Prognostic factors in pathologic fractures secondary to metastatic tumors.
Pathological fractures caused by metastases sharply decrease the quality of life and increase mortality rates for patients with malignant neoplasias. Orthopedic advances in osteosynthesis and endoprosthesis have been beneficial in the prevention and treatment of such fractures. The objective of our study was to determine which prognostic factors for pathologic fractures treated in our Service were significant. This was a retrospective study enrolling 112 patients treated for pathologic fractures secondary to metastatic tumors between April 1994 and December 2004 in our Service. Patients were analyzed according to sex, age, bone metastasis site, visceral metastases, origin of primary tumor, treatment type, serum hemoglobin, and survival. The most affected site was the femur (44%), the most frequent primary tumor was breast cancer (25%); the most frequently employed surgical treatment was unconventional endoprosthesis (66%). Sex, age, primary tumor, site affected, non-bone metastasis, and clinical versus surgical treatment variables were not good predictors for survival. The only significant predictor was the type of surgery employed. Patients who received an endoprosthesis presented a worse prognosis (21.6 months) than patients undergoing osteosynthesis (47.8 months). Patients undergoing osteosynthesis, with a less morbid surgical technique and earlier rehabilitation, had longer survival times than patients who received endoprostheses. Our case series is similar to international ones, where the most frequent primary tumor is breast tumor, followed by tumors of undetermined origin, prostate, and lung tumors.


Targeting epidermal growth factor receptor in head and neck cancer: lessons learned from cetuximab.
As early detection strategies have not been successful, most patients with head and neck cancer (HNC) present with advanced (stages III and IV) disease. Oral cavity tumors are treated primarily with surgical resection and advanced tumors of the pharynx and larynx are generally treated with combined modality therapy (chemoradiation). The major advances in the management of HNC have evolved from the integration of targeted therapeutics into treatment regimens. Presently, the most important target for new therapeutic strategies in HNC is the epidermal growth factor receptor (EGFR) and so far only cetuximab, a monoclonal antibody targeting EGFR, has been approved by the United States Food and Drug Administration in the HNC population as a radiation-sensitizing agent for patients undergoing primary radiation-based treatment and for patients with recurrent or metastatic disease. Other receptor and non-receptor kinase targeting strategies are under active clinical investigation as well. The increasing number of molecular targeting strategies in clinical development underscores the need to identify which HNC patients will respond to specific therapies. This article focuses on the current preclinical and clinical evidence of monoclonal antibodies targeting EGFR in HNC. We will first review the mechanisms of action of cetuximab, its clinical trials and side-effect profiles, and its present clinical application. Then, the current development status of other molecular antibodies and two molecular inhibitors, gefitinib and erlotinib, will be examined. Finally, by focusing on cetuximab, the current issues in EGFR targeting will be reviewed and we propose future directions of EGFR targeting. We hope that this review will provide further insight into the future directions of targeted therapy in the management of advanced HNC.


Sibling relatedness rather than father absence predicts earlier age at menarche in ELSPAC cohort.
Many studies during the past 50 years have found an association between father absence and earlier menarche. In connection with these findings, several evolutionary theories assume that father absence is a causal factor accelerating reproductive development. However, a recent study analysing data from the Avon Longitudinal Study of Parents and Children (ALSPAC) found that father absence does not predict age at menarche when adjusted for sibling relatedness. In this study, we have replicated these results in the Czech section of the European Longitudinal Study of Pregnancy and Childhood (ELSPAC), which used the same questionnaires as ALSPAC to study a geographically distinct population. Our results support the conclusion that sibling relatedness rather than father absence predicts age at menarche. Furthermore, our results show that age at menarche in 1990s UK and Czech cohorts is very similar despite socioeconomic differences between the two countries.


Morphological and genetic divergence in Swedish postglacial stickleback (Pungitius pungitius) populations.
An important objective of evolutionary biology is to understand the processes that govern phenotypic variation in natural populations. We assessed patterns of morphological and genetic divergence among coastal and inland lake populations of nine-spined stickleback in northern Sweden. Coastal populations are either from the Baltic coast (n = 5) or from nearby coastal lakes (n = 3) that became isolated from the Baltic Sea (< 100 years before present, ybp). Inland populations are from freshwater lakes that became isolated from the Baltic approximately 10,000 ybp; either single species lakes without predators (n = 5), or lakes with a recent history of predation (n = 5) from stocking of salmonid predators (~50 ybp). Coastal populations showed little variation in 11 morphological traits and had longer spines per unit of body length than inland populations. Inland populations were larger, on average, and showed greater morphological variation than coastal populations. A principal component analysis (PCA) across all populations revealed two major morphological axes related to spine length (PC1, 47.7% variation) and body size (PC2, 32.9% variation). Analysis of PCA scores showed marked similarity in coastal (Baltic coast and coastal lake) populations. PCA scores indicate that inland populations with predators have higher within-group variance in spine length and lower within-group variance in body size than inland populations without predators. Estimates of within-group PST (a proxy for QST) from PCA scores are similar to estimates of FST for coastal lake populations but PST >FST for Baltic coast populations. PST >FST for PC1 and PC2 for inland predator and inland no predator populations, with the exception that PST <FST for body size in inland populations lacking predators. Baltic coast and coastal lake populations show little morphological and genetic variation within and between groups suggesting that these populations experience similar ecological conditions and that time since isolation of coastal lakes has been insufficient to demonstrate divergent morphology in coastal lake populations. Inland populations, on the other hand, showed much greater morphological and genetic variation characteristic of long periods of isolation. Inland populations from lakes without predators generally have larger body size, and smaller spine length relative to body size, suggesting systematic reduction in spine length. In contrast, inland populations with predators exhibit a wider range of spine lengths relative to body size suggesting that this trait is responding to local predation pressure differently among these populations. Taken together the results suggest that predation plays a role in shaping morphological variation among isolated inland populations. However, we cannot rule out that a causal relationship between predation versus other genetic and environmental influences on phenotypic variation not measured in this study exists, and this warrants further investigation.


Oral HPV infection in a bone marrow transplantation patient: a case report with atypical clinical presentation and unexpected outcome.
HPV (Human Papilloma Virus) is one of the most prevalent infections worlwide. Oral HPV infection may be associated with different diseases of oral cavitie. Although oral HPV infection occurs frequently, it rarely causes lesions. An increased rate of oral HPV-induced lesions is observed in people with an impaired immune system. The most common conditions induced by oral HPV infection are focal epithelial hyperplasia, oral condylomas and oral papillomas. We reported a case of oral HPV lesion in a bone marrow transplantation patient with atypical clinical presentation and unexpected outcome.


Bubble evolution and properties in homogeneous nucleation simulations.
We analyze the properties of naturally formed nanobubbles in Lennard-Jones molecular dynamics simulations of liquid-to-vapor nucleation in the boiling and the cavitation regimes. The large computational volumes provide a realistic environment at unchanging average temperature and liquid pressure, which allows us to accurately measure properties of bubbles from their inception as stable, critically sized bubbles, to their continued growth into the constant speed regime. Bubble gas densities are up to 50% lower than the equilibrium vapor densities at the liquid temperature, yet quite close to the gas equilibrium density at the lower gas temperatures measured in the simulations: The latent heat of transformation results in bubble gas temperatures up to 25% below those of the surrounding bulk liquid. In the case of rapid bubble growth-typical for the cavitation regime-compression of the liquid outside the bubble leads to local temperature increases of up to 5%, likely significant enough to alter the surface tension as well as the local viscosity. The liquid-vapor bubble interface is thinner than expected from planar coexistence simulations by up to 50%. Bubbles near the critical size are extremely nonspherical, yet they quickly become spherical as they grow. The Rayleigh-Plesset description of bubble-growth gives good agreement in the cavitation regime.


Cholesterol induces specific spatial and orientational order in cholesterol/phospholipid membranes.
In lipid bilayers, cholesterol facilitates the formation of the liquid-ordered phase and enables the formation of laterally ordered structures such as lipid rafts. While these domains have an important role in a variety of cellular processes, the precise atomic-level mechanisms responsible for cholesterol's specific ordering and packing capability have remained unresolved. Our atomic-scale molecular dynamics simulations reveal that this ordering and the associated packing effects in membranes largely result from cholesterol's molecular structure, which differentiates cholesterol from other sterols. We find that cholesterol molecules prefer to be located in the second coordination shell, avoiding direct cholesterol-cholesterol contacts, and form a three-fold symmetric arrangement with proximal cholesterol molecules. At larger distances, the lateral three-fold organization is broken by thermal fluctuations. For other sterols having less structural asymmetry, the three-fold arrangement is considerably lost. We conclude that cholesterol molecules act collectively in lipid membranes. This is the main reason why the liquid-ordered phase only emerges for Chol concentrations well above 10 mol% where the collective self-organization of Chol molecules emerges spontaneously. The collective ordering process requires specific molecular-scale features that explain why different sterols have very different membrane ordering properties: the three-fold symmetry in the Chol-Chol organization arises from the cholesterol off-plane methyl groups allowing the identification of raft-promoting sterols from those that do not promote rafts.


Adaptive dynamic resource allocation in annual eusocial insects: environmental variation will not necessarily promote graded control.
According to the classical model of Macevicz and Oster, annual eusocial insects should show a clear dichotomous "bang-bang" strategy of resource allocation; colony fitness is maximised when a period of pure colony growth (exclusive production of workers) is followed by a single reproductive period characterised by the exclusive production of sexuals. However, in several species graded investment strategies with a simultaneous production of workers and sexuals have been observed. Such deviations from the "bang-bang" strategy are usually interpreted as an adaptive (bet-hedging) response to environmental fluctuations such as variation in season length or food availability. To generate predictions about the optimal investment pattern of insect colonies in fluctuating environments, we slightly modified Macevicz and Oster's classical model of annual colony dynamics and used a dynamic programming approach nested into a recurrence procedure for the solution of the stochastic optimal control problem. 1) The optimal switching time between pure colony growth and the exclusive production of sexuals decreases with increasing environmental variance. 2) Yet, for reasonable levels of environmental fluctuations no deviation from the typical bang-bang strategy is predicted. 3) Model calculations for the halictid bee Lasioglossum malachurum reveal that bet-hedging is not likely to be the reason for the graded allocation into sexuals versus workers observed in this species. 4) When environmental variance reaches a critical level our model predicts an abrupt change from dichotomous behaviour to graded allocation strategies, but the transition between colony growth and production of sexuals is not necessarily monotonic. Both, the critical level of environmental variance as well as the characteristic pattern of resource allocation strongly depend on the type of function used to describe environmental fluctuations. Up to now bet-hedging as an evolutionary response to variation in season length has been the main argument to explain field observations of graded resource allocation in annual eusocial insect species. However, our model shows that the effect of moderate fluctuations of environmental conditions does not select for deviation from the classical bang-bang strategy and that the evolution of graded allocation strategies can be triggered only by extreme fluctuations. Detailed quantitative observations on resource allocation in eusocial insects are needed to analyse the relevance of alternative explanations, e.g. logistic colony growth or reproductive conflict between queen and workers, for the evolution of graded allocation strategies.


Is a dual-sensor pacemaker appropriate in patients with sino-atrial disease? Results from the DUSISLOG study.
Rate-responsive pacemakers (PMs) are often supplied with accelerometer (XL) and minute ventilation (MV) sensors to provide a physiologic rate response according to patient needs. No information is available about the real benefit of dual-sensor rate-responsive pacing on the daily life of patients. DUSISLOG (Dual Sensor vs Single Sensor comparison using patient activity LOGbook) is a two-arm prospective, randomized, multicenter study that enrolled 105 patients who received a rate-responsive PM (Insignia), Guidant Corp.). After 1 month of DDD pacing at 60 ppm lower rate, a single sensor (XL or MV, randomized) was activated for 3 months at the manufacturer's suggested nominal settings, followed by a 3-month period with dual sensors optimized with automatic response. During the last month of each period, the following data concerning patient physical activity were retrieved from PM diagnostics (Activity Log): mean percentage of physical activity, mean intensity of activity. Quality of life (QoL) scores and 6-minute walk test (WT) were also recorded. Single-sensor rate-responsive pacing resulted in symptomatic benefit equally with XL and MV sensors while no additional benefit was found using dual sensor. In a subgroup analysis, patients (17%) with marked chronotropic incompetence and with 0% atrial sensing received benefits from single sensor with an additional advantage from sensor (QoL: +21 +/- 14% P < 0.05; WT: +17 +/- 7% P < 0.02). In most patients with rate-responsive devices, a single sensor is sufficient to achieve a satisfactory rate response. A dual sensor combination and optimization provides an additional benefit only in a selected population with an advanced atrial chronotropic disease.


Testing the children: do non-genetic health-care providers differ in their decision to advise genetic presymptomatic testing on minors? A cross-sectional study in five countries in the European Union.
Within Europe many guidelines exist regarding the genetic testing of minors. Predictive and presymptomatic genetic testing of minors is recommended for disorders for which medical intervention/preventive measures exist, and for which early detection improves future medical health. This study, which is part of the larger 5th EU-framework "genetic education" (GenEd) study, aimed to evaluate the self-reported responses of nongenetic health-care providers in five different EU countries (Germany, France, Sweden, the United Kingdom, and the Netherlands) when confronted with a parent requesting presymptomatic testing on a minor child for a treatable disease. A cross-sectional study design using postal, structured scenario-based questionnaires that were sent to 8129 general practitioners (GPs) and pediatricians, between July 2004 and October 2004, addressing self-reported management of a genetic case for which early medical intervention during childhood is beneficial, involving a minor. Most practitioners agreed on testing the oldest child, aged 12 years (81.5% for GPs and 87.2% for pediatricians), and not testing the youngest child, aged 6 months (72.6% for GPs and 61.3% for pediatricians). After multivariate adjustment there were statistical differences between countries in recommending a genetic test for the child at the age of 8 years. Pediatricians in France (50%) and Germany (58%) would recommend a test, whereas in the United Kingdom (22%), Sweden (30%), and the Netherlands (32%) they would not. Even though presymptomatic genetic testing in minors is recommended for disorders for which medical intervention exists, EU physicians are uncertain at what age starting to do so in young children.


Risk of hepatocellular carcinoma in chronic hepatitis B: assessment and modification with current antiviral therapy.
In the treatment of chronic hepatitis B (CHB), the ultimate goal is preventing hepatitis B virus (HBV)-associated liver disease, including hepatocellular carcinoma (HCC). Recently published studies show that in CHB patients treated with the currently recommended first-line nucleos(t)ide analogs (NAs) entecavir or tenofovir, annual HCC incidences range from 0.01% to 1.4% in non-cirrhotic patients, and from 0.9% to 5.4% in those with cirrhosis. In Asian studies including matched untreated controls, current NA therapy consistently resulted in a significantly lower HCC incidence in patients with cirrhosis, amounting to an overall HCC risk reduction of ∼30%; in non-cirrhotic patients, HCC risk reduction was overall ∼80%, but this was only observed in some studies. For patients of Caucasian origin, no appropriate comparative studies are available to date to evaluate the impact of NA treatment on HCC. Achievement of a virologic response under current NA therapy was associated with a lower HCC risk in Asian, but not Caucasian studies. Studies comparing entecavir or tenofovir with older NAs generally found no difference in HCC risk reduction between agents, except for one study which used no rescue therapy in patients developing lamivudine resistance. Overall, these data indicate that with the current, potent NAs, HCC risk can be reduced but not eliminated, probably due to risk factors that are not amenable to change by antiviral therapy, or events that may have taken place before treatment initiation. Validated pre- and on-therapy HCC risk calculators that inform the best practice for HCC surveillance and facilitate patient counseling would be of great practical value.


Cost-effectiveness of integrated collaborative care for comorbid major depression in patients with cancer.
Comorbid major depression is associated with reduced quality of life and greater use of healthcare resources. A recent randomised trial (SMaRT, Symptom Management Research Trials, Oncology-2) found that a collaborative care treatment programme (Depression Care for People with Cancer, DCPC) was highly effective in treating depression in patients with cancer. This study aims to estimate the cost-effectiveness of DCPC compared with usual care from a health service perspective. Costs were estimated using UK national unit cost estimates and health outcomes measured using quality-adjusted life-years (QALYs). Incremental cost-effectiveness of DCPC compared with usual care was calculated and scenario analyses performed to test alternative assumptions on costs and missing data. Uncertainty was characterised using cost-effectiveness acceptability curves. The probability of DCPC being cost-effective was determined using the UK National Institute for Health and Care Excellence's (NICE) cost-effectiveness threshold range of £ 20,000 to £ 30,000 per QALY gained. DCPC cost on average £ 631 more than usual care per patient, and resulted in a mean gain of 0.066 QALYs, yielding an incremental cost-effectiveness ratio of £ 9549 per QALY. The probability of DCPC being cost-effective was 0.9 or greater at cost-effectiveness thresholds above £ 20,000 per QALY for the base case and scenario analyses. Compared with usual care, DCPC is likely to be cost-effective at the current thresholds used by NICE. This study adds to the weight of evidence that collaborative care treatment models are cost-effective for depression, and provides new evidence regarding their use in specialist medical settings.


Splitting hairs: differentiating between entomological activity, taphonomy, and sharp force trauma on hair.
The analysis of hair can provide useful information for the correct evaluation of forensic cases, but studies of trauma on hair are extremely rare. Hair may present lesions caused by traumatic events or by animals: in fact, signs of sharp force weapons on hair may provide important information for the reconstruction of the manner of death, and, for example, may suggest fetishist practice. This study stemmed from a judicial case where it was fundamental to distinguish between sharp force lesions and insect activity on hair. In order to highlight differences between sharp force lesions and insect feeding activity, different experiments were performed with high power microscopy: hair samples were subjected to several lesions by blunt and sharp force trauma; then samples were used as pabulum for two taxa of insects: the common clothes moth (Tineola bisselliella Lepidoptera, Tineidae) and the carpet beetle (Anthrenus sp., Coleoptera, Dermestidae). Hairs were examined from a macroscopic and microscopic point of view by stereomicroscopy and scanning electron microscopy (SEM): the morphological characteristics of the lesions obtained from the different experimental samples were compared. Results show that sharp force trauma produces lesions with regular edges, whereas insects leave concave lesions caused by their "gnawing" activity. These two types of lesions are easily distinguishable from breaking and tearing using SEM. This study demonstrates that insect activity leaves very specific indications on hair and sheds some light on different hair lesions that may be found in forensic cases.


Characterization of the Vitrocell® 24/48 in vitro aerosol exposure system using mainstream cigarette smoke.
Only a few exposure systems are presently available that enable cigarette smoke exposure of living cells at the air-liquid interface, of which one of the most versatile is the Vitrocell® system (Vitrocell® Systems GmbH). To assess its performance and optimize the exposure conditions, we characterized a Vitrocell® 24/48 system connected to a 30-port carousel smoking machine. The Vitrocell® 24/48 system allows for simultaneous exposure of 48 cell culture inserts using dilution airflow rates of 0-3.0 L/min and exposes six inserts per dilution. These flow rates represent cigarette smoke concentrations of 7-100%. By characterizing the exposure inside the Vitrocell® 24/48, we verified that (I) the cigarette smoke aerosol distribution is uniform across all inserts, (II) the utility of Vitrocell® crystal quartz microbalances for determining the online deposition of particle mass on the inserts, and (III) the amount of particles deposited per surface area and the amounts of trapped carbonyls and nicotine were concentration dependent. At a fixed dilution airflow of 0.5 L/min, the results showed a coefficient of variation of 12.2% between inserts of the Vitrocell® 24/48 module, excluding variations caused by different runs. Although nicotine and carbonyl concentrations were linear over the tested dilution range, particle mass deposition increased nonlinearly. The observed effect on cell viability was well-correlated with increasing concentration of cigarette smoke. Overall, the obtained results highlight the suitability of the Vitrocell® 24/48 system to assess the effect of cigarette smoke on cells under air-liquid interface exposure conditions, which is closely related to the conditions occurring in human airways.


Parenteral glutathione monoester enhances tissue antioxidant stores.
Glutathione (GSH) is a potent endogenous antioxidant that protects major organs from oxidant injury. However, present nutrition regimens may inadequately support tissue stores of this tripeptide during critical illness. To determine whether GSH reserves can be enhanced in vivo with intravenous (IV) supplements, rats underwent central venous catheterization, were given chow and water ad libitum during a 2-day recovery period, and were then randomized to receive one of three treatments as an IV bolus: (1) dextrose, (2) glutathione (GSH), or (3) glutathione monoethyl ester. GSH monoethyl ester is transported into cells more easily than is GSH. Tissue and plasma samples were analyzed for GSH at 2 and 4 hours after drug administration. Liver, renal, and ileal mucosal GSH were significantly increased in the GSH-monoethyl ester rats compared with dextrose-treated animals. In addition, plasma GSH was dramatically increased after monoester injection. In contrast, GSH administration depressed liver GSH stores and did not significantly affect GSH concentration in the other organs analyzed. Plasma GSH concentration was elevated 2 hours after GSH administration. We conclude that: (1) the monoethyl ester of glutathione can be used in vivo to enhance tissue and plasma GSH concentration and (2) IV GSH administration does not significantly increase tissue GSH levels and may paradoxically depress hepatic GSH in normal rats. Because the malnourished and critically ill are likely to have depleted GSH stores, nutrition strategies that include the provision of GSH monoester may lend additional support to those organs that are at risk for injury from oxygen free radicals during catabolic states.


The oldest North American primate and mammalian biogeography during the Paleocene-Eocene Thermal Maximum.
Undoubted primates first appear almost synchronously in the fossil records of Asia, Europe, and North America. This temporal pattern has complicated efforts to reconstruct the early dispersal history of primates in relation to global climate change and eustatic fluctuations in sea level. Here, I describe fossils from the Tuscahoma Formation on the Gulf Coastal Plain of Mississippi documenting an anatomically primitive species of Teilhardina that is older than other North American and European primates. Consistent with its antiquity, a phylogenetic analysis of dental characters recognizes Teilhardina magnoliana, sp. nov., as the most basal member of this genus currently known from either North America or Europe. Its stratigraphic provenance demonstrates that primates originally colonized North America near the base of the Paleocene-Eocene Thermal Maximum (PETM), but before an important fall in eustatic sea level. Correlation based on carbon isotope stratigraphy and sequence stratigraphy indicates that the earliest North American primates inhabited coastal regions of the continent for thousands of years before they were able to colonize the Rocky Mountain Interior. The transient provincialism displayed by early North American primates corresponds to similar biogeographic patterns noted among fossil plants. Decreased precipitation in the Rocky Mountain Interior during the early part of the PETM may have been an important factor in maintaining biotic provincialism within North America at this time. These results underscore the need to obtain multiple, geographically dispersed records bearing on significant macroevolutionary events such as the PETM.


Long-term results of transcatheter closure of patent ductus arteriosus in infants using amplatzer duct occluder.
Patent ductus arteriosus (PDA) is one of the most frequently seen congenital heart diseases. Its closure is recommended because of the risk of infective endocardis, as well as morbidity and mortality in the long. The aim of this study was to assess the long term results of the transcatheter closure of PDA in infants using amplatzer duct occlude (ADO). From May 2004 to September 2011, forty eight infants underwent transcatheter closure of PDA. A lateral or right anterior oblique view aortogram was done to locate PDA and to measure its size. Before discharge, repeat aortogram was performed to evaluate eventual residual shunt and to confirm the appropriate deployment of the ADO. Follow up evaluations were done with transthoracic echocardiography at discharge, 1 month, 6 months, 12 months and yearly thereafter. The mean age of patients at procedure was 9.18±2.32 (range 3 to 12) months, mean weight 6.73±1.16 (range 4.5 to 10.1) kg. The PDA occluded completely in 20 out of the 48 patients. Twenty four patients had trivial or mild shunt and two patients had moderate residual shunt which disappeared in one patient within 24 hours and other patient with moderate shunt in 1 month. One patient (age 8 months) had mild LPA stenosis. The device emobolization occurred in two patients, immediately after the procedure in one and during night in the other patient. The long term results suggested that transcatheter closure of PDA using Amplatzer duct occluder is a safe and effective treatment in infants less than 1 year of age with minimal complications.


Health plan use of immunization information systems for quality measurement.
To evaluate a health plan's business case for using a state immunization information system (IIS) as the primary data source for members' immunization histories. Case study of Priority Health, a Michigan managed care organization, to investigate use of IIS data for Healthcare Effectiveness Data and Information Set (HEDIS) compliance, quality measurement, and a provider incentive program. Primary data were collected through key informant interviews and group discussions with Priority Health and IIS managers. Priority Health's information systems were populated with claims data and supplemental data, before chart reviews, to simulate immunization and health plan quality measures for 2004 to 2007 in the absence of IIS data. Simulated rates were compared with historical rates that included IIS data. The study included a cost-benefit analysis. For 2007, IIS data increased observed immunization rates from 6.49 to 54.13 percentage points for childhood immunizations and 57.63 to 77.97 percentage points for adolescent immunizations. The HEDIS administrative rate for childhood immunizations doubled from 43.38% in 2003 to 88.08% in 2007. The most significant source of savings was in administration of the health plan's Physician Incentive Program, which saw 18,881 fewer chart reviews from 2004 to 2007 when IIS data were used compared with when they were not used. Total costs of using IIS data were estimated to be $14,318 and net benefits were $107,854 -- corresponding to a benefit-to-cost ratio of 8.06. Health plans using a state IIS as a single point of data entry may realize cost savings and have improved assurance of immunization coverage.


First Report of Alfalfa mosaic virus Infecting Tedera (Bituminaria bituminosa (L.) C.H. Stirton var. albomarginata and crassiuscula) in Australia.
Tedera (Bituminaria bituminosa (L.) C.H. Stirton vars albomarginata and crassiuscula) is being established as a perennial pasture legume in southwest Australia because of its drought tolerance and ability to persist well during the dry summer and autumn period. Calico (bright yellow mosaic) leaf symptoms occurred on occasional tedera plants growing in genetic evaluation plots containing spaced plants at Newdegate in 2007 and Buntine in 2010. Alfalfa mosaic virus (AlMV) infection was suspected as it often causes calico in infected plants (1,2) and infects perennial pasture legumes in local pastures (1,3). Because AlMV frequently infects Medicago sativa (alfalfa) in Australia and its seed stocks are commonly infected (1,3), M. sativa buffer rows were likely sources for spread by aphids to healthy tedera plants. When leaf samples from plants with typical calico symptoms from Newdegate (2007) and Buntine (2010) were tested by ELISA using poyclonal antisera to AlMV, Bean yellow mosaic virus (BYMV) and Cucumber mosaic virus (CMV), only AlMV was detected. When leaf samples from 864 asymptomatic spaced plants belonging to 34 tedera accessions growing at Newdegate and Mount Barker in 2010 were tested by ELISA, no AlMV, BYMV, or CMV were detected, despite presence of M. sativa buffer rows. A culture of AlMV isolate EW was maintained by serial planting of infected seed of M. polymorpha L. (burr medic) and selecting seed-infected seedlings (1,3). Ten plants each of 61 accessions from the local tedera breeding program were grown at 20°C in an insect-proof air conditioned glasshouse. They were inoculated by rubbing leaves with infective sap containing AlMV-EW or healthy sap (five plants each) using Celite abrasive. Inoculations were always done two to three times to the same plants. When both inoculated and tip leaf samples from each plant were tested by ELISA, AlMV was detected in 52 of 305 AlMV-inoculated plants belonging to 36 of 61 accessions. Inoculated leaves developed local necrotic or chlorotic spots or blotches, or symptomless infection. Systemic invasion was detected in 20 plants from 12 accessions. Koch's postulates were fulfilled in 12 plants from nine accessions (1 to 2 of 5 plants each), obvious calico symptoms developing in uninoculated leaves, and AlMV being detected in symptomatic samples by ELISA, inoculation of sap to diagnostic indicator hosts (2) and RT-PCR with AlMV CP gene primers. Direct RT-PCR products were sequenced and lodged in GenBank. When complete nucleotide CP sequences (666 nt) of two isolates from symptomatic tedera samples and two from alfalfa (Aq-JX112758, Hu-JX112759) were compared with that of AlMV-EW, those from tedera and EW were identical (JX112757) but had 99.1 to 99.2% identities to the alfalfa isolates. JX112757 had 99.4% identity with Italian tomato isolate Y09110. Systemically infected tedera foliage sometimes also developed vein clearing, mosaic, necrotic spotting, leaf deformation, leaf downcurling, or chlorosis. Later-formed leaves sometimes recovered, but plant growth was often stunted. No infection was detected in the 305 plants inoculated with healthy sap. To our knowledge, this is the first report of AlMV infecting tedera in Australia or elsewhere. References: (1) B. A. Coutts and R. A. C. Jones. Ann. Appl. Biol. 140:37, 2002. (2) E. M. J. Jaspars and L. Bos. Association of Applied Biologists, Descriptions of Plant Viruses No. 229, 1980. (3) R. A. C. Jones. Aust. J. Agric. Res. 55:757, 2004.


Impact of smoking status on survival after cytoreductive nephrectomy for metastatic renal cell carcinoma.
To assess the association of smoking status with standard clinicopathological features and overall survival (OS) in a large multi-institutional cohort of patients with metastatic renal cell carcinoma (mRCC) treated with cytoreductive nephrectomy (CNT). A total of 613 patients with mRCC treated with CNT in US and Europe institutions between 1990 and 2013 were included. Smoking history comprised smoking status, smoking duration in years, number of cigarettes per day and years since smoking cessation. Cumulative smoking exposure was categorized as light short term, heavy long term and moderate. Association between smoking history and OS was assessed by Cox regression logistic analysis. One hundred and seventy-one patients (27.9 %) never smoked, 193 (31.5 %) were former smokers and 249 (40.6 %) were current smokers. Smoking status was associated with a higher number of metastases (p < 0.001) and an abnormal preoperative corrected calcium level (p = 0.01). Median follow-up was 16 (IQR 7-24) months. Current smokers had a shorter OS than never and former smokers (log rank, p = 0.004). Smoking status was significantly associated with OS in univariable analysis (HR 1.45; 95 % CI 1.16-1.82; p < 0.001), and in multivariable analysis that adjusted for established prognostic factors (HR 1.46; 95 % CI 1.16-1.84; p = 0.002). Daily consumption of more than 20 cigarettes, more than 20 years of smoking exposure and heavy long exposure were all independent prognosticators of worse OS. Current smoking and a higher cumulative smoking exposure are associated with a higher risk of death in patients with mRCC treated with CNT. Even at this stage, smoking negatively affects kidney cancer outcomes.


Hes1 expression is reduced in Tbx1 null cells and is required for the development of structures affected in 22q11 deletion syndrome.
22q11 deletion syndrome (22q11DS) is characterised by aberrant development of the pharyngeal apparatus and the heart with haploinsufficiency of the transcription factor TBX1 being considered the major underlying cause of the disease. Tbx1 mutations in mouse phenocopy the disorder. In order to identify the transcriptional dysregulation in Tbx1-expressing lineages we optimised fluorescent-activated cell sorting of beta-galactosidase expressing cells (FACS-Gal) to compare the expression profile of Df1/Tbx1(lacZ) (effectively Tbx1 null) and Tbx1 heterozygous cells isolated from mouse embryos. Hes1, a major effector of Notch signalling, was identified as downregulated in Tbx1(-)(/)(-) mutants. Hes1 mutant mice exhibited a partially penetrant range of 22q11DS-like defects including pharyngeal arch artery (PAA), outflow tract, craniofacial and thymic abnormalities. Similar to Tbx1 mice, conditional mutagenesis revealed that Hes1 expression in embryonic pharyngeal ectoderm contributes to thymus and pharyngeal arch artery development. These results suggest that Hes1 acts downstream of Tbx1 in the morphogenesis of pharyngeal-derived structures.


Is serum or plasma more appropriate for intersubject comparisons in metabolomic studies? An assessment in patients with small-cell lung cancer.
In clinical analyses, the most appropriate biofluid should be analyzed for optimal assay performance. For biological fluids, the most readily accessible is blood, and metabolomic analyses can be performed either on plasma or serum. To determine the optimal agent for analysis, metabolic profiles of matched human serum and plasma were assessed by gas chromatography/time-of-flight mass spectrometry and ultrahigh-performance liquid chromatography mass spectrometry (in positive and negative electrospray ionization modes). Comparison of the two metabolomes, in terms of reproducibility, discriminative ability and coverage, indicated that they offered similar analytical opportunities. An analysis of the variation between 29 small-cell lung cancer (SCLC) patients revealed that the differences between individuals are markedly similar for the two biofluids. However, significant differences between the levels of some specific metabolites were identified, as were differences in the intersubject variability of some metabolite levels. Glycerophosphocholines, erythritol, creatinine, hexadecanoic acid, and glutamine in plasma, but not in serum, were shown to correlate with life expectancy for SCLC patients, indicating the utility of metabolomic analyses in clinical prognosis and the particular utility of plasma in relation to the clinical management of SCLC.


Disentangling the impact of low cognitive ability and inattention on social behavior and peer relationships. Conduct Problems Prevention Re search Group.
Examined the shared and unique contributions of low cognitive ability and inattention to the development of social behavior problems and peer relationships of children at the time of school entry. Kindergarten and first-grade assessments of cognitive ability, inattention and prosocial and aggressive behavior were collected for a multisite, normative sample. Sociometric assessments of peer relationships were collected at the end of first grade. Cognitive ability and inattention both contributed to the prediction of social behavior and peer relationships. Low cognitive ability was particularly predictive of prosocial skill deficits, and social behavior mediated the relation between cognitive ability and social preference. Inattention predicted both prosocial skill deficits and elevated aggressive-disruptive behavior problems. Behavior problems partially mediated the relation between inattention and social preference. Identified subgroups of children with elevated levels of inattention or low cognitive ability showed different patterns of peer problems, with low acceptance characteristic of the low cognitive ability (only) group and high dislike ratings characteristic of the inattentive and inattentive/low-ability group. Implications are discussed for the design of early intervention and prevention programs.


Oxidant effects on californian coastal sage scrub.
Causes for the reduced cover of native species of coastal sage scrub in certain southern Californian sites wvere sought among 43 habitat variables. The mean annual concentration of oxidants (which averaged 18 parts per 100 million on the 11 most polluted sites) is statistically indicated as the most likely causal factor. Sites of high oxidant levels in the region are also characterized by declining species richness and equitability.


Atlanto-axial rotatory fixation. (Fixed rotatory subluxation of the atlanto-axial joint).
In seventeen cases of irreducible atlanto-axial rotatory subluxation (here called fixation), the striking features were the delay in diagnosis and the persistent clinical and roentgenographic deformities. All patients had torticollis and restricted, often painful neck motion, and seven young patients with long-standing deformity had flattening on one side of the face. The diagnosis was suggested by the plain roentgenograms and tomograms and confirmed by persistence of the deformity as demonstrated by cineroentgenography. Treatment included skull traction, followed by atlanto-axial arthrodesis if necessary. Of the thirteen patients treated by atlanto-axial arthrodesis, eleven had good results, one had a fair result, and one had not been followed for long enough to determine the result. Of the remaining four patients, one treated conservatively had not been followed for long enough to evaluate the result, two declined surgery, and one died while in traction as the result of cord transection produced by further rotation of the atlas on the axis despite the traction.


The price of fame: the impact of stimulus familiarity on proactive interference resolution.
Interference from previously learned information, known as proactive interference (PI), limits our memory retrieval abilities. Previous studies of PI resolution have focused on the role of short-term familiarity, or recency, in causing PI. In the present study, we investigated the impact of long-term stimulus familiarity on PI resolution processes. In two behavioral experiments and one event-related fMRI experiment, long-term familiarity was manipulated through the use of famous and nonfamous stimuli, and short-term familiarity was manipulated through the use of recent and nonrecent probe items in an item recognition task. The right middle frontal gyrus demonstrated greater sensitivity to famous stimuli, suggesting that long-term stimulus familiarity plays a role in influencing PI resolution processes. Further examination of the effect of long-term stimulus familiarity on PI resolution revealed a larger behavioral interference effect for famous stimuli, but only under speeded response conditions. Thus, models of memory retrieval--and of the cognitive control mechanisms that guide retrieval processes--should consider the impact of and interactions among sources of familiarity on multiple time scales.


Should we adjust for gestational age when analysing birth weights? The use of z-scores revisited.
Birth weight is the single most important risk indicator for neonatal and infant mortality and morbidity, which has led to the idiom that 'every ounce counts'. Birth weight in turn, however, tends to vary widely across populations as a result of differential fetal growth velocity with such demographic factors as ethnicity, maternal and paternal height and altitude of residence. Accordingly, it has been acknowledged that the appraisal of birth weight should rely on its position relative to the birth weight distribution of the background population. This is commonly done by standardizing birth weight through its deviation from the population mean in the given gestational age stratum, as can be obtained from population-customized birth weight nomograms. This issue was recently revisited in 'Human Reproduction' through a plea for reporting birth weight as z-scores. In this article, we argue that adjustment for factors, such as gestational age, which may lie on the causal pathway from exposures present at the time of conception [e.g. single-embryo transfer (SET) versus double-embryo transfer (DET)] to birth weight, may induce bias, regardless of whether the adjustment happens via stratification, regression or through the use of z-scores.


Stimulation of macrophage phagocytic but not bactericidal activity by colony-stimulating factor 1.
The ability of mouse peritoneal cells to phagocytose and lyse Listeria monocytogenes was measured after the cells were incubated with purified murine macrophage-specific colony-stimulating factor (CSF-1). Activation of combined phagocytic and bacteriolytic ability required 24 h, with an optimal dose of 1,000 U of CSF-1 per ml. No activation was achieved with a shorter period of incubation, known to be sufficient for GM-CSF to stimulate phagocytosis by granulocytes, and there was no advantage in longer exposure. After 24 h in 1,000 U of CSF-1, macrophages showed visibly increased spreading on the plastic petri dish. Activated cells examined microscopically showed an increase in the number of phagocytic cells and in the numbers of bacteria per phagocytic cell. This increased phagocytic ability was evident also in the increase in the amount of radioactivity associated with the cells following a 30-min incubation with radiolabeled bacteria. When these cells were carefully washed, the percentage of this initial uptake released during the next 2 h was not increased by pretreatment of the cells with CSF-1, showing that the effect of this growth factor was on phagocytosis of the bacteria not on the killing mechanisms per se.


The role of BRAF V600E mutation as a potential marker for prognostic stratification of papillary thyroid carcinoma: a long-term follow-up study.
Abstract Papillary carcinoma is the most prevalent malignancy of thyroid gland, and its incidence has been recently increased. The BRAF(V600E) mutation is the most frequent genetic alteration in papillary thyroid carcinoma (PTC). The role of BRAF(V600E) mutation as a potential prognostic factor has been controversially reported in different studies, with short-term follow-up. In this study, we evaluated the role of BRAF(V600E) mutation as a potential marker for prognostic stratification of patients with PTC in long-term follow-up. We studied 69 PTC patients with a mean follow-up period of 63.9 months (median: 60 m). The BRAF(V600E) mutation was analyzed by PCR-single-strand conformational polymorphism and sequencing. The correlation between the presence or absence of the BRAF(V600E) mutation, clinicopathological features and prognosis of PTC patients were studied. The BRAF(V600E) mutation was found in 28 of 69 (40.6%) PTC patients, and it was significantly more frequent in older patients (p < 0.001), in advanced tumor stages (p = 0.006) and in patients with history of radiation exposure (p = 0.037). Incomplete response to treatment in PTC patients was significantly correlated with certain clinicopathological characteristics (follow-up time, distant metastases, advanced stage, first thyroglobulin (fTg) level, history of reoperation and external radiotherapy and delay in iodine therapy) but it was not related to the presence of BRAF(V600E) mutation. Prevalence of BRAF(V600E) mutation was 40.6% in patients with papillary thyroid cancer in northeast of Iran. The BRAF(V600E) mutation was associated with older age and advanced tumor stage but was not correlated with incomplete response during follow-up.


Neutrophil transit time and localization within the megakaryocyte define morphologically distinct forms of emperipolesis.
Neutrophils transit through megakaryocytes in a process termed emperipolesis, but it is unknown whether this interaction is a single type of cell-in-cell interaction or a set of distinct processes. Using a murine in vitro model, we characterized emperipolesis by live-cell spinning disk microscopy and electron microscopy. Approximately half of neutrophils exited the megakaryocyte rapidly, typically in 10 minutes or less, displaying ameboid morphology as they passed through the host cell (fast emperipolesis). The remaining neutrophils assumed a sessile morphology, most remaining within the megakaryocyte for at least 60 minutes (slow emperipolesis). These neutrophils typically localized near the megakaryocyte nucleus. By ultrastructural assessment, all internalized neutrophils remained morphologically intact. Most neutrophils resided within emperisomes, but some could be visualized exiting the emperisome to enter the cell cytoplasm. Neutrophils in the cytoplasm assumed close contact with the platelet-forming demarcation membrane system or the perinuclear endoplasmic reticulum. These findings reveal that megakaryocyte emperipolesis reflects at least 2 distinct processes differing in transit time and morphology, fast and slow emperipolesis, suggesting divergent physiologic functions.


Surgical indication and outcome in patients with postoperative retethered cord syndrome.
After untethering of spinal dysraphism, some patients present with neurological deterioration, defined as retethered cord syndrome. It is known that surgical untethering is an option for improving the symptoms of retethered cord syndrome. Previous reports have shown that postoperative improvement in retethered cord syndrome was noted in the majority of patients presenting with pain, and in more patients with motor weakness than in those with urological symptoms. The authors speculate that subjective symptoms may be detected while symptoms are still reversible. In contrast, changes in urological function are less easy to diagnose, and delays in treatment may be complicated by advanced symptoms. In this study, patients with retethered cord syndrome were evaluated to investigate the benefits of performing routine urodynamic study to detect detrusor overactivity, which is considered to be a subclinical change of urological function, and to investigate the efficacy of early untethering surgery on the symptoms of retethered cord syndrome. Surgical indications and outcomes of 78 untethering operations (20 for myelomeningocele, 58 for spinal lipoma) for retethered cord syndrome were examined. Diagnosis of retethered cord syndrome was defined by a multidisciplinary spina bifida team, and included routine urodynamic study. Preoperative symptoms included urological symptoms (70%), lower-extremity symptoms (45%), and others. The most frequent urological symptom was detrusor overactivity detected by urodynamic study (88.7%). Urinary incontinence was only found in 9.4% of patients. Postoperatively, progressive motor weakness improved in all patients, and sensory symptoms improved in 94%. Urological symptoms improved in 80% of the patients with urinary incontinence and in 75% of the patients with detrusor overactivity. Postoperative urodynamic study showed a significant increase in bladder volume (p < 0.05). The most common complication was temporary lower leg paresthesia that recovered at follow-up. Aggravated dysuria was noted in 3 patients. Early untethering operations offer symptomatic relief to patients with retethered cord syndrome. Urodynamic study findings, especially detrusor overactivity, are considered to be the most significant indicators for early diagnosis of retethered cord syndrome.


Interleukin-1 alpha modulates collagen gene expression in cultured synovial cells.
The effects of porcine interleukin-1 (IL-1) alpha on collagen production were studied in cultured human rheumatoid synovial cells. Addition of 0.05-5 ng of IL-1/ml into the cultures resulted in a dose-dependent decreased rate of collagen released into the medium over 24 h. To determine whether this inhibition was due to secondary action of prostaglandin E2 (PGE2) secreted in response to IL-1, cultures were incubated in presence of various inhibitors of arachidonate metabolism. Depending on the cell strains, these inhibitors were able to suppress or diminish the effect of IL-1, suggesting that PGE2 is involved in the mechanism. Depression of collagen production caused by IL-1 mainly affected type I collagen and therefore led to a change in the type I/type III collagen ratio in the extracellular medium. Steady-state levels of mRNA for types I and III procollagens were estimated by dot-blot hybridization and compared with the amounts of respective collagens produced in the same cultures. IL-1 generally increased procollagen type I mRNA, but to a variable extent, as did indomethacin (Indo). Depending on the cell strain, the combination of indo and IL-1 could elevate the mRNA level of type I procollagen compared with Indo alone. These results did not correlate with the production rate of collagen in the medium, which was diminished by exposure to IL-1. The level of mRNA for collagen type III was not greatly changed by incubation with IL-1, and a better correlation was generally observed with the amount of type III collagen found in the medium. These data suggest that an additional control mechanism at translational or post-translational level must exist, counterbalancing the stimulatory effect of IL-1 on collagen mRNA transcription. It is likely that IL-1 could modulate the production of collagen in synovial cells by an interplay of different mechanisms, some of them limiting the effect of primary elevation of the steady-state mRNA level.


Quantifying the lifetime circadian rhythm of physical activity: a covariate-dependent functional approach.
Objective measurement of physical activity using wearable devices such as accelerometers may provide tantalizing new insights into the association between activity and health outcomes. Accelerometers can record quasi-continuous activity information for many days and for hundreds of individuals. For example, in the Baltimore Longitudinal Study on Aging physical activity was recorded every minute for [Formula: see text] adults for an average of [Formula: see text] days per adult. An important scientific problem is to separate and quantify the systematic and random circadian patterns of physical activity as functions of time of day, age, and gender. To capture the systematic circadian pattern, we introduce a practical bivariate smoother and two crucial innovations: (i) estimating the smoothing parameter using leave-one-subject-out cross validation to account for within-subject correlation and (ii) introducing fast computational techniques that overcome problems both with the size of the data and with the cross-validation approach to smoothing. The age-dependent random patterns are analyzed by a new functional principal component analysis that incorporates both covariate dependence and multilevel structure. For the analysis, we propose a practical and very fast trivariate spline smoother to estimate covariate-dependent covariances and their spectra. Results reveal several interesting, previously unknown, circadian patterns associated with human aging and gender.


Impact of Donor Type in Patients with AML Given Allogeneic Hematopoietic Cell Transplantation After Low-Dose TBI-Based Regimen.
Purpose: We assessed the impact of donor type in acute myeloid leukemia (AML) patients transplanted with 2 Gy total body irradiation (TBI)-based nonmyeloablative conditioning regimen.Patients and Methods: Data from 1,715 adult patients, with AML in CR1 or CR2 were included in this retrospective survey.Results: Donors consisted either of HLA-matched sibling donors (MSD, n = 701), 10/10 HLA-matched unrelated donors (MUD, n = 611), HLA-haploidentical donors (haplo, n = 112) or single or double umbilical cord bloods (CBT, n = 291). Chronic graft-versus-host disease (GVHD) was less frequent in CBT (28%) and in haplo (30%) patients than in MSD (50%) and MUD (51%) recipients (P < 0.001). Two-year incidence of relapse was 32%, 30%, 34%, and 34% in MSD, MUD, CBT and haplo patients, respectively (P = 0.7). Two-year overall (OS) and GVHD-free relapse-free survival (GRFS) were 59% and 29% in MSD patients, 56% and 39% in CBT recipients, 53% and 23% in MUD recipients, and 43% and 37% in haplo patients, respectively. In multivariate analyses, MUD patients had lower GRFS than MSD patients beyond day 100 (HR 1.3, P = 0.001) while CBT was associated with a better GRFS than MSD beyond day 100 (HR 0.6, P = 0.002).Conclusions: In this large cohort of AML patients transplanted following low-dose TBI-based conditioning, the relapse incidence was not affected by donor type suggesting that the intensity of GVL effects might be comparable with these four transplant approaches. Furthermore, CBT was associated with better GRFS beyond day 100 than MSD while the opposite was observed for MUD. Clin Cancer Res; 24(12); 2794-803. ©2018 AACR.


An evaluation of the toxicity and bioaccumulation of bismuth in the coastal environment using three species of macroalga.
Bismuth is a heavy metal whose biogeochemical behaviour in the marine environment is poorly defined. In this study, we exposed three different species of macroalga (the chlorophyte, Ulva lactuca, the phaeophyte, Fucus vesiculosus, and the rhodophyte, Chondrus crispus) to different concentrations of Bi (up to 50 μg L(-1)) under controlled, laboratory conditions. After a period of 48-h, the phytotoxicity of Bi was measured in terms of chlorophyll fluorescence quenching, and adsorption and internalisation of Bi determined by ICP after EDTA extraction and acid digestion, respectively. For all algae, both the internalisation and total accumulation of Bi were proportional to the concentration of aqueous metal. Total accumulation followed the order: F. vesiculosus > C. crispus > U. lactuca; with respective accumulation factors of about 4200, 1700 and 600 L kg(-1). Greatest internalisation (about 33% of total accumulated Bi) was exhibited by C. crispus, the only macroalga to display a phytotoxic response in the exposures. A comparison of the present results with those reported in the literature suggests that Bi accumulation by macroalgae is significantly lower than its accumulation by marine plankton (volume concentration factors of 10(5) to 10(7)), and that the phytotoxicity of Bi is low relative to other heavy metals like Ag and Tl.


Pharmacology and Structural Analysis of Ligand Binding to the Orthosteric Site of Glutamate-Like GluD2 Receptors.
The GluD2 receptor is a fundamental component of postsynaptic sites in Purkinje neurons, and is required for normal cerebellar function. GluD2 and the closely related GluD1 are classified as members of the ionotropic glutamate receptor (iGluR) superfamily on the basis of sequence similarity, but do not bind l-glutamate. The amino acid neurotransmitter D-Ser is a GluD2 receptor ligand, and endogenous D-Ser signaling through GluD2 has recently been shown to regulate endocytosis of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-type iGluRs during synaptic plasticity in the cerebellum, such as long-term depression. Here, we investigate the pharmacology of the orthosteric binding site in GluD2 by examining the activity of analogs of D-Ser and GluN1 glycine site competitive antagonists at GluD2 receptors containing the lurcher mutation (GluD2(LC)), which promotes spontaneous channel activation. We identify several compounds that modulate GluD2(LC), including a halogenated alanine analog as well as the kynurenic acid analog 7-chloro-4-oxo-1H-quinoline-2-carboxylic acid (7-chlorokynurenic acid; 7-CKA). By correlating thermodynamic and structural data for 7-CKA binding to the isolated GluD2 ligand binding domain (GluD2-LBD), we find that binding 7-CKA to GluD2-LBD differs from D-Ser by inducing an intermediate cleft closure of the clamshell-shaped LBD. The GluD2 ligands identified here can potentially serve as a starting point for development of GluD2-selective ligands useful as tools in studies of the signaling role of the GluD2 receptor in the brain.


Multilayered optical memory with bits stored as refractive index change. II. Numerical results of a waveguide multilayered optical memory.
In terms of the electromagnetic theory described in Part I of our current investigations [J. Opt. Soc. Am. A24, 1776 (2007)], the numerical method for and results of numerical computations corresponding to the electromagnetic theory of a waveguide multilayered optical memory are presented. Here the characteristics of the cross talk and the modulation contrast, the power of readout signals, the variation of the power of the readout signals with the scanning position along the track, and the distribution of the light intensity at the detector are investigated in detail. Results show that the polarization of the reading light, the feature sizes of bits, and the distances between the two adjacent tracks and the two adjacent bits on the same track have significant effects on the distribution of the light intensity at the detector, the power of the readout signals, the cross talk, and the modulation contrast. In addition, the optimal polarization of the reading light is also suggested.


Anisotropy of water diffusion in the myocardium of the rat.
Pulsed field gradient nuclear magnetic resonance methods combined with nuclear magnetic resonance imaging were used to determine the water diffusion anisotropy in perfused rat hearts at 37 degrees C. It was found that the observed diffusion coefficient D(app) (apparent diffusion coefficient) depends on the orientation of the applied gradient g. When g is parallel to the epicardial surface, the observed diffusivity is D(app) parallel = 1.8 +/- 0.4 x 10(-9) m2.s-1, whereas when g is perpendicular to it, diffusivity is D(app) perpendicular = 2.5 +/- 0.5 x 10(-9) m2.s-1. To better characterize this directional dependence, images of the second-order diffusion tensor D of the myocardium were obtained. These data demonstrate several essential features of cardiac myoarchitecture, including the helicity of fiber orientation with respect to the ventricular axis and the variation of fiber pitch angle with transmural depth. Diffusion anisotropy may be quantified in a coordinate-independent manner by the eigenvalues of the diffusion tensor. In the myocardial midwall, these eigenvalues were E1 = 3.29 +/- 0.57, E2 = 2.01 +/- 0.42, and E3 = 0.77 +/- 0.58 x 10(-9) m2.s-1 (mean +/- SD). These data suggest that myocardial water diffusion is essentially unrestricted parallel to the myofibers. They further show that failure to measure the complete diffusion tensor may lead to substantial underestimates of diffusion anisotropy in the myocardium.


Mammography screening and the increase in breast cancer incidence in Hawaii.
This ecological study investigated the association between mammography utilization and breast cancer incidence in Hawaii with the hypothesis that geographic areas with high mammography use have higher breast cancer incidence than geographic areas with low mammography use. Insurance claims for mammograms received during 1992 and 1993 were combined with breast cancer incidence data from the Hawaii Tumor Registry and data from the 1990 Census ZIP File. The claims data were obtained from four private and three public health plans and covered approximately 85% of women 40 years of age and older. Age-specific breast cancer incidence rates for the 79 ZIP code areas were regressed on mammography rates and selected aggregate demographic variables using multiple linear regression. An estimated 42% of women 40 years of age and older had received at least 1 mammogram during 1992 and 1993, with the highest rate (45%) in women ages 50-64 years old. Overall, 23% of the variation in age-specific breast cancer incidence could be predicted by mammography utilization, 23% by increasing age, and 4% by higher education. The relationship between mammography use and breast cancer incidence was strongest for women 50-64 years old and for localized disease. The magnitude of the association between breast cancer incidence and mammography utilization was comparable to the increase in breast cancer rates observed in Hawaii during the mid-1980s, supporting the hypothesis that the sharp increase in breast cancer incidence was attributable to screening and early detection. However, the long-term 1% increase in breast cancer incidence requires alternate explanations.


Negative Skeletal Effects of Locally Produced Adiponectin.
Epidemiological studies show that high circulating levels of adiponectin are associated with low bone mineral density. The effect of adiponectin on skeletal homeostasis, on osteoblasts in particular, remains controversial. We investigated this issue using mice with adipocyte-specific over-expression of adiponectin (AdTg). MicroCT and histomorphometric analysis revealed decreases (15%) in fractional bone volume in AdTg mice at the proximal tibia with no changes at the distal femur. Cortical bone thickness at mid-shafts of the tibia and at the tibiofibular junction was reduced (3-4%) in AdTg mice. Dynamic histomorphometry at the proximal tibia in AdTg mice revealed inhibition of bone formation. AdTg mice had increased numbers of adipocytes in close proximity to trabecular bone in the tibia, associated with increased adiponectin levels in tibial marrow. Treatment of BMSCs with adiponectin after initiation of osteoblastic differentiation resulted in reduced mineralized colony formation and reduced expression of mRNA of osteoblastic genes, osterix (70%), Runx2 (52%), alkaline phosphatase (72%), Col1 (74%), and osteocalcin (81%). Adiponectin treatment of differentiating osteoblasts increased expression of the osteoblast genes PPARγ (32%) and C/ebpα (55%) and increased adipocyte colony formation. These data suggest a model in which locally produced adiponectin plays a negative role in regulating skeletal homeostasis through inhibition of bone formation and by promoting an adipogenic phenotype.


Estimated burden of serious human fungal diseases in Turkey.
The current number of fungal infections occurring each year in Turkey is unknown. We estimated the burden of serious human fungal diseases based on the population at risk, existing epidemiological data from 1920 to 2017 and modelling previously described by the LIFE program (http://www.LIFE-worldwide.org). Among the population of Turkey (80.8 million in 2017), approximately 1 785 811 (2.21%) people are estimated to suffer from a serious fungal infection each year. The model used predicts high prevalences of allergic fungal rhinosinusitis episodes (312 994 cases) (392/100 000), of severe asthma with fungal sensitisation (42 989 cases) (53.20 cases/100 000 adults per year), of allergic bronchopulmonary aspergillosis (32 594 cases) (40.33/100 000), of fungal keratitis (26 671 cases) (33/100 000) and of chronic pulmonary aspergillosis (5890 cases) (7.29/100 000). The estimated annual incidence for invasive aspergillosis is lower (3911 cases) (4.84/100 000 annually). Among about 22.5 million women aged 15-50 years, recurrent vulvovaginal candidiasis is estimated to occur in 1 350 371 (3342/100 000) females. The burden of three superficial fungal infections was also estimated: tinea pedis (1.79 million), tinea capitis (43 900) and onychomycosis (1.73 million). Given that the modelling estimates reported in the current study might be substantially under- or overestimated, formal epidemiological and comprehensive surveillance studies are required to validate or modify these estimates.


Methicillin resistance and the biofilm phenotype in Staphylococcus aureus.
Antibiotic resistance and biofilm-forming capacity contribute to the success of Staphylococcus aureus as a human pathogen in both healthcare and community settings. These virulence factors do not function independently of each other and the biofilm phenotype expressed by clinical isolates of S. aureus is influenced by acquisition of the methicillin resistance gene mecA. Methicillin-sensitive S. aureus (MSSA) strains commonly produce an icaADBC operon-encoded polysaccharide intercellular adhesin (PIA)-dependent biofilm. In contrast, the release of extracellular DNA (eDNA) and cell surface expression of a number of sortase-anchored proteins, and the major autolysin have been implicated in the biofilm phenotype of methicillin-resistant S. aureus (MRSA) isolates. Expression of high level methicillin resistance in a laboratory MSSA strain resulted in (i) repression of PIA-mediated biofilm production, (ii) down-regulation of the accessory gene regulator (Agr) system, and (iii) attenuation of virulence in murine sepsis and device infection models. Here we review the mechanisms of MSSA and MRSA biofilm production and the relationships between antibiotic resistance, biofilm and virulence gene regulation in S. aureus.


Plasmid-Borne Antimicrobial Resistance of Staphylococcus aureus Isolated in a Hospital in Lisbon, Portugal.
Plasmids play a key role in the genetic plasticity and survival of Staphylococcus aureus in challenging environments. Although many S. aureus plasmids have been described, still few studies portray the plasmid content of a given S. aureus population. The aim of this work was to characterize the plasmids carried by a collection of 53 S. aureus isolates collected in a large hospital in Lisbon, Portugal, and investigate their role in conferring resistance to several antimicrobial agents. Plasmids were present in 44 out of the 53 isolates and were grouped into eleven AccI restriction profiles. Plasmid curing of representative strains and comparison of antimicrobial susceptibility profiles between pairs of isogenic strains proved to be a valuable guidance tool in the identification of plasmid-located resistance genes. The plasmids harbored several resistance genes, namely blaZ (resistance to β-lactams), erm(C) (resistance to macrolides, lincosamides, and streptogramin B), cadA (resistance to cadmium and zinc), cadD (resistance to cadmium), and qacA and smr (resistance to biocides and dyes). This study demonstrates the impact of plasmids on the resistance properties of S. aureus, highlighting their role in the dissemination of antibiotic, heavy metal, and biocide resistance genes, and survival of this major pathogen in the hospital environment.


Structure and chemistry of graphene oxide in liquid water from first principles.
Graphene oxide is a rising star among 2D materials, yet its interaction with liquid water remains a fundamentally open question: experimental characterization at the atomic scale is difficult, and modeling by classical approaches cannot properly describe chemical reactivity. Here, we bridge the gap between simple computational models and complex experimental systems, by realistic first-principles molecular simulations of graphene oxide (GO) in liquid water. We construct chemically accurate GO models and study their behavior in water, showing that oxygen-bearing functional groups (hydroxyl and epoxides) are preferentially clustered on the graphene oxide layer. We demonstrated the specific properties of GO in water, an unusual combination of both hydrophilicity and fast water dynamics. Finally, we evidence that GO is chemically active in water, acquiring an average negative charge of the order of 10 mC m-2. The ab initio modeling highlights the uniqueness of GO structures for applications as innovative membranes for desalination and water purification.


Contractions of the squid stellate ganglion.
Optical recording methods were used to characterize the intrinsic movements of squid stellate ganglia. Ganglionic contractions were rhythmic and occurred at a mean frequency of 8 min-1. Contractions were eliminated when Na+ in the external saline were replaced by Tris, but were only slowed when Na+ was replaced by sucrose. This suggests that Na+ plays some role in generating the contractions, but the complete abolition produced by Tris-containing saline may be due to a secondary pharmacological action of this ion. The Na+ channel blocker, tetrodotoxin, had no effect on contractions. Contractions were eliminated by removal of external Ca2+, by treatment with the inorganic Ca2+ channel blockers Mn2+ and Cd2+, or by treatment with the organic dihydropyridine Ca2+ channel blockers nitrendipine and nimodipine. Thus, extracellular Ca2+ plays an important role in generating the contractions. Because dihydropyridines eliminate contractions, but not synaptic transmission, they offer a means of studying transmission at the giant synapse of the stellate ganglion without having to contend with ganglionic movement. Electron microscopy of stellate ganglia revealed the presence of two types of cell that contained the organized arrays of cytoskeletal elements usually associated with contractile cells. One type was a pericyte that surrounded blood vessels within the stellate ganglion. The second type was distributed throughout the ganglion and resembled a smooth muscle cell. Either of these cell types might generate ganglionic contractions.


Proton MR spectroscopic changes in Parkinson's diseases after thalamotomy.
To investigate whether there are significant changes in regional brain metabolism in patients with Parkinson's disease before and after thalamotomy using proton magnetic resonance spectroscopy (1H MRS). Fifteen patients underwent 15 stereotactic thalamotomies for control of medically refractory parkinsonian tremor. Single-voxel 1H MRS was carried out on a 1.5 T unit using stimulated-echo acquisition mode (STEAM) sequence (TR/TM/TE, 2000/14/20 ms). Spectra were obtained from substantia nigra, thalamus and putamen areas with volumes of interests (7-8 ml) in patients before and after the surgery. Metabolite ratios of NAA/Cho, NAA/Cr and Cho/Cr were calculated from relative peak area measurements. We evaluated alterations of metabolite ratios in brain metabolism in Parkinson's disease patients with clinical outcome following thalamotomy. NAA/Cho ratios showed generally low levels in substantia nigra and thalamus in Parkinson's disease patients with clinical improvement following thalamotomy. In 80% (12/15) patients, decreased NAA/Cho ratios were observed from the selected voxels in substantia nigra after thalamic surgery (P<0.05). The ratios were also significantly decreased in thalamus in 67% (10/15) patients with clinical improvement (P<0.05). Our results suggest that NAA/Cho ratio may be a valuable criterion for evaluation of Parkinson's disease patients with the clinical improvement following surgery. 1H MRS may be a useful utility for the aid in better understanding the pathophysiologic process in Parkinson's disease patients on the basis of the variation of NAA/Cho ratio.


Spinodal decomposition in a model colloid-polymer mixture in microgravity.
We study phase separation in a deeply quenched colloid-polymer mixture in microgravity on the International Space Station using small-angle light scattering and direct imaging. We observe a clear crossover from early-stage spinodal decomposition to late-stage, interfacial-tension-driven coarsening. Data acquired over 5 orders of magnitude in time show more than 3 orders of magnitude increase in domain size, following nearly the same evolution as that in binary liquid mixtures. The late-stage growth approaches the expected linear growth rate quite slowly.


Effect of antibiotic stewardship programmes on Clostridium difficile incidence: a systematic review and meta-analysis.
Despite vigorous infection control measures, Clostridium difficile continues to cause significant disease burden. Antibiotic stewardship programmes (ASPs) may prevent C. difficile infections by limiting exposure to certain antibiotics. Our objective was to perform a meta-analysis of published studies to assess the effect of ASPs on the risk of C. difficile infection in hospitalized adult patients. Searches of PubMed, Web of Science, Cumulative Index to Nursing and Allied Health Literature and two Cochrane databases were conducted to find all published studies on interventions related to antibiotic stewardship and C. difficile. Two investigators independently assessed study eligibility and extracted data. Risk of bias was assessed using the Downs and Black tool. Risk ratios were pooled using random effects models. Heterogeneity was evaluated using the I(2) statistic. The final search yielded 891 articles; 78 full articles were reviewed and 16 articles were identified for inclusion. Included articles used quasi-experimental (interrupted time series or before-after) or observational (case-control) study designs. When the results of all studies were pooled in a random effects model, a significant protective effect (pooled risk ratio 0.48; 95% CI: 0.38, 0.62) was observed between ASPs and C. difficile incidence. When stratified by intervention type, a significant effect was found for restrictive ASPs (complete removal of drug or prior approval requirement). Furthermore, ASPs were particularly effective in geriatric settings. Restrictive ASPs can be used to reduce the risk of C. difficile infection.


The social organization of fish shoals: a test of the predictive power of laboratory experiments for the field.
By contrast with a multitude of laboratory studies on the social organization of fish, relatively little is know about the size, composition and dynamics of free-ranging fish shoals. We give an overview of the available information on fish shoals and assess to what degree the predictions made from laboratory studies are consistent with field data. The section on shoal choice behaviour in the laboratory is structured so that the evidence for different shoaling preferences is discussed in the context of their mechanisms and functions. Predictions based on experiments in captivity regarding preferences for conspecifics, individuals of similar body length and unparasitized fish were highly consistent with field observations on free-ranging shoals whereas preferences for familiar conspecifics and kin remain to be conclusively demonstrated in the field. In general, there is a shortage of studies in which shoaling preferences have been investigated both in the laboratory and the field, and field studies have so far been largely descriptive revealing little about the underlying mechanisms of observed patterns. Given the great importance of fish shoals both in fundamental and applied research, an advancement of our knowledge of their social organization should significantly contribute to a better understanding of a whole range of topics including reciprocal altruism, group-living and self-organization.


Archaeology. Sedimentary DNA from a submerged site reveals wheat in the British Isles 8000 years ago.
The Mesolithic-to-Neolithic transition marked the time when a hunter-gatherer economy gave way to agriculture, coinciding with rising sea levels. Bouldnor Cliff, is a submarine archaeological site off the Isle of Wight in the United Kingdom that has a well-preserved Mesolithic paleosol dated to 8000 years before the present. We analyzed a core obtained from sealed sediments, combining evidence from microgeomorphology and microfossils with sedimentary ancient DNA (sedaDNA) analyses to reconstruct floral and faunal changes during the occupation of this site, before it was submerged. In agreement with palynological analyses, the sedaDNA sequences suggest a mixed habitat of oak forest and herbaceous plants. However, they also provide evidence of wheat 2000 years earlier than mainland Britain and 400 years earlier than proximate European sites. These results suggest that sophisticated social networks linked the Neolithic front in southern Europe to the Mesolithic peoples of northern Europe.


Myasthenic patients' IgG causes redistribution of acetylcholine receptors: freeze-fracture studies.
Immunoglobulin from patients with myasthenia gravis (MG) accelerates the degradation of acetylcholine receptors (AChRs) of skeletal muscle by a mechanism dependent on receptor cross-linking. However, the intermediate steps between cross-linking and endocytosis and degradation are not known. We have used freeze-fracture electron microscopy to study the effects of myasthenic immunoglobulin on the distribution of AChRs in the surface membranes of cultured rat skeletal muscle. Large, angular intramembrane particles were identified as AChRs. These particles were present in three configurations: distributed individually; in "hot spots"; and in clusters of two to 60 particles. Large depressions (greater than 100 nm in diameter) were thought to be endocytotic pits; they occurred preferentially in hot spots, and approximately half of the depressions were closely associated with clusters of AChRs. In control myotubes, hot spots contained a high density of AChR particles that were evenly, rather than randomly, distributed. Exposure to myasthenic patients' IgG induced clustering of the particles within such hot spots. In non-hot spot regions, control myotubes had mainly individually distributed AChRs, while clusters were seen only rarely. The addition of myasthenic IgG caused a rapid increase, followed by a gradual decrease, in the incidence of individual clusters as well as an increase in cluster size. This redistribution of particles was dependent on cross-linking by the myasthenic anti-AChR antibodies. Monovalent Fab fragments of myasthenic IgG had no effect on the distribution of AChR particles. However, addition of a second "piggyback" antibody to cross-link Fab-AChR complexes caused a redistribution of AChR particles like that due to the original myasthenic IgG. These findings indicate that cross-linking of AChRs by divalent antibody causes clustering of AChR particles, which may play an important role in their accelerated endocytosis and degradation.


Electrical stimulation-induced release of beta-endorphin from genetically modified neuro-2a cells.
The quantity of therapeutic gene products released from genetically engineered cells can be controlled externally at different levels. The widely used approach of controlling expression, however, generally has the disadvantage that chemical substances must be applied for stimulation. An alternative strategy aims at controlling gene products at posttranslational levels such as secretion. The secretion of a therapeutic agent can be regulated if the agent is targeted to the regulated secretory pathway and stored in the secretory granules until its release. In this article we address the question of whether the release of beta-endorphin, an opioid with a potent analgesic effect, could be induced by electrically stimulating stably transfected Neuro-2a cells. Throughout this study we used the human proopiomelanocortin (POMC) gene, which is the precursor molecule for human beta-endorphin. We analyzed its subcellular localization and found it in the regulated secretory pathway in Neuro-2a cells. Using electrical field stimulation we were able to identify a stimulation pattern that significantly increased the release of beta-endorphin-immunoreactive material, although to a limited extent. This result indicates that electrical stimulation of secretion could be used to manipulate the amount of a therapeutic agent released from transplanted cells.


The involvement of AU-rich element-binding proteins in p38 mitogen-activated protein kinase pathway-mediated mRNA stabilisation.
The p38 mitogen-activated protein kinase (MAPK) pathway plays an important role in the post-transcriptional regulation of inflammatory genes. p38 has been found to regulate both the translation and the stability of inflammatory mRNAs. The mRNAs regulated by p38 share common AU-rich elements (ARE) present in their 3'-untranslated regions. AREs act as mRNA instability determinants but also confer stabilisation of the mRNA by the p38 pathway. In recent years, AREs have shown to be binding sites for numerous proteins including HuR, TTP, AUF1, AUF2, FBP1, FBP2 (KSRP), TIA-1, and TIAR. However, it is unclear which protein is responsible for mRNA stabilisation by p38. This review gives an overview of the major ARE-binding proteins and discusses reasons for and against their involvement in p38-mediated mRNA stabilisation.


Mathematical models for explaining the Warburg effect: a review focussed on ATP and biomass production.
For producing ATP, tumour cells rely on glycolysis leading to lactate to about the same extent as on respiration. Thus, the ATP synthesis flux from glycolysis is considerably higher than in the corresponding healthy cells. This is known as the Warburg effect (named after German biochemist Otto H. Warburg) and also applies to striated muscle cells, activated lymphocytes, microglia, endothelial cells and several other cell types. For similar phenomena in several yeasts and many bacteria, the terms Crabtree effect and overflow metabolism respectively, are used. The Warburg effect is paradoxical at first sight because the molar ATP yield of glycolysis is much lower than that of respiration. Although a straightforward explanation is that glycolysis allows a higher ATP production rate, the question arises why cells do not re-allocate protein to the high-yield pathway of respiration. Mathematical modelling can help explain this phenomenon. Here, we review several models at various scales proposed in the literature for explaining the Warburg effect. These models support the hypothesis that glycolysis allows for a higher proliferation rate due to increased ATP production and precursor supply rates.


Associations between general practice characteristics with use of urgent referrals for suspected cancer and endoscopies: a cross-sectional ecological study.
Large variation in measures of diagnostic activity has been described previously between English general practices, but related predictors remain understudied. To examine associations between general practice population and characteristics, with the use of urgent referrals for suspected cancer, and use of endoscopy. Cross-sectional observational study of English general practices. We examined practice-level use (/1000 patients/year) of urgent referrals for suspected cancer, gastroscopy, flexible sigmoidoscopy and colonoscopy. We used mixed-effects Poisson regression to examine associations with the sociodemographic profile of practice populations and other practice attributes, including the average age, sex and country of qualification of practice doctors. The sociodemographic characteristics of registered patients explained much of the between-practice variance in use of urgent referrals (32%) and endoscopic investigations (18-25%), all being higher in practices with older and more socioeconomically deprived patients. Practice-level attributes explained a substantial amount of between-practice variance in urgent referral (19%) but little of the variance in endoscopy (3%-4%). Adjusted urgent referral rates were higher in training practices and those with younger GPs. Practices with mean doctor ages of 41 and 57 years (at the 10th/90th centiles of the national distribution) would have urgent referral rates of 24.1 and 19.1/1000 registered patients, P < 0.001. Most between-practice variation in use of urgent referrals and endoscopies seems to reflect health need. Some practice characteristics, such as the mean age of GPs, are associated with appreciable variation in use of urgent referrals, though these associations do not seem strong enough to justify targeted interventions.


Natural killer cell activity in rats infused with Intralipid.
The effect of Intralipid on the natural killer (NK) cell activity of healthy male Fisher 344 adult rats was investigated. They were cannulated via the right jugular vein and continuously infused for five days with: normal saline plus heparin, 5% Intralipid plus heparin, or 10% Intralipid plus heparin. Control groups comprised of cannulated rats receiving no infusion and rats undergoing no operative procedures. Following the five-day infusion, rats were exsanguinated under ether anesthesia and mononuclear cells (MNC) harvested from the peripheral blood. NK activity was measured in a standard four hour 51Cr release assay against YAC-1 target cells. NK cell activity in rats infused with 5% Intralipid did not differ significantly from rats in both control groups or rats infused with saline. Infusion of rats with 10% Intralipid resulted in a significant increase in NK activity compared with all other groups.


Exclusive breastfeeding rates in a multiethnic population at a community hospital.
To evaluate exclusive breastfeeding (EB) rates in a multiethnic community population and study various factors that could influence selection of feeding method. Electronic medical records of 100 patients who delivered from January to August 2009 in a community hospital were reviewed retrospectively. Patients who breastfed exclusively were compared with those whose children obtained some or all nutrition from bottle-feeding during the hospitalization immediately following delivery (NEB). Continuation rates at the infant's initial follow-up examination were assessed. The Asian populations had the highest EB (50%) and continuity rate. Single status and educational status were the only factors other than ethnicity found on univariate analysis to have an impact on the mode of feeding (p < 0.05). Employment, obesity, mode of delivery, birth weight, and sex of newborn did not have a significant effect on the type of feeding. Using multiple regression, only educational status had a significant association with exclusive breastfeeding, with an odds ratio of 2.1 (p = 0.038). EB was not well accepted by non-Asian populations. Because educational level was associated with breastfeeding, ways of encouraging those with limited education to practice breastfeeding should be developed.


Potentially suboptimal prescribing for older veteran nursing home patients with dementia.
Nursing home patients with dementia may be more likely to suffer adverse drug events from suboptimal prescribing. Previous studies have not used national samples, nor have they examined multiple types of suboptimal prescribing by dementia severity. To examine the prevalence of and factors associated with potentially suboptimal prescribing in older veteran nursing home patients with dementia. This is a retrospective descriptive study of 1303 veterans 65 years or older admitted between January 1, 2004, and June 30, 2005, with dementia for long stays (90+ days) to 133 Veterans Affairs Community Living Centers. Dementia severity was determined by the Cognitive Performance Scale and functional status dependences. Overall, 70.2% with mild-moderate dementia (n = 1076) had underuse because they did not receive an acetylcholinesterase inhibitor (AChEI), and 27.2% had evidence of inappropriate use because of a drug-disease or drug-drug-disease interaction. Of the 227 with severe dementia, 36.1% had overuse by receiving an AChEI or lipid-lowering or other agents, and 25.1% had evidence of inappropriate use as a result of a drug-disease or drug-drug interaction. Multinomial logistic regression analyses among those with mild to moderate dementia identified that living in the South versus other regions was the single factor associated with all 3 types of suboptimal prescribing. In those with severe dementia, antipsychotic use was associated with all 3 suboptimal prescribing types. Potentially suboptimal prescribing was common in older veteran nursing home patients with dementia. Clinicians should develop a heightened awareness of these problems. Future studies should examine associations between potentially suboptimal prescribing and health outcomes in patients with dementia.


Richer than we thought: neurophysiological methods reveal rich-club network development is frequency- and sex-dependent.
A set of highly connected brain regions called the "rich-club" are vital in integrating information across the functional connectome. Although the literature has identified some changes in rich-club organization with age, little is known about potential sex-specific developmental trajectories, and neurophysiologically relevant frequency-dependent changes have not been established. Here we examine the frequency- and sex-dependent development of rich-club organization using magnetoencephalography in a large normative sample (N = 383) over a wide age span (4-39 years). We report strong divergence between males and females across alpha, beta, and gamma frequencies. While males show increased or no change in rich-club organization with age, females show a consistent, non-linear trajectory that increases through childhood, shifting direction in early adolescence. Using neurophysiological modalities for capturing complex inter-relations between oscillatory dynamics, age, and sex, we establish diverging, sex-specific developmental trajectories of the brain's core functional organization, critically important to our understanding of brain health and disease.


Alpha thalassaemia and extended alpha globin genes in Sri Lanka.
The α-globin genes were studied in nine families with unexplained hypochromic anaemia and in 167 patients with HbE β thalassaemia in Sri Lanka. As well as the common deletion forms of α(+) thalassaemia three families from an ethnic minority were found to carry a novel form of α(0) thalassaemia, one family carried a previously reported form of α(0) thalassaemia, --(THAI), and five families had different forms of non-deletional thalassaemia. The patients with HbE β thalassaemia who had co-inherited α thalassaemia all showed an extremely mild phenotype and reduced levels of HbF and there was a highly significant paucity of α(+) thalassaemia in these patients compared with the normal population. Extended α gene arrangements, including ααα, αααα and ααααα, occurred at a low frequency and were commoner in the more severe phenotypes of HbE β thalassaemia. As well as emphasising the ameliorating effect of α thalassaemia on HbE β thalassaemia the finding of a novel form of α(0) thalassaemia in an ethnic minority, together with an unexpected diversity of forms of non-deletion α thalassaemia in Sri Lanka, further emphasises the critical importance of micro-mapping populations for determining the frequency of clinically important forms of the disease.


Epidemiological studies of natural sources of radiation and childhood cancer: current challenges and future perspectives.
The empirical estimation of cancer risks in children associated with low-dose ionising radiation (<100 mSv) remains a challenge. The main reason is that the required combination of large sample sizes with accurate and comprehensive exposure assessment is difficult to achieve. An international scientific workshop, 'Childhood cancer and background radiation', organised by the Institute of Social and Preventive Medicine of the University of Bern, brought together researchers in this field to evaluate how epidemiological studies of background radiation and childhood cancer can best improve our understanding of the effects of low-dose ionising radiation. This review summarises and evaluates the findings of these studies with regard to their methodological differences, identifies key limitations and challenges, and proposes ways to move forward. Large childhood cancer registries, such as those in Great Britain, France and Germany, now permit the conducting of studies that should have sufficient statistical power to detect the effects predicted by standard risk models. Nevertheless, larger studies or pooled studies will be needed to investigate disease subgroups. The main challenge is to accurately assess children's individual exposure to radiation from natural sources and from other sources, as well as potentially confounding non-radiation exposures, in such large study populations. For this, the study groups should learn from each other to improve exposure estimation and develop new ways to validate exposure models with personal dosimetry.