Optimizing respiratory management in resource-limited settings.
This review focuses on the emerging body of literature regarding the management of acute respiratory failure in low- and middle-income countries (LMICs). The aim is to abstract management principles that are of relevance across a variety of settings where resources are severely limited. Mechanical ventilation is an expensive intervention associated with considerable mortality and a high rate of iatrogenic complications in many LMICs. Recent case series report crude mortality rates for ventilated patients of between 36 and 72%. Measures to avert the need for invasive mechanical ventilation in LMICs are showing promise: bubble continuous positive airway pressure has been demonstrated to decrease mortality in children with acute respiratory failure and trials suggest that noninvasive ventilation can be conducted safely in settings where resources are low. The management of patients with acute respiratory failure in LMICs should focus on avoiding intubation where possible, improving the safety of mechanical ventilation and expediting weaning. Future directions should involve the development and trialing of robust and context-appropriate respiratory support technology.


The challenge for a European network of biobanks for rare diseases taken up by RD-Connect.
Access to biological materials is a key prerequisite for scientific research in any medical field and in particular for research into rare diseases (RDs), for which obtaining high-quality samples and the related clinical data remains a major hurdle. RD biobanks play a pivotal role in making such materials and data available to the scientific community. In order to increase the effectiveness of RD biobanks, three major challenges need to be met: maximise access to rare biological samples stored in RD biobanks spread globally by the international scientific community, promote networking among such biobanks to share quality standards and procedures and allow collaboration with RD registries and databases, and finally adopt an efficient management model compliant with legal and ethical issues and ensuring biobank sustainability. The European program RD-Connect, funded under the FP7 program, addresses all of these issues through an articulated action plan aimed at building a network of European RD biobanks. Ultimately, RD-Connect will offer access to precious, quality-controlled biological samples from RD patients through an online, searchable, dynamic catalogue in the context of an integrated platform that links RD patient registries to biobanks and to clinical bioinformatics data for RD research.


Lack of cortisol response in patients with posttraumatic stress disorder (PTSD) undergoing a diagnostic interview.
According to DSM-IV, the diagnosis of posttraumatic stress disorder (PTSD) requires the experience of a traumatic event during which the person's response involved intense fear, helplessness, or horror. In order to diagnose PTSD, clinicians must interview the person in depth about his/her previous experiences and determine whether the individual has been traumatized by a specific event or events. However, asking questions about traumatic experiences can be stressful for the traumatized individual and it has been cautioned that subsequent "re-traumatization" could occur. This study investigated the cortisol response in traumatized refugees with PTSD during a detailed and standardized interview about their personal war and torture experiences. Participants were male refugees with severe PTSD who solicited an expert opinion in the Psychological Research Clinic for Refugees of the University of Konstanz. 17 patients were administered the Vivo Checklist of War, Detention, and Torture Events, a standardized interview about traumatic experiences, and 16 subjects were interviewed about absorption behavior. Self-reported measures of affect and arousal, as well as saliva cortisol were collected at four points. Before and after the experimental intervention, subjects performed a Delayed Matching-to-Sample (DMS) task for distraction. They also rated the severity of selected PTSD symptoms, as well as the level of intrusiveness of traumatic memories at that time. Cortisol excretion diminished in the course of the interview and showed the same pattern for both groups. No specific response was detectable after the supposed stressor. Correspondingly, ratings of subjective well-being, memories of the most traumatic event(s) and PTSD symptoms did not show any significant difference between groups. Those in the presumed stress condition did not perform worse than persons in the control condition after the stressor. However, both groups performed poorly in the DMS task, which is consistent with memory and concentration problems demonstrated in patients with PTSD. A comprehensive diagnostic interview including questions about traumatic events does not trigger an HPA-axis based alarm response or changes in psychological measures, even for persons with severe PTSD, such as survivors of torture. Thus, addressing traumatic experiences within a safe and empathic environment appears to impose no unacceptable additional load to the patient.


Therapeutic Strategies Targeting Amyloid-β in Alzheimer's Disease.
Alzheimer's disease (AD) is a neurodegenerative disorder linked to protein misfolding and aggregation. AD is pathologically characterized by senile plaques formed by extracellular Amyloid-β (Aβ) peptide and Intracellular Neurofibrillary Tangles (NFT) formed by hyperphosphorylated tau protein. Extensive synaptic loss and neuronal degeneration are responsible for memory impairment, cognitive decline and behavioral dysfunctions typical of AD. Amyloidosis has been implicated in the depression of acetylcholine synthesis and release, overactivation of N-methyl-D-aspartate (NMDA) receptors and increased intracellular calcium levels that result in excitotoxic neuronal degeneration. Current drugs used in AD treatment are either cholinesterase inhibitors or NMDA receptor antagonists; however, they provide only symptomatic relief and do not alter the progression of the disease. Aβ is the product of Amyloid Precursor Protein (APP) processing after successive cleavage by β- and γ-secretases while APP proteolysis by α-secretase results in non-amyloidogenic products. According to the amyloid cascade hypothesis, Aβ dyshomeostasis results in the accumulation and aggregation of Aβ into soluble oligomers and insoluble fibrils. The former are synaptotoxic and can induce tau hyperphosphorylation while the latter deposit in senile plaques and elicit proinflammatory responses, contributing to oxidative stress, neuronal degeneration and neuroinflammation. Aβ-protein-targeted therapeutic strategies are thus a promising disease-modifying approach for the treatment and prevention of AD. This review summarizes recent findings on Aβ-protein targeted AD drugs, including β-secretase inhibitors, γ-secretase inhibitors and modulators, α-secretase activators, direct inhibitors of Aβ aggregation and immunotherapy targeting Aβ, focusing mainly on those currently under clinical trials.


Characterization of human immunodeficiency virus type 1 matrix revertants: effects on virus assembly, Gag processing, and Env incorporation into virions.
The matrix protein of human immunodeficiency virus type 1 (HIV-1) has been postulated to serve a variety of functions in the virus life cycle. Previously, we introduced a large number of mutations into the HIV-1 matrix and determined the effects on virus replication. These studies identified domains involved in virus assembly and release and envelope glycoprotein incorporation into virions. Here we describe the identification and characterization of viral revertants containing second-site changes in the matrix which compensate for the effects of four of the original mutations on matrix function. Specifically, mutations at matrix residues 4 and 6 severely impaired virus assembly and release; substitutions at residues 4 and 6 reversed the phenotype of the amino acid 4 change while second-site mutations at matrix positions 10, 69, and 97 partially or fully reversed the phenotype of the amino acid 6 substitution. A mutation at matrix residue 62 reversed the effect of a position 34 change which blocks envelope glycoprotein incorporation into virions, and substitutions at residues 27 and 51 reversed the phenotype of a position 86 mutation which redirects virus assembly to the cytoplasm. In addition to determining the effects of the compensatory changes in the context of the original mutations, we also introduced and analyzed the second-site changes alone in the context of the wild-type molecular clone. The data presented here define potential intermolecular and intramolecular interactions which occur in the matrix during the virus life cycle and have implications for our understanding of the relationship between matrix structure and function.


Six Zn(II) and Cd(II) coordination polymers assembled from a similar binuclear building unit: tunable structures and luminescence properties.
Six Zn(ii) and Cd(ii) coordination polymers were constructed by treating a 2-substituted 8-hydroxyquinolinate ligand containing a pyridyl group with zinc or cadmium salts, and characterized by a variety of techniques. Interestingly, based on a similar binuclear Zn(ii) or Cd(ii) building unit, the supramolecular structures of the six coordination polymers () exhibit an unprecedented structural diversification due to the different choices of metal salts. and represent a novel 2D framework containing 1D infinite right- and left-handed helical chains. and are 2D coordination frameworks based on binuclear Cd(ii) building units. For and , the L ligands can bridge binuclear building units forming a 1D infinite chain. Interestingly, the adjacent Cd2O2 planes of the 1D chain in are in parallel with each other, while the dihedral angle between the two Zn2O2 planes in is 83.43°. Photoluminescence properties revealed that the six coordination polymers exhibit redshifted emission maximum compared with the free ligand HL, which can be ascribed to an increased conformational rigidity and the fabrication of coplanar binuclear building units M2L2 in . Coordination polymers also display distinct fluorescence lifetimes and quantum yields because of their different metal centers and supramolecular structures.


In vitro influence of Mycoplasma penetrans on activation of peripheral T lymphocytes from healthy donors or human immunodeficiency virus-infected individuals.
Mycoplasma penetrans is a mycoplasma species newly isolated from the urine of human immunodeficiency virus (HIV)-infected individuals and presents the only case in which an association has been found between antibodies against a mycoplasma and HIV infection. To further explore the effects of M. penetrans on the immune system, we studied the influence of this mycoplasma on peripheral blood mononuclear cells (PBMCs) from healthy donors and HIV-infected individuals. M. penetrans induced, in addition to blastogenesis of PBMCs, a significant proliferative response associated with the expression of some activation markers such as CD69, HLA-DR, and CD25. This M. penetrans-dependent lymphocyte activation was observed not only in healthy donors but also in HIV-infected persons at different stages of the disease. In addition, our study revealed that both CD4+ and CD8+ T lymphocytes were responsive to M. penetrans. Interestingly, the mitogenic activity of M. penetrans was associated with mycoplasma cells but not with the supernatants of mycoplasma culture. The potent stimulating activity of M. penetrans on T lymphocytes from HIV-infected individuals is of particular interest in view of the supposed contribution of immune activation to HIV replication and disease progression.


Genome-wide interrogation of hepatic FXR reveals an asymmetric IR-1 motif and synergy with LRH-1.
We used mouse hepatic chromatin enriched with an FXR antibody and chromatin immunoprecipitation-sequencing (ChIP-seq) to evaluate FXR binding on a genome-wide scale. This identified 1656 FXR-binding sites and 10% were located within 2 kb of a transcription start site which is much higher than predicted by random occurrence. A motif search uncovered a canonical nuclear receptor IR-1 site, consistent with in vitro DNA-binding studies reported previously. A separate nuclear receptor half-site for monomeric receptors such as LRH-1 was co-enriched and FXR activation of four newly identified promoters was significantly augmented by an LRH-1 expression vector in a co-transfection assay. There were 1038 genes located within 20 kb of a peak and a gene set enrichment analysis showed that genes identified by our ChIP-seq analysis are highly correlated with genes activated by an FXR-VP16 adenovirus in primary mouse hepatocytes providing functional relevance to the genome-wide binding study. Gene Ontology analysis showed FXR-binding sites close to many genes in lipid, fatty acid and steroid metabolism. Other broad gene clusters related to metabolism, transport, signaling and glycolysis were also significantly enriched. Thus, FXR may have a much wider role in cellular metabolism than previously appreciated.


Multi-Platform Sequencing Approach Reveals a Novel Transcriptome Profile in Pseudorabies Virus.
Third-generation sequencing is an emerging technology that is capable of solving several problems that earlier approaches were not able to, including the identification of transcripts isoforms and overlapping transcripts. In this study, we used long-read sequencing for the analysis of pseudorabies virus (PRV) transcriptome, including Oxford Nanopore Technologies MinION, PacBio RS-II, and Illumina HiScanSQ platforms. We also used data from our previous short-read and long-read sequencing studies for the comparison of the results and in order to confirm the obtained data. Our investigations identified 19 formerly unknown putative protein-coding genes, all of which are 5' truncated forms of earlier annotated longer PRV genes. Additionally, we detected 19 non-coding RNAs, including 5' and 3' truncated transcripts without in-frame ORFs, antisense RNAs, as well as RNA molecules encoded by those parts of the viral genome where no transcription had been detected before. This study has also led to the identification of three complex transcripts and 50 distinct length isoforms, including transcription start and end variants. We also detected 121 novel transcript overlaps, and two transcripts that overlap the replication origins of PRV. Furthermore, in silico analysis revealed 145 upstream ORFs, many of which are located on the longer 5' isoforms of the transcripts.


Human gut-on-a-chip inhabited by microbial flora that experiences intestinal peristalsis-like motions and flow.
Development of an in vitro living cell-based model of the intestine that mimics the mechanical, structural, absorptive, transport and pathophysiological properties of the human gut along with its crucial microbial symbionts could accelerate pharmaceutical development, and potentially replace animal testing. Here, we describe a biomimetic 'human gut-on-a-chip' microdevice composed of two microfluidic channels separated by a porous flexible membrane coated with extracellular matrix (ECM) and lined by human intestinal epithelial (Caco-2) cells that mimics the complex structure and physiology of living intestine. The gut microenvironment is recreated by flowing fluid at a low rate (30 μL h(-1)) producing low shear stress (0.02 dyne cm(-2)) over the microchannels, and by exerting cyclic strain (10%; 0.15 Hz) that mimics physiological peristaltic motions. Under these conditions, a columnar epithelium develops that polarizes rapidly, spontaneously grows into folds that recapitulate the structure of intestinal villi, and forms a high integrity barrier to small molecules that better mimics whole intestine than cells in cultured in static Transwell models. In addition, a normal intestinal microbe (Lactobacillus rhamnosus GG) can be successfully co-cultured for extended periods (>1 week) on the luminal surface of the cultured epithelium without compromising epithelial cell viability, and this actually improves barrier function as previously observed in humans. Thus, this gut-on-a-chip recapitulates multiple dynamic physical and functional features of human intestine that are critical for its function within a controlled microfluidic environment that is amenable for transport, absorption, and toxicity studies, and hence it should have great value for drug testing as well as development of novel intestinal disease models.


Sub-lethal hyperthermia promotes epithelial-to-mesenchymal-like transition of breast cancer cells: implication of the synergy between hyperthermia and chemotherapy.
Thermotherapy has demonstrated a potential to be an effective non-surgical technique to treat breast cancer. Despite its advantages, including low toxicity and high repeatability, thermotherapy is typically required to be applied in combination with other treatments since the residual tumor cells that survive after hyperthermal treatment often cause recurrence. In this study, we confirmed that breast cancer cells tolerate temperature of up to 47 °C by synthesizing a large amount of heat shock proteins. Further changes in the molecular properties of the heat-exposed cells were investigated using western blotting, quantitative reverse transcription polymerase chain reaction, and immunocytochemistry. We found that low-temperature hyperthermia promoted epithelial-to-mesenchymal-like transition (EMT), as observed by the increased mesenchymal marker expression levels while decreasing epithelial markers. Moreover, cell morphology changed from cobblestone-like to a more spindle-like appearance, in addition to significantly enhanced cell motility upon heat treatment. These results all support that sub-lethal hyperthermal stress induces EMT. In addition, we examined changes in the chemo-sensitivity of the heat-treated cells. Addition of a chemo-drugs caused increased cytotoxicity of the heat-treated cells compared to the cells that were not co-treated with heat. Our study demonstrates that thermotherapy alone may cause undesirable EMT, which could be well overcome through a synergistic effect when applied with chemotherapy.


Altered local and systemic immune profiles underlie lymph node metastasis in breast cancer patients.
Cancer-mediated immune dysfunction contributes to tumor progression and correlates with patient outcome. Metastasis to tumor draining lymph nodes (TDLNs) is an important step in breast cancer progression and is used to predict patient outcome and survival. Although lymph nodes are important immune organs, the role of immune cells in TDLNs has not been thoroughly investigated. We hypothesized that the host immune response in node negative (NN) patients is more intact and thereby can resist tumor invasion compared to node positive (NP) patients. As such, lymph node metastasis requires breakdown of the host immune response in addition to escape of cancer cells from the tumor. To investigate the immunological differences between NN and NP breast cancer patients, we purified and profiled immune cells from the three major compartments where cancer and immune cells interact: tumor, TDLNs and peripheral blood. Significant down-regulation of genes associated with immune-related pathways and up-regulation of genes associated with tumor-promoting pathways was consistently observed in NP patients' TDLNs compared to NN patients. Importantly, these signatures were seen even in NP patients' tumor-free TDLNs, suggesting that such immune changes are not driven solely by local tumor invasion. Furthermore, similar patterns were also observed in NP patients' tumor and blood immune cells, suggesting that immunological differences between NN and NP patients are systemic. Together, these findings suggest that alterations in overall immune function may underlie risk for LN metastasis in breast cancer patients.


Developing a Delphi-Based Comprehensive Core Set from the International Classification of Functioning, Disability, and Health Framework for the Rehabilitation of Patients with Burn Injuries.
Burn injuries cause disability and functional limitations in daily living. In a 2015 fire explosion in Taiwan, 499 young people sustained burn injuries. The construction of an effective and comprehensive rehabilitation program that enables patients to regain their previous function is imperative. The International Classification of Functioning, Disability, and Health (ICF) includes multiple dimensions that can contribute to meeting this goal. An ICF core set was developed in this study for Taiwanese patients with burns. A consensus process using three rounds of the Delphi technique was employed. A multidisciplinary team of 30 experts from various institutions was formed. The questionnaire used in this study comprised 162 ICF second-level categories relevant to burn injuries. A 5-point Likert scale was used, and participants assigned a weight to the effect of each category on daily activities after burns. The consensus among ratings was assessed using Spearman's ρ and semi-interquartile range indices. The core set for post-acute SCI was developed from categories that attained a mean score of ≥4.0 in the third round of the Delphi exercise. The core ICF set contained 68 categories. Of these, 19 comprised the component of body functions, 5 comprised body structures, 37 comprised activities and participation, and 7 comprised environmental factors. This preliminary core set offers a comprehensive system for disability assessment and verification following burn injury. The core set provides information for effective rehabilitation strategy setting for patients with burns. Further feasibility and validation studies are required in the future.


An experimental study on fear of public speaking using a virtual environment.
This paper examines a necessary condition for successful exploitation of a virtual environment (VE) in therapeutic intervention for fear of public speaking. The condition is that clients experience a degree of anxiety in the VE that is similar to what they would have been expected to experience in a similar real world setting. We refer to this as a "presence" response. The experimental study involved 20 people who were confident public speakers and 16 who were phobic, assessed on a standard psychological scale. Half of each group spoke within a VE depicting an empty seminar room, and the other half within the same room but populated by a neutrally behaving virtual audience of five people. Three responses were measured--a questionnaire-based measure of anxiety, a measure of self-focused attention on somatic responses, and actual heart rate. On all responses, the people with phobia showed a significant increase in signs of anxiety when speaking to the virtual audience compared to the empty room, whereas the confident people did not. The result was strong in spite of the relatively low representational and behavioral fidelity of the virtual characters.


Characterisation of antibody responses in pigs induced by recombinant oncosphere antigens from Taenia solium.
Recombinant antigens cloned from the oncosphere life cycle stage of the cestode parasite Taenia solium (T. solium) have been proven to be effective as vaccines for protecting pigs against infections with T. solium. Previous studies have defined three different host protective oncosphere antigens, TSOL18, TSOL16 and TSOL45. In this study, we evaluated the potential for combining the antigens TSOL16 and TSOL18 as a practical vaccine. Firstly, in a laboratory trial, we compared the immunogenicity of the combined antigens (TSOL16/18) versus the immunogenicity of the antigens separately. Secondly, in a field trial, we tested the ability of the TSOL16/18 vaccine to induce detectable antibody responses in animals living under environmental stress and traditionally reared in areas where T. solium cysticercosis is endemic; and finally, we characterised the immune response of the study population. Pigs of 8-16 weeks of age were vaccinated with 200 μg each of TSOL16 and TSOL18, plus 5mg of Quil-A. Specific total IgG, IgG(1) and IgG(2) antibody responses induced by TSOL16 and TSOL18 were determined with ELISA. The immunogenicity of both antigens was retained in the combined TSOL16/18 vaccine. The combined vaccine TSOL16/18 induced detectable specific anti-TSOL18 antibody responses in 100% (113/113) and specific anti-TSOL16 in 99% (112/113) of the vaccinated animals measured at 2 weeks following the booster vaccination. From the two IgG antibody subtypes analysed we found there was stronger response to IgG(2).


Happier People Live More Active Lives: Using Smartphones to Link Happiness and Physical Activity.
Physical activity, both exercise and non-exercise, has far-reaching benefits to physical health. Although exercise has also been linked to psychological health (e.g., happiness), little research has examined physical activity more broadly, taking into account non-exercise activity as well as exercise. We examined the relationship between physical activity (measured broadly) and happiness using a smartphone application. This app has collected self-reports of happiness and physical activity from over ten thousand participants, while passively gathering information about physical activity from the accelerometers on users' phones. The findings reveal that individuals who are more physically active are happier. Further, individuals are happier in the moments when they are more physically active. These results emerged when assessing activity subjectively, via self-report, or objectively, via participants' smartphone accelerometers. Overall, this research suggests that not only exercise but also non-exercise physical activity is related to happiness. This research further demonstrates how smartphones can be used to collect large-scale data to examine psychological, behavioral, and health-related phenomena as they naturally occur in everyday life.


Comparison of attitudes towards persons with dementia, knowledge of dementia and ageism amongst students in Taiwan and Japan: A cross-sectional study.
This study aimed to compare the attitudes towards people with dementia, knowledge of dementia and ageism amongst Taiwanese and Japanese dental hygiene students. A total of 328 students participated in this cross-sectional study. Attitudes, knowledge and ageism were assessed using self-reports. Participants' association with older adults or persons with dementia was also assessed. Primary outcomes included attitude, knowledge and ageism amongst students. Secondary outcomes were the factors related to their desire to work with persons with dementia. Data of 175 Taiwanese and 91 Japanese students were analysed. There were significantly more Japanese (69.2%) than Taiwanese (33.2%) students without experience of cohabitation with older adults. More Taiwanese (45.1%) than Japanese students (30.8%) gave a neutral answer regarding their desire to work with persons with dementia. Japanese students scored significantly higher on the attitude and ageism scales than did Taiwanese students; however, the scores of knowledge assessment were approximately the same. Attitude or ageism did not correlate with knowledge amongst students from either country. Logistic regression analysis revealed that the desire to work with persons having dementia was related to ageism and the relationship with these people, irrespective of country. Although the students had comparable levels of knowledge, there existed significant difference in the attitudes and the degree of ageism between students from Taiwan vs Japan. This finding may prompt improvement of education on dementia, where differences in nationality and lifestyle, including the rate of ageing and family structure, are taken into consideration.


Detection and quantification of hippocampal synaptophysin messenger RNA in schizophrenia using autoclaved, formalin-fixed, paraffin wax-embedded sections.
Most in situ hybridization histochemistry studies of messenger RNA in human brain have been carried out on frozen tissue. Recently, autoclaving has been reported to enable routinely processsed material to be used for in situ localization of messenger RNA. We have investigated whether autoclaving also permits in situ hybridization histochemistry to be used quantitatively. To do this, we targeted synaptophysin messenger RNA with a 35S-labelled oligonucleotide probe in autoclaved, formalin-fixed, paraffin wax-embedded sections of the hippocampal formation of 11 schizophrenics and 11 controls. We compared the results with those seen on frozen sections from adjacent blocks, which had been used previously to demonstrate a loss of the messenger RNA in schizophrenia. Synaptophysin messenger RNA was readily detected in the autoclaved sections. The hybridization signal correlated strongly with that seen in the frozen sections. We found a similar pattern and magnitude of decreased synaptophysin messenger RNA in schizophrenia in the autoclaved sections as we had in the frozen sections, including the selective preservation of synaptophysin messenger RNA in CA1. The reduction of synaptophysin messenger RNA was replicated when six subjects with schizophrenia not included in the earlier study were considered separately. We conclude that autoclaving renders formalin-fixed, paraffin wax-embedded sections of human brain suitable for quantitative in situ hybridization histochemistry. This has considerable implications, given the wider availability, better morphology and easier handling of fixed than frozen human brain tissue. Using this material, we confirmed the finding of decreased synaptophysin messenger RNA in the hippocampal formation in schizophrenia, furthering the evidence for synaptic pathology in this region in the disorder.


Selenium Status Is Not Associated with Cognitive Performance: A Cross-Sectional Study in 154 Older Australian Adults.
Selenium was suggested to play a role in modulating cognitive performance and dementia risk. Thus, this study aimed to investigate the association between selenium status and cognitive performance, as well as inflammatory and neurotrophic markers in healthy older adults. This cross-sectional study included 154 older adults (≥60 years) from Victoria, Australia. Participants were assessed for cognitive performance (Cogstate battery), dietary selenium intake (two 24-h food recalls), plasma selenium concentration, inflammatory markers (interleukin (IL)-6, -8, -10, tumor necrosis factor-alpha and adiponectin) and neurotrophic factors (brain-derived neurotrophic factor, vascular endothelial growth factor and insulin-like growth factor 1). Dietary selenium intake was adequate for 85% of all participants. The prevalence of selenium deficiency was low; only 8.4% did not have the minimum concentration in plasma required for optimization of iodothyronine 5' deiodinases activity. Multiple linear regression analysis revealed that plasma selenium was not associated with cognitive performance, inflammatory markers nor neurotrophic factors, independent of age, sex, body mass index (BMI), habitual physical activity, APOE status, education, and history of cardiovascular disease. The lack of association might be due to the optimization of selenoproteins synthesis as a result of adequate selenium intake. Future prospective studies are recommended to explore potential associations of selenium status with age-associated cognitive decline.


Case detection, diagnosis, and treatment of patients with primary aldosteronism: an endocrine society clinical practice guideline.
Our objective was to develop clinical practice guidelines for the diagnosis and treatment of patients with primary aldosteronism. The Task Force comprised a chair, selected by the Clinical Guidelines Subcommittee (CGS) of The Endocrine Society, six additional experts, one methodologist, and a medical writer. The Task Force received no corporate funding or remuneration. Systematic reviews of available evidence were used to formulate the key treatment and prevention recommendations. We used the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) group criteria to describe both the quality of evidence and the strength of recommendations. We used "recommend" for strong recommendations and "suggest" for weak recommendations. Consensus was guided by systematic reviews of evidence and discussions during one group meeting, several conference calls, and multiple e-mail communications. The drafts prepared by the task force with the help of a medical writer were reviewed successively by The Endocrine Society's CGS, Clinical Affairs Core Committee (CACC), and Council. The version approved by the CGS and CACC was placed on The Endocrine Society's Web site for comments by members. At each stage of review, the Task Force received written comments and incorporated needed changes. We recommend case detection of primary aldosteronism be sought in higher risk groups of hypertensive patients and those with hypokalemia by determining the aldosterone-renin ratio under standard conditions and that the condition be confirmed/excluded by one of four commonly used confirmatory tests. We recommend that all patients with primary aldosteronism undergo adrenal computed tomography as the initial study in subtype testing and to exclude adrenocortical carcinoma. We recommend the presence of a unilateral form of primary aldosteronism should be established/excluded by bilateral adrenal venous sampling by an experienced radiologist and, where present, optimally treated by laparoscopic adrenalectomy. We recommend that patients with bilateral adrenal hyperplasia, or those unsuitable for surgery, optimally be treated medically by mineralocorticoid receptor antagonists.


Multilayer Exponential Family Factor models for integrative analysis and learning disease progression.
Current diagnosis of neurological disorders often relies on late-stage clinical symptoms, which poses barriers to developing effective interventions at the premanifest stage. Recent research suggests that biomarkers and subtle changes in clinical markers may occur in a time-ordered fashion and can be used as indicators of early disease. In this article, we tackle the challenges to leverage multidomain markers to learn early disease progression of neurological disorders. We propose to integrate heterogeneous types of measures from multiple domains (e.g., discrete clinical symptoms, ordinal cognitive markers, continuous neuroimaging, and blood biomarkers) using a hierarchical Multilayer Exponential Family Factor (MEFF) model, where the observations follow exponential family distributions with lower-dimensional latent factors. The latent factors are decomposed into shared factors across multiple domains and domain-specific factors, where the shared factors provide robust information to perform extensive phenotyping and partition patients into clinically meaningful and biologically homogeneous subgroups. Domain-specific factors capture remaining unique variations for each domain. The MEFF model also captures nonlinear trajectory of disease progression and orders critical events of neurodegeneration measured by each marker. To overcome computational challenges, we fit our model by approximate inference techniques for large-scale data. We apply the developed method to Parkinson's Progression Markers Initiative data to integrate biological, clinical, and cognitive markers arising from heterogeneous distributions. The model learns lower-dimensional representations of Parkinson's disease (PD) and the temporal ordering of the neurodegeneration of PD.


Treatment of cytomegalovirus retinopathy in patients with acquired immunodeficiency syndrome. Use of the experimental drug 9-[2-hydroxy-1-(hydroxymethyl)ethoxymethyl]guanine.
Cytomegalovirus (CMV) retinopathy, a relentlessly progressive disease that results in permanent blindness, is the most common opportunistic infection of the eye in patients with the acquired immunodeficiency syndrome. Twenty patients with the acquired immunodeficiency syndrome with CMV retinopathy were treated with a new, experimental, antiviral drug, 9-[2-hydroxy-1-(hydroxymethyl)ethoxymethyl]guanine (BW B759U), in dosages ranging from 5.0 to 14.0 mg/kg/d for a ten- to 20-day course. In 19 patients (95%), treatment halted the progression of infection and decreased retinal opacification, hemorrhage, and vasculitis. Vision remained stable in most cases. Six patients received no additional treatment. Fourteen patients received continued treatment with a lower maintenance dosage. Retinal disease reactivated in all patients who did not receive maintenance therapy immediately after initial treatment, indicating persistence of live virus despite drug therapy. Reactivation of disease also developed in four (40%) of ten patients receiving continuous, uninterrupted maintenance therapy for longer than three weeks. Reversible neutropenia, requiring cessation of treatment, developed in five (25%) of 20 patients on initial treatment and five (36%) of 14 patients receiving maintenance therapy. Rhegmatogenous retinal detachment was a late complication in four patients. BW B759U appears to be useful in the management of CMV retinopathy by reducing or delaying visual loss.


Towards a physically more active lifestyle based on one's own values: study design of a randomized controlled trial for physically inactive adults.
This randomised controlled trial demonstrates the effectiveness of a value-based intervention program to encourage a physically more active lifestyle among physically inactive adults aged 30 to 50 years. The conceptual framework of the program is based on an innovative behavioural therapy called Acceptance and Commitment Therapy (ACT) that aims to increase an individual's psychological flexibility and support behaviour change towards a higher quality and more meaningful life. Participants will be randomly allocated to a feedback group (FB) or an Acceptance and Commitment based (ACT+FB) group. Both the groups will receive written feedback about their objectively measured physical activity levels and offered an opportunity to attend a body composition analysis. In addition, the Acceptance and Commitment based group will attend six group sessions and be given a pedometer for self-monitoring of their daily physical activity throughout the 9-week intervention. The group sessions aim to clarify individual values and enhance committed actions towards the goal of achieving a more meaningful life. Participants will also be taught new skills to work on subjective barriers related to physical activity. Physical activity will be measured objectively by an accelerometer over seven consecutive days and by self-reported questionnaires at the baseline, as well as at 3, 6, 9 and 15 months after the baseline measures. In addition, psychological well-being will be measured through the questionnaires, which assess mindfulness skills, psychological flexibility, psychological distress and depressive symptoms. This study's objective is to demonstrate a research protocol for a randomized controlled study motivating a physically more active lifestyle based on one's own values among physically inactive adults. The aim of the study is to evaluate the feasibility and intervention efficacy on physical activity and psychological well-being, and discuss challenges in motivating physically inactive adults towards physically more active lifestyles. ClinicalTrials.gov, number NCT01796990.


[Health among persons with intellectual disability in Spain: the European POMONA-II study].
International studies show that both the pattern of health and the healthcare provided for persons with intellectual disability (ID) and the general population are different. To obtain data about the state of health of persons with ID and to compare them with data about the general population. The P15 set of health indicators was used in a sample of 111 subjects with ID. The health data that were found were compared according to the subjects' type of residence and the 2006 National Health Survey was used to compare these data with those for the general population. RESULTS; The sample with ID presented 25 times more cases of epilepsy and twice as many cases of obesity. Twenty per cent presented pain in the mouth and the presence of sensory and mobility problems, as well as psychosis, was high. We also found, however, a low presence of pathologies like diabetes, hypertension, osteoarthritis and osteoporosis. They also displayed a lower rate of participation in prevention and health promotion programmes, a higher number of hospital admissions and a lower usage of emergency services. The pattern of health of persons with ID differs from that of the general population, and they use healthcare services differently. It is important to develop programmes of health promotion and professional training that are specifically designed to attend to the needs of persons with ID. Likewise, it is also necessary to implement health surveys that include data about this population.


"Social marketing" for early neonatal care: saving newborn lives in Pakistan.
According to the World Health Organization and the United Nations Children's Fund, developing countries carry a large share of neonatal mortality in the world. According to UNICEF, almost 450 newborn children die every hour, mostly from preventable causes. Restricted access to quality and hygienic delivery services and limited knowledge about handling the newborn aggravate the situation. South Asia, and Pakistan in particular, have reduced their child and infant mortality during the last decade; however, neonatal mortality still remains unacceptably high. There are multiple reasons, mainly related to practices and behaviours of communities and traditional birth attendants. Rural and poor populations suffer most in Pakistan, where three out of five deliveries still occur at home. Traditional community practices and conservative norms drastically affect neonatal health outcomes. Preventing sepsis at the umbilical cord, keeping the baby at the correct temperature after birth and early initiation of exclusive breastfeeding are three simple strategies or messages that need to be disseminated widely to prevent many neonatal mortalities and morbidities. Since inappropriate practices in handling newborns are directly linked with persistent and unremitting behaviours among health providers and the community at large, we suggest doing robust "social marketing" for saving newborn lives. The objective of the paper is to present a social-marketing strategy and a marketing mix that will help address and surmount actual barriers and promote alternative behaviours in early neonatal care.


Frequency and phase contributions to the detection of temporal luminance modulation.
Observers detected a temporally modulated luminance pattern embedded in dynamic noise. A Gabor function with a carrier frequency, in separate conditions of 0, 1.56, or 3.12 Hz, modulated signal contrast. Classification images were constructed in the time, temporal frequency, and temporal phase domains. As stimulus frequency increased, amplitudes of the phase images decreased and amplitudes of the frequency images increased, indicating a corresponding shift in the observers' criteria. The reduced use of phase attenuated time-domain images from signal-absent trials, but physical interactions between signal and noise components tended to preserve time-domain images from signal-present trials. The results illustrate a frequency-dependent strategy shift in detection that may reflect a degree of stimulus uncertainty in the time domain.


An Automated System for the Detection and Classification of Retinal Changes Due to Red Lesions in Longitudinal Fundus Images.
People with diabetes mellitus need annual screening to check for the development of diabetic retinopathy (DR). Tracking small retinal changes due to early diabetic retinopathy lesions in longitudinal fundus image sets is challenging due to intra- and intervisit variability in illumination and image quality, the required high registration accuracy, and the subtle appearance of retinal lesions compared to other retinal features. This paper presents a robust and flexible approach for automated detection of longitudinal retinal changes due to small red lesions by exploiting normalized fundus images that significantly reduce illumination variations and improve the contrast of small retinal features. To detect spatio-temporal retinal changes, the absolute difference between the extremes of the multiscale blobness responses of fundus images from two time points is proposed as a simple and effective blobness measure. DR related changes are then identified based on several intensity and shape features by a support vector machine classifier. The proposed approach was evaluated in the context of a regular diabetic retinopathy screening program involving subjects ranging from healthy (no retinal lesion) to moderate (with clinically relevant retinal lesions) DR levels. Evaluation shows that the system is able to detect retinal changes due to small red lesions with a sensitivity of at an average false positive rate of 1 and 2.5 lesions per eye on small and large fields-of-view of the retina, respectively.


Effects of movement imagery and electromyography-triggered feedback on arm hand function in stroke patients in the subacute phase.
To investigate the effects of movement imagery-assisted electromyography (EMG)-triggered feedback (focused on paretic wrist dorsiflexors) on the arm-hand function of stroke patients. Single-blinded, longitudinal, multicentre randomized controlled trial. Measurements were performed (on average) 54 days post stroke (baseline), three months later (post training) and at 12 months post baseline. Two rehabilitation centres. Twenty-seven patients with a first-ever, ischaemic, subacute stroke. A reference group received conventional electrostimulation, while the experimental group received arm-hand function training based on EMG-triggered feedback combined with movement imagery. Both groups were trained for three months, 5 days/week, 30 minutes/day, in addition to their therapy as usual. Arm-hand function was evaluated using the upper extremity-related part of the Brunnstrom Fugl-Meyer test and the Action Research Arm test. During training, Brunnstrom Fugl-Meyer scores improved 8.7 points and Action Research Arm scores by 19.4 points (P < 0.0001) in both groups relative to baseline results, rising to 13.3 and 28.4 points respectively at one year follow-up (P < 0.0001). No between-group differences were found at any time. EMG-triggered feedback stimulation did not lead to more arm-hand function improvement relative to conventional electrostimulation. However, in contrast to many clinical reports, a significant improvement was still observed in both groups nine months after treatment ceased.


Evidence for the involvement of ZNF804A in cognitive processes of relevance to reading and spelling.
Previous studies have shown that individuals with schizophrenia and dyslexia display common neurocognitive abnormalities. The aim of the present study was to determine whether known schizophrenia-risk genes contribute to dyslexia risk or to disease-relevant cognitive functions. For this purpose, we genotyped the schizophrenia-associated risk variants within zinc-finger protein 804A (ZNF804A), transcription-factor 4 and neurogranin in a large dyslexia case-control sample. We tested all variants for association with dyslexia (927 cases, 1096 controls), and with eight language-relevant cognitive processes (1552 individuals). We observed six significant associations between language-relevant traits and the ZNF804A-variant rs1344706. Interestingly, the ZNF804A schizophrenia risk variant was associated with a better cognitive performance in our data set. This finding might be consistent with a previously reported ZNF804A association in schizophrenia, in which patients carrying the schizophrenia-risk allele at rs1344706 showed a better performance in two memory tests. In conclusion, the present study provides evidence that ZNF804A might have a role in cognitive traits of relevance to reading and spelling, and underlines the phenotypic complexity that might be associated with ZNF804A.


Impaired antibody memory to varicella zoster virus in HIV-infected children: low antibody levels and avidity*.
HIV-infected children have impaired antibody responses after exposure to certain antigens. Our aim was to determine whether HIV-infected children had lower varicella zoster virus (VZV) antibody levels compared with HIV-infected adults or healthy children and, if so, whether this was attributable to an impaired primary response, accelerated antibody loss, or failure to reactivate the memory VZV response. In a prospective, cross-sectional and retrospective longitudinal study, we compared antibody responses, measured by enzyme-linked immunosorbent assay (ELISA), elicited by VZV infection in 97 HIV-infected children and 78 HIV-infected adults treated with antiretroviral therapy, followed over 10 years, and 97 age-matched healthy children. We also tested antibody avidity in HIV-infected and healthy children. Median anti-VZV immunoglobulin G (IgG) levels were lower in HIV-infected children than in adults (264 vs. 1535 IU/L; P<0.001) and levels became more frequently unprotective over time in the children [odds ratio (OR) 17.74; 95% confidence interval (CI) 4.36-72.25; P<0.001]. High HIV viral load was predictive of VZV antibody waning in HIV-infected children. Anti-VZV antibodies did not decline more rapidly in HIV-infected children than in adults. Antibody levels increased with age in healthy (P=0.004) but not in HIV-infected children. Thus, antibody levels were lower in HIV-infected than in healthy children (median 1151 IU/L; P<0.001). Antibody avidity was lower in HIV-infected than healthy children (P<0.001). A direct correlation between anti-VZV IgG level and avidity was present in HIV-infected children (P=0.001), but not in healthy children. Failure to maintain anti-VZV IgG levels in HIV-infected children results from failure to reactivate memory responses. Further studies are required to investigate long-term protection and the potential benefits of immunization.


Impact of Amendments on the Physical Properties of Soil under Tropical Long-Term No Till Conditions.
Tropical regions have been considered the world's primary agricultural frontier; however, some physico-chemical deficiencies, such as low soil organic matter content, poor soil structure, high erodibility, soil acidity, and aluminum toxicity, have affected their productive capacity. Lime and gypsum are commonly used to improve soil chemical fertility, but no information exists about the long-term effects of these products on the physical attributes and C protection mechanisms of highly weathered Oxisols. A field trial was conducted in a sandy clay loam (kaolinitic, thermic Typic Haplorthox) under a no-tillage system for 12 years. The trial consisted of four treatments: a control with no soil amendment application, the application of 2.1 Mg ha-1 phosphogypsum, the application of 2.0 Mg ha-1 lime, and the application of lime + phosphogypsum (2.0 + 2.1 Mg ha-1, respectively). Since the experiment was established in 2002, the rates have been applied three times (2002, 2004, and 2010). Surface liming effectively increased water-stable aggregates > 2.0 mm at a depth of up to 0.2 m; however, the association with phosphogypsum was considered a good strategy to improve the macroaggregate stability in subsoil layers (0.20 to 0.40 m). Consequently, both soil amendments applied together increased the mean weight diameter (MWD) and geometric mean diameter (GMD) in all soil layers, with increases of up to 118 and 89%, respectively, according to the soil layer. The formation and stabilization of larger aggregates contributed to a higher accumulation of total organic carbon (TOC) on these structures. In addition to TOC, the MWD and aggregate stability index were positively correlated with Ca2+ and Mg2+ levels and base saturation. Consequently, the increase observed in the aggregate size class resulted in a better organization of soil particles, increasing the macroporosity and reducing the soil bulk density and penetration resistance. Therefore, adequate soil chemical management plays a fundamental role in improving the soil's physical attributes in tropical areas under conservative management and highly affected by compaction caused by intensive farming.


An examination of targeted gene neighborhoods in strawberry.
Strawberry (Fragaria spp.) is the familiar name of a group of economically important crop plants and wild relatives that also represent an emerging system for the study of gene and genome evolution. Its small stature, rapid seed-to-seed cycle, transformability and miniscule basic genome make strawberry an attractive system to study processes related to plant physiology, development and crop production; yet it lacks substantial genomics-level resources. This report addresses this deficiency by characterizing 0.71 Mbp of gene space from a diploid species (F. vesca). The twenty large genomic tracks (30-52 kb) captured as fosmid inserts comprise gene regions with roles in flowering, disease resistance, and metabolism. A detailed description of the studied regions reveals 131 Blastx-supported gene sites and eight additional EST-supported gene sites. Only 15 genes have complete EST coverage, enabling gene modelling, while 76 lack EST support. Instances of microcolinearity with Arabidopsis thaliana were identified in twelve inserts. A relatively high portion (25%) of targeted genes were found in unanticipated tandem duplications. The effectiveness of six FGENESH training models was assessed via comparisons among ab initio predictions and homology-based gene and start/stop codon identifications. Fourteen transposable-element-related sequences and 158 simple sequence repeat loci were delineated. This report details the structure and content of targeted regions of the strawberry genome. The data indicate that the strawberry genome is gene-dense, with an average of one protein-encoding gene or pseudogene per 5.9 kb. Current overall EST coverage is sparse. The unexpected gene duplications and their differential patterns of EST support suggest possible subfunctionalization or pseudogenization of these sequences. This report provides a high-resolution depiction of targeted gene neighborhoods that will aid whole-genome sequence assembly, provide valuable tools for plant breeders and advance the understanding of strawberry genome evolution.


Particle handling during interception feeding by four species of heterotrophic nanoflagellates.
High resolution video-microscopy was used to observe grazing patterns of the heterotrophic nanoflagellates Cafeteria roenbergensis, Bodo saltans, Spumella sp., and Ochromonas sp. Spumella and Ochromonas enclose food particles with pseudopodia while Cafeteria and Bodo engulf particles by invagination of the cell surface. The following parameters of the feeding process were quantified: frequency of flagellar beating, speed of particles in different positions of the feeding current, food size selection, feeding rate, and the time budget for the handling of particles. The mean handling times differed between 94 s for Cafeteria and 4 s for Ochromonas for ingested particles. Handling times for ingested particles were significantly longer than for non-captured particles. Long handling times were calculated to be disadvantageous only for flagellates which propel a high water volume per hour (esp. Ochromonas) or live in a bacteria-rich environment. Our model calculations may provide a reasonable theoretical explanation for a concentration-dependent behavioural variability of the feeding strategy of different heterotrophic nanoflagellates (HNF) species.


Effects of spontaneous respiration on canine left ventricular function.
The purpose of this study was to determine the mechanism of the decrease in left ventricular stroke volume during spontaneous inspiration. We determined the transmural pressures of the left heart by measuring left atrial and diastolic left ventricular pressures relative to esophageal pressure. We estimated the directional changes in end-systolic and end-diastolic volumes of the left ventricle by determining the transit time of sound transmission between two ultrasonic crystals facing each other across the minor axis of the left ventricle. Left ventricular stroke volume decreased with spontaneous inspiratory effort as pleural pressure fell, regardless of whether lung volume increased or remained constant. The stroke volume was decreased during the fall in pleural pressure because of an increase in end-systolic volume with an essentially unchanged diastolic volume. Thus, the decrease in stroke volume was due to a decrease in ejection, rather than a decrease in filling of the left ventricle. We believe that left ventricular ejection was impeded by the fall in pressure around the heart relative to the pressure in the aorta. In spite of the essentially constant diastolic volume, diastolic left ventricular transmural pressure rose, suggesting that spontaneous inspiration decreases the diastolic compliance of the left ventricle. The change in diastolic compliance contributed to the decrease in stroke volume but was not the primary cause.


Contextualizing ethics: ventilators, H1N1 and marginalized populations.
If the H1N1 pandemic worsens, there may not be enough ventilated beds to care for all persons with respiratory failure. To date, researchers who explicitly discuss the ethics of intensive care unit admission and the allocation of ventilators during an influenza pandemic have based criteria predominantly on the principles of utility and efficiency, that is, promoting actions that maximize the greatest good for the greatest number of people. However, haphazardly applying utility and efficiency potentially disadvantages marginalized populations who might be at increased risk of severe reactions to H1N1. In Canada, Aboriginals represent 3% of Canadians, yet 11% of H1N1 cases requiring hospitalization involve Aboriginal persons. Aboriginal persons suffer from high rates of obesity due to socio-economic inequalities. Obesity is also a risk factor for severe H1N1 reactions. Yet, since obesity is found to increase the duration of stay in ventilated beds and a long stay is not considered an optimal use of ventilators, applying the principles of utility and efficiency may magnify existing social inequalities. Although promoting utility and efficiency is important, other ethical principles, such as equity and need, require thoughtful consideration and implementation. Furthermore, since public resources are being used to address a public health hazard, the viewpoints of the public, and specifically stakeholders who will be disproportionately affected, should inform decision-makers. Finally, giving attention to the needs and rights of marginalized populations means that ventilators should not be allocated based on criteria that exacerbate the social injustices faced by these groups of people.


Predictive value of IL-18 and SC5b-9 for neurocognitive dysfunction after cardiopulmonary bypass.
Neurological injury after cardiopulmonary bypass (CPB) continues to be a major problem after cardiac surgery. The aim of this study was to investigate the predictive value of Interleukin-18 (IL-18) and SC5b-9 as biochemical markers of neurocognitive dysfunction after cardiac surgery. A total of 30 patients undergoing elective cardiac surgery using CPB were recruited. Blood samples were obtained for IL-18 and SC5b-9 concentrations before induction, 24, 48, 72, 96 and 120 h post-CPB and 6 weeks after operation. In addition, patients underwent a standard battery of neuropsychometric tests before operation and at day 5 and 6 weeks after operation. Serum concentration of IL-18, but not SC5b-9, was significantly different between patients with and without neurocognitive dysfunction; serum IL-18 concentration significantly increased in patients with neurocognitive dysfunction (P = 0.018). Neurological outcome was significantly dependent on peak difference in IL-18 concentration at day 5 (P = 0.033), but not on peak difference in SC5b-9 concentration (P = 0.16). Eight patients had neurocognitive dysfunction at day 5 and three had neurocognitive dysfunction at 6 weeks. In a very small number of patients, no significant association was demonstrated between IL-18 or SC5b-9 concentrations and neurocognitive dysfunction at 6 weeks. IL-18 has the potential as a useful marker of neurological dysfunction, requiring further investigation.


Molecular recognition: comparative study of a tunable host-guest system by using a fluorescent model system and collision-induced dissociation mass spectrometry on dendrimers.
Host-guest interactions between the periphery of adamantylurea-functionalized dendrimers (host) and ureido acetic acid derivatives (guest) were shown to be specific, strong and spatially well-defined. The binding becomes stronger when using phosphonic or sulfonic acid derivatives. In the present work we have quantified the binding constants for the host-guest interactions between two different host motifs and six different guest molecules. The host molecules, which resemble the periphery of a poly(propylene imine) dendrimer, have been fitted with an anthracene-based fluorescent probe. The two host motifs differ in terms of the length of the spacer between a tertiary amine and two ureido functionalities. The guest molecules all contain an acidic moiety (either a carboxylic acid, a phosphonic acid, or a sulfonic acid) and three of them also contain an ureido moiety capable of forming multiple hydrogen bonds to the hosts. The binding constants for all 12 host-guest complexes have been determined by using fluorescence titrations by monitoring the increase in fluorescence of the host upon protonation by the addition of the guest. The binding constants could be tuned by changing the design of the acidic part of the guest. The formation of hydrogen bonds gives, in all cases, higher association constants, demonstrating that the host is more than a proton sensor. The host with the longer spacer (propyl) shows higher association constants than the host with the shorter spacer (ethyl). The gain in association constants are higher when the urea function is added to the guests for the host with the longer spacer, indicating a better fit. Collision-induced dissociation mass spectrometry (CID-MS) is used to study the stability of the six motifs using the corresponding third generation dendrimer. A similar trend is found when the six different guests are compared.


Effect of intensive treatment of hyperglycaemia on microvascular outcomes in type 2 diabetes: an analysis of the ACCORD randomised trial.
Hyperglycaemia is associated with increased risk of cardiovascular complications in people with type 2 diabetes. We investigated whether reduction of blood glucose concentration decreases the rate of microvascular complications in people with type 2 diabetes. ACCORD was a parallel-group, randomised trial done in 77 clinical sites in North America. People with diabetes, high HbA(1c) concentrations (>7.5%), and cardiovascular disease (or >or=2 cardiovascular risk factors) were randomly assigned by central randomisation to intensive (target haemoglobin A(1c) [HbA(1c)] of <6.0%) or standard (7.0-7.9%) glycaemic therapy. In this analysis, the prespecified composite outcomes were: dialysis or renal transplantation, high serum creatinine (>291.7 micromol/L), or retinal photocoagulation or vitrectomy (first composite outcome); or peripheral neuropathy plus the first composite outcome (second composite outcome). 13 prespecified secondary measures of kidney, eye, and peripheral nerve function were also assessed. Investigators and participants were aware of treatment group assignment. Analysis was done for all patients who were assessed for microvascular outcomes, on the basis of treatment assignment, irrespective of treatments received or compliance to therapies. ACCORD is registered with ClinicalTrials.gov, number NCT00000620. 10 251 patients were randomly assigned, 5128 to the intensive glycaemia control group and 5123 to standard group. Intensive therapy was stopped before study end because of higher mortality in that group, and patients were transitioned to standard therapy. At transition, the first composite outcome was recorded in 443 of 5107 patients in the intensive group versus 444 of 5108 in the standard group (HR 1.00, 95% CI 0.88-1.14; p=1.00), and the second composite outcome was noted in 1591 of 5107 versus 1659 of 5108 (0.96, 0.89-1.02; p=0.19). Results were similar at study end (first composite outcome 556 of 5119 vs 586 of 5115 [HR 0.95, 95% CI 0.85-1.07, p=0.42]; and second 1956 of 5119 vs 2046 of 5115, respectively [0.95, 0.89-1.01, p=0.12]). Intensive therapy did not reduce the risk of advanced measures of microvascular outcomes, but delayed the onset of albuminuria and some measures of eye complications and neuropathy. Seven secondary measures at study end favoured intensive therapy (p<0.05). Microvascular benefits of intensive therapy should be weighed against the increase in total and cardiovascular disease-related mortality, increased weight gain, and high risk for severe hypoglycaemia. US National Institutes of Health; National Heart, Lung, and Blood Institute; National Institute of Diabetes and Digestive and Kidney Diseases; National Institute on Aging; National Eye Institute; Centers for Disease Control and Prevention; and General Clinical Research Centers.


Significance of Conducting 2 Types of Fecal Tests in Patients With Ulcerative Colitis.
We compared the diagnostic accuracy of the fecal calprotectin (FCP) test vs the fecal immunochemical blood test (FIT) in determining the endoscopic severity and predicting outcomes of patients with ulcerative colitis (UC). We performed a nationwide study of 879 patients with UC, enrolled at medical centers across Japan, from March 2015 to March 2017. We collected data on fecal biomarkers, endoscopic severities, and other clinical indices from Cohort 1 (n = 427) and assessed the diagnostic accuracy of FCP measurement and FIT results in determining clinical severity, based on Mayo score, and endoscopic remission, based on Mayo endoscopic sub-score (MES) or UC endoscopic index of severity. We also followed 452 patients in clinical remission from UC (Cohort 2) for 12 months and evaluated the associations of FCP levels and FIT results with clinical recurrence. The levels of FCP and FIT each correlated with the MES and UC endoscopic index of severity. There were no significant differences in the areas under the curve of FCP vs FIT in distinguishing patients with MES≤1 from those with MES≥2 (P = .394) or in distinguishing patients with MES=0 from those with MES≥1 (P = .178). Among 405 patients in clinical remission at baseline, 38 (9.4%) had UC recurrences within 3 months and 90 (22.2%) had recurrences within 12 months. FCP≥146 mg/kg (hazard ratio [HR], 4.83; 95% confidence interval [CI], 2.80-8.33) and FIT≥77 ng/mL (HR, 2.92; 95% CI, 1.76-4.83) were independently associated with clinical recurrence within 12 months. UC recurred within 12 months in 69% of patients with levels of FCP≥146 mg/kg and FIT ≥77 ng/mL; this value was significantly higher than the rate of recurrence in patients with levels of FCP≥146 mg/kg and FIT <77 ng/mL (31.5%, P < .001) or patients with levels of FCP<146 mg/kg and FIT ≥77 ng/mL (30.0%, P < .001). In a nationwide study of patients with UC in Japan, we found that the level of FCP and FIT could each identify patients with endoscopic markers of disease severity (MES≥2). The combination of FCP and FIT results can identify patients in remission who are at risk for disease recurrence. Clinical Trials Registry no: UMIN000017650 (http://www.umin.ac.jp/ctr/).


In situ differentiation and generation of functional liver organoids from human iPSCs in a 3D perfusable chip system.
Liver organoids derived from human pluripotent stem cells (PSCs) represent a new type of in vitro liver model for understanding organ development, disease mechanism and drug testing. However, engineering liver organoids with favorable functions in a controlled cellular microenvironment remains challenging. In this work, we present a new strategy for engineering liver organoids derived from human induced PSCs (hiPSCs) in a 3D perfusable chip system by combining stem cell biology with microengineering technology. This approach enabled formation of hiPSC-based embryoid bodies (EBs), in situ hepatic differentiation, long-term 3D culture and generation of liver organoids in a perfusable micropillar chip. The generated liver organoids exhibited favorable growth and differentiation of hepatocytes and cholangiocytes, recapitulating the key features of human liver formation with cellular heterogeneity. The liver organoids in perfused cultures displayed improved cell viability and higher expression of endodermal genes (SOX17 and FOXA2) and mature hepatic genes (ALB and CYP3A4) under perfused culture conditions. In addition, the liver organoids showed a marked enhancement of hepatic-specific functions, including albumin and urea production and metabolic capabilities, indicating the role of mechanical fluid flow in promoting the functions of the liver organoids. Moreover, the liver organoids exhibited hepatotoxic response after exposure to acetaminophen (APAP) in a dose- and time-dependent manner. The established liver organoid-on-a-chip system may provide a promising platform for engineering stem cell-based organoids with applications in regenerative medicine, disease modeling and drug testing.


The correlation of canine patellar luxation and the anteversion angle as measured using magnetic resonance images.
Measurements from magnetic resonance (MR) images can be used to examine the anteversion angle (AT-angle) and its influence on the lateromedial or mediolateral luxating forces on the patella. The AT-angle of the femoral neck was measured with the aid of MR imaging in 45 pelvic limbs without patellar instability, in 33 limbs with patellar luxation and in 6 limbs with rupture of the cranial cruciate ligament. The limbs with medial patellar luxation were divided into three groups based on clinical examination. The mean (range) AT-angle was 7.6 degrees (0 degrees to 24 degrees) in the "normal" group, 8.6 degrees (-10 degrees to 29 degrees) in the group "grade II," and -0.4 degrees in the group "grade III" (-28 degrees to 12 degrees). A mean (range) AT-angle of 4.8 (-4 degrees to 11 degrees) was measured in the pelvic limbs with rupture of the cranial cruciate ligament. Compared to literature that described AT-angles based on radiographs of normal limbs, reduced AT-angles were found in this study due to different lines of measurement of the femoral neck. This study documents that the AT-angle of the femoral neck does not influence patellar instability. This study also demonstrates that MR images can be used to make exact measurements of the canine AT-angle that represent the true anatomy of the femoral neck.


No acute effects of grape juice on appetite, implicit memory and mood.
Animal experiments document effects of grape juice on cognitive performance and motor skills, and observational studies in humans suggest an inverse association between flavonoid intake and cognitive decline. These effects may be related to the antioxidant properties of polyphenols. Juice consumption and flavonoid intake may also affect appetite. To study the acute effects of grape juice consumption on appetite, mood and implicit memory during a time of increased lethargy - the post-lunch dip. Thirty-five participants with a mean age of 26 years who smoked a mean of 11 cigarettes/day for 8 years were included in the study. It included a practice session and two treatment sessions. All sessions involved consumption of grape juice or an energy-matched placebo with lunch followed by assessments of mood, implicit memory, appetite and food intake. Mood decreased over time for both treatments, but there were no differences after lunch between grape juice and placebo for any measure. This study did not document any acute effects of grape juice consumption on mood, implicit memory, appetite or food intake in smokers.


Vertebral fractures in ankylosing spondylitis are associated with lower bone mineral density in both central and peripheral skeleton.
To study the prevalence and risk factors for vertebral fractures (VF) in ankylosing spondylitis (AS) and the relation between VF, measures of disease activity, and bone mineral density (BMD) in different measurement sites. Patients with AS (modified New York criteria) underwent examination, answered questionnaires, and gave blood samples. Lateral spine radiographs were scored for VF (Genant score) and syndesmophyte formation through modified Stoke Ankylosing Spondylitis Spine Score (mSASSS). BMD was measured with dual-energy x-ray absorptiometry in the hip, radius, and lumbar spine in anteroposterior and lateral projections with estimation of volumetric BMD (vBMD). Two hundred four patients (57% men) with a mean age of 50 ± 13 years and disease duration 15 ± 11 years were included. VF were diagnosed in 24 patients (12%), but were previously noted clinically in only 3 of the 24. Patients with VF were significantly older (p = 0.004), had longer disease duration (p = 0.011), higher Bath Ankylosing Spondylitis Metrology Index (p = 0.011), mSASSS (p = 0.035), and Bath Ankylosing Spondylitis patient global score-2 (BASG-2) (p = 0.032) and were more often smokers (p = 0.032). All women with a VF were postmenopausal. BMD was significantly lower at all measuring sites in the patients with VF. In logistic regression, high BASG-2, low BMD in femoral neck, and low lumbar vBMD were independently associated with presence of VF. VF in AS are common but are often not diagnosed. VF are associated with advanced age, longstanding disease, impaired back mobility, syndesmophyte formation, and lower BMD in both the central and peripheral skeleton. BMD in the femoral neck, total hip, and estimated vBMD showed the strongest association with VF.


Multifunctional temozolomide-loaded lipid superparamagnetic nanovectors: dual targeting and disintegration of glioblastoma spheroids by synergic chemotherapy and hyperthermia treatment.
Aiming at finding new solutions for fighting glioblastoma multiforme, one of the most aggressive and lethal human cancer, here an in vitro validation of multifunctional nanovectors for drug delivery and hyperthermia therapy is proposed. Hybrid magnetic lipid nanoparticles have been fully characterized and tested on a multi-cellular complex model resembling the tumor microenvironment. Investigations of cancer therapy based on a physical approach (namely hyperthermia) and on a pharmaceutical approach (by exploiting the chemotherapeutic drug temozolomide) have been extensively carried out, by evaluating its antiproliferative and pro-apoptotic effects on 3D models of glioblastoma multiforme. A systematic study of transcytosis and endocytosis mechanisms has been moreover performed with multiple complimentary investigations, besides a detailed description of local temperature increments following hyperthermia application. Finally, an in-depth proteomic analysis corroborated the obtained findings, which can be summarized in the preparation of a versatile, multifunctional, and effective nanoplatform able to overcome the blood-brain barrier and to induce powerful anti-cancer effects on in vitro complex models.


Predictive medicine: outcomes, challenges and opportunities in the Synergy-COPD project.
Chronic Obstructive Pulmonary Disease (COPD) is a major challenge for healthcare. Heterogeneities in clinical manifestations and in disease progression are relevant traits in COPD with impact on patient management and prognosis. It is hypothesized that COPD heterogeneity results from the interplay of mechanisms governing three conceptually different phenomena: 1) pulmonary disease, 2) systemic effects of COPD and 3) co-morbidity clustering. To assess the potential of systems medicine to better understand non-pulmonary determinants of COPD heterogeneity. To transfer acquired knowledge to healthcare enhancing subject-specific health risk assessment and stratification to improve management of chronic patients. Underlying mechanisms of skeletal muscle dysfunction and of co-morbidity clustering in COPD patients were explored with strategies combining deterministic modelling and network medicine analyses using the Biobridge dataset. An independent data driven analysis of co-morbidity clustering examining associated genes and pathways was done (ICD9-CM data from Medicare, 13 million people). A targeted network analysis using the two studies: skeletal muscle dysfunction and co-morbidity clustering explored shared pathways between them. (1) Evidence of abnormal regulation of pivotal skeletal muscle biological pathways and increased risk for co-morbidity clustering was observed in COPD; (2) shared abnormal pathway regulation between skeletal muscle dysfunction and co-morbidity clustering; and, (3) technological achievements of the projects were: (i) COPD Knowledge Base; (ii) novel modelling approaches; (iii) Simulation Environment; and, (iv) three layers of Clinical Decision Support Systems. The project demonstrated the high potential of a systems medicine approach to address COPD heterogeneity. Limiting factors for the project development were identified. They were relevant to shape strategies fostering 4P Medicine for chronic patients. The concept of Digital Health Framework and the proposed roadmap for its deployment constituted relevant project outcomes.


Task Complexity and Image Clarity Facilitate Motor and Visuo-Motor Activities in Mirror Therapy in Post-stroke Patients.
Introduction: Mirror therapy is effective in the recovery of upper-limb function among post-stroke patients. An important component of mirror therapy is imagining finger movements. This study aimed to determine the influence of finger movement complexity and mirror image clarity on facilitating motor and visuo-motor activities in post-stroke patients. Methods: Fifteen post-stroke patients and 18 right-handed healthy participants performed simple or complex finger tapping while viewing mirror images of these movements at varying levels of clarity. The physical setup was identical to typical mirror therapy. Functional near infrared spectroscopy (fNIRS) was used to capture the brain activities elicited in the bilateral primary motor cortices (M1) and the precuneus using a block experimental design. Results: In both study groups, the "complex finger-tapping task with blurred mirror image" condition resulted in lower intensity (p < 0.01) and authenticity (p < 0.01) of the kinesthetic mirror illusion, and higher levels of perceived effort in generating the illusion (p < 0.01), relative to the "simple finger-tapping with clear mirror image" condition. Greater changes in the oxygenated hemoglobin (HbO) concentration were recorded at the ipsilesional and ipsilateral M1 in the "complex finger-tapping task with blurred mirror image" condition relative to that recorded in the "simple finger-tapping task with clear mirror image" condition (p = 0.03). These HbO concentration changes were not significant in the precuneus. Post-stroke patients showed greater changes than their healthy counterparts at the ipsilesional M1 (F = 5.08; p = 0.03; partial eta squared = 0.14) and the precuneus (F = 7.71; p < 0.01; partial eta squared = 0.20). Conclusion: The complexity and image clarity of the finger movements increased the neural activities in the ipsilesional motor cortex in the post-stroke patients. These findings suggest plausible roles for top-down attention and working memory in the treatment effects of mirror therapy. Future research can aim to corroborate these findings by using a longitudinal design to examine the use of mirror therapy to promote upper limb motor recovery in post-stroke patients.


Do cholinergic nerves innervating rat mesenteric arteries regulate vascular tone?
Vascular blood vessels have various types of cholinergic acetylcholine receptors (AChR), but the source of ACh has not been confirmed. Perivascular adrenergic nerves and nonadrenergic calcitonin gene-related peptide (CGRP)-containing (CGRPergic) nerves innervate rat mesenteric arteries and regulate vascular tone. However, function of cholinergic innervation remains unknown. The present study investigated cholinergic innervation by examining effects of cholinesterase inhibitor (neostigmine), a muscarinic AChR antagonist (atropine), and a nicotinic AChR antagonist (hexamethonium) on adrenergic nerve-mediated vasoconstriction and CGRPergic nerve-mediated vasodilation in rat mesenteric vascular beds without endothelium. In preparations treated with capsaicin (CGRP depletor) or in the presence of N(ω)-nitro-l-arginine methyl ester (nonselective nitric oxide synthase inhibitor), perivascular nerve stimulation (PNS; 2-12 Hz) evoked a frequency-dependent vasoconstriction. In the same preparations, exogenous norepinephrine induced a concentration-dependent vasoconstriction. Atropine, hexamethonium, and neostigmine had no effect on vasoconstrictor responses to PNS and norepinephrine injections. In denuded preparations, these cholinergic agents did not affect the PNS (12 Hz)-evoked release of norepinephrine in perfusate. In preconstricted preparations without endothelium in the presence of guanethidine (adrenergic neuron blocker), PNS (1-4 Hz) induced a frequency-dependent vasodilation, which was not affected by atropine, hexamethonium, and neostigmine. In denuded preparations treated with capsaicin and guanethidine, PNS did not induce vascular responses, and atropine, neostigmine, and physostigmine had no effect on PNS. Immunohistochemistry study showed choline acetyltransferase-immunopositive fibers, which were resistant to capsaicin and 6-hydroxydopamine (adrenergic toxin). These results suggest that rat mesenteric arteries have cholinergic innervation, which is different from adrenergic and capsaicin-sensitive nerves and not associated with vascular tone regulation.


In-hospital paediatric accidents: an integrative review of the literature.
Paediatric hospitals can be perceived by children, parents, health professionals as 'safe' places, but accidents do occur. To review publications relating to in-hospital paediatric accidents and highlight the state-of-the-science concerning this issue especially in relation to falls, and the evolution of research addressing this issue. Integrative review of papers published before March 2011 on accidents and falls occurred in hospitalized children. Electronic databases (PubMed, Cumulative Index to Nursing and Allied Health Literature and Cochrane Library databases) and further hand searching through references were searched. The inclusion criteria were articles involving observational, quasi-experimental or experimental studies in English or Italian. Exclusion criteria were articles addressing the outcomes of falls caused by suspect violence on children. Thirteen studies in English were included. Of the 13 studies conducted between 1963 and 2010, 10 had been conducted in the last 5 years; 10 in the USA. The studies were divided into two categories: contextualization and prevention of the 'accident' or 'fall' phenomenon (10 studies), and fall risk assessment (three studies). The most frequent type of design was observational explorative/descriptive. Several areas of investigation were explored (hazardous environment, children's characteristics correlated to accidents/falls, characteristics of the accidents/falls and their outcomes, paediatric fall risk factors and risk assessment tools, fall risk prevention programmes, parents' perceptions of accident/fall risks, etc.). No comparable methods were used to investigate the contextualization and prevention of the 'accident' and 'fall' phenomena; proposed fall risk assessment tools were not evaluated for their reliability and validity. Consensus would be needed around the approach to accidents in terms of: the definition of 'accident' and 'fall'; 'fall-related injury' and respective classifications; the frequency and rate calculation methods; the tools used to assess the risk of falls; and evidence-based practice aimed at preventing them.


Musculoskeletal Complaints (Pain and/or Stiffness) and Their Impact on Mortality in the General Population. The Tromsø Study.
The long-term consequences of chronic pain and/or stiffness from the musculoskeletal system (musculoskeletal complaints: MSCs) have not been well explored. The aims of this study were to investigate whether MSCs reported at baseline influence all-cause and cause-specific mortality during 21 years follow-up of a general Northern Norwegian adult population. A total of 26,977 men and women aged 25-97 years who participated in the 1994-1995 survey of the Tromsø study (response rate 77%) were included in the present prospective cohort study. Baseline data were collected from the 1994-1995 survey and information on death and emigration was taken from the National Register of Norway. Cox regression analyses were performed to examine if MSCs predicted risk of mortality. 5693 (21.1%) participants died during follow-up. Mean time between entry into the survey and death or emigration was 18.6 years (standard deviation 4.87) for all-cause mortality. There was an increased risk of death among those with MSCs at baseline in the crude Cox regression model. However, the multivariable model revealed no significant association between MSCs at baseline and all-cause mortality by sex (women: hazard ratio [HR] = 0.93, 95% confidence interval [CI]: 0.85-1.01; men: HR = 0.93, 95%CI: 0.85-1.01). Furthermore, no significant associations were found between widespread MSCs at baseline and all-cause mortality in multivariable models (women: HR = 0.90, 95%CI: 0.80-1.01; men HR = 0.87, 95%CI: 0.76-1.00). Analyses on cause-specific mortality did not reveal any significant results. MSCs are not independently associated with increased risk of death from cardiovascular disease, cancer, or death from all causes.


Olanzapine and haloperidol in first episode psychosis: two-year data.
Few studies have assessed the comparative efficacy and safety of atypical and typical antipsychotic medications in patients within their first episode of psychosis. This study examined the effectiveness of the atypical antipsychotic olanzapine and the typical antipsychotic haloperidol in patients experiencing their first episode of a schizophrenia-related psychotic disorder over a 2-year treatment period. Two hundred and sixty-three patients were randomized to olanzapine or haloperidol in a doubleblind, multisite, international 2-year study. Clinical symptoms and side effects were assessed at baseline and longitudinally following randomization for the duration of the study. Olanzapine and haloperidol treatment were both associated with substantial and comparable reductions in symptom severity (the primary outcome measure) over the course of the study. However, the treatment groups differed on two secondary efficacy measures. Patients were less likely to discontinue treatment with olanzapine than with haloperidol: mean time (in days) in the study was significantly greater for those treated with olanzapine compared to haloperidol (322.09 vs. 230.38, p<0.0085). Moreover, remission rates were greater in patients treated with olanzapine as compared to those treated with haloperidol (57.25% vs. 43.94%, p<0.036). While extrapyramidal side effects were greater in those treated with haloperidol, weight gain, cholesterol level and liver function values were greater in patients treated with olanzapine. The data from this study suggest some clinical benefits for olanzapine as compared to haloperidol in first episode patients, which must be weighed against those adverse effects that are more likely with olanzapine.


Effect of percutaneous mitral vavuloplasty on pregnant mother and foetus--a tertiary care hospital experience from a developing country.
This study evaluated the short and long-term consequences of Percutaneous Mitral Valvuloplasty (PMV) in pregnant patients and their offspring, in a tertiary care setting, Karachi, Pakistan. The hospital database was used to retrieve all patients who underwent PMV during pregnancy in the period 1998-2007. The follow up data of the patients and the born children were obtained from the hospital records and also by contacting the patients via phone. Six patients underwent PMV but follow-up was available for 5 patients only. All 5 patients were admitted due to severe mitral stenosis with symptoms of dyspnea and palpitation. Mean age was 27 +/- 5.3 years with a mean gestational age at the time of procedure of 22.20 +/- 1.6 weeks. The mean valve area increased from 0.94 +/- 0.22 cm2 preoperatively to 1.62 +/- 0.50 cm2 post-operatively. The ejection fraction changed from a mean of 50 +/- 11.7% to 56 +/- 2.2%. There were no maternal deaths, abortions or stillbirths. Developmental milestones were achieved at the appropriate ages in all babies. PMV appears to be a safe and effective intervention for patients with severe MS during pregnancy. Mitral stenosis, Percutaneous Mitral


A prospective natural-history study of coronary atherosclerosis.
Atherosclerotic plaques that lead to acute coronary syndromes often occur at sites of angiographically mild coronary-artery stenosis. Lesion-related risk factors for such events are poorly understood. In a prospective study, 697 patients with acute coronary syndromes underwent three-vessel coronary angiography and gray-scale and radiofrequency intravascular ultrasonographic imaging after percutaneous coronary intervention. Subsequent major adverse cardiovascular events (death from cardiac causes, cardiac arrest, myocardial infarction, or rehospitalization due to unstable or progressive angina) were adjudicated to be related to either originally treated (culprit) lesions or untreated (nonculprit) lesions. The median follow-up period was 3.4 years. The 3-year cumulative rate of major adverse cardiovascular events was 20.4%. Events were adjudicated to be related to culprit lesions in 12.9% of patients and to nonculprit lesions in 11.6%. Most nonculprit lesions responsible for follow-up events were angiographically mild at baseline (mean [±SD] diameter stenosis, 32.3±20.6%). However, on multivariate analysis, nonculprit lesions associated with recurrent events were more likely than those not associated with recurrent events to be characterized by a plaque burden of 70% or greater (hazard ratio, 5.03; 95% confidence interval [CI], 2.51 to 10.11; P<0.001) or a minimal luminal area of 4.0 mm(2) or less (hazard ratio, 3.21; 95% CI, 1.61 to 6.42; P=0.001) or to be classified on the basis of radiofrequency intravascular ultrasonography as thin-cap fibroatheromas (hazard ratio, 3.35; 95% CI, 1.77 to 6.36; P<0.001). In patients who presented with an acute coronary syndrome and underwent percutaneous coronary intervention, major adverse cardiovascular events occurring during follow-up were equally attributable to recurrence at the site of culprit lesions and to nonculprit lesions. Although nonculprit lesions that were responsible for unanticipated events were frequently angiographically mild, most were thin-cap fibroatheromas or were characterized by a large plaque burden, a small luminal area, or some combination of these characteristics, as determined by gray-scale and radiofrequency intravascular ultrasonography. (Funded by Abbott Vascular and Volcano; ClinicalTrials.gov number, NCT00180466.).


Five-year outcomes of chronic total occlusion treatment with a biolimus A9-eluting biodegradable polymer stent versus a sirolimus-eluting permanent polymer stent in the LEADERS all-comers trial.
Few data are available on long-term follow-up of drug-eluting stents in the treatment of chronic total occlusion (CTO). The LEADERS CTO sub-study compared the long-term results in CTO and non-CTO lesions of a Biolimus A9™-eluting stent (BES) with a sirolimus-eluting stent (SES). Among 1,707 patients enrolled in the prospective, multi-center, all-comers LEADERS trial, 81 with CTOs were treated with either a BES (n = 45) or a SES (n = 36). The primary endpoint was the occurrence of major adverse cardiac events (MACE): cardiac death, myocardial infarction (MI) and clinically-indicated target vessel revascularization (TVR). At 5 years, the rate of MACE was numerically higher in the CTO group than in the non-CTO group (29.6% vs. 23.3%; p = 0.173), with a significant increase in the incidence of target lesion revascularization (TLR) (21.0 vs. 12.6; p = 0.033), but no difference in stent thrombosis (ST). Patients with CTO receiving a BES demonstrated a lower incidence of MACE (22.2% vs. 38.9%; p = 0.147) with a significant reduction in TLR compared to patients receiving a SES (11.1% vs. 33.3%, p = 0.0214) with an incidence similar to that observed in the non-CTO group treated with BES (11.6%). Definite ST at 5 years nearly halved in the BES group (4.4% vs. 8.3%, p = 0.478) with no ST in the BES group after the first year (0% vs. 8.3%, p for interaction = 0.009). The use of a BES showed a reduction in MACE, TVR, TLR, and ST over time in the CTO subset with similar outcome as for non-CTO lesions.


Preparation and in-vitro evaluation of indomethacin nanoparticles.
During the last two decades one of the most important problems in drug formulations has been low aqueous solubility of new molecules. However, numerous techniques, such as milling, co-solvent solubilization and solid dispersion have been used conventionally for aqueous solubility enhancement and the rate of solubility. Recently, nanoparticle engineering processes have been developed and reported for pharmaceutical applications to increase the dissolution rate of low-soluble drugs which in turn may leads to substantial increases in bioavailability. In this study, a controlled precipitation method was used to produce indomethacin nano-solid suspension in a polymeric matrix (as a model), in order to increase the solubility and rate of the dissolution of poorly soluble model drug. Nano-solid suspension of indomethacin in polyvinyl pyrrolidine (PVP) was prepared by controlled precipitation technique, characterized by differential scanning calorimetry (DSC), X-ray diffraction (XRD), Fourier Transform Infrared Spectroscopy (FTIR) and evaluated for in vitro solubility and dissolution rate. Absence of thermal and diffractional peaks in DSC and XRD studies indicated that indomethacin interacts with PVP in solid phase. The solubility of indomethacin in nano-solid suspension compared to crystalline form was increased to about four-fold. It was found that particle size distribution depend to the polymer MW and drug: polymer ratios. Spectroscopy methods and Transmission Electron Microscopy (TEM) images showed that indomethacin dispersed as amorphous nanosize particles in freeze dried powder. Enhanced solubility and dissolution rate of indomethacin compared to physical mixtures and crystalline form of indomethacin (polymorph I), demonstrated that it interacts with PVP via hydrogen bond and probably forming eutectic mixture.


Comorbidity and survival of elderly head and neck carcinoma patients.
Alcohol and tobacco, the primary etiologic agents for head and neck carcinoma (HNCA), cause other chronic diseases and may contribute to the high prevalence of comorbid conditions and generally poor survival of persons with HNCA. The authors explored the prognostic role of comorbidity in persons with HNCA using Health Care Finance Administration Medicare (HCFA) files linked with the appropriate files of the Surveillance, Epidemiology, and End Results (SEER) Program. The Charlson comorbidity index was applied to in-patient data from the HCFA files. The SEER data were used to ascertain survival and identify persons with HNCA diagnosed from 1985 to 1993 (n = 9386). In a proportional hazards regression model adjusted for age and historic stage at diagnosis, race, gender, marital status, socioeconomic status, histologic grade, anatomic site, treatment, and pre-1991 diagnosis, Charlson index scores of 0, 1, and 2+ had estimated relative hazards (RHs) with 95 confidence intervals (CIs) of 1.00, 1.33 (95% CI, 1.21-1.47), and 1.83 (95% CI, 1.64-2.05), respectively (P value for trend < 0.0001). The adjusted RH for a Charlson index score of 1 or more compared with 0, using stratified models, was found to be greater in whites (RH, 1.55; 95% CI, 1.43-1.67) than blacks (RH, 1.24; 95% CI, 0.96-1.60), local (RH, 1.72; 95% CI, 1.50-1.96) versus distant stage (RH, 1.25; 95% CI, 1.00-1.56), and age 65-74 years (RH, 1.53; 95% CI, 1.38-1.69) versus age 85+ years (RH, 1.42; 95% CI, 1.09-1.84). This study establishes comorbidity as a predictor of survival in an elderly HNCA population and lends support to the inclusion of comorbidity assessment in prognostic staging of patients with HNCA diagnosed after 65 years of age.


Transcriptional and epigenetic regulation of the p53 tumor suppressor gene.
The p53 tumor suppressor is one of the most studied molecules in cancer research. Despite the fact that there is a detailed understanding involving multiple aspects of the p53-associated biology, many aspects of its transcriptional regulation are still not well clarified. Limited information is available on how the p53 gene is transcriptional and epigenetically regulated. The p53 gene expression is tightly controlled through a variety of transcription factors, miRNAs, its anti-sense RNA Wrap53, the insulator protein CTCF and very likely by other genetic and epigenetic mechanisms. It's the intent of this article to review in depth important aspects concerning the transcriptional regulation of the p53 gene and perhaps serve as a stepping-stone to begin a conceptual change on how future p53 research can be approached.