Antigenic structure of transmissible gastroenteritis virus. II. Domains in the peplomer glycoprotein.
The antigenic structure of the peplomer glycoprotein E2 of the porcine transmissible gastroenteritis coronavirus (TGEV) was explored using a panel of 23 hybridoma antibodies (MAbs). The topography of the epitopes was established by means of a competition radioimmunoassay. Four main antigenic sites, termed A, B, C and D, were thus clearly delineated. Most of the neutralization-mediating determinants were found to cluster in the A-B area, which has been shown to be highly conserved among TGEV strains. Cooperative enhancement of binding to sites B and D was observed following attachment of MAbs relevant to site A. Additional epitopes were identified on E2 by MAbs that selectively recognized its intracellular precursor. Functional mapping was also performed using neutralization-resistant variants. Analysis of their reactivity confirmed part of the epitope linkages defined by the first approach. The overall lower frequency of such variants altered at site A suggested that some of the epitopes may play an essential function.


Rare genetic variants in SEC24D modify orofacial cleft phenotypes.
As one of the most common structural birth defects, orofacial clefts (OFCs) have been studied for decades, and recent studies have demonstrated that there are genetic differences between the different phenotypic presentations of OFCs. However, the contribution of rare genetic variation genome-wide to different subtypes of OFCs has been understudied, with most studies focusing on common genetic variation or rare variation within targeted regions of the genome. Therefore, we used whole-genome sequencing data from the Gabriella Miller Kids First Pediatric Research Program to conduct a gene-based burden analysis to test for genetic modifiers of cleft lip (CL) vs cleft lip and palate (CLP). We found that there was a significantly increased burden of rare variants in SEC24D in CL cases compared to CLP cases (p=6.86×10-7). Of the 15 variants within SEC24D, 53.3% were synonymous, but overlapped a known craniofacial enhancer. We then tested whether these variants could alter predicted transcription factor binding sites (TFBS), and found that the rare alleles destroyed binding sites for 9 transcription factors (TFs), including Pax1 (p=0.0009), and created binding sites for 23 TFs, including Pax6 (p=6.12×10-5) and Pax9 (p= 0.0001), which are known to be involved in normal craniofacial development, suggesting a potential mechanism by which these synonymous variants could have a functional impact. Overall, this study demonstrates that rare genetic variation contributes to the phenotypic heterogeneity of OFCs and suggests that regulatory variation may also contribute and warrant further investigation in future studies of genetic variants controlling risk to OFC.


A Systems Approach to Evaluate One Health Initiatives.
Challenges calling for integrated approaches to health, such as the One Health (OH) approach, typically arise from the intertwined spheres of humans, animals, and ecosystems constituting their environment. Initiatives addressing such wicked problems commonly consist of complex structures and dynamics. As a result of the EU COST Action (TD 1404) "Network for Evaluation of One Health" (NEOH), we propose an evaluation framework anchored in systems theory to address the intrinsic complexity of OH initiatives and regard them as subsystems of the context within which they operate. Typically, they intend to influence a system with a view to improve human, animal, and environmental health. The NEOH evaluation framework consists of four overarching elements, namely: (1) the definition of the initiative and its context, (2) the description of the theory of change with an assessment of expected and unexpected outcomes, (3) the process evaluation of operational and supporting infrastructures (the "OH-ness"), and (4) an assessment of the association(s) between the process evaluation and the outcomes produced. It relies on a mixed methods approach by combining a descriptive and qualitative assessment with a semi-quantitative scoring for the evaluation of the degree and structural balance of "OH-ness" (summarised in an OH-index and OH-ratio, respectively) and conventional metrics for different outcomes in a multi-criteria-decision-analysis. Here, we focus on the methodology for Elements (1) and (3) including ready-to-use Microsoft Excel spreadsheets for the assessment of the "OH-ness". We also provide an overview of Element (2), and refer to the NEOH handbook for further details, also regarding Element (4) (http://neoh.onehealthglobal.net). The presented approach helps researchers, practitioners, and evaluators to conceptualise and conduct evaluations of integrated approaches to health and facilitates comparison and learning across different OH activities thereby facilitating decisions on resource allocation. The application of the framework has been described in eight case studies in the same Frontiers research topic and provides first data on OH-index and OH-ratio, which is an important step towards their validation and the creation of a dataset for future benchmarking, and to demonstrate under which circumstances OH initiatives provide added value compared to disciplinary or conventional health initiatives.


Phenotypic expression of autoimmune autistic disorder (AAD): a major subset of autism.
Autism causes incapacitating neurologic problems in children that last a lifetime. The author of this article previously hypothesized that autism may be caused by autoimmunity to the brain, possibly triggered by a viral infection. This article is a summary of laboratory findings to date plus new data in support of an autoimmune pathogenesis for autism. Autoimmune markers were analyzed in the sera of autistic and normal children, but the cerebrospinal fluid (CSF) of some autistic children was also analyzed. Laboratory procedures included enzyme-linked immunosorbent assay and protein immunoblotting assay. Autoimmunity was demonstrated by the presence of brain autoantibodies, abnormal viral serology, brain and viral antibodies in CSF, a positive correlation between brain autoantibodies and viral serology, elevated levels of proinflammatory cytokines and acute-phase reactants, and a positive response to immunotherapy. Many autistic children harbored brain myelin basic protein autoantibodies and elevated levels of antibodies to measles virus and measles-mumps-rubella (MMR) vaccine. Measles might be etiologically linked to autism because measles and MMR antibodies (a viral marker) correlated positively to brain autoantibodies (an autoimmune marker)--salient features that characterize autoimmune pathology in autism. Autistic children also showed elevated levels of acute-phase reactants--a marker of systemic inflammation. The scientific evidence is quite credible for our autoimmune hypothesis, leading to the identification of autoimmune autistic disorder (AAD) as a major subset of autism. AAD can be identified by immune tests to determine immune problems before administering immunotherapy. The author has advanced a speculative neuroautoimmune (NAI) model for autism, in which virus-induced autoimmunity is a key player. The latter should be targeted by immunotherapy to help children with autism.


MicroRNA-182 modulates chemosensitivity of human non-small cell lung cancer to cisplatin by targeting PDCD4.
Overexpression of microRNA-182 (miR-182) is found in various human cancers, including non-small cell lung cancer (NSCLC). Our aim is to investigate the association of miR-182 expression with the sensitivity of NSCLC to cisplatin. TaqMan RT-PCR or Western blot assay was performed to detect the expression of mature miR-182 and programmed cell death 4 (PDCD4) protein. miR-182 and (or) PDCD4 depleted cell lines were generated using miR-182 inhibitor and (or) siRNA. The viabilities of treated cells were analyzed using MTT assay. The expression level of miR-182 in A549 cell line was significantly higher than that in NHBE cell line (p < 0.01). Transfection of miR-182 inhibitor induced sensitivity of A549 cells to cisplatin. A549 cells transfected with PDCD4 siRNA became more resistant to cisplatin therapy. We found an increase PDCD4 protein level following the transfection of miR-182 inhibitor using Western blot analysis. In addition, the enhanced growth-inhibitory effect by miR-182 inhibitor was weakened after the addition of PDCD4 siRNA. The results of the present study demonstrated that overexpression of miR-182 may involve in chemoresistance of NSCLC cells to cisplatin by down-regulating PDCD4. The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1793467320130186.


XMRV: does this virus hold the key to myalgic encephalomyelitis/CFS?
In October 2009 a team of researchers from the Whittemore Peterson Institute, in association with the National Cancer Institute and the Cleveland Clinic in the USA, made a discovery that could potentially open the door to useful treatments for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). The researchers, led by Judy Mikovits, discovered a significant correlation between ME/CFS and an infectious retrovirus called xenotropic murine leukaemia virus-related virus (XMRV). XMRV is classified as a gammaretrovirus, belonging to the same broad family as HIV, but more closely related to a group of viruses that cause cancers such as leukaemia. XMRV is the first member of the gammaretrovirus genus of retroviruses to be found in humans; the research to fully understand the connection between ME/CFS and XMRV, as well as what it means to have the virus, is ongoing. The disastrous impact of AIDS on human health has significantly raised the profile of retroviruses as human pathogens, and XMRV has potentially serious health implications not only for patients, but also for those caring for people with ME/CFS.


Using impairment and cognitions to predict walking in osteoarthritis: A series of n-of-1 studies with an individually tailored, data-driven intervention.
First, this study compares the ability of an integrated model of activity and activity limitations, the International Classification of Functioning, Disability and Health (ICF), and the Theory of Planned Behaviour (TPB) to predict walking within individuals with osteoarthritis. Second, the effectiveness of a walking intervention in these individuals is determined. A series of n-of-1 studies with an AB intervention design was used. Diary methods were used to study four community-dwelling individuals with lower-limb osteoarthritis. Data on impairment symptoms (pain, pain on movement, and joint stiffness), cognitions (intention, self-efficacy, and perceived controllability), and walking (step count) were collected twice daily for 12 weeks. At 6 weeks, an individually tailored, data-driven walking intervention using action planning or a control cognition manipulation was delivered. Simulation modelling analysis examined cross-correlations and differences in baseline and intervention phase means. Post-hoc mediation analyses examined theoretical relationships and multiple regression analyses compared theoretical models. Cognitions, intention in particular, were better and more consistent within individual predictors of walking than impairment. The walking intervention did not increase walking in any of the three participants receiving it. The integrated model and the TPB, which recognize a predictive role for cognitions, were significant predictors of walking variance in all participants, whilst the biomedical ICF model was only predictive for one participant. Despite the lack of evidence for an individually tailored walking intervention, predictive data suggest that interventions for people with osteoarthritis that address cognitions are likely to be more effective than those that address impairment only. Further within-individual investigation, including testing mediational relationships, is warranted. What is already known on this subject? N-of-1 methods have been used to study within-individual predictors of walking in healthy and chronic pain populations An integrated biomedical and behavioural model of activity and activity limitations recognizes the roles of impairment and psychology (cognitions) Interventions modifying cognitions can increase physical activity in people with mobility limitations What does this study add? N-of-1 methods are suitable to study within-individual predictors of walking and interventions in osteoarthritis An integrated and a psychological model are better predictors of walking in osteoarthritis than a biomedical model There was no support for an individually tailored, data-driven walking intervention.


The roles of energy and material efficiency in meeting steel industry CO2 targets.
Identifying strategies for reducing greenhouse gas emissions from steel production requires a comprehensive model of the sector but previous work has either failed to consider the whole supply chain or considered only a subset of possible abatement options. In this work, a global mass flow analysis is combined with process emissions intensities to allow forecasts of future steel sector emissions under all abatement options. Scenario analysis shows that global capacity for primary steel production is already near to a peak and that if sectoral emissions are to be reduced by 50% by 2050, the last required blast furnace will be built by 2020. Emissions reduction targets cannot be met by energy and emissions efficiency alone, but deploying material efficiency provides sufficient extra abatement potential.


A comparison of prostate cancer survival in England, Norway and Sweden: a population-based study.
The objective of the study was to compare patterns of survival 2001-2004 in prostate cancer patients from England, Norway and Sweden in relation to age and period of follow-up. Excess mortality in men with prostate cancer was estimated using nation-wide cancer register data using a period approach for relative survival. 179,112 men in England, 23,192 in Norway and 59,697 in Sweden were included. In all age groups, England had the lowest survival, particularly so among men aged 80+. Overall age-standardised five-year survival was 76.4%, 80.3% and 83.0% for England, Norway and Sweden, respectively. The majority of the excess deaths in England were confined to the first year of follow-up. The results indicate that a small but important group of older patients present at a late stage and succumb early to their cancers, possibly in combination with severe comorbidity, and this situation is more common in England than in Norway or Sweden.


Immunopathology of bullous pemphigoid, an autoimmune and inflammatory skin blistering disease.
Bullous pemphigoid (BP) was first described by Lever in 1953 as a subepidermal blistering disease. Key immunohistological features of BP include dermo-epidermal junction (DEJ) separation, an inflammatory cell infiltrate in the upper dermis, and autoantibodies directed against two emidesmosomal antigens, BP230 and BP180. In 1993, an IgG passive transfer mouse model of BP was developed by administering rabbit anti-murine BP180 antibodies to neonatal mice. This model recapitulates the key features of human BP. Systematic dissection of this BP model has revealed that subepidermal blistering is initiated by anti-BP180 antibodies and mediated by complement activation, mast cell degranulation, and neutrophil infiltration. Proteinases and reactive oxygen species released by infiltrating neutrophils work together to damage the basement membrane zone (BMZ), causing a subepidermal blister. Recently, another novel mouse model for BP has been developed by active immunization. C57BL/6J mice actively immunized with murine BP180 develop BP-like skin lesions. The IgG passive transfer and active models of BP provide us with invaluable in vivo systems not only for dissecting cellular and humoral responses in BP but also for developing effective therapies for this disease.


Failure of bone morphogenetic protein receptor trafficking in pulmonary arterial hypertension: potential for rescue.
Heterozygous germline mutations in the gene encoding the bone morphogenetic protein type II receptor cause familial pulmonary arterial hypertension (PAH). We previously demonstrated that the substitution of cysteine residues in the ligand-binding domain of this receptor prevents receptor trafficking to the cell membrane. Here we demonstrate the potential for chemical chaperones to rescue cell-surface expression of mutant BMPR-II and restore function. HeLa cells were transiently transfected with BMPR-II wild type or mutant (C118W) receptor constructs. Immunolocalization studies confirmed the retention of the cysteine mutant receptor mainly in the endoplasmic reticulum. Co-immunoprecipitation studies of Myc-tagged BMPR-II confirmed that the cysteine-substituted ligand-binding domain mutation, C118W, is able to associate with BMP type I receptors. Furthermore, following treatment with a panel of chemical chaperones (thapsigargin, glycerol or sodium 4-phenylbutyrate), we demonstrated a marked increase in cell-surface expression of mutant C118W BMPR-II by FACS analysis and confocal microscopy. These agents also enhanced the trafficking of wild-type BMPR-II, though to a lesser extent. Increased cell-surface expression of mutant C118W BMPR-II was associated with enhanced Smad1/5 phosphorylation in response to BMPs. These findings demonstrate the potential for rescue of mutant BMPR-II function from the endoplasmic reticulum. For the C118W mutation in the ligand-binding domain of BMPR-II, cell-surface rescue leads to at least partial restoration of BMP signalling. We conclude that enhancement of cell-surface trafficking of mutant and wild-type BMPR-II may have therapeutic potential in familial PAH.


Multidisciplinary biopsychosocial rehabilitation for neck and shoulder pain among working age adults.
Multidisciplinary biopsychosocial rehabilitation programs for neck and shoulder pain require substantial staff and financial resources. Despite questionable scientific evidence of their effectiveness, they are widely used. Neck and shoulder complaints are common among working age adults and they are often associated with physical work load and stress. Pain in the neck and shoulder area cause biopsychosocial difficulties for the patient, especially if disability due to pain is prolonged. To help patients with biopsychosocial problems, or to prevent their development, multidisciplinary biopsychosocial programs are used for rehabilitation for patients with neck and shoulder pain. Nevertheless, multidisciplinary treatment programmes are often laborious and rather long processes and require good collaboration between the patient, the rehabilitation team and the work place. The objective of this systematic review was to determine the effectiveness of multidisciplinary biopsychosocial rehabilitation for neck and shoulder pain among working age adults. The reviewed studies for this review were electronically identified from MEDLINE, EMBASE, PsycLIT, CENTRAL, Medic, the Science Citation Index, reference checking and consulting experts in the rehabilitation field. The original search was planned and performed for more broad area of musculoskeletal disorders. Trials on neck and shoulder pain were separated afterwards. The literature search was updated in November 2002 by electronically searching MEDLINE and EMBASE. From all references identified in our original search, we selected randomized controlled trials (RCTs) and non-randomized controlled clinical trials (CCTs). Trials had to assess the effectiveness of biopsychosocial rehabilitation for working age adults suffering from neck and shoulder pain. The rehabilitation program was required to be multidisciplinary, i.e., it had to consist of a physician's consultation plus either a psychological, social or vocational intervention, or a combination of these. Four reviewers blinded to journal and author selected the trials that met the specified inclusion criteria. Two experts in the field of rehabilitation evaluated the clinical relevance and applicability of the findings of the selected studies for actual clinical use. Two other reviewers blinded to journal and author extracted the data and assessed the main results and the methodological quality of the studies, using standardized forms. Finally, a qualitative analysis was performed to evaluate the level of scientific evidence for the effectiveness of multidisciplinary biopsychosocial rehabilitation. After screening 1808 abstracts, and the references of 65 reviews, we found only two relevant studies that satisfied our criteria. No more studies were found for this update. One of the studies was considered to be a methodologically low quality RCT and the other one was a methodologically low quality CCT. The clinical relevance of included studies was satisfactory. There was limited scientific evidence for the effectiveness of multidisciplinary biopsychosocial rehabilitation for neck and shoulder pain. We conclude that there appears to be little scientific evidence for the effectiveness of multidisciplinary biopsychosocial rehabilitation compared with other rehabilitation facilities for neck and shoulder pain. Multidisciplinary rehabilitation is a commonly used intervention for chronic neck and shoulder complaints, therefore we see an urgent need for high quality trials in this field.


Interaction between tumour-infiltrating B cells and T cells controls the progression of hepatocellular carcinoma.
The nature of the tumour-infiltrating leucocytes (TILs) is known to impact clinical outcome in carcinomas, including hepatocellular carcinoma (HCC). However, the role of tumour-infiltrating B cells (TIBs) remains controversial. Here, we investigate the impact of TIBs and their interaction with T cells on HCC patient prognosis. Tissue samples were obtained from 112 patients with HCC from Singapore, Hong Kong and Zurich and analysed using immunohistochemistry and immunofluorescence. RNA expression of CD19, CD8A, IFNG was analysed using quantitative PCR. The phenotype of freshly isolated TILs was analysed using flow cytometry. A mouse model depleted of mature B cells was used for functional study. Tumour-infiltrating T cells and B cells were observed in close contact with each other and their densities are correlated with superior survival in patients with HCC. Furthermore, the density of TIBs was correlated with an enhanced expression of granzyme B and IFN-γ, as well as with reduced tumour viability defined by low expression of Ki-67, and an enhanced expression of activated caspase-3 on tumour cells. CD27 and CD40 costimulatory molecules and TILs expressing activation marker CD38 in the tumour were also correlated with patient survival. Mice depleted of mature B cells and transplanted with murine hepatoma cells showed reduced tumour control and decreased local T cell activation, further indicating the important role of B cells. The close proximity of tumour-infiltrating T cells and B cells indicates a functional interaction between them that is linked to an enhanced local immune activation and contributes to better prognosis for patients with HCC.


Powered irrigation with suction evacuation for chronic rhinosinusitis in the office setting: A pilot study.
Bacterial infections in the form of adherent biofilms are frequently implicated in the pathogenesis and recalcitrance of chronic rhinosinusitis. The Hydrodebrider, a disposable powered irrigation and suction device, has been developed specifically to remove biofilm from the paranasal sinuses. We conducted a prospective study to evaluate the tolerability and efficacy of the Hydrodebrider in the office setting with the use of local anesthesia. Of the original 13 adults we recruited, 10 completed the entire study protocol. All enrolled patients had previously undergone sinus surgery that involved the creation of a maxillary antrostomy large enough to allow placement of a Hydrodebrider device, and the endoscopic findings in all patients were consistent with chronic sinusitis. The standard visual analog scale for pain (range: 0 to 10) was used to measure tolerability. The 20-Item Sino-Nasal Outcome Test (SNOT-20) for symptoms was completed at baseline and at 1 and 8 weeks after the procedure. The mean pain score obtained immediately after the procedure was only 2.3, indicating that the procedure was well tolerated. The mean SNOT-20 score trended toward improvement during the first week, but then returned to near-preprocedure levels at 8 weeks. In conclusion, powered irrigation with suction is a well-tolerated procedure in the office setting and might be a useful short-term adjunct in the management of recalcitrant chronic sinusitis.


Specific domains of FoxD4/5 activate and repress neural transcription factor genes to control the progression of immature neural ectoderm to differentiating neural plate.
FoxD4/5, a forkhead transcription factor, plays a critical role in establishing and maintaining the embryonic neural ectoderm. It both up-regulates genes that maintain a proliferative, immature neural ectoderm and down-regulates genes that promote the transition to a differentiating neural plate. We constructed deletion and mutant versions of FoxD4/5 to determine which domains are functionally responsible for these opposite activities, which regulate the critical developmental transition of neural precursors to neural progenitors to differentiating neural plate cells. Our results show that up-regulation of genes that maintain immature neural precursors (gem, zic2) requires the Acidic blob (AB) region in the N-terminal portion of the protein, indicating that the AB is the transactivating domain. Additionally, down-regulation of those genes that promote the transition to neural progenitors (sox) and those that lead to neural differentiation (zic, irx) involves: 1) an interaction with the Groucho co-repressor at the Eh-1 motif in the C-terminus; and 2) sequence downstream of this motif. Finally, the ability of FoxD4/5 to induce the ectopic expression of neural precursor genes in the ventral ectoderm also involves both the AB region and the Eh-1 motif; FoxD4/5 accomplishes ectopic neural induction by both activating neural precursor genes and repressing BMP signaling and epidermal genes. This study identifies the specific, conserved domains of the FoxD4/5 protein that allow this single transcription factor to regulate a network of genes that controls the transition of a proliferative neural ectodermal population to a committed neural plate population poised to begin differentiation.


Comparison of distal and proximal centralising devices in hip arthroplasty.
Centralising devices were introduced to ensure that the prosthesis is implanted in a neutral position and that a cement mantle of optimal thickness is achieved proximally and distally. A distal centralising device (DCD) is compared with a proximal midshaft centralising device (PCD) to test which one provides a more neutral prosthetic alignment. Thirty consecutive patients undergoing hemiarthroplasties for femoral neck fractures were studied prospectively. Patients were blindly randomised to receive either a femoral component with proximal midshaft centraliser or distal centraliser. Both components were implanted following the manufacturer's protocol. Postoperative true anteroposterior and lateral radiographs were made to assess the stem position. There was no statistically significant difference between the two groups in zones 1, 2, 3, 4, 5, 6 and 7 in both anteroposterior and lateral radiographic measurements. DCP and PCD both have similar centralisation and cement mantle. Future studies should be done to evaluate their long-term effect.


Epilepsy in cerebrovascular diseases: Review of experimental and clinical data with meta-analysis of risk factors.
Seizures may occur in close temporal association with a stroke or after a variable interval. Moreover, epilepsy is often encountered in patients with leukoaraiosis. Although early post-stroke seizures have been studied extensively, less attention has been paid to post-stroke epilepsy (PSE) and to epilepsy associated with leukoaraiosis (EAL). The aim of this paper is to review data concerning pathophysiology, prognosis, and treatment of PSE and EAL. We performed an extensive literature search to identify experimental and clinical articles on PSE and EAL. We also conducted a systematic review of risk factors for PSE and EAL among eligible studies. PSE is caused by enhanced neuronal excitability within and near the scar. The role played by white matter changes in EAL remains to be elucidated. Meta-analysis showed that cortical involvement (odds ratio [OR] 3.71, 95% confidence interval [CI] 2.34-5.90, p < 0.001), cerebral hemorrhage (OR 2.41, 95% CI 1.57-3.70, p < 0.001), and early seizures (OR 4.43, 95% CI 2.36-8.32, p < 0.001) are associated with an increased risk of PSE. As regards EAL, no prospective, population-based studies evaluated the role of different variables on seizure risk. Studies about the management of PSE are limited. PSE is generally well controlled by drugs. Data about risk factors, prognosis, and treatment of EAL are lacking. Pathophysiology and risk factors are well defined for PSE but need to be elucidated for EAL. Management of PSE and EAL relies on the clinician's judgment and should be tailored on an individual basis.


Modulating the binding of polycyclic aromatic hydrocarbons inside a hexacationic cage by anion-π interactions.
We report the template-directed synthesis of BlueCage(6+), a macrobicyclic cyclophane composed of six pyridinium rings fused with two central triazines and bridged by three paraxylylene units. These moieties endow the cage with a remarkably electron-poor cavity, which makes it a powerful receptor for polycyclic aromatic hydrocarbons (PAHs). Upon forming a 1:1 complex with pyrene in acetonitrile, however, BlueCage⋅6 PF6 exhibits a lower association constant Ka than its progenitor ExCage⋅6 PF6. A close inspection reveals that the six PF6(-) counterions of BlueCage(6+) occupy the cavity in a fleeting manner as a consequence of anion-π interactions and, as a result, compete with the PAH guests. This conclusion is supported by a one order of magnitude increase in the Ka value for pyrene in BlueCage(6+) when the PF6(-) counterions are replaced by much bulkier anions. The presence of anion-π interactions is supported by X-ray crystallography, and confirms the presence of a PF6(-) counterion inside its cavity.


Hardware Development and Locomotion Control Strategy for an Over-Ground Gait Trainer: NaTUre-Gaits.
Therapist-assisted body weight supported (TABWS) gait rehabilitation was introduced two decades ago. The benefit of TABWS in functional recovery of walking in spinal cord injury and stroke patients has been demonstrated and reported. However, shortage of therapists, labor-intensiveness, and short duration of training are some limitations of this approach. To overcome these deficiencies, robotic-assisted gait rehabilitation systems have been suggested. These systems have gained attentions from researchers and clinical practitioner in recent years. To achieve the same objective, an over-ground gait rehabilitation system, NaTUre-gaits, was developed at the Nanyang Technological University. The design was based on a clinical approach to provide four main features, which are pelvic motion, body weight support, over-ground walking experience, and lower limb assistance. These features can be achieved by three main modules of NaTUre-gaits: 1) pelvic assistance mechanism, mobile platform, and robotic orthosis. Predefined gait patterns are required for a robotic assisted system to follow. In this paper, the gait pattern planning for NaTUre-gaits was accomplished by an individual-specific gait pattern prediction model. The model generates gait patterns that resemble natural gait patterns of the targeted subjects. The features of NaTUre-gaits have been demonstrated by walking trials with several subjects. The trials have been evaluated by therapists and doctors. The results show that 10-m walking trial with a reduction in manpower. The task-specific repetitive training approach and natural walking gait patterns were also successfully achieved.


Reproducing static and dynamic biodiversity patterns in tropical forests: the critical role of environmental variance.
Ecological communities are subjected to stochasticity in the form of demographic and environmental variance. Stochastic models that contain only demographic variance (neutral models) provide close quantitative fits to observed species-abundance distributions (SADs) but substantially underestimate observed temporal species-abundance fluctuations. To provide a holistic assessment of whether models with demographic and environmental variance perform better than neutral models, the fit of both to SADs and temporal species-abundance fluctuations at the same time has to be tested quantitatively. In this study, we quantitatively test how closely a model with demographic and environmental variance reproduces total numbers of species, total abundances, SADs and temporal species-abundance fluctuations for two tropical forest tree communities, using decadal data from long-term monitoring plots and considering individuals larger than two size thresholds for each community. We find that the model can indeed closely reproduce these static and dynamic patterns of biodiversity in the two communities for the two size thresholds, with better overall fits than corresponding neutral models. Therefore, our results provide evidence that stochastic models incorporating demographic and environmental variance can simultaneously capture important static and dynamic biodiversity patterns arising in tropical forest communities.


Collective learning for the emergence of social norms in networked multiagent systems.
Social norms such as social rules and conventions play a pivotal role in sustaining system order by regulating and controlling individual behaviors toward a global consensus in large-scale distributed systems. Systematic studies of efficient mechanisms that can facilitate the emergence of social norms enable us to build and design robust distributed systems, such as electronic institutions and norm-governed sensor networks. This paper studies the emergence of social norms via learning from repeated local interactions in networked multiagent systems. A collective learning framework, which imitates the opinion aggregation process in human decision making, is proposed to study the impact of agent local collective behaviors on the emergence of social norms in a number of different situations. In the framework, each agent interacts repeatedly with all of its neighbors. At each step, an agent first takes a best-response action toward each of its neighbors and then combines all of these actions into a final action using ensemble learning methods. Extensive experiments are carried out to evaluate the framework with respect to different network topologies, learning strategies, numbers of actions, influences of nonlearning agents, and so on. Experimental results reveal some significant insights into the manipulation and control of norm emergence in networked multiagent systems achieved through local collective behaviors.


Improving EEG-Based Driver Fatigue Classification Using Sparse-Deep Belief Networks.
This paper presents an improvement of classification performance for electroencephalography (EEG)-based driver fatigue classification between fatigue and alert states with the data collected from 43 participants. The system employs autoregressive (AR) modeling as the features extraction algorithm, and sparse-deep belief networks (sparse-DBN) as the classification algorithm. Compared to other classifiers, sparse-DBN is a semi supervised learning method which combines unsupervised learning for modeling features in the pre-training layer and supervised learning for classification in the following layer. The sparsity in sparse-DBN is achieved with a regularization term that penalizes a deviation of the expected activation of hidden units from a fixed low-level prevents the network from overfitting and is able to learn low-level structures as well as high-level structures. For comparison, the artificial neural networks (ANN), Bayesian neural networks (BNN), and original deep belief networks (DBN) classifiers are used. The classification results show that using AR feature extractor and DBN classifiers, the classification performance achieves an improved classification performance with a of sensitivity of 90.8%, a specificity of 90.4%, an accuracy of 90.6%, and an area under the receiver operating curve (AUROC) of 0.94 compared to ANN (sensitivity at 80.8%, specificity at 77.8%, accuracy at 79.3% with AUC-ROC of 0.83) and BNN classifiers (sensitivity at 84.3%, specificity at 83%, accuracy at 83.6% with AUROC of 0.87). Using the sparse-DBN classifier, the classification performance improved further with sensitivity of 93.9%, a specificity of 92.3%, and an accuracy of 93.1% with AUROC of 0.96. Overall, the sparse-DBN classifier improved accuracy by 13.8, 9.5, and 2.5% over ANN, BNN, and DBN classifiers, respectively.


Hypoglycemic Event Frequency and the Effect of Continuous Glucose Monitoring in Adults with Type 1 Diabetes Using Multiple Daily Insulin Injections.
The benefits of continuous glucose monitoring (CGM) in type 1 diabetes have been established among adults using insulin pumps. The DIAMOND randomized clinical trial examined the effectiveness of using CGM in improving glycemic control in participants using insulin injections. The frequency of hypoglycemic events in this trial has not been previously examined. Adults with type 1 diabetes using multiple daily insulin injections (MDI) with A1C values of 7.5% to 9.9% and not using CGM were randomized to adopt CGM (CGM group, n = 105) or continue with usual care (control group, n = 53). CGM data were collected from both groups at the beginning of the study and after 3 and 6 months. A hypoglycemic event was defined as a series of at least CGM values less than 3.0 mmol/L, separated by 20 min or more, with no intervening values of 3.0 mmol/L or more. Hypoglycemic event rates per 24 h were compared using a linear model adjusted for the baseline event rate per 24 h, baseline A1C, and site as a random effect. In the CGM group, the median hypoglycemic event rate fell by 30% (0.23 per 24 h at baseline and 0.16 per 24 h at follow-up) while in the control group the rate was nearly unchanged (0.31 per 24 h at baseline and 0.30 per 24 h at follow-up; p value = 0.03). In the DIAMOND randomized controlled trial, participants in the CGM group experienced a greater reduction in hypoglycemic event rate than participants receiving usual care in the control group. Clinicaltrials.gov Identifier: NCT02282397.


Climate sensitivity estimated from temperature reconstructions of the Last Glacial Maximum.
Assessing the impact of future anthropogenic carbon emissions is currently impeded by uncertainties in our knowledge of equilibrium climate sensitivity to atmospheric carbon dioxide doubling. Previous studies suggest 3 kelvin (K) as the best estimate, 2 to 4.5 K as the 66% probability range, and nonzero probabilities for much higher values, the latter implying a small chance of high-impact climate changes that would be difficult to avoid. Here, combining extensive sea and land surface temperature reconstructions from the Last Glacial Maximum with climate model simulations, we estimate a lower median (2.3 K) and reduced uncertainty (1.7 to 2.6 K as the 66% probability range, which can be widened using alternate assumptions or data subsets). Assuming that paleoclimatic constraints apply to the future, as predicted by our model, these results imply a lower probability of imminent extreme climatic change than previously thought.


Evaluation of the Wilma-SIE Virtual Screening Method in Community Structure-Activity Resource 2013 and 2014 Blind Challenges.
Prospective assessments of the Wilma-SIE (solvated interaction energy) platform for ligand docking and ranking were performed during the 2013 and 2014 editions of the Community Structure-Activity Resource (CSAR) blind challenge. Diverse targets like a steroid-binding protein, a serine protease (factor Xa), a tyrosine kinase (Syk), and a nucleotide methyltransferase (TrmD) were included. Pose selection was achieved with high precision; in all 24 tests Wilma-SIE top-ranked the native pose among carefully generated sets of decoy conformations. Good separation for the native pose was also observed indicating robustness in pose scoring. Cross-docking was also accomplished with high accuracy for the various systems, with ligand median-RMSD values around 1 Å from the crystal structures. Larger deviations were occasionally obtained due to the rigid-target approach even if multiple target structures were used. Affinity ranking of congeneric ligands after cross-docking was reasonable for three of the four systems, with Spearman ranking coefficients around 0.6. Poor affinity ranking for FXa is possibly due to missing structural domains, which are present during measurements. Assignment of protonation states is critical for affinity scoring with the SIE function, as shown here for the Syk system. Including the FiSH model improved cross-docking but worsened affinity predictions, pointing to the need for further fine-tuning of this newer solvation model. The consistently strong performance of the Wilma-SIE platform in recent CSAR and SAMPL blind challenges validates its applicability for virtual screening on a broad range of molecular targets.


Autologous stem cell transplantation in elderly patients with multiple myeloma in Korea: the KMM1807 study.
Autologous stem cell transplantation (ASCT) is not frequently performed for elderly patients multiple myeloma (MM) in Korea, despite its being a standardized approach for young patients. Medical records of 150 patients from 15 Korean institutions who received ASCT at age ≥ 64 years were analyzed retrospectively. Patients included had symptomatic MM, and had received their first ASCT at age ≥ 64 following induction chemotherapy. The main outcome was the response after ASCT. Overall survival (OS) and progression-free survival (PFS) were also analyzed. Median time to ASCT was 6.3 months. Complete response plus stringent complete response rate increased from 36 (24.0%) to 105 (70.0%) after ASCT, and high-quality response (≥ very good partial response) increased from 96 (64.0%) to 125 (83.3%). With a median follow-up of 32.6 months after ASCT, 5-year OS and PFS were 59.7% and 22.8%, respectively. Febrile neutropenia occurred in 43.5%, and nausea (21.3%) and stomatitis (13.2%) were common grade 3-4 non-hematologic adverse events. Of 44 deaths, disease progression (n = 23) was the most common cause of mortality, followed by infection (n = 13). Treatment-related death occurred in four cases (2.7%). ASCT is an effective and safe option for elderly MM patients and is associated with superior clinical outcomes.


Understanding Health Information Seeking from an Actor-Centric Perspective.
This paper presents a conceptual approach for discussing health information seeking among poor households in Africa and Asia. This approach is part of a larger research endeavor aimed at understanding how health systems are adapting; with possibilities and constraints emerging. These health systems can be found in a context of the changing relationships between states, markets and civil society in low and middle income countries. The paper starts from an understanding of the health sector as a "health knowledge economy", organized to provide people with access to knowledge and advice. The use of the term "health knowledge economy" draws attention to the ways the health sector is part of a broader knowledge economy changing the way individuals and households obtain and use specialist information. The paper integrates an actor centric approach with the theory of planned behavior. It seeks to identify the actors engaged in the health knowledge economy as a precursor to longer term studies on the uptake of innovations integrating health services with mobile phones, commonly designated as mHealth, contributing to an understanding of the potential vulnerabilities of poor people, and highlighting possible dangers if providers of health information and advice are strongly influenced by interest groups.


Case Report: Safety and Efficacy of Denosumab in Four Children With Noonan Syndrome With Multiple Giant Cell Lesions of the Jaw.
Noonan syndrome is a genetic disorder caused by mutations in the RAS/MAPK pathway. Multiple giant cell lesions are a rare sequelae of disruptions in this pathway, termed Noonan-like multiple giant cell lesions (NL/MGCLs). Medical management of these tumors rather than surgical intervention is preferential as the lesions are benign but locally destructive and recurring. This case series describes four male pediatric patients with Noonan syndrome and multiple giant cell lesions of the jaw treated with denosumab, a monoclonal antibody to receptor activator of nuclear factor kappa B ligand (RANKL), which has been approved for the treatment of malignant giant cell tumors in adults but not evaluated for safety or efficacy in children. All four pediatric patients responded clinically and radiographically to the treatment. Adverse events occurred in a predictable pattern and included hypocalcemia and joint pain during the initiation of treatment and symptomatic hypercalcemia after the cessation of treatment. Growth was not significantly impaired in these skeletally immature patients. This case series demonstrates how a weight-adjusted denosumab dose can effectively treat NL/MGCLs and provides laboratory data for consideration of the timing of monitoring for known side effects.


A cultural consultation service in East London: experiences and outcomes from implementation of an innovative service.
This paper reports on a feasibility study and evaluation of a new type of cultural consultation service (CCS). This multi-component and systemic complex intervention was offered over 18 months to specialist mental health providers in one of the poorest regions of the UK. The service received 900 clinically related contacts and 99 in-depth consultations. Service users who were referred to the CCS had high levels of clinical needs with an average score of 15.9 on the Health of the Nation Outcomes Scale. Overall, Global Assessment of Function scores improved and there were trends for improvements in symptoms. The level of routine care (and by implication associated costs) significantly reduced after CCS intervention, due to a reduction in use of accident and emergency (A&E) services, psychiatrists and community psychiatric nurses (CPNs)/case managers. Cost analysis indicates that savings amounted to £497 per patient. The cost of intervention was no greater than usual care, and may reduce spend per patient over a 3-month follow-up and perhaps longer. More specifically, clinicians felt the cultural consultation service helped to improve the treatment plan (71%), engagement (50%), medication compliance (21%) and earlier discharge (7%).


The complete genome sequence and comparative genome analysis of the high pathogenicity Yersinia enterocolitica strain 8081.
The human enteropathogen, Yersinia enterocolitica, is a significant link in the range of Yersinia pathologies extending from mild gastroenteritis to bubonic plague. Comparison at the genomic level is a key step in our understanding of the genetic basis for this pathogenicity spectrum. Here we report the genome of Y. enterocolitica strain 8081 (serotype 0:8; biotype 1B) and extensive microarray data relating to the genetic diversity of the Y. enterocolitica species. Our analysis reveals that the genome of Y. enterocolitica strain 8081 is a patchwork of horizontally acquired genetic loci, including a plasticity zone of 199 kb containing an extraordinarily high density of virulence genes. Microarray analysis has provided insights into species-specific Y. enterocolitica gene functions and the intraspecies differences between the high, low, and nonpathogenic Y. enterocolitica biotypes. Through comparative genome sequence analysis we provide new information on the evolution of the Yersinia. We identify numerous loci that represent ancestral clusters of genes potentially important in enteric survival and pathogenesis, which have been lost or are in the process of being lost, in the other sequenced Yersinia lineages. Our analysis also highlights large metabolic operons in Y. enterocolitica that are absent in the related enteropathogen, Yersinia pseudotuberculosis, indicating major differences in niche and nutrients used within the mammalian gut. These include clusters directing, the production of hydrogenases, tetrathionate respiration, cobalamin synthesis, and propanediol utilisation. Along with ancestral gene clusters, the genome of Y. enterocolitica has revealed species-specific and enteropathogen-specific loci. This has provided important insights into the pathology of this bacterium and, more broadly, into the evolution of the genus. Moreover, wider investigations looking at the patterns of gene loss and gain in the Yersinia have highlighted common themes in the genome evolution of other human enteropathogens.


Effect of glucose, pyruvate, and insulin on type 1 angiotensin II receptor expression in SV40-immortalized rabbit proximal tubule epithelial cells.
Ambient glucose concentrations alter type 1 angiotensin II receptor (AT1R) expression in renal tissues. The direction of change in AT1R density may depend on the specific cell type and the capacity for that cell type to use glucose as an energy substrate. Given the effects of angiotensin II (Ang II) in proximal tubule epithelia, glucose-mediated fluctuations in AT1R expression could significantly alter tubular Na(+)-H+ exchange and volume reabsorption. To determine if glucose influenced AT1R expression in cultured proximal tubule epithelial cells, SV40-immortalized rabbit proximal tubule epithelial cells (RPTEC) were exposed to 25 mmol (hi-glc) or 5 mmol glucose-containing serum-free medium (lo-glc) for seven to nine days, with or without an alternative energy substrate, pyruvate. AT1R expression, assessed by quantitative reverse-transcription polymerase chain reaction and specific 125I-Ang II binding, decreased in lo-glc medium (% reduction AT1R mRNA expression: 52 +/- 8%; N = 6; P < 0.005 vs. hi-glc; % reduction specific 125I-Ang II binding: 48 +/- 12%; N = 12; P < 0.03 vs. hi-glc). AT1R mRNA expression and specific 125I-Ang II binding recovered to hi-glc levels following the addition of pyruvate [60 mmol] to lo-glc cells. To ascertain if a growth factor that increases glucose uptake in vivo also altered AT1R expression, RPTEC were cultured in hi-glc medium with or without exogenous insulin [100 nM]. Insulin addition increased AT1R mRNA expression and specific 125I-Ang II binding in a concentration-dependent manner. However, insulin (100 nM) addition to lo-glc cells did not significantly increase specific 125I-Ang II binding. These results suggest that AT1R expression in SV40-immortalized rabbit proximal tubule cells is significantly affected by the availability of energy substrate. Ultimately, changes in proximal tubule AT1R expression, mediated by elevated glucose concentrations and insulin, could contribute to sodium-dependent hypertension in the setting of hyperinsulinemia and hyperglycemia.


Hypothalamic and pituitary clusterin modulates neurohormonal responses to stress.
Clusterin is a sulfated glycoprotein abundantly expressed in the pituitary gland and hypothalamus of mammals. However, its physiological role in neuroendocrine function is largely unknown. In the present study, we investigated the effects of intracerebroventricular (ICV) administration of clusterin on plasma pituitary hormone levels in normal rats. Single ICV injection of clusterin provoked neurohormonal changes seen under acute stress condition: increased plasma adrenocorticotropic hormone (ACTH), corticosterone, GH and prolactin levels and decreased LH and FSH levels. Consistently, hypothalamic and pituitary clusterin expression levels were upregulated following a restraint stress, suggesting an involvement of endogenous clusterin in stress-induced neurohormonal changes. In the pituitary intermediate lobe, clusterin was coexpressed with proopiomelanocortin (POMC), a precursor of ACTH. Treatment of clusterin in POMC expressing AtT-20 pituitary cells increased basal and corticotropin-releasing hormone (CRH)-stimulated POMC promoter activities and intracellular cAMP levels. Furthermore, clusterin treatment triggered ACTH secretion from AtT-20 cells in a CRH-dependent manner, indicating that increased clusterin under stressful conditions may augment CRH-stimulated ACTH production and release. In summary, hypothalamic and pituitary clusterin may function as a modulator of neurohormonal responses under stressful conditions.


Guided preparedness planning with lay communities: enhancing capacity of rural emergency response through a systems-based partnership.
Community disaster preparedness plans, particularly those with content that would mitigate the effects of psychological trauma on vulnerable rural populations, are often nonexistent or underdeveloped. The purpose of the study was to develop and evaluate a model of disaster mental health preparedness planning involving a partnership among three, key stakeholders in the public health system. A one-group, post-test, quasi-experimental design was used to assess outcomes as a function of an intervention designated Guided Preparedness Planning (GPP). The setting was the eastern-, northern-, and mid-shore region of the state of Maryland. Partner participants were four local health departments (LHDs), 100 faith-based organizations (FBOs), and one academic health center (AHC)-the latter, collaborating entities of the Johns Hopkins University and the Johns Hopkins Health System. Individual participants were 178 community residents recruited from counties of the above-referenced geographic area. Effectiveness of GPP was based on post-intervention assessments of trainee knowledge, skills, and attitudes supportive of community disaster mental health planning. Inferences about the practicability (feasibility) of the model were drawn from pre-defined criteria for partner readiness, willingness, and ability to participate in the project. Additional aims of the study were to determine if LHD leaders would be willing and able to generate post-project strategies to perpetuate project-initiated government/faith planning alliances (sustainability), and to develop portable methods and materials to enhance model application and impact in other health jurisdictions (scalability). The majority (95%) of the 178 lay citizens receiving the GPP intervention and submitting complete evaluations reported that planning-supportive objectives had been achieved. Moreover, all criteria for inferring model feasibility, sustainability, and scalability were met. Within the span of a six-month period, LHDs, FBOs, and AHCs can work effectively to plan, implement, and evaluate what appears to be an effective, practical, and durable model of capacity building for public mental health emergency planning.


High response rates and prolonged survival in patients with corticotroph pituitary tumors and refractory Cushing disease from capecitabine and temozolomide (CAPTEM): a case series.
Rarely, corticotrophic pituitary tumors take on an aggressive form characterized by rapid growth, invasion into local structures, compression of cranial nerves, and possible spread to distant sites. When conventional surgery, radiation therapy, and hormones fail to control progression and symptoms, alternative therapies are needed. A novel chemotherapeutic regimen of capecitabine and temozolomide (CAPTEM), originally designed in our laboratory, demonstrated dramatic antineoplastic effects against corticotrophic pituitary tumors. We present a case series of 4 patients with aggressive, adrenocorticotrophic hormone--producing pituitary tumors who had previously depleted all surgical, radiation, and hormonal therapies and were then treated with CAPTEM. Dramatic clinical improvements in neurological deficits and Cushing symptoms were evident in all patients after treatment was initiated. Confirmed by radiographic imaging, 2 of 4 patients demonstrated complete regression of disease, 1 patient had a 75% regression, and the fourth patient has ongoing stable disease for > 4.5 years at the time of this writing. Immunohistochemical analysis of patients' tumor samples showed low O-methyguanyl methyltransferase expression and adequate levels of mismatch repair enzymes (MLH-1, MSH-2, MSH-6, and PMS-2), which are important for the in vivo efficacy of CAPTEM. This is the first report of prolonged antitumor response to and radiographic complete remissions as a result of CAPTEM in patients with aggressive pituitary tumors who had exhausted all other therapies.


The impact of foster care on development.
Foster care is a protective intervention designed to provide out of home placement to children living in at-risk home environments. This study employs prospective longitudinal data (N = 189) to investigate the effects of foster care on the development of child behavior and psychological functioning taking into account baseline adaptation prior to placement and socioeconomic status at the time of placement. Comparisons were made among three groups: children who experienced foster care, those who were maltreated but remained in the home, and children who had not experienced foster care or maltreatment despite their similarly at-risk demographic characteristics. In the current sample, children placed in out of home care exhibited significant behavior problems in comparison to children who received adequate care, and using the same pre- and postplacement measure of adaptation, foster care children showed elevated levels of behavior problems following release from care. Similarly, children placed into unfamiliar foster care showed higher levels of internalizing problems compared with children reared by maltreating caregivers, children in familiar care, and children who received adequate caregiving. Findings suggest that outcomes related to foster care may vary with type of care and beyond the effects associated with maltreatment history, baseline adaptation, and socioeconomic status.


Comparison of two interferon-gamma assays and tuberculin skin test for tracing tuberculosis contacts.
The tuberculin skin test (TST) has low specificity. QuantiFERON-TB Gold (QFT-G) and T-SPOT.TB are based on interferon (IFN)-gamma responses to Mycobacterium tuberculosis-specific antigens. A novel in-tube format of QFT-G (QFT-GIT) offers logistical advantages. To compare TST, QFT-GIT, and T-SPOT.TB in bacillus Calmette-Guérin unvaccinated contacts and correlate results with measures of recent exposure. When a supermarket employee with smear-positive tuberculosis had infected most close contacts, a contact investigation among more than 20,000 customers was performed. We recruited subjects randomly on the day of TST administration (n = 469) and subjects with TST of more than 0 mm on the day of TST reading (n = 316). QFT-GIT and T-SPOT.TB were performed. Demographic data and measures of exposure were collected. TST results were analyzed at a cutoff of 10 or 15 mm. Blood tests were interpreted following the manufacturers' criteria and by varying cutoff levels. Among 785 study participants, TST results were associated with age, whereas positive IFN-gamma responses were significantly associated with cumulative shopping time, most markedly for QFT-GIT. Among participants with a TST of 15 mm or greater, sensitivity of QFT-GIT and T-SPOT.TB was 42.2 and 51.3%, respectively. Interassay agreement was 89.6% (kappa = 0.59). By varying cutoff values, agreement between the IFN-gamma assays was optimal at 93.6% (kappa = 0.71) using a cutoff of 0.20 IU/ml for QFT-GIT and 13 spots for T-SPOT.TB. Blood test results were associated with exposure, whereas the TST was not. A possible lack of sensitivity of IFN-gamma assays in detecting individuals with TST of 15 mm or greater, despite negative bacillus Calmette-Guérin vaccination status, warrants further investigation into alternative cutoff values.


Lipid peroxidation and antioxidant systems in the blood of young rats subjected to chronic fluoride toxicity.
Wistar albino rats were exposed to 30 or 100 ppm fluoride in drinking water during their fetal, weanling and post-weaning stages of life up to puberty. Extent of lipid peroxidation and response of the antioxidant systems in red blood cells and plasma to prolonged fluoride exposure were assessed in these rats in comparison to the control rats fed with permissible level (0.5 ppm) of fluoride. Rats treated with 100 ppm fluoride showed enhanced lipid peroxidation as evidenced by elevated malondialdehyde (MDA) levels in red blood cells but, 30 ppm fluoride did not cause any appreciable change in RBC MDA level. 30 ppm fluoride-intake resulted in increased levels of total and reduced glutathione in red blood cells and ascorbic acid in plasma while 100 ppm fluoride resulted in decreases in these levels. The activity of RBC glutathione peroxidase was elevated in both the fluoride-treated groups, more pronounced increase was seen with 100 ppm. Reduced to total glutathione ratio in RBC and uric acid levels in plasma decreased in both the groups. RBC superoxide dismutase activity decreased significantly on high-fluoride treatment. These results suggest that long-term high-fluoride intake at the early developing stages of life enhances oxidative stress in the blood, thereby disturbing the antioxidant defense of rats. Increased oxidative stress could be one of the mediating factors in the pathogenesis of toxic manifestations of fluoride.


Syntenic relationships between the U and M genomes of Aegilops, wheat and the model species Brachypodium and rice as revealed by COS markers.
Diploid Aegilops umbellulata and Ae. comosa and their natural allotetraploid hybrids Ae. biuncialis and Ae. geniculata are important wild gene sources for wheat. With the aim of assisting in alien gene transfer, this study provides gene-based conserved orthologous set (COS) markers for the U and M genome chromosomes. Out of the 140 markers tested on a series of wheat-Aegilops chromosome introgression lines and flow-sorted subgenomic chromosome fractions, 100 were assigned to Aegilops chromosomes and six and seven duplications were identified in the U and M genomes, respectively. The marker-specific EST sequences were BLAST-ed to Brachypodium and rice genomic sequences to investigate macrosyntenic relationships between the U and M genomes of Aegilops, wheat and the model species. Five syntenic regions of Brachypodium identified genome rearrangements differentiating the U genome from the M genome and from the D genome of wheat. All of them seem to have evolved at the diploid level and to have been modified differentially in the polyploid species Ae. biuncialis and Ae. geniculata. A certain level of wheat-Aegilops homology was detected for group 1, 2, 3 and 5 chromosomes, while a clearly rearranged structure was showed for the group 4, 6 and 7 Aegilops chromosomes relative to wheat. The conserved orthologous set markers assigned to Aegilops chromosomes promise to accelerate gene introgression by facilitating the identification of alien chromatin. The syntenic relationships between the Aegilops species, wheat and model species will facilitate the targeted development of new markers specific for U and M genomic regions and will contribute to the understanding of molecular processes related to allopolyploidization.


Reactivation of hepatic EPO synthesis in mice after PHD loss.
The kidney controls erythropoietin production in adults, and the anemia that can accompany renal failure is a major medical problem. The liver controls erythropoietin production during fetal life but is silenced shortly after birth. Erythropoietin transcription is controlled by hypoxia-inducible factor (HIF), which is inhibited by three prolyl hydroxylases (PHD1, PHD2, and PHD3). Systemic PHD2 inactivation has been found to increase renal, but not hepatic, erythropoietin production. In contrast, we show here that simultaneous genetic inactivation of all three PHD paralogs in mice reactivates hepatic erythropoietin production and stimulates red blood synthesis, suggesting that pan-PHD inhibitory drugs might be useful for the treatment of anemia caused by chronic kidney disease.


Effect of unconjugated hyperbilirubinemia on neonatal autonomic functions: evaluation by heart rate variability.
Serum bilirubin levels beyond the physiological limits, may lead to alterations in autonomic regulation in a newborn infant. Heart rate variability (HRV), is a noninvasive and quantitative marker of the activity of the autonomic nervous system (ANS). To date, few studies have demonstrated the undesirable effects of severe unconjugated hyperbilirubinemia (UHB) on autonomic functions, and only one study has used HRV as a marker of the autonomic activity. However, the relationship between altered cardiac autonomic functions and UHB by using the HRV derived from 24-hour Holter electrocardiography (ECG) recording has not been investigated previously. We aimed to assess whether a relationship exists between severe UHB and cardiac autonomic dysfunction by evaluating HRV via 24-hour Holter ECG recording. This single-center, prospective, case-control study was conducted on 50 full-term newborn infants with severe UHB requiring phototherapy and 50 healthy infants as controls. HRV assessment was performed by using 24-hour Holter ECG recording. There was no significant difference in terms of mean average heart rate, mean maximum heart rate and mean RR duration between the groups. However, mean minimum heart rate was significantly lower in the study group. When 24-hour time and frequency domain parameters were compared, time and frequency domain parameters rMSDD as well as high frequency (HF), which represent parasymphathetic activity, were significantly higher in the study group. Furthermore, low frequency to high frequency (LF/HF) ratio, that serves as an indicator of sympathovagal balance, was significantly lower in the study group. Severe UHB may cause cardiac autonomic dysfunction in favor of parasympathetic predominance in jaundiced neonates.


Pathophysiologic effects of anatoxin-a(s) in anaesthetized rats: the influence of atropine and artificial respiration.
The pathophysiologic effects of anatoxin-a(s) from the cyanobacterium Anabaena flos-aquae NRC-525-17 were investigated in anaesthetized adult male Sprague Dawley rats given the toxin by continuous intravenous infusion until death. Rats (n = 6) pretreated with atropine sulfate (50 mg/kg) intraperitoneally survived significantly longer (P less than 0.05) than non-atropinized rats (n = 6), suggesting that the muscarinic effects of anatoxin-a(s) were important in the lethal syndrome. In contrast to rats only given toxin, rats that were pretreated with atropine had a decrease in heart rate and mean blood pressure that followed profound reductions in respiratory tidal and minute volume, suggesting that neuromuscular blockade of the muscles of respiration was the cause of death. Even when survival time of rats was increased by pretreatment with atropine, phrenic nerve amplitude increased, indicating a lack of a depressive effect of anatoxin-a(s) on central mediation of respiration. Rats (n = 3) continuously ventilated during toxin infusion survived a dose more than 4 fold greater than a consistently lethal dose of the toxin. Thus, the cardiovascular effects of anatoxin-a(s) alone could not account for the death of rats. Electromyographic activity recorded from the diaphragms of rats (n = 5) during continuous toxin administration revealed an increase in muscular electrical activity that became more random and finally decreased prior to death, suggesting a toxin-induced neuromuscular blockade in vivo which ultimately was the cause of death of the anatoxin-a(s) dosed rats.


Allele-specific expression of imprinted genes in mouse migratory primordial germ cells.
In somatic cells, imprinted genes are expressed monoallelically according to parent-of-origin. In contrast, in 11.5 days post-coitum primordial germ cells (PGCs), and later stage germ cells, these same genes are expressed biallelically, suggesting that imprints inherited from the gametes are largely erased by this stage. To determine when in germ cell development this biallelic expression phenomenon commences, we isolated migrating PGCs by flow cytometry and determined the allele-specific expression of four imprinted genes - Snrpn, Igf2, H19 and Igf2r. The first three genes were expressed monoallelically, while the latter gene was expressed biallelically. These results show that inherited imprints regulating monoallelic expression are largely intact in migrating PGCs.


Validation of test performance characteristics and minimal clinically important difference of the 6-minute walk test in patients with idiopathic pulmonary fibrosis.
The 6-minute walk test distance (6MWD) has been shown to be a valid and responsive outcome measure in patients with idiopathic pulmonary fibrosis (IPF). The analyses were based, however, on a single phase 3 trial and require validation in an independent cohort. To confirm the performance characteristics and estimates of minimal clinically important difference (MCID) of 6MWD in an independent cohort of patients with IPF. Patients randomized to placebo in the phase 3 CAPACITY trials who had a baseline 6MWD measurement were included in these analyses. The 6MWD and other functional parameters (lung function, dyspnea, and health-related quality of life) were measured at baseline and 24-week intervals. Validity and responsiveness were examined using Spearman correlation coefficients. The MCID was estimated using distribution- and anchor-based methods. The analysis comprised 338 patients. Baseline 6MWD was significantly correlated with lung function measures, patient-reported outcomes, and quality-of-life measures (validity). Compared with baseline 6MWD, change in 6MWD (responsiveness) showed stronger correlations with change in lung function parameters and quality-of-life measures. Dyspnea measured by the University of California San Diego Shortness of Breath Questionnaire showed the strongest correlations with 6MWD (baseline: coefficient -0.35; 48-week change: coefficient -0.37; both p < 0.001). The distribution-based analyses of MCID using standard error of measurement yielded an MCID of 37 m, and distribution-based analyses by effect size resulted in 29.2 m. The MCID by anchor-based analysis using criterion referencing (health events of hospitalization or death) was 21.7 m. The 6MWD is a valid and responsive clinical endpoint, which provides objective and clinically meaningful information regarding functional status and near-term prognosis. These results confirm previous findings in an independent cohort of patients with IPF.


Molecular Drivers of Crystallization Kinetics for Drugs in Supersaturated Aqueous Solutions.
In this study, we explore molecular properties of importance in solution-mediated crystallization occurring in supersaturated aqueous drug solutions. Furthermore, we contrast the identified molecular properties with those of importance for crystallization occurring in the solid state. A literature data set of 54 structurally diverse compounds, for which crystallization kinetics from supersaturated aqueous solutions and in melt-quenched solids were reported, was used to identify molecular drivers for crystallization kinetics observed in solution and contrast these to those observed for solids. The compounds were divided into fast, moderate, and slow crystallizers, and in silico classification was developed using a molecular K-nearest neighbor model. The topological equivalent of Grav3 (related to molecular size and shape) was identified as the most important molecular descriptor for solution crystallization kinetics; the larger this descriptor, the slower the crystallization. Two electrotopological descriptors (the atom-type E-state index for -Caa groups and the sum of absolute values of pi Fukui(+) indices on C) were found to separate the moderate and slow crystallizers in the solution. The larger these descriptors, the slower the crystallization. With these 3 descriptors, the computational model correctly sorted the crystallization tendencies from solutions with an overall classification accuracy of 77% (test set).


Potential future uses of calcimimetics in patients with chronic kidney disease.
Cinacalcet has proven effective in the treatment of secondary hyperparathyroidism (SHPT) in dialysis patients, and it may also have benefits in stage 3 and 4 chronic kidney disease (CKD). The efficacy of cinacalcet in the treatment of SHPT was investigated in a study of 54 patients with stage 3 and 4 CKD not receiving dialysis. A significant number of these patients achieved at least a 30% reduction in parathyroid hormone (PTH) from baseline with cinacalcet therapy compared with placebo (56% versus 19%; P = 0.006). Another potential use of cinacalcet is in the treatment of persistent hyperparathyroidism (HPT) after kidney transplantation. The pathophysiologic considerations for persistent HPT in patients who have undergone renal transplantation are different from those in stage 3 and 4 CKD. Post-transplant patients with normal graft function often present with hypercalcaemia, low serum phosphorus and persistently elevated levels of PTH. In eight small open-label studies including a total of 83 patients with persistent HPT after successful kidney transplantation, cinacalcet treatment effectively corrected hypercalcaemia and significantly reduced elevated PTH levels. These studies suggest that cinacalcet therapy is an effective therapy in controlling hyperparathyroidism in patients with stage 3 and 4 CKD and in post-transplant patients with persistent hyperparathyroidism.


Guiding TRAIL to cancer cells through Kv10.1 potassium channel overcomes resistance to doxorubicin.
Resisting cell death is one of the hallmarks of cancer, and represents a common problem resulting in ineffective cancer therapy. To overcome resistance to apoptosis, we designed an antibody-based therapy strategy using Kv10.1 as a target. Kv10.1 is a voltage-gated potassium channel, which has been identified as a tumor marker several years ago. The agent consists of a Kv10.1-specific single-chain antibody fused to the soluble tumor necrosis factor-related apoptosis-inducing ligand (scFv62-TRAIL). We combined scFv62-TRAIL with different chemotherapeutic drugs, all of which failed to induce apoptosis when used alone. In the combination, we could overcome the resistance and selectively induce apoptosis. Among the drugs, doxorubicin showed the most promising effect. Additionally, we observed improved efficacy by pre-treating the cells with doxorubicin before scFv62-TRAIL application. Expression analysis of the TRAIL death receptors suggests a doxorubicin-induced increase in the abundance of receptors as the mechanism for sensitization. Furthermore, we confirmed the anti-tumor effect and efficacy of our combination strategy in vivo in SCID mice bearing subcutaneous tumors. In conclusion, we propose a novel strategy to overcome resistance to chemotherapy in cancer cells. Doxorubicin and scFv62-TRAIL reciprocally sensitize the cells to each other, specifically in Kv10.1-positive tumor cells.


Terminal sedation: promoting ethical nursing practice.
This article discusses ethical aspects of 'terminal sedation' in relation to end-of-life care. An examination of the literature reveals there are different definitions and explanations of terminal sedation. Some definitions appear compatible with the values of palliative care and nursing, whereas others could arguably be perceived as deserving of the term 'euthanasia in disguise'. The authors suggest that 'palliative sedation' is a more helpful term and argue that, when defined and understood appropriately, it is a defensible and ethical practice. Nurses should be clear about the purpose of their profession, honest about their intentions and respect the autonomy and dignity of the patients for whom they provide care. The doctrine or principle of 'double effect' has been put forward to support the practice of terminal sedation. The authors examine this doctrine and caution that nurses and other professions need to approach it critically in relation to terminal sedation. Vignettes are used to illustrate aspects of the discussion.


Relation of visual function to retinal nerve fiber layer thickness in multiple sclerosis.
To examine the relation of visual function to retinal nerve fiber layer (RNFL) thickness as a structural biomarker for axonal loss in multiple sclerosis (MS), and to compare RNFL thickness among MS eyes with a history of acute optic neuritis (MS ON eyes), MS eyes without an optic neuritis history (MS non-ON eyes), and disease-free control eyes. Cross-sectional study. Patients with MS (n = 90; 180 eyes) and disease-free controls (n = 36; 72 eyes). Retinal never fiber layer thickness was measured using optical coherence tomography (OCT; fast RNFL thickness software protocol). Vision testing was performed for each eye and binocularly before OCT scanning using measures previously shown to capture dysfunction in MS patients: (1) low-contrast letter acuity (Sloan charts, 2.5% and 1.25% contrast levels at 2 m) and (2) contrast sensitivity (Pelli-Robson chart at 1 m). Visual acuity (retroilluminated Early Treatment Diabetic Retinopathy charts at 3.2 m) was also measured, and protocol refractions were performed. Retinal nerve fiber layer thickness measured by OCT, and visual function test results. Although median Snellen acuity equivalents were better than 20/20 in both groups, RNFL thickness was reduced significantly among eyes of MS patients (92 mum) versus controls (105 mum) (P<0.001) and particularly was reduced in MS ON eyes (85 mum; P<0.001; accounting for age and adjusting for within-patient intereye correlations). Lower visual function scores were associated with reduced average overall RNFL thickness in MS eyes; for every 1-line decrease in low-contrast letter acuity or contrast sensitivity score, the mean RNFL thickness decreased by 4 mum. Scores for low-contrast letter acuity and contrast sensitivity correlate well with RNFL thickness as a structural biomarker, supporting validity for these visual function tests as secondary clinical outcome measures for MS trials. These results also suggest a role for ocular imaging techniques such as OCT in trials that examine neuroprotective and other disease-modifying therapies. Although eyes with a history of acute optic neuritis demonstrate the greatest reductions in RNFL thickness, MS non-ON eyes have less RNFL thickness than controls, suggesting the occurrence of chronic axonal loss separate from acute attacks in MS patients.


Subjective Beliefs, Memory and Functional Health: Change and Associations over 12 Years in the Australian Longitudinal Study of Ageing.
Neither subjective memory beliefs, nor remembering itself, can be isolated from the overall context in which one is aging, nor are the drivers of memory complaints well specified. Sense of control is an important self-regulatory resource that drives cognitive and physical health over the lifespan. Existing findings are equivocal concerning both the extent of stability or change in control beliefs over time as well as their contribution to changes in behavior. Subjective beliefs may play a role when engaging memory processes or identifying memory complaints, and it has been argued that self-regulatory potential in general may be limited by age-related changes in the domains of health and cognition. We aimed to examine trajectories of change and shed light on relationships among subjective beliefs and indicators of memory and functional health. Participants' data were drawn from four measurement occasions over up to a 12-year period (1992-2004) from the Australian Longitudinal Study of Ageing (ALSA), a population-based study of older adults [age 65-100 years; mean age(SD) at the first and final occasion 78.2 (6.7) and 84.9 (4.9) years, respectively]. Participants completed three questionnaires assessing subjective beliefs concerning (1) memory knowledge and control, (2) health control, and (3) expectancy of control over a range of lifestyle situations. Memory comprised a recall composite. Functional health tapped mobility and disability. Latent growth curve models incorporated informative covariates (baseline age, gender, self-rated health, education, and chronic conditions). While subjective memory control beliefs, but not subjective knowledge of memory tasks, improved over 12 years, neither was associated with level of memory performance. Knowledge of memory tasks was linked to a significant memory decline. Beliefs about memory, health, and lifestyle were interrelated. Declines in remembering and health were also coupled; moreover, changes in both were coupled with change in lifestyle control beliefs. This is the first examination of individual differences in changes in, and relationships among, psychological domains of subjective beliefs about memory, health, and lifestyle, and objective remembering and functional health in very late life. Findings point to a system of coupled changes in memory and health in late life that is related to underlying beliefs about control over lifestyle.


Mining for pairs: shared clinic visit dates identify steady HIV-positive partnerships.
Here we examined the hypothesis that some stable HIV-infected partnerships can be found in cohort studies, as the patients frequently attend the clinic visits together. Using mathematical approximations and shuffling to derive the probabilities of sharing a given number of visits by chance, we identified and validated couples that may represent either transmission pairs or serosorting couples in a stable relationship. We analysed 434 432 visits for 16 139 Swiss HIV Cohort Study patients from 1990 to 2014. For 89 pairs, the number of shared visits exceeded the number expected. Of these, 33 transmission pairs were confirmed on the basis of three criteria: an extensive phylogenetic tree, a self-reported steady HIV-positive partnership, and risk group affiliation. Notably, 12 of the validated transmission pairs (36%; 12 of 33) were of a mixed ethnicity with a large median age gap [17.5 years; interquartile range (IQR) 11.8-22 years] and these patients harboured HIV-1 of predominantly non-B subtypes, suggesting imported infections. In the context of the surge in research interest in HIV transmission pairs, this simple method widens the horizons of research on within-pair quasi-species exchange, transmitted drug resistance and viral recombination at the biological level and targeted prevention at the public health level.


[AIDS in rural Minas Gerais state (Southeastern Brazil): a cultural approach].
To describe behaviors facilitating HIV/AIDS exposure in rural population. A qualitative study was conducted comprising 52 patients who attended a STD/AIDS outpatient clinic in 2002 and 2003. In-depth open and semi-structured interviews were carried out with subjects (30 males, 22 females) at the clinic or at home in rural municipalities in the northern area of Minas Gerais state, Southeastern Brazil. Interviews were transcribed and analyzed considering categories such as disease, work, social life, prior HIV/AIDS knowledge, and lifestyle. Content analysis was used for result interpretation. Interviewees perceived AIDS as a "big city disease", an "outsider's disease", dissociated from local culture. They were all infected through either heterosexual or homosexual sex. Rural-urban migration is a major factor for HIV infection in the area as people migrate to search for jobs. Popular beliefs about HIV/AIDS disease contributes to HIV vulnerability of this population. There is a need to apprehend their cultural beliefs to better understand their ways of thinking and to focus on these local beliefs when disseminating HIV/AIDS information.


A scatter-based prototype framework and multi-class extension of support vector machines.
We provide a novel interpretation of the dual of support vector machines (SVMs) in terms of scatter with respect to class prototypes and their mean. As a key contribution, we extend this framework to multiple classes, providing a new joint Scatter SVM algorithm, at the level of its binary counterpart in the number of optimization variables. This enables us to implement computationally efficient solvers based on sequential minimal and chunking optimization. As a further contribution, the primal problem formulation is developed in terms of regularized risk minimization and the hinge loss, revealing the score function to be used in the actual classification of test patterns. We investigate Scatter SVM properties related to generalization ability, computational efficiency, sparsity and sensitivity maps, and report promising results.


Acute administration of interleukin-6 does not increase secretion of glucagon-like peptide-1 in mice.
Interleukin 6 (IL-6) is a cytokine secreted from skeletal muscle in response to exercise which, based on animal and cell studies, has been suggested to contribute to glucose metabolism by increasing secretion of the incretin hormone glucagon-like peptide-1 (GLP-1) and affecting secretion of insulin and glucagon from the pancreatic islets. We investigated the effect of IL-6 on GLP-1 secretion in GLP-1 producing cells (GLUTag) and using the perfused mouse small intestine (harboring GLP-1 producing cells). Furthermore, the direct effect of IL-6 on insulin and glucagon secretion was studied using isolated perfused mouse pancreas. Incubating GLUTag cells with 1000 ng/mL of IL-6 for 2 h did not significantly increase secretion of GLP-1 whereas 10 mmol/L glucose (positive control) did. Similarly, IL-6 (100 ng/mL) had no effect on GLP-1 secretion from perfused mouse small intestine whereas bombesin (positive control) increased secretion. Finally, administering IL-6 (100 ng/mL) to perfused mouse pancreases did not significantly increase insulin or glucagon secretion regardless of perfusate glucose levels (3.5 vs. 12 mmol/L glucose). Acute effects of IL-6 therefore do not seem to include a stimulatory effect on GLP-1 secretion in mice.


NEAT1 polyA-modulating antisense oligonucleotides reveal opposing functions for both long non-coding RNA isoforms in neuroblastoma.
Many long non-coding RNAs (lncRNA) are highly dysregulated in cancer and are emerging as therapeutic targets. One example is NEAT1, which consists of two overlapping lncRNA isoforms, NEAT1_1 (3.7 kb) and NEAT1_2 (23 kb), that are functionally distinct. The longer NEAT1_2 is responsible for scaffolding gene-regulatory nuclear bodies termed paraspeckles, whereas NEAT1_1 is involved in paraspeckle-independent function. The NEAT1 isoform ratio is dependent on the efficient cleavage and polyadenylation of NEAT1_1 at the expense of NEAT1_2. Here, we developed a targeted antisense oligonucleotide (ASO) approach to sterically block NEAT1_1 polyadenylation processing, achieving upregulation of NEAT1_2 and abundant paraspeckles. We have applied these ASOs to cells of the heterogeneous infant cancer, neuroblastoma, as we found higher NEAT1_1:NEAT1_2 ratio and lack of paraspeckles in high-risk neuroblastoma cells. These ASOs decrease NEAT1_1 levels, increase NEAT1_2/paraspeckles and concomitantly reduce cell viability in high-risk neuroblastoma specifically. In contrast, overexpression of NEAT1_1 has the opposite effect, increasing cell proliferation. Transcriptomic analyses of high-risk neuroblastoma cells with altered NEAT1 ratios and increased paraspeckle abundance after ASO treatment showed an upregulation of differentiation pathways, as opposed to the usual aggressive neuroblastic phenotype. Thus, we have developed potential anti-cancer ASO drugs that can transiently increase growth-inhibiting NEAT1_2 RNA at the expense of growth-promoting NEAT1_1 RNA. These ASOs, unlike others that degrade lncRNAs, provide insights into the importance of altering lncRNA polyadenylation events to suppress tumorigenesis as a strategy to combat cancer.


Between-case standardized effect size analysis of single case designs: Examination of the two methods.
An increasing movement in single case research is to employ statistical analyses as one form of data analysis. Researchers have proposed different statistical approaches. The purpose of this paper is to examine the utility and discriminant validity of two novel types of between-case standardized effect size analyses with two existing systematic reviews. The between-case analyses found greater effect sizes for the studies in the object play review and smaller effect sizes for studies of sensory intervention, which were consistent with the overall conclusions reached in the original systematic reviews. These findings provide evidence of discriminant validity, although concerns remain around the methods' utility across different single case research designs. Future directions for research and development also are provided.


Innovations in telemedicine for cardiovascular care.
Cardiovascular disease is one of the main fields of application for telemedicine, with benefits in almost all areas in the continuum of cardiovascular disease. The greatest impact has been shown in the early diagnosis of cardiovascular disease, in second consultation, between non-cardiologist and cardiologist and between cardiologists, and in follow-up and secondary prevention of cardiovascular disease. At present, the main area of implementation for telemedicine in cardiovascular disease is represented by pre-hospital triage, with telemedicine electrocardiogram in acute myocardial infarction. Significant results have also been achieved in the second opinion consultation of pediatric subjects with congenital cardiovascular disease, home-monitoring and the management of patients affected by chronic heart failure or with an implanted device. However, there is significant room for further improvement in delivering telemedicine assistance even in 'very-remote' populations, such as detainees, patients in developing countries or in underdeveloped areas of developed countries.


Investigation by polymerase chain reaction of enteroviral infection in patients with chronic fatigue syndrome.
1. Chronic fatigue syndrome is characterized by muscle fatigue and pain at rest, symptoms which are usually exacerbated with exercise. Although various studies have shown minor, non-specific morphological and biochemical changes in muscle of patients with chronic fatigue syndrome, no consistent defect has been identified. Some have suggested that an enteroviral infection in muscle may cause the chronic muscle fatigue seen in patients with chronic fatigue syndrome, with acute infection directly and irreversibly impairing mitochondrial function, and persistent infection depressing muscle protein synthesis and metabolism. 2. To clarify the involvement of enterovirus infection in chronic fatigue syndrome, muscle biopsies from a group of patients with chronic fatigue syndrome were examined for the presence of enteroviral RNA by reverse transcriptase-polymerase chain reaction techniques in relation to functional studies of muscle mitochondria and the muscle RNA/DNA ratio. 3. Fifty-eight percent of patients reported an uncharacterized 'viral infection' before the onset of their illness, but none of the muscle samples from 34 patients contained detectable amounts of enteroviral RNA. Muscle tissue had a general reduction in the RNA/DNA ratio and mitochondrial enzyme activities with no specific abnormality in the activity of enzymes encoded partially on the mitochondrial genome (cytochrome-c oxidase) or nuclear genome (citrate synthase, succinate reductase). 4. These data provide no evidence of an enteroviral infection in muscle of patients with chronic fatigue syndrome, although this does not exclude a role of enterovirus in initiating the disease process. The general reduction in RNA/DNA ratio and mitochondrial enzyme activities is consistent with a general reduction in habitual activity.


Cdc14-dependent dephosphorylation of a kinetochore protein prior to anaphase in Saccharomyces cerevisiae.
The budding yeast Cdc14 phosphatase reverses Cdk1 phosphorylation to promote mitotic exit. Although Cdc14 activity is thought to be restricted to anaphase, we found that dephosphorylation of the Dsn1 kinetochore protein in metaphase requires Cdc14. These data suggest that there is a nonnucleolar pool of active Cdc14 prior to anaphase.


CRPS: A contingent hypothesis with prostaglandins as crucial conversion factor.
CRPS is an acute pain disease expressed as chronic pain with a severe loss of tissue and function. CRPS usually occurs after minor injuries and then progresses in a way that is scarcely controllable, or completely uncontrollable. This article addresses the functional control mechanism of a biological organism, a comparison of techniques, and the way the negative feedback mechanisms fail in regulated feedback systems. The measurement and regulation system is controlled at the local, regional, and central levels in a biological system. Locally generated substances such as prostaglandins and hormones, as well as the central nervous system, play important roles in this process. Prostaglandins fulfil many conversion functions and are involved in vasoactive processes, pain, and inflammation. They play an intermediating role between the activity of the autonomic nervous system and local occurrences. The insufficiently explored conversion function of prostaglandins as a ubiquitously present cofactor may be related to the development of CRPS at sites which have had minor injuries in the past. Chronic Regional Pain Syndrome (CRPS) is a moderately prevalent disease, which occurs more frequently with age. Even though there are diseases known to have a precipitating effect on the aetiology of CRPS, for example Carpal tunnel syndrome, the mechanism of onset is unknown. The disease falls under the category of chronic pain, and seldom has an effective treatment based on scientific research. The economic and psychosocial aspects of the disease are substantial. CRPS is the final position of a positive feedback measurement and control system. Homoeostasis is directed by measurement and control processes. In electronics, a rapid conversion system, which quickly adapts to changing circumstances, superimposed with a delayed conversion system, which ensures a stable basis of homoeostasis. Measured changes are compensatorily controlled. An analogy is expected for a Complex Adaptive System such as a living organism. Hormonal systems are slow systems, suitable for stabilising activity. Neural reflex systems function quickly. Prostaglandins that come from local tissue may be the link between the slow and rapid control. In electronics, negative feedback can convert into a feedback loop which results in the dysregulation, which is what prostaglandins do in biochemistry. A dysregulated feedback control mechanism only has two positions: a zero position and a final position. The process is not easily influenced by other factors. Only phase shifting and signal weakness can affect the feedback process. Theoretically, prostaglandins can also affect this process.


C-reactive protein by pregnancy and lactational status among Filipino young adult women.
Pregnancy and lactation involve adaptations in immune regulation, but little is known about cross-cultural variation in inflammatory changes during pregnancy or lactation. Here we report concentrations of C-reactive protein (CRP) in a large cross-sectional sample of healthy Filipino women who vary in parity, gestational, and lactational status, and who come from a population previously described as having low CRP. Fasting plasma CRP was measured among female participants (ages 20.8-22.4 years) in the Cebu Longitudinal Health and Nutrition Survey (n = 822). Median CRP was 0.2 mg/l in nulliparous women and peaked at 2.0 mg/l in women in their 3rd trimester of pregnancy. Parous but post-partum women had higher CRP compared to nulliparous women, which was largely explained by body composition differences as reflected in waist circumference and skinfold measures. Among post-partum women with infants, CRP was similar in women who were currently breastfeeding compared to those who were not. At Cebu, women late in gestation have 10-fold higher C-reactive protein compared to nulliparous women, with no evidence that lactation is inflammatory. These population-based findings are similar with findings from prior clinic-based studies and are consistent with the maternal immunological adaptations initiated during pregnancy. The tendency of human females to spend more time than females of other great apes in gestation rather than lactation suggests that the human life history strategy involved increased time spent by reproductively aged females in a pro-inflammatory state.


Anesthesia and the development of surgery (1846-1896).
The hypothesis that the introduction of anesthesia in 1846 accelerated the development of surgery was tested by compiling statistics on the types of operations performed in this country and abroad in the absence of anesthesia (prior to 1846) and over the 50-year period after 1846. Prior to 1846, surgery involved the extremities and superficial parts of the body almost exclusively. The same was generally true for 50 years following 1846. The introduction of anesthesia was necessary before surgery could advance, but control of infection, establishment of the sciences of pathology and physiology, and development of professionalism in clinical medicine and surgery based on research and teaching were also required. Almost a half-century lapsed after the introduction of anesthesia before surgery advanced significantly beyond the stage it was at prior to the introduction of anesthesia in 1846.