Safety and efficacy of LY2951742, a monoclonal antibody to calcitonin gene-related peptide, for the prevention of migraine: a phase 2, randomised, double-blind, placebo-controlled study.
Migraine remains poorly treated, with few effective preventive drugs available. We assessed the safety and efficacy of LY2951742, a fully humanised monoclonal antibody to calcitonin gene-related peptide, for migraine prevention. We did a randomised, double-blind, placebo-controlled, phase 2 proof-of-concept study at 35 centres in the USA. Patients aged 18-65 years with four to 14 migraine headache days per month were randomly assigned (1:1) to LY2951742 or placebo by a computerised randomisation scheme. LY2951742 (150 mg) or placebo were given as a subcutaneous injection once every 2 weeks for 12 weeks. The primary endpoint was the mean change in number of migraine headache days per 28-day period assessed at 9-12 weeks. Safety was assessed over 24 weeks, including the 12-week treatment period and the subsequent 12 weeks after study drug administration. Patients and treating investigators were masked to treatment allocation. Analyses were by intention to treat. A mixed-effects model of repeated measures was used, including patient baseline value, treatment, visit, and treatment-by-visit interaction as fixed effects, and patients as random effects. Safety measures were analysed according to the treatment received. This study has been completed and is registered with ClinicalTrials.gov, NCT01625988. Between July 31, 2012, and Sept 18, 2013, 218 patients were randomly assigned to LY2951742 (n=108, but one patient withdrew before treatment) or placebo (n=110). The mean change from baseline to week 12 in the number of migraine headache days was -4·2 (SD 3·1; 62·5% decrease) in the LY2951742 group compared with -3·0 (SD 3·0; 42·3% decrease) in the placebo group (least-squares mean difference -1·2, 90% CI -1·9 to -0·6; p=0·0030). Adverse events that occurred more frequently with LY2951742 than with placebo included injection site pain, erythema, or both (21 [20%] of 107 vs seven [6%] of 110), upper respiratory tract infections (18 [17%] vs ten [9%]), and abdominal pain (six [6%] vs three [3%]). There were two serious adverse events reported in the treatment arm and four in the placebo arm, none of which were deemed to be related to the study drug. These results provide preliminary evidence that LY2951742 might be beneficial in migraine prevention and provide support for the role of calcitonin gene-related peptide in the pathogenesis of migraine. Further controlled studies are needed to assess the safety and efficacy of monoclonal calcitonin gene-related peptide antibodies for the preventive treatment of migraine. Arteaus Therapeutics.


A feasibility study of Dreampad™ on sleep, wandering and agitated behaviors in people living with dementia.
This feasibility study examined Dreampad™, a sleeping device, on sleep, wandering and agitated behaviors in people living with dementia. Four nursing home residents (2 males and 2 females; mean age = 89.8 years (SD = 7.2); mean MMSE scores = 9.3 (SD = 8.7)) used Dreampad™ daily over 4-weeks when they slept. Agitation was assessed pre- and post-intervention. Wandering and sleeping patterns were assessed using a wearable actigraphy device over 24 hours at baseline and every week during the intervention. Dreampad™ was deemed acceptable and feasible for use with people living with dementia by family and care staff. No support for Dreampad™ in improving sleep or behaviors of agitation and wandering was found. Challenges in using the wearable actigraphy device are reported. Attention is needed to ensure consistent use of Dreampad™ by people living with dementia and their wear adherence of the actigraphy device. Further rigorous research is warranted and can be guided by the study outcomes.


Sox2 is dispensable for primary melanoma and metastasis formation.
Tumor initiation and metastasis formation in many cancers have been associated with emergence of a gene expression program normally active in embryonic or organ-specific stem cells. In particular, the stem cell transcription factor Sox2 is not only expressed in a variety of tumors, but is also required for their formation. Melanoma, the most aggressive skin tumor, derives from melanocytes that during development originate from neural crest stem cells. While neural crest stem cells do not express Sox2, expression of this transcription factor has been reported in melanoma. However, the role of Sox2 in melanoma is controversial. To study the requirement of Sox2 for melanoma formation, we therefore performed CRISPR-Cas9-mediated gene inactivation in human melanoma cells. In addition, we conditionally inactivated Sox2 in a genetically engineered mouse model, in which melanoma spontaneously develops in the context of an intact stroma and immune system. Surprisingly, in both models, loss of Sox2 did neither affect melanoma initiation, nor growth, nor metastasis formation. The lack of a tumorigenic role of Sox2 in melanoma might reflect a distinct stem cell program active in neural crest stem cells and during melanoma formation.


Sub-telomere directed gene expression during initiation of invasive aspergillosis.
Aspergillus fumigatus is a common mould whose spores are a component of the normal airborne flora. Immune dysfunction permits developmental growth of inhaled spores in the human lung causing aspergillosis, a significant threat to human health in the form of allergic, and life-threatening invasive infections. The success of A. fumigatus as a pathogen is unique among close phylogenetic relatives and is poorly characterised at the molecular level. Recent genome sequencing of several Aspergillus species provides an exceptional opportunity to analyse fungal virulence attributes within a genomic and evolutionary context. To identify genes preferentially expressed during adaptation to the mammalian host niche, we generated multiple gene expression profiles from minute samplings of A. fumigatus germlings during initiation of murine infection. They reveal a highly co-ordinated A. fumigatus gene expression programme, governing metabolic and physiological adaptation, which allows the organism to prosper within the mammalian niche. As functions of phylogenetic conservation and genetic locus, 28% and 30%, respectively, of the A. fumigatus subtelomeric and lineage-specific gene repertoires are induced relative to laboratory culture, and physically clustered genes including loci directing pseurotin, gliotoxin and siderophore biosyntheses are a prominent feature. Locationally biased A. fumigatus gene expression is not prompted by in vitro iron limitation, acid, alkaline, anaerobic or oxidative stress. However, subtelomeric gene expression is favoured following ex vivo neutrophil exposure and in comparative analyses of richly and poorly nourished laboratory cultured germlings. We found remarkable concordance between the A. fumigatus host-adaptation transcriptome and those resulting from in vitro iron depletion, alkaline shift, nitrogen starvation and loss of the methyltransferase LaeA. This first transcriptional snapshot of a fungal genome during initiation of mammalian infection provides the global perspective required to direct much-needed diagnostic and therapeutic strategies and reveals genome organisation and subtelomeric diversity as potential driving forces in the evolution of pathogenicity in the genus Aspergillus.


Regulation of NF-kappaB, Th activation, and autoinflammation by the forkhead transcription factor Foxo3a.
Forkhead (Fox) transcription factors play key roles in immunoregulation. Members of the Foxo subfamily have been implicated in the regulation of the cell cycle and/or apoptosis, but their specific immunological contexts remain largely undefined. We demonstrate here that Foxo3a, the predominant Foxo member expressed in peripheral lymphoid organs, plays a critical role in lymphoid homeostasis. Foxo3a deficiency leads to spontaneous lymphoproliferation, associated with inflammation of several organs, in the absence of overt apoptotic defects. These findings correlated with the presence of hyperactivated helper T cells, which proliferated more vigorously and produced more Th1 and Th2 cytokines than their wild-type counterparts. Foxo3a inhibits NF-kappaB activation, whose overactivity was responsible for T cell hyperactivity in Foxo3a-deficient mice. Thus, Foxo3a regulates helper T cell activation and tolerance by inhibiting NF-kappaB activity, reinforcing a generalized role for the forkhead proteins in the maintenance of T cell tolerance through the inhibition of inflammatory transcriptional activities.


HIV infection in older patients in the HAART era.
An increasing number of patients over 50 years of age are now living with HIV, owing to highly active antiretroviral therapy (HAART) that prolongs survival on the one hand and to late diagnosis of patients living with occult HIV infection on the other hand. Most studies have shown that compared with younger patients, patients over 50 generally have a slower immunological response to HAART and experience more rapid clinical progression, despite a better virological response. Low thymic output probably plays a role in the poorer CD4 cell response in patients initiating HAART over 50 years. Management of HIV infection in older patients is particularly complex, mainly because they are more likely to have co-morbidities necessitating specific medications that may interact with antiretroviral drugs. More controlled studies of HAART efficacy and tolerability in such patients are needed to establish specific management guidelines. Information campaigns targeting older patients and their doctors are also needed to ensure timely diagnosis of HIV infection and antiretroviral treatment initiation.


Effects of 6-meals-a-day feeding and 6-meals-a-day feeding combined with adrenalectomy on daily gene expression rhythms in rat epididymal white adipose tissue.
The master clock in the hypothalamic suprachiasmatic nucleus (SCN) is assumed to synchronize the tissue-specific rhythms of the peripheral clocks with the environmental day/night changes via neural, humoral and/or behavioral connections. The feeding rhythm is considered an important Zeitgeber for peripheral clocks, as daytime feeding reverses (clock) gene rhythms in the periphery, but not in the SCN. In this study, we investigated the necessity of a daily feeding rhythm for maintaining gene expression rhythms in epididymal white adipose tissue (eWAT). We showed that 7 of 9 rhythmic metabolic/adipokine genes, but not clock genes, lost their rhythmicity upon exposure to 6-meals-a-day feeding. Previously, we showed comparable effects of adrenalectomy on eWAT; therefore, subsequently we investigated the effect of simultaneous disruption of these humoral and behavioral signaling pathways, by exposing adrenalectomized animals to 6-meals-a-day feeding. Interestingly, under these conditions, all the clock genes and 10 of 11 rhythmic metabolic/adipokine genes lost their rhythmicity. These data indicate that adrenal hormones and feeding rhythm are indispensable for maintaining daily rhythms in metabolic/adipokine gene, but not clock gene, expression in eWAT. In contrast, at least one of these two signals should be present in order for eWAT clock gene rhythms to be maintained.


Early life risk factors for prostate cancer: a population-based case-control study in Sweden.
We undertook a population-based case-control study to investigate early life risk factors for prostate cancer. Information on dietary habits during childhood and adolescence, childhood environment, pubertal development, and physical activity was collected by face-to-face interviews with 256 (74.6%) of all eligible cases and 252 (76.6%) of all selected controls, frequency matched by age. All potential controls were screened for prostate cancer with negative findings. Odds ratios with 95% confidence intervals were estimated by logistic regression. Analyses of localized (T0-2' M0) and more advanced cancers were made separately. In general, there was no clear association between diet and prostate cancer risk. An increased risk associated with childhood living in more densely populated, compared with rural, areas was found (odds ratio = 2.1; 95% confidence interval = 1.3-3.5); this effect was most apparent for localized cancers (odds ratio = 3.2' 95% confidence interval = 1.7-6.2). There was no substantial association between adult height or body mass index and prostate cancer, but exercise appeared negatively associated with risk (P value for trend, 0.13). We conclude that our study provides some indications that exposures early in life are important in the etiology of prostate cancer.


Clinical performance of screw- versus cement-retained fixed implant-supported reconstructions--a systematic review.
To assess the survival outcomes and reported complications of screw- and cement-retained fixed reconstructions supported on dental implants. A Medline (PubMed), Embase, and Cochrane electronic database search from 2000 to September 2012 using MeSH and free-text terms was conducted. Selected inclusion and exclusion criteria guided the search. All studies were first reviewed by abstract and subsequently by full-text reading by two examiners independently. Data were extracted by two examiners and statistically analyzed using a random effects Poisson regression. From 4,324 abstracts, 321 full-text articles were reviewed. Seventy-three articles were found to qualify for inclusion. Five-year survival rates of 96.03% (95% confidence interval [CI]: 93.85% to 97.43%) and 95.55% (95% CI: 92.96% to 97.19%) were calculated for cemented and screw-retained reconstructions, respectively (P = .69). Comparison of cement and screw retention showed no difference when grouped as single crowns (I-SC) (P = .10) or fixed partial dentures (I-FDP) (P = .49). The 5-year survival rate for screw-retained full-arch reconstructions was 96.71% (95% CI: 93.66% to 98.31). All-ceramic reconstruction material exhibited a significantly higher failure rate than porcelain-fused-to-metal (PFM) in cemented reconstructions (P = .01) but not when comparing screw-retained reconstructions (P = .66). Technical and biologic complications demonstrating a statistically significant difference included loss of retention (P ≤ .01), abutment loosening (P ≤ .01), porcelain fracture and/or chipping (P = .02), presence of fistula/suppuration (P ≤ .001), total technical events (P = .03), and total biologic events (P = .02). Although no statistical difference was found between cement- and screw-retained reconstructions for survival or failure rates, screw-retained reconstructions exhibited fewer technical and biologic complications overall. There were no statistically significant differences between the failure rates of the different reconstruction types (I-SCs, I-FDPs, full-arch I-FDPs) or abutment materials (titanium, gold, ceramic). The failure rate of cemented reconstructions was not influenced by the choice of a specific cement, though cement type did influence loss of retention.


microRNA-181a promotes the oncogene S100A2 and enhances papillary thyroid carcinoma growth by mediating the expression of histone demethylase KDM5C.
Papillary thyroid carcinoma (PTC) is an endocrine malignancy. Increasing evidence highlights microRNAs (miRNAs) as important participants in PTC. Here, we investigated the role of miR-181a in PTC. A microarray-based analysis was performed to identify the differential expression of miR-181a in PTC, which was validated with RT-qPCR. Protein expression of the proliferation-related factor Ki-67 and apoptosis- and migration-related factors in PTC was assessed with immunoblot analysis. A dual-luciferase reporter gene assay was adopted to verify the relationship between miR-181a and lysine demethylase 5C (KDM5C). Chromatin immunoprecipitation (ChIP) was used to detect the level of the H3K4me3 modification on S100 calcium-binding protein A2 (S100A2). Cell viability, apoptosis, and invasion and migration abilities were evaluated by Cell Counting Kit-8 (CCK-8), flow cytometry, and transwell assays, respectively. The in vitro results were verified in in vivo nude mouse models. miR-181a was highly expressed in PTC tissues and cell lines. Silencing miR-181a repressed the proliferation and migration of PTC cells. KDM5C was identified as the target gene of miR-181a and represses S100A2 expression through histone demethylation to diminish the migration and proliferation of PTC cells. miR-181a depletion suppressed tumor growth. Collectively, these results suggest that highly expressed miR-181a promotes the proliferation of PTC cells by increasing the expression of the oncogene S100A2. This study contributes to the advancement of miR-181a-targeted therapeutics.


Blood eosinophil levels as a biomarker in COPD.
Chronic obstructive pulmonary disease (COPD) is a heterogeneous disorder and patients respond differently to treatment. Blood eosinophils are a potential biomarker to stratify patient subsets for COPD therapy. We reviewed the value of blood eosinophils in predicting exacerbation risk and response to corticosteroid treatment in the available literature (PubMed articles in English; keywords: "COPD" and "eosinophil"; published prior to May 2017). Overall, clinical data suggest that in patients with a history of COPD exacerbations, a higher blood eosinophil count predicts an increased risk of future exacerbations and is associated with improved response to treatment with inhaled corticosteroids (in combination with long-acting bronchodilator[s]). Blood eosinophils are therefore a promising biomarker for phenotyping patients with COPD, although prospective studies are needed to assess blood eosinophils as a biomarker of corticosteroid response for this.


SERS of semiconducting nanoparticles (TiO(2) hybrid composites).
Raman scattering of molecules adsorbed on the surface of TiO(2) nanoparticles was investigated. We find strong enhancement of Raman scattering in hybrid composites that exhibit charge transfer absorption with TiO(2) nanoparticles. An enhancement factor up to approximately 10(3) was observed in the solutions containing TiO(2) nanoparticles and biomolecules, including the important class of neurotransmitters such as dopamine and dopac (3,4-dihydroxy-phenylacetic acid). Only selected vibrations are enhanced, indicating molecular specificity due to distinct binding and orientation of the biomolecules coupled to the TiO(2) surface. All enhanced modes are associated with the asymmetric vibrations of attached molecules that lower the symmetry of the charge transfer complex. The intensity and the energy of selected vibrations are dependent on the size and shape of nanoparticle support. Moreover, we show that localization of the charge in quantized nanoparticles (2 nm), demonstrated as the blue shift of particle absorption, diminishes SERS enhancement. Importantly, the smallest concentration of adsorbed molecules shows the largest Raman enhancements suggesting the possibility for high sensitivity of this system in the detection of biomolecules that form a charge transfer complex with metal oxide nanoparticles. The wavelength-dependent properties of a hybrid composite suggest a Raman resonant state. Adsorbed molecules that do not show a charge transfer complex show weak enhancements probably due to the dielectric cavity effect.


Neuroimaging with magnetoencephalography: A dynamic view of brain pathophysiology.
Magnetoencephalography (MEG) is a noninvasive, silent, and totally passive neurophysiological imaging method with excellent temporal resolution (∼1 ms) and good spatial precision (∼3-5 mm). In a typical experiment, MEG data are acquired as healthy controls or patients with neurologic or psychiatric disorders perform a specific cognitive task, or receive sensory stimulation. The resulting data are generally analyzed using standard electrophysiological methods, coupled with advanced image reconstruction algorithms. To date, the total number of MEG instruments and associated users is significantly smaller than comparable human neuroimaging techniques, although this is likely to change in the near future with advances in the technology. Despite this small base, MEG research has made a significant impact on several areas of translational neuroscience, largely through its unique capacity to quantify the oscillatory dynamics of activated brain circuits in humans. This review focuses on the clinical areas where MEG imaging has arguably had the greatest impact in regard to the identification of aberrant neural dynamics at the regional and network level, monitoring of disease progression, determining how efficacious pharmacologic and behavioral interventions modulate neural systems, and the development of neural markers of disease. Specifically, this review covers recent advances in understanding the abnormal neural oscillatory dynamics that underlie Parkinson's disease, autism spectrum disorders, human immunodeficiency virus (HIV)-associated neurocognitive disorders, cerebral palsy, attention-deficit hyperactivity disorder, cognitive aging, and post-traumatic stress disorder. MEG imaging has had a major impact on how clinical neuroscientists understand the brain basis of these disorders, and its translational influence is rapidly expanding with new discoveries and applications emerging continuously.


Detecting drug effects on short-term memory function using a combined delayed matching and non-matching to position task.
Operant delayed non-matching-to-position (DNMTP) and delayed matching-to-position (DMTP) have become standard techniques to investigate drug effects on short-term memory function in rats. However, these two tasks are normally conducted in isolation. Using two standard drugs, the 5HT1A agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), and the muscarinic antagonist scopolamine, this study looked at a two-choice operant task that essentially involved a mixed DNMTP/DMTP paradigm. Thus, DNMTP trials were interspersed with DMTP trials in a random sequence for the duration of a session. 8-OH-DPAT (0.03 mg/kg) slightly but significantly improved response accuracy in a delay-dependent fashion during DMTP but not DNMTP trials. The highest dose of 8-OH-DPAT (0.1 mg/kg) impaired accuracy during DNMTP trials independent of delay and had no significant effect during DMTP trials. Scopolamine (0.1 mg/kg) produced delay-dependent deficits in accuracy during DMTP trials but delay-independent impairments during DNMTP trials. Because both 8-OH-DPAT and scopolamine produced delay-dependent effects with DMTP trials types and either had no effect (8-OH-DPAT) or produced delay-independent impairments (scopolamine) during DNMTP trials types, it is suggested that DMTP trials had a greater dependence on short-term working memory function than DNMTP trials that probably relied more on positional (mediating) strategies for solving the task. Therefore, we believe that this mixed DNMTP/DMTP task offers greater potential for more reliable and discerning interpretation of data regarding short-term memory function in rodents than either of the paradigms performed in isolation.


What is new for an old molecule? Systematic review and recommendations on the use of resveratrol.
Resveratrol is a natural compound suggested to have beneficial health effects. However, people are consuming resveratrol for this reason without having the adequate scientific evidence for its effects in humans. Therefore, scientific valid recommendations concerning the human intake of resveratrol based on available published scientific data are necessary. Such recommendations were formulated after the Resveratrol 2010 conference, held in September 2010 in Helsingør, Denmark. Literature search in databases as PUBMED and ISI Web of Science in combination with manual search was used to answer the following five questions: (1)Can resveratrol be recommended in the prevention or treatment of human diseases?; (2)Are there observed "side effects" caused by the intake of resveratrol in humans?; (3)What is the relevant dose of resveratrol?; (4)What valid data are available regarding an effect in various species of experimental animals?; (5)Which relevant (overall) mechanisms of action of resveratrol have been documented? The overall conclusion is that the published evidence is not sufficiently strong to justify a recommendation for the administration of resveratrol to humans, beyond the dose which can be obtained from dietary sources. On the other hand, animal data are promising in prevention of various cancer types, coronary heart diseases and diabetes which strongly indicate the need for human clinical trials. Finally, we suggest directions for future research in resveratrol regarding its mechanism of action and its safety and toxicology in human subjects.


Early warning and prevention of pneumonia in acute leukemia by patient education, spirometry, and positive expiratory pressure: A randomized controlled trial.
Long-lasting neutropenia associated with acute myeloid leukemia (AML) and its treatment gives rise to a high risk of pneumonia. The use of broad-spectrum antibiotic prophylaxis during outpatient management has not completely protected patients against admission due to infections and neutropenic fever, emphasizing the need to approach infection protection with complementary efforts. In a randomized controlled design, we examined the applicability of patient-performed daily spirometry [forced expiratory volume in one second (FEV1)] as an early warning tool and explored the effectiveness of positive expiratory pressure (PEP) in preventing pneumonia among 80 AML patients. Twenty-five incidences of pneumonia were detected among 23 patients (6 interventions, 17 controls), giving a prevalence of 28.75% during 5420 days of observation. We found a significant difference in incidence between intervention versus control group (2.17 per 1000 days vs. 6.52 per 1000 days, P = 0.021, respectively). A cross point at 80-76% of the personal FEV1 reference value showed high sensitivity and specificity on pneumonia development. Our data demonstrate the feasibility of educating AML patients in their continuous daily measurement of FEV1 and use of PEP. Daily measures of FEV1 may be an important early warning tool for assessment of pulmonary deterioration during critical phases of neutropenia. We suggest that strategic patient education in the use of spirometry and PEP should be part of standard of care for AML patients undergoing induction chemotherapy.


A new role for sphingosine: Up-regulation of Fam20C, the genuine casein kinase that phosphorylates secreted proteins.
Fam20C is an atypical kinase implicated in bio-mineralization and phosphate homeostasis disorders, and has recently been shown to account for the activity of an orphan enzyme ("genuine casein kinase", G-CK) previously characterized for its ability to phosphorylate casein and a plethora of secreted proteins at serine residues specified by the S-x-E/pS motif. Fam20C/G-CK activity is only appreciable in the presence of high Mn2+ concentration (>1 mM), and is negligible if Mn2+ is replaced by physiological Mg2+ concentrations. Here we show that sphingosine (but not its biological precursor ceramide) not only stimulates several-fold Fam20C activity in the presence of Mn2+, but also confers a comparable activity to Fam20C assayed with Mg2+. Activation by sphingosine is evident using a variety of substrates, and is accounted for by both higher Vmax and decreased KmATP, as judged from kinetics run with the β(28-40) substrate peptide and a physiological substrate, BMP-15. Sphingosine also protects Fam20C from thermal inactivation. Consistent with the in vitro results, by treating Fam20C expressing HEK293T cells with myriocin, a potent inhibitor of the sphingosine biosynthetic pathway, the activity of Fam20C released into the conditioned medium is substantially decreased corroborating the concept that sphingosine (or related metabolite(s)) is a co-factor required by Fam20C to optimally display its biological functions. None of the small molecule kinase inhibitors tested so far were able to inhibit Fam20C. Interestingly however fingolimod, an immunosuppressive drug structurally related to sphingosine, used for the treatment of multiple sclerosis, is a powerful activator of Fam20C, both wild type and its pathogenic, loss of function, T268M mutant. This article is part of a Special Issue entitled: Inhibitors of Protein Kinases.


Geraniol ameliorates TNBS-induced colitis: Involvement of Wnt/β-catenin, p38MAPK, NFκB, and PPARγ signaling pathways.
Geraniol, a natural component of plant essential oils, exhibits potent chemopreventive effects in the colon; however, its possible role/mechanisms in experimental colitis have not been elucidated, which is the aim of this study. To fulfill this goal, rats were treated for 11days with geraniol and/or sulfasalazine using a TNBS-induced colitis model. Geraniol significantly hindered the colitis-clinical signs (weight loss, colon edema,ulcerative area, colon/spleen mass indices) and opposed the altered oxidative/nitrosative stress. It restored the depleted total antioxidant capacity and lessened the elevated levels of nitric oxide and lipid peroxide. TNBS induced apoptosis and inflammatory cell infiltration, whereas geraniol curtailed these effects by diminishing the levels of caspase-3, intercellular adhesion molecule-1, and myeloperoxidase. The anti-inflammatory effect was documented by inhibiting the colon contents of prostaglandin E2 and interleukin-1β. In order to delve into the anti-colitic signaling pathways, geraniol inhibited the content/expression of glycogen synthase kinase (GSK)-3β, β-catenin, p38 mitogen activated protein kinase (p38MAPK), and nuclear factor kappa B (NFκB), but upregulated that of peroxisome proliferator activated receptor γ (PPARγ). These effects were comparable to those of sulfasalazine, the standard drug, whereas its combination with geraniol mediated effects that surpassed either treatment alone. Geraniol in the current study improved experimental colitis partly via its antioxidant, anti-inflammatory, and immunosuppressive potentials, possibly by modulating the Wnt/GSK-3β/β-catenin, p38MAPK, NFκB, and PPARγ signaling pathways. The study also revealed that geraniol represents a valuable asset against colitis alone or in combination with the conventional anti-colitic therapies.


A randomized controlled study of a web-based performance improvement system for substance abuse treatment providers.
We report here the results of a randomized, controlled trial evaluating the efficacy of a semiautomated performance improvement system ("patient feedback") that enables real-time monitoring of patient outcomes in outpatient substance abuse treatment clinics. The study involved 118 clinicians working at 20 community-based outpatient substance abuse treatment clinics in the northeast United States. Ten clinics received 12 weeks of the patient feedback performance improvement intervention, and 10 clinics received no intervention during the 12 weeks. More than 1,500 patients provided anonymous ratings of therapeutic alliance, treatment satisfaction, and drug/alcohol use. There was no evidence of an intervention effect on the primary drug and alcohol use scales. There was also no evidence of an intervention effect on secondary measures of therapeutic alliance. Clinician-rated measures of organizational functioning and job satisfaction also showed no intervention effect. Possible insights from these findings and alternative methods of utilizing feedback reports to enhance clinical outcomes are proposed.


The Neurobiology and Psychology of Pedophilia: Recent Advances and Challenges.
A pedophilic disorder is recognized for its impairment to the individual and for the harm it may cause to others. Pedophilia is often considered a side issue and research into the nature of pedophilia is delayed in comparison to research into other psychiatric disorders. However, with the increasing use of neuroimaging techniques, such as functional and structural magnetic resonance imaging (sMRI, fMRI), together with neuropsychological studies, we are increasing our knowledge of predisposing and accompanying factors contributing to pedophilia development. At the same time, we are faced with methodological challenges, such as group differences between studies, including age, intelligence, and comorbidities, together with a lack of careful assessment and control of child sexual abuse. Having this in mind, this review highlights the most important studies investigating pedophilia, with a strong emphasis on (neuro-) biological studies, combined with a brief explanation of research into normal human sexuality. We focus on some of the recent theories on the etiology of pedophilia such as the concept of a general neurodevelopmental disorder and/or alterations of structure and function in frontal, temporal, and limbic brain areas. With this approach, we aim to not only provide an update and overview but also a framework for future research and to address one of the most significant questions of how pedophilia may be explained by neurobiological and developmental alterations.


Validity and reliability of a linear positional transducer across commonly practised resistance training exercises.
This study investigated the validity and reliability of the GymAware PowerTool (GPT). Thirteen resistance trained participants completed three visits, consisting of three repetitions of free-weight back squat, bench press, deadlift (80% one repetition maximum), and countermovement jump. Bar displacement, peak and mean velocity, peak and mean force, and jump height were calculated using the GPT, a three-dimensional motion capture system (Motion Analysis Corporation; 150 Hz), and a force plate (Kistler; 1500 Hz). Least products regression were used to compare agreeability between devices. A within-trial one-way ANOVA, typical error (TE; %), and smallest worthwhile change (SWC) were used to assess reliability. Regression analysis resulted in R2 values of >0.85 for all variables excluding deadlift mean velocity (R2 = 0.54-0.69). Significant differences were observed between visits 3-2 for bench press bar displacement (0.395 ± 0.055 m; 0.383 ± 0.053 m), and deadlift bar displacement (0.557 ± 0.034 m; 0.568 ± 0.034 m). No other significant differences were found. Low to moderate TE (0.6-8.8%) were found for all variables, with SWC ranging 1.7-7.4%. The data provides evidence that the GPT can be used to measure kinetic and kinematic outputs, however, care should be taken when monitoring deadlift performance.


Antitumor activity of indomethacin in mice bearing advanced colon 26 carcinoma compared with those with early transplants.
The antitumor activity of indomethacin (IND) was investigated in mice bearing advanced colon 26 adenocarcinoma compared with its early transplants. Treatment with 0.001% IND in drinking water retarded the growth of tumor when commenced at Day 1 after the tumor inoculation. The suppression of the tumor growth by IND continued up to 4 to 5 weeks as long as the size of the tumor remained small. On the other hand, IND given to mice bearing a large burden of the tumor at 2 weeks after the inoculation had facilitated the tumor growth. IND reduced tumor-associated PGE2 production in mice bearing either small or large burdens of the tumors. These results indicate that the antitumor activity of IND depends on tumor size and therefore is not simply associated with the reduction of PGE2 levels. We found that colon 26 caused changes in parameters reported for tumor cachexia, such as weight loss, wasting of muscle and adipose tissues and hypoglycemia, when it grew to around 1 g at 2-3 weeks after the tumor inoculation. IND given to the mice with large burdens of colon 26 alleviated the cachexia of the mice, resulting in the increase of the survival time even though the growth of the tumor had been facilitated. It is possible that IND affects the tumor growth and survival by reversing tumor-induced disorders in homeostasis.


Use of nucleotide composition analysis to infer hosts for three novel picorna-like viruses.
Nearly complete genome sequences of three novel RNA viruses were acquired from the stool of an Afghan child. Phylogenetic analysis indicated that these viruses belong to the picorna-like virus superfamily. Because of their unique genomic organization and deep phylogenetic roots, we propose these viruses, provisionally named calhevirus, tetnovirus-1, and tetnovirus-2, as prototypes of new viral families. A newly developed nucleotide composition analysis (NCA) method was used to compare mononucleotide and dinucleotide frequencies for RNA viruses infecting mammals, plants, or insects. Using a large training data set of 284 representative picornavirus-like genomic sequences with defined host origins, NCA correctly identified the kingdom or phylum of the viral host for >95% of picorna-like viruses. NCA predicted an insect host origin for the 3 novel picorna-like viruses. Their presence in human stool therefore likely reflects ingestion of insect-contaminated food. As metagenomic analyses of different environments and organisms continue to yield highly divergent viral genomes NCA provides a rapid and robust method to identify their likely cellular hosts.


Influence of food companies' brand mascots and entertainment companies' cartoon media characters on children's diet and health: a systematic review and research needs.
Reducing the extent and persuasive power of marketing unhealthy foods to children worldwide are important obesity prevention goals. Research is limited to understand how brand mascots and cartoon media characters influence children's diet. We conducted a systematic review of five electronic databases (2000-2014) to identify experimental studies that measured how food companies' mascots and entertainment companies' media characters influence up to 12 diet-related cognitive, behavioural and health outcomes for children under 12 years. Eleven studies met the inclusion criteria. Studies used 21 unique popular media characters, but no brand mascots. Results suggest that cartoon media character branding can positively increase children's fruit or vegetable intake compared with no character branding. However, familiar media character branding is a more powerful influence on children's food preferences, choices and intake, especially for energy-dense and nutrient-poor foods (e.g. cookies, candy or chocolate) compared with fruits or vegetables. Future research should use a theoretically grounded conceptual model and larger and more diverse samples across settings to produce stronger findings for mediating and moderating factors. Future research can be used to inform the deliberations of policymakers, practitioners and advocates regarding how media character marketing should be used to support healthy food environments for children.


Exposure to Chlamydia pneumoniae infection and age-related macular degeneration: the Blue Mountains Eye Study.
To assess cross-sectional and longitudinal associations between exposure to Chlamydia pneumoniae infection and age-related macular degeneration (AMD) in the nested case-control sample drawn from the Blue Mountains Eye Study (BMES) cohort. The BMES examined 3654 persons aged 49 to 97 years during 1992 through 1994 (BMES I survey). Survivors from this cohort (n = 2335; 75%) and 1174 persons who moved in this area or reached an eligible age were examined during 1997 through 2000 (BMES II survey, n = 3509). One hundred ninety-seven AMD cases and 433 control subjects matched for age, sex and smoking status, were drawn from the BMES II survey. Photographic macular grading followed the Wisconsin grading system. Plasma samples were analyzed with an enzyme-linked immunosorbent assay to determine antibody titers to the elementary bodies from C. pneumoniae AR39. Associations between seroreactivity to C. pneumoniae and prevalent and incident AMD were assessed by using logistic regression models. There were 159 early and 38 late AMD cases. Of them, 87 cases of early and 22 of late AMD developed between the baseline and follow-up examinations. After adjustment for age, gender, and smoking, no significant association was evident between C. pneumoniae antibody titer and any prevalent early or late AMD (OR 1.02, 95% CI 0.66-1.56 comparing upper with lower tertile of antibody titer). Findings were similar when early or late AMD was analyzed separately. Analysis confined to incident AMD also showed no significant association with the incidence of either early (OR 0.92, 95% CI 0.52-1.64) or late (OR 1.85, 95% CI 0.57-6.05) AMD. The results did not change after adjustment for family history of AMD and cardiovascular disease. In this nested case-control sample of an older Australian population we found no association between C. pneumoniae antibody titers and early AMD. The study has insufficient power to assess an association with late AMD.


EMMPRIN is associated with S100A4 and predicts patient outcome in colorectal cancer.
Proteolytic enzymes and their regulators have important biological roles in colorectal cancer by stimulating invasion and metastasis, which makes these factors attractive as potential prognostic biomarkers. The expression of extracellular matrix metalloproteinase inducer (EMMPRIN) was characterised using immunohistochemistry in primary tumours from a cohort of 277 prospectively recruited colorectal cancer patients, and associations with expression of S100A4, clinicopathological parameters and patient outcome were investigated. One hundred and ninety-eight samples (72%) displayed positive membrane staining of the tumour cells, whereas 10 cases (4%) were borderline positive. EMMPRIN expression was associated with shorter metastasis-free, disease-specific and overall survival in both univariate and multivariate analyses. The prognostic impact was largely confined to TNM stage III, and EMMPRIN-negative stage III patients had an excellent prognosis. Furthermore, EMMPRIN was significantly associated with expression of S100A4, and the combined expression of these biomarkers conferred an even poorer prognosis. However, there was no evidence of direct regulation between the two proteins in the colorectal cancer cell lines HCT116 and SW620 in siRNA knockdown experiments. EMMPRIN is a promising prognostic biomarker in colorectal cancer, and our findings suggest that it could be used in the selection of stage III patients for adjuvant therapy.


Autologous endothelial progenitor cell-seeding technology and biocompatibility testing for cardiovascular devices in large animal model.
Implantable cardiovascular devices are manufactured from artificial materials (e.g. titanium (Ti), expanded polytetrafluoroethylene), which pose the risk of thromboemboli formation. We have developed a method to line the inside surface of Ti tubes with autologous blood-derived human or porcine endothelial progenitor cells (EPCs). By implanting Ti tubes containing a confluent layer of porcine EPCs in the inferior vena cava (IVC) of pigs, we tested the improved biocompatibility of the cell-seeded surface in the prothrombotic environment of a large animal model and compared it to unmodified bare metal surfaces (Figure 1). This method can be used to endothelialize devices within minutes of implantation and test their antithrombotic function in vivo. Peripheral blood was obtained from 50 kg Yorkshire swine and its mononuclear cell fraction cultured to isolate EPCs. Ti tubes (9.4 mm ID) were pre-cut into three 4.5 cm longitudinal sections and reassembled with heat-shrink tubing. A seeding device was built, which allows for slow rotation of the Ti tubes. We performed a laparotomy on the pigs and externalized the intestine and urinary bladder. Sharp and blunt dissection was used to skeletonize the IVC from its bifurcation distal to the right renal artery proximal. The Ti tubes were then filled with fluorescently-labeled autologous EPC suspension and rotated at 10 RPH x 30 min to achieve uniform cell-coating. After administration of 100 USP/kg heparin, both ends of the IVC and a lumbar vein were clamped. A 4 cm veinotomy was performed and the device inserted and filled with phosphate-buffered saline. As the veinotomy was closed with a 4-0 Prolene running suture, one clamp was removed to de-air the IVC. At the end of the procedure, the fascia was approximated with 0-PDS (polydioxanone suture), the subcutaneous space closed with 2-0 Vicryl and the skin stapled closed. After 3 - 21 days, pigs were euthanized, the device explanted en-block and fixed. The Ti tubes were disassembled and the inner surfaces imaged with a fluorescent microscope. We found that the bare metal Ti tubes fully occluded whereas the EPC-seeded tubes remained patent. Further, we were able to demonstrate a confluent layer of EPCs on the inside blood-contacting surface. Concluding, our technology can be used to endothelialize Ti tubes within minutes of implantation with autologous EPCs to prevent thrombosis of the device. Our surgical method allows for testing the improved biocompatibility of such modified devices with minimal blood loss and EPC-seeded surface disruption.


The cost of uncomplicated childhood fevers to Kenyan households: implications for reaching international access targets.
Fever is the clinical hallmark of malaria disease. The Roll Back Malaria (RBM) movement promotes prompt, effective treatment of childhood fevers as a key component to achieving its optimistic mortality reduction goals by 2010. A neglected concern is how communities will access these new medicines promptly and the costs to poor households when they are located in rural areas distant to health services. We assemble data developed between 2001 and 2002 in Kenya to describe treatment choices made by rural households to treat a child's fever and the related costs to households. Using a cost-of-illness approach, we estimate the expected cost of a childhood fever to Kenyan households in 2002. We develop two scenarios to explore how expected costs to households would change if more children were treated at a health care facility with an effective antimalarial within 48 hours of fever onset. 30% of uncomplicated fevers were managed at home with modern medicines, 38% were taken to a health care facility (HCF), and 32% were managed at home without the use of modern medicines. Direct household cash expenditures were estimated at $0.44 per fever, while the total expected cost to households (cash and time) of an uncomplicated childhood fever is estimated to be $1.91. An estimated mean of 1.42 days of caretaker time devoted to each fever accounts for the majority of household costs of managing fevers. The aggregate cost to Kenyan households of managing uncomplicated childhood fevers was at least $96 million in 2002, equivalent to 1.00% of the Kenyan GDP. Fewer than 8% of all fevers were treated with an antimalarial drug within 24 hours of fever onset, while 17.5% were treated within 48 hours at a HCF. To achieve an increase from 17.5% to 33% of fevers treated with an antimalarial drug within 48 hours at a HCF (Scenario 1), children already being taken to a HCF would need to be taken earlier. Under this scenario, direct cash expenditures would not change, and total household costs would fall slightly to $1.86 because caretakers also save time with prompt treatment if the child has malaria. The management of uncomplicated childhood fevers imposes substantial costs on Kenyan households. Achieving substantial improvements in the numbers of fevers treated within 48 hours at a HCF with an effective antimalarial drug (Scenario 1) will not impose additional costs on households. Achieving additional improvements in fevers treated promptly at a HCF (Scenario 2) will impose additional costs on some households roughly equal to average cash expenses for transportation to a HCF. Additional financing mechanisms that further reduce the costs of accessing care at a HCF and/or that make artemisinin-based combination therapies (ACTs) accessible for home management need to be developed and evaluated as a top priority.


A practical method of measuring the human temporal contrast sensitivity function.
One of the more significant indicators of neural age-related loss and disease is reduced temporal processing speed. It would, therefore, be useful to have an accurate and practical device that measures the full range of an individual's temporal processing abilities (characterized as the temporal contrast sensitivity function, TCSF). 70 subjects (15-84 yrs) were tested. A small tabletop device utilizing electronic control of light-emitting diodes (LEDs) was constructed that delivered a 1-degree, 660 nm test (the modulation depth of which could be adjusted directly by the subject) centered within a 10-degree 660 nm surround. The method provided a TCSF that had a shape consistent with past studies (peaking around 8 Hz). Also consistent with past work, the largest age-decline was found at the highest frequencies and for the central fovea (r = 0.47, p<0.0001, ~2 Hz per decade). Psychophysical assessment of temporal vision offers an easy and dynamic measure of central visual function.


Rehabilitation following spinal cord injury: how animal models can help our understanding of exercise-induced neuroplasticity.
Spinal cord injury is a devastating condition that is followed by long and often unsuccessful recovery after trauma. The state of the art approach to manage paralysis and concomitant impairments is rehabilitation, which is the only strategy that has proven to be effective and beneficial for the patients over the last decades. How rehabilitation influences the remodeling of spinal axonal connections in patients is important to understand, in order to better target these changes and define the optimal timing and onset of training. While clinically the answers to these questions remain difficult to obtain, rodent models of rehabilitation like bicycling, treadmill training, swimming, enriched environments or wheel running that mimic clinical rehabilitation can be helpful to reveal the axonal changes underlying motor recovery. This review will focus on the different animal models of spinal cord injury rehabilitation and the underlying changes in neuronal networks that are improved by exercise and rehabilitation.


Short stature and growth hormone therapy. A national study of physician recommendation patterns.
To determine current expert opinion and recommendations regarding the controversial issue of the use of growth hormone (GH) to treat short children who do not have classical GH deficiency (non-GHD children). Analysis of a national survey mailed to 534 US physician experts on the management of short stature (pediatric endocrinologists) with a response rate of 81.3%. The experts' GH treatment recommendations. The physicians reported that approximately 58% of their current patients undergoing GH therapy have classical GH deficiency, while 42% have other conditions. The proportion of physicians who recommended GH treatment of short non-GHD children ranged from 1% to 74% over all case scenarios presented. The likelihood of GH being recommended depended on the physiological growth characteristics of the child (ie, the child's height, growth rate, and predicted adult height), contingency factors (ie, strong family wishes or a reduction in GH cost), and physician beliefs (ie, the impact of short stature on well-being, the effectiveness of GH therapy). Each of these factors exerted highly significant, independent, and additive effects on decisions to recommend GH. Our results indicate that many pediatric endocrinologists consider GH treatment appropriate for selected short non-GHD children, going beyond current Food and Drug Administration-approved indications for GH. Decisions to recommend GH for a non-GHD child rest on a combination of medical, social, and perceptual factors; variations in treatment patterns stem from variations in these influences. Future GH use will likely be determined not only by the results of controlled trials, but also by family preferences, producer pricing, and physician perceptions of the value of height and GH therapy.


Eos negatively regulates human γ-globin gene transcription during erythroid differentiation.
Human globin gene expression is precisely regulated by a complicated network of transcription factors and chromatin modifying activities during development and erythropoiesis. Eos (Ikaros family zinc finger 4, IKZF4), a member of the zinc finger transcription factor Ikaros family, plays a pivotal role as a repressor of gene expression. The aim of this study was to examine the role of Eos in globin gene regulation. Western blot and quantitative real-time PCR detected a gradual decrease in Eos expression during erythroid differentiation of hemin-induced K562 cells and Epo-induced CD34+ hematopoietic stem/progenitor cells (HPCs). DNA transfection and lentivirus-mediated gene transfer demonstrated that the enforced expression of Eos significantly represses the expression of γ-globin, but not other globin genes, in K562 cells and CD34+ HPCs. Consistent with a direct role of Eos in globin gene regulation, chromatin immunoprecipitaion and dual-luciferase reporter assays identified three discrete sites located in the DNase I hypersensitivity site 3 (HS3) of the β-globin locus control region (LCR), the promoter regions of the Gγ- and Aγ- globin genes, as functional binding sites of Eos protein. A chromosome conformation capture (3C) assay indicated that Eos may repress the interaction between the LCR and the γ-globin gene promoter. In addition, erythroid differentiation was inhibited by enforced expression of Eos in K562 cells and CD34+ HPCs. Our results demonstrate that Eos plays an important role in the transcriptional regulation of the γ-globin gene during erythroid differentiation.


Altered neural processing of threat in alcohol-dependent men.
Stress-response biological systems are altered in alcohol-dependent individuals and are reported to predict future relapse. This study was designed to assess neural disruptions in alcohol-dependent participants when exposed to a conditioned stimulus (CS) warning of the impending onset of a universal, nonpersonalized stressor. Fifteen alcohol-dependent men abstinent for 3 to 5 weeks and 15 age- and race-similar healthy controls were studied. Anticipatory anxiety was induced by a CS paired with an uncertain, physically painful unconditioned stressor. Neural response was assessed using functional magnetic resonance imaging. Both groups experienced significant, similar levels of anticipatory anxiety in response to the high-threat relative to the low-threat CS. Whereas control participants markedly increased the blood oxygen level-dependent (BOLD) amplitude in cortical-limbic-striatal regions during the high-threat, relative to low-threat, stimulus, alcohol-dependent participants decreased BOLD amplitude in the pregenual anterior cingulate cortex (pgACC), medial prefrontal cortex (mPFC), medial orbitofrontal cortex, posterior cingulate cortex (PCC), bilateral parietal/occipital cortex, and right hippocampus. Alcohol-dependent participants significantly deactivated pgACC/mPFC and PCC clusters, relative to controls, during the high- versus low-threat stimulus. This difference was due to a decrease in %BOLD amplitude during the high-threat stimulus in the alcohol-dependent, but not the control, participants. Alcohol-dependent men show cortical-limbic-striatal deactivation during anticipatory anxiety, particularly in regions associated with emotional regulation. These findings suggest a lack of engagement of affective regulatory mechanisms during high-stress situations in alcohol-dependent men.


Bis-Monophospholyl Dysprosium Cation Showing Magnetic Hysteresis at 48 K.
Single-molecule magnets (SMMs) have potential applications in high-density data storage, but magnetic relaxation times at elevated temperatures must be increased to make them practically useful. Bis-cyclopentadienyl lanthanide sandwich complexes have emerged as the leading candidates for SMMs that show magnetic memory at liquid nitrogen temperatures, but the relaxation mechanisms mediated by aromatic C5 rings have not been fully established. Here we synthesize a bis-monophospholyl dysprosium SMM [Dy(Dtp)2][Al{OC(CF3)3}4] (1, Dtp = {P(CtBuCMe)2}) by the treatment of in-situ-prepared "[Dy(Dtp)2(C3H5)]" with [HNEt3][Al{OC(CF3)3}4]. SQUID magnetometry reveals that 1 has an effective barrier to magnetization reversal of 1760 K (1223 cm-1) and magnetic hysteresis up to 48 K. Ab initio calculation of the spin dynamics reveals that transitions out of the ground state are slower in 1 than in the first reported dysprosocenium SMM, [Dy(Cpttt)2][B(C6F5)4] (Cpttt = C5H2tBu3-1,2,4); however, relaxation is faster in 1 overall due to the compression of electronic energies and to vibrational modes being brought on-resonance by the chemical and structural changes introduced by the bis-Dtp framework. With the preparation and analysis of 1, we are thus able to further refine our understanding of relaxation processes operating in bis-C5/C4P sandwich lanthanide SMMs, which is the necessary first step toward rationally achieving higher magnetic blocking temperatures in these systems in the future.


A Needs-led Framework for Understanding the Impact of Caring for a Family Member With Dementia.
Approximately half the care for people with dementia is provided by families. It is therefore imperative that research informs ways of maintaining such care. In this study, we propose that a needs-led approach can provide a useful, novel means of conceptualizing the impact of caring on the lives of family carers. Our aim was to develop and present a needs-led framework for understanding how providing care impacts on carers' fulfilment of needs. In this qualitative study, we conducted 42 semistructured interviews with a purposively diverse sample of family carers to generate nuanced contextualized accounts of how caring impacted on carers' lives. Our inductive thematic analysis focused upon asking: "What need is being impacted here?" in order to generate a needs-led framework for understanding. Nine themes were widely endorsed. Each completed the sentence: "Being a carer impacts on fulfilling my need to/for….": Freedom; feel close to my relative; feel in control of my life; be my own person; protect my relative; share/express my thoughts and feelings; take care of myself; feel connected to the people around me; get things done. These needs echo those from other research areas, with relational needs emerging as particularly central. The needs-led approach offers a perspective that is able to capture both stresses and positive aspects of caregiving. We recommend that clinical interviewing using Socratic questioning to discover human needs that are being impacted by caring would provide a valuable starting point for care planning.


Aortic arch malformations.
Although anomalies of the aortic arch and its branches are relatively uncommon malformations, they are often associated with congenital heart disease. Isolated lesions may be clinically significant when the airways are compromised by a vascular ring. In this article, the development and imaging appearance of the aortic arch system and its various malformations are reviewed.


Volcanic aerosols and lunar eclipses.
The moon is visible during total lunar eclipses due to sunlight refracted into the earth's shadow by the atmosphere. Stratospheric aerosols can profoundly affect the brightness of the eclipsed moon. Observed brightnesses of 21 lunar eclipses during 1960-1982 are compared with theoretical calculations based on refraction by an aerosol-free atmosphere to yield globally averaged aerosol optical depths. Results indicate the global aerosol loading from the 1982 eruption of El Chichón is similar in magnitude to that from the 1963 Agung eruption.


Transcriptome analyses of the honeybee response to Nosema ceranae and insecticides.
Honeybees (Apis mellifera) are constantly exposed to a wide variety of environmental stressors such as parasites and pesticides. Among them, Nosema ceranae and neurotoxic insecticides might act in combination and lead to a higher honeybee mortality. We investigated the molecular response of honeybees exposed to N. ceranae, to insecticides (fipronil or imidacloprid), and to a combination of both stressors. Midgut transcriptional changes induced by these stressors were measured in two independent experiments combining a global RNA-Seq transcriptomic approach with the screening of the expression of selected genes by quantitative RT-PCR. Although N. ceranae-insecticide combinations induced a significant increase in honeybee mortality, we observed that they did not lead to a synergistic effect. According to gene expression profiles, chronic exposure to insecticides had no significant impact on detoxifying genes but repressed the expression of immunity-related genes. Honeybees treated with N. ceranae, alone or in combination with an insecticide, showed a strong alteration of midgut immunity together with modifications affecting cuticle coatings and trehalose metabolism. An increasing impact of treatments on gene expression profiles with time was identified suggesting an absence of stress recovery which could be linked to the higher mortality rates observed.


Freshening of the Ross Sea during the late 20th century.
Ocean measurements in the Ross Sea over the past four decades, one of the longest records near Antarctica, reveal marked decreases in shelf water salinity and the surface salinity within the Ross Gyre. These changes have been accompanied by atmospheric warming on Ross Island, ocean warming at depths of approximately 300 meters north of the continental shelf, a more negative Southern Oscillation Index, and thinning of southeast Pacific ice shelves. The freshening appears to have resulted from a combination of factors, including increased precipitation, reduced sea ice production, and increased melting of the West Antarctic Ice Sheet.


Choice of Model for Estimation of Adsorption Isotherm Parameters in Gradient Elution Preparative Liquid Chromatography.
The inverse method is a numerical method for fast estimation of adsorption isotherm parameters directly from a few overloaded elution profiles and it was recently extended to adsorption isotherm acquisition in gradient elution conditions. However, the inverse method in gradient elution is cumbersome due to the complex adsorption isotherm models found in gradient elution. In this case, physicochemically correct adsorption models have very long calculation times. The aim of this study is to investigate the possibility of using a less complex adsorption isotherm model, with fewer adjustable parameters, but with preserved/acceptable predictive abilities. We found that equal or better agreement between experimental and predicted elution profiles could be achieved with less complex models. By being able to select a model with fewer adjustable parameters, the calculation times can be reduced by at least a factor of 10.


Determination of optical constants of thin film from reflectance spectra.
We present a method of determining optical constants n and k of a thin film using only the reflectance R(omega) curve (normal incidence reflectance spectroscopy). The method is based on the simultaneous use of Fresnel laws and dispersion relations between n and k of the film, via an iterative process. To illustrate the method, optical constants in the VUV of a film grown on InP were determined. A second example with a SnO(2) film shows how the method can reduce the effect of experimental errors when two sets of spectroscopic data are available.


Isolation of the native form of chicken gizzard myosin light-chain kinase.
A simple and rapid procedure for the purification of the native form of chicken gizzard myosin light-chain kinase (Mr 136000) is described which eliminates problems of proteolysis previously encountered. During this procedure, a calmodulin-binding protein of Mr 141000, which previously co-purified with the myosin light-chain kinase, is removed and shown to be a distinct protein on the basis of lack of kinase activity, different chymotryptic peptide maps, lack of cross-reactivity with a monoclonal antibody to turkey gizzard myosin light-chain kinase, and lack of phosphorylation by the purified catalytic subunit of cyclic AMP-dependent protein kinase. This Mr-141000 calmodulin-binding protein is identified as caldesmon on the basis of Ca2+-dependent interaction with calmodulin, subunit Mr, Ca2+-independent interaction with skeletal-muscle F-actin, Ca2+-dependent competition between calmodulin and F-actin for caldesmon, and tissue content.


Primary prevention of CVD: physical activity.
Increasing physical activity has been associated with reduced risk of mortality and of cardiovascular disease (CVD). The proportion of people doing no physical activity in a week varies between countries, but can reach nearly 25% in Europe and the Americas. We conducted a systematic review and aimed to answer the following clinical questions: Does counselling people to increase physical activity lead to increased physical activity in healthy people without existing CVD? What are the health benefits of increasing physical activity in relation to cardiovascular outcomes in healthy people without existing CVD? We searched: Medline, Embase, The Cochrane Library, and other important databases up to September 2008 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). We found 21 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. In this systematic review, we present information relating to the effectiveness and safety of the following interventions: counselling people to increase physical activity, and to perform higher-intensity exercise programmes.


Oscillator-interference models of path integration do not require theta oscillations.
Navigation and path integration in rodents seems to involve place cells, grid cells, and theta oscillations (4-12 Hz) in the local field potential. Two main theories have been proposed to explain the neurological underpinnings of how these phenomena relate to navigation and to each other. Attractor network (AN) models revolve around the idea that local excitation and long-range inhibition connectivity can spontaneously generate grid-cell-like activity patterns. Oscillator interference (OI) models propose that spatial patterns of activity are caused by the interference patterns between neural oscillators. In rats, these oscillators have a frequency close to the theta frequency. Recent studies have shown that bats do not exhibit a theta cycle when they crawl, and yet they still have grid cells. This has been interpreted as a criticism of OI models. However, OI models do not require theta oscillations. We explain why the absence of theta oscillations does not contradict OI models and discuss how the two families of models might be distinguished experimentally.


Studies of salivary flow in borderline hypertension: effects of drugs acting on structures innervated by the autonomic nervous system.
Salivary flow and the influence of drugs on this were studied in subjects with borderline hypertension and in normotensive subjects. Saliva production at rest was lower in borderline hypertensive subjects than in normotensive subjects. Plasma catecholamine levels were similar in both groups of subjects studied. Intravenous injections of propranolol and phentolamine did not enhance saliva secretion in the borderline hypertensive group, whereas atropine caused the secretion to decrease in both groups. Intravenous infusions of neostigmine led to a dose-dependent increase of salivary flow. The dose-response curve for the stimulating effect of neostigmine on saliva production was shifted to the right in borderline hypertensive as compared with normotensive subjects. The results of the study support the assumption that in subjects with borderline hypertension parasympathetic influence on the salivary glands is reduced.


Enhanced surface acoustic wave cell sorting by 3D microfluidic-chip design.
We demonstrate an acoustic wave driven microfluidic cell sorter that combines advantages of multilayer device fabrication with planar surface acoustic wave excitation. We harness the strong vertical component of the refracted acoustic wave to enhance cell actuation by using an asymmetric flow field to increase cell deflection. Precise control of the 3-dimensional flow is realized by topographical structures implemented on the top of the microchannel. We experimentally quantify the effect of the structure dimensions and acoustic parameter. The design attains cell sorting rates and purities approaching those of state of the art fluorescence-activated cell sorters with all the advantages of microfluidic cell sorting.


Non-invasive assessment of liver fibrosis in chronic hepatitis B.
The goal of this review is to provide a comprehensive picture of the role, clinical applications and future perspectives of the most widely used non-invasive techniques for the evaluation of hepatitis B virus (HBV) infection. During the past decade many non-invasive methods have been developed to reduce the need for liver biopsy in staging fibrosis and to overcome whenever possible its limitations, mainly: invasiveness, costs, low reproducibility, poor acceptance by patients. Elastographic techniques conceived to assess liver stiffness, in particular transient elastography, and the most commonly used biological markers will be assessed against their respective role and limitations in staging hepatic fibrosis. Recent evidence highlights that both liver stiffness and some bio-chemical markers correlate with survival and major clinical end-points such as liver decompensation, development of hepatocellular carcinoma and portal hypertension. Thus the non-invasive techniques here discussed can play a major role in the management of patients with chronic HBV-related hepatitis. Given their prognostic value, transient elastography and some bio-chemical markers can be used to better categorize patients with advanced fibrosis and cirrhosis and assign them to different classes of risk for clinically relevant outcomes. Very recent data indicates that the combined measurements of liver and spleen stiffness enable the reliable prediction of portal hypertension and esophageal varices development.


Evaluation of take-home exposure and risk associated with the handling of clothing contaminated with chrysotile asbestos.
The potential for para-occupational (or take-home) exposures from contaminated clothing has been recognized for the past 60 years. To better characterize the take-home asbestos exposure pathway, a study was performed to measure the relationship between airborne chrysotile concentrations in the workplace, the contamination of work clothing, and take-home exposures and risks. The study included air sampling during two activities: (1) contamination of work clothing by airborne chrysotile (i.e., loading the clothing), and (2) handling and shaking out of the clothes. The clothes were contaminated at three different target airborne chrysotile concentrations (0-0.1 fibers per cubic centimeter [f/cc], 1-2 f/cc, and 2-4 f/cc; two events each for 31-43 minutes; six events total). Arithmetic mean concentrations for the three target loading levels were 0.01 f/cc, 1.65 f/cc, and 2.84 f/cc (National Institute of Occupational Health and Safety [NIOSH] 7402). Following the loading events, six matched 30-minute clothes-handling and shake-out events were conducted, each including 15 minutes of active handling (15-minute means; 0.014-0.097 f/cc) and 15 additional minutes of no handling (30-minute means; 0.006-0.063 f/cc). Percentages of personal clothes-handling TWAs relative to clothes-loading TWAs were calculated for event pairs to characterize exposure potential during daily versus weekly clothes-handling activity. Airborne concentrations for the clothes handler were 0.2-1.4% (eight-hour TWA or daily ratio) and 0.03-0.27% (40-hour TWA or weekly ratio) of loading TWAs. Cumulative chrysotile doses for clothes handling at airborne concentrations tested were estimated to be consistent with lifetime cumulative chrysotile doses associated with ambient air exposure (range for take-home or ambient doses: 0.00044-0.105 f/cc year).


Monoclonal antibodies against Lgr5 identify human colorectal cancer stem cells.
In colorectal cancer (CRC), a subpopulation of tumor cells, called cancer stem cell (CSC) fraction, is suggested to be responsible for tumor initiation, growth, and metastasis. The search for a reliable marker to identify these CSCs is ongoing as current markers, like CD44 and CD133, are more broadly expressed and therefore are not highly selective and currently also lack function in CSC biology. Here, we analyzed whether the Wnt target Lgr5, which has earlier been identified as a marker for murine intestinal stem cells, could potentially serve as a functional marker for CSCs. Fluorescence-activated cell sorting-based detection of Lgr5, using three newly developed antibodies, on primary colorectal tumor cells revealed a clear subpopulation of Epcam+ Lgr5+ cells. Similarly, primary CRC-derived spheroid cultures, known to be enriched for CSCs, contain high levels of Lgr5+ cells, which decrease upon in vitro differentiation of these CSCs. Selection of the Lgr5(high) CRC cells identified the clonogenic fraction in vitro as well as the tumorigenic population in vivo. Finally, we confirm that Lgr5 expression is dependent on the Wnt pathway and show that Lgr5 overexpression induces clonogenic growth. We thus provide evidence that Lgr5 is, next to a functional intestinal stem cell marker, a selective marker for human colorectal CSCs.


Prognostic value of circulating tumor cells in advanced gastric cancer patients receiving chemotherapy.
The identification of circulating tumor cells (CTCs) may provide important prognostic information in several types of solid tumors, including gastric cancer. The aim of this study was to investigate whether CTC count may be used to predict survival in patients with advanced gastric cancer treated with chemotherapy. The CELLection™ Epithelial Enrich kit was used to isolate and purify CTCs from samples of peripheral blood. Immunofluorescent staining was used for CTC counting. High CTC counts were associated with poor tumor differentiation and high serum CEA levels (P=0.021 and 0.005, respectively). After 3 months, 16 patients with decreasing CTC counts after the first cycle of chemotherapy obtained complete response, partial response or stable disease, while 13 patients with increasing CTC counts developed progressive disease. The patients with decreasing CTC counts also exhibited longer progression-free survival (PFS) (P≤0.001) and overall survival (OS) (P=0.002) compared with those with increasing CTC counts. Among all 59 patients, those with a CTC count of ≤2 cells/5 ml blood exhibited longer PFS (P≤0.001) and OS (P≤0.001) compared with those with a CTC count of >2 cells/5 ml blood. The multivariate analysis suggested that an increase of the CTC count after the first cycle of chemotherapy was only an independent prognostic marker of poor PFS (P=0.019). However, a baseline CTC count of >2 cells/5 ml blood was an independent poor prognostic marker for PFS (P=0.008) and OS (P=0.001) in all 59 patients. Our study suggested that patients with a low baseline CTC count or decrease of the CTC count after the first cycle of chemotherapy may benefit significantly from palliative chemotherapy. In conclusion, CTC count may be a good chemotherapy monitoring marker and an ideal prognostic marker for patients receiving palliative chemotherapy.


Emerging Function and Clinical Significance of Exosomal circRNAs in Cancer.
Exosomes are a type of extracellular vesicles (EVs) secreted by almost all cells, with a diameter range of 30-150 nm and a lipid bilayer membrane. Exosomes are now considered as vital mediators of intercellular communication and participate in multiple cellular processes, such as signal transduction and antigen presentation. Recently, circular RNAs (circRNAs), a novel class of noncoding RNAs (ncRNAs), have been found to be abundant and stable in exosomes. Increasing evidence indicates that exosome-derived circRNAs act as signaling molecules to regulate cancer growth, angiogenesis, invasion, metastasis, and sensitivity to chemotherapy. Moreover, circulating exosomal circRNAs can reflect the progression and malignant characteristics of cancer, implying their great potential as promising, non-invasive biomarkers for cancer diagnosis and prognosis. In this review, we summarize the recent progress on the functional roles of exosomal circRNAs in cancer progression, discussing their potential as promising biomarkers and therapeutic targets in cancer. Comprehensive elucidation of molecular mechanisms relevant to the implications of exosomal circRNAs in cancer progression will be conducive to the development of innovative diagnostic and therapeutic approaches in cancer.


Lenticular mitoprotection. Part A: Monitoring mitochondrial depolarization with JC-1 and artifactual fluorescence by the glycogen synthase kinase-3β inhibitor, SB216763.
Dissipation of the electrochemical gradient across the inner mitochondrial membrane results in mitochondrial membrane permeability transition (mMPT), a potential early marker for the onset of apoptosis. In this study, we demonstrate a role for glycogen synthase kinase-3β (GSK-3β) in regulating mMPT. Using direct inhibition of GSK-3β with the GSK-3β inhibitor SB216763, mitochondria may be prevented from depolarizing (hereafter referred to as mitoprotection). Cells treated with SB216763 showed an artifact of fluorescence similar to the green emission spectrum of the JC-1 dye. We demonstrate the novel use of spectral deconvolution to negate the interfering contributing fluorescence by SB216763, thus allowing an unfettered analysis of the JC-1 dye to determine the mitochondrial membrane potential. Secondary cultures of virally transfected human lens epithelial cells (HLE-B3) were exposed to acute hypoxic conditions (approximately 1% O₂) followed by exposure to atmospheric oxygen (approximately 21% O₂). The fluorescent dye JC-1 was used to monitor the extent of mitochondrial depolarization upon exposure of inhibitor treatment relative to the control cells (mock inhibition) in atmospheric oxygen. Annexin V-fluorescein isothiocyanate/propidium iodide staining was implemented to determine cell viability. Treatment of HLE-B3 cells with SB216763 (12 µM), when challenged by oxidative stress, suppressed mitochondrial depolarization relative to control cells as demonstrated with JC-1 fluorescent dye analysis. Neither the control nor the SB216763-treated HLE-B3 cells tested positive with annexin V-fluorescein isothiocyanate/propidium iodide staining under the conditions of the experiment. Inhibition of GSK-3β activity by SB216763 blocked mMPT relative to the slow but consistent depolarization observed with the control cells. We conclude that inhibition of GSK-3β activity by the GSK-3β inhibitor SB216763 provides positive protection against mitochondrial depolarization.


Reactive oxygen species regulate nucleostemin oligomerization and protein degradation.
Nucleostemin (NS) is a nucleolar-nucleoplasmic shuttle protein that regulates cell proliferation, binds p53 and Mdm2, and is highly expressed in tumor cells. We have identified NS as a target of oxidative regulation in transformed hematopoietic cells. NS oligomerization occurs in HL-60 leukemic cells and Raji B lymphoblasts that express high levels of c-Myc and have high intrinsic levels of reactive oxygen species (ROS); reducing agents dissociate NS into monomers and dimers. Exposure of U2OS osteosarcoma cells with low levels of intrinsic ROS to hydrogen peroxide (H(2)O(2)) induces thiol-reversible disulfide bond-mediated oligomerization of NS. Increased exposure to H(2)O(2) impairs NS degradation, immobilizes the protein within the nucleolus, and results in detergent-insoluble NS. The regulation of NS by ROS was validated in a murine lymphoma tumor model in which c-Myc is overexpressed and in CD34+ cells from patients with chronic myelogenous leukemia in blast crisis. In both instances, increased ROS levels were associated with markedly increased expression of NS protein and thiol-reversible oligomerization. Site-directed mutagenesis of critical cysteine-containing regions of nucleostemin altered both its intracellular localization and its stability. MG132, a potent proteasome inhibitor and activator of ROS, markedly decreased degradation and increased nucleolar retention of NS mutants, whereas N-acetyl-L-cysteine largely prevented the effects of MG132. These results indicate that NS is a highly redox-sensitive protein. Increased intracellular ROS levels, such as those that result from oncogenic transformation in hematopoietic malignancies, regulate the ability of NS to oligomerize, prevent its degradation, and may alter its ability to regulate cell proliferation.


Stratification of Hepatocellular Carcinoma Patients Based on Acetate Utilization.
Hepatocellular carcinoma (HCC) is a deadly form of liver cancer that is increasingly prevalent. We analyzed global gene expression profiling of 361 HCC tumors and 49 adjacent noncancerous liver samples by means of combinatorial network-based analysis. We investigated the correlation between transcriptome and proteome of HCC and reconstructed a functional genome-scale metabolic model (GEM) for HCC. We identified fundamental metabolic processes required for cell proliferation using the network centric view provided by the GEM. Our analysis revealed tight regulation of fatty acid biosynthesis (FAB) and highly significant deregulation of fatty acid oxidation in HCC. We predicted mitochondrial acetate as an emerging substrate for FAB through upregulation of mitochondrial acetyl-CoA synthetase (ACSS1) in HCC. We analyzed heterogeneous expression of ACSS1 and ACSS2 between HCC patients stratified by high and low ACSS1 and ACSS2 expression and revealed that ACSS1 is associated with tumor growth and malignancy under hypoxic conditions in human HCC.


Targeting the chemokines in cardiac repair.
Chemokines are a family of chemotactic cytokines that play an essential role in leukocyte trafficking. Upregulation of both CC and CXC chemokines is a hallmark of the inflammatory and reparative response following myocardial infarction. Release of danger signals from dying cells and damaged extracellular matrix activates innate immune pathways that stimulate chemokine synthesis. Cytokineand chemokine-driven adhesive interactions between endothelial cells and leukocytes mediate extravasation of immune cells into the infarct. CXC chemokines (such as interleukin-8) are bound to glycosaminoglycans on the endothelial surface and activate captured neutrophils, inducing expression of integrins. CC chemokines (such as monocyte chemoattractant protein (MCP)-1) mediate recruitment of proinflammatory and phagocytotic mononuclear cells into the infarct. CC Chemokines may also regulate late infiltration of the healing infarct with inhibitory leukocytes that suppress inflammation and restrain the post-infarction immune response. Non-hematopoietic cells are also targeted by chemokines; in healing infarcts, the CXC chemokine Interferon-γ inducible Protein (IP)-10 exerts antifibrotic actions, inhibiting fibroblast migration. Another member of the CXC subfamily, Stromal cell-derived Factor (SDF)-1, may protect the infarcted heart by activating pro-survival signaling in cardiomyocytes, while exerting angiogenic actions through chemotaxis of endothelial progenitors. Several members of the chemokine family may be promising therapeutic targets to attenuate adverse remodeling in patients with myocardial infarction.


Hydrogen-bonding interactions of uric acid complexes with water/melamine by mid-infrared spectroscopy.
Hydrogen (H)-bonding interactions of uric acid (UA) with water have been investigated via IR-UV double resonance measurements in the mid-IR region. Comparison of the present results with those obtained previously in the near-IR region enables us to examine microscopic hydration effects that are specific to the H-bonding acceptor sites of UA. It is shown that hydration of the C8O site promotes the mode coupling of this stretch with the C2O stretch. The occurrence of this coupling is manifested in the IR intensity pattern, in which the transition associated with the in-phase contribution C8O + C2O is significantly suppressed, whereas the corresponding out-of-phase contribution gives rise to a strong peak. We also measured the mid-IR spectra of the 1 : 1 complex formed between UA and melamine (MEL) and carried out a structural analysis using the spectroscopic signature of the H-bonding derived from the result of the monohydrated cluster. It is shown that the complex possesses a triple H-bonding structure with the C2O acceptor site of UA H-bonded to MEL. Furthermore, the IR-depleted UV spectroscopy technique was employed in order to ascertain whether other structural isomers are present in the probe UV spectra.


Real-time determination of aggregated alpha-synuclein induced membrane disruption at neuroblastoma cells using scanning ion conductance microscopy.
Parkinson's disease (PD) is recognized as the second most common neurodegenerative disorder and has affected approximately one million people in the United States alone. A large body of evidence has suggested that deposition of aggregated alpha-synuclein (α-Syn), a brain protein abundant near presynaptic termini, in intracellular protein inclusions (Lewy bodies) results in neuronal cell damage and ultimately contributes to the progression of PD. However, the exact mechanism is still unclear. One hypothesis is that α-Syn aggregates disrupt the cell membrane's integrity, eventually leading to cell death. We used scanning ion conductance microscopy (SICM) to monitor the morphological changes of SH-SY5Y neuroblastoma cells and observed dramatic disruption of the cell membrane after adding α-Syn aggregates to the culturing media. This work demonstrates that SICM can be applied as a new approach to studying the cytotoxicity of α-Syn aggregates.


Blood-brain barrier penetration of an Aβ-targeted, arginine-rich, d-enantiomeric peptide.
The application of small peptides targeting amyloid beta (Aβ) is one of many drug development strategies for the treatment of Alzheimer's disease (AD). We have previously identified several peptides consisting solely of D-enantiomeric amino acid residues obtained from mirror-image phage display selection, which bind to Aβ in different assembly states and eliminate toxic Aβ aggregates. Some of these D-peptides show both diagnostic and therapeutic potential in vitro and in vivo. Here we have analysed the similarity of the arginine-rich D-peptide D3 to the arginine-rich motif (ARM) of the human immunodeficiency virus type 1 transactivator of transcription (HIV-Tat) protein, and examined its in vivo blood-brain barrier (BBB) permeability using wild type mice and transgenic mouse models of Alzheimer's disease. We are able to demonstrate that D3 rapidly enters the brain where it can be found associated with amyloid plaques suggesting a direct penetration of BBB.


Inhaled nitric oxide improves hemodynamics in patients with acute pulmonary hypertension after high-risk cardiac surgery.
Severe pulmonary hypertension and right-sided circulatory failure (RSCF) represent an increasing cause of morbidity and mortality in patients undergoing high-risk cardiac surgery. Increased pulmonary vascular resistance in the setting of cardiopulmonary bypass (CPB) may further lead to decrease blood flow across the pulmonary vascular bed; thereby decreasing left ventricular filling and cardiac output. Current management techniques for RSCF include both nonspecific vasodilator and inotropic agents (often limited by systemic hypotension) and the placement of right ventricular assist devices (associated with increased perioperative morbidity). Inhaled nitric oxide (NOi) represents a novel, specific pulmonary vasodilator that has been proven efficacious in these clinical settings. We evaluated 34 patients in 38 operations who underwent cardiac surgery at Columbia Presbyterian Medical Center, and who received NOi (20 ppm) through a modified ventilatory circuit for hemodynamically significant elevations in pulmonary vascular resistance. Nine patients underwent cardiac transplantation, three patients bilateral lung transplantation, 16 patients left ventricular assist device placement and 10 patients routine cardiac surgery. Patients receiving NOi exhibited substantial reductions in mean pulmonary artery pressure (mPAP) (34.6 +/- 2.0 to 26.0 +/- 1.7 mmHg, p < 0.0001), with improvements in systemic hemodynamics, mean arterial pressure (68 +/- 3.1 to 75.9 +/- 2.0 mmHg, p = 0.006). In five cases, patients could not be weaned from CPB until NOi was administered. Patients were maintained on NOi from 6 to 240 h postoperatively (median duration 36 h). Inhaled NO induces substantial reductions in mPAP and increases in both cardiac index and systemic blood pressure in patients displaying elevated pulmonary hemodynamics after high-risk cardiac surgery. NO is, therefore, a useful adjunct in these patients in whom acute pulmonary hypertension threatens right ventricular function and hemodynamic stability.


Effects of multivalent hexacyanoferrates and their ion pairs on water molecule dynamics measured with terahertz spectroscopy.
The valency of aqueous solutes plays a large role in determining the extent of ion-water dynamics, which can greatly influence the chemical and physical properties of solutions. In these experiments, broadband Fourier transform terahertz spectroscopy is used to probe perturbations to the low-frequency dynamics of water molecules by three different multivalent hexacyanoferrate salts. K3Fe(CN)6, K4Fe(CN)6 and Na4Fe(CN)6 were investigated as a function of concentration up to their solubility limits using spectral subtractions and fitting with damped harmonic lineshapes. Regions with subtle nonlinearities in amplitude with respect to solute concentration provide insight into ion-pairing events. The extent of nonlinearity suggests that ion pairs are major constituents in solution for all concentrations measured and is consistent with ion-pairing observed at millimolar concentrations by potentiometric and spectroscopic measurements. A lower estimate for the number of water molecules that are influenced by each ion is obtained from the damped harmonic fits. Values of 19, 28 and 25 water molecules with perturbed dynamics are obtained for KFe(CN)62-, KFe(CN)63- and NaFe(CN)63- ion pairs, respectively. These values represent dynamical perturbations into a second solvation shell and are consistent with the long-range structural effects observed in recent aqueous nanodrop spectroscopy experiments. Furthermore, the spectral absorptions for hexacyanoferrates are in agreement with a wide range of solutes studied previously using the developing methodology for interpreting terahertz spectra.


Magnesium transport in prokaryotes.
Possessing the largest hydrated radius, the smallest ionic radius, and the highest charge density among the biologically relevant cations, Mg(2+) provides an interesting problem for transport into living cells. Transport systems for Mg(2+) have been characterized primarily in Salmonella typhimurium because the well-developed genetics of Gram-negative bacteria make cloning and studying the transporters a viable proposition. The CorA transport system is expressed constitutively and is the major Mg(2+) transporter in Eubacteria and Archaea. It has three transmembrane domains, a uniquely large periplasmic domain, and no sequence homology to other proteins. The MgtE Mg(2+) transporter also lacks sequence homology to other proteins, and it is unclear if Mg(2+) transport is its primary function. The MgtA and MgtB Mg(2+) transporters have sequence homology to P-type ATPases. They are more closely related to the mammalian Ca(2+)-ATPases than to the prokaryotic P-type ATPases. MgtA and MgtB mediate Mg(2+) influx with, rather than against, the Mg(2+) electrochemical gradient. Unlike corA and mgtE, the mgtA and mgtC/mgtB loci are regulated, being induced by the two-component regulatory system PhoP/PhoQ. PhoQ is a Mg(2+) membrane sensor kinase that phosphorylates the transcription factor PhoP under Mg(2+)-limiting conditions. This factor then induces transcription of mgtA and mgtCB. MgtC, which is encoded by the first gene in the mgtCB operon, has no sequence homology to any known protein and is essential for S. typhimurium virulence in mice and macrophages, but does appear to be a Mg(2+) transporter. The physiological roles of these Mg(2+) transporters and their mechanisms are not yet completely clear, but initial data indicate that Mg(2+) transporters are unique transport systems with unusual mechanisms for mediating Mg(2+) movement through the membrane.


[Real-time elastography in the diagnosis of prostate cancer: personal experience].
Prostate cancer is the most common cancer in men. In the future, a significant further increase in the incidence of prostate cancer is expected. The indication to perform a prostate biopsy is digital rectal examination suspicious for prostate cancer, total prostate specific antigen (PSA) value, free PSA/total PSA ratio, PSA density and PSA velocity, and an evidence of hypoechoic area at transrectal ultrasound scan. Unfortunately the specificity and sensibility are still poor. The aim of this retrospective study is to evaluate the specificity and sensibility of real time elastography versus ultrasound transrectal B-mode scan. We retrospectively evaluated 108 pts. having undergone TRUS-guided transrectal prostate biopsy (10 samples). The indication for biopsy is: digital rectal examination, total prostate specific antigen (PSA) value, PSA ratio, PSA density and PSA velocity suspicious for prostate cancer, and/or an evidence of hypoechoic area at transrectal ultrasound scan, and/or hard area at real-time elastography. The mean age of patients is 66.8 years, mean PSA 6.5 ng/mL, and mean ratio 16.5%. We compared the histopathological findings of needle prostate biopsies with the results of transrectal ultrasound and transrectal real-time elastography. 32/108 (29.6%) pts. were positive for prostate cancer (mean Gleason score 7.08), mean PSA 14 ng/mL and mean ratio 9.5%. Transrectal ultrasound scan shows a sensibility of 69% and specificity of 68%. Transrectal ultrasound scan shows a VPP of 51.4%. Transrectal ultrasound scan shows a VPN of 80.9%. Real-time elastography shows a sensibility of 56% and specificity of 85.7%. Real-time elastography shows a VPP of 60.1%. Real-time elastography shows a VPN of 83%. Elastography has a significantly higher specificity for the detection of prostate cancer than the conventionally used examinations including DRE and TRUS. It is a useful real-time diagnostic method because it is not invasive, and simultaneous evaluation is possible while performing TRUS.


mRNA profiling of rat islet tumors reveals nkx 6.1 as a beta-cell-specific homeodomain transcription factor.
Development of a high capacity multiplex reverse transcriptase-polymerase chain reaction protocol has allowed us to screen lineage related rat islet tumors classified as alpha-, beta-, and delta-like as judged by their hormone profile for differential expression of more than 50 selected genes. We find that in addition to insulin the insulinoma express the normal beta-cell markers Pdx-1, IAPP, and Glut-2, and that these markers are absent from the glucagonoma: a reflection of the normal alpha-cell. Furthermore, this study suggests that the GLP-1, glucagon, GIP, IGF-1, and insulin receptors as well as E-cadherin, R-cadherin, Id-1, and Id-2 are differentially expressed within the islet of Langerhans. Importantly, insulinoma-specific expression of the recently cloned homeodomain protein Nkx 6.1 predicted beta-cell-specific expression in the normal islet. Immunohistochemistry using antibodies raised against recombinant Nkx 6.1 did indeed localize Nkx 6.1 expression exclusively to the nuclei of normal islet beta-cells. Apart from pancreatic islets only the antral part of the stomach contained Nkx 6.1 mRNA. We conclude that multiplex reverse transcriptase-polymerase chain reaction-based mRNA profiling is a powerful tool to identify differentially expressed genes within phenotypically related cells and propose that Nkx 6.1 is involved in specifying the unique characteristics of the beta-cell.


Longitudinal Trends in Costs of Palliative Radiation for Metastatic Prostate Cancer.
In recent years, palliative treatment of prostate cancer metastases has been characterized by the use of more complex radiation treatment, despite a lack of evidence demonstrating a clinical benefit of these technologies in the palliative setting. The impact of adoption of these technologies on the costs of palliative radiation treatment in patients with metastatic prostate cancer remains poorly understood in the general patient population. The study was a retrospective analysis of Surveillance, Epidemiology and End Results (SEER) Medicare data of men aged 66 and older who died from metastatic prostate cancer between 2000 and 2007 and received radiation therapy for bony metastases in the last year of life. Direct costs were obtained from Medicare carrier and outpatient facility payments for all radiation treatment claims and adjusted to 2008 dollars. A total of 1705 men met study inclusion criteria. Total Medicare payments for radiation therapy for bony metastases in the last year of life increased by 44.4% from an average of $2,763 in 2000 to $3,989 in 2007, with the proportion of all payments accrued within hospital-based settings increasing from 48% to 57%. Complexity of radiation therapy techniques over the same period was characterized by use of less simple (30.1% to 23.3%) and more complex (59.9% versus 66.7%) radiation therapy. From 2000-2003 to 2004-2007, the use of shorter treatment courses (≤5 fractions) decreased from 22% to 14%, and the use of single fraction treatment courses decreased by half (6.3% to 2.9%; P≤.001). Between 2000 and 2007, palliative radiation therapy for bony prostate cancer metastases was characterized by the use of more advanced treatment technologies and prolonged radiation treatment courses. Further research investigating barriers to cost-effective palliation is warranted.