Over-expression of Thioredoxin-1 mediates growth, survival, and chemoresistance and is a druggable target in diffuse large B-cell lymphoma.
Diffuse Large B cell lymphomas (DLBCL) are the most prevalent of the non-Hodgkin lymphomas and are currently initially treated fairly successfully, but frequently relapse as refractory disease, resulting in poor salvage therapy options and short survival. The greatest challenge in improving survival of DLBCL patients is overcoming chemo-resistance, whose basis is poorly understood. Among the potential mediators of DLBCL chemo-resistance is the thioredxoin (Trx) family, primarily because Trx family members play critical roles in the regulation of cellular redox homeostasis, and recent studies have indicated that dysregulated redox homeostasis also plays a key role in chemoresistance. In this study, we showed that most of the DLBCL-derived cell lines and primary DLBCL cells express higher basal levels of Trx-1 than normal B cells and that Trx-1 expression level is associated with decreased patients survival. Our functional studies showed that inhibition of Trx-1 by small interfering RNA or a Trx-1 inhibitor (PX-12) inhibited DLBCL cell growth, clonogenicity, and also sensitized DLBCL cells to doxorubicin-induced cell growth inhibition in vitro. These results indicate that Trx-1 plays a key role in cell growth and survival, as well as chemoresistance, and is a potential target to overcome drug resistance in relapsed/refractory DLBCL.


Untangling social-ecological interactions: A methods portfolio approach to tackling contemporary sustainability challenges in fisheries.
Meeting the objectives of sustainable fisheries management requires attention to the complex interactions between humans, institutions and ecosystems that give rise to fishery outcomes. Traditional approaches to studying fisheries often do not fully capture, nor focus on these complex interactions between people and ecosystems. Despite advances in the scope and scale of interactions encompassed by more holistic methods, for example ecosystem-based fisheries management approaches, no single method can adequately capture the complexity of human-nature interactions. Approaches that combine quantitative and qualitative analytical approaches are necessary to generate a deeper understanding of these interactions and illuminate pathways to address fisheries sustainability challenges. However, combining methods is inherently challenging and requires understanding multiple methods from different, often disciplinarily distinct origins, demanding reflexivity of the researchers involved. Social-ecological systems' research has a history of utilising combinations of methods across the social and ecological realms to account for spatial and temporal dynamics, uncertainty and feedbacks that are key components of fisheries. We describe several categories of analytical methods (statistical modelling, network analysis, dynamic modelling, qualitative analysis and controlled behavioural experiments) and highlight their applications in fisheries research, strengths and limitations, data needs and overall objectives. We then discuss important considerations of a methods portfolio development process, including reflexivity, epistemological and ontological concerns and illustrate these considerations via three case studies. We show that, by expanding their methods portfolios, researchers will be better equipped to study the complex interactions shaping fisheries and contribute to solutions for sustainable fisheries management.


Development and validation of the PROcedural Sedation Assessment Survey (PROSAS) for assessment of procedural sedation quality.
More than 20 million invasive procedures are performed annually in the United States. The vast majority are performed with moderate sedation or deep sedation, yet there is limited understanding of the drivers of sedation quality and patient satisfaction. Currently, the major gap in quality assurance for invasive procedures is the lack of procedural sedation quality measures. To develop and validate a robust, patient-centered measure of procedural sedation quality, the PROcedural Sedation Assessment Survey (PROSAS). Through a series of interviews with patients, proceduralists, nurses, anesthesiologists, and an interactive patient focus group, major domains influencing procedural sedation quality were used to create a multipart survey. The pilot survey was administered and revised in sequential cohorts of adults receiving moderate sedation for GI endoscopy. After revision, the PROSAS was administered to a validation cohort. GI endoscopy unit. A expert panel of proceduralists, nurses, and anesthesiologists, an initial survey development cohort of 40 patients, and a validation cohort of 858 patients undergoing sedation for outpatient GI endoscopy with additional surveys completed by the gastroenterologist, procedure nurse, and recovery nurse. Survey characteristics of the PROSAS. Patients were able to independently complete the PROSAS after procedural sedation before discharge. Of the patients, 91.6% reported minimal discomfort; however, 8.4% of patients reported significant discomfort and 2.4% of patients experienced hemodynamic and/or respiratory instability. There was a high correlation between patient-reported intraprocedure discomfort and both clinician assessments of procedural discomfort and patient recall of procedural pain 24 to 48 hours post procedure (P < .001 for all), suggesting high external validity. Single-center study, variability of sedation technique between providers, inclusion of patients with chronic pain taking analgesics. The PROSAS is a clinically relevant, patient-centered, easily administered instrument that allows for standardized evaluation of procedural sedation quality. The PROSAS may be useful in both research and clinical settings.


PrP genotypes of captive and free-ranging Rocky Mountain elk (Cervus elaphus nelsoni) with chronic wasting disease.
The PrP gene encodes the putative causative agent of the transmissible spongiform encephalopathies (TSEs), a heterogeneous group of fatal, neurodegenerative disorders including human Creutzfeldt-Jakob disease, bovine spongiform encephalopathy, ovine scrapie and chronic wasting disease (CWD) of North American deer and elk. Polymorphisms in the PrP gene are associated with variations in relative susceptibility, pathological lesion patterns, incubation times and clinical course of TSEs of humans, mice and sheep. Sequence analysis of the PrP gene from Rocky Mountain elk showed only one amino acid change (Met to Leu at cervid codon 132). Homozygosity for Met at the corresponding polymorphic site (Met to Val) in humans (human codon 129) predisposes exposed individuals to some forms of Creutzfeldt-Jakob disease. In this study, Rocky Mountain elk homozygous for PrP codon 1 32 Met were over-represented in both free-ranging and farm-raised CWD-affected elk when compared to unaffected control groups.


Effect of intradialytic exercise on echocardiographic findings in hemodialysis patients.
Cardiovascular disease is the major cause of death in hemodialysis patients. Regular aerobic or intradialytic exercise may play a role in reducing cardiovascular mortality in these patients. The aim of this study was to evaluate the relationship between intradialytic exercise and echocardiographic findings. Forty patients were enrolled in the study from Shahrekord Hemodialysis Center. They were randomly assigned into the exercise and control groups. In the exercise group, the patients had a 30-minute exercise program per dialysis session, 3 times a week, for 3 months. Electrocardiography and echocardiography were done at the beginning of the study and 3 months later. The mean age and body mass index of the patients were 43.2 +/- 10.5 years and 21.7 +/- 5.4 kg/m2, respectively. Left ventricular ejection fraction increased and systolic pulmonary artery pressure and right ventricular size decreased significantly after the study in the exercise group patients. Our results showed the improvement of cardiac systolic and diastolic function in patients who had physical exercise during dialysis sessions. Regular intradialysis exercise can be suggested for hemodialysis patients without cardiac disease.


The effect of TCM acupuncture on hot flushes among menopausal women (ACUFLASH) study: a study protocol of an ongoing multi-centre randomised controlled clinical trial.
After menopause, 10-20% of all women have nearly intolerable hot flushes. Long term use of hormone replacement therapy involves a health risk, and many women seek alternative strategies to relieve climacteric complaints. Acupuncture is one of the most frequently used complementary therapies in Norway. We designed a study to evaluate whether Traditional Chinese Medicine acupuncture-care together with self-care is more effective than self-care alone to relieve climacteric complaints. The study is a multi-centre pragmatic randomised controlled trial with two parallel arms. Participants are postmenopausal women who document > or =7 flushes/24 hours and who are not using hormone replacement therapy or other medication that may influence flushes. According to power calculations 200 women are needed to detect a 50% reduction in flushes, and altogether 286 women will be recruited to allow for a 30% dropout rate. The treatment group receives 10 sessions of Traditional Chinese Medicine acupuncture-care and self-care; the control group will engage in self-care only. A team of experienced Traditional Chinese Medicine acupuncturists give acupuncture treatments. The study tests acupuncture as a complete treatment package including the therapeutic relationship and expectation. The intervention period lasts for 12 weeks, with follow up at 6 and 12 months. Primary endpoint is change in daily hot flush frequency in the two groups from baseline to 12 weeks; secondary endpoint is health related quality of life, assessed by the Women's Health Questionnaire. We also collect data on Traditional Chinese Medicine diagnoses, and we examine treatment experiences using a qualitative approach. Finally we measure biological variables, to examine potential mechanisms for the effect of acupuncture. The study is funded by The Research Council of Norway.


Favorable climate change response explains non-native species' success in Thoreau's woods.
Invasive species have tremendous detrimental ecological and economic impacts. Climate change may exacerbate species invasions across communities if non-native species are better able to respond to climate changes than native species. Recent evidence indicates that species that respond to climate change by adjusting their phenology (i.e., the timing of seasonal activities, such as flowering) have historically increased in abundance. The extent to which non-native species success is similarly linked to a favorable climate change response, however, remains untested. We analyzed a dataset initiated by the conservationist Henry David Thoreau that documents the long-term phenological response of native and non-native plant species over the last 150 years from Concord, Massachusetts (USA). Our results demonstrate that non-native species, and invasive species in particular, have been far better able to respond to recent climate change by adjusting their flowering time. This demonstrates that climate change has likely played, and may continue to play, an important role in facilitating non-native species naturalization and invasion at the community level.


Biallelic Variants in UBA5 Link Dysfunctional UFM1 Ubiquitin-like Modifier Pathway to Severe Infantile-Onset Encephalopathy.
The ubiquitin fold modifier 1 (UFM1) cascade is a recently identified evolutionarily conserved ubiquitin-like modification system whose function and link to human disease have remained largely uncharacterized. By using exome sequencing in Finnish individuals with severe epileptic syndromes, we identified pathogenic compound heterozygous variants in UBA5, encoding an activating enzyme for UFM1, in two unrelated families. Two additional individuals with biallelic UBA5 variants were identified from the UK-based Deciphering Developmental Disorders study and one from the Northern Finland Intellectual Disability cohort. The affected individuals (n = 9) presented in early infancy with severe irritability, followed by dystonia and stagnation of development. Furthermore, the majority of individuals display postnatal microcephaly and epilepsy and develop spasticity. The affected individuals were compound heterozygous for a missense substitution, c.1111G>A (p.Ala371Thr; allele frequency of 0.28% in Europeans), and a nonsense variant or c.164G>A that encodes an amino acid substitution p.Arg55His, but also affects splicing by facilitating exon 2 skipping, thus also being in effect a loss-of-function allele. Using an in vitro thioester formation assay and cellular analyses, we show that the p.Ala371Thr variant is hypomorphic with attenuated ability to transfer the activated UFM1 to UFC1. Finally, we show that the CNS-specific knockout of Ufm1 in mice causes neonatal death accompanied by microcephaly and apoptosis in specific neurons, further suggesting that the UFM1 system is essential for CNS development and function. Taken together, our data imply that the combination of a hypomorphic p.Ala371Thr variant in trans with a loss-of-function allele in UBA5 underlies a severe infantile-onset encephalopathy.


Leucocyte glutamate dehydrogenase in various hereditary ataxias.
Leucocyte Glutamate Dehydrogenase (GDH) activity was measured in 44 patients with various forms of ataxia and 44 age and sex-matched normal controls. The only significant change found was a moderate decrease in activity in Friedreich's ataxia and a few patients with OPCA. This decreased activity is not primary to the disease but probably reflects a regulatory defect affecting mitochondrial membranes in these patients.


Anti-Neuronal IgG4 Autoimmune Diseases and IgG4-Related Diseases May Not Be Part of the Same Spectrum: A Comparative Study.
IgG4 is associated with two emerging groups of rare diseases: 1) IgG4 autoimmune diseases (IgG4-AID) and 2) IgG4-related diseases (IgG4-RLD). Anti-neuronal IgG4-AID include MuSK myasthenia gravis, LGI1- and Caspr2-encephalitis and autoimmune nodo-/paranodopathies (CNTN1/Caspr1 or NF155 antibodies). IgG4-RLD is a multiorgan disease hallmarked by tissue-destructive fibrotic lesions with lymphocyte and IgG4 plasma cell infiltrates and increased serum IgG4 concentrations. It is unclear whether IgG4-AID and IgG4-RLD share relevant clinical and immunopathological features. We collected and analyzed clinical, serological, and histopathological data in 50 patients with anti-neuronal IgG4-AID and 19 patients with IgG4-RLD. A significantly higher proportion of IgG4-RLD patients had serum IgG4 elevation when compared to IgG4-AID patients (52.63% vs. 16%, p = .004). Moreover, those IgG4-AID patients with elevated IgG4 did not meet the diagnostic criteria of IgG4-RLD, and their autoantibody titers did not correlate with their serum IgG4 concentrations. In addition, patients with IgG4-RLD were negative for anti-neuronal/neuromuscular autoantibodies and among these patients, men showed a significantly higher propensity for IgG4 elevation, when compared to women (p = .005). Last, a kidney biopsy from a patient with autoimmune paranodopathy due to CNTN1/Caspr1-complex IgG4 autoantibodies and concomitant nephrotic syndrome did not show fibrosis or IgG4+ plasma cells, which are diagnostic hallmarks of IgG4-RLD. Our observations suggest that anti-neuronal IgG4-AID and IgG4-RLD are most likely distinct disease entities.


Thermoregulatory differences in African mole-rat species from disparate habitats: Responses and limitations.
Individuals and populations possess physiological adaptations to survive local environmental conditions. To occur in different regions where ambient temperature varies, animals must adopt appropriate thermoregulatory mechanisms. Failure to adjust to environmental challenges may result in species distributional range shifts or decreased viability. African mole-rats (Bathyergidae) occupy various habitats in sub-Saharan Africa from deserts to montane regions to mesic coastal areas. We examined thermoregulatory characteristics of three African mole-rat species originating from disparate (montane, savannah, and arid/semi-arid) habitats. Animals were exposed to various ambient temperatures, whilst core body temperature and the surface temperature of different body parts were measured. Oxygen consumption was determined as a measure of heat production. Core body temperatures of Natal (montane) mole-rats (Cryptomys hottentotus natalensis) increased significantly at ambient temperatures >24.5 °C, while those of the highveld (Cryptomys hottentotus pretoriae) (savannah) and Damaraland (Fukomys damarensis) (arid/semi-arid) mole-rats remained within narrower ranges. In terms of surface temperature variation, while pedal surfaces were important in regulating heat loss in Natal and Damaraland mole-rats at high ambient temperatures, the ventral surface was important for heat dissipation in Damaraland and highveld mole-rats. This study provides evidence of the variation and limitations of thermo-physiological mechanisms for three mole-rat species relative to their habitats. Information on physiological adaptations to particular habitats may inform predictive modelling of species movements, declines, and extinctions in response to a changing environment, such as climate change.


Role of lipoprotein (a) and TGF-beta 1 in atherosclerosis of hemodialysis patients.
Atherosclerotic vascular disease is a major cause of death for uremic patients who are on hemodialysis (HD). Recent evidence suggests that lipoprotein (a) [Lp(a)] may aggravate atherosclerosis by inhibiting activation of transforming growth factor-beta 1 (TGF-beta 1). Plasma Lp(a) and plasma TGF-beta 1 activation in HD patients (n = 51), chronic renal failure patients not subjected to hemodialysis (non-HD-CRF; n = 12), and healthy volunteers (control; n = 13) were investigated. Plasma Lp(a) was significantly higher in HD (18.75 +/- 1.62 mg/ml) and non-HD-CRF patients (25.0 +/- 8.4 mg/ml) than in control subjects (10.9 +/- 5.8 mg/ml). The degree of atherosclerosis in HD patients was assessed by measuring the intima-media thickness (IMT) and plaque score with the use of an ultrasound scanner. IMT and plaque score were higher in HD and non-HD-CRF patients than in controls. A significant positive correlation was found in HD patients between Lp(a) and IMT (r = 0. 377, P < 0.01) as well as between Lp(a) and plaque score (r = 0.43, P < 0.01). Plasma total TGF-beta 1 significantly increased in HD (119.8 +/- 53.5 ng/ml) and non-HD-CRF patients (93.2 +/- 25.0 ng/ml) compared with control subjects (17.7 +/- 6.4 ng/ml), whereas the plasma level of mature (active) TGF-beta1 did not differ among the groups. When plasma TGF-beta 1 and supernatant TGF-beta 1 from cultured peripheral mononuclear cells were compared before and after an HD session, neither total nor mature TGF-beta 1 showed a significant difference between the values before and after an HD session. There were no significant relationships between plasma total TGF-beta 1 and IMT or plaque score, between mature TGF-beta 1 and IMT or plaque score, or between mature TGF-beta 1 and Lp(a). In conclusion, Lp(a) may be an important atherogenic factor in CRF patients. However, it was not clarified whether Lp(a) exerts its effect by inhibiting TGF-beta 1 activation in CRF patients.


Long-term morphology of a healing bone-tendon interface: a histological observation in the sheep model.
The purpose of this study was to examine and describe the sequence of events involved in long-term biological reconstruction of a tendon-bone interface following surgical reattachment. Patellar tendon re-attachment in the adult sheep was used to investigate and describe the biological components involved in healing and repair of a tendon enthesis. Light microscopy was used to describe the healing morphology at time intervals of 8, 12, 26, 52 and 104 weeks. By 8 weeks a collagen continuum was observed between the tendon and bone. Over time this fibrous bridge became anchored into the original tissues (tendon and bone), with the resultant enthesis resembling more a fibrous rather than the original fibrocartilagenous enthesis. The associated collagen fibrils between the two tissues gradually changed in morphology over time to reflect the fibres seen in the original tendon tissue. The fibrous tissue of the forming enthesis remained hypercellular when compared with the controls. The resultant long-term morphology may be a reflection of functional adaptation rather than anatomical replication.


Neuroinflammatory responses to traumatic brain injury: etiology, clinical consequences, and therapeutic opportunities.
Traumatic brain injury (TBI) is a serious public health problem accounting for 1.4 million emergency room visits by US citizens each year. Although TBI has been traditionally considered an acute injury, chronic symptoms reminiscent of neurodegenerative disorders have now been recognized. These progressive neurodegenerative-like symptoms manifest as impaired motor and cognitive skills, as well as stress, anxiety, and mood affective behavioral alterations. TBI, characterized by external bumps or blows to the head exceeding the brain's protective capacity, causes physical damage to the central nervous system with accompanying neurological dysfunctions. The primary impact results in direct neural cell loss predominantly exhibiting necrotic death, which is then followed by a wave of secondary injury cascades including excitotoxicity, oxidative stress, mitochondrial dysfunction, blood-brain barrier disruption, and inflammation. All these processes exacerbate the damage, worsen the clinical outcomes, and persist as an evolving pathological hallmark of what we now describe as chronic TBI. Neuroinflammation in the acute stage of TBI mobilizes immune cells, astrocytes, cytokines, and chemokines toward the site of injury to mount an antiinflammatory response against brain damage; however, in the chronic stage, excess activation of these inflammatory elements contributes to an "inflamed" brain microenvironment that principally contributes to secondary cell death in TBI. Modulating these inflammatory cells by changing their phenotype from proinflammatory to antiinflammatory would likely promote therapeutic effects on TBI. Because neuroinflammation occurs at acute and chronic stages after the primary insult in TBI, a treatment targeting neuroinflammation may have a wider therapeutic window for TBI. To this end, a better understanding of TBI etiology and clinical manifestations, especially the pathological presentation of chronic TBI with neuroinflammation as a major component, will advance our knowledge on inflammation-based disease mechanisms and treatments.


Type-I interferon signaling through ISGF3 complex is required for sustained Rip3 activation and necroptosis in macrophages.
Myeloid cells play a critical role in perpetuating inflammation during various chronic diseases. Recently the death of macrophages through programmed necrosis (necroptosis) has emerged as an important mechanism in inflammation and pathology. We evaluated the mechanisms that lead to the induction of necrotic cell death in macrophages. Our results indicate that type I IFN (IFN-I) signaling is a predominant mechanism of necroptosis, because macrophages deficient in IFN-α receptor type I (IFNAR1) are highly resistant to necroptosis after stimulation with LPS, polyinosinic-polycytidylic acid, TNF-α, or IFN-β in the presence of caspase inhibitors. IFN-I-induced necroptosis occurred through both mechanisms dependent on and independent of Toll/IL-1 receptor domain-containing adaptor inducing IFN-β (TRIF) and led to persistent phosphorylation of receptor-interacting protein 3 (Rip3) kinase, which resulted in potent necroptosis. Although various IFN-regulatory factors (IRFs) facilitated the induction of necroptosis in response to IFN-β, IRF-9-STAT1- or -STAT2-deficient macrophages were highly resistant to necroptosis. Our results indicate that IFN-β-induced necroptosis of macrophages proceeds through tonic IFN-stimulated gene factor 3 (ISGF3) signaling, which leads to persistent expression of STAT1, STAT2, and IRF9. Induction of IFNAR1/Rip3-dependent necroptosis also resulted in potent inflammatory pathology in vivo. These results reveal how IFN-I mediates acute inflammation through macrophage necroptosis.


"Green" synthesized versus chemically synthesized zinc oxide nanoparticles: In vivo antihyperglycemic activity and pharmacokinetics.
Zinc is one of the most studied trace elements, commonly used as supplement in diabetes treatment. By its involvement in the synthesis, secretion of insulin, promotion of insulin sensitivity and its multiple enzymatic functions it is known to contribute to reduce hyperglycemia. Researchers have shown that zinc administered under the form of zinc oxide nanoparticles (ZnONPs) is more effective than under its ionic form. Studies evaluating the antihyperglycemic activity of these nanocarriers include both ZnONPs synthesised using plants (i.e. green synthesized) or chemically synthesized. The present work aims to compare green synthesized ZnONPs with the marketed chemically synthesized ones. Green ZnONPs were synthesized using the aqueous extract of the stem bark of the medicinal plant Panda oleosa and zinc nitrate hexahydrate. Both nanocarriers were compared in terms of optical properties, morphology, composition, chemical functions, resistance to oxidation, in vivo antihyperglycemic activity via oral glucose tolerance test (OGTT) and pharmacokinetics in relation to zinc in C57BL/6J mice. A UV absorption peak was observed at 354 nm and 374 nm for the green and marketed ZnONPs, respectively. The shape and hydrodynamic diameters were anisotropic and of 228.8 ± 3.0 nm for the green ZnONPs and spherical and of 225.6 ± 0.9 nm for the marketed ZnONPs. Phenolic compounds accounted for 2.58 ± 0.04% of the green ZnONPs and allowed them to be more stable and unaffected by an oxidizing agent during the experiment, while the marketed chemically synthesized ZnONPs aggregated with or without contact with an oxidizing agent. No significant differences were observed on the amounts of zinc absorbed when comparing green ZnONPs, chemically synthesized ZnONPs and zinc sulfate in a pharmacokinetics study in normoglycemic mice. When evaluating the in vivo hypoglycemic activity of the nanocarriers in obese/diabetic mice, green synthesized ZnONPs displayed a significant hypoglycemic effect compared with the chemically synthesized nanoparticles following an OGTT. Altogether, these data indicate that phytocompounds, as catechin derivatives and polyphenols, attached to the green synthesized ZnONPs' surface, could contribute to their hypoglycemic activity. The comparison thus demonstrated that green synthesized ZnONPs are significantly more efficient than chemically ones at reducing hyperglycemia regardless of their absorption.


The impact of atopy on neutrophil activity in middle ear effusion from children and adults with chronic otitis media.
To identify the relationship of neutrophil activity to allergy as reflected by the level of myeloperoxidase (MPO) in ears of atopic patients with chronic otitis media with effusion (OME) by objective testing. Evidence of neutrophils was measured in the effusion of atopic patients with chronic OME. Atopy was determined by intradermal and/or in vitro testing of allergic reaction to 10 inhalants, 2 molds, and 5 foods. Effusion MPO was measured prospectively in 138 ears from 106 consecutive patients with chronic OME. A total of 86 (81%) of 106 patients with OME tested atopic by in vitro or in vivo testing. Excluding 36 ears with purulence, the mean MPO level was 3132 microg/L in 84 atopic vs 142 microg/L in 18 nonatopic ears (P<.001). A total of 78 (90%) of 87 patients with OME were atopic. The surprising finding of marked elevation of effusion MPO in atopic patients but very low levels in nonatopic patients (P < .001) suggests that atopy may contribute to elevated levels of neutrophil activity in OME. An atopic patient may respond differently from a nonatopic one to the microbial or viral products of acute inflammation owing to the presence of primed inflammatory cells. This study provides confirmation on a cellular level that neutrophils are an integral part of the inflammatory process in OME to a disproportionate degree among atopic patients.


X-chromosome inactivation: molecular mechanisms from the human perspective.
X-chromosome inactivation is an epigenetic process whereby one X chromosome is silenced in mammalian female cells. Since it was first proposed by Lyon in 1961, mouse models have been valuable tools to uncover the molecular mechanisms underlying X inactivation. However, there are also inherent differences between mouse and human X inactivation, ranging from sequence content of the X inactivation center to the phenotypic outcomes of X-chromosome abnormalities. X-linked gene dosage in males, females, and individuals with X aneuploidies and X/autosome translocations has demonstrated that many human genes escape X inactivation, implicating cis-regulatory elements in the spread of silencing. We discuss the potential nature of these elements and also review the elements in the X inactivation center involved in the early events in X-chromosome inactivation.


Multiplexed ultrafast fiber laser emitting multi-state solitons.
Ultrafast fiber lasers have been serving as an ideal playground for spreading the extensive industrial applications and exploring the optics nonlinear dynamics. Here, we report a bidirectional fiber laser scheme for validating the possibility of a multiplexed laser system, which is passively mode-locked by the nonlinear polarization rotation (NPR) technique. In particular, the proposed fiber laser consists of one main cavity and two counter-propagating branches with different dispersion distributions. Thus, different formation mechanisms are introduced into the lasing oscillator. Consequently, stable conventional solitons (CSs) and dissipative solitons (DSs) are respectively formed in the clockwise (CW) and counterclockwise (CCW) directions of the same lasing oscillator. Moreover, attributing to the strong birefringence filtering effect, the wavelength selection mechanism is induced. Through the proper management of intra-cavity birefringence, wideband wavelength tuning and switchable multi-wavelength operations are experimentally observed. The central wavelength of CS can be continuously tuned from 1560 nm to 1602 nm. Additionally, the evolution process of different multi-wavelength operations is also elucidated. Benefiting from this multiplexed laser scheme, bidirectional lasing oscillation, multi-state soliton emission, wavelength tuning and multi-wavelength operations are synchronously realized in a single laser cavity. To the best of our knowledge, it is the first time for such a multiplexed fiber laser has been reported. The results provide information for multifunctional ultrafast fiber laser system, which is potentially set for telecommunications, fiber sensing and optics signal processing, etc.


Bach Goes to Town.
Donald A. Tomalia is one of the pioneers in the field of dendrimers, who is still active at the age of 80 years-old. The present contribution is a journey through his scientific contributions from the early beginning until his discovery of the poly(amidoamine), (PAMAM)-dendrimers.


Cost-effectiveness of non-invasive methods for assessment and monitoring of liver fibrosis and cirrhosis in patients with chronic liver disease: systematic review and economic evaluation.
Liver biopsy is the reference standard for diagnosing the extent of fibrosis in chronic liver disease; however, it is invasive, with the potential for serious complications. Alternatives to biopsy include non-invasive liver tests (NILTs); however, the cost-effectiveness of these needs to be established. To assess the diagnostic accuracy and cost-effectiveness of NILTs in patients with chronic liver disease. We searched various databases from 1998 to April 2012, recent conference proceedings and reference lists. We included studies that assessed the diagnostic accuracy of NILTs using liver biopsy as the reference standard. Diagnostic studies were assessed using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool. Meta-analysis was conducted using the bivariate random-effects model with correlation between sensitivity and specificity (whenever possible). Decision models were used to evaluate the cost-effectiveness of the NILTs. Expected costs were estimated using a NHS perspective and health outcomes were measured as quality-adjusted life-years (QALYs). Markov models were developed to estimate long-term costs and QALYs following testing, and antiviral treatment where indicated, for chronic hepatitis B (HBV) and chronic hepatitis C (HCV). NILTs were compared with each other, sequential testing strategies, biopsy and strategies including no testing. For alcoholic liver disease (ALD), we assessed the cost-effectiveness of NILTs in the context of potentially increasing abstinence from alcohol. Owing to a lack of data and treatments specifically for fibrosis in patients with non-alcoholic fatty liver disease (NAFLD), the analysis was limited to an incremental cost per correct diagnosis. An analysis of NILTs to identify patients with cirrhosis for increased monitoring was also conducted. Given a cost-effectiveness threshold of £20,000 per QALY, treating everyone with HCV without prior testing was cost-effective with an incremental cost-effectiveness ratio (ICER) of £9204. This was robust in most sensitivity analyses but sensitive to the extent of treatment benefit for patients with mild fibrosis. For HBV [hepatitis B e antigen (HBeAg)-negative)] this strategy had an ICER of £28,137, which was cost-effective only if the upper bound of the standard UK cost-effectiveness threshold range (£30,000) is acceptable. For HBeAg-positive disease, two NILTs applied sequentially (hyaluronic acid and magnetic resonance elastography) were cost-effective at a £20,000 threshold (ICER: £19,612); however, the results were highly uncertain, with several test strategies having similar expected outcomes and costs. For patients with ALD, liver biopsy was the cost-effective strategy, with an ICER of £822. A substantial number of tests had only one study from which diagnostic accuracy was derived; therefore, there is a high risk of bias. Most NILTs did not have validated cut-offs for diagnosis of specific fibrosis stages. The findings of the ALD model were dependent on assuptions about abstinence rates assumptions and the modelling approach for NAFLD was hindered by the lack of evidence on clinically effective treatments. Treating everyone without NILTs is cost-effective for patients with HCV, but only for HBeAg-negative if the higher cost-effectiveness threshold is appropriate. For HBeAg-positive, two NILTs applied sequentially were cost-effective but highly uncertain. Further evidence for treatment effectiveness is required for ALD and NAFLD. This study is registered as PROSPERO CRD42011001561. The National Institute for Health Research Health Technology Assessment programme.


Hermaphroditic liquid-crystal microlens.
We demonstrate a flat microlens that exhibits hermaphroditic focusing properties. When the input polarization is parallel (perpendicular) to the liquid-crystal directors, the lens exhibits a positive (negative) focal length. To select the proper polarization, we could rotate the polarizer (or the lens) mechanically or by use of an electrically controlled twisted nematic liquid-crystal cell. Details of the lens structure and of the device's fabrication and performance are described.


[Delayed effects of prenatal exposure to phenobarbital on intelligence--Phenemal].
Two double-blind studies were conducted on two independent samples of adult men prenatally exposed to phenobarbital and matched control samples using two different measures of general intelligence (WAIS and a draft board test (BPP)). The two studies included 33 and 81 exposed adult men respectively, and the two control groups included 52 and 101 unexposed men matched on a wide spectrum of maternal variables recorded pre- and perinatally. Based on data from control subjects, regression models were built relating intelligence scores to relevant pre-exposure matching variables. Models generated predicted scores for each exposed subject. Men exposed prenatally to phenobarbital had significantly lower verbal intelligence scores than predicted. Lower socioeconomic status and being the offspring of an unwanted pregnancy increased the magnitude of the negative effects. Exposure which includes the last trimester was the most detrimental. Physicians are urged to use increased caution in prescribing such medications during pregnancy or to premature neonates.


Associations between hypertension and genes in the renin-angiotensin system.
The genes of the renin-angiotensin system have been subjected to intense molecular scrutiny in cardiovascular disease studies, but their contribution to risk is still uncertain. In this study, we sampled 192 African American and 153 European American families (602 and 608 individuals, respectively) to evaluate the contribution of variations in genes that encode renin-angiotensin system components of susceptibility to hypertension. We genotyped 25 single-nucleotide polymorphisms in the renin-angiotensin system genes ACE, AGT, AGTR1, and REN. The family-based transmission/disequilibrium test was performed with each single-nucleotide polymorphism and with the multilocus haplotypes. Two individual single-nucleotide polymorphisms were significantly associated with hypertension among African Americans, and this result persisted when both groups were combined. The associations were confirmed in haplotype analysis for REN, AGTR1, and ACE in African Americans. Consistent but less significant evidence was found in European Americans. We also randomly sampled unrelated individuals across families to obtain 84 cases and 108 controls among the African Americans and 41 cases and 113 controls in the European Americans. Single-nucleotide polymorphism and haplotype analyses again showed consistent, albeit weaker, results. Thus, in this biracial population sample, we find evidence that interindividual variation in the renin-angiotensin system genes contributes to hypertension risk.


Gender's effect on willingness-to-pay for community-based insurance in Burkina Faso.
The purpose was to study gender's effect on willingness-to-pay (WTP) for community-based insurance (CBI) in order to provide information for deciding enrolment unit and setting premium in Burkina Faso. A two-stage cluster sampling was used in the household survey, with each household having the same probability of being selected. One thousand one hundred and seventy-eight men and 1236 women in the 800 households were interviewed. The bidding game approach was used to elicit WTP. We found that compared to male, female had less education, lower income and expenditure, less episodes of diseases and lower ratio of becoming household head, but higher marriage rate. These characteristics influenced the WTP difference between men and women. Men were willing to pay 3666 CFA ($4.89) to join CBI, 928 CFA higher than women were. Education and economic status positively influenced WTP, implying higher years of schooling and economic status and higher WTP. Age and distance to health facility negatively influenced WTP, thus higher age and longer distance and less WTP. Based on the results from this study, we suggest that CBI should be enrolled on the basis of households or villages in order to protect vulnerable persons, such as the aged, women and the poor. In setting premium a policy-maker needs to take into account costs of the CBI benefits package, possible subsidies from government and other agencies and WTP information. WTP should never be taken as a premium because it only provides some information for the respondents' financial acceptability for a certain benefits package.


Biological internal fixation: its background, methods, requirements, potential and limits.
The surgical treatment of fractures made essential progress when stable internal fixation allowing for immediate painless mobility of soft tissues and articulations was postulated and achieved. This step required basic understanding of biomechanics of fixation and of bone reaction to compression and micromotion. The definition of teaching modalities and the clinical documentation were further steps leading to general acceptance of this type of treatment. After a period of interest, which was focussed mainly on biomechanics it became obvious that biology was not only important for reliable bone and soft tissue healing but especially important for good local resistance to infection and quick solid bridging. The surgical approach with special care to the viability of the bone as a tissue is called biological internal fixation. Similar attempts were seen in the past but it appears that now an procedures and implants have been developed that maintain undisturbed blood supply thus avoiding extended contact necrosis. The advantage of biological internal fixation consists in reducing severe biological complications on the expense of less important mechanical shortcomings. Biological internal fixation is best, when the bone is alive at the onset of surgery and remains so. The present paper focussing especially on the development of implant technology for flexible biological internal fixation should not distract from the needs of necrotic bone for long-term stable compression fixation achieved by conventional techniques. Key words: biological internal fixation, osteosynthesis.


Correlation of Tear Film Osmolarity and 2 Different MMP-9 Tests With Common Dry Eye Tests in a Cohort of Non-Dry Eye Patients.
Given that early-stage dry eye is difficult to diagnose, the purpose of this study was to evaluate the performance of matrix metalloproteinase 9 (MMP-9) and tear film osmolarity (TFO) in a cohort of elderly patients with potential dry eye disease (DED). A group of 20 patients, aged 60 years and above, previously undiagnosed with DED were selected. The following DED tests were performed: tear osmolarity, MMP-9 (InflammaDry), Schirmer test, tear film break-up time, Ocular Surface Disease Index (OSDI) questionnaire, corneal fluorescein staining, and conjunctival lissamine green staining. MMP-9 concentrations in tears collected through Schirmer strips were analyzed by an MMP-9 enzyme-linked immunosorbent assay [ELISA]. Subjects were classified by symptoms (classification A: OSDI ≥10, n = 9), based on suspected mild dry eye (classification B: n = 14), TFO difference >8 mOsm/L between both eyes (classification C: n = 13), and TFO cutoff at 308 mOsm/L (classification D: >308 mOsm/L, n = 11). Eleven percent (1/9) of the symptomatic and 14% (2/14) of the suspected mild dry eye were positive for MMP-9. InflammaDry MMP-9 tests were confirmed to be accurate through an ELISA. Sixty-seven percent (6/9) of the symptomatic and 64% (9/14) of the suspected mild dry eye were positive for tear osmolarity. None of the evaluated tear film parameters showed a significant correlation, although tear osmolarity and symptoms trended toward significance (r = 0.433, P = 0.06), whereas MMP-9 and corneal staining showed a positive association (r = 0.376, P = 0.10). Similar to corneal staining, the MMP-9 is likely a late-stage sign that is rarely overexpressed in mild subjects, whereas tear osmolarity tends to be a more frequent early indicator of ocular surface disequilibrium within mild subjects.


Network connectivity and local transcriptomic vulnerability underpin cortical atrophy progression in Parkinson's disease.
Parkinson's disease pathology is hypothesized to spread through the brain via axonal connections between regions and is further modulated by local vulnerabilities within those regions. The resulting changes to brain morphology have previously been demonstrated in both prodromal and de novo Parkinson's disease patients. However, it remains unclear whether the pattern of atrophy progression in Parkinson's disease over time is similarly explained by network-based spreading and local vulnerability. We address this gap by mapping the trajectory of cortical atrophy rates in a large, multi-centre cohort of Parkinson's disease patients and relate this atrophy progression pattern to network architecture and gene expression profiles. Across 4-year follow-up visits, increased atrophy rates were observed in posterior, temporal, and superior frontal cortices. We demonstrated that this progression pattern was shaped by network connectivity. Regional atrophy rates were strongly related to atrophy rates across structurally and functionally connected regions. We also found that atrophy progression was associated with specific gene expression profiles. The genes whose spatial distribution in the brain was most related to atrophy rate were those enriched for mitochondrial and metabolic function. Taken together, our findings demonstrate that both global and local brain features influence vulnerability to neurodegeneration in Parkinson's disease.


A phosphatidylinositol transfer protein integrates phosphoinositide signaling with lipid droplet metabolism to regulate a developmental program of nutrient stress-induced membrane biogenesis.
Lipid droplet (LD) utilization is an important cellular activity that regulates energy balance and release of lipid second messengers. Because fatty acids exhibit both beneficial and toxic properties, their release from LDs must be controlled. Here we demonstrate that yeast Sfh3, an unusual Sec14-like phosphatidylinositol transfer protein, is an LD-associated protein that inhibits lipid mobilization from these particles. We further document a complex biochemical diversification of LDs during sporulation in which Sfh3 and select other LD proteins redistribute into discrete LD subpopulations. The data show that Sfh3 modulates the efficiency with which a neutral lipid hydrolase-rich LD subclass is consumed during biogenesis of specialized membrane envelopes that package replicated haploid meiotic genomes. These results present novel insights into the interface between phosphoinositide signaling and developmental regulation of LD metabolism and unveil meiosis-specific aspects of Sfh3 (and phosphoinositide) biology that are invisible to contemporary haploid-centric cell biological, proteomic, and functional genomics approaches.


[Stage-based treatment of gouty arthritis by combination therapy of traditional Chinese and Western medicines: a randomized controlled trial].
To evaluate the clinical therapeutic effect of the combination therapy of traditional Chinese and Western medicines in treating gouty arthritis based on the stage of disease, and to explore a safe, effective and reasonable therapeutic regimen for prevention and treatment of gouty arthritis. One hundred and sixty-six cases of gouty arthritis were divided into three groups randomly, 58 cases in traditional Chinese drug (TCD)-treated group, 56 cases in Western medicine (WM)-treated group and 52 cases in TCD plus WM-treated group. They were all treated for 12 weeks. In the acute stage, patients in TCD-treated group were treated with Huzhang Gout Granule and Jinhuang Ointment, and patients in WM-treated group were treated with diclofenac sodium dual release enteric-coated capsules. In the intermission, patients in TCD-treated group were given Yinlian Gout Granule, and patients in WM-treated group were given benzbromarone or allopurinol. Patients in TCD plus WM-treated group were given both TCD and WM. Clinical symptom score and blood uric acid (BUA) level were measured. The effect initiating time, relapse rate, efficacy rate and the incidence rate of adverse effects were also studied. There were no significant differences in the efficacy rate and effect initiating time among the three groups in the acute stage. The clinical symptom score and BUA level were obviously reduced in three groups. In the intermission, BUA level in the WM-treated group and TCD plus WM-treated group were obviously reduced. Although there was a drop tendency in the BUA level in TCD-treated group, there was no statistical difference. The relapse rates in TCD-, WM- and TCD plus WM-treated groups were 12.07%, 26.79% and 9.62%, respectively. There was statistical difference in relapse rates among the three groups (P<0.05). The relapse rate was decreased in TCD plus WM-treated group as compared with those in TCD-treated and WM-treated groups. The average clinical symptom scores during recurrence in the three groups were (10.00+/-3.61), (12.38+/-1.85) and (10.75+/-1.89), respectively. The incidence of adverse effects in TCD-treated group (3.45%) was lower than the other two groups (21.43% and 15.38%). The combination therapy of traditional Chinese and Western medicines based on the stage of disease can control the symptoms of gouty arthritis in the acute stage, improve joint function, and can control the BUA level during the intermission, prevent recurrence and relieve the adverse effects.


Omega-3 polyunsaturated fatty acids in Alzheimer's disease: key questions and partial answers.
The current rise in the prevalence of Alzheimer's disease (AD) is unfortunately not matched by new treatment options. In the last 10 years, epidemiological, preclinical and clinical data have enlightened the possible preventive action of omega-3 polyunsaturated fatty acids (n-3 PUFA) in AD and other diseases. While the contribution of recent studies to our general knowledge is priceless, many important new questions have been raised. In the present review, we aim at addressing some of these timely interrogations. First, the transport of n-3 PUFA across the blood-brain barrier is underscored based on preclinical data. Second, the relative contribution of two neuroactive n-3 PUFA found in fish oil, docosahexaenoic acid (DHA; 22:6 n-3) and eicosapentaenoic acid (EPA, 20:5 n-3), remains unclear and is reviewed. Third, clinical trials on neurodegenerative diseases consistently remind us that treating early is critical, and this is likely to be the case with n-3 PUFA in AD as well. Fourth, we draw attention to the possibility that the current knowledge translation approach to make health recommendations might have to be adapted to non-patentable endogenous compounds like n-3 PUFA. We propose that answers to these critical questions will be instrumental toward a rational use of n-3 PUFA in AD.


Antimicrobial Consumption and Susceptibility of Neisseria gonorrhoeae: A Global Ecological Analysis.
Aims: The reasons why antimicrobial resistance in Neisseria gonorrhoeae has emerged explosively in certain populations but not others are poorly understood. We hypothesized that population level consumption of antimicrobials plays a role. Methods: Using susceptibility data from the World Health Organizations Global Gonococcal Antimicrobial Surveillance Programme and antimicrobial consumption data from the IMS Health MIDAS database we built linear regression models with country-level cephalosporin, macrolide, and fluoroquinolone consumption (standard doses/1,000 population/year) as the explanatory variable and 1-year lagged ceftriaxone, azithromycin, and ciprofloxacin resistance as the outcome variables. These were performed at two time points 2008/2009 and 2013/2014. Results: The association between antimicrobial resistance and consumption at the level of individual countries was positive in all six assessments. In four instances the positive associations were statistically significant (cephalosporins 2008: coefficient 0.0005 [95% confidence interval (CI) 0.0002-0.0007] and 2013: coefficient 0.0003 [95% CI 0.0002-0.0004]; macrolides 2013: coefficient 0.0005 [95% CI 0.00002-0.001]; fluoroquinolones 2013: coefficient 0.02 [95% CI 0.006-0.031]). Conclusions: Differences in population level consumption of particular antimicrobials may play a role in explaining the variations in the emergence of antimicrobial resistance in N. gonorrhoeae.


Synthesis and the biological evaluation of 2-benzenesulfonylalkyl-5-substituted-sulfanyl-[1,3,4]-oxadiazoles as potential anti-hepatitis B virus agents.
Current treatments for chronic hepatitis B virus (HBV) infection include the use of interferon-alpha and of nucleoside analogs lamivudine, adefovir and entecavir. However, the use of interferon-alpha has many side effects while that of nucleosidic inhibitors can lead to the emergence of resistant viruses. Hence, new drugs for the treatment of HBV infection are still highly desired. Oxadiazoles have been observed to exhibit antiviral activities against RNA viruses. In this study, a facile synthesis of 2-benzenesulfonylalkyl-5-substituted-sulfanyl-[1,3,4]-oxadiazoles is reported. The compounds were then evaluated for their anti-HBV activity. 1-[2-[5-(1-Benzenesulfonyl-propyl)-[1,3,4]oxadiazol-2-yl-sulfanyl]-ethyl]-4-(2-methoxy-phenyl)-piperazine (1i) was able to inhibit the expression of the viral antigens, HBsAg and HBeAg in a concentration-dependent manner with no cytotoxic effects and without any effects on the expression of viral transcripts. Concentration- and time-dependent reductions in virion production were also observed. The inhibition of virion production was comparable to that of lamivudine and EC(50) values of 1.63 and 2.96 microM were obtained for compound 1i and lamivudine, respectively. Thus, in addition to the antiviral effects on RNA viruses, oxadiazoles also have anti-HBV activities.


Psychometric properties of the Persian version of Proactive-Safety Role Orientation questionnaire (PRO-SAFE).
Participation and initiative of workers are effective in promoting safety in the workplace. Proactive-Safety Role Orientation questionnaire (PRO-SAFE) is a proper tool to evaluate the psychological drivers that support the proactive orientation of individuals toward workplace safety. This study was conducted to translate and measure the psychometric properties of the Persian version of PRO-SAFE. The PRO-SAFE was translated into Persian using procedures for translation and cross-cultural adaptation. To collect data, 252 employees of a steel complex were selected. To measure the validity of the questionnaire, face, content, convergent, and construct validity was utilized. The questionnaire's reliability was evaluated by assessing its internal consistency. The mean of the content validity index and content validity ratio was equal to 0.83 and 0.85, respectively. We found a positive correlation between PRO-SAFE and safety behavior dimensions (r = 0.372 to 0.792, P < 0.001). Confirmatory factor analysis showed the Persian version of the PRO-SAFE questionnaire had an excellent six-factor model consistent with the original questionnaire. Cronbach's alpha of the Persian version of the PRO-SAFE questionnaire was obtained between 0.717 to 0.880. The Persian version of the PRO-SAFE questionnaire was found to have appropriate psychometric properties, indicating that it can be confidently used as a valid tool for assessing proactive role orientation toward safety management among Iranian employees.


[Pharmaceutical care for drug-related problems in inpatients].
Drug therapy-induced high morbidity results in pharmacists participating in the prevention and solution of drug-related problems (DRPs). To assess DRP prevalence amongst inpatients, and the clinical results derived from pharmaceutical intervention. DRPs detected during 6 months at Hospital Comarcal de Sant Bernabé were recorded and classified, and their severity established. Pharmaceutical intervention was evaluated by using two codes: impact and clinical significance. Interventions were reassessed by another pharmacist and a physician, and the degree of agreement was calculated. The prevalence of DRPs amongst inpatients was 10.8%. A total of 425 DRPs was detected, with a mean of 1.51 DRPs/patient. The highest percentage involved inappropriate drugs (26%), overdosing (22%), and inadequate dosing (22%). Eighty-four percent of DRPs were a severity level 2. Drugs mainly involved were antibiotics (21.6%), anti-ulcer agents (21.8%), and analgesic-anti-inflammatory compounds (8.1%). In all, 58% of interventions impacted on treatment effectiveness, and 42% on toxicity. Intervention acceptance was 91%. Seventy percent of interventions were appropriate and highly significant. The percentage of agreements in reassessments exceeded 88%. Pharmaceutical care allows DRPs to be prevented and solved. Methodology validation makes it safer in daily practice.


Autism in context 2: Assessment, intervention and services in Australia.
Continuing from part 1, part 2 of the autism spectrum disorders review explores clinical practice and service delivery aspects of autism spectrum disorders including current assessment approaches in Australia, family-centred models of care, and key service structure and delivery issues. Treatments including behavioural interventions, established and emergent medication, and complementary and alternative therapies are discussed. The key role of paediatricians as both individual child and family care providers and advocates, as well as agents of service reform in Australia, is evident. Much still needs to be done.


Increased induction of sister chromatid exchange by diethylstilbestrol in lymphocytes from pregnant and premenopausal women.
Cultures of whole blood from pregnant women (4 to 6 months), premenopausal women, postmenopausal women, and normal men were grown in the presence of varying concentrations (1 x 10(-5) M, 2 x 10(-5) M, and 4 x 10(-5) M) of diethylstilbestrol (DES), a synthetic estrogen and known carcinogen, to see if it had sex-related cytogenetic effects. DES induced sister chromatid exchanges in lymphocytes from pregnant and premenopausal women but had only a small effect at the highest concentration (4 x 10(-5) M) in lymphocytes from men and postmenopausal women. At all concentrations, the average number of sister chromatid exchanges was higher in lymphocytes from pregnant women than in those from premenopausal women. In lymphocytes from both a man and a pregnant woman, DES strongly inhibited cell proliferation in vitro. When lymphocytes from a man and a pregnant woman were cocultured in the presence of DES, only the lymphocytes of the woman responded with an increase in sister chromatid exchanges. This indicated that there is no interaction between DES and a factor present in the blood but that DES acts directly on each cell.


[The immunization of adults against respiratory syncytial virus infection].
The results of the comparative study of the immunological effectiveness of experimental samples of respiratory syncytial (RS) viral vaccine, prepared from a live attenuated strain and introduced in a single administration to young adults by the intranasal, intradermal and combined intranasal-intradermal) routes, are presented. The effectiveness of intranasal immunization was inversely related to the level of previously existing humoral (serum, secretory) antibodies. Intradermal immunization enhanced the frequency of the formation of serum antibodies in persons having had such antibodies before the introduction of RS vaccine. The most active formation of serum and secretory antibodies was ensured by the combined (intranasal-intradermal) method of the administration of live RS vaccine which proved to be particularly effective in persons having had antibodies in the blood and secretions prior to immunization.


Home treatment for patients with cancer-associated venous thromboembolism.
Patients hospitalised with acute venous thromboembolism (VTE), and notably patients with pulmonary embolism, often remain in hospital for extended periods due to the perceived risk of complications. However, several studies have shown that home treatment of selected patients is feasible and safe, with a low incidence of adverse events. This may offer clear benefits for patients' quality of life, hospital planning and cost to the health service. Nonetheless, there is a need for a VTE risk-stratification tool specifically addressing prognosis in patients with cancer. This may aid in the selection of low-risk patients with cancer and VTE who are suitable for outpatient treatment. Although several prognostic scores have been proposed, we suggest using a pragmatic clinical decision-making tool such as the Hestia criteria for selecting patients for home care in everyday clinical practice. Once patients have been discharged, it is mandatory to monitor patients regularly (we suggest after 3 days, 10 days, 1 month and 3 months, or more frequently if needed) with the involvement of a multidisciplinary team, so that appropriate and timely remedial action can be taken in case of warning signs of complications. If patients are selected carefully and monitored effectively, many patients who experience acute VTE can be cared for safely at home.


A comprehensive assessment of external exposure to persistent halogenated organic pollutants for residents in an e-waste recycling site, South China.
Human skin wipes from 30 participants, air, dust, and food items were collected from a former electronic waste site in South China to provide a comprehensive understanding of residents' exposure to halogenated flame retardants (HFRs) and polychlorinated biphenyls (PCBs). The total concentration of halogenated organic pollutants (HOPs) in the dust, air, food and skin wipes ranged 240-25000 ng/g, 130-2500 pg/m3, 0.08-590 ng/g wet weight, and 69-28000 ng/m2, respectively. Wild fish, vegetables, and air were dominated by PCBs, whereas dust, livestock, and poultry were dominated by HFRs. The HOP concentrations were several orders of magnitude higher in local foodstuffs than in market foodstuffs. The chemical composition on the forehead was remarkably different from that on the hand. The importance of different exposure routes depends on the residents' food choices, except decabromodiphenyl ethane (DBDPE). For residents who consumed a 100-foot diet (mainly egg) and local wild fish, diet ingestion overwhelmed other exposure routes, and PCBs were mainly contributed by fish and HFRs by egg. For residents who consumed market food, the dermal absorption of most PCB congeners and dust ingestion of highly brominated flame retardants were relatively prominent. Inhalation was found to be a crucial route for pentabromoethylbenzene (PBEB).


The biomechanical disadvantage of dysplastic hips.
Developmental dysplasia of the hip (DDH) is strongly associated with an increased risk for hip osteoarthritis. Skeletal deformities undeniably contribute to detrimental biomechanical loading in dysplastic hips, but cannot explain all types of damage and symptoms that patients with DDH experience. Characterizing the geometry and function of the muscles spanning the hip is a logical next step in our progression of knowledge about DDH pathomechanics. In this study, we compared skeletal geometry, muscle volumes, intramuscular fatty infiltration, moment arms, and isometric strength in patients with DDH (N = 20) to healthy controls (N = 15). Femoral coverage was significantly less in patients (p < 0.001, Cohen's d effect size = 2.2), femoral neck-shaft angles were larger (p = 0.001, d = 1.3), and hip joint centers (HJCs) were more lateral (p = 0.001, d = 1.3). These skeletal abnormalities were associated with smaller abductor muscle moment arms in patients with DDH (e.g., gluteus medius [GMED]: p = 0.001, d = 1.2). Patients with DDH also had larger GMED volumes (p = 0.02, d = 0.83), but no differences in fatty infiltration, compared to controls. Isometric strength of the hip abductors, extensors, and flexors was lower in patients, but not significantly different from controls. The abnormal skeletal geometry, lateralized HJC, and reduced muscle moment arms represent a chronic biomechanical disadvantage under which patients with DDH operate. This phenomenon causes increased demand on the abductor muscles and results in high medially and superiorly directed joint reaction forces, which can explain reports of superomedial femoral cartilage damage in patients. The abnormal muscle geometry and function, in context with abnormal skeletal structure, are likely strong, but underappreciated, contributors to damaging loads in DDH.


Dietary indicators for assessing the adequacy of population zinc intakes.
The assessment of dietary zinc intakes is an important component of evaluating the risk of zinc deficiency in populations, and for designing appropriate food-based interventions, including fortification, to improve zinc intakes. The prevalence of inadequate zinc intakes can describe the relative magnitude of the risk of zinc deficiency in the population and identify subpopulations at elevated risk. As a cornerstone to evaluating the adequacy of population zinc intakes globally, a set of internationally appropriate dietary reference intakes must be defined. The World Health Organization/Food and Agriculture Organization/International Atomic Energy Agency (WHO/FAO/IAEA) and the Food and Nutrition Board/US Institute of Medicine (FNB/IOM) have presented estimated average requirements (EAR) for dietary zinc intake, and, more recently, the International Zinc Nutrition Consultative Group (IZiNCG) presented a revised set of recommendations for international use. A prevalence of inadequate zinc intakes greater than 25% is considered to represent an elevated risk of population zinc deficiency. As the requirement estimates are derived from smaller, clinical studies and, for children, most components of the estimates are extrapolated from data for adults, it was desirable to evaluate their internal validity. The estimated physiological requirements for adult men and women appear to adequately predict zinc status as determined by biochemical indicators of status and/or zinc balance. With the use of data from available studies, the reported prevalence of low serum zinc concentration and the estimated prevalence of inadequate zinc intakes predict similar levels of risk of zinc deficiency, particularly among pregnant and nonpregnant women. Conformity between these two indicators is less consistent for children, suggesting that further data and/or direct studies of zinc requirements among children are needed.


The effect of light rail transit on body mass index and physical activity.
The built environment can constrain or facilitate physical activity. Most studies of the health consequences of the built environment face problems of selection bias associated with confounding effects of residential choice and transportation decisions. To examine the cross-sectional associations between objective and perceived measures of the built environment; BMI; obesity (BMI>30 kg/m(2)); and meeting weekly recommended physical activity (RPA) levels through walking and vigorous exercise. To assess the effect of using light rail transit (LRT) system on BMI, obesity, and weekly RPA levels. Data were collected on individuals before (July 2006-February 2007) and after (March 2008-July 2008) completion of an LRT system in Charlotte NC. BMI, obesity, and physical activity levels were calculated for a comparison of these factors pre- and post-LRT construction. A propensity score weighting approach adjusted for differences in baseline characteristics among LRT and non-LRT users. Data were analyzed in 2009. More-positive perceptions of one's neighborhood at baseline were associated with a -0.36 (p<0.05) lower BMI; 15% lower odds (95% CI=0.77, 0.94) of obesity; 9% higher odds (95% CI=0.99, 1.20) of meeting weekly RPA through walking; and 11% higher odds (95% CI=1.01, 1.22) of meeting RPA levels of vigorous exercise. The use of LRT to commute to work was associated with an average -1.18 reduction in BMI (p<0.05) and an 81% reduced odds (95% CI=0.04, 0.92) of becoming obese over time. The results of this study suggest that improving neighborhood environments and increasing the public's use of LRT systems could provide improvements in health outcomes for millions of individuals.


Two Drosophila suppressors of cytokine signaling (SOCS) differentially regulate JAK and EGFR pathway activities.
The Janus kinase (JAK) cascade is an essential and well-conserved pathway required to transduce signals for a variety of ligands in both vertebrates and invertebrates. While activation of the pathway is essential to many processes, mutations from mammals and Drosophila demonstrate that regulation is also critical. The SOCS (Suppressor Of Cytokine Signaling) proteins in mammals are regulators of the JAK pathway that participate in a negative feedback loop, as they are transcriptionally activated by JAK signaling. Examination of one Drosophila SOCS homologue, Socs36E, demonstrated that its expression is responsive to JAK pathway activity and it is capable of downregulating JAK signaling, similar to the well characterized mammalian SOCS. Based on sequence analysis of the Drosophila genome, there are three identifiable SOCS homologues in flies. All three are most similar to mammalian SOCS that have not been extensively characterized: Socs36E is most similar to mammalian SOCS5, while Socs44A and Socs16D are most similar to mammalian SOCS6 and 7. Although Socs44A is capable of repressing JAK activity in some tissues, its expression is not regulated by the pathway. Furthermore, Socs44A can enhance the activity of the EGFR/MAPK signaling cascade, in contrast to Socs36E. Two Drosophila SOCS proteins have some overlapping and some distinct capabilities. While Socs36E behaves similarly to the canonical vertebrate SOCS, Socs44A is not part of a JAK pathway negative feedback loop. Nonetheless, both SOCS regulate JAK and EGFR signaling pathways, albeit differently. The non-canonical properties of Socs44A may be representative of the class of less characterized vertebrate SOCS with which it shares greatest similarity.


Alkaline phosphatase levels as a prognostic factor in metastatic colorectal cancer treated with the FOLFOX 4 regimen: a monoinstitutional retrospective study.
Metastatic colorectal cancer has a heterogeneous behavior, and a set of patients will have minimal response and rapid disease progression. To understand this heterogeneity, studies have evaluated biological and clinical prognostic factors. Alkaline phosphatase seems to be a key prognostic factor, so we have reviewed the outcomes of our patients with respect to alkaline phosphatase levels. Between January 2003 and December 2008, we treated with the FOLFOX 4 regimen 103 consecutive patients with metastatic colorectal cancer. Thirty-two patients had alkaline phosphatase > or =300 U/l. Median time to progression was 4 months for patients with high alkaline phosphatase levels and 8 months for those with low alkaline phosphatase levels. Median overall survival was 8 and 17.5 months, respectively. Only 3 patients in the high alkaline phosphatase group obtained partial response (9.4%) compared to 3 complete responses and 24 partial responses (41.5%) in low alkaline phosphatase group. Toxicity was substantially different, with more grade 3-4 neutropenia, diarrhea and oral mucositis in the high than low alkaline phosphatase group. Alkaline phosphatase is an uncomplicated and potent prognostic factor. Patients with high alkaline phosphatase levels had a poor prognosis.


Gossypol as oral contraceptive for male: trial case report.
Gossypol has been used as oral contraceptive for man in People's Republic of China. There are also some reports of studies in which gossypol acetic acid is used in animal experiments. In this study we used tablet preparation of gossypol, which is actually used as oral contraceptive for male in People's Republic of China, on a volunteer. The administration of 20 mg/day gossypol tablets for 19 days resulted in a tendency of decreasing sperm density and total sperm count, but had no effect on serum LH, FSH, PRL or testosterone. Furthermore, the volunteer had no complaints of side effects and his general laboratory findings were normal. Ten days after the termination of gossypol administration, sperm density returned to its preadministrative level. Our study suggests gossypol may be effective as a male oral contraceptive with no acute side effect.


Proteomic characterization of epicardial-myocardial signaling reveals novel regulatory networks including a role for NF-κB in epicardial EMT.
Signaling between the epicardium and underlying myocardium is crucial for proper heart development. The complex molecular interactions and regulatory networks involved in this communication are not well understood. In this study, we integrated mass spectrometry with bioinformatics to systematically characterize the secretome of embryonic chicken EPDC-heart explant (EHE) co-cultures. The 150-protein secretome dataset established greatly expands the knowledge base of the molecular players involved in epicardial-myocardial signaling. We identified proteins and pathways that are implicated in epicardial-myocardial signaling for the first time, as well as new components of pathways that are known to regulate the crosstalk between epicardium and myocardium. The large size of the dataset enabled bioinformatics analysis to deduce networks for the regulation of specific biological processes and predicted signal transduction nodes within the networks. We performed functional analysis on one of the predicted nodes, NF-κB, and demonstrate that NF-κB activation is an essential step in TGFβ2/PDGFBB-induced cardiac epithelial-to-mesenchymal transition. In summary, we have generated a global perspective of epicardial-myocardial signaling for the first time, and our findings open exciting new avenues for investigating the molecular basis of heart development and regeneration.


Structural analysis of raw and commercial farm edible bird nests.
Edible bird nests (EBNs) are consumed worldwide for various health benefits. EBNs are nests built from the saliva of swiftlets of Aerodramus species. The global market for EBNs is on the rise, especially from Hong Kong and mainland China. In the past, EBNs were harvested mainly from natural caves; however in the recent years, there has been a rapid growth of swiftlet farming. Little is known about the actual composition of EBNs except for protein, carbohydrate, ash and lipid contents, amino acids, vitamins and macro/ micronutrients. Besides the biochemical components of EBNs, are there any other structures that are associated with EBNs? This paper reports on the structural analysis of raw unprocessed farm and processed commercial EBNs. The raw EBNs were purchased from swiftlet farms in five locations in Peninsula Malaysia: Kuala Sanglang (Perlis; 6° 16' 0"N, 100° 12' 0"E), Pantai Remis (Perak; 4º 27' 0" N, 100º 38' 0" E), Kluang (Johor; 02º 012 303N 103º 192 583E), Kajang (Selangor; 2º 59' 0"N, 101º 47' 0"E) and Kota Bharu (Kelantan; 6º 8' 0"N, 102º 15' 0"E). The commercial nests were purchased from five different Chinese traditional medicinal shops (Companies A-E). A portion of each EBN was randomly broken into small fragments, attached to carbon tape and coated with gold and palladium particles for examination and photography under a scanning electron microscope. Structural analysis revealed the presence of mites, fungi, bacteria and feather strands on both the raw and commercial nests. Mite eggshells and faecal pellets, and body parts of other arthropods were seen only in the raw nests. The commercial nests had a variety of unidentified structures and substances coated on the nests' surfaces that were not found on the raw nests. The presence of these contaminants may jeopardise the quality of EBNs and pose health risks to consumers. Further identification of the mites and their allergens, fungi and bacteria are on-going and will be reported separately.


Improving Community Advisory Board Engagement in Precision Medicine Research to Reduce Health Disparities.
Community Advisory Boards (CABs) are used in efforts to reduce health disparities; however, there is little documentation in the literature regarding their use in precision medicine research. In this case study, an academic-CAB partnership developed a questionnaire and patient educational materials for two precision smoking cessation interventions that involved use of genetic or genetically-informed information. The community-engaged research (CEnR) literature provided a framework for enhancing benefits to CAB members involved in developing research documents for use with a low-income, ethnically diverse population of smokers.The academic partners integrated three CEnR strategies: 1) in-meeting statements acknowledging their desire to learn from community partners, 2) in-meeting written feedback to and from community partners, and 3) a survey to obtain CAB member feedback post-meetings. Strategies 1 and 2 yielded modifications to pertinent study materials, as well as suggestions for improving meeting operations that were then adopted, as appropriate, by the academic partners. The survey indicated that CAB members valued the meeting procedure changes which appeared to have contributed to improvements in attendance and satisfaction with the meetings. Further operationalization of relevant partnership constructs and development of tools for measuring these aspects of community-academic partnerships is warranted to support community engagement in precision medicine research studies.


Analysis of a mutant of Autographa california nuclear polyhedrosis virus with a defect in the morphogenesis of the occlusion body macromolecular lattice.
A mutant (m-29) of Autographa californica nuclear polyhedrosis virus (AcMNPV) grew in Spodoptera frugiperda and Trichoplusia ni cells but did not form typical intranuclear occlusion bodies (OB); instead, small particles (95 to 180 nm diam.) were produced in copious amounts within nuclei. Ultrastructural studies showed that the particles did not occlude enveloped nucleocapsids and that they lacked a macromolecular paracrystalline lattice and a structure equivalent to the occlusion body envelope. The particles within nuclei stained in an immunofluorescence test with antipolyhedrin antibody and when extracted from cells the major polypeptide of a particle preparation was indistinguishable from polyhedrin when examined on SDS--polyacrylamide gels and had an identical peptide pattern following proteolysis with V8 protease. Other elements believed to be implicated in OB morphogenesis such as a proliferation of intranuclear membranes, enveloped bundles of nucleocapsids, patches of fibrous material and fibrous sheets were present in normal amounts. No alteration in the synthesis or processing of polypeptides was seen in mutant-infected cells. Analysis of m-29 DNA with BamHI, EcoRI and HindIII restriction endonucleases revealed that the HindIII restriction site at the F/V junction of viral DNA was absent in the mutant. No other modifications in the restriction patterns were detected. It is proposed that an alteration in the amino acid sequence of polyhedrin towards the--NH2 terminus of the polypeptide may account for the growth characteristics of the mutant.


Congenital heart disease and heart failure.
The syndrome of heart failure in adult non-congenital heart disease patients includes myocardial disease and ventricular dysfunction. In the presence of congenital abnormalities the cause of heart failure is often multi-factorial and can be a result of the underlying anomaly, surgical intervention, or ventricular dysfunction. Despite the possible clinical similarities, the two conditions are fundamentally different. In congenital heart disease the neurohormonal system is already abnormal even in the absence of clinical manifestations of heart failure and, in many cases, exercise intolerance is related to cyanosis. The approach to heart failure management in the two etiologies might be similar. Preventative attempts to preserve ventricular function in coronary or valve disease parallels early reparative therapy in congenital heart disease Pharmacological therapy is common for the two conditions, despite the limited number of evidence-based recommendations for congenital diseases. In drug-resistant patients, cardiac electrical resynchronization is an established therapy for treating ventricular asynchrony in non-congenital heart failure sufferers, but has only recently been adopted in selected congenital cases. Due to this, congenital heart disease patients are managed in highly specialized unites in close cooperation with cardiologists and surgeons. The ideal follow-up protocol for such patients remains to be determined, particularly in those individuals with subclinical signs of residual cardiac dysfunction. Heart Fail Monit 2008;6(1):2-8.


Development and evaluation of a short version of the quality of life questionnaire for dementia.
There are many quality of life (QOL) instruments for evaluating dementia patients. The QOL questionnaire for Dementia (QOL-D) is one of such instruments and a validated objective measure of QOL for patients with dementia. It comprises 31 items encompassing six domains. However, with 31 items, its length is a disadvantage. The purpose of this study was to develop a short version of QOL-D (short QOL-D). We used data from two studies. The participants were 264 inpatients with dementia in the first sample and 395 outpatients at a memory clinic in the second sample. We used maximum likelihood factor analysis with promax rotation to reduce the number of items. We produced a nine-item version of QOL-D (short QOL-D) with positive (six items) and negative (three items) dimensions. The correlation coefficients of short and total versions of QOL-D were 0.892-0.918 for total scores, 0.903-0.936 for positive dimension scores, and 0.788-0.837 for negative dimension scores. Total short QOL-D scores showed a significant correlation to the Geriatric Depression Scale score and the apathy score of the Neuropsychiatric Inventory. The short QOL-D produced results comparable with that of the full version. Reducing the number of items may make administration of the instrument easier.


Uptake and trafficking of liposomes to the endoplasmic reticulum.
Liposomes are vesicular structures consisting of an aqueous core surrounded by a lipid bilayer. Apart from the cytosol and lysosomes, no other intracellular compartment has been successfully targeted using liposomal delivery. Here, we report the development of liposomes capable of specific targeting to the endoplasmic reticulum (ER) and associated membranes. Using competition and inhibitor assays along with confocal microscopy, we have determined that ER liposomes utilize scavenger and low-density lipoprotein receptors for endocytosis and enter cells through a caveolin- and microtubule-dependent mechanism. They traffic intact to the ER, where fusion with the ER membrane occurs after 22-25 min, which was confirmed by fluorescence-dequenching assays. Once inside the ER, tagged lipids intercalate with the ER membrane and are subsequently incorporated into ER-assembling entities, such as the ER-budding viruses hepatitis C virus (HCV) and bovine viral diarrhea virus (BVDV), lipid droplets, and secreted lipoproteins. ER liposomes are superior to cytosolic liposome formulations for the intracellular delivery of aqueous cargo, such as HIV-1 antivirals, and are especially suited for the prolonged delivery of lipids and lipophilic drugs into human cells.


[Long-term risk of osteoporotic fracture in Belgium].
This work has been realised to estimate the lifetime risk of osteoporotic fracture for Belgian men and women aged 50 and 60 years. Estimates were based on a microsimulation Markov model. They take account of the incidence of fracture as well as of life expectancy. Several approaches have been taken to model life expectancy. Our estimates also take account of future mortality reductions based on official estimates and secular trends in life expectancy. Lifetime risk of osteoporotic population (bone mineral density below -2.5 T-score) was also estimated. Lifetime risk of hip fracture and any major osteoporotic fracture (hip, clinical vertebral or wrist) were 20.5% and 39% respectively for women aged 60 years. Corresponding values for men were 7.9% and 14.8% and for osteoporotic women 32.3% and 53.4%. Our lifetime risk estimates re-emphasize that osteoporosis is a major public health problem and that its societal burden is likely to increase due to demographic changes.


Connexin 43 channels are essential for normal bone structure and osteocyte viability.
Connexin (Cx) 43 serves important roles in bone function and development. Targeted deletion of Cx43 in osteoblasts or osteocytes leads to increased osteocyte apoptosis, osteoclast recruitment, and reduced biomechanical properties. Cx43 forms both gap junction channels and hemichannels, which mediate the communication between adjacent cells or between cell and extracellular environments, respectively. Two transgenic mouse models driven by a DMP1 promoter with the overexpression of dominant negative Cx43 mutants were generated to dissect the functional contribution of Cx43 gap junction channels and hemichannels in osteocytes. The R76W mutant blocks the gap junction channel, but not the hemichannel function, and the Δ130-136 mutant inhibits activity of both types of channels. Δ130-136 mice showed a significant increase in bone mineral density compared to wild-type (WT) and R76W mice. Micro-computed tomography (µCT) analyses revealed a significant increase in total tissue and bone area in midshaft cortical bone of Δ130-136 mice. The bone marrow cavity was expanded, whereas the cortical thickness was increased and associated with increased bone formation along the periosteal area. However, there is no significant alteration in the structure of trabecular bone. Histologic sections of the midshaft showed increased apoptotic osteocytes in Δ130-136, but not in WT and R76W, mice which correlated with altered biomechanical and estimated bone material properties. Osteoclasts were increased along the endocortical surface in both transgenic mice with a greater effect in Δ130-136 mice that likely contributed to the increased marrow cavity. Interestingly, the overall expression of serum bone formation and resorption markers were higher in R76W mice. These findings suggest that osteocytic Cx43 channels play distinctive roles in the bone; hemichannels play a dominant role in regulating osteocyte survival, endocortical bone resorption, and periosteal apposition, and gap junction communication is involved in the process of bone remodeling.


Localization of 5-HT2A, 5-HT3, 5-HT5A and 5-HT7 receptor-like immunoreactivity in the rat cerebellum.
Although serotonin (5-hydroxytryptamine, 5-HT) is known to exert a modulatory action on cerebellar function, our current knowledge of the nature of receptor subtypes mediating serotonergic activity in this part of the brain remains fragmentary. In this study, we report the presence and distribution of 5-HT3, 5-HT5A and 5-HT7 receptor-like immunoreactivity in the rat cerebellum using immunofluorescence histochemistry. 5-HT3 immunoreactivity was found in fibers sparsely distributed throughout the cerebellum. Most of them were seen in the cerebellar cortex as fine varicose 5-HT3-positive axonal processes. 5-HT5A immunoreactivity, on the other hand, was observed in neuronal somata of the cerebellar cortex and deep cerebellar nuclei. Based upon cell morphology and the use of cell-specific markers, Purkinje cells, molecular layer interneurons and Golgi cells were found to be 5-HT5A immunopositive. In addition, the use of cell-specific markers allowed us to identify previously reported large 5-HT2A-positive cells in the granular layer as being Golgi cells. Finally, 5-HT7 immunoreactivity was observed only in Purkinje cells. Corroborating previous radioligand-binding, in situ hybridization and immunohistochemical studies, our data relate serotonin receptor subtypes to specific cerebellar cell types and may consequently contribute to the elucidation of serotonergic actions in the cerebellum.


Comparison of 2 Radiographic Techniques for Measurement of Tibiofemoral Joint Space Width.
No consensus is available regarding the best method for measuring tibiofemoral joint space width (JSW) on radiographs to quantify joint changes after injury. Studies that track articular cartilage thickness after injury frequently use patients' uninjured contralateral knees as controls, although the literature supporting this comparison is limited. (1) To compare JSW measurements using 2 established measurement techniques in healthy control participants and (2) to determine whether the mean JSW of the uninjured contralateral knee in a cohort with anterior cruciate ligament (ACL) reconstruction is different from that obtained from a true control population. Cohort study (diagnosis); Level of evidence, 2. Medial and lateral JSWs were measured on standardized, bilateral, semiflexed metatarsophalangeal positioning, posteroanterior radiographs of 60 healthy individuals (26 females; mean ± SD age, 25 ± 6.2 years; no history of knee injury) via 2 published techniques: a computerized surface-delineation method (surface-fit method) and a manual digitization method (midpoint method). Bland-Altman method was used to examine the agreement between JSW measurements obtained with the 2 methods and to examine the agreement between measurements obtained on left and right knees within a participant for each measurement method. Within- and between-participant variance components and intraclass correlation coefficients (ICCs) were computed for JSW measurements corresponding to each method. Two-sample t tests were used to compare the surface-fit method measurements of mean JSW of the true control group (n = 60) with the previously published mean JSW measurements from the Multicenter Orthopaedics Outcomes Network (MOON) nested cohort of 262 contralateral uninjured knees 2 to 3 years after ACL reconstruction. For JSW in the medial compartment, the surface-fit method had lower within-participant interknee variability (σ2within, 0.064; 95% CI, 0.04-0.09) compared with the midpoint method (σ2within, 0.28; 95% CI, 0.20-0.43) and a higher ICC (0.93 vs 0.65; P < .001). Lateral JSW values were similar for the surface-fit method (σ2within, 0.27; 95% CI, 0.18-0.43) and the midpoint method (σ2within, 0.20; 95% CI, 0.14-0.31), with ICCs of 0.75 and 0.77, respectively (P = .80). With the surface-fit method, mean JSW measurements of the medial and lateral compartments of a control population were not significantly different from the contralateral uninjured knees of patients after ACL reconstruction. For measuring medial JSW, the surface-fit method was less variable across knees within a participant than the midpoint method, as evidenced by larger ICCs and lower interknee variability. For measuring lateral JSW, the 2 methods were similar. The JSW measurements of uninjured contralateral knees of patients with ACL reconstruction at 2 to 3 years postsurgery were not significantly different from those of a cohort of healthy control participants. Future work should be performed to demonstrate the validity of these methods for documenting change over time in the ACL-reconstructed knee.


Association of air pollution exposure and increased coronary artery disease risk: the modifying effect of genetic susceptibility.
Both genetic factors and air pollution are risk factors for coronary artery disease (CAD), but their combined effects on CAD are uncertain. The study aimed to comprehensively investigate their separate, combined and interaction effects on the onset of CAD. We utilized data from the UK Biobank with a recruitment of 487,507 participants who were free of CAD at baseline from 2006 to 2010. We explored the separate, combined effect or interaction association among genetic factors, air pollution and CAD with the polygenic risk score (PRS) and Cox proportional hazard models. The hazard ratios (HRs) [95% confidence interval (CI)] of CAD for 10-µg/m3 increases in PM2.5, NO2 and NOx concentrations were 1.25 (1.09, 1.44), 1.03 (1.01, 1.05) and 1.01 (1.00, 1.02), respectively. Participants with high PRS and air pollution exposure had a higher risk of CAD than those with the low genetic risk and low air pollution exposure, and the HRs (95% CI) of CAD in the PM2.5, PM10, NO2 and NOx high joint exposure groups were 1.56 (1.48, 1.64), 1.55(1.48, 1.63), 1.57 (1.49, 1.65), and 1.57 (1.49, 1.65), respectively. Air pollution and genetic factors exerted significant additive effects on the development of CAD (relative excess risk due to the interaction [RERI]: 0.12 (0.05, 0.19) for PM2.5, 0.17 (0.10, 0.24) for PM10, 0.14 (0.07, 0.21) for NO2, and 0.17 (0.10, 0.24) for NOx; attributable proportion due to the interaction [AP]: 0.09 (0.04, 0.14) for PM2.5, 0.12 (0.07, 0.18) for PM10, 0.11 (0.06, 0.16) for NO2, and 0.13 (0.08, 0.18) for NOx). Exposure to air pollution was significantly related to an increased CAD risk, which could be further strengthened by CAD gene susceptibility. Additionally, there were positive additive interactions between genetic factors and air pollution on the onset of CAD. This can provide a more comprehensive, precise and individualized scientific basis for the risk assessment, prevention and control of CAD.


Infliximab aggregates produced in severe and mild elevated temperature stress conditions induce an extended specific CD4 T-cell response.
Aggregation has been widely described as a factor contributing to therapeutic antibody immunogenicity. Although production of high-affinity anti-drug antibodies depends on the activation of CD4 T lymphocytes, little is known about the T-cell response induced by antibody aggregates, especially for aggregates produced in mild conditions resulting from minor handling errors of vials. Large insoluble infliximab (IFX) aggregates produced in severe elevated temperature stress conditions have been previously shown to induce human monocyte-derived dendritic cell (moDC) maturation. We here showed that large IFX aggregates recruit in vitro a significantly higher number of CD4 T-cells compared to native IFX. Moreover, a larger array of T-cell epitopes encompassing the entire variable regions was evidenced compared to the native antibody. We then compared the responses of moDCs to different types of aggregates generated by submitting IFX to mild conditions of various times of incubation at an elevated temperature. Decreasing stress duration reduced aggregate size and quantity, and subsequently altered moDC activation. Of importance, IFX aggregates generated in mild conditions and not altering moDC phenotype generated an in vitro T-cell response with a higher frequency of CD4 T cells compared to native IFX. Moreover, cross-reactivity studies of aggregate-specific T cells showed that some T cells could recognize both native and aggregated IFX, while others responded only to IFX aggregates. Taken together, our results suggest that aggregation of antibodies in mild elevated temperature stress conditions is sufficient to alter moDC phenotype in a dose-dependent manner and to increase T-cell response.


[Psychotherapeutic correction of affective disorders in women participating in the program of assisted reproductive technologies].
To study peculiarities of mental disorders in women during treatment of sterility using current reproductive technologies (extracorporeal fertilization), 512 women, mean age 33,6+3,7 years and sterility duration 3,1+/-2,2 years (from 1 to 5 years) have been examined. A number of attempts to treat sterility varied from 1 to 10. In 266 (52%) patients, borderline mental disorders have been found. Anxiety and depressive disorders made up 31,2%. A significant role of stress in their manifestation and a negative influence of mental disorders on treatment outcome and possibility of remission has been revealed. The use of cognitive-behavioral psychotherapy resulted in the decrease of expression of mental disorders and adequately prepared patients to the treatment thus improving its results.


MRI apparent diffusion coefficient reflects histopathologic subtype, axonal disruption, and tumor fraction in diffuse-type grade II gliomas.
The apparent diffusion coefficient (ADC) determined from MR diffusion tensor imaging (DTI) has shown promise for distinguishing World Health Organization grade II astrocytoma (AS) from the more prognostically favorable grade II oligodendroglioma (OD). Since mixed oligoastrocytomas (OAs) with codeletions in chromosomes 1p and 19q confer prognoses similar to those of OD, we questioned whether a previously determined ADC-based criterion for distinguishing OD and AS would hold on an independent set of gliomas that included OA with codeleted or intact 1p/19q chromosomes. We also questioned whether the ADC is associated with the tumor microstructure. ADC colormaps generated from presurgical DTI scans were used to guide the collection of biopsies from each tumor. The median normalized ADC distinguished OD from AS with 91% sensitivity and 92% specificity. 1p/19q codeleted OAs were always classified as ODs, while 1p/19q intact OAs were always classified as ASs. There were positive associations between the ADC and both the SMI-31 score of axonal disruption and the fraction of tumor cells in the biopsies. The ADC of OD and 1p/19q codeleted OA was more associated with tumor fraction, while the ADC of AS and 1p/19q intact OA was more associated with SMI-31 score. We conclude that our previously determined threshold median ADC can distinguish grade II OD and AS on a new patient cohort and that the distinctions extend to OA with codeleted and intact 1p/19q chromosomes. Further, the ADC in grade II gliomas is associated with the fraction of tumor cells and degree of axonal disruption in tumor subregions.


Inositol hexakisphosphate is bound in the ADAR2 core and required for RNA editing.
We report the crystal structure of the catalytic domain of human ADAR2, an RNA editing enzyme, at 1.7 angstrom resolution. The structure reveals a zinc ion in the active site and suggests how the substrate adenosine is recognized. Unexpectedly, inositol hexakisphosphate (IP6) is buried within the enzyme core, contributing to the protein fold. Although there are no reports that adenosine deaminases that act on RNA (ADARs) require a cofactor, we show that IP6 is required for activity. Amino acids that coordinate IP6 in the crystal structure are conserved in some adenosine deaminases that act on transfer RNA (tRNA) (ADATs), related enzymes that edit tRNA. Indeed, IP6 is also essential for in vivo and in vitro deamination of adenosine 37 of tRNAala by ADAT1.