Advances in small molecule inhibitors of androgen receptor for the treatment of advanced prostate cancer.
Current treatments for localized prostate cancer include brachytherapy, external beam radiation, surgery, and active surveillance. Unfortunately, 20-40% of prostate cancer patients will experience recurrence and require hormonal therapies. These therapies involve androgen ablation by chemical or surgical castration and application of antiandrogens. Hormonal therapy is initially effective, but will inevitably fail and the disease will progress to lethal castration-resistant prostate cancer (CRPC) from which patients succumb within 2 years. CRPC is considered to be dependent on transcriptionally active androgen receptors (AR). This article reviews recent advances in the discovery and development of small molecule inhibitors of AR. A PubMed database search was performed for articles focused on small molecule inhibitors of AR for potential development for the treatment of prostate cancer. Compounds with broad effects on other pathways were not included. Currently, there are several novel antiandrogens being tested in the clinic that have improved affinity for the AR and work by different mechanisms to the current battery of approved antiandrogens that are discussed. Small molecule inhibitors that interact with regions other than the AR ligand-binding pocket have been also been discovered. These small molecules include allosteric inhibitors of the LBD, compounds that alter AR conformation, and antagonists to the AR NTD and are highlighted. CRPC is dependent upon transcriptionally active AR. Survival improvement may be achieved by complete blockade of all AR activity using novel small molecule inhibitors with unique mechanisms of action.


Factors affecting the achievement of Japanese-style deep knee flexion after total knee arthroplasty using posterior-stabilized prosthesis with high-flex knee design.
Achievement of very deep knee flexion after total knee arthroplasty (TKA) can play a critical role in the satisfaction of patients who demand a floor-sitting lifestyle and engage in high-flexion daily activities (e.g., seiza-sitting). Seiza-sitting is characterized by the knees flexed >145º and feet turned sole upwards underneath the buttocks with the tibia internally rotated. The present study investigated factors affecting the achievement of seiza-sitting after TKA using posterior-stabilized total knee prosthesis with high-flex knee design. Subjects comprised 32 patients who underwent TKA with high-flex knee prosthesis and achieved seiza-sitting (knee flexion >145º) postoperatively. Another 32 patients served as controls who were capable of knee flexion >145º preoperatively, but failed to achieve seiza-sitting postoperatively. Accuracy of femoral and tibial component positions was assessed in terms of deviation from the ideal position using a two-dimensional to three-dimensional matching technique. Accuracies of the component position, posterior condylar offset ratio and intraoperative gap length were compared between the two groups. The proportion of patients with >3º internally rotated tibial component was significantly higher in patients who failed at seiza-sitting (41 %) than among patients who achieved it (13 %, p = 0.021). Comparison of intraoperative gap length between patient groups revealed that gap length at 135º flexion was significantly larger in patients who achieved seiza-sitting (4.2 ± 0.4 mm) than in patients who failed at it (2.7 ± 0.4 mm, p = 0.007). Conversely, no significant differences in gap inclination were seen between the groups. From the perspective of surgical factors, accurate implant positioning, particularly rotational alignment of the tibial component, and maintenance of a sufficient joint gap at 135º flexion appear to represent critical factors for achieving >145º of deep knee flexion after TKA.


Progress towards a representative network of Southern Ocean protected areas.
Global threats to ocean biodiversity have generated a worldwide movement to take actions to improve conservation and management. Several international initiatives have recommended the adoption of marine protected areas (MPAs) in national and international waters. National governments and the Commission for the Conservation of Antarctic Marine Living Resources have successfully adopted multiple MPAs in the Southern Ocean despite the challenging nature of establishing MPAs in international waters. But are these MPAs representative of Southern Ocean biodiversity? Here we answer this question for both existing and proposed Antarctic MPAs, using benthic and pelagic regionalizations as a proxy for biodiversity. Currently about 11.98% of the Southern Ocean is protected in MPAs, with 4.61% being encompassed by no-take areas. While this is a relatively large proportion of protection when compared to other international waters, current Antarctic MPAs are not representative of the full range of benthic and pelagic ecoregions. Implementing additional protected areas, including those currently under negotiation, would encompass almost 22% of the Southern Ocean. It would also substantially improve representation with 17 benthic and pelagic ecoregions (out of 23 and 19, respectively) achieving at least 10% representation.


Graphdiyne: a superior carbon additive to boost the activity of water oxidation catalysts.
A new carbon allotrope, graphdiyne (GDY), with a highly π-conjugated structure of sp- and sp2-hybridized carbon networks, has recently emerged and been used as a superior carbon additive to boost the activity of water oxidation catalysts. In this work, a hybrid GDY/NiFe-LDH electrocatalyst was prepared by a facile hydrothermal treatment, which shows an outstanding catalytic activity with a low overpotential of 260 mV at 10 mA cm-2 catalytic current density and good durability towards oxygen evolution in 1.0 M KOH solution. Density functional theory (DFT) calculations prove that the sp- and sp2-hybridized GDY shows both superior electron capture and excellent electron transfer ability compared to that of the conventional sp2-hybridized carbon materials.


Surface wipe sampling for antineoplastic (chemotherapy) and other hazardous drug residue in healthcare settings: Methodology and recommendations.
Surface wipe sampling for various hazardous agents has been employed in many occupational settings over the years for various reasons such as evaluation of potential dermal exposure and health risk, source determination, quality or cleanliness, compliance, and others. Wipe sampling for surface residue of antineoplastic and other hazardous drugs in healthcare settings is currently the method of choice to determine surface contamination of the workplace with these drugs. The purpose of this article is to review published studies of wipe sampling for antineoplastic and other hazardous drugs, to summarize the methods in use by various organizations and researchers, and to provide some basic guidance for conducting surface wipe sampling for these drugs in healthcare settings. Recommendations on wipe sampling methodology from several government agencies and organizations were reviewed. Published reports on wipe sampling for hazardous drugs in numerous studies were also examined. The critical elements of a wipe sampling program and related limitations were reviewed and summarized. Recommendations and guidance are presented concerning the purposes of wipe sampling for antineoplastic and other hazardous drugs in the healthcare setting, technical factors and variables, sampling strategy, materials required, and limitations. The reporting and interpretation of wipe sample results is also discussed. It is recommended that all healthcare settings where antineoplastic and other hazardous drugs are handled consider wipe sampling as part of a comprehensive hazardous drug "safe handling" program. Although no standards exist for acceptable or allowable surface concentrations for these drugs in the healthcare setting, wipe sampling may be used as a method to characterize potential occupational dermal exposure risk and to evaluate the effectiveness of implemented controls and the overall safety program. A comprehensive safe-handling program for antineoplastic drugs may utilize wipe sampling as a screening tool to evaluate environmental contamination and strive to reduce contamination levels as much as possible, using the industrial hygiene hierarchy of controls.


Chronic fatigue syndrome (CFS): Suggestions for a nutritional treatment in the therapeutic approach.
Chronic fatigue syndrome (CFS) is known as a multi-systemic and complex illness, which induces fatigue and long-term disability in educational, occupational, social, or personal activities. The diagnosis of this disease is difficult, due to lacking a proper and suited diagnostic laboratory test, besides to its multifaceted symptoms. Numerous factors, including environmental and immunological issues, and a large spectrum of CFS symptoms, have recently been reported. In this review, we focus on the nutritional intervention in CFS, discussing the many immunological, environmental, and nutritional aspects currently investigated about this disease. Changes in immunoglobulin levels, cytokine profiles and B- and T- cell phenotype and declined cytotoxicity of natural killer cells, are commonly reported features of immune dysregulation in CFS. Also, some nutrient deficiencies (vitamin C, vitamin B complex, sodium, magnesium, zinc, folic acid, l-carnitine, l-tryptophan, essential fatty acids, and coenzyme Q10) appear to be important in the severity and exacerbation of CFS symptoms. This review highlights a far-driven analysis of mineral and vitamin deficiencies among CFS patients.


On improving the speed and reliability of T2-relaxation-under-spin-tagging (TRUST) MRI.
A T(2) -relaxation-under-spin-tagging technique was recently developed to estimate cerebral blood oxygenation, providing potentials for noninvasive assessment of the brain's oxygen consumption. A limitation of the current sequence is the need for long repetition time, as shorter repetition time causes an over-estimation in blood R(2). This study proposes a postsaturation T(2)-relaxation-under-spin-tagging by placing a nonselective 90° pulse after the signal acquisition to reset magnetization in the whole brain. This scheme was found to eliminate estimation bias at a slight cost of precision. To improve the precision, echo time of the sequence was optimized and it was found that a modest echo time shortening of 3.4 ms can reduce the estimation error by 49%. We recommend the use of postsaturation T(2)-relaxation-under-spin-tagging sequence with a repetition time of 3000 ms and a echo time of 3.6 ms, which allows the determination of global venous oxygenation with scan duration of 1 min 12 s and an estimation precision of ± 1% (in units of oxygen saturation percentage).


Number processing and calculation in Brazilian children aged 7-12 years.
Numerical cognition is based on two components - number processing and calculation. Its development is influenced by biological, cognitive, educational, and cultural factors. The objectives of the present study were to: i) assess number processing and calculation in Brazilian children aged 7-12 years from public schools using the Zareki-R (Battery of neuropsychological tests for number processing and calculation in children, Revised; von Aster & Dellatolas, 2006) in order to obtain normative data for Portuguese speakers; ii) identify how environment, age, and gender influences the development of these mathematical skills; iii) investigate the construct validity of the Zareki-R by the contrast with the Arithmetic subtest of WISC-III. The sample included 172 children, both genders, divided in two groups: urban (N = 119) and rural (N = 53) assessed by the Zareki-R. Rural children presented lower scores in one aspect of number processing; children aged 7-8 years demonstrated an inferior global score than older; boys presented a superior performance in both number processing and calculation. Construct validity of Zareki-R was demonstrated by high to moderate correlations with Arithmetic subtest of WISC-III. The Zareki-R therefore is a suitable instrument to assess the development of mathematical skills, which is influenced by factors such as environment, age, and gender.


Genetic elimination of dengue vector mosquitoes.
An approach based on mosquitoes carrying a conditional dominant lethal gene (release of insects carrying a dominant lethal, RIDL) is being developed to control the transmission of dengue viruses by vector population suppression. A transgenic strain, designated OX3604C, of the major dengue vector, Aedes aegypti, was engineered to have a repressible female-specific flightless phenotype. This strain circumvents the need for radiation-induced sterilization, allows genetic sexing resulting in male-only releases, and permits the release of eggs instead of adult mosquitoes. OX3604C males introduced weekly into large laboratory cages containing stable target mosquito populations at initial ratios of 8.5-101 OX3604Ctarget eliminated the populations within 10-20 weeks. These data support the further testing of this strain in contained or confined field trials to evaluate mating competitiveness and environmental and other effects. Successful completion of the field trials should facilitate incorporation of this approach into area-wide dengue control or elimination efforts as a component of an integrated vector management strategy.


Determination of Protein Secondary Structure from Infrared Spectra Using Partial Least-Squares Regression.
Infrared (IR) spectra contain substantial information about protein structure. This has previously most often been exploited by using known band assignments. Here, we convert spectral intensities in bins within Amide I and II regions to vectors and apply machine learning methods to determine protein secondary structure. Partial least squares was performed on spectra of 90 proteins in H2O. After preprocessing and removal of outliers, 84 proteins were used for this work. Standard normal variate and second-derivative preprocessing methods on the combined Amide I and II data generally gave the best performance, with root-mean-square values for prediction of ∼12% for α-helix, ∼7% for β-sheet, 7% for antiparallel β-sheet, and ∼8% for other conformations. Analysis of Fourier transform infrared (FTIR) spectra of 16 proteins in D2O showed that secondary structure determination was slightly poorer than in H2O. Interval partial least squares was used to identify the critical regions within spectra for secondary structure prediction and showed that the sides of bands were most valuable, rather than their peak maxima. In conclusion, we have shown that multivariate analysis of protein FTIR spectra can give α-helix, β-sheet, other, and antiparallel β-sheet contents with good accuracy, comparable to that of circular dichroism, which is widely used for this purpose.


What promotes sustained return to work of employees on long-term sick leave? Perspectives of vocational rehabilitation professionals.
The aim of this study was to (i) explore promoting factors for sustained return to work (RTW), according to vocational rehabilitation professionals (VRP) that are amenable to change for employees who have been on sick leave >18 months and (ii) gain insight into crucial aspects of interventions. Semi-structured interviews were carried out with 23 VRP. All interviews were transcribed fully verbatim. An inductive analysis of the transcripts was performed, using a process of identifying, coding, and categorizing the primary patterns in the data. Key influenceable promoting factors for sustained RTW by long-term sick-listed employees include: employee-based vocational guidance; integral, effective communication between the sick-listed employee and all RTW stakeholders; personal factors; a supportive work environment; and a stimulating social environment. Crucial aspects of interventions include: gathering information and setting priorities; improving qualifications; influencing cognitions; monitoring the sick-listed employee through the rehabilitation process; offering tailor-made interventions at different stages within a personal time-bound action plan; and preparing the employee and the work environment for RTW. Sustained RTW for long-term sick-listed employees can be achieved by focusing on the influenceable promoting factors for RTW. The use of combined interventions in a holistic approach involving the worker and his environment is considered the best way to address the multicausality of work disability and could help maximize RTW outcomes.


Color generation in butterfly wings and fabrication of such structures.
The wings of the morpho butterfly demonstrate an iridescent blue color over wide viewing angles. The mechanism that generates this blue color is studied. Optical and transmission electron microscopy of the butterfly wings reveal a complex wing structure with as many as 24 layers with periodic structures. The color generation is caused by interference of the multilayer structure as well as diffraction. It is possible to specially design grating structures so that a specific blue color can be generated and observed over wider angles. To demonstrate the grating concept, complex multigratings are designed and fabricated with electron-beam lithography. The light-diffraction properties of these gratings are presented.


Hydroxyurea therapy for children with sickle cell disease: describing how caregivers make this decision.
Hydroxyurea (HU) is underutilized in children with sickle cell disease (SCD) because caregivers frequently decline HU when it is offered. This study explores what impacts this decision. Caregivers of children with clinically severe SCD whose children were offered HU previously were interviewed. We used a qualitative analytical approach to analyze their telephone interview transcripts. Caregivers who chose HU (n = 9) reported their children had severe SCD, sought detailed information about HU, and accepted HU as a preventative therapy. In contrast, caregivers who did not choose HU (n = 10) did not perceive their children as having severe SCD and did not question their child's provider about HU. This study identifies specific areas that providers should address to when they discuss HU with families so that they can make informed decisions. Our study also uncovered factors that are important to consider when designing future interventions to improve hydroxyurea acceptance and when developing decision-aid tools to assist caregivers of children with SCD who are considering disease modifying therapies.


Design of Bifunctional Pyclen-Based Lanthanide Luminescent Bioprobes for Targeted Two-Photon Imaging.
In the past, Lanthanide Luminescent Bioprobes (LLBs) based on pyclen-bearing π-extended picolinate antennas were synthesized and demonstrated well-adapted optical properties for biphotonic microscopy. The objective of this work is to develop a strategy to design bifunctional analogues of the previously studied LLBs presenting an additional reactive chemical group to allow their coupling to biological vectors to reach deep in vivo targeted two-photon bioimaging. Herein, we elaborated a synthetic scheme allowing the introduction of a primary amine on the para position of the macrocyclic pyridine unit. The photophysical and bioimaging studies demonstrate that the introduction of the reactive function does not alter the luminescent properties of the LLBs paving the way for further applications.


How urban agglomeration improve the emission efficiency?A spatial econometric analysis of the Yangtze River Delta urban agglomeration in China.
Urban areas consume more than 66% of the world's energy and generate more than 70% of global greenhouse gas (GHG) emissions. With the world's population expected to reach 10 billion by 2100, and with nearly 90% of people living in urban areas, a critical question for planetary sustainability is how the size of cities affects energy use and carbon dioxide (CO2) emissions. Are urban agglomerations more energy and emission efficient than smaller cities? Does urban agglomeration exhibit gains from economies of scale concerning emissions? Here, we examine the relationship between urban agglomeration and CO2 emissions for urban agglomeration in the Yangtze River Delta in China using a STIRPAT (Stochastic Impacts by Regression on Population, Affluence and Technology) model considering the spatial effects. Also, it examines the influence of economic development, industrial structure, opening-up level, and technology progress on carbon emissions by exploring the spatial agglomeration and spillover effects. Our major finding is that urban size has a negative correlation to carbon emissions, demonstrating that urban agglomeration is more emission efficient. In addition, our results showed that carbon emission driving factors, such as technology progress, opening-up, and population, have spatial dependence and spatial spillover effects. It means a city's carbon emissions are not only influenced by its own factors but also have an impact on neighboring cities. Therefore, cross-city or urban agglomeration policy, and actions of reducing carbon emissions, are necessary, whilst also developing a low-carbon economy by increasing the proportion of high-tech industry through technological progress and developing vigorous resource-saving and an environmentally friendly tertiary industry.


99mTc labelled cationic lipophilic complexes in malignant and benign tumors: the role of SPET and pinhole-SPET in breast cancer, differentiated thyroid carcinoma and hyperparathyroidism.
Single photon emission tomography (SPET) represents an indispensable diagnostic tool in nuclear medicine. Due to better contrast resolution, cross sectional and 3D images, SPET plays a useful complementary tool to bidimensional planar scintigraphy in certain clinical conditions, while representing the procedure of choice in others. However, high resolution SPET with pinhole collimator (P-SPET) can improve conventional SPET sensitivity with parallel hole collimators. This review summarizes data on the employment of conventional SPET and P-SPET in breast cancer, differentiated thyroid cancer (DTC) and hyperparathyroidism patients, using the cationic lipophilic complexes [(99m)Tc]metoxy isobutyl isonitrile (sestaMIBI) and [(99m)Tc]tetrofosmin as oncotropic radiotracers. In breast cancer patients, SPET with these radiotracers can play an important complementary role to planar scintimammography in detecting primary tumors, especially when non palpable and small in size, whereas SPET and particularly P-SPET represents the procedure of choice in preoperative axillary lymph node status evaluation in which planar is almost always irrelevant. In DTC follow-up patients, SPET and P-SPET with cationic lipophilic radiotracers are indicated in both locoregional and distant metastasis detection, especially in patients with high Tg serum levels and negative radioiodine scanning in whom these procedures represent a reliable alternative to diagnostic (131)I scanning. Moreover, the combined use of [(99m)Tc]tetrofosmin P-SPET and US can identify recurrences and lymph node metastases in the neck, both fixing and non fixing iodine, downstaged or negative at (131)I scanning. SPET can also be a useful complementary tool to planar parathyroid scintigraphy in the detection and localization of small and ectopic parathyroid adenomas in the neck or mediastinum, while neck P-SPET seems to also significantly increase planar sensitivity in hyperplastic glands. SPET and P-SPET are indicated in persistent and recurrent hyperparathyroidism including from carcinoma.


Prevalence of incidental prostate cancer: A systematic review of autopsy studies.
Prostate cancer screening may detect nonprogressive cancers, leading to overdiagnosis and overtreatment. The potential for overdiagnosis can be assessed from the reservoir of prostate cancer in autopsy studies that report incidental prostate cancer rates in men who died of other causes. We aimed to estimate the age-specific incidental cancer prevalence from all published autopsy studies. We identified eligible studies by searches of Medline and Embase, forward and backward citation searches and contacting authors. We screened the titles and abstracts of all articles; checked the full-text articles for eligibility and extracted clinical and pathology data using standardized forms. We extracted mean cancer prevalence, age-specific cancer prevalence and validity measures and then pooled data from all studies using logistic regression models with random effects. The 29 studies included in the review dated from 1948 to 2013. Incidental cancer was detected in all populations, with no obvious time trends in prevalence. Prostate cancer prevalence increased with each decade of age, OR = 1.7 (1.6-1.8), and was higher in studies that used the Gleason score, OR = 2.0 (1.1-3.7). No other factors were significantly predictive. The estimated mean cancer prevalence increased in a nonlinear fashion from 5% (95% CI: 3-8%) at age <30 years to 59% (95% CI: 48-71%) by age >79 years. There was substantial variation between populations in estimated cancer prevalence. There is a substantial reservoir of incidental prostate cancer which increases with age. The high risk of overdiagnosis limits the usefulness of prostate cancer screening.


Stage-specific accumulation of the terminal differentiation factor LIN-29 during Caenorhabditis elegans development.
The Caenorhabditis elegans gene lin-29 is required for the terminal differentiation of the lateral hypodermal seam cells during the larval-to-adult molt. We find that lin-29 protein accumulates in the nuclei of these cells, consistent with its predicted role as a zinc finger transcription factor. The earliest detectable LIN-29 accumulation in seam cell nuclei is during the last larval stage (L4), following the final seam cell division, which occurs during the L3-to-L4 molt. LIN-29 accumulates in all hypodermal nuclei during the L4 stage. The time of LIN-29 appearance in the hypodermis is controlled by the heterochronic gene pathway: LIN-29 accumulates in the hypodermis abnormally early, during the third larval stage, in loss-of-function lin-14, lin-28 and lin-42 mutants, and fails to accumulate in hypodermis of lin-4 mutants. LIN-29 also accumulates stage-specifically in the nuclei of a variety of non-hypodermal cells during development. Its accumulation is dependent upon the upstream heterochronic genes in some, but not all, of these non-hypodermal cells.


Negative impact on growth and photosynthesis in the green alga Chlamydomonas reinhardtii in the presence of the estrogen 17α-ethynylestradiol.
It is well known that estrogenic compounds affect development of fertilized eggs of many species of birds, fish and amphibians through disrupted activity of carbonic anhydrase (CA). The most potent activity comes from the most commonly occurring synthetic sterol, 17α-Ethynylestradiol (EE2). Less is known about the responses of aquatic phytoplankton to these compounds. Here we show for the first time that, in comparision to the control, the addition of 7 µM EE2 reduced the growth rate of the green alga Chlamydomonas reinhardtii by 68% for cells grown at high CO2. When cells were grown in ambient air (low Ci) with a fully activated carbon concentrating mechanism through the induction of CA activity, the growth rates were reduced by as much as 119%. A reduced growth rate could be observed at EE2 concentrations as low as 10 pM. This was accompanied by a reduced maximum capacity for electron transport in photosystem II as determined by a lower FV/FM for low Ci-grown cells, which indicates the involvement of CAH3, a CA specifically located in the thylakoid lumen involved in proton pumping across the thylakoid membranes. These results were in agreement with an observed reduction in the chloroplastic affinity for Ci as shown by a strong increase in the Michaelis-Menten K0.5 for HCO3-. In itself, a lowering of the growth rate of a green alga by addition of the sterol EE2 warrants further investigation into the potential environmental impact by the release of treated waste water.


Pro-Inflammatory Cytokines Predict Relapse-Free Survival after One Month of Interferon-α but Not Observation in Intermediate Risk Melanoma Patients.
E1697 was a phase III trial of adjuvant interferon (IFN)-α2b for one month (Arm B) versus observation (Arm A) in patients with resected melanoma at intermediate risk. We evaluated the levels of candidate serum cytokines, the HLA genotype, polymorphisms of CTLA4 and FOXP3 genes and the development of autoantibodies for their association with relapse free survival (RFS) in Arm A and Arm B among 268 patients with banked biospecimens. ELISA was used to test 5 autoantibodies. Luminex/One Lambda LABTypeRSSO was used for HLA Genotyping. Selected CTLA4 and FOXP3 Single nucleotide polymorphisms (SNPs) and microsatellites were tested for by polymerase chain reaction (PCR). Sixteen serum cytokines were tested at baseline and one month by Luminex xMAP multiplex technology. Cox Proportional Hazards model was applied and the Wald test was used to test the marginal association of each individual marker and RFS. We used the Lasso approach to select the markers to be included in a multi-marker Cox Proportional Hazards model. The ability of the resulting models to predict one year RFS was evaluated by the time-dependent ROC curve. The leave-one-out method of cross validation (LOOCV) was used to avoid over-fitting of the data. In the multi-marker modeling analysis conducted in Arm B, one month serum IL2Rα, IL-12p40 and IFNα levels predicted one year RFS with LOOCV AUC = 82%. Among the three markers selected, IL2Rα and IFNα were the most stable (selected in all the cross validation cycles). The risk score (linear combination of the 3 markers) separated the RFS curves of low and high risk groups well (p = 0.05). This model did not hold for Arm A, indicating a differential marker profile in Arm B linked to the intervention (adjuvant therapy). Early on-treatment proinflammatory serum markers (IL2Rα, IL-12p40, IFNα) significantly predict RFS in our cohort of patients treated with adjuvant IFN-α2b and warrant further study.


Behavioural correlates of the P3b event-related potential in school-age children.
The latency and amplitude of the P3b component of event-related potentials (ERPs) have been related to behavioural performance on several attention and memory tasks in adult populations. However, the extent to which these results apply to children is unknown. This study examined the neurobehavioral correlates of the P3b component in a longitudinal sample of school-age children from Arctic Québec. Children (N=110; mean age=11.3years) were assessed on an ERP auditory oddball paradigm and a neurobehavioral evaluation targeting several aspects of cognition, including the Stewart Extended Continuous Performance Test (E-CPT), California Verbal Learning Test (CVLT), Stroop Color-Word Interference Test, and five subtests from the Wechsler Intelligence Scale for Children-Fourth edition (WISC-IV). P3b latency was positively related to reaction time measures and negatively associated with performance on the WISC-IV Digit Span Forward subtest. Amplitude of the P3b was associated with shorter completion time on the Stroop test and better delayed recognition memory performance among children who did not use semantic strategies on the CVLT. Profile analyses revealed no difference in scalp distribution of the P3b according to performance on these tests. The results are consistent with previous studies with older participants and suggest that, despite age-related differences in waveform and scalp distribution, the P3b component relates to similar neurocognitive processes in children and adults.


Effect of humeral condylar resection on strength and functional outcome after semiconstrained total elbow arthroplasty.
Under certain conditions it is standard practice to excise ununited humeral condyles during insertion of a semiconstrained total elbow prosthesis. Since the osseous origins of the common extensors and flexor-pronator muscles are lost, it has been postulated that this excision has a negative effect on strength. We are not aware of any previous study in which this issue has been investigated with use of standardized, objective testing of muscle strength. We used objective testing to determine the effect of condylar resection on the muscle strength of the elbow, forearm, wrist, and hand in thirty-two patients who had undergone total elbow arthroplasty. To eliminate bias, the normal, contralateral limb served as the control, and all strength values are given as a percentage of the normal side. The humeral condyles were intact in sixteen patients and had been resected in the other sixteen. Patient demographics were similar in the two groups. There were no significant differences between the two groups with regard to strength of pronation (103% of the normal side in the group with intact condyles compared with 89% in the group with resection of the condyles; p = 0.40), supination (68% compared with 89%; p = 0.49), wrist flexion (66% compared with 56%; p = 0.46), wrist extension (75% compared with 65%; p = 0.40), or grip strength (83% compared with 72%; p = 0.40). There was also no difference between the two groups with regard to the Mayo Elbow Performance Score (79 points in the group with intact condyles compared with 77 points in the group with resection of the condyles; p = 0.67). Condylar resection has a minimal, clinically irrelevant effect on forearm, wrist, and hand strength and no effect on the Mayo Elbow Performance Score following total elbow arthroplasty. Thus, the findings of our study support the practice of condylar resection, which simplifies total elbow arthroplasty for many conditions.


Experimental chronic hypoxic neuropathy: relevance to diabetic neuropathy.
The cardinal electrophysiological abnormalities in experimental diabetic (EDN) and experimental galactose (EGN) neuropathy, models in which endoneurial hypoxia has been demonstrated, are a slowing in nerve conduction velocity (NCV) and a resistance to ischemic conduction block (RICB). These electrophysiological abnormalities are also present in human diabetic neuropathy, where microangiopathy has been demonstrated to be more severe than in EDN so that endoneurial hypoxia is also likely to be present. We examined the effects of endoneurial hypoxia per se on normal nerves. In rats subjected to chronic hypoxia (10% O2) for up to 10 wk, the two electrophysiological abnormalities had developed by 4 wk and were very similar in degree to those seen in EDN and EGN. These abnormalities occurred in the absence of hyperglycemia, nerve sorbitol accumulation, or myoinositol reduction. Resting O2 consumption was reduced, the percent increase in nerve lactate under anoxic stress was increased, and nerve free sugars were normal. Hexokinase and phosphofructokinase activities were not altered substantially when studied under conditions of O2 excess. These findings indicate that hypoxia per se will cause conduction slowing and suggest that the hypoxic nerve develops RICB because of a reduced energy requirement and an increased efficiency of anaerobic glycolysis, but without major changes in the activity of its controlling glycolytic enzymes.


Extinction of the tumor necrosis factor locus, and of genes encoding the lipopolysaccharide signaling pathway.
The tumor necrosis factor (TNF-alpha or TNF) gene is activated by both lipopolysaccharide (LPS) and cycloheximide in RAW 264.7 macrophages, whereas neither stimulus activates the gene in 3T3 fibroblasts. Moreover, the pattern of CG methylation within the TNF gene is readily distinguishable in DNA derived from cells of these two types. These findings would suggest that the TNF gene has been rendered inaccessible to transcription in the 3T3 cell environment. When RAW 264.7 cells are fused with 3T3 cells, an immortal pentaploid hybrid results. In the hybrid cell, all three TNF genes contributed by the RAW 264.7 cell parent become highly methylated according to the pattern observed in the 3T3 cell parent. Permanently transfected chloramphenicol acetyl transferase (CAT) reporter constructs, bearing 2.2 kb of upstream sequence (including the entire TNF promoter and 5'-untranslated region [UTR]) as well as 1.0 kb of downstream sequence (including the entire TNF 3'-UTR and termination sequence), are accessible in both RAW 264.7 cells and 3T3 cells, but are silenced in transition from the RAW 264.7 cell to the hybrid cell environment. Moreover, the endotoxin signaling pathway is abrogated, as assessed by transient transfection of hybrid cells with LPS-responsive CAT reporter constructs. It would therefore appear that the fusion of 3T3 cells and RAW 264.7 cells activates a system that silences the TNF gene, as well as the LPS signaling pathway. This system may operate to determine TNF gene accessibility and LPS responsiveness in the course of cell differentiation. The DNA sequences targeted within the TNF gene are included in the CAT reporter construct; therefore, the silencing element has been circumscribed to a region of DNA 3.2 kb in length.


Developmental expression of morphoregulatory genes in the mouse embryo: an analytical approach using a novel technology.
The molecular techniques of in situ transcription and antisense RNA amplification (IST/aRNA) have allowed for the monitoring of coordinate changes in the expression of multiple genes simultaneously. However, the analysis of their concurrent behavior during murine embryogenesis has been problematic. Studies involving the investigation of temporal and spatial gene expression during embryogenesis have focused solely on the analysis of isolated, single gene events. Such an approach has failed to provide an integrative picture of genetic control over the varied and complicated cellular processes governing embryogenesis. In order to interpret the enormous amount of gene expression data generated by these procedures, we have attempted to develop an analytical framework by employing the statistical concepts of principal components analysis (PCA). For the current study, we performed IST/aRNA on neural tubes dissected from the highly inbred LM/Bc murine strain collected during four gestational time periods. A subset of these genes, representing a partial signaling pathway in the developing neuroepithelium, was then subjected to PCA. Here, we report that PCA highlighted the transcriptional interplay among the genes p53, wee-1, Tgf beta-2, and bcl-2 such that the combined reciprocal regulation of their gene products is suggestive of a predominant proliferative state for the developing neuroepithelium. The application of PCA to the gene expression data has elucidated previously unknown interrelationships among cell cycle genes, growth, and transcription factors on a transcriptional level during critical stages of neurulation. The information gleaned from this analysis, while not definitive, suggests distinct hypotheses to guide future research.


Diversity of DNA fingerprints of Mycobacterium tuberculosis isolates in the United States.
To investigate the diversity of IS6110 fingerprints of Mycobacterium tuberculosis isolates in the United States and to determine if matching IS6110 fingerprints represent recent interstate tuberculosis transmission, we performed restriction fragment length polymorphism analysis of M. tuberculosis isolates from 1,326 patients in three geographically separated states. Seven hundred ninety-five different IS6110 fingerprint patterns were generated, and pattern diversity was similar in each state. Ninety-six percent of the fingerprint patterns were observed in only one state, demonstrating that most IS6110 fingerprint patterns are confined to a single geographic location. Of the IS6110 fingerprint patterns that were shared by isolates from more than one state, most isolates with 1 to 5 IS6110 copies were separable by pTBN12 fingerprinting whereas those with > 15 copies were not. One high-copy-number M. tuberculosis strain had identical IS6110 and pTBN12 fingerprints and included 57 isolates from three states. Epidemiological data demonstrated significant recent transmission of tuberculosis within each city but not among the states. This suggests that identical fingerprints of isolates from geographically separate locations most likely reflect interstate tuberculosis transmission in the past, with subsequent intrastate spread of disease. Further evaluation of M. tuberculosis strains that cause outbreaks in different geographic locations will provide insight into the epidemiological and bacteriological factors that facilitate the spread of tuberculosis.


New national Biobank of The Danish Center for Strategic Research on Type 2 Diabetes (DD2).
Long-term storage of biological samples from patients has become increasingly important in studies of disease control and treatment. The first nationwide Danish diabetes project, ie, The Danish Center for Strategic Research in Type II Diabetes (DD2), aims to improve treatment and the long-term outcome of patients with newly diagnosed type 2 diabetes (T2D). The DD2 project includes establishment of a biobank with samples from 50,000 patients with newly diagnosed T2D. This paper describes how blood and urine samples from 10,000 patients per year are collected, handled, and stored. The biobank includes whole blood, DNA, and plasma and urine samples, all frozen at -80°C. Sampling tubes have been standardized and are sent to hospital outpatient clinics and general practitioners where samples are taken, handled, aliquoted, and returned by mail overnight in standardized cryostorage tubes. When received at the biobank, samples are frozen without further treatment. From each patient, 24 cryostorage tubes are stored. Each tube is labeled with a barcode that links the data to other information available in a clinical databank registry. When patients are enrolled in DD2, a questionnaire is filled out and a quality monitoring system ensures that patients, samples, and questionnaires can be linked together at all times. The biobank is located at Vejle Hospital and the Danish National Biobank at Statens Serum Institut. As of the end of March 2012, samples from 1186 patients have been stored, and currently samples from 8-10 patients arrive per day. We have established the first national biobank in Denmark where blood, DNA, and plasma and urine samples from patients with newly diagnosed T2D are systematically collected and stored. This biobank enables sophisticated analysis of genetic variation and response to treatment, as well as disease marker studies that better classify disease status, progression, and complications.


Super Talbot effect in indefinite metamaterial.
The Talbot effect (or the self-imaging effect) can be observed for a periodic object with a pitch larger than the diffraction limit of an imaging system, where the paraxial approximation is applied. In this paper, we show that the super Talbot effect can be achieved in an indefinite metamaterial even when the period is much smaller than the diffraction limit in both two-dimensional and three-dimensional numerical simulations, where the paraxial approximation is not applied. This is attributed to the evanescent waves, which carry the information about subwavelength features of the object, can be converted into propagating waves and then conveyed to far field by the metamaterial, where the permittivity in the propagation direction is negative while the transverse ones are positive. The indefinite metamaterial can be approximated by a system of thin, alternating multilayer metal and insulator (MMI) stack. As long as the loss of the metamaterial is small enough, deep subwavelength image size can be obtained in the super Talbot effect.


Replacing prelinguistic behaviors with functional communication.
This study evaluated the effectiveness of a teacher-implemented intervention package designed to replace prelinguistic behaviors with functional communication. Four young children with autism participated in a multiple-probe design across three communicative functions. Initially, three existing communication functions were selected for each child. Next, the existing prelinguistic behaviors that the children used to achieve these functions were identified. Replacement forms that were considered more recognizable and symbolic were defined to achieve these same functions. After a baseline phase, teachers received inservice training, consultation, and feedback on how to encourage, acknowledge, and respond to the replacement forms. During intervention, the replacement forms increased and prelinguistic behaviors decreased in most cases. The results suggested that the teacher-implemented intervention was effective in replacing prelinguistic behaviors with alternative forms of functional communication.


Impact of cognitive behavioral therapy for insomnia disorder on sleep and comorbid symptoms in military personnel: a randomized clinical trial.
To compare the efficacy of cognitive behavioral therapy for insomnia (CBTi) disorder and a Control condition on reducing insomnia and comorbid symptoms in a sample of active duty military personnel. Randomized clinical trial of 151 active duty US Army personnel at Fort Hood, Texas. This study replicated Original (n = 66) findings (CBTi outperformed Control) in a follow-on sample (n = 85) on diary-assessed sleep efficiency (d = 1.04), total sleep time (d = 0.38), sleep latency (d = -0.93), number of awakenings (d = -0.56), wake time after sleep onset (d = -0.91), sleep quality (d = 1.00), and the Insomnia Severity Index (d = -1.36) in active duty soldiers. CBTi also outperformed Control in the combined sample (N = 151) on four of the five subscales of the Multidimensional Fatigue Inventory (d = -0.32 to -0.96) and the mental health subscale on the Veterans RAND 12-Item Health Survey (d = 0.37). Exploratory analyses also showed CBTi outperformed Control on nicotine (d = -0.22) and caffeine (d = -0.47) use reduction. Significant within-group differences were found for both groups on depression, anxiety, and posttraumatic stress disorder symptoms, but there was no group by time interaction for these symptoms or for use of hypnotics or alcohol. CBTi was an effective treatment for insomnia and comorbid symptoms including daytime fatigue, general mental health, nicotine, and caffeine use. Clinicaltrials.gov; Identifier: NCT01549899; "Comparing Internet and In-Person Brief Cognitive Behavioral Therapy of Insomnia".


A 10-gene classifier for distinguishing head and neck squamous cell carcinoma and lung squamous cell carcinoma.
The risk of developing metastatic squamous cell carcinoma for patients with head and neck squamous cell carcinoma (HNSCC) is very high. Because these patients are often heavy tobacco users, they are also at risk for developing a second primary cancer, with squamous cell carcinoma of the lung (LSCC) being the most common. The distinction between a lung metastasis and a primary LSCC is currently based on certain clinical and histologic criteria, although the accuracy of this approach remains in question. Gene expression patterns derived from 28 patients with HNSCC or LSCC from a single center were analyzed using penalized discriminant analysis. Validation was done on previously published data for 134 total subjects from four independent Affymetrix data sets. We identified a panel of 10 genes (CXCL13, COL6A2, SFTPB, KRT14, TSPYL5, TMP3, KLK10, MMP1, GAS1, and MYH2) that accurately distinguished these two tumor types. This 10-gene classifier was validated on 122 subjects derived from four independent data sets and an average accuracy of 96% was shown. Gene expression values were validated by quantitative reverse transcription-PCR derived on 12 independent samples (seven HNSCC and five LSCC). The 10-gene classifier was also used to determine the site of origin of 12 lung lesions from patients with prior HNSCC. The results suggest that penalized discriminant analysis using these 10 genes will be highly accurate in determining the origin of squamous cell carcinomas in the lungs of patients with previous head and neck malignancies.


Global burden of maternal and child undernutrition and micronutrient deficiencies.
Maternal and child undernutrition and micronutrient deficiencies affect approximately half of the world's population. These conditions include intrauterine growth restriction (IUGR), low birth weight, protein-energy malnutrition, chronic energy deficit of women, and micronutrient deficiencies. Although the rates of stunting or chronic protein-energy malnutrition are increasing in Africa, the absolute numbers of stunted children are much higher in Asia. The four common micronutrient deficiencies include those of iron, iodine, vitamin A, and zinc. All these conditions are responsible directly or indirectly for more than 50% of all under-5 deaths globally. According to more recent estimates, IUGR, stunting and severe wasting are responsible for one third of under-5 mortality. About 12% of deaths among under-5 children are attributed to the deficiency of the four common micronutrients. Despite tremendous progress in different disciplines and unprecedented improvement with many health indicators, persistently high undernutrition rates are a shame to the society. Human development is not possible without taking care to control undernutrition and micronutrient deficiencies. Poverty, food insecurity, ignorance, lack of appropriate infant and young child feeding practices, heavy burden of infectious illnesses, and poor hygiene and sanitation are factors responsible for the high levels of maternal and child undernutrition in developing countries. These factors can be controlled or removed by scaling up direct nutrition interventions and eliminating the root conditions including female illiteracy, lack of livelihoods, lack of women's empowerment, and poor hygiene and sanitation.


State-estimation approach to the nonstationary optical tomography problem.
We propose a new numerical approach to the nonstationary optical (diffusion) tomography (OT) problem. The assumption in the method is that the absorption and/or diffusion coefficients are nonstationary in the sense that they may exhibit significant changes during the time that is needed to measure data for one traditional image frame. In the proposed method, the OT problem is formulated as a state-estimation problem. Within the state-estimation formulation, the absorption and/or diffusion coefficients are considered a stochastic process. The objective is to estimate a sequence of states for the process when the state evolution model for the process, the observation model for OT experiments, and data on the exterior boundary are given. In the proposed method, the state estimates are computed by using Kalman filtering techniques. The performance of the proposed method is evaluated on the basis of synthetic data. The simulations also illustrate that further improvements to the results in nonstationary applications can be obtained by adjustment of the measurement protocol.


Economic evaluation of cholinesterase inhibitor therapy for dementia: comparison of Alzheimer's disease and Dementia with Lewy bodies.
To assess the cost effectiveness of cholinesterase inhibitor (ChEI) treatment in patients with Alzheimer's disease (AD) and Dementia with Lewy bodies (DLB). We used 4-month open label follow-up data from routine memory clinic patients. There were 852 patients with AD and 112 with DLB. We applied three predictive models to estimate clinical and economic outcomes at five years, comparing AD and DLB patients with hypothetical untreated controls. The mean improvement in MMSE in 852 AD patients was 0.57 (SD 3.4) at 4 months, and in the subgroup with baseline MMSE of 10-20 (moderate) was 1.6 (SD 3.7). Overall, the 112 DLB patients improved by 1.4 (SD 3.7). DLB patients with an MMSE 10-20 improved by 3.1 (SD 4.5) points. These efficacy data were input into the SHTAC, microsimulation and Markov models and produced estimated costs per QALY gained (CQG) for all AD of pound194,066, pound67,904 and pound123,935 respectively. In comparison, the CQGs for all DLB were pound46,794, pound2,706 and pound35,922. For the moderate subgroups only the SHTAC and microsimulation models were applicable. These gave CQG estimates for moderate AD of pound39,664 and cost saving respectively. For moderate DLB, both estimates were cost saving. The cost per QALY gained of cholinesterase treatment of all patients with DLB (including those with MMSE outside the 10-20 range) is comparable to that of patients with moderate AD, and is probably cost saving.


Trends in Effectiveness of Organizational eHealth Interventions in Addressing Employee Mental Health: Systematic Review and Meta-analysis.
Mental health conditions are considered the leading cause of disability, sickness absence, and long-term work incapacity. eHealth interventions provide employees with access to psychological assistance. There has been widespread implementation and provision of eHealth interventions in the workplace as an inexpensive and anonymous way of addressing common mental disorders. This updated review aimed to synthesize the literature on the efficacy of eHealth interventions for anxiety, depression, and stress outcomes in employee samples in organizational settings and evaluate whether their effectiveness has improved over time. Systematic searches of relevant articles published from 2004 to July 2020 of eHealth intervention trials (app- or web-based) focusing on the mental health of employees were conducted. The quality and bias of all studies were assessed. We extracted means and SDs from publications by comparing the differences in effect sizes (Hedge g) in standardized mental health outcomes. We meta-analyzed these data using a random-effects model. We identified a tripling of the body of evidence, with 75 trials available for meta-analysis from a combined sample of 14,747 articles. eHealth interventions showed small positive effects for anxiety (Hedges g=0.26, 95% CI 0.13-0.39; P<.001), depression (Hedges g=0.26, 95% CI 0.19-0.34; P<.001), and stress (Hedges g=0.25, 95% CI 0.17-0.34; P<.001) in employees' after intervention, with similar effects seen at the medium-term follow-up. However, there was evidence of no increase in the effectiveness of these interventions over the past decade. This review and meta-analysis confirmed that eHealth interventions have a small positive impact on reducing mental health symptoms in employees. Disappointingly, we found no evidence that, despite the advances in technology and the enormous resources in time, research, and finance devoted to this area for over a decade, better interventions are being produced. Hopefully, these small effect sizes do not represent optimum outcomes in organizational settings. PROSPERO CRD42020185859; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=185859.


Additive threats from pathogens, climate and land-use change for global amphibian diversity.
Amphibian population declines far exceed those of other vertebrate groups, with 30% of all species listed as threatened by the International Union for Conservation of Nature. The causes of these declines are a matter of continued research, but probably include climate change, land-use change and spread of the pathogenic fungal disease chytridiomycosis. Here we assess the spatial distribution and interactions of these primary threats in relation to the global distribution of amphibian species. We show that the greatest proportions of species negatively affected by climate change are projected to be found in Africa, parts of northern South America and the Andes. Regions with the highest projected impact of land-use and climate change coincide, but there is little spatial overlap with regions highly threatened by the fungal disease. Overall, the areas harbouring the richest amphibian faunas are disproportionately more affected by one or multiple threat factors than areas with low richness. Amphibian declines are likely to accelerate in the twenty-first century, because multiple drivers of extinction could jeopardize their populations more than previous, mono-causal, assessments have suggested.


Autism Spectrum Disorders: Multiple Routes to, and Multiple Consequences of, Abnormal Synaptic Function and Connectivity.
Autism spectrum disorders (ASDs) are a heterogeneous group of neurodevelopmental disorders of genetic and environmental etiologies. Some ASD cases are syndromic: associated with clinically defined patterns of somatic abnormalities and a neurobehavioral phenotype (e.g., Fragile X syndrome). Many cases, however, are idiopathic or non-syndromic. Such disorders present themselves during the early postnatal period when language, speech, and personality start to develop. ASDs manifest by deficits in social communication and interaction, restricted and repetitive patterns of behavior across multiple contexts, sensory abnormalities across multiple modalities and comorbidities, such as epilepsy among many others. ASDs are disorders of connectivity, as synaptic dysfunction is common to both syndromic and idiopathic forms. While multiple theories have been proposed, particularly in idiopathic ASDs, none address why certain brain areas (e.g., frontotemporal) appear more vulnerable than others or identify factors that may affect phenotypic specificity. In this hypothesis article, we identify possible routes leading to, and the consequences of, altered connectivity and review the evidence of central and peripheral synaptic dysfunction in ASDs. We postulate that phenotypic specificity could arise from aberrant experience-dependent plasticity mechanisms in frontal brain areas and peripheral sensory networks and propose why the vulnerability of these areas could be part of a model to unify preexisting pathophysiological theories.


Modification of a Defect-Based Fatigue Assessment Model for Al-Si-Cu Cast Alloys.
Cast parts usually inherit internal defects such as micro shrinkage pores due to the manufacturing process. In order to assess the fatigue behaviour in both finite-life and long-life fatigue regions, this paper scientifically contributes towards a defect-based fatigue design model. Extensive fatigue and fracture mechanical tests were conducted whereby the crack initiating defect size population was fractographically evaluated. Complementary in situ X-ray computed tomography scans before and during fatigue testing enabled an experimental estimation of the lifetime until crack initiation, acting as a significant input for the fatigue model. A commonly applied fatigue assessment approach introduced by Tiryakioglu was modified by incorporating the long crack threshold value, which additionally enabled the assessment of the fatigue strength in the long-life fatigue regime. The presented design concept was validated utilising the fatigue test results, which revealed a sound agreement between the experiments and the model. Only a minor deviation of up to about five percent in case of long-life fatigue strength and up to about 9% in case of finite-lifetime were determined. Thus, the provided extension of Tiryakioglu's approach supports a unified fatigue strength assessment of cast aluminium alloys in both the finite- and long-life regimes.


Micromagnet arrays for on-chip focusing, switching, and separation of superparamagnetic beads and single cells.
Nonlinear magnetophoresis (NLM) is a novel approach for on-chip transport and separation of superparamagnetic (SPM) beads, based on a travelling magnetic field wave generated by the combination of a micromagnet array (MMA) and an applied rotating magnetic field. Here, we present two novel MMA designs that allow SPM beads to be focused, sorted, and separated on-chip. Converging MMAs were used to rapidly collect the SPM beads from a large region of the chip and focus them into synchronised lines. We characterise the collection efficiency of the devices and demonstrate that they can facilitate on-chip analysis of populations of SPM beads using a single-point optical detector. The diverging MMAs were used to control the transport of the beads and to separate them based on their size. The separation efficiency of these devices was determined by the orientation of the magnetisation of the micromagnets relative to the external magnetic field and the size of the beads and relative to that of micromagnets. By controlling these parameters and the rotation of the external magnetic field we demonstrated the controlled transport of SPM bead-labelled single MDA-MB-231 cells. The use of these novel MMAs promises to allow magnetically-labelled cells to be efficiently isolated and then manipulated on-chip for analysis with high-resolution chemical and physical techniques.


Immuno-therapeutic potential of haematopoietic and mesenchymal stem cell transplantation in MS.
In the last few years there has been extraordinary progress in the field of stem cell research. Two types of stem cells populate the bone marrow: haematopoietic stem/progenitor cells (HSC) and mesenchymal stem cells (MSC). The capacity of HSC to repopulate the blood has been known and exploited therapeutically for at least four decades. Today, haematopoietic stem cell transplantation (HSCT) holds a firm place in the therapy of some haematological malignancies, and a potential role of HSCT for treatment of severe autoimmune diseases has been explored in small-scale clinical studies. Multiple sclerosis (MS) is the noncancerous immune mediated disease for which the greatest number of transplants has been performed to date. The results of clinical studies are double-faced: on the one hand, HSCT has demonstrated powerful effects on acute inflammation, arresting the development of focal CNS lesions and clinical relapses; on the other hand, the treatment did not arrest chronic worsening of disability in most patients with secondary progressive MS, suggesting limited or no beneficial effects on the chronic processes causing progressive disability. MSC are a more recent addition to the range of experimental therapies being developed to treat MS. While interest in MSC usage was originally raised by their potential capacity to differentiate into different cell lineages, recent work showing their interesting immunological properties has led to a revised concept, envisioning their utilization for immuno-modulatory purposes. In this review we will summarize the current clinical and experimental evidence on HSC and MSC and outline some key questions warranting further investigation in this exciting research area.


Respiratory chain signalling is essential for adaptive remodelling following cardiac ischaemia.
Cardiac ischaemia-reperfusion (I/R) injury has been attributed to stress signals arising from an impaired mitochondrial electron transport chain (ETC), which include redox imbalance, metabolic stalling and excessive production of reactive oxygen species (ROS). The alternative oxidase (AOX) is a respiratory enzyme, absent in mammals, that accepts electrons from a reduced quinone pool to reduce oxygen to water, thereby restoring electron flux when impaired and, in the process, blunting ROS production. Hence, AOX represents a natural rescue mechanism from respiratory stress. This study aimed to determine how respiratory restoration through xenotopically expressed AOX affects the re-perfused post-ischaemic mouse heart. As expected, AOX supports ETC function and attenuates the ROS load in post-anoxic heart mitochondria. However, post-ischaemic cardiac remodelling over 3 and 9 weeks was not improved. AOX blunted transcript levels of factors known to be up-regulated upon I/R such as the atrial natriuretic peptide (Anp) whilst expression of pro-fibrotic and pro-apoptotic transcripts were increased. Ex vivo analysis revealed contractile failure at nine but not 3 weeks after ischaemia whilst label-free quantitative proteomics identified an increase in proteins promoting adverse extracellular matrix remodelling. Together, this indicates an essential role for ETC-derived signals during cardiac adaptive remodelling and identified ROS as a possible effector.


The sociocultural framing of public attitudes to sharing the costs of social care for older people in England.
Twelve synchronous online focus groups were conducted, each involving four to six members of the general public who had expressed in-principle support for sharing the costs of social care for older people between service users and government. These explored participants' reasons for preferring a shared approach and their views on how costs should be shared, with particular attention given to the sociocultural frames employed. Four main sociocultural frames were identified, reflecting dominant discourses concerning (i) the financial burden of meeting social care need ('scarcity' frame) (ii) the core purpose of social care ('medicalised conception of care' frame) (iii) the role and perceived limitations of the private market ('consumer' frame), and (iv) fundamental concerns about safety, security and belonging ('loss and abandonment' frame). Of these four frames, the 'scarcity' frame was dominant, with views about how costs should be shared overwhelmingly formulated upon assumptions of insufficient resources. This was reflected in concerns about affordability and the consequent need for the financial burden to be shared between individuals and government, and resulted in a residual vision for care and anxieties about care quality, cliff-edge costs and abandonment. The concept of shared funding was also employed rhetorically to suggest an equitable approach to managing financial burden, reflected in phrases such as 'splitting the difference'. Whilst out-of-pocket payments were sometimes seen as useful or necessary in the context of scarce public resources, the idea of shared funding was sometimes interpreted more flexibly to include individual contributions made in a range of ways, including tax, social insurance payments and wider social and economic contributions to society. Despite the dominance of the 'scarcity' frame, participants favoured greater government contribution than currently. These four frames and their associated discourses provide insight into how the public 'hear' and make sense of the debate about social care funding and, specifically, how apparent support for shared public-private funding is structured. Government and those hoping to influence the future of social care funding need to promote a vision of funding reform and win support for it by actively engaging with the sociocultural frames that the public recognise and engage with, with all of their apparent inconsistencies and contradictions.


Chronic Kidney Disease in Non-Diabetic Older Adults: Associated Roles of the Metabolic Syndrome, Inflammation, and Insulin Resistance.
The aims of the study were to examine the association between CKD and the metabolic syndrome (MetS) and its components in older adults. We also explored two possible pathways linking the metabolic syndrome with CKD: inflammation as measured by high sensitivity C-Reactive Protein (hsCRP) and insulin resistance as measured by HOMA-IR. Community-dwelling non-diabetic 70+ adults from the Einstein Aging Study participated in the study. We defined CKD as eGFR below 60mL/min/1.73m2. MetS was defined according to recent guidelines from the National Cholesterol Education Program. Binary logistic regressions were used to assess the association between the metabolic syndrome, its components and CKD with adjustments for demographics, HOMA-IR and hsCRP. Of 616 participants (mean age = 79.3 years, 65.5% female), 25% had MetS and 26.5% had CKD. Participants with CKD had a significantly higher prevalence of the MetS than individuals without CKD (34.4% vs. 24.3%). Binary logistic regression models showed that CKD was associated with MetS (OR = 1.72, 95%CI = 1.13-2.61). The association was unaltered by adjustment for hsCRP but altered by adjustment for HOMA-IR. As the number of MetS components increased the relative odds of CKD also increased. None of the individual components was independently associated with CKD. MetS is associated with CKD in non-diabetic older adults. Results showed that as the number of MetS components increased so did the odds for CKD. HOMA-IR seems to be in the casual pathway linking MetS to CKD.


A mixed-methods evaluation of a Recovery College in South East Essex for people with mental health difficulties.
Recovery Colleges aim to assist people with mental health difficulties in the journey to recovery through education. They bring together professional and lived experience of mental health challenges in a non-stigmatising college environment and operate on college principles. All courses are designed to contribute towards well-being and recovery. Despite the ever-growing number of Recovery Colleges (both in the UK and internationally), the evaluative evidence is limited; comprising mostly non-peer-reviewed evaluations, audits and case studies. The present article comprises a mixed-methods evaluation of a newly established Recovery College in South East Essex, UK. The evaluation comprised questionnaires of mental well-being and social inclusion at baseline and 3 and 6 month follow-up, in addition to three focus groups. There were significant improvements in both mental well-being and social inclusion from baseline to 6 month follow-up (25 participants completed the measure of well-being at both time points and 19 completed the measure of social inclusion). This was supported by additional free-text questionnaire comments and focus group findings (17 participants participated across the focus groups), with reports of increased confidence, reduced anxiety and increased social inclusion/reduced social isolation. Additionally, at 6 month follow-up a majority of respondents were planning on attending courses external to the Recovery College, volunteering and/or gaining paid employment. Challenges and recommendations identified through the focus groups indicate the importance for standardisation of processes (which is particularly important when multiple organisations are involved in the running of a Recovery College), as well as consideration of longer-running courses. Funders should continue to invest in the Recovery College movement as the growing evidence-base is demonstrating how these colleges can help address the high prevalence of mental health difficulties, by promoting mental well-being and social inclusion.


Evaluation of the difference of eight model applications to assess diffuse annual nutrient losses from agricultural land.
The capability of eight nutrient models to predict annual nutrient losses (nitrogen and phosphorus) at catchment scale have been studied in the EUROHARP project. The methodologies involved in these models differ profoundly in their complexity, level of process representation and data requirements. This evaluation is focused on model performance in three core catchments: the Vansjø-Hobøl (Norway), the Ouse (Yorkshire, UK) and the Enza (Italy). These three different model applications have been evaluated by comparing calculated annual nutrient loads (total N or nitrate and total P), based on observed flow and total nitrogen or nitrate and total phosphorus concentrations, and the annual nutrient loads that were simulated by the eight nutrient models. Four statistics have been applied for this purpose: the root mean squared error (RMSE), the mean absolute error (MAE), the mean error (ME), and Nash-Sutcliffe's model efficiency (NS). The results show that all model approaches can predict the calculated annual discharges. Depending on the observed statistics (RMSE, MAE, ME and NS) the scores of the model application differed, therefore no overall 'best model' could be identified. Although the water and nutrient loads from (sub)catchments can be predicted, the modelled pathways of nutrients within agricultural land and the nutrient losses to surface waters from agricultural land vary among the catchments and among those model approaches which are able to make this distinction.


Treatment of Drug-Resistant Tuberculosis. An Official ATS/CDC/ERS/IDSA Clinical Practice Guideline.
Background: The American Thoracic Society, U.S. Centers for Disease Control and Prevention, European Respiratory Society, and Infectious Diseases Society of America jointly sponsored this new practice guideline on the treatment of drug-resistant tuberculosis (DR-TB). The document includes recommendations on the treatment of multidrug-resistant TB (MDR-TB) as well as isoniazid-resistant but rifampin-susceptible TB.Methods: Published systematic reviews, meta-analyses, and a new individual patient data meta-analysis from 12,030 patients, in 50 studies, across 25 countries with confirmed pulmonary rifampin-resistant TB were used for this guideline. Meta-analytic approaches included propensity score matching to reduce confounding. Each recommendation was discussed by an expert committee, screened for conflicts of interest, according to the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology.Results: Twenty-one Population, Intervention, Comparator, and Outcomes questions were addressed, generating 25 GRADE-based recommendations. Certainty in the evidence was judged to be very low, because the data came from observational studies with significant loss to follow-up and imbalance in background regimens between comparator groups. Good practices in the management of MDR-TB are described. On the basis of the evidence review, a clinical strategy tool for building a treatment regimen for MDR-TB is also provided.Conclusions: New recommendations are made for the choice and number of drugs in a regimen, the duration of intensive and continuation phases, and the role of injectable drugs for MDR-TB. On the basis of these recommendations, an effective all-oral regimen for MDR-TB can be assembled. Recommendations are also provided on the role of surgery in treatment of MDR-TB and for treatment of contacts exposed to MDR-TB and treatment of isoniazid-resistant TB.


Ion channels in EEG: isolating channel dysfunction in NMDA receptor antibody encephalitis.
See Roberts and Breakspear (doi:10.1093/brain/awy136) for a scientific commentary on this article.Neurological and psychiatric practice frequently lack diagnostic probes that can assess mechanisms of neuronal communication non-invasively in humans. In N-methyl-d-aspartate (NMDA) receptor antibody encephalitis, functional molecular assays are particularly important given the presence of NMDA antibodies in healthy populations, the multifarious symptomology and the lack of radiological signs. Recent advances in biophysical modelling techniques suggest that inferring cellular-level properties of neural circuits from macroscopic measures of brain activity is possible. Here, we estimated receptor function from EEG in patients with NMDA receptor antibody encephalitis (n = 29) as well as from encephalopathic and neurological patient controls (n = 36). We show that the autoimmune patients exhibit distinct fronto-parietal network changes from which ion channel estimates can be obtained using a microcircuit model. Specifically, a dynamic causal model of EEG data applied to spontaneous brain responses identifies a selective deficit in signalling at NMDA receptors in patients with NMDA receptor antibody encephalitis but not at other ionotropic receptors. Moreover, though these changes are observed across brain regions, these effects predominate at the NMDA receptors of excitatory neurons rather than at inhibitory interneurons. Given that EEG is a ubiquitously available clinical method, our findings suggest a unique re-purposing of EEG data as an assay of brain network dysfunction at the molecular level.


One-dimension-based spatially ordered architectures for solar energy conversion.
The severe consequences of fossil fuel consumption have resulted in a need for alternative sustainable sources of energy. Conversion and storage of solar energy via a renewable method, such as photocatalysis, holds great promise as such an alternative. One-dimensional (1D) nanostructures have gained attention in solar energy conversion because they have a long axis to absorb incident sunlight yet a short radial distance for separation of photogenerated charge carriers. In particular, well-ordered spatially high dimensional architectures based on 1D nanostructures with well-defined facets or anisotropic shapes offer an exciting opportunity for bridging the gap between 1D nanostructures and the micro and macro world, providing a platform for integration of nanostructures on a larger and more manageable scale into high-performance solar energy conversion applications. In this review, we focus on the progress of photocatalytic solar energy conversion over controlled one-dimension-based spatially ordered architecture hybrids. Assembly and classification of these novel architectures are summarized, and we discuss the opportunity and future direction of integration of 1D materials into high-dimensional, spatially organized architectures, with a perspective toward improved collective performance in various artificial photoredox applications.


Growth of infectious salmon anaemia virus in CHSE-214 cells and evidence for phenotypic differences between virus strains.
Infectious salmon anaemia virus (ISAV) is a new orthomyxovirus-like virus. Thirteen isolates of ISAV (11 from Canada, one from Norway and one from Scotland) were studied for their replication in the CHSE-214 cell line compared with that in the SHK-1 cell line. All isolates replicated in SHK-1 cells, producing CPE between 3 and 12 days post-inoculation (p.i.). Six Canadian isolates also replicated in CHSE-214 cells, with production of CPE between 4 and 17 days p.i. Analysis of a one-step growth curve of ISAV in CHSE-214 cells showed that progeny virions remained predominantly cell-associated, accounting for the focalized nature of the CPE in the cell monolayer. One isolate (HKS 36) replicated in CHSE-214 cells, as shown by positive RT-PCR results of blind passages, but was non-cytopathic. All of the isolates were analysed for genetic heterogeneity by RT-PCR and RFLP with EcoRI and XhoI in a fraction of genome segment 2. The Canadian isolates showed a different RFLP profile to those of isolates Glesvaer/2/90 from Norway and 390/98 from Scotland. Structural proteins of four isolates, 'Back Bay 98', RPC/NB-877, RPC/NB-049 and Glesvaer/2/90, were examined further by SDS-PAGE. All viruses showed four major polypeptides, designated here as VP1-VP4, in Coomassie blue-stained gels. In isolates Glesvaer/2/90 and RPC/NB-877, these viral proteins had estimated molecular masses of 74, 53, 46 and 26.5 kDa, respectively. Viral proteins in isolates 'Back Bay 98' and RPC/NB-049 were of similar sizes, except that VP3 was 43 kDa. Taken together, these results show that there are phenotypic differences among strains of ISAV.


The presentation and outcome of HIV-related disease in Nairobi.
The range of clinical presentations of HIV-related disease in Africa has not been adequately described, despite the fact that many hospitals have to rely heavily on clinical diagnosis. Six hundred adult medical patients seen in the Casualty Department of the main Government hospital in Nairobi were enrolled in a study of the presentation and outcome of HIV-related disease: 506 of these patients were admitted, of whom 19 per cent (95) were HIV seropositive. The remaining 94 were dealt with as outpatients: 11 percent (10) of these were seropositive. A history of prior treatment for sexually transmitted disease and, if male, being uncircumcised, were associated with being seropositive. Three presentations were strongly associated with HIV infection: acute fever with no focus except the gastrointestinal tract (enteric fever-like illness), acute cough with fever (community-acquired pneumonia) and chronic diarrhoea with wasting. The WHO clinical case definition (CCD) for AIDS missed a substantial amount of HIV-related morbidity (sensitivity 39 per cent) and misidentified many seronegative patients (positive predictive value 59 per cent). In comparison with the Centers for Disease Control surveillance definition for AIDS, the CCD was specific (91 per cent) and sensitive (79 per cent) but only had a positive predictive values of 30 per cent: the CCD may therefore be a poor surveillance tool for AIDS. Seropositive patients were much more likely to die than were seronegative patients (39 per cent vs. 15 per cent mortality). Enteric fever-like illness was the presentation which most commonly proved fatal. A wider spectrum of disease is associated with underlying HIV immunosuppression than has previously been described in Africa.


Academic and molecular matrices: a study of the transformations of connective tissue research at the University of Manchester (1947-1996).
This paper explores the different identities adopted by connective tissue research at the University of Manchester during the second half of the 20th century. By looking at the long-term redefinition of a research programme, it sheds new light on the interactions between different and conflicting levels in the study of biomedicine, such as the local and the global, or the medical and the biological. It also addresses the gap in the literature between the first biomedical complexes after World War II and the emergence of biotechnology. Connective tissue research in Manchester emerged as a field focused on new treatments for rheumatic diseases. During the 1950s and 60s, it absorbed a number of laboratory techniques from biology, namely cell culture and electron microscopy. The transformations in scientific policy during the late 70s and the migration of Manchester researchers to the US led them to adopt recombinant DNA methods, which were borrowed from human genetics. This resulted in the emergence of cell matrix biology, a new field which had one of its reference centres in Manchester. The Manchester story shows the potential of detailed and chronologically wide local studies of patterns of work to understand the mechanisms by which new biomedical tools and institutions interact with long-standing problems and existing affiliations.


Abdominal compartment syndrome secondary to chronic constipation.
Abdominal compartment syndrome (ACS) is defined as an elevated intraabdominal pressure with evidence of organ dysfunction. The majority of published reports of ACS are in neonates with abdominal wall defects and in adults following trauma or burns, but it is poorly described in children. We describe the unusual presentation of an 11-year-old boy with a long history of chronic constipation who developed acute ACS requiring resuscitative measures and emergent disimpaction. He presented with a 2-week history of increasing abdominal pain, nausea, diminished appetite and longstanding encopresis. On exam, he was emaciated with a massively distended abdomen with a palpable fecaloma. Abdominal XR confirmed these findings. Within 24 hours of presentation, he became tachycardic and oliguric with orthostatic hypotension. Following two enemas, he acutely deteriorated with severe hypotension, marked tachycardia, acute respiratory distress, and a declining mental status. Endotracheal intubation, fluid boluses, and vasopressors were commenced, followed by emergent surgical fecal disimpaction. This resulted in rapid improvement in vital signs. He has been thoroughly investigated and no other condition apart from functional constipation has been identified. Although ACS secondary to constipation is extremely unusual, this case illustrates the need to actively treat constipation and what can happen if it is not.


Prefabricated composite veneers: historical perspectives, indications and clinical application.
Veneering anterior teeth is a well-established technique, which was brought to Dentistry by Dr Pincus as early as 1937. From the mid-1970s, boosted by the development of composites and adhesive techniques, various concepts emerged including direct composite restorations, prefabricated composite veneers and of course, individualized porcelain indirect veneers. The prefabricated composite veneer option was however soon abandoned due to former technological limitations. Recently, the creation of a new shade guide comprising enamel shells revitalized this "old idea," and in combination with a high pressure and temperature molding process followed by a laser surface vitrification, a novel, improved composite prefabricated system (Venear, Edelweiss Dentistry) was born. This paper provides an overview of the potential indications and clinical protocol of this original veneering technique.


Gold nanoparticle assembly microfluidic reactor for efficient on-line proteolysis.
A microchip reactor coated with a gold nanoparticle network entrapping trypsin was designed for the efficient on-line proteolysis of low level proteins and complex extracts originating from mouse macrophages. The nanostructured surface coating was assembled via a layer-by-layer electrostatic binding of poly(diallyldimethylammonium chloride) and gold nanoparticles. The assembly process was monitored by UV-visible spectroscopy, atomic force microscopy, and quartz crystal microbalance. The controlled adsorption of trypsin was theoretically studied on the basis of the Langmuir isotherm model, and the fitted Gamma(max) and K values were estimated to be 1.2 x 10(-7) mol/m(2) and 4.1 x 10(5) M(-1), respectively. An enzymatic kinetics assay confirmed that trypsin, which was entrapped in the biocompatible gold nanoparticle network with a high loading capacity, preserved its bioactivity. The maximum proteolytic rate of the adsorbed trypsin was 400 mM/(min.microg). Trace amounts of proteins down to femtomole per analysis were digested using the microchip reactor, and the resulting tryptic products were identified by MALDI-TOF MS/MS. The protein mixtures extracted from the mouse macrophages were efficiently identified by on-line digestion and LC-ESI-MS/MS analysis.


Chronic pharmacological mGlu5 inhibition corrects fragile X in adult mice.
Fragile X syndrome (FXS) is the most common form of inherited intellectual disability. Previous studies have implicated mGlu5 in the pathogenesis of the disease, but a crucial unanswered question is whether pharmacological mGlu5 inhibition is able to reverse an already established FXS phenotype in mammals. Here we have used the novel, potent, and selective mGlu5 inhibitor CTEP to address this issue in the Fmr1 knockout mouse. Acute CTEP treatment corrects elevated hippocampal long-term depression, protein synthesis, and audiogenic seizures. Chronic treatment that inhibits mGlu5 within a receptor occupancy range of 81% ± 4% rescues cognitive deficits, auditory hypersensitivity, aberrant dendritic spine density, overactive ERK and mTOR signaling, and partially corrects macroorchidism. This study shows that a comprehensive phenotype correction in FXS is possible with pharmacological intervention starting in young adulthood, after development of the phenotype. It is of great interest how these findings may translate into ongoing clinical research testing mGlu5 inhibitors in FXS patients.


Chaotic Red Queen coevolution in three-species food chains.
Coevolution between two antagonistic species follows the so-called 'Red Queen dynamics' when reciprocal selection results in an endless series of adaptation by one species and counteradaptation by the other. Red Queen dynamics are 'genetically driven' when selective sweeps involving new beneficial mutations result in perpetual oscillations of the coevolving traits on the slow evolutionary time scale. Mathematical models have shown that a prey and a predator can coevolve along a genetically driven Red Queen cycle. We found that embedding the prey-predator interaction into a three-species food chain that includes a coevolving superpredator often turns the genetically driven Red Queen cycle into chaos. A key condition is that the prey evolves fast enough. Red Queen chaos implies that the direction and strength of selection are intrinsically unpredictable beyond a short evolutionary time, with greatest evolutionary unpredictability in the superpredator. We hypothesize that genetically driven Red Queen chaos could explain why many natural populations are poised at the edge of ecological chaos. Over space, genetically driven chaos is expected to cause the evolutionary divergence of local populations, even under homogenizing environmental fluctuations, and thus to promote genetic diversity among ecological communities over long evolutionary time.


Adaptable defense: a nudibranch mucus inhibits nematocyst discharge and changes with prey type.
Nudibranchs that feed on cnidarians must defend themselves from the prey's nematocysts or risk their own injury or death. While a nudibranch's mucus has been thought to protect the animal from nematocyst discharge, an inhibition of discharge by nudibranch mucus has never been shown. The current study investigated whether mucus from the aeolid nudibranch Aeolidia papillosa would inhibit nematocyst discharge from four species of sea anemone prey. Sea anemone tentacles were contacted with mucus-coated gelatin probes, and nematocyst discharge was quantified and compared with control probes of gelatin only. Mucus from A. papillosa inhibited the discharge of nematocysts from sea anemone tentacles. This inhibition was specifically limited to the anemone species on which the nudibranch had been feeding. When the prey species was changed, the mucus changed within 2 weeks to inhibit the nematocyst discharge of the new prey species. The nudibranchs apparently produce the inhibitory mucus rather than simply becoming coated in anemone mucus during feeding. Because of the intimate association between most aeolid nudibranchs and their prey, an adaptable mucus protection could have a significant impact on the behavior, distribution, and life history of the nudibranchs.


Sirolimus-eluting stents vs paclitaxel-eluting stents in patients with coronary artery disease: meta-analysis of randomized trials.
Placement of sirolimus-eluting stents or paclitaxel-eluting stents has emerged as the predominant percutaneous treatment strategy in patients with coronary artery disease (CAD). Whether there are any differences in efficacy and safety between these 2 drug-eluting stents is unclear. To compare outcomes of sirolimus-eluting and paclitaxel-eluting coronary stents on the basis of data generated by randomized head-to-head clinical trials. PubMed and the Cochrane Central Register of Controlled Trials, conference proceedings from major cardiology meetings, and Internet-based sources of information on clinical trials in cardiology from January 2003 to April 2005. Randomized trials comparing the sirolimus-eluting stent with the paclitaxel-eluting stent in patients with CAD reporting the outcomes of interest (target lesion revascularization, angiographic restenosis, stent thrombosis, myocardial infarction [MI], death, and the composite of death or MI) during a follow-up of at least 6 months. Two reviewers independently identified studies and abstracted data on sample size, baseline characteristics, and outcomes of interest. Six trials, including 3669 patients, met the selection criteria. No significant heterogeneity was found across trials. Target lesion revascularization, the primary outcome of interest, was less frequently performed in patients who were treated with the sirolimus-eluting stent (5.1%) vs the paclitaxel-eluting stent (7.8%) (odds ratio [OR], 0.64; 95% confidence interval [CI], 0.49-0.84; P = .001). Similarly, angiographic restenosis was less frequently observed among patients assigned to the sirolimus-eluting stent (9.3%) vs the paclitaxel-eluting stent (13.1%) (OR, 0.68; 95% CI, 0.55-0.86; P = .001). Event rates for sirolimus-eluting vs paclitaxel-eluting stents were 0.9% and 1.1%, respectively, for stent thrombosis (P = .62); 1.4% and 1.6%, respectively, for death (P = .56); and 4.9% and 5.8%, respectively, for the composite of death or MI (P = .23). Patients receiving sirolimus-eluting stents had a significantly lower risk of restenosis and target vessel revascularization compared with those receiving paclitaxel-eluting stents. Rates of death, death or MI, and stent thrombosis were similar.


The impact of geographic unit of analysis on socioeconomic inequalities in cancer survival and distant summary stage - a population-based study.
When using area-level disadvantage measures, size of geographic unit can have major effects on recorded socioeconomic cancer disparities. This study examined the extent of changes in recorded socioeconomic inequalities in cancer survival and distant stage when the measure of socioeconomic disadvantage was based on smaller Census Collection Districts (CDs) instead of Statistical Local Areas (SLAs). Population-based New South Wales Cancer Registry data were used to identify cases diagnosed with primary invasive cancer in 2000-2008 (n=264,236). Logistic regression and competing risk regression modelling were performed to examine socioeconomic differences in odds of distant stage and hazard of cancer death for all sites combined and separately for breast, prostate, colorectal and lung cancers. For all sites collectively, associations between socioeconomic disadvantage and cancer survival and distant stage were stronger when the CD-based socioeconomic disadvantage measure was used compared with the SLA-based measure. The CD-based measure showed a more consistent socioeconomic gradient with a linear upward trend of risk of cancer death/distant stage with increasing socioeconomic disadvantage. Site-specific analyses provided similar findings for the risk of death but less consistent results for the likelihood of distant stage. The use of socioeconomic disadvantage measure based on the smallest available spatial unit should be encouraged in the future. Implications for public health: Disadvantage measures based on small spatial units can more accurately identify socioeconomic cancer disparities to inform priority settings in service planning.


Identification of prognostic biomarkers for prostate cancer.
This paper describes a process for the identification of genes that can report on the aggressiveness of prostate tumors and thereby add to the information provided by current pathologic analysis. Expression profiling data from over 100 laser capture microdissection derived samples from nonneoplastic epithelium; Gleason patterns 3, 4, and 5 and node metastasis prostate cancer were used to identify genes at abnormally high levels in only some tumors. These variably overexpressed genes were stratified by their association with aggressive phenotypes and were subsequently filtered to exclude genes with redundant expression patterns. Selected genes were validated in a case-control study in which cases (systemic progression within 5 years) and controls (no systemic progression at 7 years of follow-up) were matched for all clinical and pathologic criteria from time of prostatectomy (n = 175). Both cases and controls, therefore, could have nodal invasion or seminal vesicle involvement at the time of initial treatment. A number of candidate variably overexpressed genes selected for their association with aggressive prostate cancer phenotype were evaluated in the case control study. The most prominent candidates were SSTR1 and genes related to proliferation, including TOP2A. The process described here identified genes that add information not available from current clinical measures and can improve the prognosis of prostate cancer.


Incidental metastatic mediastinal atypical carcinoid in a patient with parathyroid adenoma: a case report.
Atypical carcinoid arising from the mediastinal tissue is a rare neuroendocrine tumor and an association with parathyroid adenoma is very unusual. We report an unusual case of atypical carcinoid of mediastinum with metastasis in a patient presenting with parathyroid adenoma, which is the first case to be reported from Pakistan. A 51-year-old Pakistani man was seen in postoperative intensive care after right parathyroidectomy and mediastinal mass resection for the management of postoperative hypocalcaemia. He had a background history of dyspnea. Examination was unremarkable. Preoperative laboratory evaluation revealed a calcium level of 12.7 mg/dl, phosphate of 1.9 mg/dl, serum albumin of 4.8 g/dl, alkaline phosphate of 94 U/L, and serum intact parathyroid hormone level 413.8 pg/ml. A technetium-99m sestamibi parathyroid scan showed right parathyroid increased tracer uptake. Further workup revealed a large mediastinal mass which was diagnosed as atypical carcinoid after Tru-Cut biopsy. He underwent right-sided parathyroidectomy and resection of the mediastinal mass. The histopathology confirmed it to be a parathyroid adenoma and atypical carcinoid tumor of his mediastinum with metastasis in his lymph node and parathyroid gland. Somatostatin receptor scintigraphy revealed a well-defined focus in his left hypochondriac region consistent with a somatostatin receptor scintigraphy-avid tumor. He was started on everolimus and planned for octreotide therapy. We describe an incidental finding of atypical carcinoid of the mediastinum in a patient diagnosed as having parathyroid adenoma. Clinical manifestations of neuroendocrine syndromes are challenging. Some tumors cluster in a non-classic description with other common neoplasms. They rarely present in isolation, remain clinically silent, and need aggressive workup with the aid of imaging and histopathology.


Word imageability effects on naming: a pilot investigation of beginning readers of Turkish.
Word imageability, a semantic variable, in naming by beginning readers of English is well documented particularly with poor readers naming high imageable words more accurately than low imageable words. The present study examined the role of imageability on word naming by 20 good and 20 poor beginning readers as a function of orthographic transparency by utilizing the peculiarities of the transparent Turkish writing system. Neither good nor poor beginning readers show any evidence of imageability for Turkish suggesting that the contribution of imageability to word naming may indeed be determined by orthographic transparency. Implications of these findings are discussed.