not subject to explicit financial incentives based on quality-of-care measures. Those who are, seem more likely to be associated with large practice settings. New approaches are needed to direct financial incentives for quality toward specialists outside of staff- or group-model HMOs if pay-for-performance programs are to succeed in influencing care.


Evolutionary Analysis Provides Insight Into the Origin and Adaptation of HCV.
Hepatitis C virus (HCV) belongs to the Hepacivirus genus and is genetically heterogeneous, with seven major genotypes further divided into several recognized subtypes. HCV origin was previously dated in a range between ∼200 and 1000 years ago. Hepaciviruses have been identified in several domestic and wild mammals, the largest viral diversity being observed in bats and rodents. The closest relatives of HCV were found in horses/donkeys (equine hepaciviruses, EHV). However, the origin of HCV as a human pathogen is still an unsolved puzzle. Using a selection-informed evolutionary model, we show that the common ancestor of extant HCV genotypes existed at least 3000 years ago (CI: 3192-5221 years ago), with the oldest genotypes being endemic to Asia. EHV originated around 1100 CE (CI: 291-1640 CE). These time estimates exclude that EHV transmission was mainly sustained by widespread veterinary practices and suggest that HCV originated from a single zoonotic event with subsequent diversification in human populations. We also describe a number of biologically important sites in the major HCV genotypes that have been positively selected and indicate that drug resistance-associated variants are significantly enriched at positively selected sites. HCV exploits several cell-surface molecules for cell entry, but only two of these (CD81 and OCLN) determine the species-specificity of infection. Herein evolutionary analyses do not support a long-standing association between primates and hepaciviruses, and signals of positive selection at CD81 were only observed in Chiroptera. No evidence of selection was detected for OCLN in any mammalian order. These results shed light on the origin of HCV and provide a catalog of candidate genetic modulators of HCV phenotypic diversity.


Obstructive sleep apnoea/hypopnoea syndrome in adults with Down syndrome.
Adults with Down syndrome are predisposed to obstructive sleep apnoea/hypopnoea syndrome (OSAHS) due to overlap between the Down syndrome phenotype and OSAHS risk factors.The prevalence of OSAHS in adults with Down syndrome is estimated at 35-42%. This is up to ten-times higher than in the general adult population.Symptoms of OSAHS, including behavioural and emotional disturbances as well as standard symptoms such as sleepiness, should be monitored as part of regular health surveillance in adults with Down syndrome.There is evidence that the use of continuous positive airway pressure (CPAP) therapy in adults with Down syndrome and comorbid OSAHS can lead to significant improvements in subjective sleepiness, behaviour and cognitive function, though further large-scale trials are required. To discuss the relationship between the phenotypic features of Down syndrome and the risk factors for obstructive sleep apnoea/hypopnoea syndrome (OSAHS).To examine the prevalence of OSAHS in adults with Down syndrome.To review recent research into the effectiveness of treatment of OSAHS in adults with Down syndrome using continuous positive airway pressure (CPAP) therapy. Obstructive sleep apnoea/hypopnoea syndrome (OSAHS) is characterised by repeated cycles of upper airway obstruction during sleep, leading to diurnal symptoms. Individuals with Down syndrome are predisposed to OSAHS due to overlap between the Down syndrome phenotype and OSAHS risk factors. Recent large studies using subjective and objective measures estimate that OSAHS affects around 40% of adults with Down syndrome, in contrast to 2-4% of the general adult population. The "double-hit" of comorbid Down syndrome and OSAHS may accelerate cognitive decline in adults with Down syndrome. However, with the appropriate care and support, OSAHS can be treated effectively in this group using continuous positive airway pressure (CPAP) therapy, improving daytime function and behaviour. Symptoms of OSAHS should be routinely monitored in this population, with testing and treatment available to all adults with Down syndrome; however, this is not currently commonplace, and health inequalities are evident.


The Ten-Group Robson Classification: A Single Centre Approach Identifying Strategies to Optimise Caesarean Section Rates.
Caesarean section (CS) rates have been increasing worldwide and have caused concerns. For meaningful comparisons to be made World Health Organization recommends the use of the Ten-Group Robson classification as the global standard for assessing CS rates. 2625 women who birthed over a 12-month period were analysed using this classification. Women with previous CS (group 5) comprised 10.9% of the overall 23.5% CS rate. Women with one previous CS who did not attempt VBAC contributed 5.3% of the overall 23.5% CS rate. Second largest contributor was singleton nulliparous women with cephalic presentation at term (5.1% of the total 23.5%). Induction of labour was associated with higher CS rate (groups 1 and 3) (24.5% versus 11.9% and 6.2% versus 2.6%, resp.). For postdates IOL we recommend a gatekeeper booking system to minimise these being performed <41 weeks. We suggest setting up dedicated VBAC clinic to support for women with one previous CS. Furthermore review of definition of failure to progress in labour not only may lower CS rates in groups 1 and 2a but also would reduce the size of group 5 in the future.


Should early amputation impact initial fluid therapy algorithms in burns resuscitation? A retrospective analysis using 3D modelling.
While the epidemiology of amputations in patients with burns has been investigated previously, the effect of an amputation on burn size and its impact on fluid management have not been considered in the literature. Fluid resuscitation volumes are based on the percentage of the total body surface area (%TBSA) burned calculated during the primary survey. There is currently no consensus as to whether the fluid volumes should be recalculated after an amputation to compensate for the new body surface area. The aim of this study was to model the impact of an amputation on burn size and predicted fluid requirement. A retrospective search was performed of the database at the Queen Elizabeth Hospital Birmingham Regional Burns Centre to identify all patients who had required an early amputation as a result of their burn injury. The search identified 10 patients over a 3-year period. Burn injuries were then mapped using 3D modelling software. BurnCase3D is a computer program that allows accurate plotting of burn injuries on a digital mannequin adjusted for height and weight. Theoretical fluid requirements were then calculated using the Parkland formula for the first 24 h, and Herndon formula for the second 24 h, taking into consideration the effects of the amputation on residual burn size. This study demonstrated that amputation can have an unpredictable effect on burn size that results in a significant deviation from predicted fluid resuscitation volumes. This discrepancy in fluid estimation may cause iatrogenic complications due to over-resuscitation in burn-injured casualties. Combining a more accurate estimation of postamputation burn size with goal-directed fluid therapy during the resuscitation phase should enable burn care teams to optimise patient outcomes.


Perceptions regarding school-based occupational therapy for children with emotional disturbances.
The purpose of this study was to identify the perceived appropriateness, extent, and types of services provided by occupational therapists to children with emotional disturbances in public schools. A nationally mailed survey was conducted of randomly selected school occupational therapists derived from the American Occupational Therapy Association School System Special Interest Section list. The sampling frame was 982 with a response rate of 48% (n = 476). Eighty-seven percent of all respondents were supportive of school occupational therapy for students with emotional disturbances, although these students made up only a small proportion of their caseload. The therapists indicated that a variety of intervention approaches were used with most targeting educational areas, especially handwriting. The most commonly reported intervention was sensory integration. Many respondents perceived that they could not provide effective interventions because they were not appropriately trained. Perceived lack of knowledge and confusion about occupational therapy's role may lead to underutilization of occupational therapy for addressing the complex needs of children with emotional disturbances. Further research and discussion are needed in the profession to arrive at consensus regarding what approaches are most appropriate and effective in schools.


Ray tracing model for the estimation of power spectral properties in laser Doppler velocimetry of retinal vessels and its potential application to retinal vessel oximetry.
A new model based on ray tracing was developed to estimate power spectral properties in laser Doppler velocimetry of retinal vessels and to predict the effects of laser beam size and eccentricity as well as absorption of laser light by oxygenated and reduced hemoglobin. We describe the model and show that it correctly converges to the traditional rectangular shape of the Doppler shift power spectrum, given the same assumptions, and that reduced beam size and eccentric alignment cause marked alterations in this shape. The changes in the detected total power of the Doppler-shifted light due to light scattering and absorption by blood can also be quantified with this model and may be used to determine the oxygen saturation in retinal arteries and veins. The potential of this approach is that it uses direct measurements of Doppler signals originating from moving red blood cells. This may open new avenues for retinal vessel oximetry.


Photoelectron spectroscopy and density functional theory studies of (FeS)mH- (m = 2-4) cluster anions: effects of the single hydrogen.
Single hydrogen containing iron hydrosulfide cluster anions (FeS)mH- (m = 2-4) are studied by photoelectron spectroscopy (PES) at 3.492 eV (355 nm) and 4.661 eV (266 nm) photon energies, and by Density Functional Theory (DFT) calculations. The structural properties, relative energies of different spin states and isomers, and the first calculated vertical detachment energies (VDEs) of different spin states for these (FeS)mH- (m = 2-4) cluster anions are investigated at various reasonable theory levels. Two types of structural isomers are found for these (FeS)mH- (m = 2-4) clusters: (1) the single hydrogen atom bonds to a sulfur site (SH-type); and (2) the single hydrogen atom bonds to an iron site (FeH-type). Experimental and theoretical results suggest such available different SH- and FeH-type structural isomers should be considered when evaluating the properties and behavior of these single hydrogen containing iron sulfide clusters in real chemical and biological systems. Compared to their related, respective pure iron sulfur (FeS)m- clusters, the first VDE trend of the diverse type (FeS)mH0,1- (m = 1-4) clusters can be understood through (1) the different electron distribution properties of their highest singly occupied molecular orbital employing natural bond orbital analysis (NBO/HSOMO), and (2) the partial charge distribution on the NBO/HSOMO localized sites of each cluster anion. Generally, the properties of the NBO/HSOMOs play the principal role with regard to the physical and chemical properties of all the anions. The change of cluster VDE from low to high is associated with the change in nature of their NBO/HSOMO from a dipole bound and valence electron mixed character, to a valence p orbital on S, to a valence d orbital on Fe, and to a valence p orbital on Fe or an Fe-Fe delocalized valence bonding orbital. For clusters having the same properties for NBO/HSOMOs, the partial charge distributions at the NBO/HSOMO localized sites additionally affect their VDEs: a more negative or less positive localized charge distribution is correlated with a lower first VDE. The single hydrogen in these (FeS)mH- (m = 2-4) cluster anions is suggested to affect their first VDEs through the different structure types (SH- or FeH-), the nature of the NBO/HSOMOs at the local site, and the value of partial charge number at the local site of the NBO/HSOMO.


Identification of the association between FABP4 gene polymorphisms and milk production traits in Sfakia sheep.
The aim of this study was to estimate the effect of variation in the fatty acid binding protein 4 gene (FABP4) on milk production traits in Greek Sfakia sheep. Polymerase chain reaction - single-stranded conformational polymorphism (PCR-SSCP) analysis was used to genotype a total of 374 Sfakia ewes for two regions of FABP4 located around exon 2-intron 2 (Region 1) and exon 3-intron 3 (Region 2). Each month, for a period of 6 months, milk samples were collected from the ewes to measure total milk yield, fat content, protein content, lactose content, non-fat solid content, pH, and somatic cell count (SCC). A general linear model was used to test the association between the variation observed in FABP4 and milk production traits. Four gene variants (A1-A4) were found in Region 1 and two variants (C1-C2) were found in Region 2. In the first region, the FABP4 genotype significantly affected ( P < 0.05 ) non-fat solid levels, fat content, and SCC. The presence of the A2 variant was significantly associated ( P < 0.05 ) with decreased SCC, while the presence of A4 was significantly associated with decreased milk yield ( P < 0.01 ), increased non-fat solid content ( P < 0.05 ), decreased fat content ( P < 0.01 ), increased lactose content ( P < 0.05 ), and increased pH ( P < 0.05 ). In the second region, FABP4 genotype had an effect ( P < 0.05 ) on protein content and the presence of the C2 variant was associated ( P < 0.05 ) with increased protein content, decreased SCC, and lower pH. The results suggest an association between variation in ovine FABP4 and milk production traits in Greek Sfakia sheep. Nevertheless, further analyses in independent sheep populations of increased size will strengthen these findings.


Single-crystal X-ray diffraction studies on structural transformations of porous coordination polymers.
X-Ray single-crystal diffraction has been the most straightforward and important technique in structural determination of crystalline materials for understanding their structure-property relationships. This powerful tool can be used to directly visualize the precise and detailed structural information of porous coordination polymers or metal-organic frameworks at different states, which are unique for their flexible host frameworks compared with conventional adsorbents. With a series of selected recent examples, this review gives a brief overview of single-crystal X-ray diffraction studies and single-crystal to single-crystal transformations of porous coordination polymers under various chemical and physical stimuli such as solvent and gas sorption/desorption/exchange, chemical reaction and temperature change.


Isolation of components of the chloroplast protein import machinery.
Components of the protein import machinery of the chloroplast were isolated by a procedure in which the import machinery was engaged in vitro with a tagged import substrate under conditions that yielded largely chloroplast envelope-bound import intermediates. Subsequent detergent solubilization of envelope membranes showed that six envelope polypeptides copurified specifically and, apparently, stoichiometrically with the import intermediates. Four of these polypeptides are components of the outer membrane import machinery and are associated with early import intermediates. Two of these polypeptides have been characterized. One is a homolog of the heat shock protein hsp70; the other one is a channel-protein candidate.


Identification and Quantification of Ascospores as the Primary Inoculum for Collar Rot of Greenhouse-Produced Tobacco Seedlings.
Collar rot, caused by Sclerotinia sclerotiorum, is a severe disease of tobacco seedlings grown in greenhouses. A semiselective medium was adapted and used to detect the presence and quantity of ascospores in commercial greenhouses. Petri dishes of the semiselective medium were placed inside and outside of greenhouses in four counties during the transplant production period in 1995 and 1996. Ascospores were present throughout the production period each year (February to April) and were confirmed to be the primary inoculum for the disease. Significant differences were observed in the number of ascospores trapped within and between counties. Peak numbers of ascospores were trapped between 10 and 12 a.m., and higher numbers of ascospores were trapped outside than inside houses. In general, distribution of ascospores inside houses was uniform unless a high concentration of apothecia was present very close to one section of the greenhouse. The semiselective medium and trapping technique used in this study may allow development of a forecasting system for collar rot of tobacco based on the presence and level of pathogen inoculum.


Egocentric and allocentric constraints in the expression of patterns of interlimb coordination.
Tasks that are easy when performed in isolation become difficult when performed simultaneously in the upper and/or lower limbs. This observation points to basic CNS constraints in the organization of patterns of interlimb coordination. The present studies provide evidence for the existence of two basic coordinative constraints whose effects may be additive under certain conditions. On one hand, the egocentric constraint denotes a general preference for moving the limbs toward or away from the longitudinal axis of the body in a symmetrical fashion and is of primary importance during the coordination of homologous limbs. On the other hand, the allocentric constraint refers to a general preference to move the limbs in the same direction in extrinsic space and pertains to the coordination of nonhomologous limbs (eg., various combinations of the upper and lower limbs). In the present context, constraints are considered as expressions of basic features of CNS operation that give way to preferred coordination patterns to which the system is naturally drawn or biased. The identification and description of these constraints is considered of critical importance to obtain a better understanding of the control of coordination patterns.


Evidence for genetic susceptibility to developing early childhood diarrhea among shantytown children living in northeastern Brazil.
To explore the genetic components of susceptibility to early childhood diarrhea (ECD), we used a quantitative genetic approach to estimate the heritability of ECD among children from two Brazilian favelas. Shared environment was used to model common exposure to environmental factors. Genetic relatedness was determined from pedigree information collected by screening household participants (n = 3,267) from two geographically related favelas located in Fortaleza, Brazil. There were 277 children within these pedigrees for whom diarrheal episodes in the first two years of life were recorded. Data on environmental exposure and pedigree relationship were combined to quantitatively partition phenotypic variance in ECD into environmental and genetic components by using a variance components approach as implemented in Sequential Oligogenic Linkage Analysis Routines program. Heritability accounted for 54% of variance in ECD and proximity of residence effect accounted for 21% (P < 0.0001). These findings suggest a substantial genetic component to ECD susceptibility and the potential importance of future genetics studies.


Brain-derived neurotrophic factor administration protects basal forebrain cholinergic but not nigral dopaminergic neurons from degenerative changes after axotomy in the adult rat brain.
Cell culture studies with dissociated primary cultures from embryonic rat brain revealed that brain-derived neurotrophic factor (BDNF) promotes the developmental differentiation of both basal forebrain cholinergic and mesencephalic dopaminergic neurons. These studies suggested that, in the adult brain, BDNF may be able to protect cholinergic and dopaminergic neurons from degenerative changes induced by axotomy, similar to the known protective action of NGF in cholinergic neurons. Testing this hypothesis, we found that intraventricular administration of recombinant human BDNF (rhBDNF) to adult rats with transections of the fimbria significantly reduces axotomy-induced degenerative changes of the cholinergic cells in the basal forebrain. No such effect was seen on the dopaminergic neurons of the ventral mesencephalon after transection of their axons ascending in the medial forebrain bundle. Injected in equal amounts, rhBDNF and recombinant human NGF had quantitatively different effects on the cholinergic neurons. BDNF sustained only part of the population of cholinergic neurons affected by the lesion, whereas the entire population was protected by NGF treatment.


Successful treatment of allergic bronchopulmonary aspergillosis with posaconazole in a child with cystic fibrosis: Case report and review of the literature.
Allergic bronchopulmonary aspergillosis (ABPA) is recognized as a rare, progressive, allergic disorder in patients with cystic fibrosis (CF) and asthma. Treatment of ABPA mainly includes systemic corticosteroids (CSs) and antifungal agents. Here, we report posaconazole treatment in a 9-year-old male child with ABPA and also review the literature on antifungal management of ABPA. The child with CF was admitted to the emergency room with complaints of fever, productive cough, and acute dyspnea. Auscultation of the lungs revealed obvious bilateral fine crackles and bilateral rhonchus. He was started with intravenous meropenem and amikacin for acute exacerbation. The patient was diagnosed with ABPA because of his failure to respond to antibiotherapy, elevated serum immunoglobulin (Ig) E, specific IgE, to Aspergillus fumigatus levels and sputum growth of A. fumigatus. He was successfully treated with posaconazole with marked clinical and laboratory improvement and no adverse effects. CSs and antifungal agents are the mainstay of therapy in patients with ABPA based on observational studies in children. Posaconazole is a useful treatment option for patients with ABPA.


Color vision in the antelope ground squirrel.
Antelope ground squirrels (Citellus leucurus) were able, after conditioning, to respond correctly to a port illuminated with light at a wavelength of 460 nanometers. This color randomly presented at one of two positions, was correctly selected in reference to a second port illuminated with light at 500, 520, 569, and 600 nanometers, or with white light of varying intensity. Luminosity was not a factor in the discrimination.


Regulatory role of parasites: impact on host population shifts with resource availability.
Effects of infections by the ciliate Lambornella clarki on larval populations of its mosquito host Aedes sierrensis were examined in laboratory and field studies. When host populations developed with sufficient food, mortality from parasites was additive and reduced the number of emerging mosquitoes. For food-limited populations, mortality was compensatory or depensatory; emerging adults were as or more abundant with higher average fitness than those from uninfected control populations. When nutrients were scarce, parasitic infections relaxed larval competition and increased per capita food by reducing host abundance. Food limitation altered larval feeding behavior, reducing horizontal transmission and subsequent mortality from parasitism.


Pathfinding in the central nervous system and periphery by identified embryonic Drosophila motor axons.
We have studied the pattern of axon outgrowth from the identified embryonic Drosophila motorneurons, RP1, RP3, RP4 and RP5, from the onset of axonogenesis to the time of arborization over target muscles. Lucifer Yellow was intracellularly injected into each of these neurons to obtain a detailed description of the morphology of their growth cones and of the pathways that they follow. We have divided the sequence of axon growth from these neurons into five major phases. In the first phase, the growth cone of each RP axon grows medially along its contralateral homologue along the anterior commissure. Each RP axon follows a separate path across the midline in the anterior commissure. After crossing the ventral midline, the axons wrap around specific contralateral RP somata. In the second phase, each axon grows posteriorly and dorsally down the contralateral longitudinal connective, fasciculating with the other RP axons. In the third phase, the axons turn into the intersegmental nerve via the anterior nerve root, then cross over to the segmental nerve, before contacting the external surfaces of intermediate muscles 15/16. They do not fasciculate with the pioneering aCC and RP2 axons at this time. In the fourth phase, the axons advance laterally across the ventral muscle group. During this phase, each axon extends processes over a number of inappropriate muscles as well as contacting its correct, target muscle. In the final phase, the processes to inappropriate muscles are withdrawn, generating the mature pattern of motor axon projections. There is no consistent, clear difference between the RP motorneurons in the relative timing of axon outgrowth.


Elemental and spectroscopic characterization of fractions of an acidic extract of oil sands process water.
'Naphthenic acids' (NAs) in petroleum produced water and oil sands process water (OSPW), have been implicated in toxicological effects. However, many are not well characterized. A method for fractionation of NAs of an OSPW was used herein and a multi-method characterization of the fractions conducted. The unfractionated OSPW acidic extract was characterized by elemental analysis, electrospray ionization-Orbitrap-mass spectrometry (ESI-MS), and an esterified extract by Fourier Transform infrared (FTIR) and ultraviolet-visible (UV) absorption spectroscopy and by comprehensive multidimensional gas chromatography-MS (GCxGC-MS). Methyl esters were fractionated by argentation solid phase extraction (Ag(+) SPE) and fractions eluting with: hexane; diethyl ether: hexane and diethyl ether, examined. Each was weighed, examined by elemental analysis, FTIR, UV, GC-MS and GCxGC-MS (both nominal and high resolution MS). The ether fraction, containing sulfur, was also examined by GCxGC-sulfur chemiluminescence detection (GCxGC-SCD). The major ions detected by ESI-MS in the OSPW extract were assigned to alicyclic and aromatic 'O2' acids; sulfur was also present. Components recovered by Ag(+) SPE were also methyl esters of alicyclic and aromatic acids; these contained little sulfur or nitrogen. FTIR spectra showed that hydroxy acids and sulfoxides were absent or minor. UV spectra, along with the C/H ratio, further confirmed the aromaticity of the hexane:ether eluate. The more minor ether eluate contained further aromatics and 1.5% sulfur. FTIR spectra indicated free carboxylic acids, in addition to esters. Four major sulfur compounds were detected by GCxGC-SCD. GCxGC-high resolution MS indicated these were methyl esters of C18 S-containing, diaromatics with ≥C3 carboxylic acid side chains.


Defining emergency department asthma visits for public health surveillance, North Carolina, 2008-2009.
When using emergency department (ED) data sets for public health surveillance, a standard approach is needed to define visits attributable to asthma. Asthma can be the first (primary) or a subsequent (2nd through 11th) diagnosis. Our study objective was to develop a definition of ED visits attributable to asthma for public health surveillance. We evaluated the effect of including visits with an asthma diagnosis in primary-only versus subsequent positions. The study was a cross-sectional analysis of population-level ED surveillance data. Of the 114 North Carolina EDs eligible to participate in a statewide surveillance system in 2008-2009, we used data from the 111 (97%) that participated during those years. Included were all ED visits with an ICD-9-CM diagnosis code for asthma in any diagnosis position (1 through 11). We formed 11 strata based on the diagnosis position of asthma and described common chief complaint and primary diagnosis categories for each. Prevalence ratios compared each category's proportion of visits that received either asthma- or cardiac-related procedure codes. Respiratory diagnoses were most common in records of ED visits in which asthma was the first or second diagnosis, while primary diagnoses of injury and heart disease were more common when asthma appeared in positions 3-11. Asthma-related chief complaints and procedures were most common when asthma was the first or second diagnosis, whereas cardiac procedures were more common in records with asthma in positions 3-11. ED visits should be defined as asthma-related when asthma is in the first or second diagnosis position.


[Individualized monitoring of the therapy with gentamycin using pharmacokinetic methods. Which method to choose?].
Gentamicin has an excellent cost/efficacy ratio for gram negative infections treatment. Its use is often limited in clinical practice by its narrow safety margins and a high incidence of toxicity. Gentamicin related nephrotoxicity is a major adverse effect, mostly in patients with other concomitant potential risk factors. As many other Authors we have found in our Internal Medicine Service during 1992 a gentamicin related nephrotoxicity incidence of 22.5%. Various empiric methods and nomograms have shown a significant incidence of error in predicting individualized gentamicin dosage regimens. Pharmacokinetics methods have demonstrated much better results regarding efficacy and toxicity. The aim of this prospective study carried out during 1993-1994 was to individualize by pharmacokinetics methods dosage regimens of gentamicin in patients with one or more concomitant risk factors of nephrotoxicity. The purpose of pharmacokinetics dosage regimens has been to achieve trough serum concentrations of gentamicin in therapeutics range-0.5 to 2 micrograms/ml-on the first 24 to 48 hours of treatment, and the maintenance in this range during all the treatment, avoiding both toxic and under therapeutic levels. The incidence of gentamicin related nephrotoxicity has been evaluated in this population. Twenty patients were studied: 18 males and 2 females aged 59.6 years (19 to 85). All had one or more potential risk factors for nephrotoxicity-65 years or more: 13, previous renal failure: 6, other nephrotoxic drugs: 10, diuretics: 4, dehydration: 5, congestive heart failure: 5, diabetes: 3, hypertension: 3. For the first 10 patients gentamicin dosage regimens have been determined by Sawchuk-Zaske pharmacokinetics method and for the subsequent 10 patients by Bayesian method. The two subpopulations had no significant differences regarding mean age, sex and potential risk factors for nephrotoxicity. Results of Sawchuk-Zaske method: 53 trough gentamicin serum concentration were obtained; 86.8% were within the therapeutic range, 7.5% were toxic and 5.7% were under therapeutic. Results of Bayesian method: 44 determinations of gentamicin through concentrations were obtained; 86.3% within therapeutic range, 2.4% were toxic and 11.3% were under therapeutic. A great variability in pharmacokinetic patient's profile has been found and explains the great variability of individualized dosage regimens of gentamicin (30 to 320 mg/day). No patients had gentamicin related nephrotoxicity. Both pharmacokinetics methods lead to a efficient and save employment of gentamicin in patients with previous renal failure and other potential risk factors for nephrotoxicity.


Fluorescence in situ hybridisation detection of erbB2 amplification in breast cancer fine needle aspirates.
To develop a method for the detection of amplification of the erbB2 oncogene in breast cancer fine needle aspirates using fluorescence in situ hybridisation (FISH) and to compare amplification with immunohistochemical detection of the erbB2 protein. A digoxigenin labelled probe to the erbB2 gene was hybridised to 15 aspirates prepared from operative breast cancer specimens. A chromosome 17 centromere probe was also hybridised to the aspirates either separately or in combination with the erbB2 probe. The aspirates were scored for erbB2 amplification and chromosome 17 centromere number. Subsequently, paraffin wax embedded sections of the tumours were stained with the antibody CB11 and scored for the presence of membrane staining. Three of the 15 tumour aspirates showed high level amplification of erbB2 detected by FISH. These three tumours also showed chromosome 17 polysomy and diffuse membrane staining by immunohistochemistry. FISH can be used to detect erbB2 amplification in fine needle aspirates and results correlate with conventional immunohistochemical staining. Difficulties were encountered in the visualisation of the signals in non-amplified cases without the use of specialised digital imaging.


CBX7 Induces Self-Renewal of Human Normal and Malignant Hematopoietic Stem and Progenitor Cells by Canonical and Non-canonical Interactions.
In this study, we demonstrate that, among all five CBX Polycomb proteins, only CBX7 possesses the ability to control self-renewal of human hematopoietic stem and progenitor cells (HSPCs). Xenotransplantation of CBX7-overexpressing HSPCs resulted in increased multi-lineage long-term engraftment and myelopoiesis. Gene expression and chromatin analyses revealed perturbations in genes involved in differentiation, DNA and chromatin maintenance, and cell cycle control. CBX7 is upregulated in acute myeloid leukemia (AML), and its genetic or pharmacological repression in AML cells inhibited proliferation and induced differentiation. Mass spectrometry analysis revealed several non-histone protein interactions between CBX7 and the H3K9 methyltransferases SETDB1, EHMT1, and EHMT2. These CBX7-binding proteins possess a trimethylated lysine peptide motif highly similar to the canonical CBX7 target H3K27me3. Depletion of SETDB1 in AML cells phenocopied repression of CBX7. We identify CBX7 as an important regulator of self-renewal and uncover non-canonical crosstalk between distinct pathways, revealing therapeutic opportunities for leukemia.