Assessment of nitrosative stress and lipid peroxidation activity in asymptomatic exposures to medical radiation: The bystander effect of ionizing radiation.
Adaptive response and bystander effect are two important phenomena involved in biological responses to ionizing radiation. To determine the bystander effect of ionizing radiation in medical exposures by measuring the serum nitric oxide (NO•), peroxynitrite (ONOO•), and malondialdehyde (MDA) levels. Twenty-five medical staff working in the Unit of Radiology and 15 medical staff working in other departments at the Al-Yarmouk teaching hospital in Baghdad, Iraq, were enrolled in the study. Venous blood was obtained from each subject for determination of NO•, ONOO•, and MDA levels. Significantly higher serum NO•, ONOO•, and MDA levels were observed in participants working in the radiology unit as compared with serum levels in those working elsewhere. There was no correlation between the lipid peroxidation activity and ONOO•/NO• ratio. The serum NO• level in subjects working in the x-ray services was significantly higher than that in subjects working in the CT and MRI services. The bystander effect of radiation could be observed in asymptomatic individuals working in the radiology unit and it was particularly well observed in people working in the X-ray services as opposed to CT and MRI services. Determination of serum nitrogen species could be a useful laboratory investigation for assessment of the bystander effect of radiation.


Implementation of multilens micro-optical systems with large numerical aperture by stacking of microlenses.
In the field of micro-optics there is a demand for objectives with large numerical aperture (NA). One example is optical storage in which a NA greater than 0.5 is required. For planar microlenses the NA is determined by means of the maximal index difference and the degree of exchange and reaches typical values of 0.13-0.2. Thus stacking is needed to build high NA objectives from planar microlenses. An additional benefit of stacking lenses is the possibility to correct for different types of aberrations. We realized two stacked systems: an array of micro-objectives with a NA of 0.45 from three microlens arrays and a confocal sensor head from four microlens arrays and one pinhole array mask.


Faecal haemoglobin concentrations vary with sex and age, but data are not transferable across geography for colorectal cancer screening.
Faecal immunochemical tests (FIT) are becoming widely used in colorectal cancer (CRC) screening. Availability of data on faecal haemoglobin concentrations (f-Hb) in three countries prompted an observational study on sex and age and the transferability of data across geography. Single estimates of f-Hb in large groups were made in Scotland, Taiwan and Italy using quantitative automated immunoturbidimetry on the Eiken OC-Sensor. Distributions were examined for men and women overall and in four different age groups. The distributions of f-Hb were not Gaussian and had kurtosis and positive skewness. The distributions were different in the three countries: f-Hb varies with sex and age in all countries, being higher in men and the elderly, but the degree of variation is inconsistent across countries, f-Hb being higher in Scotland than in Taiwan than in Italy, possibly due to different lifestyles. At any cut-off concentration, more men are declared positive than women and more older people are declared positive than younger individuals. Our analysis supports the view that setting and using a single f-Hb cut-off in any CRC screening programme is far from ideal. We suggest that individualisation is the optimum approach with f-Hb, alone or with other important factors such as sex and age, used to determine important personal issues such as need for colonoscopy, screening interval between tests and risk of future CRC. Whether there is merit in monitoring f-Hb in individuals over time remains an interesting research question for the future.


Next generation sequencing and comparative analyses of Xenopus mitogenomes.
Mitochondrial genomes comprise a small but critical component of the total DNA in eukaryotic organisms. They encode several key proteins for the cell's major energy producing apparatus, the mitochondrial respiratory chain. Additionally, their nucleotide and amino acid sequences are of great utility as markers for systematics, molecular ecology and forensics. Their characterization through nucleotide sequencing is a fundamental starting point in mitogenomics. Methods to amplify complete mitochondrial genomes rapidly and efficiently from microgram quantities of tissue of single individuals are, however, not always available. Here we validate two approaches, which combine long-PCR with Roche 454 pyrosequencing technology, to obtain two complete mitochondrial genomes from individual amphibian species. We obtained two new xenopus frogs (Xenopus borealis and X. victorianus) complete mitochondrial genome sequences by means of long-PCR followed by 454 of individual genomes (approach 1) or of multiple pooled genomes (approach 2), the mean depth of coverage per nucleotide was 9823 and 186, respectively. We also characterised and compared the new mitogenomes against their sister taxa; X. laevis and Silurana tropicalis, two of the most intensely studied amphibians. Our results demonstrate how our approaches can be used to obtain complete amphibian mitogenomes with depths of coverage that far surpass traditional primer-walking strategies, at either the same cost or less. Our results also demonstrate: that the size, gene content and order are the same among xenopus mitogenomes and that S. tropicalis form a separate clade to the other xenopus, among which X. laevis and X. victorianus were most closely related. Nucleotide and amino acid diversity was found to vary across the xenopus mitogenomes, with the greatest diversity observed in the Complex 1 gene nad4l and the least diversity observed in Complex 4 genes (cox1-3). All protein-coding genes were shown to be under strong negative (purifying selection), with genes under the strongest pressure (Complex 4) also being the most highly expressed, highlighting their potentially crucial functions in the mitochondrial respiratory chain. Next generation sequencing of long-PCR amplicons using single taxon or multi-taxon approaches enabled two new species of Xenopus mtDNA to be fully characterized. We anticipate our complete mitochondrial genome amplification methods to be applicable to other amphibians, helpful for identifying the most appropriate markers for differentiating species, populations and resolving phylogenies, a pressing need since amphibians are undergoing drastic global decline. Our mtDNAs also provide templates for conserved primer design and the assembly of RNA and DNA reads following high throughput "omic" techniques such as RNA- and ChIP-seq. These could help us better understand how processes such mitochondrial replication and gene expression influence xenopus growth and development, as well as how they evolved and are regulated.


Effectiveness of Disseminating School Physical Activity Information on Facebook during a Pandemic: A Mixed-Method Analysis.
Social media is an important communication tool during times of crisis because of its vast reach. Understanding the effectiveness of sharing public health guidance and promoting schoolchildren's physical activity during the COVID-19 pandemic can inform dissemination best practices. We classified 418 posts from parent/community members of a school-based physical activity Facebook group by content type, and used concurrent mixed methods to examine (1) differences in dissemination effectiveness (reactions, shares, and comments) between two pandemic phases and (2) themes and sentiments of comments. Phase I included school closures through the release of national school re-entry guidelines (March 1, 2020 - May 15, 2020) and Phase II extended through the school year start (May 16, 2020 - August 1, 2020). Policy and guidance posts prompted more comments while feel-good stories produced more reactions compared to other content types. Members reacted more during Phase II, which mainly consisted of policy and guidance (86%). Four major themes of information and resources, personal disclosures, questions and concerns, and support for educators emerged. Sharing public health guidance for schoolchildren on social media was an effective strategy to disseminate information when in-person discourse was limited. Creating social media spaces where discussion is encouraged can provide social and emotional support for parents/community members.


Prediction of the potency of mammalian cyclooxygenase inhibitors with ensemble proteochemometric modeling.
Cyclooxygenases (COX) are present in the body in two isoforms, namely: COX-1, constitutively expressed, and COX-2, induced in physiopathological conditions such as cancer or chronic inflammation. The inhibition of COX with non-steroideal anti-inflammatory drugs (NSAIDs) is the most widely used treatment for chronic inflammation despite the adverse effects associated to prolonged NSAIDs intake. Although selective COX-2 inhibition has been shown not to palliate all adverse effects (e.g. cardiotoxicity), there are still niche populations which can benefit from selective COX-2 inhibition. Thus, capitalizing on bioactivity data from both isoforms simultaneously would contribute to develop COX inhibitors with better safety profiles. We applied ensemble proteochemometric modeling (PCM) for the prediction of the potency of 3,228 distinct COX inhibitors on 11 mammalian cyclooxygenases. Ensemble PCM models ([Formula: see text], and RMSEtest = 0.71) outperformed models exclusively trained on compound ([Formula: see text], and RMSEtest = 1.09) or protein descriptors ([Formula: see text] and RMSEtest = 1.10) on the test set. Moreover, PCM predicted COX potency for 1,086 selective and non-selective COX inhibitors with [Formula: see text] and RMSEtest = 0.76. These values are in agreement with the maximum and minimum achievable [Formula: see text] and RMSEtest values of approximately 0.68 for both metrics. Confidence intervals for individual predictions were calculated from the standard deviation of the predictions from the individual models composing the ensembles. Finally, two substructure analysis pipelines singled out chemical substructures implicated in both potency and selectivity in agreement with the literature. Graphical AbstractPrediction of uncorrelated bioactivity profiles for mammalian COX inhibitors with Ensemble Proteochemometric Modeling.


Two sides of the medallion: poor treatment tolerance but better survival by standard chemotherapy in elderly patients with advanced-stage diffuse large B-cell lymphoma.
We investigated treatment of unselected elderly patients with diffuse large B-cell lymphoma (DLBCL) and its subsequent impact on treatment tolerance and survival. Data from all 419 advanced-stage DLBCL patients, aged 75 or older and newly diagnosed between 1997 and 2004, were included from five regional population-based cancer registries in The Netherlands. Subsequent data on comorbidity, performance status, treatment, motives for adaptations or refraining from chemotherapy and toxic effects was collected from the medical records. Follow-up was completed until 1st January 2009. Only 46% of patients received the standard therapy [aggressive chemotherapy with cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP)-like chemotherapy]. Motives for withholding chemotherapy were refusal by patient/family, poor performance status or estimated short life expectancy. Of all patients receiving CHOP-like chemotherapy, only 56% could complete at least six cycles. Grade 3 or 4 toxicity occurred in 67% of patients receiving standard therapy. The independent effect of therapy on survival remained after correction for the age-adjusted International Prognostic Index. Standard therapy was applied less often in elderly patients with a subsequent independent negative impact on survival. Furthermore, high toxicity rate and the impossibility of the majority of patients to complete treatment were seen. This implies that better treatment strategies should be devised including a proper selection of senior patients for this aggressive chemotherapy.


Modulation of Bax and Bcl-2 genes by secondary metabolites produced by Penicillium rubens JGIPR9 causes the apoptosis of cancer cell lines.
Search for an efficient anti-cancer compound of natural origin with well-defined mechanisms of action is an important scientific pursuit today, due to cancer being the second leading cause for the death of affected people. The members of the genus Penicillium are one of the important sources of bioactive compounds. In the present study, Penicillium rubens, isolated from a garden soil in Madurai district of Tamil Nadu, was found to produce a highly promising anti-cancer metabolite. The percentage viabilities of HepG2, HeLa and MCF-7 cancer cells treated with the bioactive fraction (P5) isolated from P. rubens, ranged between 40-50% after 96 h. Apoptosis induction was found to be the major reason for the observed reduction in cancer cell proliferation and cell count which was confirmed by caspase activity, DNA fragmentation, clonogenic assay, cell cycle analysis and LDH assays. The upregulation of proapoptotic Bax, coupled with the downregulation of anti-apoptotic Bcl-2 expressions were confirmed by RT-qPCR and flow cytometry methods. The current study also indicated an upregulation of p53 which further strengthened the apoptogenic property of P5 fraction. Non-toxicity of P5 was demonstrated on normal peripheral lymphocytes. The analysis of P5 fraction through GC-MS indicated the presence of indole-2, 3-(4,4-dimethyl-3-thiosemicarbazone) as one of the major compounds.


Confocal Raman microscopy: common errors and artefacts.
Confocal Raman microscopy is a powerful tool for research and analysis in the chemical, materials and life sciences, particularly for non-destructive depth profiling of transparent systems. Unfortunately, many Raman microscopes are not optimally configured for this purpose, and so yield unnecessarily low signal-to-noise spectra with poor spatial resolution and grossly incorrect depth scales. This review discusses the aberrations and artefacts that can arise and describes how these can be avoided by adhering to a few basic principles that are well known to optical microscopists but which were largely ignored in the spectroscopic community for many years.


Evaluation of BDE-47-induced neurodevelopmental toxicity in zebrafish embryos.
There are growing concerns about the neurodevelopmental toxicity of polybrominated diphenyl ethers (PBDEs), but the toxicological phenotypes and mechanisms are not well elucidated. Here, zebrafish (Danio rerio) were exposed to 2,2',4,4'-tetrabromodiphenyl ether (BDE-47) from 4 to 72 h post-fertilization (hpf). The results showed that BDE-47 stimulated the production of dopamine and 5-hydroxytryptamine, but inhibited expression of Nestin, GFAP, Gap43, and PSD95 in 24 hpf embryos. Importantly, we unraveled the inhibitory effects of BDE-47 on neural crest-derived melanocyte differentiation and melanin syntheses process, evidenced by disrupted expression of wnt1, wnt3, sox10, mitfa, tyrp1a, tyrp1b, tryp2, and oca2 gene in 72 hpf embryos and decreased tyrosinase activities in embryos at 48 and 72 hpf. The transcriptional activities of myosin VAa, kif5ba, rab27a, mlpha, and cdc42 genes, which are associated with intracellular transport process, were also disturbed during zebrafish development. Ultimately, these alterations led to fast spontaneous movement and melanin accumulation deficit in zebrafish embryos upon BDE-47 exposure. Our results provide an important extension for understanding the neurodevelopmental effects of PBDEs and facilitate the comprehensive evaluation of neurotoxicity in embryos.


A follow-up on quantitative and qualitative olfactory dysfunction and other symptoms in patients recovering from COVID-19 smell loss.
Sudden smell loss is a specific early symptom of COVID-19, which, prior to the emergence of Omicron, had estimated prevalence of ~40% to 75%. Chemosensory impairments affect physical and mental health, and dietary behavior. Thus, it is critical to understand the rate and time course of smell recovery. The aim of this cohort study was to characterize smell function and recovery up to 11 months post COVID-19 infection. This longitudinal survey of individuals suffering COVID-19-related smell loss assessed disease symptoms and gustatory and olfactory function. Participants (n=12,313) who completed an initial survey (S1) about respiratory symptoms, chemosensory function and COVID-19 diagnosis between April and September 2020, were invited to complete a follow-up survey (S2). Between September 2020 and February 2021, 27.5% participants responded (n=3,386), with 1,468 being diagnosed with COVID-19 and suffering co-occurring smell and taste loss at the beginning of their illness. At follow-up (median time since COVID-19 onset ~200 days), ~60% of women and ~48% of men reported less than 80% of their pre-illness smell ability. Taste typically recovered faster than smell, and taste loss rarely persisted if smell recovered. Prevalence of parosmia and phantosmia was ~10% of participants in S1 and increased substantially in S2: ~47% for parosmia and ~25% for phantosmia. Persistent smell impairment was associated with more symptoms overall, suggesting it may be a key marker of long-COVID illness. The ability to smell during COVID-19 was rated slightly lower by those who did not eventually recover their pre-illness ability to smell at S2. While smell ability improves for many individuals who lost it during acute COVID-19, the prevalence of parosmia and phantosmia increases substantially over time. Olfactory dysfunction is associated with broader persistent symptoms of COVID-19, and may last for many months following acute COVID-19. Taste loss in the absence of smell loss is rare. Persistent qualitative smell symptoms are emerging as common long-term sequelae; more research into treatment options is strongly warranted given that even conservative estimates suggest millions of individuals may experience parosmia following COVID-19. Healthcare providers worldwide need to be prepared to treat post COVID-19 secondary effects on physical and mental health.


The paraventricular thalamus controls a central amygdala fear circuit.
Appropriate responses to an imminent threat brace us for adversities. The ability to sense and predict threatening or stressful events is essential for such adaptive behaviour. In the mammalian brain, one putative stress sensor is the paraventricular nucleus of the thalamus (PVT), an area that is readily activated by both physical and psychological stressors. However, the role of the PVT in the establishment of adaptive behavioural responses remains unclear. Here we show in mice that the PVT regulates fear processing in the lateral division of the central amygdala (CeL), a structure that orchestrates fear learning and expression. Selective inactivation of CeL-projecting PVT neurons prevented fear conditioning, an effect that can be accounted for by an impairment in fear-conditioning-induced synaptic potentiation onto somatostatin-expressing (SOM(+)) CeL neurons, which has previously been shown to store fear memory. Consistently, we found that PVT neurons preferentially innervate SOM(+) neurons in the CeL, and stimulation of PVT afferents facilitated SOM(+) neuron activity and promoted intra-CeL inhibition, two processes that are critical for fear learning and expression. Notably, PVT modulation of SOM(+) CeL neurons was mediated by activation of the brain-derived neurotrophic factor (BDNF) receptor tropomysin-related kinase B (TrkB). As a result, selective deletion of either Bdnf in the PVT or Trkb in SOM(+) CeL neurons impaired fear conditioning, while infusion of BDNF into the CeL enhanced fear learning and elicited unconditioned fear responses. Our results demonstrate that the PVT-CeL pathway constitutes a novel circuit essential for both the establishment of fear memory and the expression of fear responses, and uncover mechanisms linking stress detection in PVT with the emergence of adaptive behaviour.


"Hey, mom, thanks!": use of focus groups in the development of place-specific materials for a community environmental action campaign.
We examined the relevance of five strategies to reduce the risk of exposure to environmental hazards for African-American and Hispanic children living in Northern Manhattan in New York City. Researchers conducting a community-wide intervention to increase awareness of environmental health hazards identified five strategies for keeping children healthy, preventing asthma, and promoting children's growth and development. These strategies were based on current scientific knowledge of environmental health and were tested and refined through a series of focus groups. The 14 focus groups were conducted with women of childbearing age living in the communities under study. The purpose of the focus groups was to test the relevancy of the five strategies and to obtain data to inform the intervention's social action campaign. Here authors discuss the process of identifying strategies for risk reduction and incorporating community residents' perceptions of risk into health risk messages. The authors argue that broader social and historical contexts are important in shaping community members' interpretations of risk and subsequent response to health education campaigns.


Genomic analysis of a key innovation in an experimental Escherichia coli population.
Evolutionary novelties have been important in the history of life, but their origins are usually difficult to examine in detail. We previously described the evolution of a novel trait, aerobic citrate utilization (Cit(+)), in an experimental population of Escherichia coli. Here we analyse genome sequences to investigate the history and genetic basis of this trait. At least three distinct clades coexisted for more than 10,000 generations before its emergence. The Cit(+) trait originated in one clade by a tandem duplication that captured an aerobically expressed promoter for the expression of a previously silent citrate transporter. The clades varied in their propensity to evolve this novel trait, although genotypes able to do so existed in all three clades, implying that multiple potentiating mutations arose during the population's history. Our findings illustrate the importance of promoter capture and altered gene regulation in mediating the exaptation events that often underlie evolutionary innovations.


Mechanotransduction in Coronary Vein Graft Disease.
Autologous saphenous veins are the most commonly used conduits in revascularization of the ischemic heart by coronary artery bypass graft surgery, but are subject to vein graft failure. The current mini review aims to provide an overview of the role of mechanotransduction signalling underlying vein graft failure to further our understanding of the disease progression and to improve future clinical treatment. Firstly, limitation of damage during vein harvest and engraftment can improve outcome. In addition, cell cycle inhibition, stimulation of Nur77 and external grafting could form interesting therapeutic options. Moreover, the Hippo pathway, with the YAP/TAZ complex as the main effector, is emerging as an important node controlling conversion of mechanical signals into cellular responses. This includes endothelial cell inflammation, smooth muscle cell proliferation/migration, and monocyte attachment/infiltration. The combined effects of expression levels and nuclear/cytoplasmic translocation make YAP/TAZ interesting novel targets in the prevention and treatment of vein graft disease. Pharmacological, molecular and/or mechanical conditioning of saphenous vein segments between harvest and grafting may potentiate targeted and specific treatment to improve long-term outcome.


Support of undermined occlusal enamel provided by restorative materials.
The purpose of this study was to test the support of occlusal enamel by amalgam (Dispersalloy), bonded amalgam (AmalgamBond Plus adhesive system with high-performance additive powder and Dispersalloy amalgam), and a bonded resin composite (Scotchbond Multi-Purpose adhesive system and Z100 resin composite). For each material, 16 human molars were prepared. The lingual cusps were removed, and the dentin supporting the facial cusps was cut away, leaving a shell of enamel. Each group of prepared teeth was restored using the materials according to manufacturers' instructions. All specimens were thermocycled (1,500 cycles, 6 degrees C to 60 degrees C, dwell time 30 seconds), then mounted vertically in cast stone. A separating disk, mounted horizontally, was used to create a flat horizontal surface approximately 1.5 mm wide at the tips of both remaining enamel cusps of each specimen. Specimens were loaded evenly across the cusp tips at a crosshead speed of 10 mm/min until the fracture occurred. Data were analyzed using analysis of variance and Tukey A post hoc analysis. No significant difference was detected among amalgam, bonded amalgam, and bonded resin composite in their ability to support occlusal enamel. Support provided for occlusal enamel by the materials, whether bonded or not, was intermediate between no support and that provided by dentin. Without further development of materials technology and evidence of efficacy, restorative materials should not be relied upon to support undermined occlusal enamel.


Association of leukocyte telomere length with oxidative stress in yoga practitioners.
Yoga is a mind-body modulation technique that has been shown to have beneficial effects on various diseases related to various systems in the body. However, the molecular basis of mechanism of action is not clear. Hence, this study was designed to study the leukocyte telomere biology and its relation with homocysteine and oxidative stress in yoga practitioners. This is a prospective case-control study involving Yoga practitioners aged 30-40 y with minimum of two years yoga practice (Yoga group) and age, gender and body mass index matched sedentary healthy general population with no medical problems (Control group). Leukocyte telomere length (LTL) was measured by using quantitative PCR (qPCR), fasting plasma homocysteine was measured by a rapid high-performance liquid chromatography assay and the oxidative stress was assessed with total antioxidant status (TAOS), malondialdehyde (MDA) measured by calorimetry. The LTL was shorter in control group than in yoga group (p<0.001). The TAOS was more in yoga group when compared to control group (p=0.008), MDA and homocysteine was high in control group when compared to Yoga group (p<0.001). Further, the LTL was positively correlated with TAOS (r=0.841, p<0.001) and negatively correlated with MDA (r=-0.931, p<0.001) and Homocysteine (r=-0.756, p<0.001). The LTL is well-preserved in people who practice Yoga regularly with lower systemic oxidative stress compared to those who have a relatively sedentary lifestyle despite lack of any medical disorders. The habitual yoga practice seems to inhibit replicative cellular senescence.


Constitutional flavonoids derived from Epimedium dose-dependently reduce incidence of steroid-associated osteonecrosis not via direct action by themselves on potential cellular targets.
Intravascular-thrombosis and extravascular-lipid-deposit are the two key pathogenic events considered to interrupt intraosseous blood supply during development of steroid-associated osteonecrosis (ON). However, there are no clinically employed agents capable of simultaneously targeting these two key pathogenic events. The present experimental study demonstrated that constitutional flavonoid glycosides derived from herb Epimedium (EF, composed of seven flavonoid compounds with common stem nuclear) exerted dose-dependent effect on inhibition of both thrombosis and lipid-deposition and accordingly reducing incidence of steroid-associated ON in rabbits, which was not via direct action by themselves rather by their common metabolite on potential cellular targets involved in the two pathogenic pathways. The underlying mechanism could be explained by counteracting endothelium injury and excessive adipogenesis. These findings encourage designing clinical trials to investigate potential of EF in prevention of steroid-associated ON.


Simplifying the audit of risk factor recording and control: A report from an international study in 11 countries.
To simplify the assessment of the recording and control of coronary heart disease risk factors in different countries and regions. The SUrvey of Risk Factors (SURF) is an international clinical audit. Data on consecutive patients with established coronary heart disease from countries in Europe, Asia and the Middle East were collected on a one-page collection sheet or electronically during routine clinic visits. Information on demographics, diagnostic category, risk factors, physical and laboratory measurements, and medications were included and key variables summarized in a Cardiovascular Health Index Score. Coronary heart disease patients (N = 10,186; 29% women) were enrolled from 79 centres in 11 countries. Recording of risk factors varied considerably: smoking was recorded in over 98% of subjects, while about 20% lacked data on laboratory measurements relevant to cardiovascular disease risk. Sixteen per cent of participants reported smoking, 29% were obese, and 46% had abdominal obesity. Sixty per cent of participants had blood pressure <140/90 mmHg (140/80 mmHg for diabetics), 48% had HbA1c<7%, 30% had low-density lipoprotein <1.8 mmol/l and 17% had a good cardiovascular health index score. There were substantial regional variations. Less than 3% of patients attended cardiac rehabilitation in Asia or the Middle East, compared with 45% in Europe. In Asia, 15% of patients had low-density lipoprotein cholesterol <1.8 mmol/l compared with 33% in Europe and 36% in the Middle East. Variations in medications were noted, with lower use of statins in Asia. SURF proved to be practical in daily practice. Results indicated poor control of risk factors with substantial variation between countries, calling for development and implementation of clinical standards of secondary prevention of coronary heart disease.


Venous drainage of the face.
The venous anatomy of the face was examined in 12 fresh cadavers. Venograms and arteriovenograms were obtained after the injection of contrast medium. In 8 of the 12 cadavers, a large loop was formed by the facial vein, the supratrochlear vein, and the superficial temporal vein, which became the main trunk vein of the face. In 4 of the 12 cadavers, the superior lateral limb of the loop vein was less well developed. The loop vein generally did not accompany the arteries of the face. Cutaneous branches of the loop vein formed a polygonal venous network in the skin, while communicating branches ran toward deep veins. These findings suggest that blood from the dermis of the face is collected by the polygonal venous network and enters the loop vein through the cutaneous branches, after which blood flows away from the face through the superficial temporal vein, the facial vein, and the communicating branches and enters the deep veins.


Fucosylated chondroitin sulfates from the body wall of the sea cucumber Holothuria forskali: conformation, selectin binding, and biological activity.
Fucosylated chondroitin sulfate (fCS) extracted from the sea cucumber Holothuria forskali is composed of the following repeating trisaccharide unit: → 3)GalNAcβ4,6S(1 → 4) [FucαX(1 → 3)]GlcAβ(1 →, where X stands for different sulfation patterns of fucose (X = 3,4S (46%), 2,4S (39%), and 4S (15%)). As revealed by NMR and molecular dynamics simulations, the fCS repeating unit adopts a conformation similar to that of the Le(x) blood group determinant, bringing several sulfate groups into close proximity and creating large negative patches distributed along the helical skeleton of the CS backbone. This may explain the high affinity of fCS oligosaccharides for L- and P-selectins as determined by microarray binding of fCS oligosaccharides prepared by Cu(2+)-catalyzed Fenton-type and photochemical depolymerization. No binding to E-selectin was observed. fCS poly- and oligosaccharides display low cytotoxicity in vitro, inhibit human neutrophil elastase activity, and inhibit the migration of neutrophils through an endothelial cell layer in vitro. Although the polysaccharide showed some anti-coagulant activity, small oligosaccharide fCS fragments had much reduced anticoagulant properties, with activity mainly via heparin cofactor II. The fCS polysaccharides showed prekallikrein activation comparable with dextran sulfate, whereas the fCS oligosaccharides caused almost no effect. The H. forskali fCS oligosaccharides were also tested in a mouse peritoneal inflammation model, where they caused a reduction in neutrophil infiltration. Overall, the data presented support the action of fCS as an inhibitor of selectin interactions, which play vital roles in inflammation and metastasis progression. Future studies of fCS-selectin interaction using fCS fragments or their mimetics may open new avenues for therapeutic intervention.


Microelectrode recording and macrostimulation in thalamic and subthalamic MRI guided stereotactic surgery.
Stereotactic neurosurgery aims at placing therapeutic lesions or chronic stimulating electrodes at very precise locations within the brain. Microelectrode recording and macrostimulation are used in addition to anatomoradiological techniques to optimize targeting. Recently, the usefulness of electrophysiological procedures has been questioned. Based on more than 500 therapeutic stereotactic lesions in the last 10 years at the thalamic and subthalamic levels, we evaluate here retrospectively the utility of the two electrophysiological procedures. In two of the three stereotactic targets considered in this study, intraoperative electrophysiological confirmation is mandatory because of the target size with respect to interindividual anatomical variations and of the more or less close vicinity of eloquent structures.


Direct current electric field regulates endothelial permeability under physiologically relevant fluid forces in a microfluidic vessel bifurcation model.
Previous in vitro studies have reported on the use of direct current electric fields (DC-EFs) to regulate vascular endothelial permeability, which is important for tissue regeneration and wound healing. However, these studies have primarily used static 2D culture models that lack the fluid mechanical forces associated with blood flow experienced by endothelial cells (ECs) in vivo. Hence, the effect of DC-EF on ECs under physiologically relevant fluid forces is yet to be systematically evaluated. Using a 3D microfluidic model of a bifurcating vessel, we report the role of DC-EF on regulating endothelial permeability when co-applied with physiologically relevant fluid forces that arise at the vessel bifurcation. The application of a 70 V m-1 DC-EF simultaneously with 1 μL min-1 low perfusion rate (generating 3.8 dyn cm-2 stagnation pressure at the bifurcation point and 0.3 dyn cm-2 laminar shear stress in the branched vessel) increased the endothelial permeability 7-fold compared to the static control condition (i.e., without flow and DC-EF). When the perfusion rate was increased to 10 μL min-1 (generating 38 dyn cm-2 stagnation pressure at the bifurcation point and 3 dyn cm-2 laminar shear stress in the branched vessel) while maintaining the same electrical stimulation, a 4-fold increase in endothelial permeability compared to the static control was observed. The lower increase in endothelial permeability for the higher fluid forces but the same DC-EF suggests a competing role between fluid forces and the applied DC-EF. Moreover, the observed increase in endothelial permeability due to combined DC-EF and flow was transient and dependent on the Akt signalling pathway. Collectively, these findings provide significant new insights into how the endothelium serves as an electro-mechanical interface for regulating vessel permeability.


In vivo two-photon imaging of neuronal and brain vascular responses in mice chronically exposed to ethanol.
The effects of ethanol on brain function have been extensively studied using a variety of in vitro and in vivo techniques. For example, electrophysiological studies using brain slices from rodents and non-human primates have demonstrated that acute and chronic exposure to ethanol alters the intrinsic excitability and synaptic signaling of neurons within cortical and sub-cortical areas of the brain. In humans, neuroimaging studies reveal alterations in measures of brain activation and connectivity in subjects with alcohol use disorder. While complementary, these methods are inherently limited due to issues related to either disruption of normal sensory input (in vitro slice studies) or resolution (whole brain imaging). In the present study, we used 2-photon laser scanning microscopy in intact animals to assess the impact of chronic ethanol exposure on sensory-evoked neuronal and vascular responses. Adult male C57BL/6J mice were exposed to four weekly cycles of chronic intermittent ethanol (CIE) exposure, while control mice were exposed to air. After withdrawal (≥72 h), a cranial window was placed over the primary visual cortex (V1), and sensory-evoked responses were monitored using the calcium indicator OGB-1. CIE exposure produced small but significant changes in response amplitude (decrease) and orientation selectivity of V1 neurons (increase). While arteriole diameter did not differ between control and CIE mice under baseline conditions, sensory-evoked dilation was enhanced in vessels from CIE-exposed mice as compared to controls. This was accompanied by a reduced latency in response to stimulation. In separate experiments, pial arteriole diameter was measured in the barrel cortex of control and CIE-exposed mice. Baseline diameter of barrel cortex arterioles was similar between control and CIE-exposed mice, but unlike vessels in V1, sensory-evoked dilation of barrel cortex arterioles was similar between the two groups. Together, the results of these studies suggest that chronic exposure to alcohol induces changes in neurovascular coupling that are region-dependent.


Imatinib mesylate is a potent inhibitor of the ABCG2 (BCRP) transporter and reverses resistance to topotecan and SN-38 in vitro.
Imatinib mesylate (Gleevec, STI571) is a kinase inhibitor selective for Bcr-Abl, activated c-Kit kinases, and platelet-derived growth factor receptor tyrosine kinase. Imatinib mesylate, similar to many other tyrosine kinase inhibitors (TKIs), such as members of the 4-anilinoquinazoline class, competes for ATP binding. Previously, 4-anilinoquinazoline TKIs have been shown to inhibit the function of the breast cancer resistance-associated drug transporter (ABCG2), reversing resistance to camptothecin derivatives topotecan and SN-38. However, the potential to inhibit ABCG2 for the 2-phenylamino-pyrimidine class of TKIs, exemplified by imatinib mesylate, has not been examined. Here, we show that imatinib mesylate potently reverses ABCG2-mediated resistance to topotecan and SN-38 and significantly increases accumulation of topotecan only in cells expressing functional ABCG2. However, overexpression of ABCG2 does not confer resistance to imatinib mesylate. Furthermore, accumulation and efflux of [(14)C]imatinib mesylate are unaltered between ABCG2-expressing and non-ABCG2-expressing cells or by ATP depletion. These results suggest that imatinib mesylate inhibits the function of ABCG2 but is not a substrate for this transporter.


Is there a link between wealth and cardiovascular disease risk factors among Hispanic/Latinos? Results from the HCHS/SOL sociocultural ancillary study.
To examine the relationship between wealth and cardiovascular disease risk factors among Hispanic/Latinos of diverse backgrounds. This cross-sectional study used data from 4971 Hispanic/Latinos, 18-74 years, who participated in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) baseline exam and the HCHS/SOL Sociocultural Ancillary Study. Three objectively measured cardiovascular disease risk factors (hypertension, hypercholesterolemia, and obesity) were included. Wealth was measured using an adapted version of the Home Affluence Scale, which included questions regarding the ownership of a home, cars, computers, and recent vacations. After adjusting for traditional socioeconomic indicators (income, employment, education), and other covariates, we found that wealth was not associated with hypertension, hypercholesterolemia or obesity. Analyses by sex showed that middle-wealth women were less likely to have hypercholesterolemia or obesity. Analyses by Hispanic/Latino background groups showed that while wealthier Central Americans were less likely to have obesity, wealthier Puerto Ricans were more likely to have obesity. This is the first study to explore the relationship between wealth and health among Hispanic/Latinos of diverse backgrounds, finding only partial evidence of this association. Future studies should utilize more robust measures of wealth, and address mechanisms by which wealth may impact health status among Hispanic/Latinos of diverse backgrounds in longitudinal designs.


Tumor O(6)-methylguanine-DNA methyltransferase inactivation by oral lomeguatrib.
A major mechanism of resistance to chlorethylnitrosureas and methylating agents involves the DNA repair protein O(6)-methylguanine-DNA methyltransferase (MGMT). We sought to determine the dose of oral 6-(4-bromo-2-thienyl) methoxy purin-2-amine (lomeguatrib), a pseudosubstrate inactivator of MGMT, required to render active protein undetectable 12 hours after dosing in prostate, primary central nervous system (CNS), and colorectal cancer patients. Lomeguatrib was administered orally as a single dose (20-160 mg) approximately 12 hours before tumor resection. Dose escalation was projected to continue until grade 2 toxicity or until complete inactivation of tumor MGMT was encountered. Total MGMT protein levels were quantified by ELISA, and active protein levels were quantified by biochemical assay. MGMT promoter methylation was determined in glioblastoma DNA by methylation-specific PCR. Thirty-seven patients were dosed with lomeguatrib, and 32 informative tumor samples were obtained. Mean total MGMT level varied between tumor types: 554 +/- 404 fmol/mg protein (+/-SD) for prostate cancer, 87.4 +/- 40.3 fmol/mg protein for CNS tumors, and 244 +/- 181 fmol/mg protein for colorectal cancer. MGMT promoter hypermethylation did not correlate with total protein expression. Consistent total MGMT inactivation required 120 mg of lomeguatrib in prostate and colorectal cancers. Complete consistent inactivation in CNS tumors was observed only at the highest dose of lomeguatrib (160 mg). Total MGMT inactivation can be achieved in prostate, primary CNS, and colorectal cancers with a single administration of 120 or 160 mg lomeguatrib. The dose needed did not correlate with mean total MGMT protein concentrations. One hundred twenty to 160 mg/d of lomeguatrib should be administered to achieve total MGMT inactivation in future studies.


Facile synthesis of anhydrous alkaline earth metal dodecaborates MB12H12 (M = Mg, Ca) from M(BH4)2.
Metal dodecaborates M2/nB12H12 are among the dehydrogenation intermediates of metal borohydrides M(BH4)n with a high hydrogen density of approximately 10 mass%, the latter is a potential hydrogen storage material. There is therefore a great need to synthesize anhydrous M2/nB12H12 in order to investigate the thermal decomposition of M2/nB12H12 and to understand its role in the dehydrogenation and rehydrogenation of M(BH4)n. In this work, anhydrous alkaline earth metal dodecaborates MB12H12 (M = Mg, Ca) have been successfully synthesized by sintering M(BH4)2 (M = Mg, Ca) and B10H14 in a stoichiometric molar ratio of 1 : 1. Thermal decomposition of MB12H12 shows multistep pathways with the formation of H-deficient monomers MB12H12-x containing icosahedral B12 skeletons and is followed by the formation of (MByHz)n polymers. Comparison of the thermal decomposition of MB12H12 and M(BH4)2 suggests different behaviours of the anhydrous MB12H12 and those formed from the decomposition of M(BH4)n.


Prolonged GABAA-mediated inhibition following single hair afferent input to single spinal dorsal horn neurones in cats.
To study the central processing mechanisms of sensory input from low threshold afferents to the spinal cord, we examined the excitatory response of single lumbar dorsal horn neurones to stimulation of hairs in the receptive field using a mechanically driven probe, and to activation of single hair follicle afferents using an intracellular current pulse to the cell bodies in the dorsal root ganglion. Experiments were done on anaesthetized, paralysed cats, spinalized at the L1 lumbar level. Responses of spinal neurones to two types of hair afferent input were characteristically different. The excitatory response to input from a single group II hair afferent (A beta; innervating guard hair follicle receptors) was multimodal, characterized by a small early depolarization followed by a sharp, large component with a slow, prolonged decay phase, whereas the response to input from a single group III hair afferent (A delta; innervating down hair follicle receptors) was unimodal. The unitary EPSPs in response to activation of group III hair afferents had a slower rise time and longer decay time constant than those in response to activation of group II hair afferents. When the receptive field of the afferent was located in the centre of the receptive field of the dorsal horn neurone, the gain of the central response was greater for the input from a single group II afferent (> 1) than that for the input from a single group III afferent (< 1). In the case of single group II hair afferents, when pairs of single action potentials or pairs of trains of action potentials were generated at intervals of 20 ms to 3 s, the response in the dorsal horn neurone to the second volley was markedly depressed at intervals of less than 2 s, without any apparent inhibition of the on-going rate of firing. The response to the second volley in single group III afferents was less depressed. This inhibition of the response to the second of a paired volley in single group II hair afferents was attenuated by administration of bicuculline, but not strychnine or naloxone. This indicates that the inhibition involves a GABAA-receptor-mediated mechanism. Bicuculline did not affect the late component of the response to single group II hair afferent input, but unmasked a late component of the response to mechanical stimulation of hairs.(ABSTRACT TRUNCATED AT 400 WORDS)


A new paper-based platform technology for point-of-care diagnostics.
Currently, the Lateral flow Immunoassays (LFIAs) are not able to perform complex multi-step immunodetection tests because of their inability to introduce multiple reagents in a controlled manner to the detection area autonomously. In this research, a point-of-care (POC) paper-based lateral flow immunosensor was developed incorporating a novel microfluidic valve technology. Layers of paper and tape were used to create a three-dimensional structure to form the fluidic network. Unlike the existing LFIAs, multiple directional valves are embedded in the test strip layers to control the order and the timing of mixing for the sample and multiple reagents. In this paper, we report a four-valve device which autonomously directs three different fluids to flow sequentially over the detection area. As proof of concept, a three-step alkaline phosphatase based Enzyme-Linked ImmunoSorbent Assay (ELISA) protocol with Rabbit IgG as the model analyte was conducted to prove the suitability of the device for immunoassays. The detection limit of about 4.8 fm was obtained.


Treating Insomnia with High Risk of Depression Using Therapist-Guided Digital Cognitive, Behavioral, and Circadian Rhythm Support Interventions to Prevent Worsening of Depressive Symptoms: A Randomized Controlled Trial.
The global disease burden of major depressive disorder urgently requires prevention in high-risk individuals, such as recently discovered insomnia subtypes. Previous studies targeting insomnia with fully automated eHealth interventions to prevent depression are inconclusive: dropout was high and likely biased, and depressive symptoms in untreated participants on average improved rather than worsened. This randomized controlled trial aimed to efficiently prevent the worsening of depressive symptoms by selecting insomnia subtypes at high risk of depression for internet-based circadian rhythm support (CRS), cognitive behavioral therapy for insomnia (CBT-I), or their combination (CBT-I+CRS), with online therapist guidance to promote adherence. Participants with an insomnia disorder subtype conveying an increased risk of depression (n = 132) were randomized to no treatment (NT), CRS, CBT-I, or CBT-I+CRS. The Inventory of Depressive Symptomatology - Self Report (IDS-SR) was self-administered at baseline and at four follow-ups spanning 1 year. Without treatment, depressive symptoms indeed worsened (d = 0.28, p = 0.041) in high-risk insomnia, but not in a reference group with low-risk insomnia. Therapist-guided CBT-I and CBT-I+CRS reduced IDS-SR ratings across all follow-up assessments (respectively, d = -0.80, p = 0.001; d = -0.95, p < 0.001). Only CBT-I+CRS reduced the 1-year incidence of clinically meaningful worsening (p = 0.002). Dropout during therapist-guided interventions was very low (8%) compared to previous automated interventions (57-62%). The findings tentatively suggest that the efficiency of population-wide preventive strategies could benefit from the possibility to select insomnia subtypes at high risk of developing depression for therapist-guided digital CBT-I+CRS. This treatment may provide effective long-term prevention of worsening of depressive symptoms. the Netherlands Trial Register (NL7359).


Conversion of phylloquinone (Vitamin K1) into menaquinone-4 (Vitamin K2) in mice: two possible routes for menaquinone-4 accumulation in cerebra of mice.
There are two forms of naturally occurring vitamin K, phylloquinone and the menaquinones. Phylloquinone (vitamin K(1)) is a major type (>90%) of dietary vitamin K, but its concentrations in animal tissues are remarkably low compared with those of the menaquinones, especially menaquinone-4 (vitamin K(2)), the major form (>90%) of vitamin K in tissues. Despite this great difference, the origin of tissue menaquinone-4 has yet to be exclusively defined. It is postulated that phylloquinone is converted into menaquinone-4 and accumulates in extrahepatic tissues. To clarify this, phylloquinone with a deuterium-labeled 2-methyl-1,4-naphthoquinone ring was given orally to mice, and cerebra were collected for D NMR and liquid chromatography-tandem mass spectrometry analyses. We identified the labeled menaquinone-4 that was converted from the given phylloquinone, and this conversion occurred following an oral or enteral administration, but not parenteral or intracerebroventricular administration. By the oral route, the phylloquinone with the deuterium-labeled side chain in addition to the labeled 2-methyl-1,4-naphthoquinone was clearly converted into a labeled menaquinone-4 with a non-deuterium-labeled side chain, implying that phylloquinone was converted into menaquinone-4 via integral side-chain removal. The conversion also occurred in cerebral slice cultures and primary cultures. Deuterium-labeled menadione was consistently converted into the labeled menaquinone-4 with all of the administration routes and the culture conditions tested. Our results suggest that cerebral menaquinone-4 originates from phylloquinone intake and that there are two routes of accumulation, one is the release of menadione from phylloquinone in the intestine followed by the prenylation of menadione into menaquinone-4 in tissues, and another is cleavage and prenylation within the cerebrum.


Purification and characterization of myotoxin IV, a phospholipase A2 variant, from Bothrops asper snake venom.
A basic myotoxic protein was purified from Bothrops asper venom. Like other basic Bothrops myotoxins, myotoxin IV induces acute muscle damage after intramuscular injection in mice and disrupts negatively charged liposomes but not positively charged ones. Furthermore, this protein exerts a weak anticoagulant effect only at concentrations of 40 micrograms/ml or higher, and is devoid of phospholipase A2 activity. Rabbit polyclonal antibodies to B. asper myotoxin II, a related lysine-49 isoform, cross-react strongly with myotoxin IV by enzyme immunoassay, indicating a high degree of antigenic similarity between these two proteins. The fact that both toxins have similar amino acid compositions and amino-terminal sequences, including leucine-5 and glutamine-11, 2 amino acid residues conserved in all lysine-49 phospholipase A2 variants purified, strongly suggests that B. asper myotoxin IV is a lysine-49 phospholipase A2.


Muscle specification in the Xenopus laevis gastrula-stage embryo.
Recent fate maps of the Xenopus laevis gastrula show that mesodermal tissue surrounding the blastopore gives rise to muscle (Keller [1991] Methods Cell Biol 36:61-113; Lane and Smith [1999] Development 126:423-434). In a significant deviation from earlier data, the new maps demonstrate that cells in the ventral half of the gastrula are precursors to a significant portion of trunk somites. However, these posterior somites are not formed until tadpole stages (stages 38-44). We therefore set out to determine the timing of muscle specification within the ventral half of the gastrula. Our approach was to generate a series of tissue explants from gastrula-stage embryos and then culture them to either stage 28 (tailbud) or stage 44 (tadpole). At each endpoint, the presence of muscle in explants was assessed with a muscle-specific antibody. Interestingly, we found that muscle tissue is detected in ventral explants. However, these explants must be cultured to the tadpole stage. This is perhaps not unexpected, as this is the point at which this tissue normally gives rise to muscle. We further show that muscle specification of the involuting marginal zone does not change over the course of gastrulation. Together, these results suggest that dorsalizing signals emanating from the midline during gastrulation are not necessary for muscle specification of the ventral half of the involuting marginal zone.


The effects of arterial carbon dioxide partial pressure and sevoflurane on capillary venous cerebral blood flow and oxygen saturation during craniotomy.
Intraoperative routine monitoring of cerebral blood flow and oxygenation remains a technological challenge. Using the physiological principle of carbon dioxide reactivity of cerebral vasculature, we investigated a recently developed neuromonitoring device (oxygen-to-see, O2C device) for simultaneous measurements of regional cerebral blood flow (rvCBF), blood flow velocity (rvVelo), oxygen saturation (srvO2), and hemoglobin amount (rvHb) at the capillary venous level in patients subjected to craniotomy. Twenty-six neurosurgical patients were randomly assigned to anesthesia with 1.4% or 2.0% sevoflurane end-tidal concentration. After craniotomy, a fiberoptic probe was applied on a macroscopically healthy surface of cerebral tissue next to the site of surgery. Simultaneous measurements in 2 and 8 mm cerebral depth were performed in each patient during lower (35 mm Hg) and higher (45 mm Hg) levels (random order) of arterial carbon dioxide partial pressure (PaCO2). The principle of these measurements relies on the combination of laser-Doppler flowmetry (rvCBF, rvVelo) and photo-spectrometry (srvO2, rvHb). Linear models were fitted to test changes of end points (rvCBF, rvVelo, srvO2, rvHb) in response to lower and higher levels of PaCO2, 1.4% and 2.0% sevoflurane end-tidal concentration, and 2 and 8 mm cerebral depth. RvCBF and rvVelo were elevated by PaCO2 independent of sevoflurane concentration in 2 and 8 mm depth of cerebral tissue (P < 0.001). Higher PaCO2 induced an increase in mean srvO2 from 50% to 68% (P < 0.001). RvVelo (P < 0.001) and srvO2 (P = 0.007) were higher in 8 compared with 2 mm cerebral depth. RvHb was not influenced by alterations in PaCO2 but positively correlated to sevoflurane concentration (P = 0.005). Increases in rvCBF and rvVelo by PaCO2 suggest preserved hypercapnic vasodilation under anesthesia with sevoflurane 1.4% and 2.0% end-tidal concentration. A consecutive increase in srvO2 implies that cerebral arteriovenous difference in oxygen was decreased by elevated PaCO2. Unchanged levels of rvHb signify that there was no blood loss during measurements. Data suggest that the device allows detection of local changes in blood flow and oxygen saturation in response to different PaCO2 levels in predominant venous cerebral microvessels.


G-quadruplexes in viruses: function and potential therapeutic applications.
G-rich nucleic acids can form non-canonical G-quadruplex structures (G4s) in which four guanines fold in a planar arrangement through Hoogsteen hydrogen bonds. Although many biochemical and structural studies have focused on DNA sequences containing successive, adjacent guanines that spontaneously fold into G4s, evidence for their in vivo relevance has recently begun to accumulate. Complete sequencing of the human genome highlighted the presence of ∼300,000 sequences that can potentially form G4s. Likewise, the presence of putative G4-sequences has been reported in various viruses genomes [e.g., Human immunodeficiency virus (HIV-1), Epstein-Barr virus (EBV), papillomavirus (HPV)]. Many studies have focused on telomeric G4s and how their dynamics are regulated to enable telomere synthesis. Moreover, a role for G4s has been proposed in cellular and viral replication, recombination and gene expression control. In parallel, DNA aptamers that form G4s have been described as inhibitors and diagnostic tools to detect viruses [e.g., hepatitis A virus (HAV), EBV, cauliflower mosaic virus (CaMV), severe acute respiratory syndrome virus (SARS), simian virus 40 (SV40)]. Here, special emphasis will be given to the possible role of these structures in a virus life cycle as well as the use of G4-forming oligonucleotides as potential antiviral agents and innovative tools.


The hypertension register of the North Karelia project.
1. One major subprogramme of the North Karelia Project was the hypertension programme which aimed at lowering of the high blood pressure among the whole population, and expecially among middle-aged men. The hypertension programme consisted of intervention integrated with the existing health care structure of the county of North Karelia. 2. The hypertension register, which was the major tool of the programme, aimed to maintain patients in treatment and to get information about the development of the programme. Registration of hypertensive subjects was continuous between 1972 and 1977 and registered patients had annual follow-up examinations. 3. After 5 years of the programme, there were approximately 17 000 registered patients which is 9.7% of the total population. 4. Proportion of drop-outs at the annual follow-up examinations was less than 10%. 83% of the registered hypertensive subjects were under drug treatment after 3 years intervention. The percentage of normotensive subjects increased significantly year by year. 5. Preliminary results from the stroke register of the North Karelia Project indicate that the incidence of stroke decreased as hypertension control was improved.


The Neecham Confusion Scale and the Delirium Observation Screening Scale: capacity to discriminate and ease of use in clinical practice.
Delirium is a frequent form of psychopathology in elderly hospitalized patients; it is a symptom of acute somatic illness. The consequences of delirium include high morbidity and mortality, lengthened hospital stay, and nursing home placement. Early recognition of delirium symptoms enables the underlying cause to be diagnosed and treated and can prevent negative outcomes. The aim of this study was to determine which of the two delirium observation screening scales, the NEECHAM Confusion Scale or the Delirium Observation Screening (DOS) scale, has the best discriminative capacity for diagnosing delirium and which is more practical for daily use by nurses. The project was conducted on four wards of a university hospital; 87 patients were included. During 3 shifts, these patients were observed for symptoms of delirium, which were rated on both scales. A DSM-IV diagnosis of delirium was made or rejected by a geriatrician. Nurses were asked to rate the practical value of both scales using a structured questionnaire. The sensitivity (0.89-1.00) and specificity (0.86-0.88) of the DOS and the NEECHAM were high for both scales. Nurses rated the practical use of the DOS scale as significantly easier than the NEECHAM. Successful implementation of standardized observation depends largely on the consent of professionals and their acceptance of a scale. In our hospital, we therefore chose to involve nurses in the choice between two instruments. During the study they were able to experience both scales and give their opinion on ease of use. In the final decision on the instrument we found that both scales were very acceptable in terms of sensitivity and specificity, so the opinion of the nurses was decisive. They were positive about both instruments; however, they rated the DOS scale as significantly easier to use and relevant to their practice. Our findings were obtained from a single site study with a small sample, so a large comparative trial to study the value of both scales further is recommended. On the basis of our experience during this study and findings from the literature with regard to the implementation of delirium guidelines, we will monitor the further implementation of the DOS Scale in our hospital with intensive consultation.


Extreme value statistics in Raman fiber lasers.
We present the numerical study of the statistical properties of the partially coherent quasi-CW high-Q cavity Raman fiber laser. The statistical properties are different for the radiation generated at one or many cavity passes. It is found that rare extreme events are generated at the far spectral wings of the spectrum. The mechanism of the extreme events generation is a turbulent-like four-wave mixing of numerous longitudinal generation modes.


Secondary prevention in coronary artery disease. Achieved goals and possibilities for improvements.
To describe presence of risk indicators of recurrence 6 months after hospitalisation due to coronary artery disease at a university clinic. The presence of risk indicators, including tobacco use, lipid levels, blood pressure and glucometabolic status, including 24-hour blood pressure monitoring and an oral glucose-tolerance test, was analysed. Of 1465 patients who were screened, 402 took part in the survey (50% previous myocardial infarction and 50% angina pectoris). Mean age was 64 years (range 40-85 years) and 23% were women. Present medications were: lipid lowering drugs (statins; 94%), beta-blockers (85%), aspirin or warfarin (100%) and ACE-inhibitors or angiotensin II blockers (66%). Values above target levels recommended in guidelines were: a) low density lipoprotein (LDL) in 40%; b) mean blood pressure (day or night) in 38% and c) smoking in 13%. Of all patients, 66% had at least one risk factor (LDL or blood pressure above target levels or current smoking). An abnormal glucose-tolerance test was found in 59% of patients without known diabetes. If no history of diabetes, 85% had either LDL or blood pressure above target levels, current smoking or an abnormal glucose-tolerance test. However, with treatment intensification to patients with elevated risk factors 56% reached target levels for blood pressure and 79% reached target levels for LDL. Six months after hospitalisation due to coronary artery disease, despite the high use of medication aimed at prophylaxis against recurrence, the majority were either above target levels for LDL or blood pressure or continued to smoke.


Addressing deficiencies in american healthcare education: a call for informed instructional design.
In a drive toward improved quality and safety in medicine, educators have emphasized the importance of lifelong learning and improved pedagogical models to effective continuing education. Scholarly understanding of disciplinary knowledge and expert thought has progressed rapidly in the past 40 years. Lessons from adult learning theory can and should be systematically applied to the design of effective, learner- centered, collaborative, and conceptually driven continuing education for physicians and surgeons. One example of this pedagogical approach is Integrated Medical Learning (IML), an instructional theory that is based on dynamic interaction between each element of the learning process, is learner centered, incorporates self-assessment, uses various formats and media to facilitate learning, and seeks to apply scientific method to educational process development. This article discusses advances in learning, instructional theory, and practice relevant to medical continuing education and outlines the conceptual basis for IML. The first iteration of IML, which took place in part at the General Scientific Sessions of the 2007 Annual Meeting of the Congress of Neurological Surgeons, will be described elsewhere. In addition to advancing goals related to educational effectiveness, IML produces novel and otherwise not easily obtainable data about current clinical knowledge, attitudes, and actual practice patterns that are relevant to clinical equipoise, study design, and medical evidence.


Carvacrol Protects against Hepatic Steatosis in Mice Fed a High-Fat Diet by Enhancing SIRT1-AMPK Signaling.
We investigated the protective effect of carvacrol against high-fat-diet-induced hepatic steatosis in mice and the potential underlying molecular mechanisms. Mice were fed a normal diet, high-fat diet, or carvacrol-supplemented high-fat diet for 10 weeks. Compared to mice fed the high-fat diet, those fed the carvacrol-supplemented diet showed significantly lower hepatic lipid levels and reduced plasma activities of alanine aminotransferase and aspartate aminotransferase and plasma concentrations of monocyte chemoattractant protein 1 and tumor necrosis factor α . Carvacrol decreased the expression of LXR α , SREBP1c, FAS, leptin, and CD36 genes and phosphorylation of S6 kinase 1 protein involved in lipogenesis, whereas it increased the expression of SIRT1 and CPT1 genes and phosphorylation of liver kinase B1, AMP-activated protein kinase, and acetyl-CoA carboxylase proteins involved in fatty acid oxidation in the liver of mice fed the high-fat diet. These results suggest that carvacrol prevents HFD-induced hepatic steatosis by activating SIRT1-AMPK signaling.


Dysfunction of fibroblasts of extrarenal origin underlies renal fibrosis and renal anemia in mice.
In chronic kidney disease, fibroblast dysfunction causes renal fibrosis and renal anemia. Renal fibrosis is mediated by the accumulation of myofibroblasts, whereas renal anemia is mediated by the reduced production of fibroblast-derived erythropoietin, a hormone that stimulates erythropoiesis. Despite their importance in chronic kidney disease, the origin and regulatory mechanism of fibroblasts remain unclear. Here, we have demonstrated that the majority of erythropoietin-producing fibroblasts in the healthy kidney originate from myelin protein zero-Cre (P0-Cre) lineage-labeled extrarenal cells, which enter the embryonic kidney at E13.5. In the diseased kidney, P0-Cre lineage-labeled fibroblasts, but not fibroblasts derived from injured tubular epithelial cells through epithelial-mesenchymal transition, transdifferentiated into myofibroblasts and predominantly contributed to fibrosis, with concomitant loss of erythropoietin production. We further demonstrated that attenuated erythropoietin production in transdifferentiated myofibroblasts was restored by the administration of neuroprotective agents, such as dexamethasone and neurotrophins. Moreover, the in vivo administration of tamoxifen, a selective estrogen receptor modulator, restored attenuated erythropoietin production as well as fibrosis in a mouse model of kidney fibrosis. These findings reveal the pathophysiological roles of P0-Cre lineage-labeled fibroblasts in the kidney and clarify the link between renal fibrosis and renal anemia.


Balloon catheter-based radiofrequency ablation monitoring in porcine esophagus using optical coherence tomography.
We present a microscopic image guidance platform for radiofrequency ablation (RFA) using a clinical balloon-catheter-based optical coherence tomography (OCT) system, currently used in the surveillance of Barrett's esophagus patients. Our integrated thermal therapy delivery and monitoring platform consists of a flexible, customized bipolar RFA electrode array designed for use with a clinical balloon OCT catheter and a processing algorithm to accurately map the thermal coagulation process. Non-uniform rotation distortion was corrected using a feature tracking-based technique, which enables robust, frame-to-frame analysis of the temporal fluctuation of the complex OCT signal. With proper noise calibration, precise delineation of the thermal therapy zone was demonstrated using cumulative complex differential variance in porcine esophagus ex vivo with the integrated OCT-RFA system, as validated by nitroblue tetrazolium chloride (NBTC) histology. The ability to directly and accurately visualize the thermal coagulation process at high resolution is critical to the precise delivery of thermal energy to a wide range of epithelial lesions.


Increased Y-chromosome resolution of haplogroup O suggests genetic ties between the Ami aborigines of Taiwan and the Polynesian Islands of Samoa and Tonga.
The Austronesian expansion has left its fingerprint throughout two thirds of the circumference of the globe reaching the island of Madagascar in East Africa to the west and Easter Island, off the coast of Chile, to the east. To date, several theories exist to explain the current genetic distribution of Austronesian populations, with the "slow boat" model being the most widely accepted, though other conjectures (i.e., the "express train" and "entangled bank" hypotheses) have also been widely discussed. In the current study, 158 Y chromosomes from the Polynesian archipelagos of Samoa and Tonga were typed using high resolution binary markers and compared to populations across Mainland East Asia, Taiwan, Island Southeast Asia, Melanesia and Polynesia in order to establish their patrilineal genetic relationships. Y-STR haplotypes on the C2 (M38), C2a (M208), O1a (M119), O3 (M122) and O3a2 (P201) backgrounds were utilized in an attempt to identify the differing sources of the current Y-chromosomal haplogroups present throughout Polynesia (of Melanesian and/or Asian descent). We find that, while haplogroups C2a, S and K3-P79 suggest a Melanesian component in 23%-42% of the Samoan and Tongan Y chromosomes, the majority of the paternal Polynesian gene pool exhibits ties to East Asia. In particular, the prominence of sub-haplogroup O3a2c* (P164), which has previously been observed at only minimal levels in Mainland East Asians (2.0-4.5%), in both Polynesians (ranging from 19% in Manua to 54% in Tonga) and Ami aborigines from Taiwan (37%) provides, for the first time, evidence for a genetic connection between the Polynesian populations and the Ami.


Cancer Survivorship Program: Implementation for Individuals With Recurrent Breast Cancer.
Patients are living longer with recurrent breast cancer, but survivorship programs for these individuals are lacking. The aims were to implement a survivorship program for individuals with recurrent breast cancer, increase their quality of life (QOL), and evaluate patient satisfaction with the program. Survivors were referred for a one-hour coaching intervention tailored to their needs based on results of the Functional Assessment of Cancer Therapy-Breast (FACT-B) survey. Satisfaction was assessed immediately and two weeks postintervention. A paired t test was used to evaluate QOL scores before and two weeks following participation. Statistically significant (p = 0.000) improvements were observed overall and in each subscale of the FACT-B survey. Patient satisfaction was high immediately postintervention and remained high at the two-week assessment.


Discovering thiamine transporters as targets of chloroquine using a novel functional genomics strategy.
Chloroquine (CQ) and other quinoline-containing antimalarials are important drugs with many therapeutic benefits as well as adverse effects. However, the molecular targets underlying most such effects are largely unknown. By taking a novel functional genomics strategy, which employs a unique combination of genome-wide drug-gene synthetic lethality (DGSL), gene-gene synthetic lethality (GGSL), and dosage suppression (DS) screens in the model organism Saccharomyces cerevisiae and is thus termed SL/DS for simplicity, we found that CQ inhibits the thiamine transporters Thi7, Nrt1, and Thi72 in yeast. We first discovered a thi3Δ mutant as hypersensitive to CQ using a genome-wide DGSL analysis. Using genome-wide GGSL and DS screens, we then found that a thi7Δ mutation confers severe growth defect in the thi3Δ mutant and that THI7 overexpression suppresses CQ-hypersensitivity of this mutant. We subsequently showed that CQ inhibits the functions of Thi7 and its homologues Nrt1 and Thi72. In particular, the transporter activity of wild-type Thi7 but not a CQ-resistant mutant (Thi7(T287N)) was completely inhibited by the drug. Similar effects were also observed with other quinoline-containing antimalarials. In addition, CQ completely inhibited a human thiamine transporter (SLC19A3) expressed in yeast and significantly inhibited thiamine uptake in cultured human cell lines. Therefore, inhibition of thiamine uptake is a conserved mechanism of action of CQ. This study also demonstrated SL/DS as a uniquely effective methodology for discovering drug targets.


Analyzing image deblurring through three paradigms.
To recover a sharp version from a blurred image is a long-standing inverse problem. In this paper, we analyze the research on this topic both theoretically and experimentally through three paradigms: 1) the deterministic filter; 2) Bayesian estimation; and 3) the conjunctive deblurring algorithm (CODA), which performs the deterministic filter and Bayesian estimation in a conjunctive manner. We point out the weaknesses of the deterministic filter and unify the limitation latent in two kinds of Bayesian estimators. We further explain why the CODA is able to handle quite large blurs beyond Bayesian estimation. Finally, we propose a novel method to overcome several unreported limitations of the CODA. Although extensive experiments demonstrate that our method outperforms state-of-the-art methods with a large margin, some common problems of image deblurring still remain unsolved and should attract further research efforts.


Combining nitric oxide release with anti-inflammatory activity preserves nigrostriatal dopaminergic innervation and prevents motor impairment in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of Parkinson's disease.
Current evidence suggests a role of neuroinflammation in the pathogenesis of Parkinson's disease (PD) and in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of basal ganglia injury. Reportedly, nonsteroidal anti-inflammatory drugs (NSAIDs) mitigate DAergic neurotoxicity in rodent models of PD. Consistent with these findings, epidemiological analysis indicated that certain NSAIDs may prevent or delay the progression of PD. However, a serious impediment of chronic NSAID therapy, particularly in the elderly, is gastric, renal and cardiac toxicity. Nitric oxide (NO)-donating NSAIDs, have a safer profile while maintaining anti-inflammatory activity of parent compounds. We have investigated the oral activity of the NO-donating derivative of flurbiprofen, [2-fluoro-α-methyl (1,1'-biphenyl)-4-acetic-4-(nitrooxy)butyl ester], HCT1026 (30 mg kg(-1) daily in rodent chow) in mice exposed to the parkinsonian neurotoxin MPTP. Ageing mice were fed with a control, flurbiprofen, or HCT1026 diet starting ten days before MPTP administration and continuing for all the experimental period. Striatal high affinity synaptosomal dopamine up-take, motor coordination assessed with the rotarod, tyrosine hydroxylase (TH)- and dopamine transporter (DAT) fiber staining, stereological cell counts, immunoblotting and gene expression analyses were used to assess MPTP-induced nigrostriatal DAergic toxicity and glial activation 1-40 days post-MPTP. HCT1026 was well tolerated and did not cause any measurable toxic effect, whereas flurbiprofen fed mice showed severe gastrointestinal side-effects. HCT1026 efficiently counteracted motor impairment and reversed MPTP-induced decreased synaptosomal [3H]dopamine uptake, TH- and DAT-stained fibers in striatum and TH+ neuron loss in substantia nigra pars compacta (SNpc), as opposed to age-matched mice fed with a control diet. These effects were associated to a significant decrease in reactive macrophage antigen-1 (Mac-1)-positive microglial cells within the striatum and ventral midbrain, decreased expression of iNOS, Mac-1 and NADPH oxidase (PHOX), and downregulation of 3-Nitrotyrosine, a peroxynitrite finger print, in SNpc DAergic neurons. Oral treatment with HCT1026 has a safe profile and a significant efficacy in counteracting MPTP-induced dopaminergic (DAergic) neurotoxicity, motor impairment and microglia activation in ageing mice. HCT1026 provides a novel promising approach towards the development of effective pharmacological neuroprotective strategies against PD.


[Elongated styloid process (Eagle's syndrome): literature review and a case report].
Eagle's syndrome occurs when an elongated styloid process or calcified stylohyoid ligament causes recurrent throat pain or foreign body sensation, dysphagia, or facial pain. Additional symptoms may include neck or throat pain with radiation to the ipsilateral ear. The symptoms related to this condition can be confused with those attributed to a wide variety of facial neuralgias. Diagnosis can usually be made on physical examination by digital palpation of the styloid process in the tonsillar fossa. The treatment of Eagle's syndrome is primarily surgical. The styloid process can be shortened through an intraoral or external approach. We report a 51-year-old woman with the symptomatology of Eagle's syndrome and literature review.


Evaluation of an empiric risk screening score to identify acute and early HIV-1 infection among MSM in Coastal Kenya.
We evaluated the University of North Carolina-Malawi Risk Screening Score (UMRSS) for detection of acute and early HIV-1 infection (AEHI) in a cohort of Kenyan MSM with approximately 8% annual HIV-1 incidence. Three components of the UMRSS (fever, diarrhea, and discordant rapid HIV tests) were also independent predictors of AEHI in our cohort. The predictive ability (area under the receiver operating characteristic curve, AUC) of the UMRSS was 0.79. A cohort-derived risk score consisting of six characteristics (fever, diarrhea, discordant rapid HIV tests, fatigue, age <30 years, and symptomatic sexually transmitted disease) had a higher AUC of 0.85. Screening for AEHI will have substantial transmission prevention benefits.


NGS-based expanded carrier screening for genetic disorders in North Indian population reveals unexpected results - a pilot study.
To determine the carrier frequency and pathogenic variants of common genetic disorders in the north Indian population by using next generation sequencing (NGS). After pre-test counselling, 200 unrelated individuals (including 88 couples) were screened for pathogenic variants in 88 genes by NGS technology. The variants were classified as per American College of Medical Genetics criteria. Pathogenic and likely pathogenic variants were subjected to thorough literature-based curation in addition to the regular filters. Variants of unknown significance were not reported. Individuals were counselled explaining the implications of the results, and cascade screening was advised when necessary. Of the 200 participants, 52 (26%) were found to be carrier of one or more disorders. Twelve individuals were identified to be carriers for congenital deafness, giving a carrier frequency of one in 17 for one of the four genes tested (SLC26A4, GJB2, TMPRSS3 and TMC1 in decreasing order). Nine individuals were observed to be carriers for cystic fibrosis, with a frequency of one in 22. Three individuals were detected to be carriers for Pompe disease (frequency one in 67). None of the 88 couples screened were found to be carriers for the same disorder. The pathogenic variants observed in many disorders (such as deafness, cystic fibrosis, Pompe disease, Canavan disease, primary hyperoxaluria, junctional epidermolysis bullosa, galactosemia, medium chain acyl CoA deficiency etc.) were different from those commonly observed in the West. A higher carrier frequency for genetic deafness, cystic fibrosis and Pompe disease was unexpected, and contrary to the generally held view about their prevalence in Asian Indians. In spite of the small sample size, this study would suggest that population-based carrier screening panels for India would differ from those in the West, and need to be selected with due care. Testing should comprise the study of all the coding exons with its boundaries in the genes through NGS, as all the variants are not well characterized. Only study of entire coding regions in the genes will detect carriers with adequate efficiency, in order to reduce the burden of genetic disorders in India and other resource poor countries.


A Smart Haptic Hand-Held Device for Neurosurgical Microdissection.
Microneurosurgery requires dexterity, precision and delicate force application in order to be carried out safely and effectively. Neurosurgeons must apply sufficient force in order to carry out microsurgical procedures effectively but not excessive force such that iatrogenic injury occurs. This paper presents a smart hand-held microsurgical instrument that indicates to the surgeon when a force-threshold has been exceeded by providing vibrotactile feedback. Many existing haptic-feedback systems, particularly master-slave robotic platforms, are large, highly complex, and costly. By comparison, the proposed device is compact, fail-safe and low cost. Two psychophysical user studies were carried out to assess the proposed vibrotactile force-threshold feedback system. A cadaveric pilot study was carried out to evaluate the device in a microdissection task. In all the studies performed, the haptic dissector device has shown to be effective in providing real-time feedback in terms of force application during microsurgical tasks.


Patterns of nerve injury and neuropathic pain in ischemic neuropathy after ligation-reperfusion of femoral artery in mice.
Ischemia is an important etiology of painful neuropathies. We generated a mouse system of ischemic neuropathy by ligation-reperfusion of the femoral artery to mimic neuropathic pain and nerve injury patterns observed clinically. Mice exhibited spontaneous neuropathic pain behaviors, which were most obvious after ischemia for 5 h. Mechanical and cold allodynia developed by post-operative day (POD) 7 and persisted through the experimental period up to POD 56. Neuropathic pain behaviors were alleviated with intraperitoneal gabapentin (50 and 100 mg/kg) in a dose-dependent manner. Large-fiber deficit assessed with nerve conduction studies was demonstrated by reduced amplitudes of the compound muscle action potential (CMAP) on POD 7 (48.4% of the control side, p < 0.001). Small-fiber impairment was demonstrated by decreased epidermal nerve density (END) on POD 7 (29.1% of the control side, p < 0.001). Reductions in CMAP amplitudes and ENDs persisted through POD 56. Our system replicated the clinical manifestations of ischemic neuropathy: (1) neuropathic pain with cold and mechanical allodynia and (2) nerve injury to both large and small fibers with pathologic and physiologic evidence. This system produced by a simple procedure provides an opportunity to investigate mechanisms and further treatments of ischemic neuropathy on genetically engineered mice.


A Polyaniline-based Sensor of Nucleic Acids.
Detection of nucleic acids is at the center of diagnostic technologies used in research and the clinic. Standard approaches used in these technologies rely on enzymatic modification that can introduce bias and artifacts. A critical element of next generation detection platforms will be direct molecular sensing, thereby avoiding a need for amplification or labels. Advanced nanomaterials may provide the suitable chemical modalities to realize label-free sensors. Conjugated polymers are ideal for biological sensing, possessing properties compatible with biomolecules and exhibit high sensitivity to localized environmental changes. In this article, a method is presented for detecting nucleic acids using the electroconductive polymer polyaniline. Simple DNA "probe" oligonucleotides complementary to target nucleic acids are attached electrostatically to the polymer, creating a sensor system that can differentiate single nucleotide differences in target molecules. Outside the specific and unbiased nature of this technology, it is highly cost effective.


Effect of Short-Term Exposure to High Particulate Levels on Cough Reflex Sensitivity in Healthy Tourists: A Pilot Study.
Previous studies have reported a relationship between particulate air pollution and respiratory symptoms or decline in lung function, but information about acute effects of short-term exposure to airborne particulate matter (PM) on cough and pulmonary function is scarce. To investigate the effect of short-term exposure to high concentrations of PM on the cough reflex threshold, urge-to-cough, pulmonary function, and cough-related quality of life in a group of healthy non-resident volunteers visiting Beijing, China. Seventeen healthy residents of Sendai, Japan, who planned to attend a meeting in Beijing, were recruited. We checked local air quality and measured cough reflex thresholds, urge-to-cough, pulmonary function, and Leicester Cough Questionnaire-acute (LCQ-acute) scores in the volunteers before, during, and after their trip to Beijing. The PM2.5 and PM10 concentrations in Beijing were significantly higher than those in Japan on the measurement days. Cough reflex thresholds, expressed as nebulized citric acid concentrations required to induce ≥ 2 and ≥ 5 coughs, were significantly lower during the stay in Beijing than before or after the visit. Vital capacity, forced expiratory volume in one second (FEV1), forced vital capacity (FVC), and FEV1/FVC were significantly lower during the stay in Beijing than before the trip. Similarly, the urge-to-cough threshold was significantly lower during the stay in Beijing than after the trip, as was the total LCQ-acute score. We tentatively concluded that short-term exposure to high PM concentrations may have adverse effects on cough reflex and urge-to-cough thresholds, pulmonary function, and cough-related quality of life.


Characterization of signaling function and expression of HLA class I molecules in medulloblastoma.
Although known for the important function in the immune system, MHC class I molecules are increasingly ascribed an alternative role in modifying signal transduction. In medulloblastoma, HLA class I molecules are associated with poor prognosis, and can induce ERK1/2 activation upon engagement with ligands that bind to incompletely assembled complexes (so called open conformers). We here demonstrate that ERK1/2 activation in medulloblastoma can occur in the absence of endogenously synthesized β2m, formally excluding involvement of closed HLA class conformation. In addition, several experimental observations suggest that heterogeneity of HLA class I expression may be a reflection of the status of original cells before transformation, rather than a consequence of immune-based selection of HLA-loss mutants. These results contribute to our understanding of an immune system-independent role of HLA class I in the pathology of medulloblastoma, and cancer in general.


Family screening for bicuspid aortic valve and aortic dilatation: a meta-analysis.
International guidelines recommend screening of first-degree relatives (FDR) of people with bicuspid aortic valves (BAVs). However, the prevalence of BAV and of aortic dilatation amongst family members is uncertain. A systematic review and meta-analysis of original reports of screening for BAV. Databases including MEDLINE, Embase, and Cochrane CENTRAL were searched from inception to December 2021 using relevant search terms. Data were sought on the screened prevalence of BAV and aortic dilatation. The protocol was specified prior to the searches being performed, and standard meta-analytic techniques were used. Twenty-three observational studies met inclusion criteria (n = 2297 index cases; n = 6054 screened relatives). The prevalence of BAV amongst relatives was 7.3% [95% confidence interval (CI) 6.1%-8.6%] overall and per family was 23.6% (95% CI 18.1%-29.5%). The prevalence of aortic dilatation amongst relatives was 9.4% (95% CI 5.7%-13.9%). Whilst the prevalence of aortic dilatation was particularly high in relatives with BAV (29.2%; 95% CI 15.3%-45.1%), aortic dilatation alongside tricuspid aortic valves was a more frequent finding, as there were many more family members with tricuspid valves than BAV. The prevalence estimate amongst relatives with tricuspid valves (7.0%; 95% CI 3.2%-12.0%) was higher than reported in the general population. Screening family members of people with BAV can identify a cohort substantially enriched for the presence of bicuspid valve, aortic enlargement, or both. The implications for screening programmes are discussed, including in particular the substantial current uncertainties regarding the clinical implications of aortic findings.


Study of the performance of different subpixel image correlation methods in 3D digital image correlation.
The three-dimensional digital image correlation (3D-DIC) method is rapidly developing and is being widely applied to engineering and manufacturing. Despite its extensive use, the error caused by different image matching algorithms is seldom discussed. An algorithm for 3D speckle image generation is proposed, and the performances of different subpixel correlation algorithms are studied. The advantage is that there is no interpolation bias of texture in the simulation before and after deformation, and the error from the interpolation of speckle can be omitted in this algorithm. An error criterion for 3D reconstruction is proposed. 3D speckle images were simulated, and the performance of four subpixel algorithms is addressed. Based on the research results of different subpixel algorithms, a first-order Newton-Raphson iteration method and gradient-based method are recommended for 3D-DIC measurement.


International Variation in Surgical Practices in Units Performing Oesophagectomy for Oesophageal Cancer: A Unit Survey from the Oesophago-Gastric Anastomosis Audit (OGAA).
Anastomotic leaks are associated with significant risk of morbidity, mortality and treatment costs after oesophagectomy. The aim of this study was to evaluate international variation in unit-level clinical practice and resource availability for the prevention and management of anastomotic leak following oesophagectomy. The Oesophago-Gastric Anastomosis Audit (OGAA) is an international research collaboration focussed on improving the care and outcomes of patients undergoing oesophagectomy. Any unit performing oesophagectomy worldwide can register to participate in OGAA studies. An online unit survey was developed and disseminated to lead surgeons at each unit registered to participate in OGAA. High-income country (HIC) and low/middle-income country (LMIC) were defined according to the World Bank whilst unit volume were defined as < 20 versus 20-59 versus ≥60 cases/year in the unit. Responses were received from 141 units, a 77% (141/182) response rate. Median annual oesophagectomy caseload was reported to be 26 (inter-quartile range 12-50). Only 48% (68/141) and 22% (31/141) of units had an Enhanced Recovery After Surgery (ERAS) program and ERAS nurse, respectively. HIC units had significantly higher rates of stapled anastomosis compared to LMIC units (66 vs 31%, p = 0.005). Routine post-operative contrast-swallow anastomotic assessment was performed in 52% (73/141) units. Stent placement and interventional radiology drainage for anastomotic leak management were more commonly available in HICs than LMICs (99 vs 59%, p < 0.001 and 99 vs 83%, p < 0.001). This international survey highlighted variation in surgical technique and management of anastomotic leak based on case volume and country income level. Further research is needed to understand the impact of this variation on patient outcomes.


Trade in health-related services.
The supervision of a domestic health system in the context of the trade environment in the 21st century needs a sophisticated understanding of how trade in health services affects, and will affect, a country's health system and policy. This notion places a premium on people engaged in the health sector understanding the importance of a comprehensive outlook on trade in health services. However, establishment of systematic comparative data for amounts of trade in health services is difficult to achieve, and most trade negotiations occur in isolation from health professionals. These difficulties compromise the ability of a health system to not just minimise the risks presented by trade in health services, but also to maximise the opportunities. We consider these issues by presenting the latest trends and developments in the worldwide delivery of health-care services, using the classification provided by the World Trade Organization for the General Agreement on Trade in Services. This classification covers four modes of service delivery: cross-border supply of services; consumption of services abroad; foreign direct investment, typically to establish a new hospital, clinic, or diagnostic facility; and the movement of health professionals. For every delivery mode we discuss the present magnitude and pattern of trade, main contributors to this trade, and key issues arising.


The role of energy cost in food choices for an Aboriginal population in northern Australia.
To explore the relationship between dietary quality and energy density of foods (MJ/kg) and energy cost ($/MJ) for an Aboriginal population living in a remote region of northern Australia. For a 3-month period in 2005, we collected food and non-alcoholic beverage supply data from food outlets available to the study population. From these data, we compared the energy density of foods with their energy cost. Energy density and energy cost of food purchases. The diet of the study population was high in refined carbohydrates and low in fresh fruit and vegetables. Foods with high energy density were associated with lower costs and contributed disproportionately to energy availability. The energy-cost differential between energy-dense, nutrient-poor foods and energy-dilute, nutrient-rich foods influences the capacity of Australian Aboriginal people living in remote communities to attain a healthy diet. This is consistent with the "economics of food choice" theory, whereby people on low incomes maximise energy availability per dollar in their food purchasing patterns, and has particular relevance for developing nutrition policy and strategies in Aboriginal communities, where poor nutrition is a major determinant of preventable chronic disease.


Reducing diabetes health disparities through community-based participatory action research: the Chicago Southeast Diabetes Community Action Coalition.
To address disproportionately high rates of diabetes morbidity and mortality in some of Chicago's medically underserved minority neighborhoods, a group of community residents, medical and social service providers, and a local university founded the Chicago Southeast Diabetes Community Action Coalition, a Centers for Disease Control and Prevention REACH 2010 Initiative. A community-based participatory action research model guided coalition activities from conceptualization through implementation. Capacity building activities included training on: diabetes, coalition building, research methods, and action planning. Other activities sought to increase coalition members' understanding of the social causes and potential solutions for health disparities related to diabetes. Trained coalition members conducted epidemiologic analyses, focus groups, a telephone survey, and a community inventory. All coalition members participated in decisions. The participatory process led to increased awareness of the complexities of diabetes in the community and to a state of readiness for social action. Data documented disparities in diabetes. The participatory action research approach (a) encouraged key stakeholders outside of the health care sector to participate (e.g., business sector, church groups); (b) permitted an examination of the sociopolitical context affecting the health of the community; (c) provided an opportunity to focus on preventing the onset of diabetes and its complications; (d) increased understanding of the importance of community research in catalyzing social action aimed at community and systems change and change among change agents.