Motion-based prediction is sufficient to solve the aperture problem.
In low-level sensory systems, it is still unclear how the noisy information collected locally by neurons may give rise to a coherent global percept. This is well demonstrated for the detection of motion in the aperture problem: as luminance of an elongated line is symmetrical along its axis, tangential velocity is ambiguous when measured locally. Here, we develop the hypothesis that motion-based predictive coding is sufficient to infer global motion. Our implementation is based on a context-dependent diffusion of a probabilistic representation of motion. We observe in simulations a progressive solution to the aperture problem similar to physiology and behavior. We demonstrate that this solution is the result of two underlying mechanisms. First, we demonstrate the formation of a tracking behavior favoring temporally coherent features independent of their texture. Second, we observe that incoherent features are explained away, while coherent information diffuses progressively to the global scale. Most previous models included ad hoc mechanisms such as end-stopped cells or a selection layer to track specific luminance-based features as necessary conditions to solve the aperture problem. Here, we have proved that motion-based predictive coding, as it is implemented in this functional model, is sufficient to solve the aperture problem. This solution may give insights into the role of prediction underlying a large class of sensory computations.


Effect of Fermented Rapeseed Meal on the Gastrointestinal Microbiota and Immune Status of Rabbit (Oryctolagus cuniculus).
The present study was conducted to determine the effect of the use of varying amounts of fermented rapeseed meal in diets for rabbits on the immune status and microbiota of segments of the GIT. Forty 35 day old rabbits used in the experiment were assigned to four groups: the control group (group C) were fed a standard diet and the experimental received 4%, 8% or 12% fermented rapeseed meal (included in place of standard soybean meal). Class A, G and M immunoglobulins were determined in the blood plasma. In the food content collected after slaughter, microbiological parameters were determined for individual sections of the digestive tract. Rabbits from the groups receiving a diet with an increased proportion of fermented rapeseed meal (8% or 12%) had lower concentrations of anaerobic bacteria and Escherichia coli in the intestinal contents. Research has shown that the increase in intake of fermented rapeseed meal was correlated with an increase in the correlations between the immunoglobulin level and the size of the microbial population in the GIT. In light of the presented results fermented rapeseed meal, by supplying valuable bioactive substances, appears to be a good component in the diet of rabbits, enhancing immune system development and helping to prevent disturbances of the gut microbiota.


Intrahepatic Sampling for the Elucidation of Antiviral Clinical Pharmacology.
Although the importance of the liver in clinical pharmacology is widely recognized, little is known in humans concerning its function in vivo at the hepatocyte level and how pharmacological functions are altered in the setting of advanced liver disease. Several recent proof-of-principle studies with first-generation DAAs have demonstrated the feasibility of serial liver sampling for pharmacological studies. These studies have begun to describe the liver-to-plasma concentration ratio and how this ratio is altered in the setting of advanced liver disease. These data are particularly relevant to individuals with substance-use disorders because many have advanced liver disease as a consequence of long-standing viral hepatitis infection or continued use of hepatotoxins such as alcohol. Future research should attempt to develop standardized and reproducible methods to assess liver drug concentration, complex drug interactions, and pharmacogenomics in humans to permit elucidation of the clinical pharmacology within the liver.


A changed climate for mental health care delivery in South Africa.
Traditional health practice was recently mainstreamed in South Africa by the promulgation of the Traditional Health Practitioners Act, No. 35 of 2004. Due to the extent of integration of mental health in the legal definition of traditional health practice, promulgation of this Act also has significant implications for mental health care delivery. This paper explored the documented interface of traditional health practice with mental health care in South Africa over the past almost 50 years. A preliminary overview of health literature was done on formal mental health care and traditional alternatives in South Africa since the 1950's. Important themes were identified as first step in a qualitative approach to identify concepts. The search yielded 143 references, between 1958 and 2004, from articles, case reports, scientific letter, theses and chapters in books. A cross section of 56 references was selected for inclusion in this review of the material. The documentation on the interface between the two parallel systems contribute to establish a context against which the promulgation of the legislation to formally integrate and regulate African traditional health practice in South Africa can be considered. South African policy makers may now have ensured that a multi-faceted, multi-cultural and multi-cosmological context for health and mental health care delivery has come to pass. To health administrators, though, the inclusion of traditional healers into the formal public health system and mental health may still prove to be too costly to implement.


Assessing progress in the national health financing system towards universal health coverage in Iran: a mixed-method study protocol.
Health financing systems have a key role in achieving universal health coverage (UHC) across the globe. However, little is known about how best to monitor health financing system progress towards UHC, especially in low- and middle-income countries. This is a protocol of a study that will aim to assess health financing system progress towards achieving UHC in Iran. An explanatory mixed-method approach will be used in two phases. In the quantitative phase, the performance of the Iranian health financing system will be assessed using a well-established set of indicators to draw on progress over 5-year intervals starting in the year 2000 up to the present. Data will be extracted from the global health expenditure database using a specific form and will be classified in accordance with each indicator. A qualitative phase will then take place considering the Kutzin et al. framework and by using health financing progress matrices. The qualitative phase will consist of two successive stages; first, a descriptive overview on the major health coverage schemes along with key attributes of each scheme. This initial mapping will be the underlying background for the second stage. In the second stage, the matrices comprised of a series of questions and relevant to the core functions of health financing and cross-cutting options will be invested in enhancing the evaluation of the ongoing reforms or policies. In this phase, data will be collected by reviewing national policy documents and in-depth interviews with key informants who will be recruited using purposive sampling. Finally, a policy discussion with key stakeholders will be held in order to review and verify the consistency between the current health financing policy and UHC goals. This study will provide a comprehensive image about the current status of the national health financing system progress towards achieving UHC in Iran. Such assessment will give detailed insight about the performance of the current financing system through identifying encountered challenges. Furthermore, some other defects in the design of the financing system are expected to appear. In all likelihood, the results will be fruitful enough to make informed decisions about interventions and policies in relation to UHC. The study protocol has been approved by the Ethics Committee for Research at Tehran University of Medical Sciences. Informed consent will be obtained from all key informants and the data will be collected and transcribed anonymously in order to maintain utmost confidentiality. The results will be disseminated in peer-reviewed journals and presented in national and international conferences and meetings.


A high performance liquid chromatography method with electrochemical detection of gamma-aminobutyric acid, glutamate and glutamine in rat brain homogenates.
Determination of gamma-aminobutyric acid (GABA), glutamate (Glu) and glutamine (Gln) in animal models has been important to understand the normal function and clinical aspects of some neurological diseases. Quantification of these amino acid transmitters has conventionally been performed by using a high performance liquid chromatography (HPLC) system. This paper describes an improved HPLC method with electrochemical detection for glutamate, glutamine and GABA determination in brain homogenates. The protocol is based on a precolumn derivatization of amino acids with o-phthalaldehyde and sodium sulfite, a separation through a C18, 5 microm particle size column and an isocratic elution. Several modifications of previous works on methanol percentage, pH, temperature, flow rate and derivatization solution concentration were done to obtain a suitable protocol for amino acid quantification in brain homogenate samples. Total elution time is 35 min approximately. Technical requirements and laboratory expenses of this new protocol are minimal. This technique showed high linearity, repeatability and accuracy.


Recognition by gamma/delta T cells.
In contrast with the study of alpha beta T cells, that of gamma delta T cells is relatively recent and stems from the discovery of their rearranged genes, rather than from any knowledge of their biological function. Thus, experiments designed to characterize their specificity and function have drawn heavily on our knowledge of alpha beta T cells. During the past few years, many studies, especially with mice lacking either alpha beta or gamma delta T cells, have demonstrated that gamma delta T cells can contribute to immune competence, but they do so in a way that is distinct from alpha beta T cells. It is also evident that gamma delta T cells may not recognize antigen the same way as do alpha beta T cells. Analysis of three protein antigens-the murine MHC class II IEk, the nonclassical MHC T10/T22, and the Herpes virus glycoprotein gI-indicates that gamma delta T cell recognition does not require antigen processing and that the proteins are recognized directly. In all three cases, recognition by these T cell clones involves neither peptides bound to these proteins nor peptides derived from them. Moreover, a group of small phosphate-containing nonpeptide compounds derived from mycobacterial extracts has been found to stimulate a major population of human peripheral gamma delta T cells in a T cell receptor (TCR)-dependent manner. This indicates that gamma delta T cells can respond to ligands that are different from those of alpha beta T cells. Analysis of complementarity determining region (CDR3) length distributions of gamma and delta chains indicates that they are more similar to those of immunoglobulins than to TCR alpha and beta. This further supports the idea that gamma delta and alpha beta T cells recognize antigens differently and suggests that gamma delta T cells may be more like immunoglobulins in their recognition properties. gamma delta T cells share many cell surface proteins with alpha beta T cells and are able to secrete lymphokines and express cytolytic activities in response to antigenic stimulation. These, together with the results cited above, indicate that gamma delta T cells can mediate cellular immune functions without a requirement for antigen processing. Thus, pathogens, damaged tissues, or even B and T cells can be recognized directly, and cellular immune responses can be initiated without a requirement for antigen degradation or specialized antigen-presenting cells. This would give gamma delta T cells greater flexibility than the more classical type of alpha beta T cell-mediated cellular immunity.


[Bronchiolitis obliterans with organizing pneumonia].
Obliterant Bronchiolitis is an anatomo-clinical entity known years ago. It is recognized as a evolutive form of different processes, including Extrinsic Allergic Alveolitis, Pneumonitis due to gas inhalation, viral processes and Rheumatoid Lung. It has been recently identified as a disease with specific characteristics in the context of interstitial idiopathic pneumonia with bronchiolar involvement and a distinctive anatomo-pathological character. From the clinical and radiological point of view it requires a broad differential diagnosis, which is confirmed definitively in the anatomopathological exam obtained through minithoracotomy. Therapeutic response to corticosteroids is good even thought it shows a trend to relapse when they are decreased or stopped. We discuss the cases of three patients who were studied recently, showing their clinical, radiological and anatomopathological features together with the therapeutic response, which is positive, in different periods of the evolution course.


Bioassay of pyrazinamide for possible carcinogenicity.
A bioassay of the tuberculostatic drug pyrazinamide for possible carcinogenicity was conducted by administering the test chemical in feed to Fischer 344 rats and B6C3F1 mice. Groups of 35 rats and 35 mice of each sex were administered pyrazinamide at one of two doses, either 5,000 or 10,000 ppm, for 78 weeks, and then observed for an additional 26 or 27 weeks. Matched controls consisted of groups of 15 untreated rats and 15 untreated mice of each sex. High-dose male mice died or were killed by week 92; all other surviving animals were killed at weeks 104 or 105. Mean body weights of the dosed male rats were slightly lower than those of the matched controls, while mean body weights of the dosed females were more nearly comparable to those of the controls. A sufficient number of rats in each group was at risk to termination of the study at weeks 104-105 for the development of late-appearing tumors. In mice, administration of pyrazinamide had no consistent effect on mean body weights. Survival to termination of the study was low, particularly among the control groups. In rats, no lesions could clearly be related to administration of the chemical. In mice, interstitial and suppurative myocarditis in the dosed animals and suppurative bronchopneumonias in both dosed and matched control mice of each sex were associated with increased deaths. In the females, there was a significant positive dose-related trend (P=0.037) in the incidence of lymphoma (matched controls 0/13, low-dose 2/25, high-dose 6/29); however, the incidences in each of the dosed groups were not significant when compared with that in the matched controls. In addition, the poor survival and the small size of the control group precluded making a clear association of the incidence of these tumors with administration of the chemical. It is concluded that under the conditions of this bioassay, the early deaths and small size of the control group precluded a conclusion regarding the carcinogenicity of pyrazinamide in female B6C3F1 mice. Pyrazinamide was not carcinogenic for Fischer 344 rats or for male mice.


2021 consensus statement for preventing and managing low back pain in elite and subelite adult rowers.
To synthesise evidence on low back pain (LBP) in adult rowers and to create a consensus statement to inform clinical practice. There were four synthesis steps that informed the consensus statement. In step one, seven expert clinicians and researchers established the scope of the consensus statement and conducted a survey of experienced and expert clinicians to explore current practice. In step two, working groups examined current evidence relating to key scope questions and summarised key issues. In step three, we synthesised evidence for each group and used a modified Delphi process to aid in the creation of the overall consensus statements. Finally, in step four, we combined information from step three with the findings of the clinician survey (and with athlete and coach input) to produce recommendations for clinical practice. The scope of the consensus statement included epidemiology; biomechanics; management; the athlete's voice and clinical expertise. Prevention and management of LBP in rowers should include education on risk factors, rowing biomechanics and training load. If treatment is needed, non-invasive management, including early unloading from aggravating activities, effective pain control and exercise therapy should be considered. Fitness should be maintained with load management and progression to full training and competition. The role of surgery is unclear. Management should be athlete focused and a culture of openness within the team encouraged. Recommendations are based on current evidence and consensus and aligned with international LBP guidelines in non-athletic populations, but with advice aimed specifically at rowers. We recommend that research in relation to all aspects of prevention and management of LBP in rowers be intensified.


Who's there and who cares: age as an indicator of social support networks for caregivers among people living with motor neurone disease.
This paper explores the social support networks available to the informal carers of people living with motor neurone disease (MND). An ethnographic case study was undertaken using eco mapping, observation and conversational interviews to collect data from 18 primary carers of people living with MND. Interviews took place in participants' homes in metropolitan, regional and rural locations. Participants discussed the content of their support network and drew lines between individuals to indicate the type and strength of relationship. Changes to the network were depicted on eco maps during subsequent interviews. While health policy-makers assume that healthy social capital exists in Australian communities and that social cohesion will ensure active and available support networks in times of illness or disability, data from this exploratory study indicated that this was not consistently the case. Support networks varied in size and composition; however, age was identified as a discriminator of the availability and consistency of support. People in older age groups identified more diverse but consistent support systems while people in younger age groups reported more fluctuations in the strength of relationships and declines in support as caregiving became more demanding. Individual assessment of support networks at regular intervals in the caregiving trajectory is vital for all carers. However carers in younger age groups may need specific support to manage the psychological crises that occur and more access to paid care. Older carers may need consistent support to handle more of the instrumental aspects of care and assistance to mobilise their support networks. Community workers should be alert to the possible need for crisis intervention when tensions in relationships threaten carers' ability to provide effective care.


Structural and chemical aspects of resistance to the antibiotic fosfomycin conferred by FosB from Bacillus cereus.
The fosfomycin resistance enzymes, FosB, from Gram-positive organisms, are M(2+)-dependent thiol tranferases that catalyze nucleophilic addition of either L-cysteine (L-Cys) or bacillithiol (BSH) to the antibiotic, resulting in a modified compound with no bacteriacidal properties. Here we report the structural and functional characterization of FosB from Bacillus cereus (FosB(Bc)). The overall structure of FosB(Bc), at 1.27 Å resolution, reveals that the enzyme belongs to the vicinal oxygen chelate (VOC) superfamily. Crystal structures of FosB(Bc) cocrystallized with fosfomycin and a variety of divalent metals, including Ni(2+), Mn(2+), Co(2+), and Zn(2+), indicate that the antibiotic coordinates to the active site metal center in an orientation similar to that found in the structurally homologous manganese-dependent fosfomycin resistance enzyme, FosA. Surface analysis of the FosB(Bc) structures show a well-defined binding pocket and an access channel to C1 of fosfomycin, the carbon to which nucleophilic addition of the thiol occurs. The pocket and access channel are appropriate in size and shape to accommodate L-Cys or BSH. Further investigation of the structures revealed that the fosfomycin molecule, anchored by the metal, is surrounded by a cage of amino acids that hold the antibiotic in an orientation such that C1 is centered at the end of the solvent channel, positioning the compound for direct nucleophilic attack by the thiol substrate. In addition, the structures of FosB(Bc) in complex with the L-Cys-fosfomycin product (1.55 Å resolution) and in complex with the bacillithiol-fosfomycin product (1.77 Å resolution) coordinated to a Mn(2+) metal in the active site have been determined. The L-Cys moiety of either product is located in the solvent channel, where the thiol has added to the backside of fosfomycin C1 located at the end of the channel. Concomitant kinetic analyses of FosB(Bc) indicated that the enzyme has a preference for BSH over L-Cys when activated by Mn(2+) and is inhibited by Zn(2+). The fact that Zn(2+) is an inhibitor of FosB(Bc) was used to obtain a ternary complex structure of the enzyme with both fosfomycin and L-Cys bound.


'Weekend on the town': discrete sessions of drug use for a sample of young psychostimulant users.
Few epidemiological studies have examined the behaviours and experiences of young adults during discrete drug-use events. This study was designed to capture a rich, detailed description of discrete occasions or 'sessions' of psychostimulant use. Participants were 220 young psychostimulant users living in Melbourne, Australia, recruited through targeted advertising in entertainment street press, on websites, at events/dance parties and through peer referral between September 2007 and March 2008. The research identified the timing, sequence, frequencies, quantities and modes of alcohol and other drug administration during the participants' most recent session of psychostimulant use and explored the contexts and settings in which drug use took place. Participants were well-educated young people who used a variety of different drugs. Their most recent session of psychostimulant use was reported as highly enjoyable and typical of their other sessions of psychostimulant use. The session lasted a median of 20 h, and in most cases, simultaneous drug use was the norm, and large quantities of alcohol, psychostimulants and other drugs were consumed. Acquisition of illicit drugs commonly occurred through social networks during the course of the session and significant sums of money were reportedly spent. Findings point to a range of priorities for future research and public health interventions aimed at young psychostimulant users, focused primarily on reducing the prevalence and consequences of simultaneous and heavy/binge drug use.


Protection of human umbilical vein endothelial cells by glycine and structurally similar amino acids against calcium and hydrogen peroxide-induced lethal cell injury.
Cultured human umbilical vein endothelial cells treated with either the calcium ionophore, ionomycin, or ionomycin plus cyanide-m-chlorophenylhydrazone had immediate severe depletion of adenosine triphosphate, (ATP) and increases of cytosolic free calcium (Caf) and then sustained lethal cell injury as manifested by release of lactate dehydrogenase and failure to exclude vital dyes within 15 minutes. Inclusion of glycine in the experimental medium prevented the enzyme leakage for at least 60 minutes without altering the ATP depletion or increases of Caf. The physiologic glycine concentration of 0.25 mmol/l gave 50% protection, and protection was complete at 1 mmol/l. Several other small neutral amino acids, L- and D-alanine, beta-alanine, 1-aminocyclopropane-1-carboxylate, alpha-aminoisobutyrate, and L-serine, had effects similar to glycine, but other amino acids and metabolic substrates did not. The endothelial cells were relatively resistant to damage from hydrogen peroxide, but sensitivity could be increased by preloading with Fe2+. In both non-loaded and Fe(2+)-loaded cells, hydrogen-peroxide-induced lactate dehydrogenase (LDH) release developing over 180 minutes was prevented by glycine in a fashion analogous to that seen with ionomycin damage. Mn2+ also partially protected against hydrogen peroxide injury but was not required for glycine's effects. These data demonstrate that striking modulatory effects of glycine and structurally similar amino acids that have previously been characterized in most detail using kidney tubule cells are strongly expressed in human umbilical vein endothelial cells and are involved in their response to Ca2+ and oxidant-mediated damage. These amino acid effects must be considered in the design of in vitro studies of endothelial cell injury and may contribute to endothelial cell pathophysiology in vivo.


Ethanol Decreases Inflammatory Response in Human Lung Epithelial Cells by Inhibiting the Canonical NF-kB-Pathway.
Alcohol (ethanol, EtOH) as significant contributor to traumatic injury is linked to suppressed inflammatory response, thereby influencing clinical outcomes. Alcohol-induced immune-suppression during acute inflammation (trauma) was linked to nuclear factor-kappaB (NF-ĸB). Here, we analyzed alcohol`s effects and mechanisms underlying its influence on NF-ĸB-signaling during acute inflammation in human lung epithelial cells. A549-cells were stimulated with interleukin (IL)-1β, or sera from trauma patients (TP) or healthy volunteers, with positive/negative blood alcohol concentrations (BAC), and subsequently exposed to EtOH (170 Mm, 1h). IL-6-release and neutrophil adhesion to A549 were analyzed. Specific siRNA-NIK mediated downregulation of non-canonical, and IKK-NBD-inhibition of canonical NF-ĸB signaling were performed. Nuclear levels of activated p50 and p52 NF-ĸB-subunits were detected using TransAm ELISA. Both stimuli significantly induced IL-6-release (39.79±4.70 vs. 0.58±0.8 pg/ml) and neutrophil adhesion (132.30±8.80 vs. 100% control, p<0.05) to A549-cells. EtOH significantly decreased IL-6-release (22.90±5.40, p<0.05) and neutrophil adherence vs. controls (105.40±14.5%, p<0.05). IL-1β-induced significant activation of canonical/p50 and non-canonical/p52 pathways. EtOH significantly reduced p50 (34.90±23.70 vs. 197.70±36.43, p<0.05) not p52 activation. Inhibition of canonical pathway was further increased by EtOH (less p50-activation), while p52 remained unaltered. Inhibition of non-canonical pathway was unchanged by EtOH. Here, alcohol`s anti-inflammatory effects are mediated via decreasing nuclear levels of activated p50-subunit and canonical NF-ĸB signaling pathway.


Remodeling and suppression of intimal hyperplasia of vascular grafts with a distal arteriovenous fistula in a rat model.
The purpose of this study was to evaluate the effects of a distal arteriovenous fistula (dAVF) on the morphologic changes occurring in arterial bypass grafts by the use of a novel experimental model. Aortofemoral bypass grafts with or without dAVFs were constructed in 36 Sprague-Dawley rats with a microsurgical technique. The bypass graft material consisted of deendothelialized autogenous tail artery (length, 25 mm; inside diameter, 0.5 mm). In 18 rats, dAVFs were constructed at the distal anastomosis. After 6 weeks, flow rates and shear stress were determined, and grafts were then harvested. Luminal, intimal, and medial cross-sectional areas were measured with computer imaging. Desmin, alpha-smooth muscle actin, and von Willebrand factor (vWF) were identified with immunohistochemistry. Endothelialization was evaluated with SEM. All bypass grafts remained patent at the time of graft harvest. Grafts with dAVFs showed increased flow rates (11.5 +/- 0.6 mL/min) compared with grafts without dAVFs (2.1 +/- 0.3 mL/min; P < .01). Shear stress was also increased in the dAVF group (340.9 +/- 23.4 dyne/cm(2) vs 113.7 +/- 12.5 dyne/cm(2); P < .01), with a corresponding suppression of intimal hyperplasia (0.059 +/- 0.011 mm(2) for dAVF grafts vs 0.225 +/- 0.009 mm(2) for non-dAVF grafts; P < .01). Staining for vWF was found in both the reendothelialized flow surface and the neointimal extracellular matrix. Remodeling of the grafts was characterized by a 50% increased luminal area, 70% decreased intimal area, and a 25% decreased medial area when a dAVF was constructed. A small animal experimental model of an arterial bypass graft can enable the evaluation of a variety of factors that influence graft patency. Increased blood flow velocity and shear stress induced by a dAVF are associated with a decrease in intimal and medial areas, which may reflect changes in cell proliferation, apoptosis, migration, or matrix deposition. Deposition of vWF was also found both in the endothelium and throughout the hyperplastic intima. These findings suggest that the hemodynamic and morphologic changes associated with dAVF may potentiate graft patency and function.


"Well, have I got cancer or haven't I?" The psycho-social issues for women diagnosed with ductal carcinoma in situ.
To explore women's experience of being diagnosed with ductal carcinoma in situ (DCIS) in relation to the following: response to the diagnosis; understanding about the diagnosis; satisfaction with information; satisfaction with the level of involvement in treatment decision-making and satisfaction with support services. An explorative descriptive qualitative design was used to facilitate an in-depth exploration of women's experiences. Five focus group interviews were conducted in New South Wales (NSW), Australia, involving 26 women diagnosed with DCIS. DCIS is a non-invasive breast disease, that in most cases will not recur if treated, and cannot of itself metastasize to other parts of the body. However, this study found that women were confused about whether or not they had cancer that could result in death. Women's confusion was compounded by the use of the term "carcinoma" and by the recommendation of treatments such as mastectomy. Women's confusion was not alleviated by appropriate information, with most women reporting dissatisfaction with the information they received specifically about DCIS. This study identifies that a diagnosis of DCIS has a significant psychological impact on women. The communication challenges highlighted in this study are not only relevant to DCIS but to any other disease in which the natural history is uncertain and the evidence about treatment effectiveness is still emerging. Further research is needed in areas such as DCIS to explore the difficulties experienced in doctor-patient communication and their impact on patient outcomes, and how to optimize doctor-patient communication.


Quality Measures For Mental Health And Substance Use: Gaps, Opportunities, And Challenges.
Following up on its Crossing the Quality Chasm report, in 2006 the Institute of Medicine issued a report that included sweeping recommendations to improve the quality of behavioral health care in the United States. To date, few of those recommendations have been implemented, and there is little evidence that behavioral health care quality has improved significantly over the past ten years. However, the advent of health care reform, parity of insurance coverage, and growing recognition of the impact of behavioral health disorders on population health and health care costs have created new demands and opportunities for expanded and innovative strategies to assess the quality of care for this patient population. We provide an overview of the current state of quality measurement in behavioral health, identify key priorities for measure development, and describe the most important challenges. We recommend a coordinated plan that would boost investment in developing, evaluating, and implementing behavioral health quality measures; conduct research to develop the evidence necessary to support a more robust set of measures; overcome barriers to the improvement and linking of data sources; and expand efforts to build the capacity of the clinical workforce, in partnership with consumers, to improve quality.


Alkylation of alpha-1 receptors with a chemically reactive analog of prazosin reveals low affinity sites for norepinephrine in rabbit aorta.
The effect of a newly synthesized irreversible blocker of the alpha-1 receptor [1-(4-amino-6,7-dimethoxy-2-quinazolnyl)-4-(2-bicyclo[2,2,2] octa-2,5-dienylcarbonyl)-piperazine; SZL-49] has been evaluated in contractile studies in rabbit aorta and binding studies in aorta and brain. SZL-49 produced long lasting inhibition of norepinephrine-induced contractions which was apparent 21 hr after drug washout. The inhibition, which was dose and time dependent, was characterized by progressive shift to the right in the norepinephrine dose-response curve. The ED50 for norepinephrine was shifted from 10(-7) M to 8 X 10(-7), 3 X 10(-6), 1 X 10(-5) and 5 X 10(-4) M after incubation (30 min) and washout of increasing concentrations of SZL-49. Surprisingly, SZL-49, irrespective of the dose or incubation time, did not decrease the maximal response of aortic rings to norepinephrine. This resulted in a norepinephrine dose-response curve after SZL-treatment that is parallel to the control. SZL-49 had no effect on the spasmogenic actions of histamine, serotonin, KCl or CaCl2. In contrast to the inhibitory pattern seen with SZL-49, incubation with 10(-7) M phenoxybenzamine shifted the norepinephrine dose-response curve to the right in a nonparallel manner and significantly depressed the maximal response obtainable with norepinephrine. Incubation with 10(-6) M phenoxybenzamine for 30 min virtually abolished the response to norepinephrine. Phenoxybenzamine (10(-7) M) was without effect on aortic rings treated with a maximally effective dose of SZL-49. Prazosin weakly antagonized the contractile actions of norepinephrine observed after SZL-49 treatment, whereas yohimbine was without effect on these norepinephrine-induced contractions. In control binding studies [3H]prazosin bound to two classes of sites in both aorta and brain preparations. Affinities and densities for these sites were K1 = 67.5 pM, K2 = 309 pM; R1 = 38.2 fmol/mg, R2 = 46.47 fmol/mg in aorta and K1 = 29.6 pM, K2 = 182 pM; R1 = 6.6 fmol/mg and R2 = 30.4 fmol/mg in brain. Treatment with increasing amounts of SZL-49 (10(-10) to 10(-8) M) progressively reduced the number of [3H]prazosin sites without altering the affinity of the sites remaining. At 10(-7) M, SZL-49 eliminated completely all specific [3H]prazosin binding. Our results indicate that the site mediating norepinephrine contraction after treatment with SZL-49 does not possess the characteristics of an alpha-1 receptor and supports the hypothesis that a low affinity site for norepinephrine and prazosin exists in vascular smooth muscle.(ABSTRACT TRUNCATED AT 400 WORDS)


Failure of clopidogrel to reduce platelet reactivity and activation following standard dosing in elective stenting: implications for thrombotic events and restenosis.
There is no information on long-term platelet reactivity and activation following elective stenting in patients treated with clopidogrel and aspirin. We measured platelet reactivity and activation at baseline and at 2 h, 24 h, 5 days and 30 days following coronary stenting (n = 94). Patients were treated with the standard aspirin (325 mg) and clopidogrel regimen (300 mg load/75 mg qd). Reactivity was measured by aggregation (5 and 20 microM ADP) and activation was determined by the expression of total and active GP IIb/IIIa. Reactivity and activation were defined as heightened when post-stent aggregation and receptor expression exceeded baseline levels, respectively. Prolonged heightened platelet reactivity was detected by both 5 and 20 microM ADP aggregation. Using 20 microM ADP aggregation, heightened reactivity occurred in 55% of patients at 2 h, 26% at 24 h, 21% at 5 days, and 15% at 30 days post-stenting. A high frequency of heightened platelet activation was detected by both total and active GP IIb/IIIa expression. Using expression of the active GP IIb/IIIa receptor as the marker, activation was greater than baseline in 27% of patients at 2 h, 20% at 24 h, 30% at 5 days, and 22% at 30 days post-stenting. This is the first report demonstrating that a significant percentage of patients receiving standard clopidogrel and aspirin therapy for coronary stenting will have post-drug platelet reactivity and activation above baseline that persists for 30 days after the procedure. These finding suggest insufficient platelet inhibition. The clinical importance of these findings should be further investigated to establish the potential link between insufficient platelet inhibition, stent thrombosis, and restenosis.


Alkaline gastro-oesophageal reflux: dual probe pH monitoring.
Although the aetiology of Barrett's oesophagus or columnar line oesophagus (CLO), remains unknown, bile reflux has been implicated as a factor in its pathogenesis. This study aimed to detect alkaline reflux in gastro-oesophageal reflux patients using dual probe pH monitoring. Thirty patients with histologically diagnosed CLO, 15 age and sex matched patients with oesophagitis (grade 1-3), and 15 healthy volunteers were studied by dual probe, 18 hour pH monitoring and analysis of the bile acid content of oesophageal refluxate. Total acid exposure and acid exposure in the upright and supine postures were greater in CLO subjects than in oesophagitis patients and controls. Furthermore, the number of reflux episodes lasting more than five minutes and the duration of the longest reflux episode were significantly greater in the CLO subjects than the oesophagitis and control subjects. Nine subjects with CLO and oesophagitis, however, were not identified as refluxers, although six had a bile acid concentration in their oesophageal aspirate higher than the 95th centile value of the controls. There was no correlation between the oesophageal pH and the bile acid contents of refluxate. It is concluded that dual probe pH monitoring is not useful in detecting alkaline refluxers. pH monitoring, although the only subjective test available to identify acid refluxers, is not a sufficiently sensitive test with which to define alkaline reflux.


Cannabinoids in health and disease.
Cannabis sativa L. preparations have been used in medicine for millenia. However, concern over the dangers of abuse led to the banning of the medicinal use of marijuana in most countries in the 1930s. Only recently, marijuana and individual natural and synthetic cannabinoid receptor agonists and antagonists, as well as chemically related compounds, whose mechanism of action is still obscure, have come back to being considered of therapeutic value. However, their use is highly restricted. Despite the mild addiction to cannabis and the possible enhancement of addiction to other substances of abuse, when combined with cannabis, the therapeutic value of cannabinoids is too high to be put aside. Numerous diseases, such as anorexia, emesis, pain, inflammation, multiple sclerosis, neurodegenerative disorders (Parkinson's disease, Huntington's disease, Tourette's syndrome, Alzheimer's disease), epilepsy, glaucoma, osteoporosis, schizophrenia, cardiovascular disorders, cancer, obesity, and metabolic syndrome-related disorders, to name just a few, are being treated or have the potential to be treated by cannabinoid agonists/antagonists/cannabinoid-related compounds. In view of the very low toxicity and the generally benign side effects of this group of compounds, neglecting or denying their clinical potential is unacceptable--instead, we need to work on the development of more selective cannabinoid receptor agonists/antagonists and related compounds, as well as on novel drugs of this family with better selectivity, distribution patterns, and pharmacokinetics, and--in cases where it is impossible to separate the desired clinical action and the psychoactivity--just to monitor these side effects carefully.


Photochemical degradation of hydroxy PAHs in ice: Implications for the polar areas.
Hydroxyl polycyclic aromatic hydrocarbons (OH-PAHs) are derived from hydroxylated PAHs as contaminants of emerging concern. They are ubiquitous in the aqueous and atmospheric environments and may exist in the polar snow and ice, which urges new insights into their environmental transformation, especially in ice. In present study the simulated-solar (λ > 290 nm) photodegradation kinetics, products and pathways of four OH-PAHs (9-Hydroxyfluorene, 2-Hydroxyfluorene, 1-Hydroxypyrene and 9-Hydroxyphenanthrene) in ice were investigated, and the corresponding implications for the polar areas were explored. It was found that the kinetics followed the pseudo-first-order kinetics with the photolysis quantum yields (Φs) ranging from 7.48 × 10(-3) (1-Hydroxypyrene) to 4.16 × 10(-2) (2-Hydroxyfluorene). These 4 OH-PAHs were proposed to undergo photoinduced hydroxylation, resulting in multiple hydroxylated intermediates, particularly for 9-Hydroxyfluorene. Extrapolation of the lab data to the real environment is expected to provide a reasonable estimate of OH-PAH photolytic half-lives (t1/2,E) in mid-summer of the polar areas. The estimated t1/2,E values ranged from 0.08 h for 1-OHPyr in the Arctic to 54.27 h for 9-OHFl in the Antarctic. In consideration of the lower temperature and less microorganisms in polar areas, the photodegradation can be a key factor in determining the fate of OH-PAHs in sunlit surface snow/ice. To the best of our knowledge, this is the first report on the photodegradation of OH-PAHs in polar areas.


A critique of existing national dental health services systems.
Dental care systems are predominantly based on the engineering and curative approach to the body, which does not necessarily improve dental health. In many western countries, including some developing countries, tooth loss is still prevalent amid sophisticated systems of dental care. The two major dental diseases, dental caries and periodontal disease, are almost entirely preventable. Against this background, a dental care system should encourage those working in it to apply known effective methods to improve and maintain the oral health of the population. The perceptions of people toward dental health have long been disregarded by the profession, to the extent that individuals are victim-blamed, irrespective of the existing socioenvironmental factors that may influence an individual's attitude towards dental services. The community must be involved in the planning and decision-making processes of any health service program to facilitate cooperation by the population in oral care.


Effects of enalapril, candesartan or both on neurohumoral activation and LV volumes and function in patients with heart failure not treated with a beta-blocker.
The long-term effects of the angiotensin-receptor blocker candesartan, the angiotensin-converting enzyme inhibitor enalapril or their combination have been incompletely studied in a large cohort of patients with heart failure not treated with beta-blockers. The objective of this study was to investigate the changes in neurohormones and LV volumes and ejection fraction in patients treated with enalapril, candesartan, or enalapril plus candesartan without concomitant beta-blocker therapy. Three hundred and ninety-two patients from the RESOLVD pilot study not treated with a beta-blocker at baseline or at any time during the trial were analyzed. Norepinephrine, endothelin-1, big endothelin-1, angiotensin-II, aldosterone, N-terminal proANP, BNP, and radionuclide angiography were measured before and after 43 weeks of treatment with candesartan alone (n = 162), or enalapril alone (n = 45), or candesartan plus enalapril (n = 185). Endpoints were assessed at baseline and after 43 weeks of therapy. LV end-diastolic and end-systolic volumes increased significantly at 43 weeks in all groups except for patients treated with enalapril plus candesartan. BNP decreased at 43 weeks only in patients receiving dual angiotensin-II suppression (-6.1 +/- 37.8 pmol/l). Angiotensin-II levels were significantly increased in patients treated with candesartan (+23.6 +/- 47.1 pg/ml; p<0.05). We conclude that angiotensin-II modulation, with enalapril and candesartan, without concomitant utilization of beta-blocker lead to a decrease in BNP and an attenuation of the increase in LV end-diastolic and end-systolic volumes without a reversal of this process in the long term.


Regulation of 2-oxoglutarate dehydrogenase synthesis in Citrobacter freundii by traces of oxygen in commercial nitrogen gas and by glutamate.
Glutamate induced the synthesis of 2-oxoglutarate dehydrogenase 50-fold during anaerobic growth of Citrobacter freundii and, in the absence of glutamate, this enzyme was even more active in cultures sparged with N2/CO2(95:5, v/v). Enzyme synthesis was partially repressed when the inlet gas was passed through heated copper but totally repressed when the inlet gas was passed through alkaline pyrogallol and reduced benzyl viologen (a treatment which would remove CO2 as well as O2). Fumarate hydratase activity also decreased but alcohol dehydrogenase and the sum of the succinate dehydrogenase and fumarate reductase activities increased when residual O2 was removed from the sparging gas. Soluble cytochromes a1 and c552.5 were detected in rigorously anaerobic cultures. Thus traces of O2 which contaminate commercial compressed N2 are sufficient to induce 2-oxoglutarate dehydrogenase synthesis and to affect significantly the synthesis and incorporation of respiratory chain components into the cytoplasmic membrane.


Evaluation of most-probable-number-PCR method with internal amplification control for the counting of total and pathogenic Vibrio parahaemolyticus in frozen shrimps.
The most-probable-number (MPN) method is often time-consuming for the isolation, detection, and quantification of Vibrio parahaemolyticus from natural sources. MPN counting of V. parahaemolyticus bacteria usually involves the isolation of typical V. parahaemolyticus colonies on selective medium, with subsequent confirmation by biochemical identification. In this study, we evaluated the use of a PCR on MPN enrichment cultures (MPN-PCR) for the direct detection of total and pathogenic V. parahaemolyticus cells in frozen shrimp. This reaction targeted the R72H, tdh, and trh sequences. An internal amplification control was added to the samples before R72H amplification. There was an excellent correlation between the results of the two methods for artificially inoculated and natural shrimp samples. Of 36 natural samples, 28 tested positive for the presence of V. parahaemolyticus, with an MPN value of 2 × 10(-1) to 9.2 × 10(1) per g. No pathogenic V. parahaemolyticus cells were detected. The test had a detection limit of one V. parahaemolyticus organism per g and was completed within two working days. These results support the use of the combination of PCR with MPN for the detection of total or potentially pathogenic V. parahaemolyticus cells in frozen shrimp.


A prospective look at the current state of open abdomens.
The present study examines the current management, closure rate, and complications of open abdomens in trauma patients admitted to an Academic Level I trauma center between May 2004 and April 2007. Variables examined include mechanism, injuries, use of antibiotics and paralytics, type of abdominal closure, days to closure, complications, ICU and hospital length of stay, and mortality. Stepwise logistic regression was performed to identify independent predictors of failed abdominal closure. Of 900 laparotomies, 93 (10%) were left open. Eighty-five (91%) patients survived for closure opportunity. Definitive fascial closure was achieved in 72 (85%) at 3.9 +/- 3.7 days (range 1-21 days). Of the remaining 13 patients, seven were closed with biologic material, five by skin grafting, and one had skin-only closure. Entero-atmospheric fistulas occurred in 14 (15%) patients. Two independent risk factors associated with failed abdominal closure were the presence of deep surgical site infection [odds ratio (OR) 17.4; 95% confidence interval (CI) 2.6-115.8, P = 0.003] and intra-abdominal abscess (OR 7.4; 95% CI 1.1-51.0, P = 0.04). In conclusion, open abdomens are commonly necessary after trauma laparotomies. Definitive fascial closure can be achieved in 85 per cent of cases. In conjunction with biologics, closure can be achieved in 93 per cent of cases. Failure to primarily close the abdomen is associated with a significantly higher risk for entero-atmospheric fistula occurrence.


Diversity and phylogenetic implications of CsCl profiles from rodent DNAs.
Buoyant density profiles of high-molecular-weight DNAs sedimented in CsCl gradients, i.e., compositional distributions of 50- to 100-kb genomic fragments, have revealed a clear difference between the murids so far studied and most other mammals, including other rodents. Sequence analyses have revealed other, related, compositional differences between murids and nonmurids. In the present study, we obtained CsCl profiles of 17 rodent species representing 13 families. The modal buoyant densities obtained for rodents span the full range of values observed in other eutherians. More remarkably, the skewness (asymmetry, mean - modal buoyant density) of the rodent profiles extends to values well below those of other eutherians. Scatterplots of these and related CsCl profile parameters show groups of rodent families that agree largely with established rodent taxonomy, in particular with the monophyly of the Geomyoidea superfamily and the position of the Dipodidae family within the Myomorpha. In contrast, while confirming and extending previously reported differences between the profiles of Myomorpha and those of other rodents, the CsCl data question a traditional hypothesis positing Gliridae within Myomorpha, as does the recently sequenced mitochondrial genome of dormouse. Analysis of CsCl profiles is presented here as a rapid, robust method for exploring rodent and other vertebrate systematics.


Translation at higher than an optimal level interferes with coupling at an intercistronic junction.
In pairs of adjacent genes co-transcribed on bacterial polycistronic mRNAs, translation of the first coding region frequently functions as a positive factor to couple translation to the distal coding region. Coupling efficiencies vary over a wide range, but synthesis of both gene products at similar levels is common. We report the results of characterizing an unusual gene pair, in which only about 1% of the translational activity from the upstream gene is transmitted to the distal gene. The inefficient coupling was unexpected because the upstream gene is highly translated, the distal initiation site has weak but intrinsic ability to bind ribosomes, and the AUG is only two nucleotides beyond the stop codon for the upstream gene. The genes are those in the filamentous phage IKe genome, which encode the abundant single-stranded DNA binding protein (gene V) and the minor coat protein that caps one tip of the phage (gene VII). Here, we have used chimeras between the related phage IKe and f1 sequences to localize the region responsible for inefficient coupling. It mapped upstream from the intercistronic region containing the gene V stop codon and the gene VII initiation site, indicating that low coupling efficiency is associated with gene V. The basis for inefficient coupling emerged when coupling efficiency was found to increase as gene V translation was decreased below the high wild-type level. This was achieved by lowering the rate of elongation and by decreasing the efficiency of suppression at an amber codon within the gene. Increasing the strength of the Shine-Dalgarno interaction with 16S rRNA at the gene VII start also increased coupling efficiency substantially. In this gene pair, upstream translation thus functions in an unprecedented way as a negative factor to limit downstream expression. We interpret the results as evidence that translation in excess of an optimal level in an upstream gene interferes with coupling in the intercistronic junction.


The tubercular badger and the uncertain curve:- The need for a multiple stressor approach in environmental radiation protection.
This article presents the results of a workshop held in Stirling, Scotland in June 2018, called to examine critically the effects of low-dose ionising radiation on the ecosphere. The meeting brought together participants from the fields of low- and high-dose radiobiology and those working in radioecology to discuss the effects that low doses of radiation have on non-human biota. In particular, the shape of the low-dose response relationship and the extent to which the effects of low-dose and chronic exposure may be predicted from high dose rate exposures were discussed. It was concluded that high dose effects were not predictive of low dose effects. It followed that the tools presently available were deemed insufficient to reliably predict risk of low dose exposures in ecosystems. The workshop participants agreed on three major recommendations for a path forward. First, as treating radiation as a single or unique stressor was considered insufficient, the development of a multidisciplinary approach is suggested to address key concerns about multiple stressors in the ecosphere. Second, agreed definitions are needed to deal with the multiplicity of factors determining outcome to low dose exposures as a term can have different meanings in different disciplines. Third, appropriate tools need to be developed to deal with the different time, space and organisation level scales. These recommendations permit a more accurate picture of prospective risks.


Commonalities across computational workflows for uncovering explanatory variants in undiagnosed cases.
Genomic sequencing has become an increasingly powerful and relevant tool to be leveraged for the discovery of genetic aberrations underlying rare, Mendelian conditions. Although the computational tools incorporated into diagnostic workflows for this task are continually evolving and improving, we nevertheless sought to investigate commonalities across sequencing processing workflows to reveal consensus and standard practice tools and highlight exploratory analyses where technical and theoretical method improvements would be most impactful. We collected details regarding the computational approaches used by a genetic testing laboratory and 11 clinical research sites in the United States participating in the Undiagnosed Diseases Network via meetings with bioinformaticians, online survey forms, and analyses of internal protocols. We found that tools for processing genomic sequencing data can be grouped into four distinct categories. Whereas well-established practices exist for initial variant calling and quality control steps, there is substantial divergence across sites in later stages for variant prioritization and multimodal data integration, demonstrating a diversity of approaches for solving the most mysterious undiagnosed cases. The largest differences across diagnostic workflows suggest that advances in structural variant detection, noncoding variant interpretation, and integration of additional biomedical data may be especially promising for solving chronically undiagnosed cases.


Inward rectifier potassium channel Kir2.2 is associated with synapse-associated protein SAP97.
The strong inwardly rectifying potassium channels Kir2.x are involved in maintenance and control of cell excitability. Recent studies reveal that the function and localization of ion channels are regulated by interactions with members of the membrane-associated guanylate kinase (MAGUK) protein family. To identify novel interacting MAGUK family members, we constructed GST-fusion proteins with the C termini of Kir2.1, Kir2.2 and Kir2.3. GST affinity-pulldown assays from solubilized rat cerebellum and heart membrane proteins revealed an interaction between all three Kir2.x C-terminal fusion proteins and the MAGUK protein synapse-associated protein 97 (SAP97). A truncated form of the C-terminal GST-Kir2.2 fusion protein indicated that the last three amino acids (S-E-I) are essential for association with SAP97. Affinity interactions using GST-fusion proteins containing the modular domains of SAP97 demonstrate that the second PSD-95/Dlg/ZO-1 (PDZ) domain is sufficient for interaction with Kir2.2. Coimmunoprecipitations demonstrated that endogenous Kir2.2 associates with SAP97 in rat cerebellum and heart. Additionally, phosphorylation of the Kir2.2 C terminus by protein kinase A inhibited the association with SAP97. In rat cardiac ventricular myocytes, Kir2.2 and SAP97 colocalized in striated bands corresponding to T-tubules. In rat cerebellum, Kir2.2 was present in a punctate pattern along SAP97-positive processes of Bergmann glia in the molecular layer, and colocalized with astrocytes and granule cells in the granule cell layer. These results identify a direct association of Kir2.1, Kir2.2 and Kir2.3 with the MAGUK family member SAP97 that may form part of a macromolecular signaling complex in many different tissues.


IntPath--an integrated pathway gene relationship database for model organisms and important pathogens.
Pathway data are important for understanding the relationship between genes, proteins and many other molecules in living organisms. Pathway gene relationships are crucial information for guidance, prediction, reference and assessment in biochemistry, computational biology, and medicine. Many well-established databases--e.g., KEGG, WikiPathways, and BioCyc--are dedicated to collecting pathway data for public access. However, the effectiveness of these databases is hindered by issues such as incompatible data formats, inconsistent molecular representations, inconsistent molecular relationship representations, inconsistent referrals to pathway names, and incomprehensive data from different databases. In this paper, we overcome these issues through extraction, normalization and integration of pathway data from several major public databases (KEGG, WikiPathways, BioCyc, etc). We build a database that not only hosts our integrated pathway gene relationship data for public access but also maintains the necessary updates in the long run. This public repository is named IntPath (Integrated Pathway gene relationship database for model organisms and important pathogens). Four organisms--S. cerevisiae, M. tuberculosis H37Rv, H. Sapiens and M. musculus--are included in this version (V2.0) of IntPath. IntPath uses the "full unification" approach to ensure no deletion and no introduced noise in this process. Therefore, IntPath contains much richer pathway-gene and pathway-gene pair relationships and much larger number of non-redundant genes and gene pairs than any of the single-source databases. The gene relationships of each gene (measured by average node degree) per pathway are significantly richer. The gene relationships in each pathway (measured by average number of gene pairs per pathway) are also considerably richer in the integrated pathways. Moderate manual curation are involved to get rid of errors and noises from source data (e.g., the gene ID errors in WikiPathways and relationship errors in KEGG). We turn complicated and incompatible xml data formats and inconsistent gene and gene relationship representations from different source databases into normalized and unified pathway-gene and pathway-gene pair relationships neatly recorded in simple tab-delimited text format and MySQL tables, which facilitates convenient automatic computation and large-scale referencing in many related studies. IntPath data can be downloaded in text format or MySQL dump. IntPath data can also be retrieved and analyzed conveniently through web service by local programs or through web interface by mouse clicks. Several useful analysis tools are also provided in IntPath. We have overcome in IntPath the issues of compatibility, consistency, and comprehensiveness that often hamper effective use of pathway databases. We have included four organisms in the current release of IntPath. Our methodology and programs described in this work can be easily applied to other organisms; and we will include more model organisms and important pathogens in future releases of IntPath. IntPath maintains regular updates and is freely available at http://compbio.ddns.comp.nus.edu.sg:8080/IntPath.


A normative database of lumbar spine ranges of motion.
The overall aim of the work was to develop a comprehensive normative database of indices for ranges of motion in the lumbar spine, in an asymptomatic sample of the general population. This was a repeated measures prospective study utilizing a reliable and valid instrument, the modified CA6000 Spine Motion Analyzer (Orthopedic Systems Inc. Union City CA & Troke/University of Brighton). The portable equipment was used to collect data in a variety of community settings (e.g. schools, GP surgeries, offices, leisure centres, emergency services stations). A total of 405 asymptomatic subjects (196 female, 209 male) aged 16-90 yr from sedentary, mixed and physically demanding occupations participated in the study and data were collected in standing, at different times of the day, following a standardized methodology for lumbar spine motion in the sagittal, coronal and horizontal planes. Age-related centile graphs were derived separately for male and female subjects in flexion, extension, left and right lateral flexion and left and right axial rotation. All 12 graphs are presented as an appendix located on the Manual Therapy website. Overall, flexion (73-40 degrees) and lateral flexion (28-14 degrees, L&R) declined 45% and 48%, respectively, across the age range. Extension (29-6 degrees) declined the greatest at 79%. By contrast, no overall decline in axial rotational RoMs was recorded, and the median RoM remained at 7 degrees each way across the age spectrum examined. A comprehensive database of indices of lumbar spine ranges of motion has thus been developed which is gender specific, age related, drawn from a wide age range and presents data for all three planes of motion. It is considered that the new database has a number of potential clinical and research applications.


Interferon-gamma induces human vascular smooth muscle cell proliferation and intimal expansion by phosphatidylinositol 3-kinase dependent mammalian target of rapamycin raptor complex 1 activation.
Interferon (IFN)-gamma, a cytokine characteristically expressed in arteriosclerotic diseases, acts directly on vascular smooth muscle cells to induce cellular proliferation and intimal expansion. Signaling by the mammalian target of rapamycin raptor complex, known as mTORC1, is associated with cell growth and is active within arteriosclerotic lesions but is not known to be triggered by proinflammatory factors in vascular smooth muscle cells. We investigated the mechanisms for the proarteriosclerotic effects of IFN-gamma in the absence of leukocytes by exploiting the species specificity of this cytokine in a chimeric model of immunodeficient mouse recipients bearing human coronary artery grafts and intravenously inoculated with adenovirus encoding a human IFN-gamma transgene. We found that IFN-gamma-mediated vascular smooth muscle cell proliferation and intimal expansion were associated with phosphorylation of the mTORC1 effector ribosomal protein S6 kinase 1, that the graft morphological changes and S6 kinase 1 activation were inhibited by the mTORC1 inhibitor rapamycin in vivo, and that IFN-gamma-induced mTORC1 signaling was dependent on phosphatidylinositol 3-kinase activity under serum-free conditions in vitro. Our work establishes an immunologic stimulus for mTORC1 signaling in vascular smooth muscle cells, emphasizes that mTORC1 activation is critical in immune-mediated vascular remodeling, and provides further mechanistic insight into the successful clinical application of rapamycin therapy for atherosclerosis and graft arteriosclerosis.


Optimization-based design of surface textures for thin-film Si solar cells.
We numerically investigate the light-absorption behavior of thin-film silicon for normal-incident light, using surface textures to enhance absorption. We consider a variety of texture designs, such as simple periodic gratings and commercial random textures, and examine arbitrary irregular periodic textures designed by multi-parameter optimization. Deep and high-index-contrast textures exhibit strong anisotropic scattering that is outside the regime of validity of the Lambertian models commonly used to describe texture-induced absorption enhancement for normal incidence. Over a 900-1100 nm wavelength range, our optimized surface texture in two dimensions (2D) enhances absorption by a factor of 2.7 πn, considerably larger than the original πn Lambertian result and exceeding by almost 50% a recent generalization of Lambertian model for periodic structures in finite spectral range. However, the πn Lambertian limit still applies for isotropic incident light, and our structure obeys this limit when averaged over all the angles. Therefore, our design can be thought of optimizing the angle/enhancement tradeoff for periodic textures.


Imbalance in Cardiovascular Surgery Medical Service Use Between Regions.
This study uses the relevance index to understand the condition of regional medical service use for cardiovascular surgery and to identify the medical service use imbalance between regions. This study calculated the relevance index of 16 metropolitan cities and provinces using resident registration address data from the Ministry of Government Administration and Home Affairs and the 2010-2014 health insurance, medical care assistance, and medical benefits claims data from the Health Insurance Review and Assessment Service. We identified developments over the 5-year time period and analyzed the level of regional imbalance regarding cardiovascular surgery through the relative comparison of relevance indexes between cardiovascular and other types of surgery. The relevance index was high in large cities such as Seoul, Daegu, and Gwangju, but low in regions that were geographically far from the capital area, such as the Gangwon and Jeju areas. Relevance indexes also fell as the years passed. Cardiovascular surgery has a relatively low relevance index compared to key types of surgery of other fields, such as neurosurgery and colorectal surgery. This study identified medical service use imbalance between regions for cardiovascular surgery. Results of this study demonstrate the need for political intervention to enhance the accessibility of necessary special treatment, such as cardiovascular surgery.


Impact of repeated methamphetamine pretreatment on intravenous self-administration of the drug in males and estrogenized or non- estrogenized ovariectomized female rats.
The female animals were already recorded to respond differently to methamphetamine (MET) abuse than males. This gender dissimilarity may be caused by the influence of estral cycles and different susceptibility to behavioural sensitization. Influences of gender and pre-exposure to MET were studied in the rat model of MET intravenous self-administration (IVSA). The fixed ratio (FR) paradigm was employed in male rats (M) and estrogenized (F-ESTR) and non-estrogenized ovariectomized female rats (F-OVX) either pre-exposed or not-exposed to MET pretreatment. In rats that were not pre-exposed to MET, F-ESTR self-administered more MET infusions than each of the other groups, but F-OVX self-administered less than each of the other groups; the same trend was apparent in the MET pretreated groups. MET pre-exposure decreased subsequent MET IVSA in all groups except F-OVX. Thus, pre-exposure to MET and the loss of inherent estrogen in females notably decreased the intake of MET by rats, suggesting that abuse liability was reduced. Estrogen's effects on MET self-administration here correspond with accumulating evidence of stronger behavioural responses of females to drugs of abuse.


Diagnostic utility of bone marrow sampling in HIV-infected patients since the advent of highly active antiretroviral therapy.
We investigated the diagnostic value of bone marrow (BM) sampling in investigation of HIV-infected patients presenting to a major London HIV treatment centre between 1999 and 2004. One hundred and fourteen consecutive patients underwent 130 BM samplings. The majority of BM aspirates were normal or showed non-diagnostic changes; microscopy revealed lymphoma in one and mycobacterial infection in two. Subsequent culture identified mycobacterial infection in nine samples. BM trephine had a diagnostic yield of 26% in patients with fever and cytopaenia (including mycobacteriosis in 14%, lymphoma in 6%, Castleman disease in 3% and "drug effect" in 3%), a yield of 20% in patients with fever, but no cytopaenia (mycobacteriosis in each case), and a yield of 19% in patients with cytopaenia in the absence of fever (lymphoma in 5% and "drug effect" in 14%). In investigation/staging of lymphoma, the diagnostic yield was 36%. The overall yield from BM sampling was 30% in patients receiving highly active antiretroviral therapy (HAART) and 23% in those not receiving HAART. In this study, BM sampling was of most diagnostic value in HIV-infected patients where fever and cytopaenia coexisted in the absence of localizing signs of infection, and in the staging/investigation of lymphoma. BM sampling had less diagnostic value in the investigation of fever without cytopaenia or cytopaenia without fever.


Topology vs. thermodynamics in chemical reactions: the instability of PH5.
The topological approach, based on Bader theory, is compared to the common thermodynamical methodology to study chemical reactivity. It is shown how the former indeed has numerous advantages and provides a more detailed description with respect to the latter about the course of the reaction. The comparison between the two approaches is performed by considering a classical reaction, i.e. the decomposition of PX5 (X = H, F). The topological investigation was supported by using different state-of-the-art topological tools, such as the source function, Espinosa indexes, delocalisation indexes, and domain-averaged Fermi hole analysis. Furthermore, in this work a new topological descriptor, the Bader energy density, PBADER, is introduced and applied to the study case. For the first time since Bader theory was introduced, the distribution of atomic energies in the atomic basins was analysed in detail and used to explain the chemical reactivity a priori.


Physical stability of a microcrystalline beta-sitosterol suspension in oil.
Sterols have been shown to reduce plasma cholesterol by blocking the absorption of cholesterol from the gut. The physical properties of crystalline plant sterols limit their use in foods. A coarse-grained structure can be avoided by recrystallisation, a method that affords a reduction in the particle size. A previous work described how to produce a microcrystalline beta-sitosterol suspension. The present study deals with the stability of that suspension. Recrystallisation was carried out by two different methods; one based on rapid the other based on slow cooling, whereby six different compositions were made containing 5-30% of beta-sitosterol and secondly either 5 or 20% water was added. The particle size and habit were evaluated during a 16 weeks storage period (+4 or -19 degrees C) by way of optical microscopy. The crystal structure and degree of crystallinity was analysed by X-ray diffraction. Suspensions can, in most cases, be stored for 16 weeks without any changes to the size and habit. The only evidence of crystal growth came from a suspension with a low sterol concentration at a temperature of +4 degrees C. This is due to the dissolution-diffusion process which is affected by temperature and viscosity. Suspensions containing higher amounts of sterol remained stable, if stored at +4 or -19 degrees C, for 16 weeks. The suspensions included both hemihydrous and monohydrous beta-sitosterol crystals. Suspensions containing less sterol showed greater amounts of monohydrated crystals. This illustrates more water penetration into the crystals. A higher sterol concentration led to a larger number of smaller crystals creating reflections similar to hemihydrated crystals.


Association of Elevated Amyloid Levels With Cognition and Biomarkers in Cognitively Normal People From the Community.
The role of amyloid in the progression of Alzheimer disease (AD) pathophysiology is of central interest to the design of randomized clinical trials. The presence of amyloid has become a prerequisite for enrollment in several secondary prevention trials for AD, yet the precise effect of elevated amyloid levels on subsequent clinical and biomarker events is less certain. To explore the effect of elevated amyloid levels on subsequent changes in cognition and biomarkers. A total of 564 cognitively normal individuals (median age, 78 years) from the Mayo Clinic Study of Aging, a population-based longitudinal study in Olmsted County, Minnesota, with serial cognitive data were selected for this study. The data used in this study were collected from January 12, 2006, to January 9, 2014. Individuals included in this study had undergone magnetic resonance imaging, fluorodeoxyglucose positron emission tomography (FDG-PET), and Pittsburgh Compound B (PiB) PET at baseline were not cognitively impaired at baseline and had at least 1 clinical follow-up. A subset of 286 individuals also underwent serial imaging. Elevated amyloid level was defined as a standardized uptake value ratio of greater than 1.5 on PiB PET. Associations with baseline amyloid status and baseline and longitudinal change in clinical and imaging measures were evaluated after adjusting for age and hippocampal volume. APOE4 effects were also evaluated. Cognitive measures of memory, language, attention/executive function, visuospatial skills, PiB levels, hippocampal and ventricular volumes, and FDG-PET measures. At baseline, 179 (31.7%) individuals with elevated amyloid levels had poorer cognition in all domains measured, reduced hippocampal volume, and greater FDG-PET hypometabolism. Elevated amyloid levels at baseline were associated with a greater rate of cognitive decline in all domains (0.04 to 0.09 z score units per year) except language and a greater rate of amyloid accumulation (1.6% per year), hippocampal atrophy (30 mm3 per year), and ventricular enlargement (565 mm3 per year). Elevated amyloid levels were also associated with an increased risk of mild cognitive impairment (hazard ratio, 2.9; 95% CI, 1.7-5.0, and hazard ratio, 1.6; 95% CI, 0.9-2.8, for PiB+ APOE4 carriers and PiB+ noncarriers, respectively, compared with PiB- noncarriers). These associations were largely independent of APOE4. In persons selected from a population-based study, elevated amyloid levels at baseline were associated with worse cognition and imaging biomarkers at baseline and with greater clinical decline and neurodegeneration. These results have implications for the design of randomized clinical trials for AD.


The impact of first-generation biofuels on the depletion of the global phosphorus reserve.
The large majority of biofuels to date is "first-generation" biofuel made from agricultural commodities. All first-generation biofuel production systems require phosphorus (P) fertilization. P is an essential plant nutrient, yet global reserves are finite. We argue that committing scarce P to biofuel production involves a trade-off between climate change mitigation and future food production. We examine biofuel production from seven types of feedstock, and find that biofuels at present consume around 2% of the global inorganic P fertilizer production. For all examined biofuels, with the possible exception of sugarcane, the contribution to P depletion exceeds the contribution to mitigating climate change. The relative benefits of biofuels can be increased through enhanced recycling of P, but high increases in P efficiency are required to balance climate change mitigation and P depletion impacts. We conclude that, with the current production systems, the production of first-generation biofuels compromises food production in the future.


Excisional treatment in women with cervical adenocarcinoma in situ (AIS): a prospective randomised controlled non-inferiority trial to compare AIS persistence/recurrence after loop electrosurgical excision procedure with cold knife cone biopsy: protocol for a pilot study.
Adenocarcinoma in situ (AIS) of the uterine cervix is the precursor to invasive endocervical adenocarcinoma. An excisional biopsy such as a cold knife cone biopsy (CKC) should be performed to exclude invasive adenocarcinoma. Loop electrosurgical excision procedure (LEEP) is an alternative modality to CKC but is controversial in AIS. There is a perception that there is a greater likelihood of incomplete excision of AIS with LEEP because the depth of excised tissue tends to be smaller and the tissue margins may show thermal artefact which can interfere with pathology assessment. In the USA, guidelines recommend that any treatment modality can be used to excise AIS, provided that the specimen remains intact with interpretable margins. However, there are no high-quality studies comparing LEEP with CKC and well-designed prospective studies are needed. If such a study were to show that LEEP was non-inferior to CKC for the outcomes of post-treatment persistence, recurrence and adenocarcinoma, LEEP could be recommended as an appropriate treatment option for AIS in selected patients. This would benefit women because, unlike CKC, LEEP does not require general anaesthesia and may be associated with reduced morbidity. The proposed exploratory study is a parallel group trial with an allocation ratio of 2:1 in favour of the intervention (LEEP: CKC). Participants are women aged ≥18 to ≤45 years diagnosed with AIS on cervical screening and/or colposcopically directed biopsy in Australia and New Zealand, who are to receive excisional treatment in a tertiary level centre. Ethical approval for the study has been granted by the St John of God Healthcare Human Research Ethics Committee (reference number #1137). Results from the study will be presented at conferences and published in a peer-reviewed scientific journal. ANZCTR registration number ACTRN12617000132347 https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=372173&isReview=true.


Probiotic supplementation in diabetic hemodialysis patients has beneficial metabolic effects.
This study determined the effects of probiotic supplementation on glycemic control, lipid concentrations, biomarkers of inflammation and oxidative stress in 60 diabetic patients on hemodialysis in a parallel randomized double-blind placebo-controlled clinical trial. Participants were initially matched based on sex, duration of dialysis and diabetes, body mass index and age. Subsequently, they were randomly divided into two groups to take either a capsule containing the probiotics Lactobacillus acidophilus, Lactobacillus casei and Bifidobacterium bifidum or placebo for 12 weeks. Based on three-day dietary records throughout the trial, there was no significant change in dietary macro- and micro-nutrients or total dietary fiber to confound results. After the 12 weeks, analysis of patients who received probiotic supplements compared with the placebo showed they had significantly decreased fasting plasma glucose (-22.0 vs. +6.6 mg/dl), serum insulin (-6.4 vs. +2.3 μIU/ml), homeostasis model of assessment-estimated insulin resistance (-2.9 vs. +2.5), homeostasis model of assessment-estimated beta-cell function (-14.1 vs. +6.1) and HbA1c (-0.4 vs. -0.1%,), and improved quantitative insulin sensitivity check index (+0.03 vs. -0.02). Additionally, compared with the placebo, probiotic supplementation resulted in significant reductions in serum high-sensitivity C-reactive protein (-1933 vs. +252 ng/ml), plasma malondialdehyde (-0.3 vs. +1.0 μmol/l), subjective global assessment scores (-0.7 vs. +0.7) and total iron binding capacity (-230 vs. +33 μg/dl), and a significant increase in plasma total antioxidant capacity (+15 vs. -88 mmol/l). Thus, probiotic supplementation for 12 weeks among diabetic hemodialysis patients had beneficial effects on parameters of glucose homeostasis, and some biomarkers of inflammation and oxidative stress.


Choline metabolism provides novel insights into nonalcoholic fatty liver disease and its progression.
Choline is an essential nutrient and the liver is a central organ responsible for choline metabolism. Hepatosteatosis and liver cell death occur when humans are deprived of choline. In the last few years, there have been significant advances in our understanding of the mechanisms that influence choline requirements in humans and in our understanding of choline's effects on liver function. These advances are useful in elucidating why nonalcoholic fatty liver disease (NAFLD) occurs and progresses sometimes to hepatocarcinogenesis. Humans eating low-choline diets develop fatty liver and liver damage. This dietary requirement for choline is modulated by estrogen and by single-nucleotide polymorphisms in specific genes of choline and folate metabolism. The spectrum of choline's effects on liver range from steatosis to development of hepatocarcinomas, and several mechanisms for these effects have been identified. They include abnormal phospholipid synthesis, defects in lipoprotein secretion, oxidative damage caused by mitochondrial dysfunction, and endoplasmic reticulum stress. Furthermore, the hepatic steatosis phenotype can be characterized more fully via metabolomic signatures and is influenced by the gut microbiome. Importantly, the intricate connection between liver function, one-carbon metabolism, and energy metabolism is just beginning to be elucidated. Choline influences liver function, and the dietary requirement for this nutrient varies depending on an individual's genotype and estrogen status. Understanding these individual differences is important for gastroenterologists seeking to understand why some individuals develop NAFLD and others do not, and why some patients tolerate total parenteral nutrition and others develop liver dysfunction.


Characterization of Age-Related Injury Patterns and Surgical Treatment of Pediatric Facial Fractures: Analysis of the National Trauma Data Bank.
Presentation of pediatric facial fractures varies widely and many injuries are encountered infrequently by most practitioners. This study summarizes injury patterns in a large cohort of facial fractures and their subsequent surgical management. Demographic and clinical characteristics of patients 18 years of age or younger admitted between 2009 and 2015 to trauma centers participating in the National Trauma Data Bank were examined. Craniofacial fractures and reconstructive procedures performed at index admission were selected based on ICD-9 and AIS codes. A multivariable analysis was used to determine independent determinants of surgical repair. Out of 60,094 pediatric patients evaluated in the US emergency departments, 48,821 patients were admitted and underwent open treatment (n = 8364; 17.1%) or closed treatment (n = 4244; 8.7%) of facial fractures. Falls were the most common mechanism of injury in infants and toddlers (<2-year-old, 44.4%, P <0.001), while motor vehicle collisions (32.9%, P <0.001) and assault (22.1%, P <0.001) were most commonly seen in adolescents (12-18-year-old). The frequency and odds of repair of facial fractures increased with advancing age, more so with open than closed treatment in adolescents (73.0%) as compared to infants and toddlers (50.3%). Children who sustained mandible fractures are the most likely to require surgical treatment at index-admission (odds ratio = 13.9, 95% confidence interval 13.1-14.8, P <0.001). Population-based data shows that pediatric fracture patterns and associated early repair vary significantly with age. Patient demographics and hospital characteristics are significant determinants of surgical treatment that should be related to clinical outcomes in future studies.


Molecular mechanisms underlying the α-tomatine-directed apoptosis in human malignant glioblastoma cell lines A172 and U-118 MG.
In the present study, the molecular mechanisms involved in the α-tomatine-induced apoptosis in human glioblastoma cell lines A172 and U-118 MG were investigated. Wright staining and ApopTag assays were conducted to confirm the apoptosis induced by α-tomatine treatment. Fura-2 assay determined an enhancement in free Ca2+ intracellularly, indicating the occurrence of Ca2+-dependent apoptosis induction. Western blot experiments were also performed to predict the apoptosis by measuring the changes in the Bax:Bcl-2 ratio. Increase of calpain activity triggered caspase-12 expression, which in turn further activated caspase-9. In addition, an increase in the ratio of Bax:Bcl-2 accounted for the mitochondrial release of cytochrome c into the cytosol for caspase-3 and caspase-9 activation. Elevated activity of calpain and caspase-3 yielded spectrin breakdown products with 145 and 120 kDa, respectively. Caspase-3 activation further cleaved the inhibitor of caspase activated DNase, while the apoptosis-inducing factor detected in the cytosol suggested that apoptosis was independent of caspase. The apoptosis induction was further supported by decreased expression levels of nuclear factor-κB and increased expression of the inhibitor of nuclear factor, IκBα. In conclusion, the presented experimental results revealed the stimulation of different molecular mechanisms for α-tomatine-mediated apoptosis in A172 and U-118 MG human glioblastoma cell lines.


Validation of a new open-source method for automatic delineation and dose assessment of the heart and LADCA in breast radiotherapy with simultaneous uncertainty estimation.
Radiotherapy has been shown to increase risks of cardiotoxicities for breast cancer patients. Automated delineation approaches are necessary for consistent and efficient assessment of cardiac doses in large, retrospective datasets, while patient-specific estimation of the uncertainty in these doses provides valuable additional data for modelling and understanding risks. In this work, we aim to validate the consistency of our previously described open-source software model for automatic cardiac delineation in the context of dose assessment, relative to manual contouring. We also extend our software to introduce a novel method to automatically quantify the uncertainty in cardiac doses based on expected inter-observer variability (IOV) in contouring. This method was applied to a cohort of 15 left-sided breast cancer patients treated in Denmark using modern tangential radiotherapy techniques. On each image set, the whole heart and left anterior descending coronary artery (LADCA) were contoured by nine independent experts; the range of doses to these nine volumes provided a reference for the dose uncertainties generated from the automatic method. Local and external atlas sets were used to test the method. Results give confidence in the consistency of automatic segmentations, with mean whole heart dose differences for local and external atlas sets of -0.20 ± 0.17 and -0.10 ± 0.14 Gy, respectively. Automatic estimates of uncertainties in doses are similar to those from IOV for both the whole heart and LADCA. Overall, this study confirms that our automated approach can be used to accurately assess cardiac doses, and the proposed method can provide a useful tool in estimating dose uncertainties.


A gonococcal porA pseudogene: implications for understanding the evolution and pathogenicity of Neisseria gonorrhoeae.
Members of the genus Neisseria, including the human pathogens Neisseria meningitidis and Neisseria gonorrhoeae, express at least one member of a family of related porins. N. meningitidis is the only species known to express a second porin, the meningococcal serosubtyping antigen PorA, the most divergent member of this family. Unexpectedly, a porA gene was identified in the gonococcal genome. Both the gonococcal and meningococcal porA loci were adjacent to a homologue of the Escherichia coli greA gene, although the IS1106 element downstream of porA in some meningococci was absent in the gonococcus. Almost identical porA loci were present in four unrelated gonococcal isolates and clinical specimens from patients with gonorrhoea. Lack of PorA expression in the gonococcus resulted from mutations in the promoter region, which prevented transcription, and frameshift mutations in the coding region of the porA gene. Hybridization and amplification experiments, showing the absence of a porA gene in seven other Neisseria species, suggested that porA was acquired by a common ancestor of the gonococcus and meningococcus but inactivated in the gonococcus on speciation. This implies that, while advantageous during colonization of the upper respiratory tract, this protein has no function in, or hinders, colonization of the urogenital tract.


Synthetic low-density lipoprotein, a novel biomimetic lipid supplement for serum-free tissue culture.
Lipid supplementation in serum-free tissue culture employs solubilization techniques to permit the addition of lipids, but these systems are potentially cytotoxic and do not present lipid in a natural form. In this research a simplified preparation method for synthetic low-density lipoprotein (sLDL) has been developed that involves microfluidization of a solvent lipid solution in a simple aqueous solution. This produces material with size and zeta potential characteristics similar to those of native LDL. sLDL supplementation in tissue culture media provides cholesterol concentrations higher than those achieved by 10% serum supplementation and existing chemically defined lipid supplements. sLDL stimulates NS0 and U937 cellular proliferation in completely serum-free media, the former in a lipid concentration dependent manner that is also related to both the receptor peptide structure employed and its concentration on the particle. The greatest NS0 cellular proliferation was obtained at the highest cholesterol concentration tested (0.5 mg/mL), which was 10 times higher than the cholesterol concentration achieved by standard 10% serum supplementation. U937 cellular proliferation was influenced by variation of sLDL's fatty acid constituents with a natural mixture producing maximal effect. Cell uptake studies in NS0 with fluorescently labeled sLDL indicated that assimilation is reduced by competition from native LDL. The planktonic nature of NS0 cell growth meant that cell binding and uptake experiments were difficult to conduct because of cellular aggregation. However, sLDL-induced U937 proliferation is ablated by the presence of an anti-LDL receptor antibody. The results indicate that sLDL uptake is via the LDL receptor and that sLDL can function as a lipid supplement for serum-free media capable of supplementation to cholesterol concentrations up to 0.5 mg/mL. Cellular uptake studies also suggest that sLDL will be useful for the targeting and delivery of materials to cells. sLDL therefore represents a new and promising synthetic biomimetic alternative to native LDL with multiple applications.


Willingness and ability to pay for unexpected dental expenses by Finnish adults.
Since 2002, adults have been able to choose oral health care services in the public sector or in the private sector in Finland. Though various subsidies for care exist in both sectors, the Public Dental Service (PDS) is a cheaper option for the patient but, on the other hand, there are no waiting lists for private care. The aim of this study was to assess middle-aged adults' use of dental services, willingness to pay (WTP) and ability to pay (ATP) for unexpected, urgent dental treatment. Postal questionnaires on use of dental services were sent to a random sample of 1500 47-59 year old adults living in three large municipalities in the Helsinki region. The initial response rate was 65.8%. Two hypothetical scenarios were presented: "What would be the highest price you would be prepared to pay to have a lost filling replaced immediately, or, at the latest, the day after losing the filling?" and " How much could you pay for unexpected dental expenses at two weeks notice, if you suddenly needed more comprehensive treatment?" Logistic regression analysis was used to analyse factors related to WTP and ATP. Most respondents (89.6%) had visited a dentist recently and a majority (76.1%) had used private services. For immediate replacement of a lost filling, almost all respondents (93.2%) were willing to pay the lower price charged in the PDS and 46.2% were willing to pay the private fee. High income and no subjective need for dental treatment were positively associated with the probability of paying a higher price. Most respondents (93.0%) were able to pay a low fee, EUR 50 and almost half (41.6%) at least EUR 300 for unexpected treatment at short notice. High income and male sex were associated with high ATP. There was a strong and statistically significant relationship between income and WTP and ATP for urgent dental care, indicating that access to publicly provided services improved equity for persons with low income.


Role of a defunctioning stoma in the management of large bowel Crohn's disease.
The faecal stream plays a significant role in the pathogenesis of Crohn's disease. This retrospective study aimed to assess the effect of faecal diversion on the natural history of refractory Crohn's colitis (RCC) and severe perianal disease (PAD). All patients undergoing a defunctioning stoma without resection for RCC or PAD between 1970 and 1997 were studied. Indications for surgery, acute clinical response, subsequent outcome and stoma rates were recorded. Some 73 patients underwent a defunctioning stoma (55 RCC and 18 PAD). Acute remission was achieved in 63 patients (48 RCC, 15 PAD). Twenty-nine patients had subsequent closure of the defunctioning stoma (25 of 48 acute responders with RCC and four of 15 acute responders with PAD). Eleven patients with RCC and two with PAD achieved good long-term function without disease relapse (median follow-up 36 months). Overall 52 patients have undergone proctocolectomy or remain with a defunctioning stoma (37 with RCC and 15 with PAD). Faecal diversion is associated with acute clinical remission in the majority of patients with RCC and PAD, but sustained benefit occurs less often. For selected patients, diversionary surgery alone offers a realistic alternative to major bowel resection.


Endothelial and Inflammation Biomarker Profiles at Diagnosis Reflecting Clinical Heterogeneity and Serving as a Prognostic Tool for Treatment Response in Two Independent Cohorts of Patients With Juvenile Dermatomyositis.
Juvenile dermatomyositis (DM) is a heterogeneous systemic immune-mediated vasculopathy. This study was undertaken to 1) identify inflammation/endothelial dysfunction-related biomarker profiles reflecting disease severity at diagnosis, and 2) establish whether such biomarker profiles could be used for predicting the response to treatment in patients with juvenile DM. In total, 39 biomarkers related to activation of endothelial cells, endothelial dysfunction, and inflammation were measured using multiplex technology in serum samples from treatment-naive patients with juvenile DM from 2 independent cohorts (n = 30 and n = 29). Data were analyzed by unsupervised hierarchical clustering, nonparametric tests with correction for multiple comparisons, and Kaplan-Meier tests with Cox proportional hazards models for analysis of treatment duration. Myositis-specific antibodies (MSAs) were measured in the patients' serum using line blot assays. Severe vasculopathy in patients with juvenile DM was associated with low serum levels of intercellular adhesion molecule 1 (Spearman's rho [rs ] = 0.465, P = 0.0111) and high serum levels of endoglin (rs = -0.67, P < 0.0001). In the discovery cohort, unsupervised hierarchical clustering analysis of the biomarker profiles yielded 2 distinct patient clusters, of which the smaller cluster (cluster 1; n = 8) exhibited high serum levels of CXCL13, CCL19, galectin-9, CXCL10, tumor necrosis factor receptor type II (TNFRII), and galectin-1 (false discovery rate <0.0001), and this cluster had greater severity of muscle disease and global disease activity (each P < 0.05 versus cluster 2). In the validation cohort, correlations between the serum levels of galectin-9, CXCL10, TNFRII, and galectin-1 and the severity of global disease activity were confirmed (rs = 0.40-0.52, P < 0.05). Stratification of patients according to the 4 confirmed biomarkers identified a cluster of patients with severe symptoms (comprising 64.7% of patients) who were considered at high risk of requiring more intensive treatment in the first 3 months after diagnosis (P = 0.0437 versus other cluster). Moreover, high serum levels of galectin-9, CXCL10, and TNFRII were predictive of a longer total treatment duration (P < 0.05). The biomarker-based clusters were not evidently correlated with patients' MSA serotypes. Results of this study confirm the heterogeneity of new-onset juvenile DM based on serum biomarker profiles. Patients with high serum levels of galectin-9, CXCL10, TNFRII, and galectin-1 may respond suboptimally to conventional treatment, and may therefore benefit from more intensive monitoring and/or treatment.