Off-Label Use of Ataluren in Four Non-ambulatory Patients With Nonsense Mutation Duchenne Muscular Dystrophy: Effects on Cardiac and Pulmonary Function and Muscle Strength.
About 15% of Duchenne muscular dystrophy (DMD) cases are caused by point mutations leading to premature stop codons and disrupted synthesis of the dystrophin protein. Stop codon read-through therapy is available with the drug Ataluren (Translarna® by PTC Therapeutics). Following positive results in ambulatory nmDMD (non-sense mutation Duchenne muscular dystrophy) patients, Ataluren received conditional approval in ambulant nmDMD patients by the EMA in 2014. However, there are limited data on non-ambulatory nmDMD patients treated with Ataluren. Here, we report our experience in four non-ambulatory nmDMD patients. Routine investigations included cardiac function, pulmonary function tests and muscle strength. We compared changes in left ventricular fractional shorting, forced volume vital capacity and BMI from two defined time periods (18-26-month period prior to and after Ataluren start). Mean age at loss of ambulation was 10.1 ± 0.5 years, mean age when initiating Ataluren treatment 14.1 ± 1.4 years. Serial echocardiography, pulmonary lung function tests, and assessment of muscle strength indicated mild attenuation of disease progression after initiation of Ataluren treatment. A possible side effect of Ataluren was a reduction in BMI. There were no adverse clinical effects or relevant abnormalities in routine laboratory values. We conclude that Ataluren appears to mildly ameliorate the clinical course in our patients with a good safety profile. However, larger clinical trials are required to assess the role of Ataluren and its long-term impact on disease progression in non-ambulant nmDMD patients.


Prenatal nicotine exposure alters the types of nicotinic receptors that facilitate excitatory inputs to cardiac vagal neurons.
Nicotinic receptors play an important role in modulating the activity of parasympathetic cardiac vagal neurons in the medulla. Previous work has shown nicotine acts via at least three mechanisms to excite brain stem premotor cardiac vagal neurons. Nicotine evokes a direct increase in holding current and facilitates both the frequency and amplitude of glutamatergic neurotransmission to cardiac vagal neurons. This study tests whether these nicotinic receptor-mediated responses are endogenously active, whether alpha4beta2 and alpha7 nicotinic receptors are involved, and whether prenatal exposure to nicotine alters the magnitude of these responses and the types of nicotinic receptors involved. Application of neostigmine (10 microM) significantly increased the holding current, amplitude, and frequency of miniature excitatory postsynaptic current (mEPSC) glutamatergic events in cardiac vagal neurons. In unexposed animals, the nicotine-evoked facilitation of mEPSC frequency, but not mEPSC amplitude or holding current, was blocked by alpha-bungarotoxin (100 nM). Prenatal nicotine exposure significantly exaggerated and altered the types of nicotinic receptors involved in these responses. In prenatal nicotine-exposed animals, alpha-bungarotoxin only partially reduced the increase in mEPSC frequency. In addition, in prenatal nicotine-exposed animals, the increase in holding current was partially dependent on alpha-7 subunit-containing nicotinic receptors, in contrast to unexposed animals in which alpha-bungarotoxin had no effect. These results indicate prenatal nicotine exposure, one of the highest risk factors for sudden infant death syndrome (SIDS), exaggerates the responses and changes the types of nicotinic receptors involved in exciting premotor cardiac vagal neurons. These alterations could be responsible for the pronounced bradycardia that occurs during apnea in SIDS victims.


Practical Utility and Accuracy of Matrix-Assisted Laser Desorption Ionization-Time of Flight Mass Spectrometry for Identification of Corynebacterium Species and Other Medically Relevant Coryneform-Like Bacteria.
Corynebacterium species and gram-positive coryneform-like bacteria (coryneforms) are increasingly reported causes of opportunistic infections in immunocompromised patients. Biochemical identification methods for these bacteria are often inaccurate. We evaluated matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) for routine Corynebacterium and coryneform identification. A total of 286 Corynebacterium species and coryneforms recovered from patients were identified by MALDI-TOF MS analysis using the Bruker Microflex instrument, Biotyper software version 3.0, and database version 3.1.66 (Bruker Daltonics, Billerica, MA) following formic acid-based, direct on-plate extraction. The spectral cutoff scores used for interpretation were 2.0 or more for species-level identification and 1.7 or more for genus level. Scores lower than 1.7 were considered as no reliable identification. The results were compared with API Coryne (bioMérieux, Durham, NC) and sequencing of 16S ribosomal RNA genes. Of the 231 Corynebacterium (19 species), 99.6% were correctly identified to the genus level and 88.7% to the species level. Of the 55 coryneforms (14 genera), 90.9% were correctly identified to the genus level and 67.3% to the species level. API Coryne was able to identify 89.2% of Corynebacterium species (species level) and 63.6% of coryneforms (genus level). Rapid on-plate testing yielded identification of more Corynebacterium species and related bacteria than biochemical methods.


Emodin enhances cytotoxicity of chemotherapeutic drugs in prostate cancer cells: the mechanisms involve ROS-mediated suppression of multidrug resistance and hypoxia inducible factor-1.
The intrinsic or acquired resistance to multiple drugs (MDR) of cancer cells remains one of the main obstacles for chemotherapy. Development of small molecule targeting to hypoxia inducible factor-1 (HIF-1) has been recently proposed as strategy for treatments of drug-resistant solid tumors. In the present study, emodin, proven as a reactive oxygen species (ROS) generator by our previous work, was applied in combination with cisplatin and other chemotherapeutic drugs in the multidrug resistant prostate carcinoma cell line DU-145 and normal human dermal fibroblasts. Results showed that emodin/cisplatin co-treatment remarkably elevated ROS level and enhanced chemosensitivity in DU-145 cells, compared with cisplatin-only treatment, but exerted little effect on non-tumor cells. The effect of co-treatment on MDR1 gene and its upstream regulator HIF-1 was then investigated in DU-145. Co-treatment downregulated MDR1 expression and promoted drug retention, and meanwhile suppressed transactivation of HIF-1 in response to hypoxia without changing expression of HIF-1 alpha. The experiments on tumor-bearing mice showed that co-treatment inhibited the tumor growth in vivo, owing to oxidative stress and MDR1 down-regulation within tumors. HIF-1 transactivation and clonegenesis were suppressed in cells isolated from the tumors. Finally, examinations for the body weight, the organ histology and the antioxidant capacity of serum suggested that no systemic toxicity related to co-treatment was discernable. In conclusions, emodin, as a novel small inhibitor of HIF-1, may be recognized an effective adjunctive to improve efficacy of cytotoxic drugs in prostate cancer cells with over-activated HIF-1 and potent MDR.


Fat- and bone marrow-impregnated small diameter PTFE grafts.
to evaluate an alternative and simple technique which consists in impregnation of a synthetic prosthesis with either autogenic omental fat or bone marrow. These tissues have been selected based on previous works and because they contain multiple cellular and extracellular compounds with biological healing properties (i.e. angiogenesis, endothelialisation, etc.). PTFE grafts of Group 1 were impregnated with fatty tissue, those of Group 2 with bone marrow and those of Group 3 served as controls. nine mongrel dogs divided among these three groups. PTFE grafts are 3 mm in diameter. in each animal, both iliac arteries were submitted to an end-to-side ilio-iliac bypass. At 3 months, pathology assessment was performed. group 1: all grafts were thrombosed and intimal hyperplasia was found occluding the anastomotic sites. Group 2: 4/6 grafts were patent and their mid-portion presented a thin neointima which did not totally cover the anastomotic sites. Group 3: 2/5 grafts were patent and their mid-portion as well as the anastomotic sites were covered with neointima which was hyperplastic in some areas. addition of bone marrow cells may contribute to improve the quality of the healing process.


Hypothalamic dopamine neurons motivate mating through persistent cAMP signalling.
Transient neuromodulation can have long-lasting effects on neural circuits and motivational states1-4. Here we examine the dopaminergic mechanisms that underlie mating drive and its persistence in male mice. Brief investigation of females primes a male's interest to mate for tens of minutes, whereas a single successful mating triggers satiety that gradually recovers over days5. We found that both processes are controlled by specialized anteroventral and preoptic periventricular (AVPV/PVpo) dopamine neurons in the hypothalamus. During the investigation of females, dopamine is transiently released in the medial preoptic area (MPOA)-an area that is critical for mating behaviours. Optogenetic stimulation of AVPV/PVpo dopamine axons in the MPOA recapitulates the priming effect of exposure to a female. Using optical and molecular methods for tracking and manipulating intracellular signalling, we show that this priming effect emerges from the accumulation of mating-related dopamine signals in the MPOA through the accrual of cyclic adenosine monophosphate levels and protein kinase A activity. Dopamine transients in the MPOA are abolished after a successful mating, which is likely to ensure abstinence. Consistent with this idea, the inhibition of AVPV/PVpo dopamine neurons selectively demotivates mating, whereas stimulating these neurons restores the motivation to mate after sexual satiety. We therefore conclude that the accumulation or suppression of signals from specialized dopamine neurons regulates mating behaviours across minutes and days.


Spatial Dynamic Subspaces Encode Sex-Specific Schizophrenia Disruptions in Transient Network Overlap and its Links to Genetic Risk.
Recent advances in resting-state fMRI allow us to study spatial dynamics, the phenomenon of brain networks spatially evolving over time. However, most dynamic studies still use subject-specific, spatially-static nodes. As recent studies have demonstrated, incorporating time-resolved spatial properties is crucial for precise functional connectivity estimation and gaining unique insights into brain function. Nevertheless, estimating time-resolved networks poses challenges due to the low signal-to-noise ratio, limited information in short time segments, and uncertain identification of corresponding networks within and between subjects. We adapt a reference-informed network estimation technique to capture time-resolved spatial networks and their dynamic spatial integration and segregation. We focus on time-resolved spatial functional network connectivity (spFNC), an estimate of network spatial coupling, to study sex-specific alterations in schizophrenia and their links to multi-factorial genomic data. Our findings are consistent with the dysconnectivity and neurodevelopment hypotheses and align with the cerebello-thalamo-cortical, triple-network, and frontoparietal dysconnectivity models, helping to unify them. The potential unification offers a new understanding of the underlying mechanisms. Notably, the posterior default mode/salience spFNC exhibits sex-specific schizophrenia alteration during the state with the highest global network integration and correlates with genetic risk for schizophrenia. This dysfunction is also reflected in high-dimensional (voxel-level) space in regions with weak functional connectivity to corresponding networks. Our method can effectively capture spatially dynamic networks, detect nuanced SZ effects, and reveal the intricate relationship of dynamic information to genomic data. The results also underscore the potential of dynamic spatial dependence and weak connectivity in the clinical landscape.


Pattern of the divergence of olfactory receptor genes during tetrapod evolution.
The olfactory receptor (OR) multigene family is responsible for the sense of smell in vertebrate species. OR genes are scattered widely in our chromosomes and constitute one of the largest gene families in eutherian genomes. Some previous studies revealed that eutherian OR genes diverged mainly during early mammalian evolution. However, the exact period when, and the ecological reason why eutherian ORs strongly diverged has remained unclear. In this study, I performed a strict data mining effort for marsupial opossum OR sequences and bootstrap analyses to estimate the periods of chromosomal migrations and gene duplications of OR genes during tetrapod evolution. The results indicate that chromosomal migrations occurred mainly during early vertebrate evolution before the monotreme-placental split, and that gene duplications occurred mainly during early mammalian evolution between the bird-mammal split and marsupial-placental split, coinciding with the reduction of opsin genes in primitive mammals. It could be thought that the previous chromosomal dispersal allowed the OR genes to subsequently expand easily, and the nocturnal adaptation of early mammals might have triggered the OR gene expansion.


[Effects of the autonomic nervous system function on the course of postoperative period in surgical removal of vocal cords polyps with Nd:YAG-laser].
The study of the effects of autonomic nervous system (ANS) function on the course of the postoperative period after removal of the vocal cord polyps with Nd:YAG laser has shown that laryngeal operations with utilization of Nd:YAG laser accelerate normalization of structural-functional condition of the vocal cords in patients with adequate autonomic support by 25-40 days compared to those with inadequate ANS function.


Anti-MET immunoPET for non-small cell lung cancer using novel fully human antibody fragments.
MET, the receptor of hepatocyte growth factor, plays important roles in tumorigenesis and drug resistance in numerous cancers, including non-small cell lung cancer (NSCLC). As increasing numbers of MET inhibitors are being developed for clinical applications, antibody fragment-based immunopositron emission tomography (immunoPET) has the potential to rapidly quantify in vivo MET expression levels for drug response evaluation and patient stratification for these targeted therapies. Here, fully human single-chain variable fragments (scFvs) isolated from a phage display library were reformatted into bivalent cys-diabodies (scFv-cys dimers) with affinities to MET ranging from 0.7 to 5.1 nmol/L. The candidate with the highest affinity, H2, was radiolabeled with (89)Zr for immunoPET studies targeting NSCLC xenografts: low MET-expressing Hcc827 and the gefitinib-resistant Hcc827-GR6 with 4-fold MET overexpression. ImmunoPET at as early as 4 hours after injection produced high-contrast images, and ex vivo biodistribution analysis at 20 hours after injection showed about 2-fold difference in tracer uptake levels between the parental and resistant tumors (P < 0.01). Further immunoPET studies using a larger fragment, the H2 minibody (scFv-CH3 dimer), produced similar results at later time points. Two of the antibody clones (H2 and H5) showed in vitro growth inhibitory effects on MET-dependent gefitinib-resistant cell lines, whereas no effects were observed on resistant lines lacking MET activation. In conclusion, these fully human antibody fragments inhibit MET-dependent cancer cells and enable rapid immunoPET imaging to assess MET expression levels, showing potential for both therapeutic and diagnostic applications.


A systematic review of the effect of thermal processing on the allergenicity of tree nuts.
Allergenicity of foods can be influenced by processing. Tree nuts are an important source of nutrition and increasingly consumed; however, processing methods are quite variable and data are currently lacking on the effects of processing on allergenicity. To perform a systematic literature review on the effects of food processing on the allergenicity of tree nuts. A systematic literature search of PubMed and Embase databases was performed, with screening of references, related articles and citations. Studies were included if they assessed the allergenicity or immunogenicity of processed nuts. The search resulted in 32 articles suitable for analysis. Clinical studies indicate that roasting reduces the allergenicity of hazelnut in individuals with a birch pollen allergy and reactivity to raw hazelnut. Thermal processing may reduce the allergenicity of the PR-10 protein in hazelnut and almond in vitro. The majority of the in vitro studies investigating the allergenicity of nonspecific lipid transfer proteins (nsLTPs) and seed storage proteins in hazelnut, almond, cashew nut, Brazil nut, walnut, pecan nut and pistachio nut show heat stability towards different thermal processing methods. Thermal processing may reduce allergenicity of PR-10 proteins in hazelnut and almond, in contrast to nsLTPs and seed storage proteins. This has important implications for source materials used for IgE testing and food challenges and diet advice.


Pilot-scale in situ bioremedation of uranium in a highly contaminated aquifer. 2. Reduction of u(VI) and geochemical control of u(VI) bioavailability.
In situ microbial reduction of soluble U(VI) to sparingly soluble U(IV) was evaluated at the site of the former S-3 Ponds in Area 3 of the U.S. Department of Energy Natural and Accelerated Bioremediation Research Field Research Center, Oak Ridge, TN. After establishing conditions favorable for bioremediation (Wu, et al. Environ. Sci. Technol. 2006, 40, 3988-3995), intermittent additions of ethanol were initiated within the conditioned inner loop of a nested well recirculation system. These additions initially stimulated denitrification of matrix-entrapped nitrate, but after 2 months, aqueous U levels fell from 5 to approximately 1 microM and sulfate reduction ensued. Continued additions sustained U(VI) reduction over 13 months. X-ray near-edge absorption spectroscopy (XANES) confirmed U(VI) reduction to U(IV) within the inner loop wells, with up to 51%, 35%, and 28% solid-phase U(IV) in sediment samples from the injection well, a monitoring well, and the extraction well, respectively. Microbial analyses confirmed the presence of denitrifying, sulfate-reducing, and iron-reducing bacteria in groundwater and sediments. System pH was generally maintained at less than 6.2 with low bicarbonate level (0.75-1.5 mM) and residual sulfate to suppress methanogenesis and minimize uranium mobilization. The bioavailability of sorbed U(VI) was manipulated by addition of low-level carbonate (< 5 mM) followed by ethanol (1-1.5 mM). Addition of low levels of carbonate increased the concentration of aqueous U, indicating an increased rate of U desorption due to formation of uranyl carbonate complexes. Upon ethanol addition, aqueous U(VI) levels fell, indicating that the rate of microbial reduction exceeded the rate of desorption. Sulfate levels simultaneously decreased, with a corresponding increase in sulfide. When ethanol addition ended but carbonate addition continued, soluble U levels increased, indicating faster desorption than reduction. When bicarbonate addition stopped, aqueous U levels decreased, indicating adsorption to sediments. Changes in the sequence of carbonate and ethanol addition confirmed that carbonate-controlled desorption increased bioavailability of U(VI) for reduction.


The intention to pursue graduate studies in nursing: a look at BScN students' self-efficacy and value influences.
The shortage of graduate-level prepared nurses is reaching critical levels. Combined with an anticipated wave of faculty retirements, a relatively older graduate student body, and an insufficient number of graduates at the Masters' and doctoral levels, the recruitment of more and younger students into graduate programs in nursing has become a priority for the profession. Current understanding of why undergraduate nursing students choose to pursue graduate studies in nursing remains vague. A non-experimental descriptive correlational study was designed and 87 useable surveys were collected from fourth-year baccalaureate nursing students at a large South-Western Ontario University (response rate = 67%). The influence of student valuation of graduate studies and self-efficacy (SE) for graduate studies on student intention to pursue graduate studies in nursing was clearly demonstrated with this study (R(2) = .52). Implications for nursing education include working towards undergraduate curricula that enhance students' valuation of and SE for graduate studies in nursing.


Fast and robust estimation of diffusional kurtosis imaging (DKI) parameters by general closed-form expressions and their extensions.
Diffusional kurtosis imaging (DKI) for clinical imaging involves time-consuming computation and demonstrates low robustness. Standard estimation of DKI parameters is based on an extension of Stejskal-Tanner's signal model with squared b-value term and is a least-squares fitting problem. The use of numerical methods for computation requires time, and estimation of DKI parameters is noise sensitive and often produces noisy results, such as images with pepper noise.In this study, we propose general closed-form solutions for DKI parameters to avoid numerical computation for least-squares fitting, solutions that can be applied to diffusion weighted imaging (DWI) datasets with any number of b-values more than three. Solutions are obtained through stationary-point conditions of an objective function that are minimized for fitting. We use 3 techniques to extend the solutions to increase robustness-b-value-dependent weighting in fitting, removal of outliers, and addition of neighbor sampling. Based on synthetic datasets and clinical datasets that both consist of 6 b-value and 3 b-value datasets, we detail and compare the 3 methods including a method by Jensen et al. are compared and investigated in detail. The synthetic data consist of several combinations of DKI parameters and some Rician noise. In addition to visually assessing result images, we also performed quantitative evaluation using a range of estimated parameters, positive-definiteness of the objective function for fitting, and root-mean-square error including estimation bias from the true value (synthetic data only). Methods that added neighbor sampling outperformed others in terms of low errors and visual smoothness. Though the solution by our method is to estimate DKI parameters in a single MPG direction, it can contribute to anisotropic analysis of diffusional kurtosis such as kurtosis tensor. More robust estimation is expected by combining techniques.


Exploring implementation and fidelity of evidence-based behavioral interventions for HIV prevention: lessons learned from the focus on kids diffusion case study.
Evidence-based interventions (EBIs) are used in public health to prevent HIV infection among youth and other groups. EBIs include core elements, features that are thought to be responsible for the efficacy of interventions. The authors evaluate experiences of organizations that adopted an HIV-prevention EBI, Focus on Kids (FOK), and their fidelity to the intervention's eight core elements. A cross-sectional telephone survey was administered to 34 staff members from organizations that had previously implemented FOK. Questions assessed how the organization adhered to, adapted, dropped, or altered the intervention. None of the organizations implemented all eight core elements. This study underscores the importance for HIV intervention researchers to clearly identify and describe core elements. More effort is needed to reflect the constraints practitioners face in nonresearch settings. To ensure intervention effectiveness, additional research and technical assistance are needed to help organizations implement HIV prevention EBIs with fidelity.


In vitro and in vivo irinotecan-induced changes in expression profiles of cell cycle and apoptosis-associated genes in acute myeloid leukemia cells.
To study irinotecan (CPT-11)-induced changes in expression profiles of genes associated with cell cycle control and apoptosis in myeloid leukemia cells in vitro and in vivo. HL60 cells were exposed to clinically achievable concentrations of 7-ethyl-10-hydroxycamptothecin (SN-38), the active metabolite of CPT-11, and blood sampled from patients with acute myeloid leukemia and chronic myeloid leukemia in myeloid blast transformation treated with CPT-11. Gene expression changes were studied by cDNA microarray and correlated with biological responses by studying DNA distributions by flow cytometry. cDNA microarray analysis showed down-regulation and up-regulation of specific cell cycle-associated genes, consistent with loss of S-phase cells and temporary delay of G(1)-S-phase transition seen by flow cytometry. Flow cytometry showed that cells in S phase during SN-38 exposure underwent apoptosis, whereas cells in G(2)-M and G(1) were delayed in G(1) and entered S phase only 6 to 8 hours after drug removal, consistent with the observed changes in gene expression. Proapoptotic changes in gene transcription included down-regulation of antiapoptotic genes and up-regulation of proapoptotic genes. Many gene expression changes observed following in vitro SN-38 exposure were also seen following in vivo administration of 10 or 15 mg/m(2) CPT-11; notably, proapoptotic changes included reduced transcription of survivin pathway-associated genes and increased transcription of death receptor 5. CPT-11-induced changes in gene expression profiles in vitro and in vivo are consistent with temporary delay in G(1)-S transition and enhanced responsiveness to apoptosis, both of which may contribute to the synergistic interactions of this drug with antimetabolites.


Electrodeposition of paracetamol oxide for intelligent portable ratiometric detection of nicotine and ethyl vanillin β-D-glucoside.
Herein, the electrodeposition of paracetamol oxide (PA ox) for the intelligent portable ratiometric detection of nicotine (NIC) and ethyl vanillin β-D-glucoside (EVG) is reported. PA ox electrodeposited on a screen-printed carbon electrode (SPCE) was used as a new fixed state ratiometric reference probe. A portable electrochemical workstation combined with a smart phone was applied as an intelligent portable electrochemical sensing platform. The sensor was studied by scanning electron microscopy (SEM), Fourier transform infrared spectrophotometry (FT-IR), ultraviolet-visible spectrophotometry (UV-vis), theoretical calculation, chronoamperometry, cyclic voltammetry (CV), electrochemical impedance spectroscopy (EIS) and square wave voltammetry (SWV). Under optimized conditions, the detection range of NIC is 10-200 μmol L-1, and the detection limit is 0.256 μmol L-1. The detection range of EVG was 10-180 μmol L-1, and the detection limit was 0.058 μmol L-1. The sensor can realize the real-time detection of NIC and EVG concentration in cigarette samples quickly and accurately, and has good anti-interference, repeatability and stability.


Communicating Emotion: Vocal Expression of Linguistic and Emotional Prosody in Children With Mild to Profound Hearing Loss Compared With That of Normal Hearing Peers.
Emotional prosody is known to play an important role in social communication. Research has shown that children with cochlear implants (CCIs) may face challenges in their ability to express prosody, as their expressions may have less distinct acoustic contrasts and therefore may be judged less accurately. The prosody of children with milder degrees of hearing loss, wearing hearing aids, has sparsely been investigated. More understanding of the prosodic expression by children with hearing loss, hearing aid users in particular, could create more awareness among healthcare professionals and parents on limitations in social communication, which awareness may lead to more targeted rehabilitation. This study aimed to compare the prosodic expression potential of children wearing hearing aids (CHA) with that of CCIs and children with normal hearing (CNH). In this prospective experimental study, utterances of pediatric hearing aid users, cochlear implant users, and CNH containing emotional expressions (happy, sad, and angry) were recorded during a reading task. Of the utterances, three acoustic properties were calculated: fundamental frequency (F0), variance in fundamental frequency (SD of F0), and intensity. Acoustic properties of the utterances were compared within subjects and between groups. A total of 75 children were included (CHA: 26, CCI: 23, and CNH: 26). Participants were between 7 and 13 years of age. The 15 CCI with congenital hearing loss had received the cochlear implant at median age of 8 months. The acoustic patterns of emotions uttered by CHA were similar to those of CCI and CNH. Only in CCI, we found no difference in F0 variation between happiness and anger, although an intensity difference was present. In addition, CCI and CHA produced poorer happy-sad contrasts than did CNH. The findings of this study suggest that on a fundamental, acoustic level, both CHA and CCI have a prosodic expression potential that is almost on par with normal hearing peers. However, there were some minor limitations observed in the prosodic expression of these children, it is important to determine whether these differences are perceptible to listeners and could affect social communication. This study sets the groundwork for more research that will help us fully understand the implications of these findings and how they may affect the communication abilities of these children. With a clearer understanding of these factors, we can develop effective ways to help improve their communication skills.


The experiences and perceptions of heavy vehicle drivers and train drivers of dangers at railway level crossings.
Heavy vehicle-train collisions have the potential to be catastrophic in terms of fatalities, environmental disaster, delays in the rail network, and extensive damage to property. Heavy vehicles, such as 'Road Trains' and 'B-Doubles', are vulnerable road users due to their size and mass and require specific risk management solutions. The present study aimed to capture the experiences of heavy vehicle drivers and train drivers at road-rail level crossings, with a view to exploring the contributing factors toward such accidents. A series of semi-structured focus groups was conducted, with a total of 17 train drivers and 26 heavy vehicle drivers taking part. Though there were some differences between the groups in perceptions of the causes of heavy vehicle-level crossing incidents, discussion in both groups centred on design issues an behavioural issues. With regard to design, the configuration of level crossings was found to affect heavy vehicle driver visibility and effective vehicle clearance. With regard to behaviour, discussion centred around wilful violation of crossing protocols, often as a time-saving measure, as well as driver complacency due to high levels of familiarity. The implications of these factors for future level crossing safety initiatives are discussed.


Secreted β3-integrin enhances natural killer cell activity against acute myeloid leukemia cells.
Integrins are a large family of heterodimeric proteins that are involved in cell adhesion, migration, and proliferation. Integrin diversity and function is regulated by alternative splicing. Membrane-bound and truncated β3-integrins were shown to be key players in cancer metastasis. However, the immunomodulatory functions of the soluble (s) β3-integrin have not been investigated yet. In this study, we described a novel form of sβ3-integrin in acute myeloid leukaemia (AML) patients. Furthermore, we assessed the role of the sβ3-integrin in the modulation of natural killer (NK)-cell activity. Levels of sβ3-integrin were analysed in plasma samples of 23 AML patients and 26 healthy donors by ELISA. The capacity of sβ3-integrin to regulate NK cell activity was investigated using proliferation, cytokine secretion, and cytotoxicity assays. Circulating sβ3-integrin was detected in the plasma of 8 AML patients. NK cells showed significantly higher proliferation rates after stimulation with sβ3-integrin and IL-2, IL-15 (73%). Significant increases in the NK cells' secreted levels of TNF-α, IFN-γ were measured in presence of sβ3-integrin. In addition, sβ3-integrin caused the upregulation of Granzyme B transcripts levels as well as FasL expression levels in NK cells. Most importantly, significantly higher K562 or AML blast target cell lysis rates were observed when NK cells were exposed to sβ3-integrin. This study reports the identification of a novel sβ3-integrin in AML patients and provides novel insights into its role in the immunomodulation of NK cell activity.


Aldose reductase deficiency protects sugar-induced lens opacification in rats.
Aldose reductase (AKR1B1), which catalyzes the reduction of glucose to sorbitol and lipid aldehydes to lipid alcohols, has been shown to be involved in secondary diabetic complications including cataractogenesis. Rats have high levels of AKR1B1 in lenses and readily develop diabetic cataracts, whereas mice have very low levels of AKR1B1 in their lenses and are not susceptible to hyperglycemic cataracts. Studies with transgenic mice that over-express AKR1B1 indicate that it is the key protein for the development of diabetic complications including diabetic cataract. However, no such studies were performed in genetically altered AKR1B1 rats. Hence, we developed siRNA-based AKR1B1 knockdown rats (ARKO) using the AKR1B1-siRNA-pSuper vector construct. Genotyping analysis suggested that more than 90% of AKR1B1 was knocked down in the littermates. Interestingly, all the male animals were born dead and only 3 female rats survived. Furthermore, all 3 female animals were not able to give birth to F1 generation. Hence, we could not establish an AKR1B1 rat knockdown colony. However, we examined the effect of AKR1B1 knockdown on sugar-induced lens opacification in ex vivo. Our results indicate that rat lenses obtained from AKR1B1 knockdown rats were resistant to high glucose-induced lens opacification as compared to wild-type (WT) rat lenses. Biochemical analysis of lens homogenates showed that the AKR1B1 activity and sorbitol levels were significantly lower in sugar-treated AKR1B1 knockdown rat lenses as compared to WT rat lenses treated with 50mM glucose. Our results thus confirmed the significance of AKR1B1 in the mediation of sugar-induced lens opacification and indicate the use of AKR1B1 inhibitors in the prevention of cataractogenesis.


IL@CQD catalyzed active ester rearrangement for the detection and removal of cyanide ions.
Carbon Quantum Dots (CQDs) have been extensively employed in various fields of science such as sensing, catalysis, and drug delivery. In this work, ionic liquid coated CQDs (IL@CQDs) have been used as catalysts for the rearrangement of a 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) amide coupling intermediate. The rearranged product was confirmed by single crystal structure analysis and it was processed into organic nanoparticles (ONPs). An optical detection method was used to scrutinize the anion sensing properties. The ONPs were found to be sensitive and selective for the recognition of highly toxic cyanide ions through enhancement in the fluorescence intensity. The cyanide ion co-ordinates with the -NH groups of the product and restricts the rotation of molecules around the single bond. The ONPs coated over silica-beads were also showing CN- recognition in the solid state. The detection limit for CN- sensing was found to be 3.8 nM, and real sample analysis depicts more than 90% accuracy in detection.


Expression Analysis of Long Non-coding RNAs in the Blood of Multiple Sclerosis Patients.
Multiple sclerosis (MS) is a chronic immune-mediated disorder of the central nervous system (CNS) with multiple genetic and environmental risk factors. Long non-coding RNAs (lncRNAs) have been recently reported to participate in the regulation of immune responses. Consequently, aberrant expression of lncRNAs has been suggested as an underlying cause of MS. In the present study, we evaluated the expression of three lncRNAs with putative roles in the regulation of immune response, namely TNF-α and heterogeneous nuclear ribonucleoprotein L (THRIL), Fas cell surface death receptor- antisense 1 (FAS-AS1), and plasmacytoma variant translocation 1 (PVT1) in circulating blood cells of 50 Iranian relapsing-remitting multiple sclerosis (RRMS) patients compared with healthy subjects by means of quantitative real-time polymerase chain reaction (PCR). We detected a significant downregulation of PVT1 and FAS-AS1 expressions in RRMS patients while a significant upregulation of THRIL in patients compared with controls (P < 0.001). Correlation analyses between lncRNA expression levels and clinical data of MS patients revealed no significant correlation between lncRNAs expression levels and Expanded Disability Status Scale (EDSS), a moderate correlation between PVT1 expression levels and duration of the disorder and no significant correlation between lncRNAs expression levels and age at onset. In addition, we demonstrated correlations between the expression levels of PVT1 and THRIL as well as expression levels of THRIL and FAS-AS1 in RRMS patients. In brief, we have demonstrated dysregulation of three lncRNAs in MS patients. Further studies are needed to explore the exact mechanisms by which these lncRNAs participate in regulation of immune responses.


Age and gender may influence the results of Roux-en-Y gastric bypass? Metabolic syndrome parameters.
Severe obesity affects the body favoring the development of serious diseases, including hypertension, diabetes mellitus, atherosclerosis and non alcoholic fatty liver disease. Bariatric procedures increased in Brazil in the last decade. The purpose of this study was to verify if gender and age in date of procedure resulted significant differences in metabolic syndrome parameters after surgery. The study involved 205 medical records of adult patients undergoing Roux-en-Y gastric bypass, stratified by gender and age groups and followed one year by a multidisciplinary team. It was observed significant decrease in body mass index, fasting glucose and insulin at all ages and both genders. Lipid profile showed significant improvements except high density lipoprotein cholesterol. Ectopic fat in the liver has decreased after 6 months in patients classified with steatosis at baseline. Patients classified as hypertensive blood pressure levels decreased 6 months after surgical intervention. Roux-en-Y gastric bypass proved to be an important tool in remission of metabolic syndrome parameters. The reduction of body mass accompanied to decrease in insulin resistance resulted in lower prevalence of comorbidities associated with obesity. The benefits were similar and extended both genders and all age groups between 18 and 65 years old.


The Medicare reforms of 1997: headlines you didn't read.
The 1997 Medicare reforms were among the most important social and health policy legislation of the past three decades. The legislation was notable in reestablishing a viable health policy process; in disproving predictions that government-run insurance would restrict consumer freedoms more than employer-based health insurance; and in ratifying market-oriented approaches as a national health paradigm. Most important, the legislation achieved a historic philosophical compromise between advocates of government health insurance and advocates of private health insurance. The political agreements came at the expense of greater regulatory capture of the Medicare program by health provider and health plan interests and at the expense of deficient consumer protections.


Iron-catalyzed cyclopropanation in 6 M KOH with in situ generation of diazomethane.
Diazomethane is a common and versatile reagent in organic synthesis whose broader use is generally impeded by its explosiveness and toxicity. Here we report that a simple iron porphyrin complex catalyzes the cyclopropanation of styrenes, enynes, and dienes under the demanding conditions [aqueous 6 molar potassium hydroxide (KOH) solution, open to air] necessary for the in situ generation of diazomethane from a water-soluble diazald derivative. A biphasic reaction medium arising from the immiscibility of the olefin substrates with water appears essential to the overall efficiency of the process. The work we describe highlights an approach to catalysis with untoward reactive intermediates, in which the conditions for their generation under operationally safe regimes dictate catalyst selection.


Thrombotic microangiopathy and associated renal disorders.
Thrombotic microangiopathy (TMA) is a pathological process involving thrombocytopenia, microangiopathic haemolytic anaemia and microvascular occlusion. TMA is common to haemolytic uraemic syndrome (HUS) associated with shiga toxin or invasive pneumococcal infection, atypical HUS (aHUS), thrombotic thrombocytopenic purpura (TTP) and other disorders including malignant hypertension. HUS complicating infection with shiga toxin-producing Escherichia coli (STEC) is a significant cause of acute renal failure in children worldwide, occurring sporadically or in epidemics. Studies in aHUS have revealed genetic and acquired factors leading to dysregulation of the alternative complement pathway. TTP has been linked to reduced activity of the ADAMTS13 cleaving protease (typically with an autoantibody to ADAMTS13) with consequent disruption of von Willebrand factor multimer processing. However, the convergence of pathogenic pathways and clinical overlap create diagnostic uncertainty, especially at initial presentation. Furthermore, recent developments are challenging established management protocols. This review addresses the current understanding of molecular mechanisms underlying TMA, relating these to clinical presentation with an emphasis on renal manifestations. A diagnostic and therapeutic approach is presented, based on international guidelines, disease registries and published trials. Early treatment remains largely empirical, consisting of plasma replacement/exchange with the exception of childhood STEC-HUS or pneumococcal sepsis. Emerging therapies such as the complement C5 inhibitor eculizumab for aHUS and rituximab for TTP are discussed, as is renal transplantation for those patients who become dialysis-dependent as a result of aHUS.


Barcode identifiers as a practical tool for reliable species assignment of medically important black yeast species.
Herpotrichiellaceous black yeasts and relatives comprise severe pathogens flanked by nonpathogenic environmental siblings. Reliable identification by conventional methods is notoriously difficult. Molecular identification is hampered by the sequence variability in the internal transcribed spacer (ITS) domain caused by difficult-to-sequence homopolymeric regions and by poor taxonomic attribution of sequences deposited in GenBank. Here, we present a potential solution using short barcode identifiers (27 to 50 bp) based on ITS2 ribosomal DNA (rDNA), which allows unambiguous definition of species-specific fragments. Starting from proven sequences of ex-type and authentic strains, we were able to describe 103 identifiers. Multiple BLAST searches of these proposed barcode identifiers in GenBank revealed uniqueness for 100 taxonomic entities, whereas the three remaining identifiers each matched with two entities, but the species of these identifiers could easily be discriminated by differences in the remaining ITS regions. Using the proposed barcode identifiers, a 4.1-fold increase of 100% matches in GenBank was achieved in comparison to the classical approach using the complete ITS sequences. The proposed barcode identifiers will be made accessible for the diagnostic laboratory in a permanently updated online database, thereby providing a highly practical, reliable, and cost-effective tool for identification of clinically important black yeasts and relatives.


DNase I-hypersensitive sites are associated with both long terminal repeats and with the intragenic enhancer of integrated human immunodeficiency virus type 1.
After reverse transcription and integration of the genome of human immunodeficiency virus (HIV) in a target cell, the viral DNA becomes packaged into chromatin. Regions of chromatin associated with regulatory functions in eukaryotes can generally be distinguished from the bulk of chromatin by an increased accessibility of the DNA to nucleases (nuclease-hypersensitive sites). In this report, the chromatin structure of the complete HIV-1 genome has been analyzed in three chronically infected cell lines of monocyte/macrophage and lymphoid origins. Digestion of purified nuclei from these cells with DNase I followed by restriction digestion and Southern blotting identified several DNase I-hypersensitive regions throughout the viral genome. Two constitutive sites were associated with the U3 region of the 5' long terminal repeat (LTR) in which the viral promoter and enhancer are located. An additional site in the R region of the 5' LTR was present only after activation of viral transcription by phorbol ester or tumor necrosis factor alpha. A fourth site was identified in all cell lines downstream of the 5' LTR (nucleotides [nt] 656 to 720), and the band corresponding to this site decreased in intensity upon activation of transcription. In the 3' LTR, a constitutive hypersensitive site was identified in all cell lines (nt 9322 to 9489). A major site (nt 4534 to 4733) was present only in a cell line of macrophage/monocyte origin in a region of the genome in which an intragenic enhancer was recently identified (E. Verdin, N. Becker, F. Bex, L. Droogmans, and A. Burny, Proc. Natl. Acad. Sci. USA 87:4874-4878, 1990). This study defines regions of the HIV genome associated with an open chromatin configuration and points to the potential regulatory role of these elements in the HIV life cycle.


Effect of short-term creatine supplementation on markers of skeletal muscle damage after strenuous contractile activity.
The protective effect of short-term creatine supplementation (CrS) upon markers of strenuous contractile activity-induced damage in human and rat skeletal muscles was investigated. Eight Ironman triathletes were randomized into the placebo (Pl; n = 4) and creatine-supplemented (CrS; n = 4) groups. Five days prior to the Ironman competition, the CrS group received creatine monohydrate (20 g day(-1)) plus maltodextrin (50 g) divided in two equal doses. The Pl group received maltodextrin (50 g day(-1)) only. The effect of CrS (5 g day(-1)/kg body weight for 5 days) was also evaluated in a protocol of strenuous contractile activity induced by electrical stimulation in rats. Blood samples were collected before and 36 and 60 h after the competition and were used to determine plasma activities of creatine kinase (CK), lactate dehydrogenase (LDH), aldolase (ALD), glutamic oxaloacetic acid transaminase (GOT), glutamic pyruvic acid transaminase (GPT), and C-reactive protein (CRP) level. In rats, plasma activities of CK and LDH, muscle vascular permeability (MVP) using Evans blue dye, muscle force and fatigue were evaluated. Activities of CK, ALD, LDH, GOT, GTP, and levels of CRP were increased in the Pl group after the competition as compared to basal values. CrS decreased plasma activities of CK, LDH, and ALD, and prevented the rise of GOT and GPT plasma activities. In rats, CrS delayed the fatigue, preserved the force, and prevented the rise of LDH and CK plasma activities and MVP in the gastrocnemius muscle. CrS presented a protective effect on muscle injury induced by strenuous contractile activities.


A study of iron complexation in a swine model.
The treatment of iron poisoning consists of supportive care and efforts to remove or retard the absorption of iron from the gastrointestinal tract. A standard but rarely challenged treatment is to render the unabsorbed iron less soluble by complexing it with bicarbonate or phosphate solution. Another therapy is the use of oral deferoxamine. Bicarbonate and phosphate therapy are known to be associated with adverse outcomes if used inappropriately. Is their use justified? To closely simulate a potentially toxic iron overdose in a 24-month-old child, a swine model was used. Twenty fasted castrated male pigs weighing an average of 14.6 kg (+/- 3.0 kg) were orally dosed with 300 mg/kg FeSO4 (60 mg Fe/kg) and randomly placed into 1 of 4 treatment groups receiving 50 ml of distilled water (control), 5% sodium bicarbonate, 5% sodium dihydrogen phosphate, or deferoxamine (10 g). Sequential serum iron levels were obtained at 0, 1, 2, 4, and 6 hr. There were no significant differences in the absorption of iron, as reflected by serum iron concentrations, in the bicarbonate and phosphate groups when compared to the control group (p greater than 0.05). Deferoxamine therapy reduced iron serum concentrations, ie iron absorption, significantly (p less than 0.05) when compared to the control, bicarbonate and phosphate groups. This study provides evidence that efforts to form digestive tract complexation of iron with bicarbonate or phosphate are of no value.


[Regulation of hydrogen sulfide level by acidophobic bacteria of Thiobacillus genus in technogenic reservoirs of sulfur mining regions].
An increase of acidophobic thione bacteria quantity in Rozdil and Yavoriv reservoirs of sulfur mining regions during 2005-2009 years, which correlates with a decrease of hydrogen sulfide content in water surface layers, was shown. The ability of acidophobic bacteria of Thiobacillus genus, isolated from "Yavorivske" lake, to oxidize effectively hydrogen sulfide added into Beijerinck medium instead of thiosulfate, was discovered. It was established, that hydrogen sulfide oxidizing efficiency by Thiobacillus sp. Yav-8, Yav-11 and Yav-14 strains is the highest (78.48-84.56%) when its content in cultivation medium was increased twice: to 2584 mg/l. An increase of sulfur quantity in sodium sulfide form from to six times as compared with its standard content in sodium thiosulfate form in the Beijerinck medium does not lead to the increase of hydrogen sulfide oxidizing efficiency by cells.


[Physicians' experience with increased use of individual reimbursement for pharmaceuticals].
Implementation of a more restrictive reimbursement policy in Norway (in June 2003) has led to an increased use of individual reimbursement (patient application ) rather than general reimbursement (based on a positive list) of important pharmaceuticals. This study investigates physicians' attitudes to and experience with increased use of individual reimbursement one year after implementation of the new directive. Questions concerning individual reimbursement were included in a questionnaire to the Research Institute of the Norwegian Medical Association's reference panel in November 2004. 993 (71 %) of 1399 physicians responded to the questionnaire and 605 (61 %) of these reported that they had referred patients to a specialist or applied for individual reimbursement within the last year. About half (48 %) reported that the scheme contributes to rational use of pharmaceuticals, but more than 70 % were dissatisfied with the scheme and 87 % reported the scheme to be complicated and resource demanding. Only 37 % reported that all individual reimbursement applications were granted approval. 57 % reported that the scheme prevented them from prescribing the pharmaceutical they considered best for a patient, and 52 % reported that patients rather choose to pay for a pharmaceutical so treatment could start immediately. Administrative time for individual reimbursement applications was estimated to an average of 2.6 hours per month per physician. The results indicate that physicians are considerably dissatisfied with the practical implications of this scheme. Comprehensive analyses of the total health consequences, costs and distributional effects of the increased use of individual reimbursement for important pharmaceuticals are needed.


The basis for the immunoregulatory role of macrophages and other accessory cells.
Macrophages handle extracellular proteins and secrete diverse bioactive molecules and, therefore, influence the physiology of many tissues. They also have an important immunoregulatory role. The immune response to proteins involves the activation of the T helper subset of lymphocytes. The T helper cell is activated only when it interacts with the protein displayed on the surface of a macrophage or other accessory cell. This interaction involves restrictive proteins encoded in the major histocompatibility gene complex as well as growth-differentiating proteins.


Fluctuation loops in noise-driven linear dynamical systems.
Understanding the spatiotemporal structure of most probable fluctuation pathways to rarely occurring states is a central problem in the study of noise-driven, nonequilibrium dynamical systems. When the underlying system does not possess detailed balance, the optimal fluctuation pathway to a particular state and relaxation pathway from that state may combine to form a looplike structure in the system phase space called a fluctuation loop. Here, fluctuation loops are studied in a linear circuit model consisting of coupled RC elements, where each element is driven by its own independent noise source. Using a stochastic Hamiltonian approach, we determine the optimal fluctuation pathways, and analytically construct corresponding fluctuation loops. To quantitatively characterize fluctuation loops, we study the time-dependent area tensor that is swept out by individual stochastic trajectories in the system phase space. At long times, the area tensor scales linearly with time, with a coefficient that precisely vanishes when the system satisfies detailed balance.


Histological studies of the effects of oral administration of Aspilia africana (Asteraceae) leaf extract on the ovaries of female Wistar rats.
Histological studies of the effects of oral administration of extract of Aspilia africana, used in ethno medical practice in Africa for the management of various ailments, on the ovarian tissues of matured female Wistar rats were studied. The rats (n=24), average weight 182 g were randomly assigned into two treatment (n=16) and a control (n=8) group. The rats in the treatment groups received 0.5 g/kg and 1 g/kg of aqueous extract of Aspilia africana orally through orogastric tube for fourteen days, while the control rats received equal volume of distilled water without the extract of Aspilia added. The rats were fed with growers' mash and were given water liberally. The rats were sacrificed on day fifteen of the experiment. The ovary was carefully dissected out and quickly fixed in 10% formal saline for routine histological study after H&E method. The histological findings indicated that the treated sections of the ovary showed cellular hypertrophy of the theca folliculi, distortion of the basement membrane, degenerative and atrophic changes in the oocyte and zona granulosa. There were marked vacuolations appearing in the stroma cells. These findings indicate that Aspilia africana consumption may probably have adverse effects on the ovaries by its deleterious effects on the oocytes and stroma cells of ovary of adult Wistar rats. It is recommended that further studies aimed at corroborating these observations be conducted.


Alterations of energy and substrate metabolism in rats with large and sustained changes in daily food intake.
Energy expenditure was measured in one-way crossed-intestine rats by use of indirect calorimetry to examine the role of energy metabolism in body weight control. The intestinal surgery was done according to Koopmans (Brain Res. Bull. 14: 595-603, 1985). The food-losing rats increased daily food intake from 70.8 to 126.3 g/day, whereas their partners decreased intake from 67.1 to 38.7 g/day (P < 0.001). Compared with levels before surgery, the food-losing rats showed slightly increased O2 consumption (1.31 vs. 1.28 1.h-1.kg-1) and metabolic rate (6.62 vs. 6.39 kcal.h-1.kg-1) and largely increased CO2 production (1.31 vs. 1.22 l.h-1.kg-1, P < 0.01), whereas in their food-gaining partners O2 consumption (1.12 vs. 1.25 l.h-1.kg-1, P < 0.01) and metabolic rate (5.76 vs. 6.26 kcal.h-1.kg-1) were significantly decreased. Respiratory quotients were higher in the food-gaining rats than in their partners (1.076 vs. 0.999, P < 0.01), indicating more fatty acid synthesis. These results suggest that daily food intake and energy expenditure increase and decrease together, despite the fact that about the same amount of food has been absorbed from the intestines of each rat.


Stroke mortality rates vary in local communities in a metropolitan area: racial and spatial disparities and correlates.
For the past decade, stroke has held steady as one of the top 4 leading causes of death in the United States. Aggregated data provide information about how the country or individual states are faring with respect to stroke mortality, but disaggregation provides data that may facilitate targeted interventions and community engagement. We analyzed deaths from stroke to residents of Chicago to calculate age-adjusted stroke mortality rates (AASMRs). We calculated AASMRs for Chicago by race/ethnicity, sex, and community area. We also examined the correlation between AASMR and (1) racial/ethnic composition of a community area and (2) median household income. The AASMR for Chicago (44.9 per 100,000 population) was significantly higher than the national rate (42.2). Within both the United States and Chicago, the highest AASMRs were found among non-Hispanic blacks, followed by non-Hispanic whites, and then Hispanics. There was a strong, positive correlation between the proportion of black residents in a community area and the AASMR (0.58). There was a strong, negative relationship between household income and the AASMR for the entire city (-0.56) and for the predominantly black community areas (-0.47). These data provide insight into where the worst stroke mortality problems reside in Chicago. We anticipate that the data can be used to work toward the development of solutions to the high stroke mortality rates observed in several of Chicago's community areas and in similar communities throughout the United States.


Feeling good about the iron rice bowl: Economic sector and happiness in post-reform urban China.
Situated in China's market transition, this study examines the relationship between economic sector and a worker's happiness in post-reform urban China. Using datasets from the Chinese General Social Surveys 2003, 2006 and 2008, we find that workers in the state sector enjoy a subjective premium in well-being - reporting significantly higher levels of happiness than their counterparts in the private sector. We also find that during a period when a large wave of workers moved from the state sector to the private sector, those remaining in the state sector reported being significantly happier than did former state sector workers who had moved, whether the move was voluntary or involuntary. We attribute the higher level of reported happiness in the state sector than in the private sector to the disparity by sector in the provision of social welfare benefits. Those who made voluntary state-to-private moves experienced a trade-off in enjoying higher payoffs while losing job security, whereas involuntary mobiles experienced downward mobility and suffered a long-term psychological penalty.


Effects of the bow on social organization in Western North America.
The bow more than doubled, likely tripled, the success of individuals bent on killing animal or human targets (Box ). The advent of this revolutionary technology generated different responses in western North America depending on subsistence and sociopolitical organization at the time of its arrival, roughly 2300 - 1300 B.P. Its effect was substantial in California and the Great Basin, particularly on group size, which in many places diminished as a consequence of the bow's reliability. The counter-intuitive result was to increase within group-relatedness enough to encourage intensification of plant resources, previously considered too costly. The bow rose to greatest direct economic importance with the arrival of the horse, and was put to most effective use by former Great Basin groups who maintained the family band system that had developed around intensive Great Basin plant procurement, adapting the same organization to a lifestyle centered on the equestrian pursuit of buffalo and warfare.


[Characteristics of the silver-stained nucleoli of tumor cells from the pleural fluid of lung cancer patients].
Tumor cell nucleoli obtained from pleural effusions of 26 patients with different morphologic types of lung cancer were evaluated by silver staining. Distinct heterogeneity of tumor cell populations, with regard to the number of nucleoli as well as their functional activity in respect to ribosomal RNA synthesis, were shown to be the most common feature of all the tumors studied, regardless of their morphologic variants. One likely cause of heterogeneity in Ag nucleolar organized region (NOR) pattern of tumor cells may be due to chromosomal losses and gains from the karyotypes of acrocentric chromosomes with active NORs. Another possible cause for heterogeneity in nucleolar activity might be due to different reactions of tumor cells towards some humoral and cellular factors of pleural fluid including T-lymphocytes.


Human immunodeficiency virus seroconversion and evolution of the hepatitis C virus quasispecies.
When chronic hepatitis C virus (HCV) infections are complicated by acquisition of human immunodeficiency virus (HIV), liver disease appears to accelerate and serum levels of HCV RNA may rise. We hypothesized that HIV might affect the HCV quasispecies by decreasing both complexity (if HIV-induced immunosuppression lessens pressure for selecting HCV substitutions) and the ratio of nonsynonymous (d(N)) to synonymous (d(S)) substitutions, because d(N) may be lower (if there is less selective pressure). To test this hypothesis, we studied the evolution of HCV sequences in 10 persons with chronic HCV infection who seroconverted to HIV and, over the next 3 years, had slow or rapid progression of HIV-associated disease. From each subject, four serum specimens were selected with reference to HIV seroconversion: (i) more than 2 years prior, (ii) less than 2 years prior, (iii) less than 2 years after, and (iv) more than 2 years after. The HCV quasispecies in these specimens was characterized by generating clones containing 1 kb of cDNA that spanned the E1 gene and the E2 hypervariable region 1 (HVR1), followed by analysis of clonal frequencies (via electrophoretic migration) and nucleotide sequences. We examined 1,320 cDNA clones (33 per time point) and 287 sequences (median of 7 per time point). We observed a trend toward lower d(N)/d(S) after HIV seroconversion in 7 of 10 subjects and lower d(N)/d(S) in those with rapid HIV disease progression. However, the magnitude of these differences was small. These results are consistent with the hypothesis that HIV infection alters the HCV quasispecies, but the number of subjects and observation time may be too low to characterize the full effect.


Evaluation of incidental renal and adrenal masses.
Incidental renal or adrenal masses are sometimes found during imaging for problems unrelated to the kidneys and adrenal glands. Knowledgeable family physicians can reliably diagnose these masses, thereby avoiding unnecessary worry and procedures for their patients. A practical and cost-efficient means of evaluating renal lesions combines ultrasonography and computed tomographic scanning, with close communication between the family physician and the radiologist. Asymptomatic patients with simple renal cysts require no further evaluation. Patients with minimally complicated renal cysts can be followed radiographically. Magnetic resonance imaging is indicated in patients with indeterminate renal masses, and referral is required in patients with symptoms or solid masses. The need for referral of patients with adrenal masses is determined by careful assessment of clinical signs and symptoms, as well as the results of screening laboratory studies and appropriate radiologic studies. Referral is indicated for patients with incidental adrenal masses more than 6 cm in greatest diameter. Appropriate laboratory screening tests include the following: a 24-hour urinary free cortisol measurement for patients with evidence of Cushing's syndrome; a 24-hour urinary metanephrine, vanillylmandelic acid or catecholamine measurement for patients with evidence of pheochromocytoma; and a serum potassium level for patients with evidence of hyperaldosteronism.


Polymerization-Like Co-Assembly of Silver Nanoplates and Patchy Spheres.
Highly anisometric nanoparticles have distinctive mechanical, electrical, and thermal properties and are therefore appealing candidates for use as self-assembly building blocks. Here, we demonstrate that ultra-anisometric nanoplates, which have a nanoscale thickness but a micrometer-scale edge length, offer many material design capabilities. In particular, we show that these nanoplates "copolymerize" in a predictable way with patchy spheres (Janus and triblock particles) into one- and two-dimensional structures with tunable architectural properties. We find that, on the pathway to these structures, nanoplates assemble into chains following the kinetics of molecular step-growth polymerization. In the same mechanistic framework, patchy spheres control the size distribution and morphology of assembled structures, by behaving as monofunctional chain stoppers or multifunctional branch points during nanoplate polymerization. In addition, both the lattice constant and the stiffness of the nanoplate assemblies can be manipulated after assembly. We see highly anisometric nanoplates as one representative of a broader class of dual length-scale nanoparticles, with the potential to enrich the library of structures and properties available to the nanoparticle self-assembly toolbox.


Novel approach to meta-analysis of tests and clinical prediction rules with three or more risk categories.
Multichotomous tests have three or more outcome or risk categories, and can provide richer information and a better fit with clinical decision-making than dichotomous tests. Our objective is to present a fully developed approach to the meta-analysis of multichotomous clinical prediction rules (CPRs) and tests, including meta-analysis of stratum specific likelihood ratios. We have developed a novel approach to the meta-analysis of likelihood ratios for multichotomous tests that avoids the need to dichotomise outcome categories, and demonstrate its application to a sample CPR. We also review previously reported approaches to the meta-analysis of the area under the receiver operating characteristic curve (AUROCC) and meta-analysis of a measure of calibration (observed:expected) for multichotomous tests or CPRs. Using data from 10 studies of the Cancer of the Prostate Risk Assessment (CAPRA) risk score for prostate cancer recurrence, we calculated summary estimates of the likelihood ratios for low, moderate and high risk groups of 0.40 (95% CI 0.32 to 0.49), 1.24 (95% CI 0.99 to 1.55) and 4.47 (95% CI 3.21 to 6.23), respectively. Applying the summary estimates of the likelihood ratios for each risk group to the overall prevalence of cancer recurrence in a population allows one to estimate the likelihood of recurrence for each risk group in that population. An approach to meta-analysis of multichotomous tests or CPRs is presented. A spreadsheet for data preparation and code for R and Stata are provided for other researchers to download and use. Combined with summary estimates of the AUROCC and calibration, this is a comprehensive strategy for meta-analysis of multichotomous tests and CPRs.


Clinical and clinicopathological features of non-suppurative meningoencephalitis in young greyhounds in Ireland.
The clinical and clinicopathological features of non-suppurative meningoencephalitis in 30 greyhounds were reviewed. The dogs were from 21 separate litters, comprised both sexes (16 males and 14 females) and ranged in age from five to 18 months. In 14 (66.7 per cent) litters, more than one case was suspected or confirmed, and the number of siblings affected within individual litters ranged from one to seven. Clinical signs were progressive and varied from five days to 12 months in duration; 12 dogs had signs of two weeks' duration or less. The rate of progression of signs was variable. Common features included dullness or lethargy (22), altered behaviour (21), proprioceptive and postural reaction deficits (18), circling (17), ataxia (17), decreased appetite (15) and weight loss (13). No consistent haematological or biochemical abnormalities were identified and serology failed to implicate Toxoplasma gondii or Neospora caninum. Cerebrospinal fluid analysis revealed mild or moderate mononuclear pleocytosis in 12 (70.6 per cent) of 17 dogs. No definitive antemortem diagnosis could be made in any affected dog.


[Life cycle of Rhodnius brethesi Matta, 1919 (Hemiptera, Reduviidae, Triatominae), a potential vector of Chagas disease in the Amazon region].
R. brethesi is a sylvatic species from the Amazon region; it has been incriminated as responsible for the transmission of Chagas disease in collectors of piacaba in this region. The aim of present study was to investigate the efficiency of these insects as potential vectors of Trypanosoma cruzi. Aspects related with feeding and defecation patterns, life time, and mortality had been observed in each instar of R. brethesi. We use 5th instar nymphs to get adults virgins, after the moulting 3 groups with 6 females and 2 males each were created to obtain eggs. After hatching, 1st instar nymphs had been weighed and kept in bottles until the next moult. Insects were fed once a week in mice. Results showed that the average period of incubation was 17 days, the number of blood meal was increasing from the 1st to the 5th instar nymph with 7 (average) to become adult, a significative numbers of the defecations occurring immediately after the bloodmeals. The total percentual of mortality was 16%. This results suggests that this species presents a good exploitation of blood meals and a brief nymphal development in laboratory conditions reflecting its behavior in sylvatic environments.


Prevalence of and risk factors for low bone mineral density in untreated HIV infection: a substudy of the INSIGHT Strategic Timing of AntiRetroviral Treatment (START) trial.
HIV infection is associated with a higher prevalence of low bone mineral density (BMD) and fractures than that found in the general population. There are limited data in HIV-positive adults, naïve to antiretroviral therapy (ART), with which to estimate the relative contribution of untreated HIV infection to bone loss. The primary objective of the Strategic Timing of AntiRetroviral Treatment (START) Bone Mineral Density Substudy is to compare the effect of immediate versus deferred initial ART on bone. We evaluated traditional, demographic, HIV-related and immunological factors for their associations with baseline hip and lumbar spine BMD, measured by dual-energy X-ray absorptiometry, using multiple regression. A total of 424 ART-naïve participants were enrolled at 33 sites on six continents; the mean age was 34 years [standard deviation (SD) 10.1 years], 79.0% were nonwhite, 26.0% were women, and 12.5% had a body mass index (BMI) < 20 kg/m(2) . Mean (SD) Z-scores were -0.41 (0.94) at the spine and -0.36 (0.88) for total hip; 1.9% had osteoporosis and 35.1% had low BMD (hip or spine T-score < -1.0). Factors independently associated with lower BMD at the hip and spine were female sex, Latino/Hispanic ethnicity, lower BMI and higher estimated glomerular filtration rate. Longer time since HIV diagnosis was associated with lower hip BMD. Current or nadir CD4 cell count and HIV viral load were not associated with BMD. In this geographically and racially diverse population of ART-naïve adults with normal CD4 cell counts, low BMD was common, but osteoporosis was rare. Lower BMD was significantly associated with traditional risk factors but not with CD4 cell count or viral load.


Molecular imaging using nanoparticle quenchers of Cerenkov luminescence.
Cerenkov luminescence (CL) imaging is an emerging technique that collects the visible photons produced by radioisotopes. Here, molecular imaging strategies are investigated that switch the CL signal off. The noninvasive molecularly specific detection of cancer is demonstrated utilizing a combination of clinically approved agents, and their analogues. CL is modulated in vitro in a dose dependent manner using approved small molecules (Lymphazurin), as well as the clinically approved Feraheme and other preclinical superparamagnetic iron oxide nanoparticles (SPIO). To evaluate the quenching of CL in vivo, two strategies are pursued. [(18) F]-FDG is imaged by PET and CL in tumors prior to and following accumulation of nanoparticles. Initially, non-targeted particles are administered to mice bearing tumors in order to attenuate CL. For targeted imaging, a dual tumor model (expressing the human somatostatin receptor subtype-2 (hSSTr2) and a control negative cell line) is used. Targeting hSSTr2 with octreotate-conjugated SPIO, quenched CL enabling non-invasive distinction between tumors' molecular expression profiles is demonstrated. In this work, the quenching of Cerenkov emissions is demonstrated in several proof of principle models using a combination of approved agents and nanoparticle platforms to provide disease relevant information including tumor vascularity and specific antigen expression.


Transient fibrosis resolves via fibroblast inactivation in the regenerating zebrafish heart.
In the zebrafish (Danio rerio), regeneration and fibrosis after cardiac injury are not mutually exclusive responses. Upon cardiac cryoinjury, collagen and other extracellular matrix (ECM) proteins accumulate at the injury site. However, in contrast to the situation in mammals, fibrosis is transient in zebrafish and its regression is concomitant with regrowth of the myocardial wall. Little is known about the cells producing this fibrotic tissue or how it resolves. Using novel genetic tools to mark periostin b- and collagen 1alpha2 (col1a2)-expressing cells in combination with transcriptome analysis, we explored the sources of activated fibroblasts and traced their fate. We describe that during fibrosis regression, fibroblasts are not fully eliminated but become inactivated. Unexpectedly, limiting the fibrotic response by genetic ablation of col1a2-expressing cells impaired cardiomyocyte proliferation. We conclude that ECM-producing cells are key players in the regenerative process and suggest that antifibrotic therapies might be less efficient than strategies targeting fibroblast inactivation.


Characterization of Na+-H+ antiport in type II alveolar epithelial cells.
The presence of a Na+-H+ exchange pathway in the plasma membrane of type II alveolar epithelial cells was explored using the pH-sensitive fluorescent probe 2,7-biscarboxyethyl-5,6-carboxyfluorescein (BCECF) to monitor changes in cytosolic pH. Freshly prepared pneumocytes suspended in medium at pH 7.4 had an intracellular pH of 7.07 +/- 0.07. Acid-loaded cells equilibrated in sodium-free buffer showed rapid cytoplasmic alkalinization when exposed to sodium. This response to sodium was inhibited greater than 90% by 10(-4) M amiloride. The presence of the K+ ionophore, valinomycin, had no effect on the rate of Na+-dependent alkalinization, indicating the electroneutrality of the system. Li+ partially supported the alkalinization process, but other monovalent cations, notably K+, Rb+, and Cs+, were without effect. Kinetic analysis for Na+ at the external binding site yielded KNat (dissociation constant) = 62 +/- 3 mM. Hill equation analysis of the data derived a Hill coefficient (n) = 1.2 +/- 0.1 for Na+, consistent with a 1:1 stoichiometry for Na+ and H+ for the transporter. The Ki for amiloride inhibition of proton efflux at the external locus was 0.45 microM. These findings define the transport pathway as Na+-H+ antiport, with kinetic parameters somewhat similar to those described for other cell types. Antiport activity was detected at intracellular pH (pHi) values of 6.8 or below, with no activity observed at pHi 7.0-7.2. It is suggested that Na+-H+ exchange is a major mechanism whereby pneumocytes recover from an acid load and that this transport pathway may play an important role in vectorial reabsorption of Na+ from the alveolar air spaces.


Factors in youth physical activity participation: from psychological aspects to environmental correlates.
Understanding influences on children's physical activity and how these vary by activity and subgroup, such as age and sex of the child, is important for informing the development of effective and targeted interventions. Two cohort studies were conducted across socioeconomic areas of Melbourne, Australia, between 2001 and 2008 among a combined sample of more than 2,700 children aged 5-6 years and 10-12 years at baseline. Data were collected via surveys, and children wore the Actigraph accelerometer for 8 days. Five individual, 10 social, and 17 physical environmental factors were significantly associated with children's physical activity. Patterns of association varied according to the age and sex of the child and also according to the type of activity. These studies provide some insights into the various levels of influence on children's physical activity. More longitudinal and intervention research is needed to better understand the mechanisms of change in children's physical activity behaviour.


Association of Genetic Polymorphisms with Abdominal Aortic Aneurysm in the Processes of Apoptosis, Inflammation, and Cholesterol Metabolism.
Background and Objectives: This study aims to identify the minor allele of the single nucleotide polymorphisms (SNPs) DAB2IP rs7025486, IL6R rs2228145, CDKN2BAS rs10757278, LPA rs3798220, LRP1 rs1466535, and SORT1 rs599839 in order to assess the risk of abdominal aortic aneurysm (AAA) formation and define the linkage among these SNPs. Materials and Methods: A case-control study with AAA patients (AAA group) and non-AAA controls (control group) was carried out in a study population. DNA was isolated from whole blood samples; the SNPs were amplified using PCR and sequenced. Results: In the AAA group of 148 patients, 87.2% of the patients were male, 64.2% had a history of smoking, and 18.2% had relatives with AAA. The mean ± SD of age, BMI, and aneurysmal diameter in the AAA group were 74.8 ± 8.3 years, 27.6 ± 4.6 kg/m2, and 56.2 ± 11.8 mm, respectively. In comparison with 50 non-AAA patients, there was a significantly elevated presence of the SNPs DAB2IP rs7025486[A], CDKN2BAS rs10757278[G], and SORT1 rs599839[G] in the AAA group (p-values 0.040, 0.024, 0.035, respectively), while LPA rs3798220[C] was significantly higher in the control group (p = 0.049). A haplotype investigation showed that the SNPs DAB2IP, CDKN2BAS, and IL6R rs2228145[C] were significantly elevated in the AAA group (p = 0.037, 0.037, and 0.046) with minor allele frequencies (MAF) of 25.5%, 10.6%, and 15.4%, respectively. Only DAB2IP and CDKN2BAS showed significantly higher occurrences of a mutation (p = 0.028 and 0.047). Except for LPA, all SNPs were associated with a large aortic diameter in AAA (p < 0.001). Linkage disequilibrium detection showed that LPA to DAB2IP, to IL6R, to CDKN2BAS, and to LRP1 rs1466535[T] had D' values of 70.9%, 80.4%, 100%, and 100%, respectively. IL6R to LRP1 and to SORT1 had values for the coefficient of determination (r2) of 3.9% and 2.2%, respectively. Conclusions: In the investigated study population, the SNPs CDKN2BAS rs10757278, LPA rs3798220, SORT1 rs599839, DAB2IP rs7025486, and IL6R rs2228145 were associated with the development of abdominal aortic aneurysms. Individuals with risk factors for atherosclerosis and/or a family history of AAA should be evaluated using genetic analysis.


Upregulation of p21Waf1/Cip1 expression in vivo by butyrate administration can be chemoprotective or chemopromotive depending on the lipid component of the diet.
The overall goal of this research was to separate out the effects of butyrate from its fiber source and determine in vivo if it upregulates colonic histone acetylation, p21(Waf1/Cip1) expression (p21) and apoptosis and if this sequela of events is protective against aberrant crypt foci (ACF) formation. Eighty Sprague-Dawley rats were provided defined diets with either corn oil or fish oil as the lipid source, +/- butyrate-containing capsules targeted for release in the colon and +/- azoxymethane (AOM) (10 rats per group). Diets were provided for 11 weeks and at termination colonocyte nuclear histone H4 and p21 expression were determined by immunohistochemistry, apoptosis was measured by the terminal deoxynucleotide transferase biotin-dUTP nick end labeling assay and aberrant crypt numbers and multiplicity were enumerated. Luminal butyrate levels were also quantified. AOM injection repressed p21 expression, which was reversed by butyrate supplementation. Although butyrate enhanced p21 expression with both dietary lipid sources, the increase in p21 resulted in an increase in apoptosis and decrease in ACF with fish oil, but had no effect on apoptosis and increased ACF with corn oil. This significant interaction between fat, butyrate (fiber) and p21 expression with one combination being protective and the other promotive of colon carcinogenesis reinforces the importance of considering diet as a key factor in chemoprevention.


Macular Layer Thickness and Effect of BMI, Body Fat, and Traditional Cardiovascular Risk Factors: The Tromsø Study.
The purpose of this study was to investigate associations between cardiovascular risk factors and the thickness of retinal nerve fiber layer (RNFL), ganglion cell-inner plexiform layer (GCIPL), and outer retina layers (ORL). In this population-based study, we included participants from the Tromsø Study: Tromsø6 (2007 to 2008) and Tromsø7 (2015 to 2016). Persons with diabetes and/or diagnosed glaucoma were excluded from this study. Retinal thickness was measured on optical coherence tomography (Cirrus HD-OCT) macula-scans, segmented on RNFL, GCIPL, and ORL and associations were analyzed cross-sectionally (N = 8288) and longitudinally (N = 2595). We used directed acyclic graphs (DAGs) for model selection, and linear regression to adjust for confounders and mediators in models assessing direct effects. Factors examined were age, sex, blood pressure, daily smoking, serum lipids, glycated hemoglobin, body mass index (BMI), total body fat percentage (BFP), and the adjustment variables refraction and height. The explained variance of cardiovascular risk factors was highest in GCIPL (0.126). GCIPL had a strong negative association with age. Women had thicker GCIPL than men at higher age and thinner ORL at all ages (P < 0.001). Systolic blood pressure was negatively associated with RNFL/GCIPL (P = 0.001/0.004), with indication of a U-shaped relationship with GCIPL in women. The negative association with BMI was strongest in men, with significant effect for RNFL/GCIPL/ORL (P = 0.001/<0.001/0.019) and in women for GCIPL/ORL (P = 0.030/0.037). BFP was negatively associated with GCIPL (P = 0.01). Higher baseline BMI was associated with a reduction in GCIPL over 8 years (P = 0.03). Cardiovascular risk factors explained 12.6% of the variance in GCIPL, with weight and blood pressure the most important modifiable factors.


The great race: virus find awakens hope for sufferers.
A nationally celebrated team of scientists this week announced a discovery that may change the face of the 1973 budget now in preparation, and may even advance the frontiers of knowledge as well. Because of the dilatory schedule of academic journals (none of which could guarantee publication before the week after next), the scientists were obliged to publish their results in the form of a press release, together with high quality micrographs which were distributed to those attending the press conference. Following is a transcript of the press conference held this week at the Center for Duplicative Results.


Development of a simple method for the determination of genistein, daidzein, biochanin A, and formononetin (biochanin B) in human urine.
A simple method was developed for the determination of free and/or total isoflavones daidzein, genistein, and their respective 4'-methoxy derivatives biochanin A and formononetin (biochanin B) at low levels in human urine. A solid-phase extraction on octadecyl silica (C(18)) columns was used for the isolation of the phytoestrogens from the matrix. An extraction on a ChemElut 1010 column connected on-line to a Florisil cartridge by a Teflon stopcock was used for effective eluate purification. A mixture of dichloromethane and ethyl acetate was used for elution of the isoflavones from the columns in tandem. The isoflavones were determined as trimethylsilyl (TMS) ethers using GC/MS-SIM after separation on an HP-5MS fused silica column. TMS ethers were obtained by using BSTFA containing 1% of TMCS. For the determination of free isoflavones 6-hydroxyflavone was used as internal standard, whereas robigenin was used in the case of total isoflavone determination. Recoveries for free isoflavones under study varied from 63.5 to 89.6% at the 25 ng mL(-)(1) level and from 63.5 to 89. 2% at the 5 ng mL(-)(1) level in urine. Analytical curves were linear between 5 and 25 ng mL(-)(1). Detection limits varied from 1 ng mL(-)(1) for formononetin to 2.3 ng mL(-)(1) for daidzein. Recoveries for total isoflavone determination after enzymatic hydrolysis with glucuronidase from Helix pomatia ranged from 56.5 to 77.1% at the 25 ng mL(-1) level.


Predicting failure of thoracic vertebrae with simulated and actual metastatic defects.
Indications for operative treatment in spinal metastatic disease depend on estimates of vertebral loadbearing capacity. There are no noninvasive diagnostic tools for estimating vertebral loadbearing capacity in the presence of a metastatic lesion. Thus, relationships between vertebral failure load and measurements from computed tomography data were investigated to determine if measurements that account for defect size and bone density can predict loadbearing capacity better than can defect size alone. Cylindrical defects were created in thoracic vertebrae of 20 anatomic specimen spinal segments, with 10 other segments serving as controls. Five vertebrae with actual metastatic defects also were tested. Vertebrae were scanned using quantitative computed tomography, and the defect size and the axial rigidity of the midvertebral cross section were calculated using an image analysis program. The spinal segments were tested to failure using a combination of axial compression and anterior flexion. Linear regressions between axial rigidity and absolute failure load showed a high positive correlation, but there was no correlation between defect size and failure load. Axial rigidity may prove useful as a noninvasive assessment of vertebral loadbearing capacity in patients with spinal metastatic disease.


Somatic mutations in adrenocortical carcinoma with primary aldosteronism or hyperreninemic hyperaldosteronism.
Several somatic mutations specific to aldosterone-producing adenomas (APAs) have been described. A small proportion of adrenocortical carcinomas (ACCs) are associated with hyperaldosteronism, either primary aldosteronism or hyperreninemic hyperaldosteronism. However, it is unknown whether they harbor mutations of the same spectrum as APAs. The objective of this study is to describe the clinical phenotype and molecular genotype of ACCs with hyperaldosteronism, particularly the analysis for common APA-associated genetic changes. Patients were identified by retrospective chart review at a specialized referral center and by positive staining for CYP11B2 of tissue microarrays. Twenty-five patients with ACC and hyperaldosteronism were initially identified by retrospective chart review, and tissue for further analysis was available on 13 tumors. Seven patients were identified by positive staining for CYP11B2 in a tissue microarray, of which two were already identified in the initial chart review. Therefore, a total number of 18 patients with a diagnosis of ACC and features of either primary aldosteronism or hyperreninemic hyperaldosteronism were therefore included in the final study. Mutational status for a select list of oncogenes, tumor suppressor genes and genes known to carry mutations in APAs were analyzed by next-generation sequencing. Review of clinical data suggested autonomous aldosterone production in the majority of cases, while for some cases, hyperreninemic hyperaldosteronism was the more likely mechanism. The mutational landscape of ACCs associated with hyperaldosteronism was not different from ACCs with a different hormonal phenotype. None of the ACCs harbored mutations of known APA-associated genes, suggesting an alternative mechanism conferring aldosterone production.


Clinical field site evaluation of the FACSCount for absolute CD3+, CD3+ CD4+, and CD3+ CD8+ cell count determinations in Thailand.
The FACSCount flow cytometer absolute CD3+, CD3+ CD4+, and CD3+ CD8+ cell counts measured at a field site hospital laboratory in Thailand were compared to FACScan absolute counts obtained at a nearby research laboratory. Correlation coefficients for 208 samples were > or = 0.95. The FACSCount was accurate, and it was easier and less expensive to operate than the FACScan. Additionally, the FACScan-generated lymphocyte percentage value was accurate for use with the FACScan SimulSET software.


Haemophilia Experiences, Results and Opportunities (HERO) Study: survey methodology and population demographics.
Psychosocial factors have a significant impact on the quality of life of persons with haemophilia (PWH). The Haemophilia Experiences, Results and Opportunities (HERO) initiative was developed to provide a greater understanding of the psychological components which influence the lives of PWH. This article describes the HERO methodology and the characteristics of respondents. Two online surveys (one for adult PWH ≥18 years and one for parents of children <18 years with haemophilia) were developed by an international advisory board and conducted in 10 countries. The surveys included demographic and treatment characteristics, relationships, sexual intimacy, quality of life, barriers to treatment and sources of information. A total of 675 PWH [age, median (range) 36 (18-86 years)] and 561 parents [39 (23-68 years)] completed the survey. PWH/parents reported haemophilia A (74%/76%), B (13%/16%) or with inhibitors (13%/8%). Spontaneous joint bleeding was reported in 76%/52% of PWH/children with haemophilia A, 67%/47% with haemophilia B and 93%/76% with inhibitors. Median number of bleeds (interquartile range) was 7 (2-20) for PWH and 4 (2-10) for children in the past year. Most PWH and children were treated with factor concentrate. PWH reported arthritis (49%) and HIV/HCV infections (18%/43%) related to haemophilia. Most PWH and parent respondents had received formal education (85%/89%) and were employed full- or part-time (60%/72%). HERO is one of the largest multinational studies focused on psychosocial issues in haemophilia, including historical and treatment information that will allow for multivariate analyses of determinants of health in haemophilia.


Novel Translucent and Strong Submicron Alumina Ceramics for Dental Restorations.
An ideal ceramic restorative material should possess excellent aesthetic and mechanical properties. We hypothesize that the high translucency and strength of polycrystalline ceramics can be achieved through microstructural tailoring. The aim of this study is to demonstrate the superior optical and mechanical properties of a new class of submicron grain-sized alumina ceramics relative to the current state-of-the-art dental ceramic materials. The translucency, the in-line transmission ( TIT) in particular, of these submicron alumina ceramics has been examined with the Rayleigh-Gans-Debye light-scattering model. The theoretical predictions related very well with the measured TIT values. The translucency parameter ( TP) and contrast ratio ( CR) of the newly developed aluminas were measured with a reflectance spectrophotometer on a black-and-white background. For comparison, the TIT, TP, and CR values for a variety of dental ceramics, mostly measured in-house but also cited from the literature, were included. The flexural strength of the aluminas was determined with the 4-point bending test. Our findings have shown that for polycrystalline alumina ceramics, an average grain size <1 µm coupled with a porosity level <0.7% could yield translucency values ( TIT, TP, CR) similar to those of the commercial high-translucency porcelains. These values are far superior to the high-translucency lithium disilicate glass-ceramic and zirconias, including the most translucent cubic-containing zirconias. The strength of these submicron grain-sized aluminas was significantly higher than that of the cubic-containing zirconia (e.g., Zpex Smile) and lithia-based glass-ceramics (e.g., IPS e.max CAD HT). A coarse-grained alumina could also reach a translucency level comparable to that of dental porcelain. However, the relatively low strength of this material has limited its clinical indications to structurally less demanding applications, such as orthodontic brackets. With a combined high strength and translucency, the newly developed submicron grain-sized alumina may be considered a suitable material for dental restorations.


[Phenomenon of pili formation in Yersinia enterocolitica].
In Y. enterocolitica strain, serovar 0:10, the capacity for the formation of pili inducing the mannose-resistant hemagglutination (MRHA) of formolated sheep red blood cells was due to the presence of plasmid pYE10. MRHA-inducing pili differed serologically from Y. pestis and Y. tuberculosis adhesion pili. Plasmid pYE10 was immobilized for transfer to cells of Escherichia coli strain HB101 (rec A) by means of pRP 4. The expression of MRHA-inducing pili in the new host the rec A-independent character of the synthesis. Y. enterocolitica cells containing pYE10 agglutinated in tissue-culture media with 10% of serum added at 37 degrees C.


Tracing the long-term legacy of childhood lead exposure: a review of three decades of the port Pirie cohort study.
Several prospective cohort studies have demonstrated that childhood lead levels show small but statistically significant adjusted associations with subsequent development in later childhood and adolescence. The Port Pirie Cohort study is one of the few prospective cohort studies to follow participants into adulthood. This paper reviews all childhood and adulthood findings of the Port Pirie Cohort study to date. Cohort members (initially, 723 infants born in/around the lead-smelting town of Port Pirie) showed a wide range of childhood blood lead levels, which peaked around 2 years old (M=21.3μg/dL, SD=1.2). At all childhood assessments, postnatal lead levels - particularly those reflecting cumulative exposure - showed small significant associations with outcomes including cognitive development, IQ, and mental health problems. While associations were substantially attenuated after adjusting for several childhood covariates, many remained statistically significant. Furthermore, average childhood blood lead showed small significant associations with some adult mental health problems for females, including anxiety problems and phobia, though associations only approached significance following covariate adjustment. Overall, there did not appear to be any age of greatest vulnerability or threshold of effect, and at all ages, females appeared more susceptible to lead-associated deficits. Together, these findings suggest that the associations between early childhood lead exposure and subsequent developmental outcomes may persist. However, as the magnitude of these effects was small, they are not discernible at the individual level, posing more of a population health concern. It appears that the combination of multiple early childhood factors best predicts later development. As such, minimising lead exposure in combination with improving other important early childhood factors such as parent-child interactions may be the best way to improve developmental outcomes.


Laparoscopic ultrasonography in the management of ovarian cysts.
The aim of the study was to determine the role of laparoscopic ultrasonography in the management of ovarian cysts extirpated by means of endoscopic surgery. Laparoscopic ultrasonography was used during endoscopic surgery in 14 consecutive patients with an adnexal mass. The diagnostic accuracies of transvaginal and laparoscopic ultrasonography were compared according to the final pathological diagnosis. Estimations of the exact location of the ovarian mass by means of laparoscopic visualization and laparoscopic ultrasonography were compared. The presence of residual tumor tissue after cyst extirpation was monitored with laparoscopic ultrasonography. Using laparoscopic ultrasound and transvaginal ultrasound the correct diagnosis was made in 12 of 14 (85.7%) and 9 of 14 (64.3%) patients, respectively (not significantly different). With laparoscopic visualization, the exact location of the ovarian tumor could be demonstrated in 57.1% (8/14) of the cases, while with laparoscopic ultrasonography precise visualization of the ovarian mass was achieved in all cases (not significantly different). Two patients were found to have residual tumor tissue in the ovary when laparoscopic ultrasonography was performed again after tumor extirpation. Laparoscopic ultrasonography seems to be useful in patients with an adnexal mass managed by endoscopic surgery, in terms of evaluating the internal characteristics and predicting the histological diagnosis of the ovarian cyst, deciding on the correct placement of the incision to prevent unnecessary trauma to the ovary, and evaluation of the ovary after cyst extirpation to expose any residual tumor tissue.