Magnolol Suppresses TGF-β-Induced Epithelial-to-Mesenchymal Transition in Human Colorectal Cancer Cells.
Tumor metastasis is the end state of a multistep process that includes dissemination of tumor cells to distant organs and requires tumor cells to adapt to different tissue microenvironments. During metastasis, tumor cells undergo a morphological change known as transdifferentiation or the epithelial-to-mesenchymal transition (EMT). In normal embryonic development, the EMT occurs in the context of morphogenesis in a variety of tissues. Over the course of this process, epithelial cells lose their cell-cell adhesion and polarity properties. In this study, we investigated whether magnolol could suppress the EMT in human colorectal cancer cells. To this end, we examined the epithelial markers E-cadherin, ZO-1, and claudin and the mesenchymal markers N-cadherin, TWIST1, Slug, and Snail. Magnolol effectively inhibited EMT in human colon cancer cell lines by upregulating epithelial markers and downregulating mesenchymal markers. The EMT is induced by the TGF-β signaling pathway. To determine whether magnolol disrupts TGF-β signaling, we examined several mediators of this pathway, and found that magnolol decreased the levels of phosphorylated (i.e., active) ERK, GSK3β, and Smad. We conclude that magnolol blocks migration in HCT116 cells by suppressing TGF-β signaling.


Early adolescent outcome of attention-deficit hyperactivity disorder in a Chinese population: 5-year follow-up study.
To examine early adolescent outcome of attention-deficit hyperactivity disorder in local Chinese children. Cohort study. A university teaching hospital in Hong Kong. A cohort of Chinese children with attention-deficit hyperactivity disorder diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders (4th edition) who attended a day hospital between January 1998 and December 2003. Data on psychopathology, academic attainment, delinquency, substance use, and other psychosocial functioning collected from multiple informants and official records. Performances of subjects were compared with a group of community controls. A total of 150 children with attention-deficit hyperactivity disorder were reassessed 6 years after initial intake assessment (mean age, 14 years; follow-up rate, 86%). Compared with the controls, their externalising and internalising disturbances were 4 and 1.5 times more common, respectively. Adolescents with attention-deficit hyperactivity disorder were more likely to smoke cigarettes and use illicit drugs. Their academic attainment was below age norms with more than one fourth repeating grades; 7% of them had been arrested by the police compared with none of the controls. They faced more difficulties in the family environment and social problem-solving. There were discrepancies between parent and patient reports about their attention-deficit hyperactivity disorder symptoms, and officially recorded youth reports of delinquency. Local Chinese children with attention-deficit hyperactivity disorder are at significant risk of multiple forms of adolescent maladjustment. Their outcome profile is similar to that reported in the West.


The pathophysiology of axonal transport in Alzheimer's disease.
Neurons communicate in the nervous system by carrying out information along the length of their axons to finally transmit it at the synapse. Proper function of axons and axon terminals relies on the transport of proteins, organelles, vesicles, and other elements from the site of synthesis in the cell body. Conversely, neurotrophins secreted from axonal targets and other components at nerve terminals need to travel toward the cell body for clearance. Molecular motors, namely kinesins and dyneins, are responsible for the movement of these elements along cytoskeletal tracks. Given the challenging structure of neurons, axonal transport machinery plays a crucial role in maintaining neuronal viability and function, allowing the proper neurotransmitter release at the presynaptic ending. On this basis, failure of axonal transport has been proposed as a key player in the development and/or progression of neurodegenerative disorders such as Alzheimer's disease (AD). Increasing evidence suggests that amyloid-β peptide, a hallmark of AD, may disrupt axonal transport and in so doing, contribute to AD pathophysiology. Here we discuss the molecular mechanisms of axonal transport with specific emphasis on the possible relationship between defective axonal transport and AD.


A design principle underlying the synchronization of oscillations in cellular systems.
Biological oscillations are found ubiquitously in cells and are widely variable, with periods varying from milliseconds to months, and scales involving subcellular components to large groups of organisms. Interestingly, independent oscillators from different cells often show synchronization that is not the consequence of an external regulator. What is the underlying design principle of such synchronized oscillations, and can modeling show that the complex consequences arise from simple molecular or other interactions between oscillators? When biological oscillators are coupled with each other, we found that synchronization is induced when they are connected together through a positive feedback loop. Increasing the coupling strength of two independent oscillators shows a threshold beyond which synchronization occurs within a few cycles, and a second threshold where oscillation stops. The positive feedback loop can be composed of either double-positive (PP) or double-negative (NN) interactions between a node of each of the two oscillating networks. The different coupling structures have contrasting characteristics. In particular, PP coupling is advantageous with respect to stability of period and amplitude, when local oscillators are coupled with a short time delay, whereas NN coupling is advantageous for a long time delay. In addition, PP coupling results in more robust synchronized oscillations with respect to amplitude excursions but not period, with applied noise disturbances compared to NN coupling. However, PP coupling can induce a large fluctuation in the amplitude and period of the resulting synchronized oscillation depending on the coupling strength, whereas NN coupling ensures almost constant amplitude and period irrespective of the coupling strength. Intriguingly, we have also observed that artificial evolution of random digital oscillator circuits also follows this design principle. We conclude that a different coupling strategy might have been selected according to different evolutionary requirements.


Helicobacter pylori antibodies and iron deficiency in female adolescents.
Iron deficiency (ID) is a common clinical problem worldwide, affecting primarily females. Helicobacter pylori (HP) infection has been shown to be associated with ID. The objective of this study was to define the prevalence of HP antibodies in female adolescents, and to find out if there was a correlation between HP infection and ID. The secondary aim was to study if regularly performed sporting activity, have any association to HP infection, in itself. A controlled clinical trial. A senior high school in Gothenburg, Sweden. All female athletes at a senior high school for top-level athletes were offered to take part, and 56 athletes took part in the study. The control group consisted of a random sample of age-matched non-athlete students of which 71 entered the study. Iron deficiency (ID) and iron deficiency anaemia (IDA) were defined by the use of levels of haemoglobin, serum iron, total iron-binding capacity, transferrin saturation, and serum ferritin, as previously described. HP IgG-antibodies were detected by ELISA. 18 of 127 (14%) adolescent females had antibodies against HP. Only 3% had IDA, while 50% had ID. In total, 66% of the HP positive females had ID compared to 48% of the negative females (p = 0.203). No correlation between sporting activity and HP infection was found. Regarding ethnicity, 11/28 of subjects from medium-high risk areas were HP-positive, compared to 7/99 coming from low-risk areas (p<0.001). The main finding of this study is that the prevalence of HP IgG antibodies was 14% in adolescent females. We could not find any difference regarding frequency of ID and IDA, between HP positive and negative individuals. Ethnicity is of great importance for the risk of HP infection, while sporting activity itself seems to have no association to HP-infection.


Rosmarinic acid attenuates acrylamide induced apoptosis of BRL-3A cells by inhibiting oxidative stress and endoplasmic reticulum stress.
Acrylamide (AA) is a common endogenous contaminant in food, with a complex toxicity mechanism. The study on liver damage to experimental animals caused by AA has aroused a great attention. Rosmarinic acid (RosA) as a natural antioxidant shows excellent protective effects against AA-induced hepatotoxicity, but the potential mechanism is still unclear. In the current study, the protective effect of RosA on BRL-3A cell damage induced by AA was explored. RosA increased the activity of SOD and GSH, reduced the content of ROS and MDA, and significantly reduced the oxidative stress (OS) damage of BRL-3A cells induced by AA. RosA pretreatment inhibited the MAPK signaling pathway activated by AA, and down-regulated the phosphorylation of JNK, ERK and p38. RosA pretreatment also reduced the production of calcium ions caused by AA. In addition, the key proteins p-IRE1α, XBP-1s, TRAF2 of the IRE1 pathway, and the expression of endoplasmic reticulum stress (ERS) characteristic proteins GRP78, p-ASK1, Caspase-12 and CHOP were also down-regulated by RosA. NAC blocked the activation of the MAPK signaling pathway and inhibited the ERS pathway. RosA reduced the rate of apoptosis and down-regulated the expression of Bax/Bcl-2 and Caspase-3, thereby inhibiting AA-induced apoptosis. In conclusion, RosA reduced the OS and ERS induced by AA in BRL-3A cells, thereby inhibiting cell apoptosis, and it could be used as a potential protective agent against AA toxicity.


Colloidal aggregates tested via nanoindentation and quasi-simultaneous 3D imaging.
The mechanical properties of aggregated colloids depend on the mutual interplay of inter-particle potentials, contact forces, aggregate structure and material properties of the bare particles. Owing to this variety of influences, experimental results from macroscopic mechanical testings were mostly compared to time-consuming, microscopic simulations rather than to analytical theories. The aim of the present paper was to relate both macroscopic and microscopic mechanical data with each other and simple analytical models. We investigated dense amorphous aggregates made from monodisperse poly-methyl methacrylate (PMMA) particles (diameter: 1.6 μm via nanoindentation in combination with confocal microscopy. The resulting macroscopic information was complemented by the three-dimensional aggregate structure as well as the microscopic strain field and strain tensor. The measured strain field and tensor were in reasonable agreement with the predictions from analytical continuum theories. Consequently, the measured force-depth curves could be analyzed within a theoretical framework that had been frequently used for nanoindentation of atomic matter such as metals, ceramics and polymers. The extracted values for hardness and effective Young's modulus represented average values characteristic of the aggregate. On the basis of of these parameters we discuss the influence of the strength of particle bonds by introducing polystyrene (PS) between the particles.


Over-expression of tau results in defective synaptic transmission in Drosophila neuromuscular junctions.
We have shown that over-expression of human tau (0N3R) in Drosophila larval motor neurons causes significant morphological and functional disruption to the neuromuscular junctions (NMJs). Tau-expressing NMJs are reduced in size with irregular and abnormal bouton structure. Immunocytochemical analysis shows that the abnormal NMJs still retain synaptotagmin expression and form active zones. Functionally, the NMJs exhibit abnormal endo/exocytosis as revealed by incorporation of the styryl dye FM1-43. Electrophysiological studies showed that with low frequency stimulation (1 Hz), evoked synaptic potentials produced from tau over-expressing motor neurons were indistinguishable from wild type, however, following high frequency stimulation (50 Hz), evoked synaptic potentials were significantly decreased. Analysis of the number and distribution of mitochondria showed that motor neurons over-expressing tau had a significant reduction in functional mitochondria in the presynaptic terminal. Collapsing the mitochondrial membrane potential in wild type larvae phenocopied the effects of tau over-expression on synaptic transmission. Our results demonstrate that tau over-expression in vivo cause a synaptic dysfunction, which may be caused by a reduced complement of functional mitochondria.


Diet as risk for lung cancer: a Swedish case-control study.
A case-control study was undertaken to study lung cancer in relation to dietary habits, occupational exposure, and living in urban or country areas. Suspect lung cancer cases in West Sweden and population controls were interviewed using a food frequency questionnaire. The study comprised 177 female and 359 male cases and 916 controls. The cases mainly comprised former and current smokers (82% female, 95% male). For the analysis, cases were divided into the histological diagnoses adenocarcinoma and squamous cell, small cell, and adenosquamous cell carcinomas, as well as into smoking categories. A high frequency of consumption of vegetables was significantly related to a lower risk for adenocarcinoma and squamous cell and adenosquamous cell carcinoma among men and adenocarcinoma among women. A low odds ratio in the highest quartile of vegetable consumption in men was seen in all smoking categories. There were no significant protective effects from fruit in the different lung cancer subgroups, although a significant trend was found for heavy-smoking females. A high consumption of milk was related to an increased risk for lung cancer, especially adenosquamous cell carcinoma. The results suggest that the protective effect or risk due to dietary factors may affect different forms of lung cancer. The results from this as well as previous studies suggest a complex interaction between diet and lung cancer risk, involving the types of lung cancer as well as consumption patterns in the population.


Bacteriuria in cats with feline lower urinary tract disease: a clinical study of 134 cases in Norway.
Feline lower urinary tract disease (FLUTD) is considered to be one of the most common diagnoses in feline patients. Several authors have concluded that feline idiopathic cystitis is the most common cause of FLUTD, whereas infectious cystitis is diagnosed in only 2% of the cases. In the period from January 2003 to February 2005, 134 cats that presented with signs of lower urinary tract disorders were included in a study at the Norwegian School of Veterinary Science. Ninety-seven percent were first opinion cases. All the cats went through a physical examination, and blood samples were collected for haematology and clinical chemistry. The urine analysis included urine stix, specific gravity, microscopic examination of the sediment and microbiological culturing. The urine samples were collected as voided mid-stream urine samples, by catheter or by cystocentesis and the method used was registered. Of the 134 cats included in the study, 37% were diagnosed as having obstructive and 63% as having non-obstructive FLUTD. In total 44 cats (33%) were diagnosed with bacteriuria, exceeding 10(3) colony forming units per millilitre (cfu/ml) and 33 (25%) of these cats had bacterial growth exceeding 10(4) cfu/ml, either alone or in combination with crystals and/or uroliths. Six cats (18%) with bacterial growth exceeding 10(4) cfu/ml were older than 8 years. No significant difference was found between the sampling methods performed with regard to bacteriuria. This study indicates that bacteriuria may have been underdiagnosed in Norwegian cats with clinical signs of FLUTD. It also confirms the importance of microbiological culturing in first opinion cases with FLUTD and that a skilled operator can get representative samples regardless the choice of method.


A truncated human chromosome 16 associated with alpha thalassaemia is stabilized by addition of telomeric repeat (TTAGGG)n.
The instability of chromosomes with breaks induced by X-irradiation led to the proposal that the natural ends of chromosomes are capped by a specialized structure, the telomere. Telomeres prevent end-to-end fusions and exonucleolytic degradation, enable the end of the linear DNA molecule to replicate, and function in cell division. Human telomeric DNA comprises approximately 2-20 kilobases (kb) of the tandemly repeated sequence (TTAGGG)n oriented 5'----3' in towards the end of the chromosome, interspersed with variant repeats in the proximal region. Immediately subtelomeric lie families of unrelated repeat motifs (telomere-associated sequences) whose function, if any, is unknown. In lower eukaryotes the formation and maintenance of telomeres may be mediated enzymatically (by telomerase) or by recombination; in man the mechanisms are poorly understood, although telomerase has been identified in HeLa cells. Here we describe an alpha thalassaemia mutation associated with terminal truncation of the short arm of chromosome 16 (within band 16p13-3) to a site 50 kb distal to the alpha globin genes, and show that (TTAGGG)n has been added directly to the site of the break. The mutation is stably inherited, proving that telomeric DNA alone is sufficient to stabilize the broken chromosome end. This mechanism may occur in any genetic disease associated with chromosome truncation.


Extracellular oxidation in cystic fibrosis airway epithelium causes enhanced EGFR/ADAM17 activity.
The EGF receptor (EGFR)/a disintegrin and metalloproteinase 17 (ADAM17) signaling pathway mediates the shedding of growth factors and secretion of cytokines and is involved in chronic inflammation and tissue remodeling. Since these are hallmarks of cystic fibrosis (CF) lung disease, we hypothesized that CF transmembrane conductance regulator (CFTR) deficiency enhances EGFR/ADAM17 activity in human bronchial epithelial cells. In CF bronchial epithelial CFBE41o- cells lacking functional CFTR (iCFTR-) cultured at air-liquid interface (ALI) we found enhanced ADAM17-mediated shedding of the EGFR ligand amphiregulin (AREG) compared with genetically identical cells with induced CFTR expression (iCFTR+). Expression of the inactive G551D-CFTR did not have this effect, suggesting that active CFTR reduces EGFR/ADAM17 activity. This was confirmed in CF compared with normal differentiated primary human bronchial epithelial cells (HBEC-ALI). ADAM17-mediated AREG shedding was tightly regulated by the EGFR/MAPK pathway. Compared with iCFTR+ cells, iCFTR- cells displayed enhanced apical presentation and phosphorylation of EGFR, in accordance with enhanced EGFR/ADAM17 activity in CFTR-deficient cells. The nonpermeant natural antioxidant glutathione (GSH) strongly inhibited AREG release in iCFTR and in primary HBEC-ALI, suggesting that ADAM17 activity is directly controlled by extracellular redox potentials in differentiated airway epithelium. Furthermore, the fluorescent redox probe glutaredoxin 1-redox-sensitive green fluorescent protein-glycosylphosphatidylinositol (Grx1-roGFP-GPI) indicated more oxidized conditions in the extracellular space of iCFTR- cells, consistent with the role of CFTR in GSH transport. Our data suggest that in CFTR-deficient airway epithelial cells a more oxidized state of the extracellular membrane, likely caused by defective GSH secretion, leads to enhanced activity of the EGFR/ADAM17 signaling axis. In CF lungs this could contribute to tissue remodeling and hyperinflammation.


Liver Abscess Caused by Infection with Community-Acquired Klebsiella quasipneumoniae subsp. quasipneumoniae.
We report a case of pyogenic liver abscess caused by community-acquired Klebsiella quasipneumoniae subsp. quasipneumoniae. The infecting isolate had 2 prominent features of hypervirulent K. pneumoniae strains: the capsular polysaccharide synthesis region for K1 serotype and the integrative and conjugative element ICEKp1, which encodes the virulence factors yersiniabactin, salmochelin, and RmpA.


Modulation of interleukin 1 beta gene expression using antisense phosphorothioate oligonucleotides.
The production of interleukin 1 beta (IL1 beta) in lipopolysaccharide (LPS) stimulated monocytes was inhibited by 98% using antisense phosphorothioate oligonucleotides complementary to the 5' untranslated and exon 6 regions of IL1 beta mRNA. A sense phosphorothioate oligonucleotide failed to inhibit IL1 beta production. The inhibition of IL1 beta synthesis was not due to reduced cell viability and [35S]methionine incorporation showed that it could not be accounted for by an overall inhibition in protein synthesis. Tumour necrosis factor (TNF) and IL1 alpha production was also inhibited but to a lesser extent than IL1 beta. The use of antisense phosphorothioate oligonucleotides to inhibit IL1 production should enable the complex pathways of IL1 regulation to be elucidated and provide information on the biological role of these cytokines.


Anatomy of motor learning. I. Frontal cortex and attention to action.
We used positron emission tomography to study new learning and automatic performance in normal volunteers. Subjects learned sequences of eight finger movements by trial and error. In a previous experiment we showed that the prefrontal cortex was activated during new learning but not during during automatic performance. The aim of the present experiment was to see what areas could be reactivated if the subjects performed the prelearned sequence but were required to pay attention to what they were doing. Scans were carried out under four conditions. In the first the subjects performed a prelearned sequence of eight key presses; this sequence was learned before scanning and was practiced until it had become overlearned, so that the subjects were able to perform it automatically. In the second condition the subjects learned a new sequence during scanning. In a third condition the subjects performed the prelearned sequence, but they were required to attend to what they were doing; they were instructed to think about the next movement. The fourth condition was a baseline condition. As in the earlier study, the dorsal prefrontal cortex and anterior cingulate area 32 were activated during new learning, but not during automatic performance. The left dorsal prefrontal cortex and the right anterior cingulate cortex were reactivated when subjects paid attention to the performance of the prelearned sequence compared with automatic performance of the same task. It is suggested that the critical feature was that the subjects were required to attend to the preparation of their responses. However, the dorsal prefrontal cortex and the anterior cingulate cortex were activated more when the subjects learned a new sequence than they were when subjects simply paid attention to a prelearned sequence. New learning differs from the attention condition in that the subjects generated moves, monitored the outcomes, and remembered the responses that had been successful. All these are nonroutine operations to which the subjects must attend. Further analysis is needed to specify which are the nonroutine operations that require the involvement of the dorsal prefrontal and anterior cingulate cortex.


Transhiatal blunt esophagectomy for carcinoma of the esophagus.
Transhiatal blunt esophagectomy has been reported as a safe and effective procedure for the palliation of carcinoma of the esophagus. Avoidance of a thoracotomy eliminates the morbidity associated with this procedure, and creation of a cervical esophagogastric anastomosis avoids the catastrophic sequelae of an intrathoracic anastomotic leak. Moreover, use of the procedure for palliation does not preclude excellent 1-year survival rates. We report early results in five consecutive patients with esophageal carcinoma who underwent transhiatal blunt esophagectomy. Five patients had 22 complications, including one with a fascial dehiscence, pyloroplasty leak, and localized mediastinal abscess requiring a second laparotomy. One patient died in the hospital postoperatively of massive aspiration pneumonitis. Our results compare favorably with those reported in the literature. We believe that transhiatal blunt esophagectomy avoids the morbidity and mortality of a thoracotomy and an intrathoracic anastomosis, yet remains a major gastrointestinal operative procedure with all of its attendant risks.


Surgical Repair of Small Bowel Fistulas: Risk Factors of Complications or Fistula Recurrence.
BACKGROUND Definitive surgical repair of persistent fistulas of the small intestine remains a surgical challenge with a high rate of re-fistulation and mortality. The aim of this study was to evaluate the type and incidence of complications after definitive surgical repair, and to identify factors predictive of severe postoperative complications or fistula recurrence. MATERIAL AND METHODS This was a retrospective study of 42 patients who underwent elective surgical repair of a persistent fistula of the small intestine. The analysis included preoperative and intraoperative parameters. RESULTS The healing rate after definitive surgery was 71.4%. Postoperative complications developed in 88.1% of patients. The mortality rate was 7.2%. Fistula recurrence was recognized in 21.4% of cases. Overall, 93 complications occurred in 37 patients. The most common complications were septic (48.0%). Hemorrhagic and digestive tract-related complications accounted for 19.0% and 15.0% of all complications, respectively. Severe complications (Clavien-Dindo grade III-V) made up 28.0% of all complications. In univariate analysis, multiple fistulas (p=0.03), higher C-reactive protein level (p=0.01), and longer time interval from admission to definitive surgery (p=0.01) were associated with an increased risk of severe complications or fistula recurrence. In multivariate analysis, only multiple fistulas were an independent risk factor for severe complications or fistula recurrence (OR=8.2, p=0.04). CONCLUSIONS Fistula complexity determines the risk of severe postoperative complications or fistula recurrence after definitive surgical repair of the persistent small intestine fistulas. Inflammatory parameters should be normalized before definitive surgery.


Impact of missing outcome data in meta-analyses of lifestyle interventions during pregnancy to reduce postpartum weight retention: An overview of systematic reviews with meta-analyses and additional sensitivity analyses.
High risk of bias associated with missing outcome data (MOD) in meta-analyses (MAs) of the effects of lifestyle interventions during pregnancy on postpartum weight retention (PPWR) casts doubt on whether such interventions can be relied upon as truly effective. This systematic overview of three MAs (19 RCTs), each with high MOD rates in the subset of RCTs included, examined how MOD were addressed in the estimation of summary intervention effects. All MAs reported beneficial and statistically significant intervention effects estimated based on complete case analyses, deemed valid if MOD was missing at random (MAR). Therefore, we conducted sensitivity analyses using pattern mixture models and informative missingness parameters (describing how the outcome in the missing participants may be related to the outcome in the completers), to ascertain the robustness of the estimates to reasonable deviations from the MAR assumption. In plausible scenarios where the response in intervention group participants with versus without MOD was worse (by just 0.5 kg), effect estimates were attenuated in all MAs and no longer statistically significant in two MAs. Statistical significance was retained when all 19 RCTs identified across MAs were examined together in a broader meta-analysis: -0.63 kg (95%CI -0.17, -0.08), but the clinical relevancy of effects of this magnitude remains unclear.


SU-E-T-259: A Statistical and Machine Learning-Based Tool for Modeling and Visualization of Radiotherapy Treatment Outcomes.
Effective radiotherapy outcomes modeling could provide physicians with better understanding of the underlying disease mechanism, enabling to early predict outcomes and ultimately allowing for individualizing treatment for patients at high risk. This requires not only sophisticated statistical methods, but user-friendly visualization and data analysis tools. Unfortunately, few tools are available to support these requirements in radiotherapy community. Our group has developed Matlab-based in-house software called DREES for statistical modeling of radiotherapy treatment outcomes. We have noticed that advanced machine learning techniques can be used as useful tools for analyzing and modeling the outcomes data. To this end, we have upgraded DREES such that it takes advantage of useful Statistics and Bioinformatics toolboxes in Matlab that provide robust statistical data modeling and analysis methods as well as user-friendly visualization and graphical interface. Newly added key features include variable selection, discriminant analysis and decision tree for classification, and k-means and hierarchical clustering functions. Also, existing graphical tools and statistical methods in DREES were replaced with a library of the Matlab toolboxes. We analyzed several radiotherapy outcomes datasets with our tools and showed that these can be effectively used for building normal tissue complication probability (NTCP) and tumor control probability (TCP) models. We have developed an integrated software tool for modeling and visualization of radiotherapy outcomes data within the Matlab programming environment. It is our expectation that this tool could help physicians and scientists better understand the complex mechanism of disease and identify clinical and biological factors related to outcomes.


Contemporary Analysis of Prognostic Factors in Patients with Unresectable Malignant Pleural Mesothelioma.
Previous prognostic scoring systems for malignant pleural mesothelioma (MPM) included patients managed surgically and predated the use of pemetrexed. We analyzed prognostic factors in a contemporary cohort of patients with unresectable MPM who received pemetrexed-based chemotherapy. This single-institution analysis included patients with MPM who were managed nonsurgically from 2000 to 2013. Variables correlated with overall survival (OS) included sex, performance status (PS), asbestos exposure, tumor laterality, histology, clinical stage, initial positron emission tomography maximum standardized uptake value, hemoglobin level, platelet count, lymphocyte count, white cell and neutrophil counts, treatment type, and clinical benefit from treatment. OS was analyzed by the Kaplan-Meier method, and significance (p < 0.05) of prognostic factors was analyzed by the log-rank test and Cox regression. A total of 191 patients met the study criteria: median age 71 years (range 46-90), 147 men (77%), 128 epithelioid tumors (67%), and 157 cases of stage III or IV MPM (82%). Median OS for all patients was 13.4 months. According to a univariate analysis, histology (p < 0.001), platelet count (< or = 450,000 versus >450,000, p < 0.001), initial PS (0-1 versus > or = 2), maximum standardized uptake value (< or = 8.1 versus >8.1, p = 0.037), and lymphocyte counts (p = 0.019) were associated with OS. According to a multivariable analysis, only histology, platelet count, and PS were independent prognostic factors. Epithelioid histology, PS, and elevated lymphocyte count at diagnosis were significantly associated with clinical benefit from first-line chemotherapy. Our results confirm the significance of elements of the Cancer and Leukemia Group B and European Organisation for Research and Treatment of Cancer prognostic scoring systems, identify factors associated with clinical benefit from chemotherapy, and emphasize the impact of histology and clinical benefit of chemotherapy on outcomes.


The heritability of clinically diagnosed attention deficit hyperactivity disorder across the lifespan.
No prior twin study has explored the heritability of clinically diagnosed attention deficit hyperactivity disorder (ADHD). Such studies are needed to resolve conflicting results regarding the importance of genetic effects for ADHD in adults. We aimed to estimate the relative contribution of genetic and environmental influences for clinically diagnosed ADHD across the lifespan with a specific focus on ADHD in adults. Information on zygosity and sex was obtained from 59514 twins born between 1959 and 2001 included in the nationwide population-based Swedish Twin Registry. Clinical data for ADHD diagnoses (i.e. stimulant or non-stimulant medication for ADHD) were obtained from the Swedish Prescribed Drug Register (PDR) and from the National Patient Register (i.e. ICD-10 diagnosis of ADHD). Twin methods were applied to clinical data of ADHD diagnoses using structural equation modeling with monozygotic (MZ) and dizygotic (DZ) twins. The best-fitting model revealed a high heritability of ADHD [0.88, 95% confidence interval (CI) 0.83-0.92] for the entire sample. However, shared environmental effects were non-significant and of minimal importance. The heritability of ADHD in adults was also substantial (0.72, 95% CI 0.56-0.84). This study shows that the heritability of clinically diagnosed ADHD is high across the lifespan. Our finding of high heritability for clinically diagnosed ADHD in adults indicates that the previous reports of low heritability are best explained by rater effects, and that gene-identification studies of ADHD in adults need to consider pervasiveness (e.g. multiple raters) and developmentally (e.g. childhood-onset criteria) informative data.


Low-energy shock wave for enhancing recruitment of endothelial progenitor cells: a new modality to increase efficacy of cell therapy in chronic hind limb ischemia.
Stem and progenitor cell therapy is a novel approach to improve neovascularization and function of ischemic tissue. Enhanced tissue expression of chemoattractant factors such as stromal cell-derived factor 1 and vascular endothelial growth factor is crucial for the recruitment of circulating endothelial progenitor cells (EPCs) during acute ischemia. In chronic ischemia, however, expression of these chemoattractants is less pronounced, which results in insufficient EPC recruitment into the target tissue. Therefore, we investigated the effect of targeted extracorporeal shock wave (SW) application in order to facilitate EPC recruitment into nonischemic and chronic ischemic tissue. Hind limb adductor muscles of nude rats were treated with 500, 1000, and 2000 impulses of focused low-energy SW (flux density level: 0.05 mJ/mm2). Twenty-four hours later, mRNA expression of the chemoattractant stromal cell-derived factor 1 was significantly increased with 1000 impulses (stromal cell-derived factor 1/GAPDH: 0.95+/-0.09) and 2000 impulses (stromal cell-derived factor 1/GAPDH: 1.17+/-0.24; both P<0.05 versus untreated). Histologically, the number of vascular endothelial growth factor-positive endothelial cells per myocyte was significantly increased with 2000 impulses (0.24+/-0.05 versus 0.09+/-0.02; P<0.01). This preconditioning effect resulted in significantly enhanced recruitment and homing of EPCs that were intravenously infused 24 hours after SW treatment (P<0.05). In a rat model of chronic hind limb ischemia, SW-facilitated EPC treatment resulted in a significant increase in relative blood flow recovery as assessed by laser Doppler imaging (P<0.05). Preconditioning of both nonischemic and chronic ischemic tissue with low-energy SW improves recruitment of circulating EPCs via enhanced expression of chemoattractant factors. Thus, SW-facilitated cell therapy may improve the efficacy of EPC treatment in patients with chronic ischemia.


Deterministic mechanical model of T-killer cell polarization reproduces the wandering of aim between simultaneously engaged targets.
T-killer cells of the immune system eliminate virus-infected and tumorous cells through direct cell-cell interactions. Reorientation of the killing apparatus inside the T cell to the T-cell interface with the target cell ensures specificity of the immune response. The killing apparatus can also oscillate next to the cell-cell interface. When two target cells are engaged by the T cell simultaneously, the killing apparatus can oscillate between the two interface areas. This oscillation is one of the most striking examples of cell movements that give the microscopist an unmechanistic impression of the cell's fidgety indecision. We have constructed a three-dimensional, numerical biomechanical model of the molecular-motor-driven microtubule cytoskeleton that positions the killing apparatus. The model demonstrates that the cortical pulling mechanism is indeed capable of orienting the killing apparatus into the functional position under a range of conditions. The model also predicts experimentally testable limitations of this commonly hypothesized mechanism of T-cell polarization. After the reorientation, the numerical solution exhibits complex, multidirectional, multiperiodic, and sustained oscillations in the absence of any external guidance or stochasticity. These computational results demonstrate that the strikingly animate wandering of aim in T-killer cells has a purely mechanical and deterministic explanation.


ComPlEx: conservation and divergence of co-expression networks in A. thaliana, Populus and O. sativa.
Divergence in gene regulation has emerged as a key mechanism underlying species differentiation. Comparative analysis of co-expression networks across species can reveal conservation and divergence in the regulation of genes. We inferred co-expression networks of A. thaliana, Populus spp. and O. sativa using state-of-the-art methods based on mutual information and context likelihood of relatedness, and conducted a comprehensive comparison of these networks across a range of co-expression thresholds. In addition to quantifying gene-gene link and network neighbourhood conservation, we also applied recent advancements in network analysis to do cross-species comparisons of network properties such as scale free characteristics and gene centrality as well as network motifs. We found that in all species the networks emerged as scale free only above a certain co-expression threshold, and that the high-centrality genes upholding this organization tended to be conserved. Network motifs, in particular the feed-forward loop, were found to be significantly enriched in specific functional subnetworks but where much less conserved across species than gene centrality. Although individual gene-gene co-expression had massively diverged, up to ~80% of the genes still had a significantly conserved network neighbourhood. For genes with multiple predicted orthologs, about half had one ortholog with conserved regulation and another ortholog with diverged or non-conserved regulation. Furthermore, the most sequence similar ortholog was not the one with the most conserved gene regulation in over half of the cases. We have provided a comprehensive analysis of gene regulation evolution in plants and built a web tool for Comparative analysis of Plant co-Expression networks (ComPlEx, http://complex.plantgenie.org/). The tool can be particularly useful for identifying the ortholog with the most conserved regulation among several sequence-similar alternatives and can thus be of practical importance in e.g. finding candidate genes for perturbation experiments.


Recent trends in metabolic engineering of microorganisms for the production of advanced biofuels.
As climate change has become one of the major global risks, our heavy dependence on petroleum-derived fuels has received much public attention. To solve such problems, production of sustainable fuels has been intensively studied over the past years. Thanks to recent advances in synthetic biology and metabolic engineering technologies, bio-based platforms for advanced biofuels production have been developed using various microorganisms. The strategies for production of advanced biofuels have converged upon four major metabolic routes: the 2-ketoacid pathway, the fatty acid synthesis (FAS) pathway, the isoprenoid pathway, and the reverse β-oxidation pathway. Additionally, the polyketide synthesis pathway has recently been attracting interest as a promising alternative biofuel production route. In this article, recent trends in advanced biofuels production are reviewed by categorizing them into three types of advanced biofuels: alcohols, biodiesel and jet fuel, and gasoline. Focus is given on the strategies of employing synthetic biology and metabolic engineering for the development of microbial strains producing advanced fuels. Finally, the prospects for future advances needed to achieve much more efficient bio-based production of advanced biofuels are discussed, focusing on designing advanced biofuel production pathways coupled with screening, modifying, and creating novel enzymes.


Pulse oximetry as a screening test for congenital heart defects in newborn infants: a test accuracy study with evaluation of acceptability and cost-effectiveness.
Screening for congenital heart defects (CHDs) relies on antenatal ultrasound and postnatal clinical examination; however, life-threatening defects often go undetected. To determine the accuracy, acceptability and cost-effectiveness of pulse oximetry as a screening test for CHDs in newborn infants. A test accuracy study determined the accuracy of pulse oximetry. Acceptability of testing to parents was evaluated through a questionnaire, and to staff through focus groups. A decision-analytic model was constructed to assess cost-effectiveness. Six UK maternity units. These were 20,055 asymptomatic newborns at ≥ 35 weeks' gestation, their mothers and health-care staff. Pulse oximetry was performed prior to discharge from hospital and the results of this index test were compared with a composite reference standard (echocardiography, clinical follow-up and follow-up through interrogation of clinical databases). Detection of major CHDs - defined as causing death or requiring invasive intervention up to 12 months of age (subdivided into critical CHDs causing death or intervention before 28 days, and serious CHDs causing death or intervention between 1 and 12 months of age); acceptability of testing to parents and staff; and the cost-effectiveness in terms of cost per timely diagnosis. Fifty-three of the 20,055 babies screened had a major CHD (24 critical and 29 serious), a prevalence of 2.6 per 1000 live births. Pulse oximetry had a sensitivity of 75.0% [95% confidence interval (CI) 53.3% to 90.2%] for critical cases and 49.1% (95% CI 35.1% to 63.2%) for all major CHDs. When 23 cases were excluded, in which a CHD was already suspected following antenatal ultrasound, pulse oximetry had a sensitivity of 58.3% (95% CI 27.7% to 84.8%) for critical cases (12 babies) and 28.6% (95% CI 14.6% to 46.3%) for all major CHDs (35 babies). False-positive (FP) results occurred in 1 in 119 babies (0.84%) without major CHDs (specificity 99.2%, 95% CI 99.0% to 99.3%). However, of the 169 FPs, there were six cases of significant but not major CHDs and 40 cases of respiratory or infective illness requiring medical intervention. The prevalence of major CHDs in babies with normal pulse oximetry was 1.4 (95% CI 0.9 to 2.0) per 1000 live births, as 27 babies with major CHDs (6 critical and 21 serious) were missed. Parent and staff participants were predominantly satisfied with screening, perceiving it as an important test to detect ill babies. There was no evidence that mothers given FP results were more anxious after participating than those given true-negative results, although they were less satisfied with the test. White British/Irish mothers were more likely to participate in the study, and were less anxious and more satisfied than those of other ethnicities. The incremental cost-effectiveness ratio of pulse oximetry plus clinical examination compared with examination alone is approximately £24,900 per timely diagnosis in a population in which antenatal screening for CHDs already exists. Pulse oximetry is a simple, safe, feasible test that is acceptable to parents and staff and adds value to existing screening. It is likely to identify cases of critical CHDs that would otherwise go undetected. It is also likely to be cost-effective given current acceptable thresholds. The detection of other pathologies, such as significant CHDs and respiratory and infective illnesses, is an additional advantage. Other pulse oximetry techniques, such as perfusion index, may enhance detection of aortic obstructive lesions. The National Institute for Health Research Health Technology programme.


Depression in Visual Impairment Trial (DEPVIT): A Randomized Clinical Trial of Depression Treatments in People With Low Vision.
The purpose of this study was to compare two interventions for depression, problem solving treatment (PST) and referral to the patient's physician, with a waiting-list control group in people with sight loss and depressive symptoms. This was an assessor-masked, exploratory, multicenter, randomized clinical trial, with concurrent economic analysis. Of 1008 consecutive attendees at 14 low-vision rehabilitation centers in Britain, 43% (n = 430) screened positive for depressive symptoms on the Geriatric Depression Scale and 85 of these attendees participated in the trial. Eligible participants were randomized in the ratio 1:1:1 to PST, referral to their physician, or a waiting-list control arm. PST is a manualized talking intervention delivered by a trained therapist who teaches people over six to eight sessions to implement a seven-step method for solving their problems. Referral to the physician involved sending a referral letter to the person's physician, encouraging him or her to consider treatment according to the stepped care protocol recommended by the U.K.'s National Institute of Health and Care Excellence. The primary outcome was change in depressive symptoms (6 months after baseline) as determined by the Beck Depression Inventory. At 6 months, Beck Depression Inventory scores reduced by 1.05 (SD 8.85), 2.11 (SD 7.60), and 2.68 (SD 7.93) in the waiting-list control, referral, and PST arms, respectively. The cost per patient of the PST intervention was £1176 in Wales and £1296 in London. Depressive symptoms improved most in the PST group and least in the control group. However, the change was small and the uncertainty of the measurements relatively large.


Pyridoxamine-amino acid chimeras in semisynthetic aminotransferase mimics.
The transaminase activity of two new semisynthetic RNase-S proteins incorporating a pyridoxamine moiety at the active site has been evaluated. A chemically competent derivative of pyridoxamine phosphate was incorporated into the C-peptide fragments of these non-covalent protein complexes in the form of an unnatural coenzyme-amino acid chimera, 'Pam'. The chimeric Pam residue integrates the heterocyclic functionality of pyridoxamine phosphate into the side chain of an alpha-amino acid and was introduced instead of Phe8 into the C-peptide sequence via standard solid phase methodology. The two semisynthetic Pam-RNase constructs were designed to probe whether the native ribonuclease catalytic machinery could be enlisted to modulate a pyridoxamine-dependent transamination reaction. Both RNase complexes, H1SP and S1SP, exhibited modest rate enhancements in the Cu(II)-assisted transamination of pyruvate to alanine under single turnover conditions, relative to 5'-deoxypyridoxamine and the uncomplexed C-peptide fragments. Furthermore, multiple turnovers of substrates were achieved in the presence of added L-phenylalanine due to recycling of the pyridoxamine moiety. The modest chiral inductions observed in the catalytic production of alanine and the differences in reactivity between the two proteins could be rationalized by the participation of a general base (His12) in complex H1SP, and by the increased tolerance for large amino acid substrates by complex S1SP, which contains serine at this position. The pyridoxamine-amino acid chimera will be useful in the future for examining the coenzyme structure/ function relationships in a native-like peptidyl architecture.


Endogenous carbon in carbonaceous meteorites.
Seven carbonaceous chondrites have been analyzed for soluble organic compounds, carbonate, and residual carbon. Carbon-13/carbon-12 isotopic mneasurements on these fractions gave the following values relative to a marine carbonate standard: carbonate, +40 to +70 per mil; residual carbon, -15 to -17 per mil; soluble organic material, -17 to -27 per mil, with one value of -5.5 per mil. These values are interpreted to indicate that carbonate, residual carbon, and part of the extractable organic material are endogenous to these meteorites.


Dual-action inhibitors of HIF prolyl hydroxylases that induce binding of a second iron ion.
Inhibition of the hypoxia-inducible factor (HIF) prolyl hydroxylases (PHD or EGLN enzymes) is of interest for the treatment of anemia and ischemia-related diseases. Most PHD inhibitors work by binding to the single ferrous ion and competing with 2-oxoglutarate (2OG) co-substrate for binding at the PHD active site. Non-specific iron chelators also inhibit the PHDs, both in vitro and in cells. We report the identification of dual action PHD inhibitors, which bind to the active site iron and also induce the binding of a second iron ion at the active site. Following analysis of small-molecule iron complexes and application of non-denaturing protein mass spectrometry to assess PHD2·iron·inhibitor stoichiometry, selected diacylhydrazines were identified as PHD2 inhibitors that induce the binding of a second iron ion. Some compounds were shown to inhibit the HIF hydroxylases in human hepatoma and renal carcinoma cell lines.


Examination of treatment completion and predicted outcome among incarcerated sex offenders.
This article addresses the prediction of treatment completion and outcome of 114 adult sex offender using variables found to predict treatment outcome in outpatient sex offender programs. The variables of reading ability, marital status, age, presence of antisocial personality disorder, offense and victim discrimination, and instant offense were used. Three outcomes of treatment were assessed: (1) those who were rejected from the program during the evaluation phase; (2) those who dropped out of treatment; and (3) those who successfully completed the program. Results indicated that only reading ability and marital status were predictive of treatment outcome, with those with high reading ability and married having the best outcome. Failure of the other variables to differentiate between groups is attributed to differences in psychopathology between incarcerated and outpatient sex offenders and differences in structure between programs.


Preliminary Results from the Viking X-ray Fluorescence Experiment: The First Sample from Chryse Planitia, Mars.
Iron, calcium, aluminum, silicon, and sulfur are major elements in the first surface sample of Mars that has been analyzed by the Viking x-ray fluorescence spectrometer. Titanium is present in minor quantities. This is consistent with the sample being a mixture of fine silicate and oxide mineral grains, with a significant proportion of sulfates, possibly hydrated. Ferric oxide is regarded as the red pigmenting agent on the martian surface, but if it coats silicate grains, the coatings must be very thin (</= 2 micrometers) or discontinuous. A high abundance of Fe, relatively low abundances of Al, Rb, Sr, and Zr, and a high Ca/K ratio are distinctive features of the spectra. Preliminary determinations indicate the following abundances (as percentages by weight): Fe, 14 +/- 2; Ti < 1; S, 2 to 5; the Ca/K ratio by weight is greater than 5.


A Systematic Review of Classification Systems for Cervical Ossification of the Posterior Longitudinal Ligament.
Systematic review. To conduct a systematic review to (1) summarize various classification systems used to describe cervical ossification of the posterior longitudinal ligament (OPLL) and (2) evaluate the diagnostic accuracy of various imaging modalities and the reliability of these classification systems. A search was performed to identify studies that used a classification system to categorize patients with OPLL. Furthermore, studies were included if they reported the diagnostic accuracy of various imaging modalities or the reliability of a classification system. A total of 167 studies were deemed relevant. Five classification systems were developed based on X-ray: the 9-classification system (0.60%); continuous, segmental, mixed, localized or focal, circumscribed and others (92.81%); hook, staple, bridge, and total types (2.40%); distribution of OPLL (2.40%); and K-line classification (4.19%). Six methods were based on computed tomography scans: free-type, contiguous-type, and broken sign (0.60%); hill-, plateau-, square-, mushroom-, irregular-, or round-shaped (5.99%); rectangular, oval, triangular, or pedunculate (1.20%); centralized or laterally deviated (1.80%); plank-, spindle-, or rod-shaped (0.60%); and rule of nine (0.60%). Classification systems based on 3-dimensional computed tomography were bridging and nonbridging (1.20%) and flat, irregular, and localized (0.60%). A single classification system was based on magnetic resonance imaging: triangular, teardrop, or boomerang. Finally, a variation of methods was used to classify OPLL associated with the dura mater (4.19%). The most common method of classification was that proposed by the Japanese Ministry of Health, Labour and Welfare. Other important methods include K-line (+/-), signs of dural ossification, and patterns of distribution.


Challenges newly-arrived migrant women in Montreal face when needing maternity care: Health care professionals' perspectives.
People who leave their country of origin, or the country of habitual residence, to establish themselves permanently in another country are usually referred to as migrants. Over half of all births in Montreal, Canada are to migrant women. To understand healthcare professionals' attitudes towards migrants that could influence their delivery of care, our objective was to explore their perspectives of challenges newly-arrived migrant women from non-Western countries face when needing maternity care. In this qualitative multiple case study, we conducted face-to-face interviews with 63 health care professionals from four teaching hospitals in Montreal, known for providing maternity care to a high volume of migrant women. Interviews were transcribed and thematically analysed. Physicians, nurses, social workers, and therapists participated; 90% were female; and 17% were themselves migrants from non-Western countries. According to participants, newly-arrived migrant women face challenges at two levels: (a) direct care (e.g., understanding Canadian health care professionals' expectations, communicating effectively with health care professionals), and (b) organizational (e.g., access to appropriate health care). Challenges women face are strongly influenced by the migrant woman's background as well as social position (e.g., general education, health literacy, socio-cultural integration) and by how health care professionals balance women's needs with perceived requirement to adhere to standard procedures and regulations. Health care professionals across institutions agreed that maternity care-related challenges faced by newly-arrived migrant women often are complex in that they are simultaneously driven by conflicting values: those based on migrant women's sociocultural backgrounds versus those related to the implementation of Canadian guidelines for maternity care in which consideration of migrant women's particular needs are not priority.


The 9-methyl group of retinal is essential for rapid Meta II decay and phototransduction quenching in red cones.
Cone photoreceptors of the vertebrate retina terminate their response to light much faster than rod photoreceptors. However, the molecular mechanisms underlying this rapid response termination in cones are poorly understood. The experiments presented here tested two related hypotheses: first, that the rapid decay rate of metarhodopsin (Meta) II in red-sensitive cones depends on interactions between the 9-methyl group of retinal and the opsin part of the pigment molecule, and second, that rapid Meta II decay is critical for rapid recovery from saturation of red-sensitive cones after exposure to bright light. Microspectrophotometric measurements of pigment photolysis, microfluorometric measurements of retinol production, and single-cell electrophysiological recordings of flash responses of salamander cones were performed to test these hypotheses. In all cases, cones were bleached and their visual pigment was regenerated with either 11-cis retinal or with 11-cis 9-demethyl retinal, an analogue of retinal lacking the 9-methyl group. Meta II decay was four to five times slower and subsequent retinol production was three to four times slower in red-sensitive cones lacking the 9-methyl group of retinal. This was accompanied by a significant slowing of the recovery from saturation in cones lacking the 9-methyl group after exposure to bright (>0.1% visual pigment photoactivated) but not dim light. A mathematical model of the turn-off process of phototransduction revealed that the slower recovery of photoresponse can be explained by slower Meta decay of 9-demethyl visual pigment. These results demonstrate that the 9-methyl group of retinal is required for steric chromophore-opsin interactions that favor both the rapid decay of Meta II and the rapid response recovery after exposure to bright light in red-sensitive cones.


The effect of functional groups in the aqueous-phase selective sensing of Fe(iii) ions by thienothiophene-based zirconium metal-organic frameworks and the design of molecular logic gates.
The synthesis of four isoreticular, water-stable Zr(iv) metal-organic frameworks (MOFs) was conducted under solvothermal conditions by using thienothiophene-based ligands. The MOFs were fully characterized by XRPD analyses, FT-IR spectroscopy and TG analyses. The ligands were systematically modified with methyl and phenyl groups for tuning the fluorescence and hydrophobic behaviour of the MOFs. The photophysical properties of free ligands and the corresponding MOFs were investigated by steady-state as well as time-resolved fluorescence experiments. The MOFs containing π-electron rich, conjugated thieno[3,2-b]thiophene units were employed for the sensing of metal ions. All the MOFs displayed high selectivity and sensitivity towards the sensing of biologically important Fe3+ ions in pure aqueous medium through the fluorescence quenching mechanism. Detailed experimental investigations suggest that the transfer of electrons from the electron-rich frameworks to the half-filled 3d orbitals of Fe3+ ions results in fluorescence quenching. Surprisingly, the electron acceptor methyl viologen (MV2+) ions exhibited a reverse trend in the quenching efficiency compared to the Fe3+ ions. Both the steric and electronic effects of the attached functional groups can be proposed to play determining roles in the fluorescence quenching mechanism. All the MOFs showed high photostability and reusability, which are beneficial for the long-term real-world detection of Fe3+ ions. Interestingly, the MOFs can be utilized to construct molecular logic gates for the efficient discrimination between Fe3+ and Fe2+ ions.


Potential epidemiologic, economic, and budgetary impacts of current rates of hepatitis C treatment in medicare and non-medicare populations.
We forecast the health and budgetary impact of hepatitis C (HCV) treatment on the Medicare program based on currently observed rates of treatment among Medicare and non-Medicare patients and identify the impact of higher rates of treatment among non-Medicare populations. We developed a computer microsimulation model to conduct an epidemiologic forecast, a budgetary impact analysis, and a cost-effectiveness analysis of the treatment of HCV based on three scenarios: 1) no treatment, 2) continuation of current-treatment rates, and 3) treatment rates among non-Medicare patients increased to match that of Medicare patients. The simulated population is based on National Health and Nutrition Examination Survey data. HCV progression rates and costs were calculated in Surveillance, Epidemiology, and End Results Program Medicare 5% claims data from the Chronic Hepatitis Cohort Study and published literature. We estimate that 13.6% of patients with HCV in the United States are enrolled in Medicare, but 75% will enter Medicare in the next 20 years. Medicare patients were over 5 times as likely to be treated in 2014-2015 as other patients. Medicare paid over $9 billion in treatment costs in both 2015 and 2016 and will total $28.4 billion from 2017-2026. Increasing treatment rates among non-Medicare patients would lead to 234,000 more patients being treated, reduce HCV mortality by 19%, and decrease Medicare costs by $18.6 billion from 2017-2026. We find that treatment remains cost-effective under most assumptions, costing $31,718 per quality adjusted life year gained. Conclusion: Medicare treats a disproportionately large share of HCV patients. Continued low rates of treatment among non-Medicare HCV patients will result in both reduced and deferred treatment, shifting future treatment costs to Medicare while increasing overall medical management costs, morbidity, and mortality. (Hepatology Communications 2017;1:99-109).


The effects of technological advances on outcomes for elderly persons with exudative age-related macular degeneration.
IMPORTANCE Exudative age-related macular degeneration (ARMD) is the major cause of blindness among US elderly. Developing effective therapies for this disease has been difficult. OBJECTIVES To assess the effects of introducing new therapies for treating exudative ARMD on vision of the affected population and other outcomes among Medicare beneficiaries newly diagnosed as having ARMD. DESIGN The study used data from a 5% sample of Medicare claims and enrollment data with a combination of a regression discontinuity design and propensity score matching to assess the effects on the introduction or receipt of new technologies on study outcomes during a 2-year follow-up period. SETTING AND PARTICIPANTS The analysis was based on longitudinal data for the United States, January 1, 1994, to December 31, 2011, for Medicare beneficiaries with fee-for-service coverage. The sample was limited to beneficiaries 68 years or older newly diagnosed as having exudative ARMD as indicated by beneficiaries having no claims with this diagnosis in a 3-year look-back period. EXPOSURES The comparisons with vision outcomes were after vs before the introduction of photodynamic therapy and anti-vascular endothelial growth factor (VEGF) therapy. The comparisons for depression and long-term care facility admission were between beneficiaries newly diagnosed as having exudative ARMD who received photodynamic therapy or anti-VEGF therapy compared with beneficiaries having the diagnosis who received no therapy for this disease. MAIN OUTCOMES AND MEASURES Onset of decrease in vision, vision loss or blindness, depression, and admission to a long-term care facility. RESULTS Among beneficiaries newly diagnosed as having exudative ARMD, the introduction of anti-VEGF therapy reduced vision loss by 41% (95% CI, 52%-68%) and onset of severe vision loss and blindness by 46% (95% CI, 47%-63%). Such beneficiaries who received anti-VEGF therapy and were not admitted to a long-term care facility during the look-back period were 19% (95% CI, 72%-91%) less likely on average to be admitted to a long-term care facility during the follow-up period. CONCLUSIONS AND RELEVANCE This study demonstrates gains in population vision from the introduction of anti-VEGF therapy for patients 68 years or older with an exudative ARMD diagnosis in community-based settings in the United States.


The current state of oligometastatic and oligoprogressive non-small cell lung cancer.
Oligometastatic disease is defined as an intermediate state between localized and widespread metastatic disease. Given that in the oligometastatic state gross tumors represent the full extent of disease, there may be a role for curative local therapy despite metastatic disease. As nearly 60% of patients with non-small cell lung cancer (NSCLC) present with metastatic disease and another 45% of patients with initially localized disease will ultimately develop distant metastases, NSCLC represents a prime disease for aggressive intervention. In this review, the definition, prognostic factors, patient selection, rationale and evidence for treatment of oligoprogressive and oligometastatic NSCLC is discussed, including recent prospective trials and future directions.


Genome comparison of barley and maize smut fungi reveals targeted loss of RNA silencing components and species-specific presence of transposable elements.
Ustilago hordei is a biotrophic parasite of barley (Hordeum vulgare). After seedling infection, the fungus persists in the plant until head emergence when fungal spores develop and are released from sori formed at kernel positions. The 26.1-Mb U. hordei genome contains 7113 protein encoding genes with high synteny to the smaller genomes of the related, maize-infecting smut fungi Ustilago maydis and Sporisorium reilianum but has a larger repeat content that affected genome evolution at important loci, including mating-type and effector loci. The U. hordei genome encodes components involved in RNA interference and heterochromatin formation, normally involved in genome defense, that are lacking in the U. maydis genome due to clean excision events. These excision events were possibly a result of former presence of repetitive DNA and of an efficient homologous recombination system in U. maydis. We found evidence of repeat-induced point mutations in the genome of U. hordei, indicating that smut fungi use different strategies to counteract the deleterious effects of repetitive DNA. The complement of U. hordei effector genes is comparable to the other two smuts but reveals differences in family expansion and clustering. The availability of the genome sequence will facilitate the identification of genes responsible for virulence and evolution of smut fungi on their respective hosts.


The effect of cheese on dental caries: a review of the literature.
The relationship between nutrition and dental health has been a topic of interest for many years. Recently, the cariostatic properties of cheese have been the subject of intensive research. Most of these studies suggest that the use of cheese as the final food in a meal will help to reduce caries. Several mechanisms by which cheese may reduce enamel demineralization have been proposed. Chewing cheese stimulates saliva flow. The alkaline nature of saliva buffers the acids formed in plaque. There is also an increased rate of sugar clearance due to the diluting action of cheese-stimulated saliva. Research has also suggested that chewing cheese may reduce the levels of cariogenic bacteria. This may be secondary to the reduced incidence of caries as conditions within a carious lesion tend to promote the growth of these organisms. The high calcium and phosphorus content seems to be another factor in the cariostatic mechanism of cheese. Both casein and whey protein seem to be involved in the reduction of enamel demineralization. Casein phosphopeptides may also be responsible for some anticariogenicity by concentrating calcium and phosphate in plaque. An overview of the effect of milk on dental caries is also presented in this review.


A history of the journal of chiropractic education: twenty-five years of service, 1987-2011.
The Journal of Chiropractic Education celebrates its 25th anniversary in the year 2011. The purpose of this article is to chronicle the history of the journal, which is unreported at this time. The entire collection of the journal was reviewed and information pertaining to important events and changes in the format, personnel, and processes of the journal were extracted. This information was used to create a chronology of the journal. The chronology was complemented with information obtained from people who were involved in the evolution of the journal and the Association of Chiropractic Colleges Educational Conferences. Starting as a humble newsletter in 1987 and produced for a small cadre of readers primarily from the United States, the journal is now a full-sized and bound peer-reviewed international journal. Initially cataloged by the Index to Chiropractic Literature and MANTIS, the indexing expanded to interdisciplinary indexing systems such as CINAHL and ultimately PubMed. The journal has grown to serve the needs of chiropractic educators from around the world with representatives on the editorial board from 39 colleges and universities from 15 different countries. The journal has grown in tandem with the profession's leading education and research conference and has been the primary repository for the scholarship of chiropractic education. The history of the journal represents a significant milestone in the development of the chiropractic profession, particularly the discipline of chiropractic education. The journal has had an interesting history and the future promises to bring more opportunities and challenges to the field of chiropractic education and to the journal.


Gravitational Transitions Increase Posterior Cerebral Perfusion and Systemic Oxidative-nitrosative Stress: Implications for Neurovascular Unit Integrity.
The present study examined if repeated bouts of micro- and hypergravity during parabolic flight (PF) alter structural integrity of the neurovascular unit (NVU) subsequent to free radical-mediated changes in regional cerebral perfusion. Six participants (5♂, 1♀) aged 29 ± 11 years were examined before, during and after a 3 h PF and compared to six sex and age-matched (27 ± 6 years) normogravity controls. Blood flow was measured in the anterior (middle cerebral artery, MCA; internal carotid artery, ICA) and posterior (vertebral artery, VA) circulation (duplex ultrasound) in-flight over the course of 15 parabolas. Venous blood was assayed for free radicals (electron paramagnetic resonance spectroscopy), nitric oxide (NO, ozone-based chemiluminescence) and NVU integrity (chemiluminescence/ELISA) in normogravity before and after exposure to 31 parabolas. While MCA velocity did not change (P > 0.05), a selective increase in VA flow was observed during the most marked gravitational transition from micro- to hypergravity (P < 0.05). Increased oxidative-nitrosative stress defined by a free radical-mediated reduction in NO and elevations in glio-vascular GFAP and S100ß were observed after PF (P < 0.05), the latter proportional to the increase in VA flow (r = 0.908, P < 0.05). In contrast, biomarkers of neuronal-axonal damage (neuron-specific enolase, neurofilament light-chain, ubiquitin carboxy-terminal hydrolase L1 and tau) did not change (P > 0.05). Collectively, these findings suggest that the cumulative effects of repeated gravitational transitions may promote minor blood-brain barrier disruption, potentially related to the combined effects of haemodynamic (posterior cerebral hyperperfusion) and molecular (systemic oxidative-nitrosative) stress.


Long-term survivors with metastatic uveal melanoma.
To report the tumor, patient, and treatment characteristics of long-term metastatic uveal melanoma survivors. A non-comparative, retrospective case series of patients from a single institution surviving >24 months with metastatic uveal melanoma (UM). Nine patients met the study criteria and their charts were reviewed. The mean age at diagnosis of UM was 44.1 years (SD +/- 14.4 years). Initial treatment modalities included enucleation (67%), brachytherapy (22%), and proton beam radiation (11%). The average time from primary tumor diagnosis to detection of metastasis was 125.9 months (SD +/- 95 months). The most common location for initial metastasis was the liver. All patients underwent treatment for metastatic disease including systemic therapy, surgical resection, and isolated hepatic perfusion. The majority of patients received treatment with a tyrosine kinase inhibitor (sorafenib, sunitinib, and/or imatinib). The median survival with metastasis was 51 months (range 27-123 months). Patients had a long disease-free interval before presentation of metastatic disease. A small subset of patients with metastatic UM has prolonged survival. Identification of these patients may be helpful for future clinical trial design.


Correlation between beta-lipoprotein levels and outcome of hepatitis C treatment.
The low-density lipoprotein receptor (LDLR) has been proposed as a candidate receptor for the hepatitis C virus (HCV). Competitive inhibition of HCV binding to the LDLR by low-density lipoprotein (LDL) has been shown in vitro. If similar inhibition occurs in vivo, an elevated serum concentration of beta-lipoproteins may reduce the efficiency of infecting hepatocytes with HCV by competitively inhibiting HCV viral receptor binding. We investigated the role of baseline lipid values in influencing the outcome of HCV treatment. We conducted a retrospective chart review of patients treated with an interferon-based regimen at our liver and gastroenterology clinics between 1998 and 2004. Of 99 patients enrolled in the study, 49 (49.5%) had HCV genotype 1 (LDL 100.2 +/- 30.2 mg/dL [mean +/- SD]), and 50 patients (50.5%) had genotype 2 or 3 (LDL 110.1 +/- 40 mg/dL) infection. Early viral response (EVR), end-of-treatment response (ETR), and sustained viral response (SVR) were documented in 99, 88, and 77 patients, respectively. LDL and cholesterol levels prior to treatment were found to be higher in patients with positive EVR, ETR, and SVR. This difference remained significant independent of age. Multivariate analysis controlling for genotype and age showed that the higher the cholesterol and LDL levels prior to treatment, the greater the odds of responding to treatment. In conclusion, having higher serum LDL and cholesterol levels before treatment may be significant prognostic indicators for treatment outcome of those with chronic hepatitis C infection, particularly in genotypes 1 and 2.


The effect of exercise in reducing desire to smoke and cigarette withdrawal symptoms is not caused by distraction.
Moderate-intensity exercise has been shown to reduce common smoking withdrawal symptoms and desire to smoke in acutely abstinent smokers. The aim of the present study was to determine if this was caused by distraction. A secondary aim was to determine whether exercise-related changes in affect were related to a reduction in symptoms. Forty 'sedentary' participants who had smoked at least 10 or more cigarettes per day for at least 3 years were assigned randomly to one of two groups. They completed either 10 minutes of moderate-intensity exercise on a stationary bicycle ergometer or 10 minutes of a cognitive distraction task (paced visual serial addition task, PVSAT) after 11-15 hours of smoking abstinence. Participants rated smoking withdrawal symptoms and desire to smoke using standard scales at 10, 5 and 0 minutes before the experimental intervention, then at 5 and 10 minutes after the start of the intervention and 5 and 10 minutes after its completion. Significant group x time interactions were observed for ratings of desire to smoke and several withdrawal symptoms (irritability, depression, restlessness, difficulty concentrating and stress). There was a reduction in ratings during and immediately following exercise that was not observed with cognitive distraction. Also it was found the effects were not mediated by changes in affect observed in the exercise condition. A brief bout of moderate-intensity exercise can lead to a rapid reduction in desire to smoke and withdrawal discomfort, which is not due to the distracting effect of exercise or the effects of mood. These findings support recommendations to smokers to use exercise as a means of helping cope with the difficulties encountered when they try to stop.


An evolutionary hypothesis for obsessive compulsive disorder: a~psychological immune system?
A new hypothesis is presented within the framework of evolutionary psychology that attempts to explain the origins of obsessive-compulsive disorder. It is suggested that obsessions and compulsions originate from the overactivity of a mental module that the majority of humans possess and has the function of generating risk scenarios without voluntary intervention. It is hypothesised that obsessional phenomena function as an off-line risk avoidance process, designed to lead to risk avoidance behaviour at a future time, thus distinguishing it from anxiety and related phenomena as on-line emotional states, designed to lead to the avoidance of immediate and direct risks. Finally, the hypothesis makes a number of specific predictions that are testable and refutable. It is contended that the present hypothesis if supported by empirical evidence could serve as a basis for future research on this important disorder.


Tetraethylammonium chloride reduces anaesthetic-induced neurotoxicity in Caenorhabditis elegans and mice.
If anaesthetics cause permanent cognitive deficits in some children, the implications are enormous, but the molecular causes of anaesthetic-induced neurotoxicity, and consequently possible therapies, are still debated. Anaesthetic exposure early in development can be neurotoxic in the invertebrate Caenorhabditis elegans causing endoplasmic reticulum (ER) stress and defects in chemotaxis during adulthood. We screened this model organism for compounds that alleviated neurotoxicity, and then tested these candidates for efficacy in mice. We screened compounds for alleviation of ER stress induction by isoflurane in C. elegans assayed by induction of a green fluorescent protein (GFP) reporter. Drugs that inhibited ER stress were screened for reduction of the anaesthetic-induced chemotaxis defect. Compounds that alleviated both aspects of neurotoxicity were then blindly tested for the ability to inhibit induction of caspase-3 by isoflurane in P7 mice. Isoflurane increased ER stress indicated by increased GFP reporter fluorescence (240% increase, P<0.001). Nine compounds reduced induction of ER stress by isoflurane by 90-95% (P<0.001 in all cases). Of these compounds, tetraethylammonium chloride and trehalose also alleviated the isoflurane-induced defect in chemotaxis (trehalose by 44%, P=0.001; tetraethylammonium chloride by 23%, P<0.001). In mouse brain, tetraethylammonium chloride reduced isoflurane-induced caspase staining in the anterior cortical (-54%, P=0.007) and hippocampal regions (-46%, P=0.002). Tetraethylammonium chloride alleviated isoflurane-induced neurotoxicity in two widely divergent species, raising the likelihood that it may have therapeutic value. In C. elegans, ER stress predicts isoflurane-induced neurotoxicity, but is not its cause.


IL-6 mediates platinum-induced enrichment of ovarian cancer stem cells.
In high-grade serous ovarian cancer (OC), chemotherapy eliminates the majority of tumor cells, leaving behind residual tumors enriched in OC stem cells (OCSC). OCSC, defined as aldehyde dehydrogenase-positive (ALDH+), persist and contribute to tumor relapse. Inflammatory cytokine IL-6 is elevated in residual tumors after platinum treatment, and we hypothesized that IL-6 plays a critical role in platinum-induced OCSC enrichment. We demonstrate that IL-6 regulates stemness features of OCSC driven by ALDH1A1 expression and activity. We show that platinum induces IL-6 secretion by cancer-associated fibroblasts in the tumor microenvironment, promoting OCSC enrichment in residual tumors after chemotherapy. By activating STAT3 and upregulating ALDH1A1 expression, IL-6 treatment converted non-OCSC to OCSC. Having previously shown altered DNA methylation in OCSC, we show here that IL-6 induces DNA methyltransferase 1 (DNMT1) expression and the hypomethylating agent (HMA) guadecitabine induced differentiation of OCSC and reduced - but did not completely eradicate - OCSC. IL-6 neutralizing antibody (IL-6-Nab) combined with HMA fully eradicated OCSC, and the combination blocked IL-6/IL6-R/pSTAT3-mediated ALDH1A1 expression and eliminated OCSC in residual tumors that persisted in vivo after chemotherapy. We conclude that IL-6 signaling blockade combined with an HMA can eliminate OCSC after platinum treatment, supporting this strategy to prevent tumor recurrence after standard chemotherapy.


Health literacy and substance use in young Swiss men.
The purpose of the present study was to describe health literacy and its association with substance use among young men. The present study was part of the Cohort Study on Substance Use Risk Factors that included 11,930 Swiss males participating in initial screening from August 2010 to July 2011. Self-completed questionnaires covered use of three substances and three components of health literacy. Roughly 22 % reported having searched the Internet for health information and 16 % for information on substances over the past 12 months. At-risk and not at-risk users of alcohol (adjusted odds ratio (AOR) = 2.50 and 1.46), tobacco (AOR = 2.51 and 1.79) and cannabis (AOR = 4.86 and 3.53) searched for information about substances significantly more often via the Internet than abstainers. Furthermore, at-risk users reported better knowledge of risks associated with substance use and a marginally better ability to understand health information than abstainers. Substance users appear to be more informed and knowledgeable about the risks of substance use than non-users. Consequently, interventions that focus only on information provision may be of limited benefit for preventing substance use.


The highly antigenic 53/25 kDa Taenia solium protein fraction with cathepsin-L like activity is present in the oncosphere/cysticercus and induces non-protective IgG antibodies in pigs.
Cathepsin L-like proteases are secreted by several parasites including Taenia solium. The mechanism used by T. solium oncospheres to degrade and penetrate the intestine and infect the host is incompletely understood. It is assumed that intestinal degradation is driven by the proteolytic activity of enzymes secreted by the oncosphere. Blocking the proteolytic activity by an antibody response would prevent the oncosphere penetration and further infection. Serine and cysteine proteases including chymotrypsin, trypsin, elastase, and cathepsin L, are secreted by T. solium and Taenia saginata oncospheres when cultured in vitro, being potential vaccine candidates. However, the purification of a sufficient quantity of proteases secreted by oncospheres to conduct a vaccine trial is costly and lengthy. A 53/25 kDa cathepsin L-like fraction partially purified from T. solium cyst fluid was described previously as an important antigen for immunodiagnostics. In this study we found that this antigen is present in the T. solium oncosphere and is also secreted by the cysticercus. This protein fraction was tested for its ability to protect pigs against an oral challenge with T. solium oncospheres in a vaccine trial. IgG antibodies against the 53/25 kDa cathepsin L-like protein fraction were elicited in the vaccinated animals but did not confer protection.


Object categorisation, object naming, and viewpoint independence in visual remembering: evidence from young children's drawings of a novel object.
A simple object-drawing task confirms a three-way association between object categorisation, viewpoint independence, and longer-term visual remembering. Young children (5- to 7-year-olds) drew a familiar object or a novel object, immediately after it had been hidden from view or on the following day. Both objects were shown from a full range of viewpoints or from just two viewpoints, from neither of which would either object normally be drawn after unrestricted viewing. When drawing from short-term memory after restricted viewing, both objects were most likely to be depicted from a seen viewpoint. When drawing from longer-term memory after restricted viewing, the novel object continued to be drawn from a seen viewpoint, but the mug was now most likely to be drawn from a preferred viewpoint from which it had not been seen. Naming the novel object with a novel count noun ("Look at this. This is a dax"), to signal that it belonged to an object category, resulted in it being drawn in the same way as the familiar object. The results concur with other evidence indicating that short-term and longer-term visual remembering are differentially associated with viewpoint-dependent representations of individual objects and viewpoint independent representations of object categories, respectively.


Expression and characterization of a truncated murine Fc gamma receptor.
We have isolated a recombinant secreted Fc gamma R beta molecule by deletion of the transmembrane and cytoplasmic domains encoding sequence from a Fc gamma R beta 1 cDNA clone, and insertion of the truncated cDNA into a eukaryotic expression vector, pcEXV-3. To express and amplify the production of the truncated Fc gamma R beta molecule, we transfected the truncated cDNA plasmid into a dihydrofolate reductase-minus CHO cell line along with a dhfr minigene, and amplified the gene products with methotrexate. The resulting cell line secretes 2-3 micrograms/ml/24 h of truncated Fc gamma R beta, which can be readily purified by affinity chromatography on IgG-Sepharose. The truncated Fc gamma R beta has a Mr of 31-33,000 on SDS-PAGE and is glycosylated. N-glycosidase F cleavage reduces the Mr to 19,000, consistent with the size of the truncated product, 176 amino acid residues. There are two disulfide bonds in the protein. Binding of immune complexes formed between DNP20BSA and anti-DNP mAbs reveals better binding of IgG1 aggregates than that of IgG2b and IgG2a aggregates. The binding of the immune complexes was somewhat better at more acidic pH, in contrast to previous experiments with binding of purified Fc gamma R to immune complex-coated beads. We were surprised to observe that the truncated Fc gamma R beta did not react with the anti-Fc gamma R mAb 6B7C. Previous work had shown that 6B7C reacts with Fc gamma R on immunoblots, fails to bind to the surface of resting B cells and peritoneal macrophages, but does bind to macrophage cell lines and LPS-stimulated B cells. We show, by binding of mAb 6B7C to a peptide conjugate, that the 6B7C epitope lies within residues 169-183 of the intact Fc gamma R beta, which is just outside the plasma membrane. The availability of the truncated Fc gamma R beta in microgram quantities should facilitate further analysis of structure and function of these receptors.


Challenges and promises for translating computational tools into clinical practice.
Computational modeling and associated methods have greatly advanced our understanding of cognition and neurobiology underlying complex behaviors and psychiatric conditions. Yet, no computational methods have been successfully translated into clinical settings. This review discusses three major methodological and practical challenges (A. precise characterization of latent neurocognitive processes, B. developing optimal assays, C. developing large-scale longitudinal studies and generating predictions from multi-modal data) and potential promises and tools that have been developed in various fields including mathematical psychology, computational neuroscience, computer science, and statistics. We conclude by highlighting a strong need to communicate and collaborate across multiple disciplines.


Pharmacosex: Reimagining sex, drugs and enhancement.
The use of drugs in sexual contexts is receiving closer attention in the media, public health bodies and communities than ever before. However, research to date is most often concerned with the sex-related drug use of lesbian, gay, bisexual, transgender and queer (LGBTQ) populations, and particularly men who have sex with men (MSM) engaging in 'chemsex'. Against a backdrop dominated by public health and medical science perspectives, this article seeks to move beyond prevailing sex on drug discourses characterised by risk and harm, or pleasure. Drawing on an expansive notion of enhancement, we explore intersections between drug consumption and sex via the concept of 'pharmacosex': the ways in which wider populations experiment with a range of illicit drugs that modify and enhance their sex lives in the context of broader processes of the pharmaceuticalisation of sexuality. Drawing on two empirical studies comprising a virtual ethnography and 45 interviews with participants across a range of gender and sexual identities who regularly combine sex and drugs, this article contributes to the growing body of research that attends to the materiality of drug consumption practices in relation to the historical and social contexts from which they emerge. Our participants reported variegated and complex modes of enhancement in relation to a wide range of psychoactive substances. Participants described enhanced emotional connectedness, bodily sensations, disinhibition and desire, but they also discussed how sex enhances drug experiences. As important but currently neglected in research literature were the therapeutic dimensions of drug-taking reported, which cannot be neatly distinguished from purely hedonic motivations. While enhancement was also experienced by participants in more challenging ways in relation to shame, regret, risk and/or harm, these experiences simultaneously afforded space for the emergence of innovative practices of risk-management, safety and care. This study exposes the diversity of practices and meanings sex-related drug use hold for participants, but also demonstrates the paucity of biomedical conceptions of sexual enhancement limited to stamina, function and libido, and the need for a more expansive approach. The study also raises questions about the extent to which contemporary discourses of self-improvement have come to 'inhabit' sexuality in the twenty-first century, and the role drugs might play in this context. By shifting the gaze from pathology to enhancement and exploring the plurality of practice, we can better understand the motivations for engaging in sex-related drug use, thereby circumventing knee-jerk counterproductive enforcement and policy responses.


Nitric oxide inhibits lipopolysaccharide-induced apoptosis in pulmonary artery endothelial cells.
Our group recently reported that cultured sheep pulmonary artery endothelial cells (SPAECs) became resistant to lipopolysaccharide (LPS)-induced apoptosis several days after constitutive synthesis of nitric oxide (NO) after adenoviral (Ad) transfer of inducible NO synthase (iNOS) or exposure to the NO donor S-nitroso-N-acetylpenicillamine (SNAP) (E. Tzeng, Y.-M. Kim, B. R. Pitt, A. Lizonova, I. Kovesdi, and T. R. Billiar. Surgery 122: 255-263, 1997). In the present study, we confirmed this observation by establishing stable transfectants after retroviral gene transfer [replication-deficient retrovirus (DFG)] of human iNOS (DFG-iNOS) SPAECs and then used all three approaches (Ad, DFG, and SNAP) to determine underlying mechanisms of this phenomenon. Continuous endogenous production of NO in itself did not cause apoptosis as assessed by phase-contrast microscopy, nuclear morphology, and internucleosomal DNA fragmentation. Prolonged (72-96 h) synthesis of NO, however, after DFG- or replication-deficient adenovirus (Ad. CMV)-iNOS or SNAP (100 microM, 96 h) inhibited LPS-induced apoptosis. The kinetics of such protection suggested that NO may be inducing other gene products. Ad-mediated transfer of manganese superoxide dismutase (MnSOD) decreased the sensitivity of wild-type SPAECs to LPS-induced apoptosis. MnSOD, however, was not induced in an NG-monomethyl-L-arginine (L-NMMA)-sensitive time-dependent fashion after Ad.CMV-iNOS. Other inducible genes that may be affected by NO and that may protect against potential oxidant-mediated LPS-induced apoptosis including 70-kDa heat shock protein, heme oxygenase-1, metallothionein, and Bcl-2 also were not elevated in an L-NMMA-sensitive, time-dependent fashion. Although the candidate gene product underlying NO-induced protection remains unclear, we did note that prolonged synthesis of NO inhibited LPS-induced activation of an interleukin-1beta-converting enzyme-like cysteine protease (cysteine protease protein-32-like) in a dithiothreitol-sensitive fashion, suggesting that S-nitrosylation of an important downstream target of convergence of apoptotic signals may contribute to the sensitivity of SPAECs to LPS.


PELICAN: a cluster-randomized controlled trial in Dutch general practices to assess a self-management support intervention based on individual goals for children with asthma.
Insufficient asthma management leads to impaired health-related quality of life (HRQL). The aim of this study is to assess whether individualized self-management (ISM) support will improve HRQL in children with asthma compared to enhanced usual care (EUC) in Dutch general practices. A cluster-randomized controlled trial with 9-month follow-up. ISM is a nurse-led intervention that is optimized to the needs of children, leading to a written action plan. Power calculation demanded inclusion of 170 children (aged 6-11 years) diagnosed with asthma and active medication use. Outcomes were HRQL of the child (Paediatric Asthma Quality of Life Questionnaire, PAQLQ-s) and several secondary outcomes. Data of 29 children (mean age 8.6 years, SD 1.7) were analyzed; ISM (n = 15) or EUC (n = 14). Logistic regression analysis (minimal clinical important difference; MCID ≥ 0.5) and descriptive analyses were performed. Despite high PAQLQ-s score at baseline (median ISM 6.35, EUC 6.02), a substantial number of subjects from both groups showed MCID of HRQL (ISM 33%, EUC 57%). Treatment differences on HRQL were not significant (OR 0.38, 95% CI 0.08, 1.69). Secondary outcomes did not show significant differences either, with exception of PAQLQ-s symptoms domain score in favor of EUC. Due to recruitment problems and underpowered analyses, no firm conclusions on the effectiveness of ISM support for childhood asthma in primary care could be drawn. Still, this study can be considered a valuable pilot study and in the future, there might be better capacity in general practices to commit to such treatment.


The spontaneously hypertensive rat: an experimental model of sulfur dioxide-induced airways disease.
Chronic obstructive pulmonary disease (COPD) is characterized by airway obstruction, inflammation, and mucus hypersecretion, features that are common in bronchitis, emphysema, and often asthma. However, current rodent models do not reflect this human disease. Because genetically predisposed spontaneously hypertensive (SH) rats display phenotypes such as systemic inflammation, hypercoagulation, oxidative stress, and suppressed immune function that are also apparent in COPD patients, we hypothesized that SH rat may offer a better model of experimental bronchitis. We, therefore, exposed SH and commonly used Sprague Dawley (SD) rats (male, 13- to 15-weeks old) to 0, 250, or 350 ppm sulfur dioxide (SO(2)), 5 h/day for 4 consecutive days to induce airway injury. SO(2) caused dose-dependent changes in breathing parameters in both strains with SH rats being slightly more affected than SD rats. Increases in bronchoalveolar lavage fluid (BALF) total cells and neutrophilic inflammation were dose dependent and significantly greater in SH than in SD rats. The recovery was incomplete at 4 days following SO(2) exposure in SH rats. Pulmonary protein leakage was modest in either strain, but lactate dehydrogenase and N-acetyl glucosaminidase activity were increased in BALF of SH rats. Airway pathology and morphometric evaluation of mucin demonstrated significantly greater impact of SO(2) in SH than in SD rats. Baseline differences in lung gene expression pattern suggested marked immune dysregulation, oxidative stress, impairment of cell signaling, and fatty acid metabolism in SH rats. SO(2) effects on these genes were more pronounced in SH than in SD rats. Thus, SO(2) exposure in SH rats may yield a relevant experimental model of bronchitis.


(‒)-Cannabidiolic Acid, a Still Overlooked Bioactive Compound: An Introductory Review and Preliminary Research.
Cannabidiolic acid (CBDA) is the main phytocannabinoid in fiber and seed-oil hemp (Cannabis sativa L.) plants, but its potential health-related capabilities have been masked for years by a greater scientific interest towards its neutral derivative cannabidiol (CBD). This review aims to collect from the literature and critically discuss all the information about this molecule, starting from its biosynthesis, and focusing on its bioactivity, as an anti-inflammatory, anti-emetic, anti-convulsant, and anti-cancerogenic drug. Furthermore, in the awareness that, despite its multiple bioactive effects, currently poor efforts have been made to achieve its reliable purification, herein, we propose a relatively simple, fast, and inexpensive procedure for its recovery from pollen of industrial hemp cultivars. Spectroscopic and spectrometric techniques allowed us to unequivocally identify pure isolated CBDA and to distinguish it from the constitutional isomer tetrahydrocannabinolic acid (THCA-A).