Diet soft drink consumption is associated with an increased risk of vascular events in the Northern Manhattan Study.
Diet and regular soft drinks have been associated with diabetes and the metabolic syndrome, and regular soft drinks with coronary heart disease. To determine the association between soft drinks and combined vascular events, including stroke. A population-based cohort study of stroke incidence and risk factors. PARTICANTS: Participants (N= 2564, 36% men, mean age 69 ± 10, 20% white, 23% black, 53% Hispanic) were from the Northern Manhattan Study. We assessed diet and regular soft drink consumption using a food frequency questionnaire at baseline, and categorized: none (<1/month, N = 1948 diet, N = 1333 regular), light (1/month-6/week, N = 453 diet, N = 995 regular), daily (≥1/day, N = 163 diet, N = 338 regular). Over a mean follow-up of 10 years, we examined the association between soft drink consumption and 591 incident vascular events (stroke, myocardial infarction, vascular death) using Cox models. Controlling for age, sex, race/ethnicity, education, smoking, physical activity, alcohol consumption, BMI, daily calories, consumption of protein, carbohydrates, total fat, saturated fat, and sodium, those who drank diet soft drinks daily (vs. none) had an increased risk of vascular events, and this persisted after controlling further for the metabolic syndrome, peripheral vascular disease, diabetes, cardiac disease, hypertension, and hypercholesterolemia (HR = 1.43, 95% CI = 1.06-1.94). There was no increased risk of vascular events associated with regular soft drinks or light diet soft drink consumption. Daily diet soft drink consumption was associated with several vascular risk factors and with an increased risk for vascular events. Further research is needed before any conclusions can be made regarding the potential health consequences of diet soft drink consumption.


Rare case of optic pathway glioma with extensive intra-ocular involvement in a child with neurofibromatosis type 1.
We present a case of a 3-year-old girl with a positive family history of neurofibromatosis type-1 (NF1) presented with best corrected visual acuity of 20/40 in the right eye and <20/400 in the left eye. External ocular examination revealed left eye proptosis of 3 mm, grade II left relative afferent pupillary defect and full range of ocular motility with no strabismus. Slit lamp examination revealed iris lisch nodules bilaterally. Dilated fundus examination of the right eye was normal. Left eye disclosed a large mass extending from the optic nerve head, with associated subretinal fluid. There was neovascularization at the optic disc as well as a superior retinal hemorrhage. Computed tomography of brain/orbits showed an enlarged left optic nerve with a large mass at the optic nerve head, with no evidence of calcification. In addition, a large left optic pathway glioma (OPG), multiple hamartomas within the brain and a smaller low-grade right OPG was also reported. The remarkable feature of our case is the rare intraocular optic nerve involvement of the OPG. Early and regular ophthalmological assessment of all NF1 suspect/confirmed cases is of paramount importance in order to detect OPG early, resulting in timely intervention and salvage of vision.


MGMT methylation analysis of glioblastoma on the Infinium methylation BeadChip identifies two distinct CpG regions associated with gene silencing and outcome, yielding a prediction model for comparisons across datasets, tumor grades, and CIMP-status.
The methylation status of the O(6)-methylguanine-DNA methyltransferase (MGMT) gene is an important predictive biomarker for benefit from alkylating agent therapy in glioblastoma. Recent studies in anaplastic glioma suggest a prognostic value for MGMT methylation. Investigation of pathogenetic and epigenetic features of this intriguingly distinct behavior requires accurate MGMT classification to assess high throughput molecular databases. Promoter methylation-mediated gene silencing is strongly dependent on the location of the methylated CpGs, complicating classification. Using the HumanMethylation450 (HM-450K) BeadChip interrogating 176 CpGs annotated for the MGMT gene, with 14 located in the promoter, two distinct regions in the CpG island of the promoter were identified with high importance for gene silencing and outcome prediction. A logistic regression model (MGMT-STP27) comprising probes cg12434587 [corrected] and cg12981137 provided good classification properties and prognostic value (kappa = 0.85; log-rank p < 0.001) using a training-set of 63 glioblastomas from homogenously treated patients, for whom MGMT methylation was previously shown to be predictive for outcome based on classification by methylation-specific PCR. MGMT-STP27 was successfully validated in an independent cohort of chemo-radiotherapy-treated glioblastoma patients (n = 50; kappa = 0.88; outcome, log-rank p < 0.001). Lower prevalence of MGMT methylation among CpG island methylator phenotype (CIMP) positive tumors was found in glioblastomas from The Cancer Genome Atlas than in low grade and anaplastic glioma cohorts, while in CIMP-negative gliomas MGMT was classified as methylated in approximately 50 % regardless of tumor grade. The proposed MGMT-STP27 prediction model allows mining of datasets derived on the HM-450K or HM-27K BeadChip to explore effects of distinct epigenetic context of MGMT methylation suspected to modulate treatment resistance in different tumor types.


Effect of Australian propolis from stingless bees (Tetragonula carbonaria) on pre-contracted human and porcine isolated arteries.
Bee propolis is a mixture of plant resins and bee secretions. While bioactivity of honeybee propolis has been reported previously, information is limited on propolis from Australian stingless bees (Tetragonula carbonaria). The aim of this study was to investigate possible vasomodulatory effects of propolis in KCl-precontracted porcine coronary arteries using an ex vivo tissue bath assay. Polar extracts of propolis produced a dose-dependent relaxant response (EC50=44.7±7.0 μg/ml), which was unaffected by endothelial denudation, suggesting a direct effect on smooth muscle. Propolis markedly attenuated a contractile response to Ca(2+) in vessels that were depolarised with 60 mM KCl, in Ca(2+)-free Krebs solution. Propolis (160 µg/ml) reduced vascular tone in KCl pre-contracted vessels to near-baseline levels over 90 min, and this effect was partially reversible with 6 h washout. Some loss in membrane integrity, but no loss in mitochondrial function was detected after 90 min exposure of human cultured umbilical vein endothelial cells to 160 µg/ml propolis. We conclude that Australian stingless bee (T. carbonaria) propolis relaxes porcine coronary artery in an endothelial-independent manner that involves inhibition of voltage-gated Ca(2+) channels. This effect is partially and slowly reversible upon washout. Further studies are required to determine the therapeutic potential of Australian stingless bee propolis for conditions in which vascular supply is compromised.


The global burden of cardiovascular disease.
Cardiovascular disease (CVD) today is responsible for approximately one-third of deaths worldwide, and that figure will surely increase in both developing and developed countries as risk factors for the disease--primarily dyslipidemia, hypertension, obesity, diabetes, physical inactivity, poor diet, and smoking--continue to increase. Although these risk factors are modifiable, to date there is a relative paucity of measures to prevent or control them, particularly in developing countries. A population strategy combined with a high-risk strategy for CVD prevention could greatly reduce the burden of disease in the coming decades. Many initiatives are working, but many more are needed. This chapter provides background on the global burden of CVD and provides the context for the subsequent chapters addressing nurses' roles in reversing the bleak predictions for the ravages of CVD if risk factors are left unchecked in the coming decades.


Catheter-related right atrial thrombus and pulmonary embolism: a case report and systematic review of the literature.
Central venous catheters (CVCs) are commonly used in clinical practice. One of the foremost complications associated with their use is the potential for symptomatic or asymptomatic thrombosis. CVC thrombosis, in turn, may not only result in vascular and catheter occlusion but also infection, pulmonary embolism, and formation of right heart thromboemboli. Thrombi within cardiac chambers are associated with an increased risk of mortality due to their potential for embolization to the pulmonary vasculature. We describe the case of a 77-year-old man, who was successfully thrombolyzed following detection of a right atrial thrombus and hemodynamically significant pulmonary embolism resulting from thrombus formation on the tip of a peripherally inserted central catheter (PICC). The present article is the first report of a PICC-related right atrial thrombus in an adult treated with thrombolysis. A systematic review of the literature suggests that the true incidence of this complication may be underestimated because the diagnosis may not be considered in asymptomatic and symptomatic patients, or may be missed by transthoracic echocardiography. The present case highlights the importance of maintaining a high index of suspicion for thromboembolic complications and heparin-induced thrombocytopenia in patients with CVCs or a PICC. It also underscores the important role of transesophageal echocardiography and thrombolysis in the diagnosis and management, respectively, of right heart thromboemboli with associated pulmonary embolism.


Effects of low AIPL1 expression on phototransduction in rods.
To investigate the impact of aryl hydrocarbon receptor-interacting protein-like (AIPL)-1 on photoreception in rods. Photoresponses of mouse rods expressing lowered amounts of AIPL1 were studied by single-cell and electroretinogram (ERG) recordings. Phototransduction protein levels and enzymatic activities were determined in biochemical assays. Ca2+ dynamics were probed with a fluorescent dye. Comparisons were made to rods expressing mutant Y99C guanylate cyclase activating protein (GCAP)-1, to understand which effects arose from elevated dark levels of cGMP and Ca2+. Except for PDE, transduction protein levels were normal in low-AIPL1 retinas, as were guanylate cyclase (GC), rhodopsin kinase (RK), and normalized phosphodiesterase (PDE) activities. Y99C and low-AIPL1 rods were more sensitive to flashes than normal, but flash responses of low-AIPL1 rods showed an abnormal delay, reduced rate of increase, and longer recovery not present in Y99C rod responses. In addition, low-AIPL1 rods but not Y99C rods failed to reach the normal light-induced minimum in Ca2+ concentration. Reduced AIPL1 delayed the photoresponse, decreased its amplification constant, slowed a rate-limiting step in its recovery, and limited the light-induced decrease in Ca2+. Not all changes were attributable to decreased PDE or to elevated cGMP and Ca2+ in darkness. Therefore, AIPL1 directly or indirectly affects more than one component of phototransduction.


Macrophage Polarization and Bone Formation: A review.
The contribution of inflammation to bone loss is well documented in arthritis and other diseases with an emphasis on how inflammatory cytokines promote osteoclastogenesis. Macrophages are the major producers of cytokines in inflammation, and the factors they produce depend upon their activation state or polarization. In recent years, it has become apparent that macrophages are also capable of interacting with osteoblasts and their mesenchymal precursors. This interaction provides growth and differentiation factors from one cell that act on the other and visa versa-a concept akin to the requirement for a feeder layer to grow hemopoietic cells or the coupling that occurs between osteoblasts and osteoclasts to maintain bone homeostasis. Alternatively, activated macrophages are the most likely candidates to promote bone formation and have also been implicated in the tissue repair process in other tissues. In bone, a number of factors, including oncostatin M, have been shown to promote osteoblast formation both in vitro and in vivo. This review discusses the different cell types involved, cellular mediators, and how this can be used to direct new bone anabolic approaches.


Effects of carrying a pregnancy and of method of delivery on urinary incontinence: a prospective cohort study.
BACKGROUND: This study was carried out to identify risk factors associated with urinary incontinence in women three months after giving birth. METHODS: Urinary incontinence before and during pregnancy was assessed at study enrolment early in the third trimester. Incontinence was re-assessed three months postpartum. Logistic regression analysis was used to assess the role of maternal and obstetric factors in causing postpartum urinary incontinence. This prospective cohort study in 949 pregnant women in Quebec, Canada was nested within a randomised controlled trial of prenatal perineal massage. RESULTS: Postpartum urinary incontinence was increased with prepregnancy incontinence (adjusted odds ratio [adj0R] 6.44, 95% CI 4.15, 9.98), incontinence beginning during pregnancy (adjOR 1.93, 95% CI 1.32, 2.83), and higher prepregnancy body mass index (adjOR 1.07/unit of BMI, 95% CI 1.03,1.11). Caesarean section was highly protective (adjOR 0.27, 95% CI 0.14, 0.50). While there was a trend towards increasing incontinence with forceps delivery (adjOR 1.73, 95% CI 0.96, 3.13) this was not statistically significant. The weight of the baby, episiotomy, the length of the second stage of labour, and epidural analgesia were not predictive of urinary incontinence. Nor was prenatal perineal massage, the randomised controlled trial intervention. When the analysis was limited to women having their first vaginal birth, the same risk factors were important, with similar adjusted odds ratios. CONCLUSIONS: Urinary incontinence during pregnancy is extremely common, affecting over half of pregnant women. Urinary incontinence beginning during pregnancy roughly doubles the likelihood of urinary incontinence at 3 months postpartum, regardless whether delivery is vaginal or by Caesarean section.


Morbidity and mortality associated with prescription cannabinoid drug use in COPD.
Respiratory-related morbidity and mortality were evaluated in relation to incident prescription oral synthetic cannabinoid (nabilone, dronabinol) use among older adults with chronic obstructive pulmonary disease (COPD). This was a retrospective, population-based, data-linkage cohort study, analysing health administrative data from Ontario, Canada, from 2006 to 2016. We identified individuals aged 66 years and older with COPD, using a highly specific, validated algorithm, excluding individuals with malignancy and those receiving palliative care (n=185 876 after exclusions). An equivalent number (2106 in each group) of new cannabinoid users (defined as individuals dispensed either nabilone or dronabinol, with no dispensing for either drug in the year previous) and controls (defined as new users of a non-cannabinoid drug) were matched on 36 relevant covariates, using propensity scoring methods. Cox proportional hazard regression was used. Rate of hospitalisation for COPD or pneumonia was not significantly different between new cannabinoid users and controls (HR 0.87; 95% CI 0.61-1.24). However, significantly higher rates of all-cause mortality occurred among new cannabinoid users compared with controls (HR 1.64; 95% CI 1.14-2.39). Individuals receiving higher-dose cannabinoids relative to controls were observed to experience both increased rates of hospitalisation for COPD and pneumonia (HR 2.78; 95% CI 1.17-7.09) and all-cause mortality (HR 3.31; 95% CI 1.30-9.51). New cannabinoid use was associated with elevated rates of adverse outcomes among older adults with COPD. Although further research is needed to confirm these observations, our findings should be considered in decisions to use cannabinoids among older adults with COPD.


Can early therapy reduce inflammation?
Serious non-AIDS events or noninfectious complications of HIV infection far outnumber AIDS events in the current combination antiretroviral therapy (ART) era and are attributed to chronic inflammation. Thus, a better understanding of why inflammation persists on ART will assist in developing better therapeutic strategies, including optimal timing of ART initiation. Markers of inflammation and coagulation, such as D-dimer, interleukin-6, C-reactive protein, soluble CD14, and soluble CD163, predict end-organ disease and mortality, whereas markers of T-cell activation appear more predictive of CD4 T-cell decline, AIDS events, or response to therapy. Initiating ART at high CD4 T-cell counts can result in less inflammation as supported by studies in acute and early HIV infection, but antiretroviral drugs may differentially affect inflammatory pathways. Decreasing inflammation in HIV-uninfected individuals may decrease morbidity, but long-term outcomes studies in HIV-infected individuals are lacking. Circulating biomarkers of inflammation are among the strongest predictors of non-AIDS outcomes in treated HIV infection. With additional investigation, they may serve in the future as specific end-organ disease surrogate endpoints and may help identify those patients at highest risk of non-AIDS events who may benefit from either early ART and/or potential adjuvant anti-inflammatory therapies.


Considerations on the use of urine markers in the management of patients with high-grade non-muscle-invasive bladder cancer.
Diagnosis and surveillance of high risk non muscle-invasive bladder cancer (NMIBC) represent specific challenges to urologists. In contrast to low/intermediate risk tumors, these tumors recur more frequently. A significant number will eventually progress to muscle-invasive bladder cancer, a life threatening disease requiring extensive therapeutic efforts. Although clinical risk factors have been identified that may predict tumor recurrence and progression, additional biomarkers are desperately needed to improve tumor diagnosis and guide clinical management of these patients. In this article, the role of molecular urine markers in the management of high risk NMIBC is analyzed. In this context, several potential indications (diagnostic, prognostic, predictive) were identified and the requirements for molecular markers were defined. In addition, current knowledge within the different indications was summarized. Significant progress has been made in the last decade studying the impact of molecular urine markers in patients with high risk NMIBC. Although we may not be ready for the inclusion of molecular markers in clinical decision-making, and many questions remain unanswered, recent studies have identified situations in which the use of molecular markers in particular in high grade tumors may prove beneficial for patient diagnosis and surveillance.


Particle radiation-induced dysregulation of protein homeostasis in primary human and mouse neuronal cells.
Space particle radiations may cause significant damage to proteins and oxidative stress in the cells within the central nervous system and pose a potential health hazard to humans in long-term manned space explorations. Dysregulation of the ubiquitin-proteasome system as evidenced by abnormal accumulation of polyubiquitin (pUb) chain linkages has been implicated in several age-related neurodegenerative disorders by mechanisms that may involve the inter-neuronal spread of toxic misfolded proteins, the induction of chronic neuroinflammation, or the inappropriate inhibition or activation of key enzymes, which could lead to dysfunction in, for example, proteolysis, or the accumulation of post-translationally-modified substrates.In this study, we employed a quantitative proteomics method to evaluate the impact of particle-radiation induced alterations in three major pUb-linked chains at lysine residues Lys-48 (K-48), Lys-63 (K-63), and Lys-11 (K-11), and probed for global proteomic changes in mouse and human neural cells that were irradiated with low doses of 250 MeV proton, 260 MeV/u silicon or 1 GeV/u iron ions. We found significant accumulation in K-48 linkage after 1 Gy protons and K-63 linkage after 0.5 Gy iron ions in human neural cells. Cells derived from different regions of the mouse brain (cortex, striatum and mesencephalon) showed differential sensitivity to particle radiation exposure. Although none of the linkages were altered after proton exposure, both K-48 and K-63 linkages in mouse striatal neuronal cells were elevated after 0.5 Gy of silicon or iron ions. Changes were also seen in proteins commonly used as markers of neural progenitor and stem cells, in DNA binding/damage repair and cellular redox pathways. In contrast, no significant changes were observed at the same time point after proton irradiation. These results suggest that the quality of the particle radiation plays a key role in the level, linkage and cell type specificity of protein homeostasis in key populations of neuronal cells.


Danon's disease as a cause of hypertrophic cardiomyopathy: a systematic survey.
Hypertrophic cardiomyopathy (HCM) is an autosomal dominant disease caused by mutations in sarcomeric genes. However, extensive genetic screening failed to identify a mutation in about a third of cases. One possible explanation is that other diseases, caused by other genes, may mimic HCM. To investigate the possible involvement of Danon's disease, an X linked lysosomal disease, in a large population of patients with HCM. A population of 197 index cases was considered; 124 were subsequently excluded because of a mutation in sarcomeric genes and 23 because of autosomal dominant inheritance. Fifty index cases were therefore included in molecular analysis (direct sequencing) of the lysosome associated membrane protein 2 (LAMP2) gene responsible for Danon's disease. Two new mutations leading to premature stop codons were identified in patients who evolved towards severe heart failure (< 25 years old): 657C>T and 173_179del. The prevalence was therefore 1% of the total population (two of 197) or 4% of enrolled index cases (two of 50). Interestingly, Danon's disease was responsible for half of the cases (two of four) with HCM and clinical skeletal myopathy but was not involved in isolated HCM (none of 41). Danon's disease may be involved in patients with previously diagnosed as HCM. A diagnosis strategy is proposed. To distinguish HCM from Danon's disease is important because the clinical evolution, prognosis, mode of inheritance, and therefore genetic counselling are very different.


Applications of nerve stimulator-guided thoracic paravertebral nerve block plus general anesthesia in small-incision lung cancer surgery.
The aim of the study was to investigate the application of nerve stimulator-guided thoracic paravertebral nerve block (TPVB) plus general anesthesia (GA) in small-incision lung cancer surgery. Forty patients scheduled for small-incision lung cancer surgery, the American Society of Anesthesiologists Grade I-II, were randomized into a TPVB-GA group (Group P) and a GA group (Group G), with 20 cases in each group. The dosage of general anesthetic, mean arterial pressure (MAP) at each time point, and heart rate (HR) of the two groups were recorded. The postoperative respiration recovery time, extubation time, incidence of adverse reactions, and postoperative visual analog scale (VAS) scores of the two groups were also observed. Group P showed stable hemodynamics, and lower MAP and HR at each time point than Group G (P < 0.05). The intraoperative dosage of general anesthetic in Group P was lower than that in Group G (P < 0.05). The respiration recovery time and extubation time in Group P were significantly shorter than those in Group G (P < 0.05); the incidence of agitation was significantly lower than that in Group G (P < 0.05). The VAS scores of Group P under quiet and cough status were also better than Group G (P < 0.05). Nerve stimulator-guided TPVB-GA is suitable for small-incision lung cancer surgery.


Maps of central visual space in ferret V1 and V2 lack matching inputs from the two eyes.
In the visual cortex, the representation of central visual space is supplied by matching geniculate inputs that are driven exclusively by one eye or the other. In layer 4 of early visual areas (V1 in primates and V1 and V2 in cat), these inputs form a nearly uniform array of small ocular dominance domains, while preserving overall topographic order within the cortical map. In ferret, however, ocular dominance domains in different regions of the visual cortex are strikingly irregular in size and shape. The exceptionally large size of domains in some regions implies a departure from the usual visuotopic matching of inputs from the two eyes. Using optical-imaging, electrophysiological, and anatomical techniques, we show that this regional variation is attributable to exclusively monocular maps of the central portions of the ipsilateral visual field in V1 and the contralateral visual field in V2. In addition, we document a complex interdigitation of V1 and V2 that entails a discontinuity in the mapping of visual space and fragmentation of V2 into isolated cortical territories. We suggest that both the monocularity of these cortical maps and the visuotopic discontinuity along the V1-V2 border derive from asymmetries in the crossed and uncrossed retinal pathways.


Solution structure of the (+)-cis-anti-benzo[a]pyrene-dA ([BP]dA) adduct opposite dT in a DNA duplex.
Minor adducts, derived from the covalent binding of anti-benzo[a]pyrene-7,8-dihydroxy-9,10-epoxide to cellular DNA, may play an important role in generating mutations and initiating cancer. We have applied a combined NMR-computational approach including intensity based refinement to determine the solution structure of the minor (+)-cis-anti-[BP]dA adduct positioned opposite dT in the d(C1-T2-C3-T4-C5-[BP]A6-C7-T8-T9-C10-C11). (d(G12-G13-A14-A15-G16-T17-G18-A19-G20+ ++-A21-G22) 11-mer duplex. The BP ring system is intercalated toward the 5'-side of the [BP]dA6 lesion site without disrupting the flanking Watson-Crick dC5.dG18 and [BP]dA6.dT17 base pairs. This structure of the (+)-cis-anti-[BP]dA.dT 11-mer duplex, containing a bay region benzo[a]pyrenyl [BP]dA adduct, is compared with the corresponding structure of the (+)-trans-anti-[BPh]dA.dT 11-mer duplex (Cosman et al., Biochemistry 32, 12488-12497, 1993), which contains a fjord region benzo[c]phenanthrenyl [BPh]dA adduct with the same R stereochemistry at the linkage site. The carcinogen intercalates toward the 5'-direction of the modified strand in both duplexes (the adduct is embedded within the same sequence context) with the buckling of the Watson-Crick [BP]dA6.dT17 base pair more pronounced in the (+)-cis-anti-[BP]dA.dT 11-mer duplex compared to its Watson-Crick [BPh]dA.dT17 base pair in the (+)-trans-anti-[BPh]dA.dT 11-mer duplex. The available structural studies of covalent polycyclic aromatic hydrocarbon (PAH) carcinogen-DNA adducts point toward the emergence of a general theme where distinct alignments are adopted by PAH adducts covalently linked to the N(6) of adenine when compared to the N(2) of guanine in DNA duplexes. The [BPh]dA and [BP]dA N(6)-adenine adducts intercalate their polycyclic aromatic rings into the helix without disruption of their modified base pairs. This may reflect the potential flexibility associated with the positioning of the covalent tether and the benzylic ring of the carcinogen in the sterically spacious major groove. By contrast, such an intercalation without modified base pair disruption option appears not to be available to [BP]dG N(2)-guanine adducts where the covalent tether and the benzylic ring are positioned in the more sterically crowded minor groove. In the case of [BP]dG adducts, the benzopyrenyl ring is either positioned in the minor groove without base pair disruption, or if intercalated into the helix, requires disruption of the modified base pair and displacement of the bases out of the helix.


Cue Recognition and Integration - Eye Tracking Evidence of Processing Differences in Sentence Comprehension in Aphasia.
We aimed at further elucidating whether aphasic patients' difficulties in understanding non-canonical sentence structures, such as Passive or Object-Verb-Subject sentences, can be attributed to impaired morphosyntactic cue recognition, and to problems in integrating competing interpretations. A sentence-picture matching task with canonical and non-canonical spoken sentences was performed using concurrent eye tracking. Accuracy, reaction time, and eye tracking data (fixations) of 50 healthy subjects and 12 aphasic patients were analysed. Patients showed increased error rates and reaction times, as well as delayed fixation preferences for target pictures in non-canonical sentences. Patients' fixation patterns differed from healthy controls and revealed deficits in recognizing and immediately integrating morphosyntactic cues. Our study corroborates the notion that difficulties in understanding syntactically complex sentences are attributable to a processing deficit encompassing delayed and therefore impaired recognition and integration of cues, as well as increased competition between interpretations.


Measuring knowledge, attitudes and behavior of nurses in medication management: cross-cultural comparisons in Italy and Malta.
Medication errors are one of the most common causes of negative events affecting patient safety all over the world. Scientific literature divides the factors that contribute to the occurrence of harmful events into factors related to the characteristics of the healthcare workers and factors related to the organization of the drug management process. The aim of the study was to examine the knowledge, attitudes and behaviours related to medication errors among Italian and Maltese nurses. Cross-sectional survey of nurses working in Intensive Care settings in Italian and Maltese hospitals was conducted. A valid and reliable questionnaire used in previous studies was adapted for online use. Despite improved reporting, The Strengthening the Reporting of Observational Studies in Epidemiology was used. Findings showed good psychometric properties and reliability. MANOVA demonstrated significant differences in nurses' perception of the pharmacist presence during medication process and of the use of computerized provider order entry. MANOVA also demonstrated significant differences in the control of vital parameters and the application of the 8 right. These findings support the contention that knowledge, attitude and behaviour of nurses is similar across different contexts in different countries wherein nurse training is harmonised and regulated through a transnational directive.


Extending the R Library PROPER to Enable Power Calculations for Isoform-Level Analysis with EBSeq.
RNA-Sequencing (RNA-Seq) has become a routine technology for investigating gene expression differences in comparative transcriptomic studies. Differential expression (DE) analysis of the isoforms of genes is just emerging now that expression (read counts) can be estimated with higher accuracy at the isoform level. Estimating the statistical power that can be achieved with a specific number of repeats is a key step in RNA-Seq analysis. The R library proper was developed to provide realistic empirical power analysis. However, proper uses differential expression methods more suited for power calculation of gene-level expression data. We propose extensions to this tool that would allow for power analysis which takes into account the specificities of isoforms expression. This was achieved by enabling the use of EBSeq, a DE approach well-tailored for isoform-level expression, as an additional analysis method within PROPER. The new extensions and exemplar code for their usage are freely available online at: https://github.com/agaye/proper_extension.


Glucose gradients of maternal vein-umbilical vein and umbilical vein-umbilical artery in normally grown and growth-retarded fetuses.
The present study was designed to investigate the roles of maternal-fetal glucose transport and fetal glucose utilization in the regulation of fetal growth. Maternal venous blood, umbilical arterial and venous blood were sampled simultaneously in 60 full-term appropriate-for gestational age (AGA) fetuses and 48 small-for-gestational-age (SGA) fetuses. The cases were divided into four groups: group 1 consisted of 35 AGA fetuses, group 2 consisted of 25 AGA fetuses, group 3 consisted of 25 SGA fetuses, and group 4 consisted of 22 SGA fetuses. The mothers of group 1 and 3 were given 2.5% glucose in 0.9% normal saline and those of groups 2 and 4 by cesarean section received normal saline or Ringer's lactate at least one hour prior to delivery of the fetus SGA fetuses were found to have hypoglycaemia of umbilical venous blood, increased (maternal vein-umbilical vein) MV-UV and decreased UV-UA (umbilical vein-umbilical artery) glucose gradients, all of which disappeared after maternal glucose supplementation. However, hypoinsulinemia and lower insulin/glucose ratio in SGA fetuses persisted either with or without maternal parenteral glucose infusion. Increased MV-UV and decreased UV-UA glucose gradients suggests placental dysfunction and poor glucose utilization in SGA fetuses. The lower fetal insulin/glucose ratio may imply pancreatic dysfunction in SGA fetuses, which did not respond to glucose challenge from the maternal side. It seems that in SGA fetuses, placental dysfunction interferes with maternal-fetal transfer with resulting fetal hypoglycemia; on the other hand, pancreatic dysfunction leads to poor glucose utilization and retarded intrauterine growth. However, the mechanism that primarily accounts for pancreatic dysfunction in these fetuses remains to be resolved.


Caspase-responsive smart gadolinium-based contrast agent for magnetic resonance imaging of drug-induced apoptosis.
Non-invasive detection of caspase-3/7 activity in vivo has provided invaluable predictive information regarding tumor therapeutic efficacy and anti-tumor drug selection. Although a number of caspase-3/7 targeted fluorescence and positron emission tomography (PET) imaging probes have been developed, there is still a lack of gadolinium (Gd)-based magnetic resonance imaging (MRI) probes that enable high spatial resolution detection of caspase-3/7 activity in vivo. Here we employ a self-assembly approach and develop a caspase-3/7 activatable Gd-based MRI probe for monitoring tumor apoptosis in mice. Upon reduction and caspase-3/7 activation, the caspase-sensitive nano-aggregation MR probe (C-SNAM: 1) undergoes biocompatible intramolecular cyclization and subsequent self-assembly into Gd-nanoparticles (GdNPs). This results in enhanced r1 relaxivity-19.0 (post-activation) vs. 10.2 mM-1 s-1 (pre-activation) at 1 T in solution-and prolonged accumulation in chemotherapy-induced apoptotic cells and tumors that express active caspase-3/7. We demonstrate that C-SNAM reports caspase-3/7 activity by generating a significantly brighter T1-weighted MR signal compared to non-treated tumors following intravenous administration of C-SNAM, providing great potential for high-resolution imaging of tumor apoptosis in vivo.


A sensitive and bright single-cell resolution live imaging reporter of Wnt/ß-catenin signaling in the mouse.
Understanding the dynamic cellular behaviors and underlying molecular mechanisms that drive morphogenesis is an ongoing challenge in biology. Live imaging provides the necessary methodology to unravel the synergistic and stereotypical cell and molecular events that shape the embryo. Genetically-encoded reporters represent an essential tool for live imaging. Reporter strains can be engineered by placing cis-regulatory elements of interest to direct the expression of a desired reporter gene. In the case of canonical Wnt signaling, also referred to as Wnt/β-catenin signaling, since the downstream transcriptional response is well understood, reporters can be designed that reflect sites of active Wnt signaling, as opposed to sites of gene transcription, as is the case with many fluorescent reporters. However, even though several transgenic Wnt/β-catenin reporter strains have been generated, to date, none provides the single-cell resolution favored for live imaging studies. We have placed six copies of a TCF/Lef responsive element and an hsp68 minimal promoter in front of a fluorescent protein fusion comprising human histone H2B to GFP and used it to generate a strain of mice that would report Wnt/β-catenin signaling activity. Characterization of developmental and adult stages of the resulting TCF/Lef:H2B-GFP strain revealed discrete and specific expression of the transgene at previously characterized sites of Wnt/β-catenin signaling. In support of the increased sensitivity of the TCF/Lef:H2B-GFP reporter, additional sites of Wnt/β-catenin signaling not documented with other reporters but identified through genetic and embryological analysis were observed. Furthermore, the sub-cellular localization of the reporter minimized reporter perdurance, and allowed visualization and tracking of individual cells within a cohort, so facilitating the detailed analysis of cell behaviors and signaling activity during morphogenesis. By combining the Wnt activity read-out efficiency of multimerized TCF/Lef DNA binding sites, together with the high-resolution imaging afforded by subcellularly-localized fluorescent fusion proteins such as H2B-GFP, we have created a mouse transgenic line that faithfully recapitulates Wnt signaling activity at single-cell resolution. The TCF/Lef:H2B-GFP reporter represents a unique tool for live imaging the in vivo processes triggered by Wnt/β-catenin signaling, and thus should help the formulation of a high-resolution understanding of the serial events that define the morphogenetic process regulated by this signaling pathway.


Great differences in performance and outcome of high-throughput sequencing data analysis platforms for fungal metabarcoding.
Along with recent developments in high-throughput sequencing (HTS) technologies and thus fast accumulation of HTS data, there has been a growing need and interest for developing tools for HTS data processing and communication. In particular, a number of bioinformatics tools have been designed for analysing metabarcoding data, each with specific features, assumptions and outputs. To evaluate the potential effect of the application of different bioinformatics workflow on the results, we compared the performance of different analysis platforms on two contrasting high-throughput sequencing data sets. Our analysis revealed that the computation time, quality of error filtering and hence output of specific bioinformatics process largely depends on the platform used. Our results show that none of the bioinformatics workflows appears to perfectly filter out the accumulated errors and generate Operational Taxonomic Units, although PipeCraft, LotuS and PIPITS perform better than QIIME2 and Galaxy for the tested fungal amplicon dataset. We conclude that the output of each platform requires manual validation of the OTUs by examining the taxonomy assignment values.


Yttrium-90 Microsphere Brachytherapy for Liver Metastases From Uveal Melanoma: Clinical Outcomes and the Predictive Value of Fluorodeoxyglucose Positron Emission Tomography.
To report outcomes after yttrium-90 microsphere brachytherapy for unresectable liver metastases from uveal melanoma and to evaluate factors predictive for overall survival (OS) and hepatic progression-free survival (PFS). A total of 71 patients were consecutively treated with microsphere brachytherapy for unresectable liver metastases from uveal melanoma between 2007 and 2012. Clinical, radiographic, and positron emission tomography-derived, functional tumor parameters were evaluated by log-rank test in univariate analysis and backwards stepwise multivariate Cox proportional hazards regression. OS and hepatic PFS were estimated by Kaplan-Meier analysis. A total of 134 procedures were performed in 71 patients with a median age of 63 years (range, 23 to 91 y). Fifty-eight patients (82%) received microsphere brachytherapy as a salvage therapy. Median hepatic PFS and OS after microsphere brachytherapy were 5.9 months (range, 1.3 to 19.1 mo) and 12.3 months (range, 1.9 to 49.3 mo), respectively. Median OS times after diagnosis of liver metastases was 23.9 months (range, 6.2 to 69.0 mo). In univariate analysis, female sex, pretreatment metabolic tumor volume, and total glycolic activity (TGA) were significantly correlated with hepatic PFS and OS. In multivariate analysis, female sex and TGA retained significance as independent predictors of hepatic PFS and OS. A low pretreatment TGA (<225 g) was associated with a significantly longer median OS than was a TGA≥225 g (17.2 vs. 9.7 mo, P=0.01). Yttrium-90 microsphere brachytherapy provided favorable survival times in patients with unresectable liver metastases from uveal melanoma. Metabolic tumor volume and TGA are predictive functional tumor parameters, which may aid patient selection and risk stratification.


[Mortality from chronic kidney disease in Peru: national trends 2003-2015].
To describe the mortality trend due to chronic kidney disease (CKD) in Peru in the period 2003-2015. Analysis of secondary data and ecological design. National mortality registries based on death certificates were analyzed. ERC was defined as CIE code 10: N18 in the basic cause. Absolute and relative frequencies of death by ERC are described. To estimate the proportion of deaths by CKD in each region of Peru, a generalized mixed linear model was used. The outcome variable was the proportion of deaths, the independent variables were each region of the country and the year. The analysis included 1,086,778 deaths, of which 25,091 (2.0 % age- and sex-adjusted) were by CKD. During the study period, the average age at death increased by 2.6 years (p<0.001); in addition, the proportion of age- and sex-adjusted CKD deaths was always higher in women. In the observation period, the region with the highest mortality from CKD was Puno (4.1%), and with the lowest mortality was Amazonas (1.1%). Those regions that showed a significantly greater increase than the others were Tacna, La Libertad, Tumbes, Apurímac, Cusco, Ica, Moquegua, Ayacucho, Huancavelica and Puno. In the 2003-2015 period, mortality from CKD in Peru has increased; this trend is observed in several regions of the country. Preventive measures, early identification, and access to treatment must be implemented to control this trend.


A consistent estimator of the evolutionary rate.
We consider a branching particle system where particles reproduce according to the pure birth Yule process with the birth rate λ, conditioned on the observed number of particles to be equal to n. Particles are assumed to move independently on the real line according to the Brownian motion with the local variance σ(2). In this paper we treat n particles as a sample of related species. The spatial Brownian motion of a particle describes the development of a trait value of interest (e.g. log-body-size). We propose an unbiased estimator Rn(2) of the evolutionary rate ρ(2)=σ(2)/λ. The estimator Rn(2) is proportional to the sample variance Sn(2) computed from n trait values. We find an approximate formula for the standard error of Rn(2) based on a neat asymptotic relation for the variance of Sn(2).


Centriole and centrosome cycle in the early Drosophila embryo.
Centriole and centrosome cycles were examined by indirect immunofluorescence and electron microscopy techniques in the early Drosophila embryo. The centrosomes, which are already divided at interphase, appear as compact spheres during prophase and metaphase, expand and flatten from anaphase to telophase and split into two units in late telophase. Centriole separation starts in late metaphase, becomes evident in anaphase and increases during telophase. Procentrioles appear during the following interphase.


Dopaminergic modulation of emotional conflict in Parkinson's disease.
Neuropsychiatric fluctuations in Parkinson's disease (PD) are frequent and disabling. One way to investigate them is to assess the ability to inhibit distractive emotional information by a modified emotional Stroop (ES) task. We compared non-depressed, non-demented PD patients with healthy controls. During an acute levodopa challenge, patients performed a modified ES task during functional MRI and a neuropsychological assessment including Visual Analog Mood (VAMS) and Apathy scales. Ten patients and 12 controls completed the study. The VAMS scores were significantly improved by the acute intake of levodopa (p = 0.02), as was the apathy score (p = 0.03). Negative ES task (i.e. fearful facial expressions with the words "happy" or "fear" written across them), induced a lengthening of the mean reaction time during the incongruent trials compared with the congruent trials in controls (relative difference = 2.7%, p < 0.001) and in ON patients (relative difference = 5.9%, p < 0.001), but not in OFF patients (relative difference = 1.7%, p = 0.28). Controls and ON patients displayed greater activation than OFF patients within the right pregenual anterior cingulate cortex (pACC), an area specifically involved in emotional conflict resolution (p < 0.001 and p < 0.008 respectively, k > 5 uncorrected). No difference in the activation of the pACC was found between controls and ON patients, suggesting a normalization of the activation following levodopa administration. These results suggest that emotional conflict processes could be dopamine-dependent. Pregenual ACC hypoactivation could be directly due to the degeneration of dopaminergic mesocorticolimbic pathway. Our results propose that neuropsychiatric fluctuations in PD patients could be partially explained by pACC hypoactivation and that adjustments of dopaminergic medication might be helpful for their treatment.


Association of the Y402H polymorphism in complement factor H gene and neovascular age-related macular degeneration in Chinese patients.
Age-related macular degeneration (AMD), with its complex traits and multiple risk factors, is the leading cause of blindness in the elderly. A strong association between a coding variant, Y402H, in the complement factor H gene (CFH) and AMD has been recently identified in white patients. This study was conducted to investigate the association between the Y402H polymorphism in CFH and neovascular AMD in Chinese patients. One hundred sixty-three Chinese patients with neovascular AMD and 232 age-matched healthy controls were enrolled in the study. Genomic DNA from white blood cells was extracted. The Y402H polymorphism in CFH, with the substitution of T to C at nucleotide position 1277 in exon 9, was determined by polymerase chain reaction-restriction fragment length polymorphism analysis. The association between the genetic polymorphism and the disease was examined by chi(2) test and logistic regression. The frequency of the risk allele, 1277C, was 11.3% in AMD patients compared with 2.8% in controls (P < 0.00001). Genotype frequency differed significantly between the two groups (1277TT 81.0%, 1277TC 15.3%, and 1277CC 3.7% in the AMD group; 1277TT 94.4%, 1277TC 5.6%, and 1277CC 0% in the control group; P < 0.0001). The 1277C allele significantly increased the risk for neovascular AMD and had an odds ratio of 4.4 (95% confidence interval [95% CI], 2.3-8.5; P < 0.00001). The allele frequency of Y402H polymorphism in CFH has an ethnic variation, with much lower 1277C frequency in Chinese than in white patients. Despite this, the polymorphism is significantly associated with neovascular AMD in the Chinese population.


Orthodontic material applications over the past century: Evolution of research methods to address clinical queries.
The advances in the field of materials as they relate to orthodontics can be divided into the actual evolution of materials applied to daily practice and the changes in research methods to study the performance and the biologic properties of the materials. Although it is evident that new materials have saturated the market during the past century, the basic concepts of attaching one appliance to the enamel to use as a grip and inserting wires into that to control the spatial orientation of a tooth are identical to the original concepts. In contrast to that, the numbers of treatises about those subjects and the complexity of instrumentation and analytic tools used in published research have advanced tremendously and at a frenetic pace. This highly specialized pattern of research may effectively raise boundaries across research areas, since the complexity of the issues allows researchers to comprehend the content of journal articles in a narrow spectrum of disciplines. The purposes of this article were to review the advances in the research methods for investigating the various properties of orthodontic materials and to assist the reader in navigating this topic. A synopsis of the materials is also provided, listing future applications that already exist at the experimental stage or are yet unavailable but with the relevant technology already presented in broader scientific disciplines.


Progressive aggregation despite chaperone associations of a mutant SOD1-YFP in transgenic mice that develop ALS.
Recent studies suggest that superoxide dismutase 1 (SOD1)-linked amyotrophic lateral sclerosis results from destabilization and misfolding of mutant forms of this abundant cytosolic enzyme. Here, we have tracked the expression and fate of a misfolding-prone human SOD1, G85R, fused to YFP, in a line of transgenic G85R SOD1-YFP mice. These mice, but not wild-type human SOD1-YFP transgenics, developed lethal paralyzing motor symptoms at 9 months. In situ RNA hybridization of spinal cords revealed predominant expression in motor neurons in spinal cord gray matter in all transgenic animals. Concordantly, G85R SOD-YFP was diffusely fluorescent in motor neurons of animals at 1 and 6 months of age, but at the time of symptoms, punctate aggregates were observed in cell bodies and processes. Biochemical analyses of spinal cord soluble extracts indicated that G85R SOD-YFP behaved as a misfolded monomer at all ages. It became progressively insoluble at 6 and 9 months of age, associated with presence of soluble oligomers observable by gel filtration. Immunoaffinity capture and mass spectrometry revealed association of G85R SOD-YFP, but not WT SOD-YFP, with the cytosolic chaperone Hsc70 at all ages. In addition, 3 Hsp110's, nucleotide exchange factors for Hsp70s, were captured at 6 and 9 months. Despite such chaperone interactions, G85R SOD-YFP formed insoluble inclusions at late times, containing predominantly intermediate filament proteins. We conclude that motor neurons, initially "compensated" to maintain the misfolded protein in a soluble state, become progressively unable to do so.


Different effects of low weight molecular heparin and unfractioned heparin on lipid profile and coagulation at haemodialysis patients.
Each haemodialysis treatment requires the application of anticoagulation medicines, which will prevent coagulation in extracorporal blood circulation. In this study we try to determine the quality of admitted anticoagulant and his effect on lipid profile on hemodialysis patients after twelve months. We were applying standard heparin and low weight molecular heparin (LWMH). During our study we was analyzed effect of anticoagulant therapy on lipid profile of hemodialysis patients. In that parameters was included triglycerides, cholesterol, lipoprotein fractions, complete blood count, Hgb, HCT; All of these parameters was analyzed in correlation with duration of hemodialysis treatment, sex and age of the patients. Our research was carried out as a prospective study, for the period of 12 months. In the study were included 60 patients (34M/26F), who were on chronic hemodialysis program. All patients were divided into two groups. The first group of patients was included 27 patients (15M/12F) who were treated with standard heparin. The second group was included 33 patients (19M/14F) treated with LWMH (enoxaparin). The average length of hemodialysis was 4.15 +/- 0.52 years. Each patient had a protocol in which is marked parameters such as flushing dialysator, creating fibrin-ring in vein and arterial dropper and the time it takes to stop the bleeding. In the results the average age amounted to 58.54 +/- 2.24 years. The average value of cholesterol in the blood was 5.38 +/- 2.26. Values of HDL-cholesterol in patients treated with LWMH were significantly lower (P<or=0.05) in the treated group compared to standard heparin. There were no significant statistical differences between both groups in relation to the level of LDL cholesterol in the blood. (p ns). LWMH had a better effect on the irrigation system and dialysator on both sex equally, compared with standard heparin. LWMH is in the female dialysis population has led to improvements in lipid profile. After the first six months of study in male patients treated with standard heparin in relation to the female part of the observed patients was significantly better anticoagulation effect in the first half of the study (1.85 +/- 0.05 compared to 2.09 +/- 0.10) (P<or=0.001). Average rating blood clots were statistically significant for standard heparin (p<or=0,001) with 1,86 at the beginning the value is fell to 1.41, while for LWMH with 1.85 at the beginning of the study amounted to 1.52 grade average. (P<or=0.05). The results of our study show that LWMH had a better rinsing effect of dialysis systems and dialysator in both sex equally, compared to standard unfractioned heparin. When the male part of the respondents in the first six months of standard heparin had a better evaluation of blood clots than women in the same group, and also better than the group on enoxaparin for both gender. LWMH in female dialysis population has led to improved lipid profiles. Patients treated with standard heparin had a statistically significant reduction in the rate of blood clots than patients who received enoxaparin (LWMH). Such differences were minimal, which can be interpreted by the fact that LWMH still derivative of the standard heparin.


The recovery of weak impulsive signals based on stochastic resonance and moving least squares fitting.
In this paper a stochastic resonance (SR)-based method for recovering weak impulsive signals is developed for quantitative diagnosis of faults in rotating machinery. It was shown in theory that weak impulsive signals follow the mechanism of SR, but the SR produces a nonlinear distortion of the shape of the impulsive signal. To eliminate the distortion a moving least squares fitting method is introduced to reconstruct the signal from the output of the SR process. This proposed method is verified by comparing its detection results with that of a morphological filter based on both simulated and experimental signals. The experimental results show that the background noise is suppressed effectively and the key features of impulsive signals are reconstructed with a good degree of accuracy, which leads to an accurate diagnosis of faults in roller bearings in a run-to failure test.


Plasmodium malariae in the Colombian Amazon region: you don't diagnose what you don't suspect.
Malaria is a worldwide public health problem; parasites from the genus Plasmodium spp. are the aetiological agent of this disease. The parasite is mainly diagnosed by microscope-based techniques. However, these have limited sensitivity. Many asymptomatic infections are sub-microscopic and can only be detected by molecular methods. This study was aimed at comparing nested PCR results to those obtained by microscope for diagnosing malaria and to present epidemiological data regarding malaria in Colombia's Amazon department. A total of 1392 blood samples (taken by venepuncture) from symptomatic patients in Colombia's Amazon department were analysed in parallel by thick blood smear (TBS) test and nested PCR for determining Plasmodium spp. infection and identifying infecting species, such as Plasmodium vivax, Plasmodium malariae and/or Plasmodium falciparum. Descriptive statistics were used for comparing the results from both tests regarding detection of the disease, typing infecting species and their prevalence in the study region. Bearing the microscope assay in mind as gold standard, PCR diagnosis performance was evaluated by statistical indicators. The present study revealed great differences between both diagnostic tests, as well as suggesting high P. malariae prevalence from a molecular perspective. This differed profoundly from previous studies in this region of Colombia, usually based on the TBS test, suggesting that diagnosis by conventional techniques could lead to underestimating the prevalence of certain Plasmodium spp. having high circulation in this area. The present results highlight the need for modifying state malaria surveillance schemes for more efficient strategies regarding the detection of this disease in endemic areas. The importance of PCR as a back-up test in cases of low parasitaemia or mixed infection is also highlighted.


Comprehensive neural networks for guilty feelings in young adults.
Feelings of guilt are associated with widespread self and social cognitions, e.g., empathy, moral reasoning, and punishment. Neural correlates directly related to the degree of feelings of guilt have not been detected, probably due to the small numbers of subjects, whereas there are growing numbers of neuroimaging studies of feelings of guilt. We hypothesized that the neural networks for guilty feelings are widespread and include the insula, inferior parietal lobule (IPL), amygdala, subgenual cingulate cortex (SCC), and ventromedial prefrontal cortex (vmPFC), which are essential for cognitions of guilt. We investigated the association between regional gray matter density (rGMD) and feelings of guilt in 764 healthy young students (422 males, 342 females; 20.7 ± 1.8 years) using magnetic resonance imaging and the guilty feeling scale (GFS) for the younger generation which comprises interpersonal situation (IPS) and rule-breaking situation (RBS) scores. Both the IPS and RBS were negatively related to the rGMD in the right posterior insula (PI). The IPS scores were negatively correlated with rGMD in the left anterior insula (AI), right IPL, and vmPFC using small volume correction. A post hoc analysis performed on the significant clusters identified through these analyses revealed that rGMD activity in the right IPL showed a significant negative association with the empathy quotient. These findings at the whole-brain level are the widespread comprehensive neural network regions for guilty feelings. Interestingly, the novel finding in this study is that the PI was implicated as a common region for feelings of guilt with interaction between the IPS and RBS. Additionally, the neural networks including the IPL were associated with empathy and with regions implicated in moral reasoning (AI and vmPFC), and punishment (AI).


Selective enhancement of low-gamma activity by tACS improves phonemic processing and reading accuracy in dyslexia.
The phonological deficit in dyslexia is associated with altered low-gamma oscillatory function in left auditory cortex, but a causal relationship between oscillatory function and phonemic processing has never been established. After confirming a deficit at 30 Hz with electroencephalography (EEG), we applied 20 minutes of transcranial alternating current stimulation (tACS) to transiently restore this activity in adults with dyslexia. The intervention significantly improved phonological processing and reading accuracy as measured immediately after tACS. The effect occurred selectively for a 30-Hz stimulation in the dyslexia group. Importantly, we observed that the focal intervention over the left auditory cortex also decreased 30-Hz activity in the right superior temporal cortex, resulting in reinstating a left dominance for the oscillatory response. These findings establish a causal role of neural oscillations in phonological processing and offer solid neurophysiological grounds for a potential correction of low-gamma anomalies and for alleviating the phonological deficit in dyslexia.


Why do people present late with advanced glaucoma? A qualitative interview study.
To explore the presentation behaviours and pathways to detection of adults who first presented to UK hospital eye services with severe glaucoma. Semistructured interviews, based on models of diagnostic delay, to obtain a descriptive self-reported account of when and how participants' glaucoma was detected. 11 patients participated (five in Aberdeen, six in Huddersfield). Four participants reported that the optometry appointment at which their glaucoma was detected was their first ever eye test or their first for over 10 years. Seven participants reported attending regular routine optometrist appointments. Their self-reported experiences and pathways to detection describe a variety of missed detection opportunities and delayed referral and treatment. The qualitative data suggest that late detection of glaucoma can result from delays at the patient level but, although based on a small sample, delays also occurred at the healthcare provider (system) level both in terms of accuracy of case detection and effective referral. We suggest that current attempts to address the significant burden of over-referral of glaucoma suspects to hospital eye services (a large proportion of which are false positives) must also focus on the issue of false negatives and on reducing missed detection and service delays.


Adult recollections of childhood memories: What details can be recalled?
In a memory survey, adult respondents recalled, dated, and described two earliest positive and negative memories that they were highly confident were memories. They then answered a series of questions that focused on memory details such as clothing, duration, weather, and so on. Few differences were found between positive and negative memories, which on average had 4/5 details and dated to the age of 6/6.5 years. Memory for details about activity, location, and who was present was good; memory for all other details was poorer or at floor. Taken together, these findings indicate that (full) earliest memories may be considerably later than previously thought and that they rarely contain the sort of specific details targeted by professional investigators. The resulting normative profile of memory details reported here can be used to evaluate overly specific childhood autobiographical memories and to identify memory details with a low probability of recall.


Cyclopropanation of α-mycolic acids is not required for cording in Mycobacterium brumae and Mycobacterium fallax.
The capacity to form microscopic cords (cording) of Mycobacterium species has been related to their virulence. The compounds responsible for cording are unknown, but a recent study has shown that cording could be related to the fine structure of α-mycolic acids. This investigation attributes the need for a proximal cyclopropane in α-mycolic acids for cording in Mycobacterium tuberculosis and Mycobacterium bovis BCG and proposes cyclopropanases as good targets for new chemotherapeutic agents. As other Mycobacterium species in addition to M. tuberculosis and M. bovis form microscopic cords, it would be of major interest to know whether the relationship between proximal cyclopropanation of α-mycolic acids and cording could be extended to non-tuberculous mycobacteria. In this study, we have examined the correlation between the cording and cyclopropanation of α-mycolic acids in two species, Mycobacterium brumae and Mycobacterium fallax. Scanning electron microscopy images showed, for the first time to our knowledge, the fine structure of microscopic cords of M. brumae and M. fallax, confirming that these two species form true cords. Furthermore, NMR analysis performed on the same cording cultures corroborates the absence of cyclopropane rings in their α-mycolic acids. Therefore, we can conclude that the correlation between cording and cyclopropanation of α-mycolic acids cannot be extended to all mycobacteria. As M. brumae and M. fallax grow rapidly and have a simple pattern of mycolic acids (only α-unsaturated mycolic acids), we propose these two species as suitable models for the study of the role of mycolic acids in cording.


Induction of hepatic antioxidant enzymes by phenolic acids in rats is accompanied by increased levels of multidrug resistance-associated protein 3 mRNA expression.
Phenolic acids are widespread in plant foods; they contain important biological and pharmacological properties, some of which were shown to be effective in preventing cancer. We investigated the modulatory effects of phenolic acids on an antioxidant system in male Sprague-Dawley rats. Rats were orally administrated gentisic acid (GEA), gallic acid (GA), ferulic acid (FA), and p-coumaric acid (p-CA) at a dosage of 100 mg/kg body weight for 14 consecutive days. At this dose, the activities of hepatic superoxide dismutase (SOD), glutathione peroxidase (GPx), and catalase were greater after administration of all 4 phenolic acids compared with the control group (P < 0.05). The activities of these enzymes in the small intestine of rats were also significantly greater after GA and p-CA treatment compared with controls. The changes in hepatic CuZnSOD, GPx, and catalase mRNA levels induced by phenolic acids were similar to those noted in the enzyme activities. Oxidized glutathione levels were lower (P < 0.05) in the liver of all phenolic acid-supplemented rats, whereas reduced glutathione was markedly higher than in control rats, especially after administration of GA and p-CA. The liver homogenates obtained from rats that had been administered phenolic acids had higher oxygen radical absorbance capacity than those obtained from control rats. Immunoblot analysis revealed an increased total level of Nrf2, a transcription factor governing the antioxidant response element in phenolic acid-supplemented rats. Phenolic acid-mediated antioxidant enzyme expression was accompanied by upregulation of multidrug resistance-associated protein Mrp3. These experiments show that modulation of phase II antioxidant enzymes and oxidative status in the liver by phenolic acids may play an important role in the protection against adverse effects related to mutagenesis and oxidative damage.


Evaluation of disparate laser beam deflection technologies by means of number and rate of resolvable spots.
We introduce a method to objectively evaluate systems of differing beam deflection technologies that commonly are described by disparate technical specifications. Using our new approach based on resolvable spots we will compare commercially available random-access beam deflection technologies, namely galvanometer scanners, piezo scanners, MEMS scanners, acousto-optic deflectors, and electro-optic deflectors.


Methylation of histone H3 Lys 4 in coding regions of active genes.
Posttranslational modifications of histone tails regulate chromatin structure and transcription. Here we present global analyses of histone acetylation and histone H3 Lys 4 methylation patterns in yeast. We observe a significant correlation between acetylation of histones H3 and H4 in promoter regions and transcriptional activity. In contrast, we find that dimethylation of histone H3 Lys 4 in coding regions correlates with transcriptional activity. The histone methyltransferase Set1 is required to maintain expression of these active, promoter-acetylated, and coding region-methylated genes. Global comparisons reveal that genomic regions deacetylated by the yeast enzymes Rpd3 and Hda1 overlap extensively with Lys 4 hypo- but not hypermethylated regions. In the context of recent studies showing that Lys 4 methylation precludes histone deacetylase recruitment, we conclude that Set1 facilitates transcription, in part, by protecting active coding regions from deacetylation.


Linear phase slope in pulse design: application to coherence transfer.
Using optimal control methods, robust broadband excitation pulses can be designed with a defined linear phase dispersion. Applications include increased bandwidth for a given pulse length compared to equivalent pulses requiring no phase correction, selective pulses, and pulses that mitigate the effects of relaxation. This also makes it possible to create pulses that are equivalent to ideal hard pulses followed by an effective evolution period. For example, in applications, where the excitation pulse is followed by a constant delay, e.g. for the evolution of heteronuclear couplings, part of the pulse duration can be absorbed in existing delays, significantly reducing the time overhead of long, highly robust pulses. We refer to the class of such excitation pulses with a defined linear phase dispersion as ICEBERG pulses (Inherent Coherence Evolution optimized Broadband Excitation Resulting in constant phase Gradients). A systematic study of the dependence of the excitation efficiency on the phase dispersion of the excitation pulses is presented, which reveals surprising opportunities for improved pulse sequence performance.


Time-lapse X-ray phase-contrast microtomography for in vivo imaging and analysis of morphogenesis.
X-ray phase-contrast microtomography (XPCμT) is a label-free, high-resolution imaging modality for analyzing early development of vertebrate embryos in vivo by using time-lapse sequences of 3D volumes. Here we provide a detailed protocol for applying this technique to study gastrulation in Xenopus laevis (African clawed frog) embryos. In contrast to μMRI, XPCμT images optically opaque embryos with subminute temporal and micrometer-range spatial resolution. We describe sample preparation, culture and suspension of embryos, tomographic imaging with a typical duration of 2 h (gastrulation and neurulation stages), intricacies of image pre-processing, phase retrieval, tomographic reconstruction, segmentation and motion analysis. Moreover, we briefly discuss our present understanding of X-ray dose effects (heat load and radiolysis), and we outline how to optimize the experimental configuration with respect to X-ray energy, photon flux density, sample-detector distance, exposure time per tomographic projection, numbers of projections and time-lapse intervals. The protocol requires an interdisciplinary effort of developmental biologists for sample preparation and data interpretation, X-ray physicists for planning and performing the experiment and applied mathematicians/computer scientists/physicists for data processing and analysis. Sample preparation requires 9-48 h, depending on the stage of development to be studied. Data acquisition takes 2-3 h per tomographic time-lapse sequence. Data processing and analysis requires a further 2 weeks, depending on the availability of computing power and the amount of detail required to address a given scientific problem.


Universal optical transmission features in periodic and quasiperiodic hole arrays.
We investigate the influence of array order in the optical transmission properties of subwavelength hole arrays, by comparing the experimental spectral transmittance of periodic and quasiperiodic hole arrays as a function of frequency. We find that periodicity and long-range order are not necessary requirements for obtaining enhanced and suppressed optical transmission, provided short-range order is maintained. Transmission maxima and minima are shown to result, respectively, from constructive and destructive interference at each hole, between the light incident upon and exiting from a given hole, and surface plasmon polaritons (SPPs) arriving from individual neighboring holes. These SPPs are launched along both illuminated and exit surfaces, by diffraction of the incident and emerging light at the neighboring individual subwavelength holes. By characterizing the optical transmission of a pair of subwavelength holes as a function of hole-hole distance, we demonstrate that a subwavelength hole can launch SPPs with an efficiency up to 35%, and with an experimentally determined launch phase phi = pi /2, for both input-side and exit-side SPPs. This characteristic phase has a crucial influence on the shape of the transmission spectra, determining transmission minima in periodic arrays at those frequencies where grating coupling arguments would instead predict maxima.


24-norUrsodeoxycholic acid is superior to ursodeoxycholic acid in the treatment of sclerosing cholangitis in Mdr2 (Abcb4) knockout mice.
Current therapy for primary sclerosing cholangitis is of limited efficacy. Multidrug resistance gene 2 knockout mice (Mdr2(-/-)) represent a well-characterized model for sclerosing cholangitis. Experiments were performed to test in such mice the therapeutic effects of 24-norUrsodeoxycholic acid, a C(23) homologue of ursodeoxycholic acid with 1 fewer methylene group in its side chain. Mdr2(-/-) mice were fed a diet containing 24-norUrsodeoxycholic acid (0.5% wt/wt) or ursodeoxycholic acid (0.5% wt/wt) as a clinical comparator for 4 weeks; controls received standard chow. Effects on serum liver tests, liver histology, markers of inflammation and fibrosis, and bile acid transport and metabolism were compared. 24-norUrsodeoxycholic acid metabolism was studied in serum, liver, bile, and urine. 24-norUrsodeoxycholic acid markedly improved liver tests and liver histology and significantly reduced hydroxyproline content and the number of infiltrating neutrophils and proliferating hepatocytes and cholangiocytes. 24-norUrsodeoxycholic acid underwent extensive phase I/II metabolism (hydroxylation, sulfation, and glucuronidation), thereby increasing the hydrophilicity of biliary bile acid secretion. There was a coordinated induction of bile acid detoxifying enzymes (Cyp2b10, Cyp3a11, and Sult2a1) and efflux pumps (Mrp3 and Mrp4). Ursodeoxycholic acid, in contrast, increased alanine transaminase and alkaline phosphatase levels, had no significant effects on hydroxyproline content, and induced biliary transporters and detoxification enzymes to a much smaller extent than 24-norUrsodeoxycholic acid. 24-norUrsodeoxycholic acid ameliorates sclerosing cholangitis in Mdr2(-/-) mice. Its therapeutic mechanisms involve (1) increasing the hydrophilicity of biliary bile acids, (2) stimulating bile flow with flushing of injured bile ducts, and (3) inducing detoxification and elimination routes for bile acids.


[Study of vitamin D status of rheumatoid arthritis patients. Rationale and design of a cross-sectional study by the osteoporosis and metabolic bone diseases study group of the Italian Society of Rheumatology (SIR)].
The fundamental role of Vitamin D has been long known in regulating calcium homeostasis and bone metabolism. An increased contribution of Vitamin D was recently described in association with a lower incidence of Rheumatoid Arthritis (RA). This must not be surprising, as the immunomodulating effects of Vitamin D are clear, which have been attributed protective effects in autoimmune disorders such as some chronic inflammatory bowel diseases, multiple sclerosis and type I diabetes. An interaction was suggested between Vitamin D metabolism and inflammation indexes through mediation of TNF-alpha which is also especially involved in osteoclastic resorption and therefore in bone loss processes. Some preliminary data would indicate an association between seasonal changes of Vitamin D serum levels, latitude and disease activity (DAS28) in RA patients. Consequently, the Osteoporosis and Metabolic Bone Diseases Study Group of SIR believes that there are grounded reasons for assessing the Vitamin D status of RA patients in order to investigate whether this is to be related to physiopathological and clinical aspects of disease other than those of bone involvement. Primary end point of the study will be to assess the levels of 25 OH Vitamin D in RA patients. Secondary endpoints will include correlation with dis-ease activity, densitometry values and bone turnover. The cross-sectional study will enroll patients of both sex genders, age ranging between 30 and 75 years according to the 1988 ACR criteria, onset of symptoms at least 2 years prior to study enrollment. Patients will be excluded suffering from osteo-metabolic diseases, liver and kidney insufficiency and those administered Vitamin D boli in the previous 12 months. Disease activity will be evaluated with the HAQ. Hemato-chemical tests and femoral and lumbar bone densitometry will be performed, unless recently undergone by patients. Blood levels of 25 OH C Vitamin D and PHT and of the two bone remodelling markers (bone alkaline phosphatase and serum CTX) will be measured, as well. Patient enrollment will start on February 2007 and will last 4 months. By the end of 2007 the study will be concluded and results will be published.


Priming cells for their final destination: microenvironment controlled cell culture by a modular ECM-mimicking feeder film.
Mammalian cell culture is the starting point in many research studies focusing on biomedical applications. However, researchers have little control over the standardized cell microenvironment parameters. Here a modular ECM-mimicking surface coating for cell culture environment is designed. This substrate is a new and versatile thin film obtained by spin-coating of concentrated gelatin crosslinked by transglutaminase. It can be modified with respect to the biochemical and biophysical needs of the final cell destination, i.e. it delivers loaded multi-growth factors and serum components and allows for cell culture in a serum-free culture medium. Also, a well-known cell behavior modulator, the substrate stiffness, is controlled exogenously by addition of nanoparticles. In addition to growth factors, antimicrobial agents such as natural peptides are added to the substrate for limiting the repeated addition of antimicrobial agents to the culture medium and to prevent the increase of resistant bacterial strains in the culture environment. Finally, this substrate contains simultaneously ECM components, growth factors, stiffening elements and antimicrobial agents. It provides a favorable microenvironment and sterile conditions. It is a free-of-maintenance system, as cells will grow without addition of serum or antimicrobial cocktails. This low cost and easy-to-use substrate could emerge as a new standard for cell culture.


Open-label study on the long-term efficacy, safety, and impact on quality of life of OROS hydromorphone ER in patients with chronic low back pain.
To investigate the efficacy, safety, and impact on quality of life of long-term administration of OROS hydromorphone ER (8-128mg) in patients with chronic low back pain. A total of 113 adults with chronic low back pain who completed a 6-week open-label study were enrolled in this 6-month extension study. The primary end point was the daily pain relief rating obtained during monthly study visits. Secondary end points included Investigator and Patient Global Evaluations, Brief Pain Inventory scores obtained at monthly study visits, and quality-of-life measures (Medical Outcomes Study Questionnaire and 36-Item Short-Form Health Survey score) obtained at monthly intervals. Mean±SD change from baseline in pain relief with OROS hydromorphone ER for the Month 6 visit was 0.9±2.55 (P=0.0007) and for the last assessment of the extension study was 0.9±2.53 (P=0.0002). At the Month 6 visit, 81.3% of investigators and 71.0% of patients rated their satisfaction of pain relief with OROS hydromorphone ER treatment as good, very good, or excellent. Changes on the 36-item Short Form Health Survey, a quality-of-life measure, were statistically significant for the physical composite scores for all extension phase time points, including Month 6 (2.1±5.34; P<0.0001) and the last assessment (2.4±5.56; P<0.0001) and mental composite scores for all extension phase time points, including Month 6 (3.3±9.52; P=0.0006) and the last assessment (3.1±9.5; P=0.0008). Treatment with OROS hydromorphone ER also resulted in significant improvement in sleep disturbances. Adverse events included gastrointestinal and central nervous system symptoms. The results support the long-term use of OROS hydromorphone ER in managing chronic moderate to severe low back pain.


Poor prospects for avian biodiversity in Amazonian oil palm.
Expansion of oil palm plantations across the humid tropics has precipitated massive loss of tropical forest habitats and their associated speciose biotas. Oil palm plantation monocultures have been identified as an emerging threat to Amazonian biodiversity, but there are no quantitative studies exploring the impact of these plantations on the biome's biota. Understanding these impacts is extremely important given the rapid projected expansion of oil palm cultivation in the basin. Here we investigate the biodiversity value of oil palm plantations in comparison with other dominant regional land-uses in Eastern Amazonia. We carried out bird surveys in oil palm plantations of varying ages, primary and secondary forests, and cattle pastures. We found that oil palm plantations retained impoverished avian communities with a similar species composition to pastures and agrarian land-uses and did not offer habitat for most forest-associated species, including restricted range species and species of conservation concern. On the other hand, the forests that the oil palm companies are legally obliged to protect hosted a relatively species-rich community including several globally-threatened bird species. We consider oil palm to be no less detrimental to regional biodiversity than other agricultural land-uses and that political pressure exerted by large landowners to allow oil palm to count as a substitute for native forest vegetation in private landholdings with forest restoration deficits would have dire consequences for regional biodiversity.


Laser remote-sensing system analysis for search and rescue.
We develop a general model of a laser remote-sensing system for search and rescue using targets marked with fluorescent dye. The dye fluoresces at a longer peak wavelength than the incident radiation, enabling a dye-covered target to be distinguished from the unshifted ground echo by the search system. The principal result is a simple expression derived for the average laser power required to search at a particular rate given a required ground energy density. A similar expression is applicable to imaging lidar systems. The example system shown indicates that active probing for lost planes may be practical.


Therapeutic Ablation of Gain-of-Function Mutant p53 in Colorectal Cancer Inhibits Stat3-Mediated Tumor Growth and Invasion.
Over half of colorectal cancers (CRCs) harbor TP53 missense mutations (mutp53). We show that the most common mutp53 allele R248Q (p53Q) exerts gain of function (GOF) and creates tumor dependence in mouse CRC models. mutp53 protein binds Stat3 and enhances activating Stat3 phosphorylation by displacing the phosphatase SHP2. Ablation of the p53Q allele suppressed Jak2/Stat3 signaling, growth, and invasiveness of established, mutp53-driven tumors. Treating tumor-bearing mice with an HSP90 inhibitor suppressed mutp53 levels and tumor growth. Importantly, human CRCs with stabilized mutp53 exhibit enhanced Jak2/Stat3 signaling and are associated with poorer patient survival. Cancers with TP53R248Q/W are associated with a higher patient death risk than are those having nonR248 mutp53. These findings identify GOF mutp53 as a therapeutic target in CRC.


Dishevelled limits Notch signalling through inhibition of CSL.
Notch and Wnt are highly conserved signalling pathways that are used repeatedly throughout animal development to generate a diverse array of cell types. However, they often have opposing effects on cell-fate decisions with each pathway promoting an alternate outcome. Commonly, a cell receiving both signals exhibits only Wnt pathway activity. This suggests that Wnt inhibits Notch activity to promote a Wnt-ON/Notch-OFF output; but what might underpin this Notch regulation is not understood. Here, we show that Wnt acts via Dishevelled to inhibit Notch signalling, and that this crosstalk regulates cell-fate specification in vivo during Xenopus development. Mechanistically, Dishevelled binds and directly inhibits CSL transcription factors downstream of Notch receptors, reducing their activity. Furthermore, our data suggest that this crosstalk mechanism is conserved between vertebrate and invertebrate homologues. Thus, we identify a dual function for Dishevelled as an inhibitor of Notch signalling and an activator of the Wnt pathway that sharpens the distinction between opposing Wnt and Notch responses, allowing for robust cell-fate decisions.


Biological metals and metal-targeting compounds in major neurodegenerative diseases.
Multiple abnormalities occur in the homeostasis of essential endogenous brain biometals in age-related neurodegenerative disorders, Alzheimer's disease, Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis. As a result, metals both accumulate in microscopic proteinopathies, and can be deficient in cells or cellular compartments. Therefore, bulk measurement of metal content in brain tissue samples reveal only the "tip of the iceberg", with most of the important changes occurring on a microscopic and biochemical level. Each of the major proteins implicated in these disorders interacts with biological transition metals. Tau and the amyloid protein precursor have important roles in normal neuronal iron homeostasis. Changes in metal distribution, cellular deficiencies, or sequestration in proteinopathies all present abnormalities that can be corrected in animal models by small molecules. These biochemical targets are more complex than the simple excess of metals that are targeted by chelators. In this review we illustrate some of the richness in the science that has developed in the study of metals in neurodegeneration, and explore its novel pharmacology.


The effects of high physical activity on pharmacokinetic drug interactions.
With the development of new drugs, it is common practice for drug manufacturers to measure their pharmacokinetic parameters. This testing involves the discovery of the absorption, distribution, metabolic, excretory and toxicological properties of drugs. The testing is usually done in non-stressful conditions at rest, however, this does not necessarily tell the entire picture as there is increasing knowledge about the effects that high levels of physical activity can have on the pharmacokinetics of some medications. This review discusses the alterations that physical activity can have on the absorption, distribution, metabolism and elimination parameters of commonly used medications, and clinical outcomes data are reported when known, demonstrating that an interaction exists between exercise and certain medications. This drug-exercise pharmacokinetic interaction alters the performance of medications especially under conditions where exercise is performed for a long period of time. Particular medications that may be affected are those with a narrow therapeutic dosing range, such as digoxin, theophylline and warfarin. Other important medications include insulin and those administered via a transdermal patch drug delivery system. For this review, a literature search was performed between 1966 and 2010. Patients and healthcare providers should be aware that exercise can adversely affect the way some medications are intended to work. Patients taking certain medications should be closely monitored when performing high amounts of physical activity.


Composition of Unrecorded Distilled Alcohol (bai jiu) Produced in Small Rural Factories in Central China.
Unrecorded traditional distilled spirits (bai jiu, ) are made and used throughout rural China for everyday use and special occasions. Nearly every town or village has a distiller to supply the demand. In rural China, distilling bai jiu is legal and regulated lightly or not at all. The World Health Organization estimates that as much as 25% of all alcohol consumed in China is unrecorded alcohol, of which an unknown portion is unrecorded bai jiu. Little is known about the composition of unrecorded Chinese spirits from rural parts of the country. This study focused on white spirits because the high ethanol (EtOH) concentration makes them more likely to contribute to health risks compared to other types of lower alcohol by volume (ABV) Chinese unrecorded alcohol. Researchers purchased samples of Chinese white spirits from small-factory distillers in central China. An independent laboratory conducted the analysis. Alcohol strength (ABV) was determined by hydrometer. Gas chromatography was used to determine the concentration of volatile organic compounds: EtOH, methanol, acetaldehyde, ethyl acetate, and higher alcohols. Samples were tested for 3 heavy metals-arsenic, cadmium, and lead. We used the guidelines developed by the Alcohol Measures for Public Health Research Alliance (AMPHORA) of the European Commission to assess risk. ABV ranged from 35.7 to 61.4%, and 58 of the 61 samples exceeded 40% ABV. The concentration of methanol, ethyl acetate, lead, arsenic, and cadmium was below AMPHORA guideline. The sum of higher alcohols exceeded the AMPHORA maximum in just 1 sample. Forty of the 61 samples had acetaldehyde levels beyond the AMPHORA guideline. The unrecorded Chinese alcohols we analyzed had a high EtOH concentration-a public health concern that is also presented by recorded alcohols. The high percentage of samples (65.5%) that had elevated acetaldehyde suggests the need to investigate the causes for this result and the need for steps to reduce acetaldehyde levels. The cumulative long-term risks of using high EtOH and high acetaldehyde Chinese spirits are heightened by the percentage of people in China who have a genetic trait for impaired acetaldehyde metabolism.


eHealth interventions to support caregivers of people with dementia may be proven effective, but are they implementation-ready?
A variety of health services delivered via the Internet, or "eHealth interventions," to support caregivers of people with dementia have shown evidence of effectiveness, but only a small number are put into practice. This study aimed to investigate whether, how and why their implementation took place. This qualitative study followed up on the 12 publications included in Boots et al.'s (2014) widely cited systematic review on eHealth interventions for informal caregivers of people with dementia, in order to explore further implementation into practice. Publicly available online information, implementation readiness (ImpRess checklist scores), and survey responses were assessed. Two interventions were freely available online, two were available in a trial context, and one was exclusively available to clinical staff previously involved in the research project. The remaining seven were unavailable. All scores on the ImpRess checklist were at 50% or lower of the total, indicating that the interventions were not ready to implement at the time of the Boots et al. (2014) review, though some interventions were scored as more implementation-ready in subsequent follow-up publications. Responses to the survey were received from six out of twelve authors. Key learnings from the survey included the importance of the involvement of stakeholders at all stages of the process, as well as the flexible adaptation and commercialization of the intervention. In general, low levels of implementation readiness were reported and often the information necessary to assess implementation readiness was unavailable. The only two freely available interventions had long-term funding from aging foundations. Authors pointed to the involvement of financial gatekeepers in the development process and the creation of a business model early on as important facilitators to implementation. Future research should focus on the factors enabling sustainable implementation.


Selective deletion of leptin receptor in neurons leads to obesity.
Animals with mutations in the leptin receptor (ObR) exhibit an obese phenotype that is indistinguishable from that of leptin deficient ob/ob mice. ObR is expressed in many tissues, including brain, and the relative importance of leptin's effects on central versus peripheral sites has not been resolved. To address this, we generated mice with neuron-specific (ObR(SynI)KO) and hepatocyte-specific (ObR(Alb)KO) disruption of ObR. Among the ObR(SynI)KO mice, the extent of obesity was negatively correlated with the level of ObR in hypothalamus and those animals with the lowest levels of ObR exhibited an obese phenotype. The obese mice with low levels of hypothalamic ObR also show elevated plasma levels of leptin, glucose, insulin, and corticosterone. The hypothalamic levels of agouti-related protein and neuropeptide Y RNA are increased in these mice. These data indicate that leptin has direct effects on neurons and that a significant proportion, or perhaps the majority, of its weight-reducing effects are the result of its actions on brain. To explore possible direct effects of leptin on a peripheral tissue, we also characterized ObR(Alb)KO mice. These mice weigh the same as controls and have no alterations in body composition. Moreover, while db/db mice and ObR(SynI)KO mice have enlarged fatty livers, ObR(Alb)KO mice do not. In summary, these data suggest that the brain is a direct target for the weight-reducing and neuroendocrine effects of leptin and that the liver abnormalities of db/db mice are secondary to defective leptin signaling in the brain.


Association of Genetic Variant at Chromosome 12q23.1 With Neuropathic Pain Susceptibility.
Neuropathic pain (NP) has important clinical and socioeconomic consequences for individuals and society. Increasing evidence indicates that genetic factors make a significant contribution to NP, but genome-wide association studies (GWASs) are scant in this field and could help to elucidate susceptibility to NP. To identify genetic variants associated with NP susceptibility. This genetic association study included a meta-analysis of GWASs of NP using 3 independent cohorts: ie, Genetics of Diabetes Audit and Research in Tayside Scotland (GoDARTS); Generation Scotland: Scottish Family Health Study (GS:SFHS); and the United Kingdom Biobank (UKBB). Data analysis was conducted from April 2018 to December 2019. Individuals with NP (ie, case participants; those with pain of ≥3 months' duration and a Douleur Neuropathique en 4 Questions score ≥3) and individuals with no pain (ie, control participants) with or without diabetes from GoDARTS and GS:SFHS were identified using validated self-completed questionnaires. In the UKBB, self-reported prescribed medication and hospital records were used as a proxy to identify case participants (patients recorded as receiving specific anti-NP medicines) and control participants. GWAS was performed using linear mixed modeling. GWAS summary statistics were combined using fixed-effect meta-analysis. A total of 51 variants previously shown to be associated with NP were tested for replication. This study included a total of 4512 case participants (2662 [58.9%] women; mean [SD] age, 61.7 [10.8] years) and 428 489 control participants (227 817 [53.2%] women; mean [SD] age, 62.3 [11.5] years) in the meta-analysis of 3 cohorts with European descent. The study found a genome-wide significant locus at chromosome 12q23.1, which mapped to SLC25A3 (rs369920026; odds ratio [OR] for having NP, 1.68; 95% CI, 1.40-2.02; P = 1.30 × 10-8), and a suggestive variant at 13q14.2 near CAB39L (rs7992766; OR, 1.09; 95% CI, 1.05-1.14; P = 1.22 × 10-7). These mitochondrial phosphate carriers and calcium binding genes are expressed in brain and dorsal root ganglia. Colocalization analyses using expression quantitative loci data found that the suggestive variant was associated with expression of CAB39L in the brain cerebellum (P = 1.01 × 10-14). None of the previously reported variants were replicated. To our knowledge, this was the largest meta-analyses of GWAS to date. It found novel genetic variants associated with NP susceptibility. These findings provide new insights into the genetic architecture of NP and important information for further studies.


Coupling bioorthogonal chemistries with artificial metabolism: intracellular biosynthesis of azidohomoalanine and its incorporation into recombinant proteins.
In this paper, we present a novel, "single experiment" methodology based on genetic engineering of metabolic pathways for direct intracellular production of non-canonical amino acids from simple precursors, coupled with expanded genetic code. In particular, we engineered the intracellular biosynthesis of L-azidohomoalanine from O-acetyl-L-homoserine and NaN3, and achieved its direct incorporation into recombinant target proteins by AUG codon reassignment in a methionine-auxotroph E. coli strain. In our system, the host's methionine biosynthetic pathway was first diverted towards the production of the desired non-canonical amino acid by exploiting the broad reaction specificity of recombinant pyridoxal phosphate-dependent O-acetylhomoserine sulfhydrylase from Corynebacterium glutamicum. Then, the expression of the target protein barstar, accompanied with efficient L-azidohomoalanine incorporation in place of L-methionine, was accomplished. This work stands as proof-of-principle and paves the way for additional work towards intracellular production and site-specific incorporation of biotechnologically relevant non-canonical amino acids directly from common fermentable sources.