Single-dose desloratadine and montelukast and allergen-induced late airway responses.
Montelukast and desloratadine synergistically inhibit the allergen-induced early asthmatic response. Montelukast also suppresses the allergen-induced late asthmatic response, but there are no reports on the effect of desloratadine or the combination on the allergen-induced late asthmatic response. Atopic asthmatics (n = 10) completed a multicentric randomised double-blind crossover study comparing single-dose placebo, 5 mg desloratadine, 10 mg montelukast and the combination administered 2 h prior to allergen inhalation challenge. Methacholine challenges were performed 24 h before and after allergen challenge. Exhaled nitric oxide measurements and sputum inflammatory cell counts were also carried out. All active treatments significantly decreased the late asthmatic response area under the curve. Combination therapy provided the greatest inhibition compared to desloratadine and montelukast. Montelukast was nonsignificantly better than desloratadine but not as effective as the combination. There was a trend towards a decrease in airway responsiveness following montelukast and combination. Montelukast, but not desloratadine or the combination, decreased exhaled NO levels 24 h after allergen. The allergen-induced increase in sputum eosinophil numbers was significantly suppressed at 7 h with desloratadine and combination therapy, and at 24 h with montelukast and combination therapy. Single-dose co-administration of desloratadine and montelukast 2 h prior to allergen inhalation clinically abolished the late asthmatic response and eosinophil recruitment.


Addition of hydroxyapatite improves stiffness, interconnectivity and osteogenic potential of a highly porous collagen-based scaffold for bone tissue regeneration.
There is an enduring and unmet need for a bioactive, load-bearing tissue-engineering scaffold, which is biocompatible, biodegradable and capable of facilitating and promoting osteogenesis when implanted in vivo. This study set out to develop a biomimetic scaffold by incorporating osteoinductive hydroxyapatite (HA) particles into a highly porous and extremely biocompatible collagen-based scaffold developed within our laboratory over the last number of years to improve osteogenic performance. Specifically we investigated how the addition of discrete quantities of HA affected scaffold porosity, interconnectivity, mechanical properties, in vitro mineralisation and in vivo bone healing potential. The results show that the addition of HA up to a 200 weight percentage (wt%) relative to collagen content led to significantly increased scaffold stiffness and pore interconnectivity (approximately 10 fold) while achieving a scaffold porosity of 99%. In addition, this biomimetic collagen-HA scaffold exhibited significantly improved bioactivity, in vitro mineralisation after 28 days in culture, and in vivo healing of a critical-sized bone defect. These findings demonstrate the regenerative potential of these biodegradable scaffolds as viable bone graft substitute materials, comprised only of bone's natural constituent materials, and capable of promoting osteogenesis in vitro and in vivo repair of critical-sized bone defects.


Preconception care: a parenting protocol: a moral inquiry into the responsibilities of future parents towards their future children.
In the Netherlands fertility doctors increasingly formulate protocols, which oblige patients to quit their unhealthy lifestyle before they are admitted to IVF procedures. We argue that moral arguments could justify parenting protocols that concern all future parents. In the first part we argue that want-to-be parents have moral responsibilities towards their future children to prevent them from harm by diminishing or eliminating risk factors before as well as during the pregnancy. This is because of the future children's potential to become of a certain type, more specifically: a person that will be the want-to-be parents' child. Want-to-be parents intend to become pregnant and therefore have an additional moral reason to diminish the risks. Also, people who become pregnant unintentionally have the responsibility to prevent their children from harm, unless they become pregnant due to contraception failure. All people not wanting to become pregnant should use contraception methods carefully. In the second part of this paper we translate the want-to-be parents' responsibilities into practice. We distinguish four determinants of risk factors: modifiability, chance, severity and effort. We examine some evidence-based risk factors based on these variables and deduce levels of responsibility. In conclusion, formulating informal requirements for want-to-be parents is morally required and therefore also for want-to-be parents in need of medical assistance. The protocols developed by fertility doctors in the Netherlands could be seen as the precursor for a general, informal Parenting Protocol that could be developed on the basis of an extended and thoroughly debated risk-responsibility analysis.


Electronic effects in mixed N-heterocyclic carbene/phosphite indenylidene ruthenium metathesis catalysts.
Five new complexes [RuCl2(SIMes)(Ind)(O-pXC5H4)] bearing different para-substituted triphenylphosphites (X = H, OCH3, CF3, Cl, SF5 and CN) were synthesised and used to study the effect of the electronic properties of the phosphite on olefin metathesis activity. Investigations of the physical properties of the new ligands and complexes were performed using physicochemical and DFT calculations. The catalytic activity of the complexes was benchmarked in challenging ring closing metathesis transformations featuring the formation of tetra-substituted double bonds. Complex [RuCl2(SIMes)(Ind)P(O-pCF3C5H4)3] (3c) exhibited a particularly high catalytic activity, superior to state-of-the-art catalysts, and was further tested on a wide range of substrates.


Intravenous iron therapy in chronic kidney disease and peritoneal dialysis patients.
Identical National Kidney Foundation Kidney Disease Outcomes Quality Initiative (K/DOQI) hematologic and iron targets apply to chronic kidney disease (CKD), peritoneal dialysis (PD), and hemodialysis (HD) patients, yet intravenous (i.v.) nondextran iron therapy is FDA approved only in HD patients. This is because oral iron has been considered adequate in CKD and PD patients, and delivering a parenteral therapy on a frequent basis to an outpatient population with notoriously poor vascular access presents logistical complexities. However, recognition of the need for more aggressive treatment of anemia in the CKD and PD population is growing. This awareness, along with the improved safety profiles of the new, nondextran irons, is tipping the risk-benefit ratio toward more widespread use of i.v. iron in these patients. This article provides a summary of the literature and of our own experience using i.v. iron therapy in CKD and PD patients. Our protocol relies on early monitoring and intervention with i.v. ferric gluconate before severe iron deficiency develops. The proactive approach allows for relatively infrequent treatments at only moderately "high" doses (250 mg) of ferric gluconate. The convergence of convenience and safety may expedite more energetic anemia prevention and treatment in PD and CKD patients.


Rhodopseudomonas palustris CGA010 Proteome Implicates Extracytoplasmic Function Sigma Factor in Stress Response.
Rhodopseudomonas palustris encodes 16 extracytoplasmic function (ECF) σ factors. To begin to investigate the regulatory network of one of these ECF σ factors, the whole proteome of R. palustris CGA010 was quantitatively analyzed by tandem mass spectrometry from cultures episomally expressing the ECF σ(RPA4225) (ecfT) versus a WT control. Among the proteins with the greatest increase in abundance were catalase KatE, trehalose synthase, a DPS-like protein, and several regulatory proteins. Alignment of the cognate promoter regions driving expression of several upregulated proteins suggested a conserved binding motif in the -35 and -10 regions with the consensus sequence GGAAC-18N-TT. Additionally, the putative anti-σ factor RPA4224, whose gene is contained in the same predicted operon as RPA4225, was identified as interacting directly with the predicted response regulator RPA4223 by mass spectrometry of affinity-isolated protein complexes. Furthermore, another gene (RPA4226) coding for a protein that contains a cytoplasmic histidine kinase domain is located immediately upstream of RPA4225. The genomic organization of orthologs for these four genes is conserved in several other strains of R. palustris as well as in closely related α-Proteobacteria. Taken together, these data suggest that ECF σ(RPA4225) and the three additional genes make up a sigma factor mimicry system in R. palustris.


Cardiovascular MR imaging after surgical correction of tetralogy of Fallot: approach based on understanding of surgical procedures.
Tetralogy of Fallot (TOF) is one of the most common congenital heart diseases for which patients are referred for postoperative magnetic resonance (MR) imaging evaluation. The most common surgical procedures for TOF repair include infundibulectomy, transannular pulmonary artery patch repair, and right ventricle-pulmonary artery conduit placement. In the past few decades, surgery has proved successful, but most patients require repeat imaging throughout their lives. MR imaging is now frequently used for morphologic and functional evaluation after TOF repair. The most common late postoperative sequelae and residual lesions include right ventricular outflow tract aneurysm and dyskinesis, conduit failure, pulmonary regurgitation, tricuspid regurgitation, right ventricular failure, residual main and branch pulmonary artery stenosis, branch pulmonary artery aneurysm, left pulmonary artery kinking, and residual or recurrent ventricular septal defect. The imaging approach for the evaluation of patients with repaired TOF should be guided by the surgical procedure used and the complications that are expected. Knowledge of the most common postoperative problems and their cardiovascular MR imaging appearances is essential for good radiology practice in this clinical setting.


Polishing of Ground Y-TZP Ceramic is Mandatory for Improving the Mechanical Behavior.
It evaluated the effect of aging by Low Temperature Degradation (LTD), executed after post- processing surface treatments (polishing, heat treatment and glazing), on the surface characteristics (micromorphology and roughness) and on the structural stability (phase transformation and mechanical behavior-flexural strength and structural reliability) of a ground yttrium-stabilized tetragonal zirconia polycrystal (Y-TZP) ceramic. Discs of Y-TZP (VITA In-Ceram YZ) were manufactured (ISO:6872-2015; 15 mm in diameter and 1.2 ± 0.2 mm in thickness) and randomly assigned into 10 groups according two factors: "aging" in 2 levels (with or without) and "surface treatment" in 5 levels (Ctrl: as-sintered; Gr: grinding with coarse diamond bur; Gr + HT: grinding plus heat treatment; Gr + Pol: grinding plus polishing; Gr + Gl: grinding plus glazing). Roughness (n=30), biaxial flexural test (n=30), phase transformation (n=2), and surface topography (n=2) analyses were performed. Aging led to an intense increase in monoclinic (m) phase content for all the tested conditions, being the as-sintered samples (Ctrl= 65.6%) more susceptible to the t-m phase transformation. Despite of increasing the m-phase content, aging was not detrimental for characteristic strength (except to the grinding condition). There was no significant reduction in the Weibull modulus after surface treatments. Additionally, heat treatment and glazing after grinding led to a decrease in characteristic strength, while polishing presented the highest characteristic strength values. Thus, polishing is mandatory after grinding the Y-TZP ceramic, while performing glazing or heat-treatment alone after grinding lead to the worst mechanical performance.


A device for gated autosynchronous luminescence detection.
The sensitive detection of delayed luminescence (τ > 100 μs) can be achieved with an optomechanical instrument, the gated autosynchronous luminescence detector (GALD). The device effectively combines an excitation chopper, a detection chopper, and a dichroic mirror into a single element. With dimensions of 12 mm (H), 32 mm (W), and 90 mm (L), it is designed for insertion into the differential interference contrast (DIC) prism slot of a BX51 Olympus microscope. The GALD described here employed a compact high-power UV LED as the excitation source to capture images of Giardia lamblia cysts indirectly labeled with a europium chelate/streptavidin conjugate. Labeled cells were clearly visible in the complete absence of autofluorescence and signal intensity was sufficient to capture high-resolution color images within several seconds. Shorter exposure intervals of 100 ms on a monochrome Andor iXON camera delivered time-gated luminescence images with a signal-to-noise ratio better than 114:1.


Functions of uterine natural killer cells are mediated by interferon gamma production during murine pregnancy.
The dominant lymphocytes in healthy human and murine implantation sites are pregnancy-associated uterine natural killer (uNK) cells. These cells produce 90% of pregnancy-induced, uterine interferon (IFN)- gamma, a cytokine that regulates expression of more than 0.5% of the mouse genome. Implantation sites in uNK cell-deficient and IFN- gamma -signal-disrupted mice display anomalies in decidua and its spiral arteries. Reconstitution of uNK cell-deficient females with bone marrow containing normal NK cell progenitors, establishes uNK cells and reverses the anomalies. Grafts from IFN- gamma(-/-)mice are restored uNK cells, but the uNK cells did not reverse the phenotypes. This review focuses on the functions of uNK cell-derived IFN- gamma and the genes that it may regulate in the pregnant uterus.


Genotype <21CAs/≥21CAs and allele <21CAs of the MANBA gene in melanoma risk and progression in a Swedish population.
Cutaneous melanoma is characterized by poor patient outcome in its later stages. The search for genetic markers is therefore crucial for the identification of populations at risk for melanoma. Highly polymorphic CA repeats in 3' proximity in the MANBA gene were examined by PCR-capillary electrophoresis in 185 Swedish melanoma patients and 441 tumor-free age- and gender-matched individuals. The associations of the polymorphisms with melanoma risk, the pigment phenotypes of the patients and tumor characteristics were analyzed. A significant difference in allelic distribution between melanoma patients and tumor-free individuals was observed. The frequency of the MANBA genotype <21CAs/≥21CAs was significantly higher in melanoma patients than in the controls. When comparing allele distribution in patients and their matched controls, the allele <21CAs was found to be associated with the female gender (39.8 vs. 31.2%, P=0.041, OR=1.46, 95% CI 1.02-2.10), but not with male gender (34.4 vs. 30.9%, P%0.39). Within the melanoma group, there were no differences in the distribution of the MANBA alleles associated with patient gender or age before or after 55 years at diagnosis, nor was there any association between the MANBA genotype and pigment phenotype or tumor sites. The MANBA allele <21CAs was, however, associated with thin melanomas at diagnosis (Breslow thickness ≤1.5 mm and Clark levels I and II). In conclusion, these data suggest that MANBA polymorphisms might be an indicator of tumor growth and progression and, together with other markers, could be used to identify individuals at increased risk of melanoma.


Repeatability and agreement of intraocular pressure measurement among three tonometers.
Elevated intraocular pressure (IOP) is one of the causes of irreversible optic nerve head damage and visual field loss. It is often measured with applanation tonometers but the use of rebound tonometry devices has been proposed as an alternative to assess IOP. Rebound tonometers have also been proposed as a method for patients to measure their own intraocular pressure (that is, self-tonometry). The purpose of this study was to determine the intrasession repeatability and the agreement of the IOP measurement with two rebound measuring principle tonometers, ICare ic100 and ICare Home with Perkins tonometer. This study involved 27 healthy volunteers (18 to 30 years old). We performed three consecutive IOP measurements with ICare Home, ICare ic100, and Perkins. The means of the three measurements from each device were calculated. Repeatability and agreement were defined according to the British Standards Institute and the International Organization for Standardization. The agreement was assessed using the method described by Bland and Altman, where 95 per cent of the differences or limits of agreement were between 1.96 standard deviations of the mean difference. All tonometers showed close measurements (Perkins 15.34 ± 3.45 mmHg, range 10.00-24.00; ICare ic100 15.40 ± 4.06 mmHg, range 9.67-23.33; and ICare Home 14.22 ± 4.72 mmHg, range 7.33-24.00). The co-efficient of variation (CV) and within-subject standard deviation (Sw) was low for ICare ic100 and Perkins (close to 6.30 per cent and one) with higher values for ICare Home (CV = 9.55% and Sw = 1.33). The intraclass correlation co-efficient showed values higher than 0.96 for all tonometers. The difference between both rebound tonometers was statistically significant (p = 0.03). The ICare ic100 tonometer provides repeatable IOP measurements close to the measurements of the Perkins IOP (good agreement); however, ICare Home provides less repeatable values, showing worse agreement with the Perkins tonometer in healthy subjects.


Increased Cerebrospinal Fluid Level of Insulin-like Growth Factor-II in Male Patients with Alzheimer's Disease.
Insulin-like growth factor-II (IGF-II) is important for brain development. Although IGF-II is abundant also in adult life, little is known of the role of IGF-II in Alzheimer's disease (AD). This was a cross-sectional study of 60 consecutive patients under primary evaluation of cognitive impairment and 20 healthy controls. The patients had AD dementia or mild cognitive impairment (MCI) diagnosed with AD dementia upon follow-up (n = 32), stable MCI (SMCI, n = 13), or other dementias (n = 15). IGF-II, IGF-binding protein-1 (IGFBP-1), and IGFBP-2 were analyzed in serum and cerebrospinal fluid (CSF). Levels of IGF-II, IGFBP-1, and IGFBP-2 were similar in all groups in the total study population. Gender-specific analyses showed that in men (n = 40), CSF IGF-II level was higher in AD compared to SMCI and controls (p < 0.01 and p < 0.05, respectively). Furthermore, CSF IGFBP-2 level was increased in AD men versus SMCI men (p < 0.01) and tended to be increased versus control men (p = 0.09). There were no between-group differences in women (n = 40). In the total study population (n = 80) as well as in men (n = 40), CSF levels of IGF-II and IGFBP-2 correlated positively with CSF levels of the AD biomarkers total-tau and phosphorylated tau protein. In men, but not women, in the early stages of AD, CSF IGF-II level was elevated, and CSF IGFBP-2 level tended to be increased, compared to healthy controls.


Destruction of Spiderwebs and Rescue of Ensnared Nestmates by a Granivorous Desert Ant (Veromessor pergandei).
Prey species rarely seek out and dismantle traps constructed by their predators. In the current study, we report an instance of targeted trap destruction by an invertebrate and a novel context for rescue behavior. We found that foragers of the granivorous desert ant (Veromessor pergandei) identify and cooperatively dismantle spiderwebs (Araneae: Theridiidae, Steatoda spp., and Asagena sp.) During group foraging, workers ensnared in webs are recovered by sisters, which transport them to the nest and groom away their silk bindings. The presence of an ensnared nestmate and chemical alarm signal significantly increased the probability of web removal and nestmate retrieval. A subset of larger-bodied foragers participated in web removal, and 6.3% became tangled or were captured by spiders. Most animals that perform rescue behavior live in small groups, but V. pergandei colonies include tens of thousands of short-lived workers. To maintain their size, large colonies must collect enough seeds to produce 650 new ants each day. We hypothesize that the removal of spiderwebs allows for an unimpeded income of seeds on a single foraging path during a brief daily temperature window. Despite the cost to individuals, webs are recognized and removed only when workers are captured in them.


Targeted single-cell RNA sequencing of transcription factors enhances the identification of cell types and trajectories.
Single-cell RNA sequencing (scRNA-seq) is a widely used method for identifying cell types and trajectories in biologically heterogeneous samples, but it is limited in its detection and quantification of lowly expressed genes. This results in missing important biological signals, such as the expression of key transcription factors (TFs) driving cellular differentiation. We show that targeted sequencing of ∼1000 TFs (scCapture-seq) in iPSC-derived neuronal cultures greatly improves the biological information garnered from scRNA-seq. Increased TF resolution enhanced cell type identification, developmental trajectories, and gene regulatory networks. This allowed us to resolve differences among neuronal populations, which were generated in two different laboratories using the same differentiation protocol. ScCapture-seq improved TF-gene regulatory network inference and thus identified divergent patterns of neurogenesis into either excitatory cortical neurons or inhibitory interneurons. Furthermore, scCapture-seq revealed a role for of retinoic acid signaling in the developmental divergence between these different neuronal populations. Our results show that TF targeting improves the characterization of human cellular models and allows identification of the essential differences between cellular populations, which would otherwise be missed in traditional scRNA-seq. scCapture-seq TF targeting represents a cost-effective enhancement of scRNA-seq, which could be broadly applied to improve scRNA-seq resolution.


25 W Raman-fiber-amplifier-based 589 nm laser for laser guide star.
We report on a 25 W continuous wave narrow linewidth (< 2.3 MHz) 589 nm laser by efficient (> 95%) coherent beam combination of two narrow linewidth (< 1.5 MHz) Raman fiber amplifiers with a Mach-Zehnder interferometer scheme and frequency doubling in an external resonant cavity with an efficiency of 86%. The results demonstrate the narrow linewidth Raman fiber amplifier technology as a promising solution for developing laser for sodium laser guide star adaptive optics.


Constructing a Swiss health space model of self-perceived health.
This study aims to analyse the relationship between self-reported health characteristics and to explore latent cultural structures in the Swiss health survey. Based on categorical principal component analysis, a conceptual model of 'health space' was constructed which can be interpreted as a collective perception of health. The first dimension of the constructed health space model reflects the 'level of general health', and the second dimension the 'composition of physical and mental health symptoms'. These dimensions may reflect deeply rooted cultural structures--the good vs. bad dichotomy as a generic categorization scheme of human thought and the body/mind dualism. These latent structures provide a framework of the health space model and allow a better interpretation of the relationships of health perception characteristics and its related socio-demographic aspects.


Slow-release sodium fluoride in the management of postmenopausal osteoporosis. A randomized controlled trial.
To test whether intermittent treatment with slow-release sodium fluoride and continuous calcium citrate supplementation inhibits vertebral fractures without causing fluoride complications. A placebo-controlled, randomized trial. Outpatient setting of specialty clinics in Dallas and Temple, Texas. Slow-release sodium fluoride (25 mg twice daily) in repeated 14-month cycles (12 months on treatment followed by 2 months off treatment) compared with placebo. Both groups took calcium citrate (400 mg calcium twice daily) continuously. 110 patients with postmenopausal osteoporosis were randomly assigned to two groups. In the slow-release sodium fluoride group, 48 of 54 patients completed more than 1 cycle of treatment (mean, 2.44 cycles/patient), whereas 51 of 56 patients in the placebo group completed at least 1 cycle (mean, 2.14 cycles/patient) in this interim analysis. Vertebral fracture rate and lumbar bone mineral content. Vertebral fractures were quantified from yearly radiographs. Bone mass was determined annually by densitometry. In the sodium fluoride group, the mean L2 to L4 bone mineral content increased by 4% to 6% in each cycle and the mean femoral neck bone density increased by 4.1% and 2.1% during the first two cycles, but the radial bone density did not change. The placebo group showed no statistical change in bone mass at any site. Compared with the placebo group, the sodium fluoride group had a lower individual new vertebral fracture rate (0.057/patient cycle compared with 0.204/patient cycle, P = 0.017), a higher fracture-free rate (83.3% compared with 64.7%, P = 0.042), and a lower group fracture rate (0.085/patient cycle compared with 0.239/patient cycle, P = 0.006). The side-effect profile was similar for the two groups; no patient developed microfractures, hip fractures, or blood loss anemia. Intermittent slow-release sodium fluoride plus continuous calcium citrate, administered for about 2.5 years, inhibits new vertebral fractures, increases the mean spinal bone mass without decreasing the radial shaft bone density, and is safe to use.


Application of the Scale for the Assessment and Rating of Ataxia (SARA) in pediatric oncology patients: A multicenter study.
Posterior cranial fossa (PCF) tumors in childhood are often associated with ataxia as well as other motor, neurobehavioral and linguistic impairment. The use of a reliable outcome measure is mandatory to evaluate the severity of impairment and monitor rehabilitation effectiveness. The aim of this work is to explore the validity of the Scale for the Assessment and Rating of Ataxia (SARA) in pediatric subjects with ataxia secondary to PCF tumor resection and evaluate the influence of age and comorbidities. Seventy eight patients (3-18 years) were recruited in 5 centers from 2016 to 2018. The age effect on SARA was analyzed by correlating total SARA scores and item scores with age and gradually excluding youngest subjects. The comorbidity effect was evaluated by comparing the ataxia-only group vs a group of subjects with ataxia + dysfunction of cranial nerves or cerebellar mutism (CM) and a group of patients with ataxia + hemiparesis. Several negative correlations between SARA scores and age were found under age 9. Differences between ataxia-only group and the other two groups were closely associated with specific comorbidities (e.g. speech disturbance in cranial nerves or CM group (p value < 0.001) and gait, stance, sitting and finger chase in the hemiparetic group (mean p value 0.022)).


Microbiological assessment along the fish production chain of the Norwegian pelagic fisheries sector--Results from a spot sampling programme.
Microbes play an important role in the degradation of fish products, thus better knowledge of the microbiological conditions throughout the fish production chain may help to optimise product quality and resource utilisation. This paper presents the results of a ten-year spot sampling programme (2005-2014) of the commercially most important pelagic fish species harvested in Norway. Fish-, surface-, and storage water samples were collected from fishing vessels and processing factories. Totally 1,181 samples were assessed with respect to microbiological quality, hygiene and food safety. We introduce a quality and safety assessment scheme for fresh pelagic fish recommending limits for heterotrophic plate counts (HPC), thermos tolerant coliforms, enterococci and Listeria monocytogenes. According to the scheme, in 25 of 41 samplings, sub-optimal conditions were found with respect to quality, whereas in 21 and 9 samplings, samples were not in compliance concerning hygiene and food safety, respectively. The present study has revealed that the quality of pelagic fish can be optimised by improving the hygiene conditions at some critical points at an early phase of the production chain. Thus, the proposed assessment scheme may provide a useful tool for the industry to optimise quality and maintain consumer safety of pelagic fishery products.


An unexpected catalyst dominates formation and radiative forcing of regional haze.
Although regional haze adversely affects human health and possibly counteracts global warming from increasing levels of greenhouse gases, the formation and radiative forcing of regional haze on climate remain uncertain. By combining field measurements, laboratory experiments, and model simulations, we show a remarkable role of black carbon (BC) particles in driving the formation and trend of regional haze. Our analysis of long-term measurements in China indicates declined frequency of heavy haze events along with significantly reduced SO2, but negligibly alleviated haze severity. Also, no improving trend exists for moderate haze events. Our complementary laboratory experiments demonstrate that SO2 oxidation is efficiently catalyzed on BC particles in the presence of NO2 and NH3, even at low SO2 and intermediate relative humidity levels. Inclusion of the BC reaction accounts for about 90-100% and 30-50% of the sulfate production during moderate and heavy haze events, respectively. Calculations using a radiative transfer model and accounting for the sulfate formation on BC yield an invariant radiative forcing of nearly zero W m-2 on the top of the atmosphere throughout haze development, indicating small net climatic cooling/warming but large surface cooling, atmospheric heating, and air stagnation. This BC catalytic chemistry facilitates haze development and explains the observed trends of regional haze in China. Our results imply that reduction of SO2 alone is insufficient in mitigating haze occurrence and highlight the necessity of accurate representation of the BC chemical and radiative properties in predicting the formation and assessing the impacts of regional haze.


Fucoidan from marine brown algae attenuates pancreatic cancer progression by regulating p53 - NFκB crosstalk.
Poor pancreatic cancer (PC) prognosis has been attributed to its resistance to apoptosis and propensity for early systemic dissemination. Existing therapeutic strategies are often circumvented by the molecular crosstalk between cell-signalling pathways. p53 is mutated in more than 50% of PC and NFκB is constitutively activated in therapy-resistant residual disease; these mutations and activations account for the avoidance of cell death and metastasis. Recently, we demonstrated the anti-PC potential of fucoidan extract from marine brown alga, Turbinaria conoides (J. Agardh) Kützing (Sargassaceae). In this study, we aimed to characterize the active fractions of fucoidan extract to identify their select anti-PC efficacy, and to define the mechanism(s) involved. Five fractions of fucoidan isolated by ion exchange chromatography were tested for their potential in genetically diverse human PC cell lines. All fractions exerted significant dose-dependent and time-dependent regulation of cell survival. Fucoidans induced apoptosis, activated caspase -3, -8 and -9, and cleaved Poly ADP ribose polymerase (PARP). Pathway-specific transcriptional analysis recognized inhibition of 57 and 38 nuclear factor κB (NFκB) pathway molecules with fucoidan-F5 in MiaPaCa-2 and Panc-1 cells, respectively. In addition, fucoidan-F5 inhibited both the constitutive and Tumor necrosis factor-α (TNFα)-mediated NFκB DNA-binding activity in PC cells. Upregulation of cytoplasmic IκB levels and significant reduction of NFκB-dependent luciferase activity further substantiate the inhibitory potential of seaweed fucoidans on NFκB. Moreover, fucoidan(s) treatment increased cellular p53 in PC cells and reverted NFκB forced-expression-related p53 reduction. The results suggest that fucoidan regulates PC progression and that fucoidans may target p53-NFκB crosstalk and dictate apoptosis in PC cells.


Iterated Prisoner's Dilemma contains strategies that dominate any evolutionary opponent.
The two-player Iterated Prisoner's Dilemma game is a model for both sentient and evolutionary behaviors, especially including the emergence of cooperation. It is generally assumed that there exists no simple ultimatum strategy whereby one player can enforce a unilateral claim to an unfair share of rewards. Here, we show that such strategies unexpectedly do exist. In particular, a player X who is witting of these strategies can (i) deterministically set her opponent Y's score, independently of his strategy or response, or (ii) enforce an extortionate linear relation between her and his scores. Against such a player, an evolutionary player's best response is to accede to the extortion. Only a player with a theory of mind about his opponent can do better, in which case Iterated Prisoner's Dilemma is an Ultimatum Game.


Improving Documentation, Compliance, and Approvals in an Electronic Dental Record at a U.S. Dental School.
The aims of this study were to improve progress note documentation by dental students, achieve accurate and timely charge capture and treatment code and note approval, and determine the effectiveness of multiple interventions in improving overall documentation of patient encounters in the clinic of one U.S. dental school. The study, conducted in 2014-15, used a logic model to create a process to address documentation issues in the clinic's electronic dental record (EDR) and to assess the effectiveness of interventions. An initial documentation review using the EDR was performed to obtain a baseline measurement. A significant correlation was noted at baseline between poor documentation and unapproved treatment codes and notes. Unapproved treatment codes and corresponding documentation were then reviewed each month. Students who had the highest number of unapproved treatment codes were identified as potentially having documentation issues. These students were contacted and met individually with the associate quality and compliance officer to review documentation and charge practices. Large group education was also provided to key learners: dental students and supervising faculty members. Education consisted of an in-service event for faculty members and a Moodle site course on documentation for students. After one year, the results showed that documentation rates improved from an overall rate of 61% to 81% of required documentation elements being present in the progress note. Although this educational intervention was successful in significantly improving documentation of treatment in the EDR, 19% of the notes at the conclusion of the study were still missing key elements. Further research is necessary to determine whether the interventions will continue to improve documentation or if additional measures need to be taken.


The relationship between illness representations, risk perception and fear of cancer recurrence in breast cancer survivors.
Fear of cancer recurrence, although distinct from distress continues to be under-evaluated, captured, or treated when standard distress scales are used to assess concerns of cancer survivors. We tested a model assessing the association of demographic and clinical factors, illness representations, and perceived risk with fear of cancer recurrence in breast cancer survivors. We recruited 117 breast cancer survivors at least one year after completing breast cancer treatment from Internet discussion boards for this cross-sectional, descriptive, correlational study. Participants completed a survey that assessed their level of fear of cancer recurrence as well as their illness representations, perceived risk of recurrence, and demographic and medical characteristics. Our model explained 62% of the variance in fear of cancer recurrence. Emotional representations (β = .46, p < .01), symptom attribution (β = .21, p < .01), timeline (β = .23, p < .01), and consequences (β = .16, p < .03) were significantly related to fear of recurrence. By contrast, the majority of clinical and demographic variables were not significant contributors to fear of recurrence. Upon completion of cancer treatment, survivors with more emotional representations of the experience and those who attribute unrelated symptoms to their breast cancer have a higher level of fear of recurrence. Evaluation of these factors during treatment may help mitigate fear of recurrence in the survivorship phase of the breast cancer trajectory. Copyright © 2016 John Wiley & Sons, Ltd.


Inhibitor-based affinity probes for the investigation of JAK signaling pathways.
The Janus Kinase (JAK) signaling pathway plays a key role for many cellular processes and has recently been correlated with neuronal disorders. In order to understand new links of JAK family members with other signaling pathways, chemical proteomics tools with broad kinase coverage are desirable. A probe that shows outstanding kinase selectivity and allows for the enrichment of up to 133 kinases including many mitogen activated kinase (MAPK) members and JAK kinases has been developed. Furthermore, this probe was applied to establish the selectivity profile of the JAK1/2 inhibitor momelotinib that is currently evaluated in clinical phase 3 studies. These results render this probe a valuable tool for the investigation of JAK and JAK related signaling pathways and the selectivity profiling of kinase inhibitors.


Crystal structures of wild-type and mutant methicillin-resistant Staphylococcus aureus dihydrofolate reductase reveal an alternate conformation of NADPH that may be linked to trimethoprim resistance.
Both hospital- and community-acquired Staphylococcus aureus infections have become major health concerns in terms of morbidity, suffering and cost. Trimethoprim-sulfamethoxazole (TMP-SMZ) is an alternative treatment for methicillin-resistant S. aureus (MRSA) infections. However, TMP-resistant strains have arisen with point mutations in dihydrofolate reductase (DHFR), the target for TMP. A single point mutation, F98Y, has been shown biochemically to confer the majority of this resistance to TMP. Using a structure-based approach, we have designed a series of novel propargyl-linked DHFR inhibitors that are active against several trimethoprim-resistant enzymes. We screened this series against wild-type and mutant (F98Y) S. aureus DHFR and found that several are active against both enzymes and specifically that the meta-biphenyl class of these inhibitors is the most potent. In order to understand the structural basis of this potency, we determined eight high-resolution crystal structures: four each of the wild-type and mutant DHFR enzymes bound to various propargyl-linked DHFR inhibitors. In addition to explaining the structure-activity relationships, several of the structures reveal a novel conformation for the cofactor, NADPH. In this new conformation that is predominantly associated with the mutant enzyme, the nicotinamide ring is displaced from its conserved location and three water molecules complete a network of hydrogen bonds between the nicotinamide ring and the protein. In this new position, NADPH has reduced interactions with the inhibitor. An equilibrium between the two conformations of NADPH, implied by their occupancies in the eight crystal structures, is influenced both by the ligand and the F98Y mutation. The mutation induced equilibrium between two NADPH-binding conformations may contribute to decrease TMP binding and thus may be responsible for TMP resistance.


Quantitative real-time RT-PCR--a perspective.
The real-time reverse transcription polymerase chain reaction (RT-PCR) uses fluorescent reporter molecules to monitor the production of amplification products during each cycle of the PCR reaction. This combines the nucleic acid amplification and detection steps into one homogeneous assay and obviates the need for gel electrophoresis to detect amplification products. Use of appropriate chemistries and data analysis eliminates the need for Southern blotting or DNA sequencing for amplicon identification. Its simplicity, specificity and sensitivity, together with its potential for high throughput and the ongoing introduction of new chemistries, more reliable instrumentation and improved protocols, has made real-time RT-PCR the benchmark technology for the detection and/or comparison of RNA levels.


Trichome-specific expression of the amorpha-4,11-diene 12-hydroxylase (cyp71av1) gene, encoding a key enzyme of artemisinin biosynthesis in Artemisia annua, as reported by a promoter-GUS fusion.
Artemisinin derivatives are effective anti-malarial drugs. In order to design transgenic plants of Artemisia annua with enhanced biosynthesis of artemisinin, we are studying the promoters of genes encoding enzymes involved in artemisinin biosynthesis. A 1,151 bp promoter region of the cyp71av1 gene, encoding amorpha-4,11-diene 12-hydroxylase, was cloned. Alignment of the cloned promoter and other cyp71av1 promoter sequences indicated that the cyp71av1 promoter may be different in different A. annua varieties. Comparison to the promoter of amorpha-4,11-diene synthase gene showed a number of putative cis-acting regulatory elements in common, suggesting a co-regulation of the two genes. The cyp71av1 promoter sequence was fused to the β-glucuronidase (GUS) reporter gene and two varieties of A. annua and Nicotiana tabacum were transformed. In A. annua, GUS expression was exclusively localized to glandular secretory trichomes (GSTs) of leaf primordia and top expanded leaves. In older leaves, there is a shift of expression to T-shaped trichomes (TSTs). Only TSTs showed GUS staining in lower leaves and there is no GUS staining in old leaves. GUS expression in flower buds was specifically localized to GSTs. The recombinant promoter carries the cis-acting regulatory elements required for GST-specific expression. The cyp71av1 promoter shows activity in young tissues. The recombinant promoter was up to 200 times more active than the wild type promoter. GUS expression in transgenic N. tabacum was localized to glandular heads. Transcript levels were up-regulated by MeJA. Wound responsiveness experiment showed that the cyp71av1 promoter does not appear to play any role in the response of A. annua to mechanical stress.


A new category-specific nutrient rich food (NRF9f.3) score adds flavonoids to assess nutrient density of fruit.
Nutrient profiling (NP) models, intended to capture the full nutritional value of plant-based foods, ought to incorporate bioactive phytochemicals, including flavonoids, in addition to standard nutrients. The well-established Nutrient Rich Food (NRF9.3) score is based on 9 nutrients to encourage (protein, fiber, vitamins A, C, D and calcium, iron, potassium, magnesium) and 3 nutrients to limit (saturated fat, added sugar, sodium). The new category-specific NRF9f.3 score kept the same algorithm based on sums of percent daily values (%DVs) but swapped vitamin D for total flavonoids from the USDA database. NRF9f.3 was applied to the USDA fruit group categories, comparing nutrient density of citrus fruit, citrus juice, dried fruit, raw and cooked fruit, berries, fruit mixtures, fruit salads, non-citrus fruit juice, and fruit nectars. Adding total flavonoids to NRF9f.3 allowed for a recalibration of fruit total nutritional value. Citrus fruits and juices had significantly higher flavanones, berries had significantly higher anthocyanidins, and dried fruit and berries had significantly higher flavan-3-ols, than other fruits (all p < 0.05). Citrus fruit, citrus juice and berries had significantly higher NRFf9.3 scores than all other fruit subcategories (p < 0,05), but were not different from each other. The more innovative NP models are both category specific and make effective use of new nutrient composition databases. NRF9.3 when applied to the fruit group discriminates primarily on fiber, vitamin C, and added sugar content. Incorporating flavonoid and polyphenol data modernizes NP models to better capture nutrient density of plant foods that can aid in dietary guidance and policy development to improve diversity and nutritional value of the diet.


Characterisation of extended-spectrum β-lactamases among Klebsiella pneumoniae isolates causing bacteraemia and urinary tract infection in Mozambique.
The aim of this study was to determine the prevalence of extended-spectrum β-lactamase (ESBL)-producing Klebsiella pneumoniae isolated from urinary tract and bloodstream infections in a rural hospital in Manhiça, Mozambique. ESBLs were investigated among ceftriaxone-non-susceptible K. pneumoniae clinical isolates recovered between 2004 and 2009. Characterisation of blaCTX-M, blaSHV, blaOXA and blaTEM genes was performed by PCR and sequencing. Epidemiological relationships were established by phylogenetic analysis, repetitive extragenic palindromic PCR (REP-PCR), pulsed-field gel electrophoresis (PFGE) and multilocus sequence typing (MLST), whilst plasmid transferability was evaluated by conjugation. In addition, the presence of class 1 and 2 integrons was studied. A total of 19 K. pneumoniae were analysed. The blaCTX-M-15 gene was found in all strains. Other ESBL genes were found concomitantly, including blaSHV-5, blaSHV-2, blaSHV-2A, blaSHV-12 and blaSHV-38. In addition, other β-lactamases such as blaTEM-1 and blaOXA-30 were also detected. REP-PCR identified 15 different epidemiological profiles. MLST analysis also showed great variability of sequence types. The blaCTX-M-15 gene showed a high transfer capacity. The presence of class 1 integrons was high. High levels of multidrug resistance were also found. In conclusion, these data show the dominance of the CTX-M-type ESBL, particularly CTX-M-15, supporting its worldwide dissemination, including in areas with limited access to third-generation cephalosporins. This finding is a matter of concern for clinical management as third-generation cephalosporins are an alternative for treating severe cases of multidrug-resistant infections in this community.


No effect of consumption of green and black tea on plasma lipid and antioxidant levels and on LDL oxidation in smokers.
Intake of flavonoids is associated with a reduced cardiovascular risk. Oxidation of LDL is a major step in atherogenesis, and antioxidants may protect LDL from oxidation. Because tea is an important source of flavonoids, which are strong antioxidants, we have assessed in a randomized, placebo-controlled study the effect of consumption of black and green tea and of intake of isolated green tea polyphenols on LDL oxidation ex vivo and on plasma levels of antioxidants and lipids. Healthy male and female smokers (aged 34+/-12 years, 13 to 16 per group) consumed during a 4-week period 6 cups (900 mL) of black or green tea or water per day, or they received as a supplement 3.6 grams of green tea polyphenols per day (equivalent to the consumption of 18 cups of green tea per day). Consumption of black or green tea had no effect on plasma cholesterol and triglycerides, HDL and LDL cholesterol, plasma vitamins C and E, beta-carotene, and uric acid. No differences were found in parameters of LDL oxidation. Intake of green tea polyphenols decreased plasma vitamin E significantly in that group compared with the control group (-11% P=.016) but had no effect on LDL oxidation ex vivo. We conclude that consumption of black or green tea (6 cups per day) has no effect on plasma lipids and no sparing effect on plasma antioxidant vitamins and that intake of a high dose of isolated green tea polyphenols decreases plasma vitamin E. Although tea polyphenols had a potent antioxidant activity on LDL oxidation in vitro, no effect was found on LDL oxidation ex vivo after consumption of green or black tea or intake of a green tea polyphenol isolate.


Initial surgical management of ulcerative colitis in the biologic era.
The initial minimum operation for ulcerative colitis is a total abdominal colectomy. Healthy patients may undergo proctectomy at the same time; however, for ill patients, proctectomy is delayed. Since the introduction of biologic medications in 2005, ulcerative colitis medical management has changed dramatically. We examined how operative management for ulcerative colitis has changed from the prebiologic to biologic eras. We conducted a retrospective review of data on patients with ulcerative colitis who were included in the Nationwide Inpatient Sample database. This study was conducted at a single university. A total of 1,547,852 patients with ulcerative colitis who were admitted to a US hospital from 1991 to 2011 were included in the study. We examined patients whose initial operation consisted of total abdominal colectomy without proctectomy versus a total proctocolectomy with or without a pouch. We also examined which operation was done at the time of the construction of an ileoanal pouch. Patients who underwent colectomy and pouch construction in the same hospitalization were compared with those who received pouch formation at a subsequent hospitalization. Ulcerative colitis-related admissions rose by 170% during the years examined, and the number of patients who required total abdominal colectomy increased by 44%. Total abdominal colectomy increased by 15%, as opposed to total proctocolectomy (p < 0.001). Pouch construction at a subsequent operation increased by 16% (p = 0.002). Since 2008, total abdominal colectomy has surpassed total proctocolectomy as the most common initial surgical intervention for ulcerative colitis. The Nationwide Inpatient Sample is a retrospective database, and we were limited to examining the variables within it. Total abdominal colectomy is currently the most common initial operation for patients with ulcerative colitis, and an ileoanal pouch is more frequently constructed at a subsequent hospitalization. These trends coincide with the initiation of biologic treatments and may imply that patients are acutely ill at the time of initial operation. Alternately, there may be surgeon-perceived bias of increased surgical risk or a shift in care to specialized surgeons for pouch construction.


Identification of MUC1 proteolytic cleavage sites in vivo.
Mucins are high molecular weight glycoproteins that provide a protective layer on epithelial surfaces and are involved in cell-cell interactions, signaling, and metastasis. The identification of several membrane-tethered mucins, including MUC1, MUC3, MUC4, and MUC12, has incited interest in the processing of these mucins and the mechanisms that govern their release from the cell surface. MUC1 consists of an extracellular subunit and a membrane-associated subunit. The two moieties are produced from a single precursor polypeptide by an early proteolytic cleavage event but remain associated throughout intracellular processing and transport to the cell surface. We identified the MUC1 proteolytic cleavage site and showed it to be identical in pancreas and colon cell lines and not to be influenced by the presence of heavily glycosylated tandem repeats. The MUC1 cleavage site shows homology with sequences in other cell-surface-associated proteins and may represent a common mechanism for processing of these molecules.


Progressive effect of beta amyloid peptides accumulation on CA1 pyramidal neurons: a model study suggesting possible treatments.
Several independent studies show that accumulation of β-amyloid (Aβ) peptides, one of the characteristic hallmark of Alzheimer's Disease (AD), can affect normal neuronal activity in different ways. However, in spite of intense experimental work to explain the possible underlying mechanisms of action, a comprehensive and congruent understanding is still lacking. Part of the problem might be the opposite ways in which Aβ have been experimentally found to affect the normal activity of a neuron; for example, making a neuron more excitable (by reducing the A- or DR-type K(+) currents) or less excitable (by reducing synaptic transmission and Na(+) current). The overall picture is therefore confusing, since the interplay of many mechanisms makes it difficult to link individual experimental findings with the more general problem of understanding the progression of the disease. This is an important issue, especially for the development of new drugs trying to ameliorate the effects of the disease. We addressed these paradoxes through computational models. We first modeled the different stages of AD by progressively modifying the intrinsic membrane and synaptic properties of a realistic model neuron, while accounting for multiple and different experimental findings and by evaluating the contribution of each mechanism to the overall modulation of the cell's excitability. We then tested a number of manipulations of channel and synaptic activation properties that could compensate for the effects of Aβ. The model predicts possible therapeutic treatments in terms of pharmacological manipulations of channels' kinetic and activation properties. The results also suggest how and which mechanisms can be targeted by a drug to restore the original firing conditions.


Positioning of follicular dendritic cells within the spleen controls prion neuroinvasion.
Peripheral infection is the natural route of transmission in most prion diseases. Peripheral prion infection is followed by rapid prion replication in lymphoid organs, neuroinvasion and progressive neurological disease. Both immune cells and nerves are involved in pathogenesis, but the mechanisms of prion transfer from the immune to the nervous system are unknown. Here we show that ablation of the chemokine receptor CXCR5 juxtaposes follicular dendritic cells (FDCs) to major splenic nerves, and accelerates the transfer of intraperitoneally administered prions into the spinal cord. Neuroinvasion velocity correlated exclusively with the relative locations of FDCs and nerves: transfer of CXCR5-/- bone marrow to wild-type mice induced perineural FDCs and enhanced neuroinvasion, whereas reciprocal transfer to CXCR5-/- mice abolished them and restored normal efficiency of neuroinvasion. Suppression of lymphotoxin signalling depleted FDCs, abolished splenic infectivity, and suppressed acceleration of pathogenesis in CXCR5-/- mice. This suggests that prion neuroimmune transition occurs between FDCs and sympathetic nerves, and relative positioning of FDCs and nerves controls the efficiency of peripheral prion infection.


[Trend of mortality from respiratory disease in elderly and the forest fires in the state of Rondônia/Brazil - period between 1998 and 2005].
The forest fires in the Amazon region have been a serious environmental problem. Few studies relate the effects of forest fires on the health of exposed populations. This article aims to study the trend of mortality from respiratory diseases in the elderly, in the period 1998 to 2005, in the state of Rondônia and to correlate with the number of fire focuses. This is a descriptive study of the type of ecological. The death certificates were obtained from the Mortality Information System and the registers of data on the focus of fire have been obtained through online database available publicly in the National Space Research Institute. The results had shown a trend of growth in mortality rates for respiratory disease and chronic obstructive pulmonary disease (COPD) among elderly over 65 years and also a growing trend in the number of focus of heat. There was a positive and significant correlation between the number of fire focuses and mortality rates respiratory diseases and COPD, which explains around 50% to 80% of deaths by diseases in the elderly in the region studied. These results demonstrate the gravity of the problem of forest fires and the impact on respiratory health of the population, mainly on mortality in the elderly.


Evidence against the existence of specific Schistosoma mansoni subpopulations which are resistant to irradiated vaccine-induced immunity.
When mice are immunized with irradiated Schistosoma mansoni cercariae a proportion of the subsequent cercarial challenge always escapes killing and matures to egg-laying adults. This report investigates the possibility that incomplete immunity in this system is governed by a genetically-determined insusceptibility of a particular schistosome subpopulation. To do this we tested whether more immunoresistant schistosomes would develop following successive passages of progeny of the resistant worms through immunized mice. Mice were immunized with 500 50 Krad-irradiated cercariae, and challenged with normal cercariae when immunity was at its peak. After five successive passages through snails and immune mice, progeny of those parasites which escaped immune killing were no more refractory to vaccine-induced resistance than the original stock maintained in nonimmune mice. Additionally, the "passaged" isolates did not differ from the original stock in their ability to induce protection following irradiation. Our results indicate that with this model of acquired resistance incomplete immunity is unlikely to be due to a subpopulation of the parasites possessing a genetically-determined insusceptibility to killing.


Labeling index in pituitary adenomas evaluated by means of MIB-1: is there a prognostic role? A critical review.
The present article presents an overview of the literature, and analyses the methods and the primary questions related to assessment of proliferation index using the Ki-67/MIB-1 labeling index in pituitary adenomas. Although atypical adenomas are characterized by their atypical morphological features by an elevated mitotic index, a Ki-67 (MIB-1) labeling index greater than 3% and extensive nuclear staining for p53, use of the proliferation index (LI) of pituitary adenomas in assessing the degree of tumor aggressiveness is a controversial topic in the literature, and there are disparate results involving many studies. A review of literature was carried out to correlate the role of Ki-67 LI and its correlation with clinical findings, tumor size, invasiveness, recurrence, adenoma subtype, adenoma doubling time, and pituitary carcinomas is addressed. The prognosis cannot be predicted on the basis of the Ki-67 LI alone. Although there is no direct relation between Ki-67 LI and some of these variables and controversial data were found regarding some topics, our review justify the use of Ki-67 in the analysis of pituitary adenomas as an additional information for clinical decision. Although assessment of proliferative may be helpful in predicting subsequent tumor recurrence or invasiveness, there are many other important and as yet unidentified factors pituitary tumors. It is clear that further research is needed to clarify these molecular mechanisms to predict those with a potentially poor clinical outcome.


Laser-raster spectrometer for time-resolved recording of transient absorption.
For measurements of transient absorption a laser-raster technique has been found to be surprisingly sensitive. It utilizes spatial separation of excitation and probing by employing a fast-flowing jet stream. The time resolution is determined by the flow velocity and the focal diameters of the continuous excitation and probing laser beams. Changes in transmission can be detected in the spectral region from 350 to 1000 nm. A dual-frequency modulation technique is used to achieve a sensitivity of 10(-4). The time resolution is 0.5 mus. The performance of this spectrometer is demonstrated by measurement of the absorption of the transient states of Rhodamine 6G dye in ethylene glycol.


RNA-binding protein HuR interacts with thrombomodulin 5'untranslated region and represses internal ribosome entry site-mediated translation under IL-1 beta treatment.
Reduction in host-activated protein C levels and resultant microvascular thrombosis highlight the important functional role of protein C anticoagulant system in the pathogenesis of sepsis and septic shock. Thrombomodulin (TM) is a critical factor to activate protein C in mediating the anticoagulation and anti-inflammation effects. However, TM protein content is decreased in inflammation and sepsis, and the mechanism is still not well defined. In this report, we identified that the TM 5' untranslated region (UTR) bearing the internal ribosome entry site (IRES) element controls TM protein expression. Using RNA probe pulldown assay, HuR was demonstrated to interact with the TM 5'UTR. Overexpression of HuR protein inhibited the activity of TM IRES, whereas on the other hand, reducing the HuR protein level reversed this effect. When cells were treated with IL-1beta, the IRES activity was suppressed and accompanied by an increased interaction between HuR and TM 5'UTR. In the animal model of sepsis, we found the TM protein expression level to be decreased while concurrently observing the increased interaction between HuR and TM mRNA in liver tissue. In summary, HuR plays an important role in suppression of TM protein synthesis in IL-1beta treatment and sepsis.


Hypnosis for dental anxiety.
Dental anxiety can be a hindrance to treatment. It is prevalent, so helping patients to overcome it should not be regarded as the province of a specialist. Hypnosis can be effective but is underused. A comparison of the conscious, alert state and hypnosis/nitrous oxide sedation is shown by electroencephalogram examples. The benefits and drawbacks of the use of hypnosis are discussed and suggestions of ways of learning and using hypnosis outlined. This paper is an overview of the common problem of dental anxiety and a pragmatic approach to overcoming it using hypnotherapy.


Effects of antibacterial agents on in vitro ovine ruminal biotransformation of the hepatotoxic pyrrolizidine alkaloid jacobine.
Ingestion of pyrrolizidine alkaloids, naturally occurring plant toxins, causes illness and death in a number of animal species. Senecio jacobaea pyrrolizidine alkaloids cause significant economic losses due to livestock poisoning, particularly in the Pacific Northwest. Some sheep are resistant to pyrrolizidine alkaloid poisoning, because ovine ruminal biotransformation detoxifies free pyrrolizidine alkaloids in digesta. Antibacterial agents modify ruminal fermentation. Pretreatment with antibacterial agents may account for some animal variability in resistance to pyrrolizidine alkaloid toxicosis, and antibacterial agents can also be used for characterizing ruminal pyrrolizidine alkaloid-biotransforming microflora. The objective of this study was to evaluate the effects of antibacterial agents on biotransformation of a predominant S. jacobaea pyrrolizidine alkaloid, jacobine, in ovine ruminal contents. Ovine ruminal jacobine biotransformation was tested in vitro with 20 independent antibacterial agents. Low amounts of rifampin and erythromycin prevented jacobine biotransformation. Chlortetracycline, lasalocid, monensin, penicillin G, and tetracycline were slightly less effective at inhibiting jacobine biotransformation. Bacitracin, crystal violet, kanamycin, and neomycin were moderately inhibitory against jacobine biotransformation. Brilliant green, chloramphenicol, gramicidin, nalidixic acid, polymyxin B SO4, sodium azide, streptomycin, sulfisoxazole, and vancomycin had little to no effect on jacobine biotransformation. The antibiotics that were most effective at inhibiting biotransformation were those that are active against gram-positive bacteria. Therefore, gram-positive bacteria are most likely critical members of the jacobine-biotransforming consortia.


Synthesis of a Naphthodiazaborinine and Its Verification by Planarization with Atomic Force Microscopy.
Aiming to study new motifs, potentially active as functional materials, we performed the synthesis of a naphthodiazaborinine (the BN isostere of the phenalenyl anion) that is bonded to a hindered di-ortho-substituted aryl system (9-anthracene). We used atomic force microscopy (AFM) and succeeded in both the verification of the original nonplanar structure of the molecule and the planarization of the skeleton by removing H atoms that cause steric hindrance. This study demonstrated that planarization by atomic manipulation is a possible route for extending molecular identification by AFM to nonplanar molecular systems that are difficult to probe with AFM directly.


Baseline Characteristics of Patients With Heart Failure and Preserved Ejection Fraction in the PARAGON-HF Trial.
To describe the baseline characteristics of patients with heart failure and preserved left ventricular ejection fraction enrolled in the PARAGON-HF trial (Prospective Comparison of Angiotensin Receptor Neprilysin Inhibitor With Angiotensin Receptor Blocker Global Outcomes in HFpEF) comparing sacubitril/valsartan to valsartan in reducing morbidity and mortality. We report key demographic, clinical, and laboratory findings, and baseline therapies, of 4822 patients randomized in PARAGON-HF, grouped by factors that influence criteria for study inclusion. We further compared baseline characteristics of patients enrolled in PARAGON-HF with those patients enrolled in other recent trials of heart failure with preserved ejection fraction (HFpEF). Among patients enrolled from various regions (16% Asia-Pacific, 37% Central Europe, 7% Latin America, 12% North America, 28% Western Europe), the mean age of patients enrolled in PARAGON-HF was 72.7±8.4 years, 52% of patients were female, and mean left ventricular ejection fraction was 57.5%, similar to other trials of HFpEF. Most patients were in New York Heart Association class II, and 38% had ≥1 hospitalizations for heart failure within the previous 9 months. Diabetes mellitus (43%) and chronic kidney disease (47%) were more prevalent than in previous trials of HFpEF. Many patients were prescribed angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (85%), β-blockers (80%), calcium channel blockers (36%), and mineralocorticoid receptor antagonists (24%). As specified in the protocol, virtually all patients were on diuretics, had elevated plasma concentrations of N-terminal pro-B-type natriuretic peptide (median, 911 pg/mL; interquartile range, 464-1610), and structural heart disease. PARAGON-HF represents a contemporary group of patients with HFpEF with similar age and sex distribution compared with prior HFpEF trials but higher prevalence of comorbidities. These findings provide insights into the impact of inclusion criteria on, and regional variation in, HFpEF patient characteristics. URL: https://www.clinicaltrials.gov. Unique identifier: NCT01920711.


Versican V2 assembles the extracellular matrix surrounding the nodes of ranvier in the CNS.
The CNS-restricted versican splice-variant V2 is a large chondroitin sulfate proteoglycan incorporated in the extracellular matrix surrounding myelinated fibers and particularly accumulating at nodes of Ranvier. In vitro, it is a potent inhibitor of axonal growth and therefore considered to participate in the reduction of structural plasticity connected to myelination. To study the role of versican V2 during postnatal development, we designed a novel isoform-specific gene inactivation approach circumventing early embryonic lethality of the complete knock-out and preventing compensation by the remaining versican splice variants. These mice are viable and fertile; however, they display major molecular alterations at the nodes of Ranvier. While the clustering of nodal sodium channels and paranodal structures appear in versican V2-deficient mice unaffected, the formation of the extracellular matrix surrounding the nodes is largely impaired. The conjoint loss of tenascin-R and phosphacan from the perinodal matrix provide strong evidence that versican V2, possibly controlled by a nodal receptor, organizes the extracellular matrix assembly in vivo.


Floral gigantism in Rafflesiaceae.
Species of Rafflesiaceae possess the world's largest flowers (up to 1 meter in diameter), yet their precise evolutionary relationships have been elusive, hindering our understanding of the evolution of their extraordinary reproductive morphology. We present results of phylogenetic analyses of mitochondrial, nuclear, and plastid data showing that Rafflesiaceae are derived from within Euphorbiaceae, the spurge family. Most euphorbs produce minute flowers, suggesting that the enormous flowers of Rafflesiaceae evolved from ancestors with tiny flowers. Given the inferred phylogeny, we estimate that there was a circa 79-fold increase in flower diameter on the stem lineage of Rafflesiaceae, making this one of the most dramatic cases of size evolution reported for eukaryotes.


Antibody responses after a single dose of ChAdOx1 nCoV-19 vaccine in healthcare workers previously infected with SARS-CoV-2.
Recent reports demonstrate robust serological responses to a single dose of messenger RNA (mRNA) vaccines in individuals previously infected with SARS-CoV-2. Data on immune responses following a single-dose adenovirus-vectored vaccine expressing the SARS-CoV-2 spike protein (ChAdOx1 nCoV-19) in individuals with previous SARS-CoV-2 infection are however limited, and current guidelines recommend a two-dose regimen regardless of preexisting immunity. We compared RBD-specific IgG and RBD-ACE2 blocking antibodies against SARS-CoV-2 wild type and variants of concern following two doses of the mRNA vaccine BNT162b2 in SARS-CoV-2 naïve healthcare workers (n=65) and a single dose of the adenovector vaccine ChAdOx1 nCoV-19 in 82 healthcare workers more than (n=45) and less than (n=37) 11 months post mild SARS-CoV-2 infection at time of vaccination. The post-vaccine levels of RBD-specific IgG and neutralizing antibodies against the SARS-CoV-2 wild type and variants of concern including Delta lineage 1.617.2 were similar or higher in participants receiving a single dose of ChAdOx1 nCoV-19 vaccine post SARS-CoV-2 infection (both more than and less than 11 months post infection) compared to SARS-CoV-2 naïve participants who received two doses of BNT162b2 vaccine. Our data support that a single dose ChAdOx1 nCoV-19 vaccine that is administered up to at least 11 months post SARS-CoV-2 infection serves as an effective immune booster. This provides a possible rationale for a single-dose vaccine regimen. A full list of funding bodies that contributed to this study can be found in the Acknowledgements section.


Torsades de Pointes in Patients with Polymyalgia Rheumatica.
Polymyalgia rheumatica (PMR) represents the most common inflammatory rheumatic disease of the elderly. It is characterized by synovitis of proximal joints and extra-articular synovial structures, along with chronic high-grade systemic inflammation. PMR is closely related to giant cell arteritis (GCA), a large-vessel vasculitis that involves the major branches of the aorta, particularly the extracranial branches of carotid artery including temporal arteries. It is currently believed that PMR and GCA may represent different manifestations of the same disease process. Chronic systemic inflammation is presently recognized as one of the key pathogenic mechanisms underlying cardiovascular disease and associated complications, including cardiac arrhythmias and sudden death. In this regard, several studies demonstrated that besides promoting structural heart disease, inflammatory activation may also be per se arrhythmogenic, via cytokine-mediated effects on cardiac electrophysiology. In particular, increasing evidence points to inflammation as a novel risk factor for QTc prolongation and related life-threatening arrhythmias, specifically Torsade de Pointes (TdP). Starting from the report of two cases of TdP occurring in PMR patients with active disease and elevated circulating IL-6 levels, we here reviewed literature data regarding heart involvement and arrhythmic events in PMR/GCA, as well as TdP risk in inflammatory diseases. Potential underlying mechanisms were dissected, by focusing on the driving role of inflammatory activation.


Physiologically Based Modelling of Darunavir/Ritonavir Pharmacokinetics During Pregnancy.
Pregnant women are usually excluded from clinical trials. Physiologically based pharmacokinetic (PBPK) modelling may provide a method to predict pharmacokinetics in pregnant women, without the need to perform extensive in vivo clinical trials. Here, we used mechanistic modelling to delineate the potential impact of drug transporters on darunavir pharmacokinetics and to identify current knowledge gaps that limit accurate PBPK modelling of darunavir/ritonavir (darunavir/r) exposure in pregnancy. Simcyp (version 13.2) was used for PBPK modelling, using physicochemical and in vitro pharmacokinetic parameters of darunavir and ritonavir from the literature. The Michaelis-Menten constant (K m) and the maximum rate of metabolite formation (V max) for cytochrome P450 3A4-mediated darunavir biotransformation and inhibition by ritonavir were determined experimentally, while the contributions of hepatocyte influx and efflux transporters were assessed by sensitivity analysis. The simulations were compared with previously published clinical pharmacokinetic data. We found that use of a well-stirred liver model overestimated darunavir exposure substantially. A permeability-limited liver model, including hepatic uptake and efflux transporters and an efficient enterohepatic circulation step, resulted in an acceptable description of darunavir/r exposure. For the 600/100 mg darunavir/r twice-daily dose and the 800/100 mg once-daily dose, the estimated pharmacokinetic parameters were within a 2-fold range of the reported data. The predicted decreases in the area under the concentration-time curve (AUC) values during pregnancy for the twice- and once-daily doses were 27 and 41%, respectively, which were in line with the observed decreases of 17-22 and 33%. In conclusion, our data support a clinically relevant role of hepatic transporters in darunavir pharmacokinetics. By including them in our model, we successfully approximated the increase in darunavir exposure mediated by ritonavir co-administration and the decrease in darunavir exposure observed during pregnancy.


Alpha-thalassaemia and population health in Southeast Asia.
Alpha-thalassaemia mutations are common. In Southeast Asia, they cause Hb H disease and Hb Barts hydrops fetalis. Fetuses with the devastating Hb Barts hydrops fetalis due to the complete lack of alpha-globin gene die in utero or shortly after birth, often during the second or third trimesters. Recent findings on patients with Hb H disease who have only one active alpha-globin gene suggest that it is not necessarily a benign disorder as previously thought. The disease burden of these syndromes and their public health importance have been largely neglected. We review the population carrier frequencies of alpha-thalassaemia, and summarize the clinical features, diagnostic approaches, counselling and management of these common genetic disorders. Several practical proposals are made that, if implemented, can begin to address the issues of collaboration and improvement for care of these common diseases in the region.


The role of adolescent physical abuse in adult intimate partner violence.
This study's primary aims were to examine whether a sample of young adults, aged 23 to 31, who had been documented as physically abused by their parent(s) during adolescence would be more likely to aggress, both physically and verbally, against their intimate partners compared with nonabused young adults and whether abuse history was (along with other risk factors) a significant predictor of intimate partner physical and emotional violence perpetration or victimization. In this longitudinal study, 67 abused and 78 nonabused adults (of an original sample of 198 adolescents) completed the Modified Conflict Tactics Scale and the Jealousy and Emotional Control Scales. Nonabused comparison adolescents were matched for age, gender, and community income. As adults, participants with abuse histories had significantly higher rates of intimate partner physical violence and verbal aggression than did comparison participants. Multivariate logistic regressions indicated that adults with histories of physical abuse were more than twice as likely to be physically violent and almost six times more likely to be verbally aggressive to their intimate partners than were comparison participants. Having had an alcohol use disorder, being married to or living with a partner, and perceiving one's partner as controlling were also significantly associated with physical violence. Jealousy and feeling controlled by one's partner were also significant predictors of verbal aggression. These findings underscore the importance of preventing adolescent abuse as a means of decreasing the incidence of intimate partner physical violence in adulthood.


Cloning and characterization of genes for the PvuI restriction and modification system.
The genes encoding the endonuclease and the methylase of the PvuI restriction and modification system were cloned in E.coli and characterized. The genes were adjacent in tandem orientation spanning a distance of 2200 bases. The PvuI endonuclease was a single polypeptide with a calculated molecular weight of 27,950 daltons. The endonuclease was easily detectable when the gene was expressed from its endogenous promotor and present on a low copy plasmid, but expression was considerably enhanced when the endonuclease gene was placed under the control of a strong promoter on a high copy plasmid. The methylase did not completely protect plasmid DNA from R.PvuI digestion until the methylase gene was placed under lac promotor control in a multicopy plasmid. In the absence of the M.PvuI methylase, expression of the R.PvuI endonuclease from the lac promotor on a multicopy plasmid was not lethal to wild type E.coli, but was lethal in a temperature-sensitive ligase mutant at the non-permissive temperature. Moreover, induction of the R.PvuI endonuclease under lambda pL promotor control resulted in complete digestion of the E.coli chromosome by R.PvuI.


Acceptability and potential impacts of innovative E-Portfolios implemented in E-Learning systems for clinical training.
There is growing evidence that use of E-portfolios has a positive effect on learning experience. However, literature has not shown sufficient data about the effectiveness of E-portfolios in medical education. This study was conducted to assess the acceptability and potential impacts of E-portfolio use for undergraduate radiography students. This cross-sectional quantitative study was conducted during the academic year 2016-2017 on students studying clinical courses. A self-administered questionnaire was distributed to the selected cohort of students. All participants completed the consent form before answering the questionnaire. Of 75 students, 66 completed the survey (response rate; 88%). Students' experience, students' learning support, and the challenges of E-portfolio use were identified. Forty-one (62%) students perceived that E-portfolios facilitated the effective organization of their work, and 40 (61%) agreed that E-portfolios enhanced their professional skills. In contrast, the students perceived a negative correlation between students' learning support and future utilization of E-portfolios (correlation coefficient -0.394, p = 0.05). Future utilization of E-portfolios was found to be positively correlated with challenges and commitment to deadlines, with correlation coefficients of 0.371 and 0.152, respectively. The study found that continuous technical support for E-portfolios throughout the course had a potential role in enhancing learning experience. Appropriate training for integrating E-portfolios into teaching and learning can potentially enrich the educational environment. Student and faculty feedback is the main cornerstone for E-portfolio success.


Screening for Lynch syndrome using risk assessment criteria in patients with ovarian cancer.
Lynch syndrome is a cancer predisposition syndrome caused by germline mutation of DNA mismatch repair (MMR) genes. Lynch syndrome only causes about 0.4% of cases of ovarian cancer, which suggests that universal screening may not be cost-efficient. However, the frequency of Lynch syndrome in ovarian cancer is unclear in the Asian population. The goal of the study was to investigate a screening strategy using family history. The subjects were 129 patients with ovarian cancer. Clinical and family history were collected using a self-administered questionnaire, and Society of Gynecologic Oncology (SGO) criteria 2007 and PREMM₅ were used for risk assessment. Microsatellite instability, immunohistochemistry, and methylation of MMR genes were analyzed. Of the 129 cases, 25 (19.4%) met the SGO criteria, and 4 of these 25 had MSI-high and MMR deficiency. Two cases had loss of MSH2 and MSH6, indicating MSH2 mutation, and the other two had loss of MLH1 and PMS2, including one without MLH1 methylation indicating MLH1 mutation. These results show that screening using family history can detect Lynch syndrome in 12.0% (3/25) of ovarian cancer cases. The 3 cases were positive for PREMM₅, but negative for Amsterdam II criteria and revised Bethesda guidelines. Genetic testing in one case with MSH2 and MSH6 deficiency confirmed the diagnosis of Lynch syndrome with MSH2 mutation. This is the first study of screening for Lynch syndrome in ovarian cancer using clinical and family history in an Asian population. This approach may be effective for diagnosis in these patients.


Mucin-Inspired, High Molecular Weight Virus Binding Inhibitors Show Biphasic Binding Behavior to Influenza A Viruses.
Multivalent binding inhibitors are a promising new class of antivirals that prevent virus infections by inhibiting virus binding to cell membranes. The design of these inhibitors is challenging as many properties, for example, inhibitor size and functionalization with virus attachment factors, strongly influence the inhibition efficiency. Here, virus binding inhibitors are synthesized, the size and functionalization of which are inspired by mucins, which are naturally occurring glycosylated proteins with high molecular weight (MDa range) and interact efficiently with various viruses. Hyperbranched polyglycerols (hPGs) with molecular weights ranging between 10 and 2600 kDa are synthesized, thereby hitting the size of mucins and allowing for determining the impact of inhibitor size on the inhibition efficiency. The hPGs are functionalized with sialic acids and sulfates, as suggested from the structure of mucins, and their inhibition efficiency is determined by probing the inhibition of influenza A virus (IAV) binding to membranes using various methods. The largest, mucin-sized inhibitor shows potent inhibition at pm concentrations, while the inhibition efficiency decreases with decreasing the molecular weight. Interestingly, the concentration-dependent IAV inhibition shows a biphasic behavior, which is attributed to differences in the binding affinity of the inhibitors to the two IAV envelope proteins, neuraminidase, and hemagglutinin.


Rationale and design of the SI! Program for health promotion in elementary students aged 6 to 11 years: A cluster randomized trial.
Unhealthy habits in children are increasing at an alarming rate. The school provides a promising setting for effective preventive strategies to improve children's lifestyle behaviors. The SI! Program is a multilevel multicomponent school-based educational intervention aimed at all stages of compulsory education in Spain. Here, we present the design of the SI! Program for Elementary School cluster-randomized controlled trial, targeting children aged 6 to 11 years. This trial aims to study the impact of different timings and intensities of exposure to SI! Program activities on elementary school children and their immediate environment (parents/caregivers, teachers, and school). The trial includes 1770 children from 48 public elementary schools in Madrid (Spain), together with their parents and teachers. Schools and their children were randomly assigned to the intervention group (the SI! curriculum-based educational program over 3 or 6 academic years) or to the control group (standard curriculum). The primary outcomes are the change from baseline at 3-year and 6-year follow-up in children's scores for knowledge, attitudes, and habits (KAH) and health factors (blood pressure, height, weight, waist circumference, and skinfold thickness). Secondary outcomes include 3-year and 6-year changes from baseline in lifestyle questionnaire scores for parents/caregivers and teachers, and in the school environment questionnaire. The overarching goal of the SI! Program is to provide an effective and sustainable health promotion program for the adoption of healthy behaviors in children. The present trial will address the impact and the optimal timing and duration of this educational intervention in the elementary school setting.


A high-resolution paleoclimate record spanning the past 25,000 years in southern East Africa.
High-resolution profiles of the mass accumulation rate of biogenic silica and other geochemical proxies in two piston cores from northern Lake Malawi provide a climate signal for this part of tropical Africa spanning the past 25,000 years. The biogenic silica mass accumulation rate was low during the relatively dry late Pleistocene, when the river flux of silica to the lake was suppressed. Millennial-scale fluctuations, due to upwelling intensity, in the late Pleistocene climate of the Lake Malawi basin appear to have been closely linked to the Northern Hemisphere climate until 11 thousand years ago. Relatively cold conditions in the Northern Hemisphere coincided with more frequent north winds over the Malawi basin, perhaps resulting from a more southward migration of the Intertropical Convergence Zone.


Trace elements and cancer risk: a review of the epidemiologic evidence.
Worldwide, there are more than 10 million new cancer cases each year, and cancer is the cause of approximately 12% of all deaths. Given this, a large number of epidemiologic studies have been undertaken to identify potential risk factors for cancer, amongst which the association with trace elements has received considerable attention. Trace elements, such as selenium, zinc, arsenic, cadmium, and nickel, are found naturally in the environment, and human exposure derives from a variety of sources, including air, drinking water, and food. Trace elements are of particular interest given that the levels of exposure to them are potentially modifiable. In this review, we focus largely on the association between each of the trace elements noted above and risk of cancers of the lung, breast, colorectum, prostate, urinary bladder, and stomach. Overall, the evidence currently available appears to support an inverse association between selenium exposure and prostate cancer risk, and possibly also a reduction in risk with respect to lung cancer, although additional prospective studies are needed. There is also limited evidence for an inverse association between zinc and breast cancer, and again, prospective studies are needed to confirm this. Most studies have reported no association between selenium and risk of breast, colorectal, and stomach cancer, and between zinc and prostate cancer risk. There is compelling evidence in support of positive associations between arsenic and risk of both lung and bladder cancers, and between cadmium and lung cancer risk.


Isolation of Muscle Stem Cells from Mouse Skeletal Muscle.
Isolation of muscle stem cells from skeletal muscle is a critical step for the study of skeletal myogenesis and regeneration. Although stem cell isolation has been performed for decades, the emergence of flow cytometry with defined cell surface markers, or transgenic mouse models, has allowed the efficient isolation of highly enriched stem cell populations. Here, we describe the isolation of mouse muscle stem cells using two different combinations of enzyme treatments allowing the release of mononucleated muscle stem cells from their niche. Mouse muscle stem cells can be further isolated as a highly enriched population by flow cytometry using fluorescent reporters or cell surface markers. We will present advantages and drawbacks of these different approaches.


The dorsomedial pathway is not just for reaching: grasping neurons in the medial parieto-occipital cortex of the macaque monkey.
Brain control of prehension is thought to rely on two specific brain circuits: a dorsomedial one (involving the areas of the superior parietal lobule and the dorsal premotor cortex) involved in the transport of the hand toward the object and a dorsolateral one (involving the inferior parietal lobule and the ventral premotor cortex) dealing with the preshaping of the hand according to the features of the object. The present study aimed at testing whether a pivotal component of the dorsomedial pathway (area V6A) is involved also in hand preshaping and grip formation to grasp objects of different shapes. Two macaque monkeys were trained to reach and grasp different objects. For each object, animals used a different grip: whole-hand prehension, finger prehension, hook grip, primitive precision grip, and advanced precision grip. Almost half of 235 neurons recorded from V6A displayed selectivity for a grip or a group of grips. Several experimental controls were used to ensure that neural modulation was attributable to grip only. These findings, in concert with previous studies demonstrating that V6A neurons are modulated by reach direction and wrist orientation, that lesion of V6A evokes reaching and grasping deficits, and that dorsal premotor cortex contains both reaching and grasping neurons, indicate that the dorsomedial parieto-frontal circuit may play a central role in all phases of reach-to-grasp action. Our data suggest new directions for the modeling of prehension movements and testable predictions for new brain imaging and neuropsychological experiments.


Evaluating the Effectiveness of an Integrated Cognitive-Behavioural Intervention (CBI) Model for Male Problem Gamblers in Hong Kong: A Matched-Pair Comparison Design.
Very few clinical cognitive-behavioural intervention (CBI) studies were conducted with the Chinese gamblers. There is a lack of attention paid to intervening in negative emotions that may also adversely affect PGs in current CBI treatment modality. This study is the first attempt to systematically and rigorously evaluate both the short-term and longer-term effects of a culturally-attuned CBI group treatment with an emotion regulation component for a group of Chinese PGs in Hong Kong. A quasi-experimental matched-pairs design was adopted and 84 participants were allocated to the CBI (N = 42) and social activity groups (N = 42). There are 3 assessment points in the study: baseline at recruitment, post-intervention at the end of CBI and social activity groups, and at 6-month follow-up. When compared to the social activity group and after controlling for general group effects, there were significantly greater decreases in the severity of gambling, gambling-related cognitions (i.e. interpretive bias), negative psychological states (i.e. stress) and money spent on gambling in the past month in the CBI group between pre- and post-intervention and between pre-intervention and 6-month follow-up. Results also indicated that both reduction in gambling-related cognitions and negative psychological states could mediate the treatment effect of the CBI on the reduction of problematic gambling behaviours. The culturally attuned integrated CBI group treatment with an emotional regulation component appeared to be effective in treating Chinese problem gamblers in Hong Kong and the effects could be sustained at 6-month follow-up.


Differential DNA damage signaling accounts for distinct neural apoptotic responses in ATLD and NBS.
The MRN complex (Mre11/RAD50/NBS1) and ATM (ataxia telangiectasia, mutated) are critical for the cellular response to DNA damage. ATM disruption causes ataxia telangiectasia (A-T), while MRN dysfunction can lead to A-T-like disease (ATLD) or Nijmegen breakage syndrome (NBS). Neuropathology is a hallmark of these diseases, whereby neurodegeneration occurs in A-T and ATLD while microcephaly characterizes NBS. To understand the contrasting neuropathology resulting from Mre11 or Nbs1 hypomorphic mutations, we analyzed neural tissue from Mre11(ATLD1/ATLD1) and Nbs1(DeltaB/DeltaB) mice after genotoxic stress. We found a pronounced resistance to DNA damage-induced apoptosis after ionizing radiation or DNA ligase IV (Lig4) loss in the Mre11(ATLD1/ATLD1) nervous system that was associated with defective Atm activation and phosphorylation of its substrates Chk2 and p53. Conversely, DNA damage-induced Atm phosphorylation was defective in Nbs1(DeltaB/DeltaB) neural tissue, although apoptosis occurred normally. We also conditionally disrupted Lig4 throughout the nervous system using Nestin-cre (Lig4(Nes-Cre)), and while viable, these mice showed pronounced microcephaly and a prominent age-related accumulation of DNA damage throughout the brain. Either Atm-/- or Mre11(ATLD1/ATLD1) genetic backgrounds, but not Nbs1(DeltaB/DeltaB), rescued Lig4(Nes-Cre) microcephaly. Thus, DNA damage signaling in the nervous system is different between ATLD and NBS and likely explains their respective neuropathology.


Enantioselective Synthesis of 8-Hydroxyquinoline Derivative, Q134 as a Hypoxic Adaptation Inducing Agent.
Hypoxia is a common feature of neurodegenerative diseases, including Alzheimer's disease that may be responsible for disease pathogenesis and progression. Therefore, the hypoxia-inducible factor (HIF)1 system, responsible for hypoxic adaptation, is a potential therapeutic target to combat these diseases by activators of cytoprotective protein induction. We have selected a candidate molecule from our cytoprotective hydroxyquinoline library and developed a novel enantioselective synthesis for the production of its enantiomers. The use of quinidine or quinine as a catalyst enabled the preparation of enantiomer-pure products. We have utilized in vitro assays to evaluate cytoprotective activity, a fluorescence-activated cell sorting (FACS) based assay measuring mitochondrial membrane potential changes, and gene and protein expression analysis. Our data showed that the enantiomers of Q134 showed potent and similar activity in all tested assays. We have concluded that the enantiomers exert their cytoprotective activity via the HIF1 system through HIF1A protein stabilization.


Female Gender Predicts Favorable Prognosis in Patients With Non-metastatic Clear Cell Renal Cell Carcinoma Undergoing Curative Surgery: Results From the International Marker Consortium for Renal Cancer (INMARC).
There is no clear consensus regarding gender differences in the prognosis of patients with clear-cell renal cell carcinoma (ccRCC). In the present study, we investigated the prognostic value of gender in patients with non-metastatic ccRCC undergoing curative surgery using the inverse probability of treatment weighting (IPTW) method to balance the difference in baseline factors between females and males. We retrospectively reviewed the International Marker Consortium for Renal Cancer (INMARC) dataset and included 2055 patients with cT1-4N0M0 ccRCC who underwent partial or radical nephrectomy. The IPTW method was used to adjust for baseline characteristics between females and males (age, race, surgery type, and pT stage), and the association of gender with recurrence-free survival (RFS) was evaluated. During the follow-up (median, 30 months), 162 (8%) patients had disease recurrence (5-year RFS rate, 88%). Female gender (n = 712; 35%) was significantly associated with a lower Fuhrman grade (unweighted, P = .022; IPTW-weighted, P < .001). Females had significantly better RFS compared with males (unweighted, 5-year RFS rate, 92% vs. 87%; P = .005; IPTW-weighted, 5-year RFS rate, 92% vs. 86%; P = .002). IPTW-weighted multivariate analysis showed that female gender was an independent predictor for better RFS (hazard ratio, 0.59; P = .005) along with lower pT stage and lower Fuhrman grade. The prognostic significance of female gender was also observed in the unweighted multivariate analysis. Female gender was significantly associated with a lower Fuhrman grade and better prognosis for patients with non-metastatic ccRCC undergoing curative surgery.


Development and preliminary psychometric testing of the centrality of pain scale.
The objective of the study was to develop and begin to evaluate a new measure of the centrality of pain in patients' lives. The study was designed as a cross-sectional survey and cognitive interviews. The study was set in an academic general internal medicine clinic. Sixty-five adult internal medicine patients with chronic nonmalignant pain (CNMP) participated in the study. We assessed content validity and clarity of the 10-item Centrality of Pain Scale (COPS) by soliciting feedback from chronic pain experts and by conducting cognitive interviews with patients with CNMP. We assessed internal consistency reliability using Cronbach's alpha. We assessed construct validity by comparing the COPS with other measures of chronic pain morbidity including pain severity, depression, anxiety, physical and mental health function, posttraumatic stress disorder, quality of life, and provider assessment. Health care providers felt the COPS had excellent face validity. Cognitive interviews revealed that patients' understanding of the items matched the intended construct, the scale measured an important concept, and items were easy to understand. The COPS had excellent internal consistency (alpha = 0.9). It was negatively associated with age (r = -0.29; P = 0.02), but not with other demographic characteristics. Higher COPS scores were associated with poorer physical (r = -0.48; P < 0.001) and mental (r = -0.39; P = 0.002) health function, quality of life (r = -0.36; P = 0.004), and provider assessment of stability (r = -0.38; P = 0.004) as well as with greater pain grade (r = 0.55; P < 0.001), and depression (r = 0.63; P < 0.001). In multivariate analyses, age, physical and mental health function, and depression were independently associated with COPS. The COPS has excellent internal consistency and construct validity. Additional studies are needed to further validate the scale.