Prevalence of Dementia and Cognitive Complaints in the Context of High Cognitive Reserve: A Population-Based Study.
This study aimed to assess the prevalence of dementia and cognitive complaints in a cross-sectional sample of Luxembourg seniors, and to discuss the results in the societal context of high cognitive reserve resulting from multilingualism. A population sample of 1,377 people representative of Luxembourg residents aged over 64 years was initially identified via the national social insurance register. There were three different levels of contribution: full participation in the study, partial participation, and non-participation. We examined the profiles of these three different samples so that we could infer the prevalence estimates in the Luxembourgish senior population as a whole using the prevalence estimates obtained in this study. After careful attention to the potential bias and of the possibility of underestimation, we considered the obtained prevalence estimates of 3.8% for dementia (with corresponding 95% confidence limits (CL) of 2.8% and 4.8%) and 26.1% for cognitive complaints (CL = [17.8-34.3]) as trustworthy. Based on these findings, we postulate that high cognitive reserve may result in surprisingly low prevalence estimates of cognitive complaints and dementia in adults over the age of 64 years, which thereby corroborates the longer disability-free life expectancy observed in the Luxembourg population. To the best of our knowledge, this study is the first to report such Luxembourgish public health data.


Double charge ordering states and spin ordering state observed in a RFe2O4 system.
Charge, spin, and lattice degrees of orderings are of great interest in the layered quantum material RFe2O4 (R = Y, Er, Yb, Tm, and Lu) system. Recently many unique properties have been found using various experimental methods. However so far the nature of the two-dimensional (2D) charge ordering (CO) state is not clear and no observation of its fine structure in energy has been reported. Here we report unambiguous observation of double 2D CO states at relatively high temperature in a polycrystalline Er0.1Yb0.9Fe2O4 using Raman scattering. The energy gaps between the 3D and the double 2D states are 170 meV (41.2 THz) and 193 meV (46.6 THz), respectively. We also observed a spin ordering (SO) state at below 210 K with characteristic energy of 45 meV (10.7 THz). Our investigation experimentally identified new fine structures of quantum orders in the system, which also extends the capability of optical methods in investigating other layered quantum materials.


Long-term efficacy and safety of aripiprazole in patients with schizophrenia, schizophreniform disorder, or schizoaffective disorder: 26-week prospective study.
To date there have been no reports of long-term efficacy of aripiprazole in Asian populations. The aim of the present study was therefore to investigate the long-term efficacy, safety and tolerability of aripiprazole in a large number of patients with schizophrenia, schizophreniform disorder, or schizoaffective disorder in Korea. This study was a prospective, multicenter, single-group, 26-week open study of patients with schizophrenia, schizophreniform disorder, or schizoaffective disorder. A total of 300 Korean patients participated in the study. The primary efficacy measure was the Positive and Negative Syndrome Scale (PANSS) total score, and secondary efficacy measures included the PANSS positive and negative subscales, Clinical Global Impression-Severity of Illness (CGI-S). Tolerability and safety were assessed by monitoring the frequency and severity of treatment-emergent adverse events, extrapyramidal symptoms (EPS), vital signs, weight, and laboratory tests. Aripiprazole produced rapid and significant improvements on all efficacy measures. As evidenced by PANSS total score, PANSS positive subscales and the CGI-S scores, first-episode drug-naive patients demonstrated significantly greater efficacy relative to patients who had previously experienced one or more episodes of relapse. Aripiprazole was associated with significant decrease of serum prolactin level. The subjects showed mild weight gain. Aripiprazole is an effective antipsychotic in the long-term treatment of both positive and negative symptoms. This study extends the findings of previous long-term studies, and has found that there is no significant difference with regard to ethnicity in response to aripiprazole.


Integrated specialized atrial fibrillation clinics reduce all-cause mortality: post hoc analysis of a randomized clinical trial.
An integrated chronic care programme in terms of a specialized outpatient clinic for patients with atrial fibrillation (AF), has demonstrated improved clinical outcomes. The aim of this study is to assess all-cause mortality in patients in whom AF management was delivered through a specialized outpatient clinic offering an integrated chronic care programme. Post hoc analysis of a Prospective Randomized Open Blinded Endpoint Clinical trial to assess all-cause mortality in AF patients. The study included 712 patients with newly diagnosed AF, who were referred for AF management to the outpatient service of a University hospital. In the specialized outpatient clinic (AF-Clinic), comprehensive, multidisciplinary, and patient-centred AF care was provided, i.e. nurse-driven, physician supervised AF treatment guided by software based on the latest guidelines. The control group received usual care by a cardiologist in the regular outpatient setting.After a mean follow-up of 22 months, all-cause mortality amounted 3.7% (13 patients) in the AF-Clinic arm and 8.1% (29 patients) in usual care [hazard ratio (HR) 0.44, 95% confidence interval (CI) 0.23-0.85; P = 0.014]. This included cardiovascular mortality in 4 AF-Clinic patients (1.1%) and 14 patients (3.9%) in usual care (HR 0.28; 95% CI 0.09-0.85; P = 0.025). Further, 9 patients (2.5%) died in the AF-Clinic arm due to a non-cardiovascular reason and 15 patients (4.2%) in the usual care arm (HR 0.59; 95% CI 0.26-1.34; P = 0.206). An integrated specialized AF-Clinic reduces all-cause mortality compared with usual care. These findings provide compelling evidence that an integrated approach should be widely implemented in AF management.


Does glucocorticoid exposure explain the association between metabolic dysfunction and tendinopathy?
While metabolic health is acknowledged to affect connective tissue structure and function, the mechanisms are unclear. Glucocorticoids are present in almost every cell type throughout the body and control key physiological processes such as energy homeostasis, stress response, inflammatory and immune processes, and cardiovascular function. Glucocorticoid excess manifests as visceral adiposity, dyslipidaemia, insulin resistance, and type 2 diabetes. As these metabolic states are also associated with tendinopathy and tendon rupture, it may be that glucocorticoids excess is the link between metabolic health and tendinopathy. To synthesise current knowledge linking glucocorticoids exposure to tendon structure and function. Narrative literature review. We provide an overview of endogenous glucocorticoid production, regulation, and signalling. Next we review the impact that oral glucocorticoid has on risk of tendon rupture and the effect that injected glucocorticoid has on resolution of symptoms. Then we highlight the clinical and mechanistic overlap between tendinopathy and glucocorticoid excess in the areas of visceral adiposity, dyslipidaemia, insulin resistance and type 2 diabetes. In these areas, we highlight the role of glucocorticoids and how these hormones might underpin the connection between metabolic health and tendon dysfunction. There are several plausible pathways through which glucocorticoids might mediate the connection between metabolic health and tendinopathy.


Identification of QTLs associated with Fusarium head blight resistance in Zhedar 2 barley.
Fusarium head blight (FHB) in barley and wheat, caused by Fusarium graminearum, is a continual problem worldwide. Primarily, FHB reduces yield and quality, and results in the production of the toxin deoxynivalenol (DON), which can affect food safety. Identification of QTLs for FHB severity, DON level and related traits heading-date (HD) and plant-height (HT) with consistent effects across a set of environments, would provide the basis for marker-assisted selection (MAS) and potentially increase the efficiency of selection for resistance. A segregating population of 75 double-haploid lines, developed from the three-way cross Zhedar 2/ND9712//Foster, was used for genome mapping and FHB severity evaluation. A linkage map of 214 RFLP, SSR and AFLP markers was constructed. Phenotypic data were collected in replicated field trials from five environments in two growing seasons. The data were analyzed using MQTL software to detect quantitative trait locus (QTL) x environment (E) interactions. Because of the presence of QTL x E, the MQM procedure in MAPQTL was applied to identify QTLs in single environments. We identified nine QTLs for FHB severity and five for low DON. Many of the disease-related QTLs identified were coincident with FHB QTLs identified in previous studies. Only two of the QTLs identified in this study were consistent across all five environments, and both were Zhedar 2 specific. Five of the FHB QTLs were associated with HD, and two were associated with HT. Regions that appear to be promising candidates for MAS and further genetic analysis include the two FHB QTLs on chromosome 2H and one on 6H, which were also associated with low DON and later heading-date in multiple environments. This study provides a starting point for manipulating Zhedar 2-derived resistance by MAS in barley to develop cultivars that will show effective resistance under disease pressure.


Enhanced serotonin availability amplifies fatigue perception and modulates the TMS-induced silent period during sustained low-intensity elbow flexions.
During maximal effort contractions, intense serotonin release via the raphe-spinal pathway spills over from the somato-dendritic compartment to activate inhibitory 5-HT1A receptors on the axon initial segment of motoneurons to reduce motoneuronal output. We investigated whether the same mechanism of central fatigue is present for low-intensity contractions, whereby weak serotonergic drive over an extended period may cause accumulation of serotonin and exacerbate central fatigue. Enhanced availability of serotonin did not directly influence motor pathways or motor performance during prolonged submaximal contraction. However, perceptions of muscle fatigue were greater, and the fatigue-induced lengthening of the silent period elicited via motor cortical stimulation was reduced with enhanced availability of serotonin. We propose that sustained low-intensity serotonergic neurotransmission influences supraspinal processes associated with fatigue, without directly influencing the output of the motor system during submaximal exercise. Enhanced availability of serotonin (5-HT) exacerbates central fatigue that occurs during maximal effort contractions. However, it is unknown if 5-HT release contributes to central fatigue during prolonged submaximal contractions. Hence, we assessed the effect that enhanced availability of 5-HT has on sustained low-intensity fatiguing contractions. Fifteen individuals (22.3 ± 2.1 years) ingested the 5-HT reuptake inhibitor paroxetine in a human, double-blinded, placebo-controlled, repeated-measures design. Participants performed a low-intensity isometric elbow flexion for 30 min (15% of maximal voluntary contraction, MVC). Throughout the protocol, brief MVCs were performed and muscle responses to transcranial magnetic stimulation (TMS) of the motor cortex, electrical stimulation of the brachial plexus, and motor point stimulation of the biceps were obtained. Ratings of perceived fatigue were also acquired. Paroxetine did not influence torque or voluntary activation during brief MVCs performed throughout the low-intensity contraction. However, paroxetine increased the perception of fatigue throughout the contraction (P = 0.005), and shortened the biceps silent period elicited via TMS during sustained submaximal contraction (P = 0.003) and brief MVCs (P = 0.011). Overall, it appears that prolonged low-intensity contractions do not cause intense 5-HT release onto motoneurons, and therefore, 5-HT does not activate inhibitory extra-synaptic 5-HT1A receptors of motoneurons to reduce their output. Although motor performance was unaffected by paroxetine, perceived fatigue was greater and intracortical inhibitory activity was reduced following the enhancement of endogenous concentrations of 5-HT during sustained submaximal contraction. Thus, 5-HT affects supraspinal processes during low-intensity contractions without directly altering motor pathways projecting to the muscle.


Initiation of anti-osteoporotic drugs in high-risk female patients starting glucocorticoid treatment: a population study in Norway.
Glucocorticoid use is a risk factor for osteoporosis and fractures. We studied whether women initiating glucocorticoid treatment also started anti-osteoporotic treatment, according to clinical guidelines. Women with versus without previous fracture were twice as likely to start anti-osteoporotic treatment within 1 year after initiating glucocorticoid treatment, but the cumulative incidences were low 9.1% vs. 4.6%, respectively. Use of glucocorticoids (GC) is a risk factor for osteoporosis and fractures, and clinical guidelines suggest that preventive treatment with anti-osteoporotic drugs (AOD) should be considered when starting GC. Women with high risk of osteoporosis comprise those with previous fractures or a known inflammatory rheumatic disease, for whom the indication of AOD is even stronger. The purpose of these analyses was to investigate whether women initiating GC treatment also started AOD, especially those with high risk of osteoporosis. We used data from the Norwegian Prescription Database to identify all women 55 years and older initiating GC treatment in Norway during 2010-2016 and to obtain information on use of AOD. Data from the Norwegian Patient Registry were used to obtain information on previous fractures and diagnoses. Among 105,477 women initiating GC treatment during 2010-2016, 3256 had started AOD and 79,638 had discontinued GC treatment after 1-year follow-up. Cumulative incidence of starting AOD after 1 year was 9.1% (95% CI: 7.9, 10.4) for women with vs. 4.6% (95% CI: 4.4%, 4.8%) for women without a previous fracture. Women with rheumatoid arthritis or another inflammatory rheumatic disease were more likely to start AOD than women with other indications. For the whole cohort, the probability of starting AOD treatment within 1 year after initiating GC increased on average 3% per year (HR = 1.03, CI: 1.01, 1.05) from 2010 to 2016. Having had a previous fracture or an inflammatory rheumatic disease increased the probability of treatment with AOD. However, the proportions starting AOD were much lower than clinically indicated.


An experimental genetically attenuated live vaccine to prevent transmission of Toxoplasma gondii by cats.
Almost any warm-blooded creature can be an intermediate host for Toxoplasma gondii. However, sexual reproduction of T. gondii occurs only in felids, wherein fertilisation of haploid macrogametes by haploid microgametes, results in diploid zygotes, around which a protective wall develops, forming unsporulated oocysts. Unsporulated oocysts are shed in the faeces of cats and meiosis gives rise to haploid sporozoites within the oocysts. These, now infectious, sporulated oocysts contaminate the environment as a source of infection for people and their livestock. RNA-Seq analysis of cat enteric stages of T. gondii uncovered genes expressed uniquely in microgametes and macrogametes. A CRISPR/Cas9 strategy was used to create a T. gondii strain that exhibits defective fertilisation, decreased fecundity and generates oocysts that fail to produce sporozoites. Inoculation of cats with this engineered parasite strain totally prevented oocyst excretion following infection with wild-type T. gondii, demonstrating that this mutant is an attenuated, live, transmission-blocking vaccine.


Soliton wavelength-division multiplexing system with channel-isolating notch filters.
We propose a wavelength-division multiplexing system in which transmission of solitons is stabilized by fixed- or sliding-frequency notch filters (a soliton rail), providing channel isolation. We demonstrate analytically and numerically that a soliton trapped in a channel between two notches is very robust. We also predict an optimum ratio between the channel separation and the soliton's spectral width. The effects of interchannel collisions are considered, and it is demonstrated that these effects can be largely eliminated by notch filters, which require a compensatory gain that is comparable with the basic gain balancing the fiber loss.


Apolipoprotein E polymorphism in Turkish subjects with Type 2 diabetes mellitus: allele frequency and relation to serum lipid concentrations.
The role of apolipoprotein E (apoE) genotypes in modulating plasma lipid and apolipoprotein levels was studied in 112 patients with Type 2 diabetes mellitus (T2DM) and 94 healthy individuals. ApoE genotypes were identified by PCR amplification and subsequent restriction endonuclease digestion. The apoE allele and genotype frequencies were similar in both the diabetic and control subjects. The apoE allele frequencies were found to be 74.3 for e3, 10.1 for e2, 15.6 for e4 in the diabetic group, and 68.1 for e3, 13.2 for e2 and 18.7 for e4 in the control group. Sex-specific genotypic distribution of apoE polymorphism did not differ between the study groups. To elucidate the association of apoE with lipid abnormalities with respect to gender, serum lipid and apolipoprotein levels were compared among apo e2 (e2/2 and e3/2), e3 (e3/3) and e4 (e4/3 and e4/4) groups of T2DM and control subjects. Apo e2 allele was found to be associated to triglycerides for both sexes, and associated to glucose, and BMI only in females. Subjects with e2 allele had higher levels of BMI, glucose and triglyceride in comparison to e3 and e4. Our data suggest that genetic variation at the apoE locus in Turkish subjects is a genetic factor that influences lipid levels. Further studies attempting to correlate apoE polymorphism with lipid profile in a large number of individuals would be helpful in establishing the true significance of this polymorphism in the Turkish population.


Effect of pantothenic acid and ascorbic acid supplementation on human skin wound healing process. A double-blind, prospective and randomized trial.
This study aimed at testing human skin wound healing improvement by a 21-day supplementation of 1.0 g ascorbic acid (AA) and 0.2 g pantothenic acid (PA). 49 patients undergoing surgery for tattoos, by the successive resections procedure, entered a double-blind, prospective and randomized study. Tests performed on both skin and scars determined: hydroxyproline concentrations, number of fibroblasts, trace element contents and mechanical properties. In the 18 supplemented patients, it was shown that in skin (day 8) Fe increased (p < 0.05) and Mn decreased (p < 0.05); in scars (day 21), Cu (p = 0.07) and Mn (p < 0.01) decreased, and Mg (p < 0.05) increased; the mechanical properties of scars in group A were significantly correlated to their contents in Fe, Cu and Zn, whereas no correlation was shown in group B. In blood, AA increased after surgery with supplementation, whereas it decreased in controls. Although no major improvement of the would healing process could be documented in this study, our results suggest that the benefit of AA and PA supplementation could be due to the variations of the trace elements, as they are correlated to mechanical properties of the scars.


Radiation-induced damages in single- and double-stranded DNA.
In the present study, we searched for possible effects of DNA strandedness (single and double), on two types of damages, frank strand breaks (FSB, observed at neutral pH) and alkali labile sites (ALS, leading to breaks at alkaline pH) induced by irradiation with gamma-rays (60Co) or fast neutrons (p34,Be). Sequencing gel electrophoresis allowed us to follow the occurrence of these damages at each nucleotide site in single (ss-ss), double (ds-ds), and half single-half double (ss-ds and ds-ss) stranded oligonucleotides. Globally, in DNA with random sequences of bases, no differences in FSB and ALS yield between the single and the double-stranded conformations were observed. One observes, however, an increased alkaline lability at some guanine sites belonging to single-stranded region of ss-ds or ds-ss. Nevertheless, strandedness influences the radiosensitivity of some particular sequences, i.e. the 5'-AATT sequences. This region is less radiosensitive than the rest of DNA in the double helical, but not in the single-stranded conformation. The results are discussed in terms of DNA conformation.


[Development of the role scale for municipal supervising public health nurses].
As public health nurses are becoming increasingly decentralized in municipalities, recommendations for allocating supervising public health nurses are being made. This study aimed to develop a scale for measuring the implementation of role of municipal supervising public health nurses and to test its reliability and validity. Scale items were developed using results of a qualitative inductive analysis of interview data, and the items were then revised following an examination of content validity by experts, resulting in a provisional scale of 17 items. A self-administered, written questionnaire was then completed by supervising public health nurses or public health nurses holding the most senior positions in all municipalities nationwide, with the exception of three prefectures in the Tohoku region (total 1,621 locations). In total, 1,036 responses were received, and 931 were used for analysis (valid response rate = 57.4%). Of these, 406 were completed by supervising public health nurses. After deleting one item as a result of item analysis and conducting principal component analysis, factor analysis was conducted using the major factor method and Promax rotation. One item with high loading on multiple factors was deleted, resulting in a scale comprising 15 items and 3 factors. The cumulative contribution ratio was 56.10%. The three factors were labeled "Promotion of health activities across the whole locality," "Coordination as a PHN role leader," and "Development of the skills of public health nurses". The reliability coefficient of the RMSP (Role Scale for Municipal Supervising Public Health Nurses) as a whole was 0.84 using the split-half method (Spearman-Brown formula) and 0.91 using Cronbach's alpha, confirming internal consistency. In terms of validity, an examination was conducted of the correlation of two RMSP scale scores (strength of awareness of role as a supervising public health nurse and confidence as a supervising public health nurse) and scores on existing scales assessing management abilities, and a significant correlation (P < 0.01) was obtained. Additionally, a comparison of the RMSP scores of decentralized local public health nurses according to rank and years of service in areas where there were no supervising public health nurses with the RMSP scores of supervising public health nurses showed that the scores of supervising public health nurses were higher. The developed scale was found to be reliable and valid for measuring the implementation of supervising public health nurses' role.


European adolescent ready-to-eat-cereal (RTEC) consumers have a healthier dietary intake and body composition compared with non-RTEC consumers.
This study aims to analyse the association of European adolescents' ready-to-eat-cereal (RTEC) consumption frequency with their dietary intake by applying the concept of diet quality index and nutritional status. From the multi-centre European HELENA study, relevant data were available in 1,215 adolescents (12.5-17.5 years). RTEC consumption was identified from a food frequency questionnaire. A diet quality index, daily nutrient intakes and daily milk/yoghurt and fruit intake were calculated from two 24-h dietary recalls. BMI, waist and hip circumference and body fat were measured for body composition. Cross-sectional regression analyses were adjusted for sex, age, socio-economic status, city and breakfast skipping. Differences in sub-regions within Europe were explored. RTEC consumers showed a more favourable daily micronutrient intake (vitamin B2, B5, B7, D, calcium, phosphorus and potassium), a better diet quality index, more frequent fruit (57 vs. 51%) and milk/yoghurt consumption (81.2 vs. 56%) and less breakfast skipping (25.1 vs. 36.7%). No differences in energy and macronutrient intake were observed. Daily RTEC consumers were 57% less likely to be overweight than RTEC non-consumers but did not differ in glucose and lipid status (N = 387). This is the first comprehensive pan-European survey elucidating socio-demographic determinants of European adolescents' RTEC consumption and indicating better dietary habits in RTEC consumers. The improved dietary profile was reflected in a more beneficial body composition. Our results have also shown the advantage of using an all-integrating diet quality index by capturing the diet complexity.


A comparison of strict face-down positioning with adjustable positioning after pars plana vitrectomy and gas tamponade for rhegmatogenous retinal detachment.
To compare face-down positioning and adjustable positioning after pars plana vitrectomy for the repair of rhegmatogenous retinal detachment. Sixty-eight eyes from 68 patients with rhegmatogenous retinal detachment were included in this study. All patients received pars plana vitrectomy with long-acting gas for tamponade and then subdivided into 2 groups: 29 were included in a face-down group and 39 were included in the adjustable positioning group. Patients were followed up for 3 months. The main outcome was the rate of anatomical retinal reattachment. Secondary outcome measures were best-corrected visual acuity and postoperative complications. Most of the preoperative baseline characteristics between the two groups were not significantly different. The anatomical success rates after primary surgery were 89.7% and 92.3% for the face-down group and the adjustable positioning group, respectively (P = 1.00). Best-corrected visual acuity at the 3-month postoperative visit was 0.74 ± 0.25 for the face-down group and 0.77 ± 0.36 for the adjustable positioning group, respectively (P = 0.41). The rates of complications were not statistically different in the two groups. Adjustable positioning after pars plana vitrectomy and gas tamponade for rhegmatogenous retinal detachment repair is effective and safe. Face-down positioning seems not to be necessary for all patients with rhegmatogenous retinal detachment.


Brain Responses to Emotional Faces in Natural Settings: A Wireless Mobile EEG Recording Study.
The detection of a human face in a visual field and correct reading of emotional expression of faces are important elements in everyday social interactions, decision making and emotional responses. Although brain correlates of face processing have been established in previous fMRI and electroencephalography (EEG)/MEG studies, little is known about how the brain representation of faces and emotional expressions of faces in freely moving humans. The present study aimed to detect brain electrical potentials that occur during the viewing of human faces in natural settings. 64-channel wireless EEG and eye-tracking data were recorded in 19 participants while they moved in a mock art gallery and stopped at times to evaluate pictures hung on the walls. Positive, negative and neutral valence pictures of objects and human faces were displayed. The time instants in which pictures first occurred in the visual field were identified in eye-tracking data and used to reconstruct the triggers in continuous EEG data after synchronizing the time axes of the EEG and eye-tracking device. EEG data showed a clear face-related event-related potential (ERP) in the latency interval ranging from 165 to 210 ms (N170); this component was not seen whilst participants were viewing non-living objects. The face ERP component was stronger during viewing disgusted compared to neutral faces. Source dipole analysis revealed an equivalent current dipole in the right fusiform gyrus (BA37) accounting for N170 potential. Our study demonstrates for the first time the possibility of recording brain responses to human faces and emotional expressions in natural settings. This finding opens new possibilities for clinical, developmental, social, forensic, or marketing research in which information about face processing is of importance.


The different role of Notch1 and Notch2 in astrocytic gliomas.
It is well known that Notch signaling plays either oncogenic or tumor suppressive role in a variety of tumors, depending on the cellular context. However, in our previous study, we found that Notch1 was overexpressed while Notch2 downregulated in the majority of astrocytic gliomas with different grades as well as in glioblastoma cell lines U251 and A172. We had knocked down Notch1 by siRNA in glioblastoma cells, and identified that the cell growth and invasion were inhibited, whereas cell apoptosis was induced either in vitro or in vivo. For further clarification of the role of Notch2 in pathogenesis of gliomas, enforced overexpression of Notch2 was carried out with transfection of Notch2 expression plasmid in glioma cells and the cell growth, invasion and apoptosis were examined in vitro and in vivo in the present study, and siRNA targeting Notch1 was used as a positive control in vivo. The results showed that upregulating Notch2 had the effect of suppressing cell growth and invasion as well as inducing apoptosis, just the same as the results of knocking down Notch1. Meanwhile, the activity of core signaling pathway-EGFR/PI3K/AKT in astrocytic glioma cells was repressed. Thus, the present study reveals, for the first time, that Notch1 and Notch2 play different roles in the biological processes of astrocytic gliomas. Knocking down the Notch1 or enforced overexpression of Notch2 both modulate the astrocytic glioma phenotype, and the mechanism by which Notch1 and 2 play different roles in the glioma growth should be further investigated.


Apical seal of root canals with gutta-percha points with calcium hydroxide.
The objective of this research was to determine if gutta-percha points with calcium hydroxide [Ca(OH)2] improve the apical seal after root canal filling and if the master point does it alone. Human single recently extracted teeth were biomechanically prepared and the root canals filled by the lateral condensation technique with ZOE and gutta-percha points, with or without calcium hydroxide. The teeth were placed into a 2% methylene blue solution in a vacuum environment for 24 h after which they were processed for stereomicroscope evaluation. Better results were observed with the teeth filled with gutta-percha points with calcium hydroxide (p=0.01). We conclude that these new points make a better apical seal and that these results can also be obtained with the calcium hydroxide master point associated with regular ones (p=0.05).


Live Imaging with Genetically Encoded Physiologic Sensors and Optogenetic Tools.
Barrier tissues such as the epidermis employ complex signal transduction systems to execute morphogenetic programs and to rapidly respond to environmental cues to promote homeostasis. Recent advances in live-imaging techniques and tools allow precise spatial and temporal monitoring and manipulation of intracellular signaling cascades. Leveraging the chemistry of naturally occurring light-sensitive proteins, genetically encoded fluorescent biosensors have emerged as robust tools for visualizing dynamic signaling events. In contrast, optogenetic protein constructs permit laser-mediated control of signal receptors and effectors within live cells, organoids, and even model organisms. In this paper, we review the basic principles underlying novel biosensors and optogenetic tools and highlight how recent studies in cutaneous biology have leveraged these imaging strategies to illuminate the spatiotemporal signals regulating epidermal development, barrier formation, and tissue homeostasis.


Extending and evaluating a warfarin dosing algorithm that includes CYP4F2 and pooled rare variants of CYP2C9.
Warfarin dosing remains challenging because of its narrow therapeutic window and large variability in dose response. We sought to analyze new factors involved in its dosing and to evaluate eight dosing algorithms, including two developed by the International Warfarin Pharmacogenetics Consortium (IWPC). we enrolled 108 patients on chronic warfarin therapy and obtained complete clinical and pharmacy records; we genotyped single nucleotide polymorphisms relevant to the VKORC1, CYP2C9, and CYP4F2 genes using integrated fluidic circuits made by Fluidigm. When applying the IWPC pharmacogenetic algorithm to our cohort of patients, the percentage of patients within 1 mg/d of the therapeutic warfarin dose increases from 54% to 63% using clinical factors only, or from 38% using a fixed-dose approach. CYP4F2 adds 4% to the fraction of the variability in dose (R) explained by the IWPC pharmacogenetic algorithm (P<0.05). Importantly, we show that pooling rare variants substantially increases the R for CYP2C9 (rare variants: P=0.0065, R=6%; common variants: P=0.0034, R=7%; rare and common variants: P=0.00018; R=12%), indicating that relatively rare variants not genotyped in genome-wide association studies may be important. In addition, the IWPC pharmacogenetic algorithm and the Gage (2008) algorithm perform best (IWPC: R=50%; Gage: R=49%), and all pharmacogenetic algorithms outperform the IWPC clinical equation (R=22%). VKORC1 and CYP2C9 genotypes did not affect long-term variability in dose. Finally, the Fluidigm platform, a novel warfarin genotyping method, showed 99.65% concordance between different operators and instruments. CYP4F2 and pooled rare variants of CYP2C9 significantly improve the ability to estimate warfarin dose.


Validation of the Amsterdam Dynamic Facial Expression Set--Bath Intensity Variations (ADFES-BIV): A Set of Videos Expressing Low, Intermediate, and High Intensity Emotions.
Most of the existing sets of facial expressions of emotion contain static photographs. While increasing demand for stimuli with enhanced ecological validity in facial emotion recognition research has led to the development of video stimuli, these typically involve full-blown (apex) expressions. However, variations of intensity in emotional facial expressions occur in real life social interactions, with low intensity expressions of emotions frequently occurring. The current study therefore developed and validated a set of video stimuli portraying three levels of intensity of emotional expressions, from low to high intensity. The videos were adapted from the Amsterdam Dynamic Facial Expression Set (ADFES) and termed the Bath Intensity Variations (ADFES-BIV). A healthy sample of 92 people recruited from the University of Bath community (41 male, 51 female) completed a facial emotion recognition task including expressions of 6 basic emotions (anger, happiness, disgust, fear, surprise, sadness) and 3 complex emotions (contempt, embarrassment, pride) that were expressed at three different intensities of expression and neutral. Accuracy scores (raw and unbiased (Hu) hit rates) were calculated, as well as response times. Accuracy rates above chance level of responding were found for all emotion categories, producing an overall raw hit rate of 69% for the ADFES-BIV. The three intensity levels were validated as distinct categories, with higher accuracies and faster responses to high intensity expressions than intermediate intensity expressions, which had higher accuracies and faster responses than low intensity expressions. To further validate the intensities, a second study with standardised display times was conducted replicating this pattern. The ADFES-BIV has greater ecological validity than many other emotion stimulus sets and allows for versatile applications in emotion research. It can be retrieved free of charge for research purposes from the corresponding author.


Hepatocyte mARC1 promotes fatty liver disease.
Non-alcoholic fatty liver disease (NAFLD) has a prevalence of ∼25% worldwide, with significant public health consequences yet few effective treatments. Human genetics can help elucidate novel biology and identify targets for new therapeutics. Genetic variants in mitochondrial amidoxime-reducing component 1 (MTARC1) have been associated with NAFLD and liver-related mortality; however, its pathophysiological role and the cell type(s) mediating these effects remain unclear. We aimed to investigate how MTARC1 exerts its effects on NAFLD by integrating human genetics with in vitro and in vivo studies of mARC1 knockdown. Analyses including multi-trait colocalisation and Mendelian randomisation were used to assess the genetic associations of MTARC1. In addition, we established an in vitro long-term primary human hepatocyte model with metabolic readouts and used the Gubra Amylin NASH (GAN)-diet non-alcoholic steatohepatitis mouse model treated with hepatocyte-specific N-acetylgalactosamine (GalNAc)-siRNA to understand the in vivo impacts of MTARC1. We showed that genetic variants within the MTARC1 locus are associated with liver enzymes, liver fat, plasma lipids, and body composition, and these associations are attributable to the same causal variant (p.A165T, rs2642438 G>A), suggesting a shared mechanism. We demonstrated that increased MTARC1 mRNA had an adverse effect on these traits using Mendelian randomisation, implying therapeutic inhibition of mARC1 could be beneficial. In vitro mARC1 knockdown decreased lipid accumulation and increased triglyceride secretion, and in vivo GalNAc-siRNA-mediated knockdown of mARC1 lowered hepatic but increased plasma triglycerides. We found alterations in pathways regulating lipid metabolism and decreased secretion of 3-hydroxybutyrate upon mARC1 knockdown in vitro and in vivo. Collectively, our findings from human genetics, and in vitro and in vivo hepatocyte-specific mARC1 knockdown support the potential efficacy of hepatocyte-specific targeting of mARC1 for treatment of NAFLD. We report that genetically predicted increases in MTARC1 mRNA associate with poor liver health. Furthermore, knockdown of mARC1 reduces hepatic steatosis in primary human hepatocytes and a murine NASH model. Together, these findings further underscore the therapeutic potential of targeting hepatocyte MTARC1 for NAFLD.


NeuroCa: integrated framework for systematic analysis of spatiotemporal neuronal activity patterns from large-scale optical recording data.
Optical recording facilitates monitoring the activity of a large neural network at the cellular scale, but the analysis and interpretation of the collected data remain challenging. Here, we present a MATLAB-based toolbox, named NeuroCa, for the automated processing and quantitative analysis of large-scale calcium imaging data. Our tool includes several computational algorithms to extract the calcium spike trains of individual neurons from the calcium imaging data in an automatic fashion. Two algorithms were developed to decompose the imaging data into the activity of individual cells and subsequently detect calcium spikes from each neuronal signal. Applying our method to dense networks in dissociated cultures, we were able to obtain the calcium spike trains of [Formula: see text] neurons in a few minutes. Further analyses using these data permitted the quantification of neuronal responses to chemical stimuli as well as functional mapping of spatiotemporal patterns in neuronal firing within the spontaneous, synchronous activity of a large network. These results demonstrate that our method not only automates time-consuming, labor-intensive tasks in the analysis of neural data obtained using optical recording techniques but also provides a systematic way to visualize and quantify the collective dynamics of a network in terms of its cellular elements.


Placental uptake and transport of ACP, a neutral nonmetabolizable amino acid, in an ovine model of fetal growth restriction.
Reductions in fetal plasma concentrations of certain amino acids and reduced amino acid transport in vesicle studies suggest impaired placental amino acid transport in human fetal growth restriction (FGR). In the present study, we tested the hypothesis of an impairment in amino acid transport in the ovine model of hyperthermia-induced FGR by determining transplacental and placental retention and total placental clearance of a branched-chain amino acid (BCAA) analog, the nonmetabolizable neutral amino acid aminocyclopentane-1-carboxylic acid (ACP), in singleton control (C) and FGR pregnancies at 135 days gestation age (dGA; term 147 dGA). At study, based on the severity of the placental dysfunction, FGR fetuses were allocated to severe (sFGR, n = 6) and moderate FGR (mFGR, n = 4) groups. Fetal (C, 3,801.91 +/- 156.83; mFGR, 2,911.33 +/- 181.35; sFGR, 1,795.99 +/- 238.85 g; P < 0.05) and placental weights (C, 414.38 +/- 38.35; mFGR, 306.23 +/- 32.41; sFGR, 165.64 +/- 28.25 g; P < 0.05) were reduced. Transplacental and total placental clearances of ACP per 100 g placenta were significantly reduced in the sFGR but not in the mFGR group, whereas placental retention clearances were unaltered. These data indicate that both entry of ACP into the placenta and movement from the placenta into fetal circulation are impaired in severe ovine FGR and support the hypothesis of impaired placental BCAA transport in severe human FGR.


Positioning Commercial Pedometers to Measure Activity of Older Adults with Slow Gait: At the Wrist or at the Waist?
Sedentary behaviour is a major risk factor for chronic disease morbidity and mortality in aging. Measuring people activity through devices such as pedometers is a recognized intervention to motivate them for more physical activity. However, the feedback provided by these devices must be accurate in order to avoid overtraining and keep users' motivation alive. If the accuracy of pedometers has been validated for healthy people, their lack of accuracy for elderly people walking at slower pace has been reported in several studies. The emergence on the consumer's market of new devices that can be worn indifferently at the wrist or at the waist raises once more this concern. In order to evaluate whether pedometers' location influences their accuracy, we have tested three pedometers at different locations, and for several paces in a comparative study. Beyond confirming the decrease of pedometers' accuracy with speed reduction, our study reveals that pedometers should be worn at the waist rather than at the wrist. This leads us to recommend wearing pedometers at the waist when monitoring population with reduced mobility.


First Report of Black Stem Caused by Botryosporium longibrachiatum on Sweet Basil in Korea.
Sweet basil, Ocimum basilicum L., is cultivated mainly for fresh consumption in Korea. In March 2009, in Icheon, Korea, several dozen plants showing symptoms of black stems were found in an organic farm that used polyethylene tunnels for production. The black stems were usually covered with a fungus that gave the appearance of hoar-frost on the stems, especially when plants were grown under a cool and humid environment. According to the farmer, black stems appear during the winter season of November to March when the tunnels were mostly closed. The relative humidity (RH) during that period was around 100% every night due to poor ventilation. Beginning the middle of April when both sides of the tunnels were open, providing good ventilation, no further disease development was observed. The fungus on the stems had an elongate, upright conidiophore, reaching 5 mm in length. At intervals along its length, the main axis of conidiophores produced lateral fertile branches in acropetal succession. Each lateral branch terminated in a cluster of four or five ampullae. Conidia were hyaline, oval, and 5.5 to 9.5 × 3.5 to 6 μm. The fungus was non-pigmented and colonies on potato dextrose agar were chalk white. Morphological and cultural characteristics of the fungus were consistent with the previous reports of Botryosporium longibrachiatum (Oudem.) Maire (3,4). Voucher specimens (n = 4) were housed at Korea University Herbarium (KUS). An isolate from KUS-F24010 was deposited in the Korean Agricultural Culture Collection (Accession No. KACC44849) and used for molecular analysis and pathogenicity tests. The complete internal transcribed spacer (ITS) region of rDNA was amplified with the primers ITS1/ITS4 and sequenced. The resulting sequence of 592 bp was deposited in GenBank (Accession No. JX666334). A BLAST search in GenBank showed that there was no comparable sequence of B. longibrachiatum and thus this was the first ITS sequence for the species submitted in GenBank. To confirm the pathogenicity, colonized mycelial plugs (3 mm in diameter) from 10-day-old PDA cultures were placed onto the stem apices (n = 10) of 2-month-old sweet basil pot plants, which were topped as normally harvested. Control plants were inoculated with uncolonized agar plugs. All plants were incubated at 22 ± 2°C in a humidified chamber with a 12-h photoperiod for 48 h, and then maintained in a greenhouse (22 ± 2°C). Three to four days after inoculation, necrotic lesions developed around the points of inoculation on all stems and expanded downwards, leading to black stems covered with the hoar-frost like fungus after 14 days. B. longibrachiatum was successfully reisolated from all inoculated stems, while control plants remained symptomless. The pathogenicity test was conducted twice with the same result. The association of B. longibrachiatum and sweet basil was previously reported (4). Several other plants including burley tobacco are also reported to be infected by this fungus (1,2). To our knowledge, this is the first etiological report of B. longibrachiatum on sweet basil globally as well as in Korea. References: (1) T. R. Anderson. Plant Dis. 67:1158, 1983. (2) D. F. Farr and A. Y. Rossman. Fungal Databases. Systematic Mycology & Microbiology Laboratory, ARS, USDA. Retrieved from http://nt.ars-grin.gov/fungaldatabases/ , September 7, 2012. (3) C. V. Subramanian. Hyphomycetes. Indian Council of Agricultural Research, New Delhi, India, 1971. (4) H. T. Tribe and R. W. S. Weber. Mycologist 15:158, 2001.


Addition of clidinium-C to the 14-day proton-pump inhibitor-based triple therapy for Helicobacter pylori eradication.
Triple therapy with a proton pump inhibitor and two antibiotics in Helicobacter pylori (HP) eradication is widely accepted, but this combination fails in a considerable number of cases. The aim of this study was to assess the effect of clidinium-C addition on HP eradication and to investigate the efficacy and safety of clidinium-C in prevention of drugs' side effects. A total of 200 histopathologically confirmed HP positive peptic ulcer enrolled in this study which were randomly assigned to two treatment groups: OAC (20 mg omeprazole bid, 1000 mg amoxicillin bid and 500 mg clarithromycin bid) and OAC + clidinium-C. The effect of treatment and adverse effects were compared 6 weeks after completion of treatment. A13C-urea breath test was performed to confirm HP eradication. A total of 184 patients (90 in group A and 94 in group B) completed the treatment protocols. HP eradication was achieved in 71.1% in OAC versus 72.3% in OCA+clidinium-C, (P=0.73). The frequencies of abdominal pain and stool abnormality, among the side effects recorded during the therapy period, were significantly lower in group B (OCA+clidinium-C) (P=0.01 and P=0.001, respectively). Addition of clidinium-C to OCA triple therapy decreases abdominal pain and frequency of stool abnormalities without affecting HP eradication rate. Based on these findings addition of clidinium-C may increase patient's compliance.


Mutations in the rrs A1401G gene and phenotypic resistance to amikacin and capreomycin in Mycobacterium tuberculosis.
The aminoglycosides amikacin (AMK)/kanamycin (KAN) and the cyclic polypeptide capreomycin (CAP) are important injectable drugs in the treatment of multidrug-resistant tuberculosis. Cross-resistance among these drug classes occurs and information on the minimum inhibitory concentrations (MICs), above the normal wild-type distribution, may be useful in identifying isolates that are still accessible to drug treatment. Isolates from the Eastern Cape Province of South Africa were subjected to DNA sequencing of the rrs (1400-1500 region) and tlyA genes. Sequencing data were compared with (i) conventional susceptibility testing at standard critical concentrations (CCs) on Middlebrook 7H11 agar and (ii) MGIT 960-based MIC determinations to assess the presence of AMK- and CAP-resistant mutants. Isolates with an rrs A1401G mutation showed high-level resistance to AMK (>20 mg/L) and decreased phenotypic susceptibility to CAP (MICs 10-15 mg/L). The MICs of CAP were below the bioavailability of the drug, which suggests that it may still be effective against multi- or extensively drug resistant tuberculosis [M(X)DR-TB]. Agar-based CC testing was found to be unreliable for resistance recognition of CAP in particular.


Decision making about mode of delivery among pregnant women who have previously had a caesarean section: A qualitative study.
To explore prospectively women's decision making regarding mode of delivery after a previous caesarean section. The evolution of decision making, women's participation in decision making, and factors affecting decision making. A qualitative study using diaries, observations and semi-structured interviews. Data were analysed thematically from both a longitudinal and a cross-sectional perspective. An antenatal unit in a large teaching hospital in Scotland and participants' homes. Twenty-six women who had previously had a caesarean section for a nonrecurrent cause. Women were influenced by their own previous experiences and expectations, and the final decision on mode of delivery often developed during the course of the pregnancy. Most acknowledged that any decision was provisional and might change if circumstances necessitated. Despite a universal desire to be involved in the process, many women did not participate actively and were uncomfortable with having responsibility for decision making. Feelings about the amount and quality of the information received regarding delivery options varied greatly, with many women wishing for information to be tailored to their individual clinical circumstances and needs. In contrast to the impression created in the media, there was no evidence of clear preferences or strong demands for elective caesarean section. Women who have had a previous caesarean section do not usually have firm ideas about mode of delivery. They look for targeted information and guidance from medical personnel based on their individual circumstances, and some are unhappy with the responsibility of deciding how to deliver in the current pregnancy.


Marginal Zone Lymphoma Complicated by Protein Losing Enteropathy.
Protein losing enteropathy (PLE) refers to excessive intestinal protein loss, resulting in hypoalbuminemia. Underlying pathologies include conditions leading to either reduced intestinal barrier or lymphatic congestion. We describe the case of a patient with long-lasting diffuse abdominal problems and PLE. Repetitive endoscopies were normal with only minimal lymphangiectasia in biopsies. Further evaluations revealed an indolent marginal zone lymphoma with minor bone marrow infiltration. Monotherapy with rituximab decreased bone marrow infiltration of the lymphoma but did not relieve PLE. Additional treatments with steroids, octreotide, a diet devoid of long-chain fatty-acids, and parenteral nutrition did not prevent further clinical deterioration with marked weight loss (23 kg), further reduction in albumin concentrations (nadir 8 g/L), and a pronounced drop in performance status. Finally, immunochemotherapy with rituximab and bendamustine resulted in hematological remission and remarkable clinical improvement. 18 months after therapy the patient remains free of gastrointestinal complaints and has regained his body weight with normal albumin levels. We demonstrate a case of PLE secondary to indolent marginal zone lymphoma. No intestinal pathologies were detected, contrasting a severe and almost lethal clinical course. Immunochemotherapy relieved lymphoma and PLE, suggesting that a high suspicion of lymphoma is warranted in otherwise unexplained cases of PLE.


Seedless assembly of colloidal crystals by inverted micro-fluidic pumping.
We propose a simple seedless approach to assemble millimeter sized monolayer single colloidal crystals with desired orientations at predetermined locations on an unstructured charged substrate. This approach utilizes the millimeter-ranged fluid flow on the bottom glass substrate induced by an ion exchange resin (IEX) fixed on top of the closed sample cell. The fluid flow increases with decreasing height of the sample cell and increasing radius R of the IEX. For a single inverted pump, millimeter sized monolayer single crystals of hexagonal close packing can be obtained. For two closely spaced (D ∼ 4R) pumps, the formed crystals have a predefined orientation along the line connecting the two IEX. By patterning IEX into different structures, colloidal crystals of different complex patterns form. The present method paves a convenient way for fabricating high quality monolayer colloidal crystals for a variety of applications.


Polymeric nanotherapeutics: clinical development and advances in stealth functionalization strategies.
Long-circulating polymeric nanotherapeutics have garnered increasing interest in research and in the clinic owing to their ability to improve the solubility and pharmacokinetics of therapeutic cargoes. Modulation of carrier properties promises more effective drug localization at the disease sites and can lead to enhanced drug safety and efficacy. In the present review, we highlight the current development of polymeric nanotherapeutics in the clinic. In light of the importance of stealth properties in therapeutic nanoparticles, we also review the advances in stealth functionalization strategies and examine the performance of different stealth polymers in the literature. In addition, we discuss the recent development of biologically inspired "self" nanoparticles, which present a differing stealth concept from conventional approaches.


Molecular cloning and comparative analyses of the genomes of simian sarcoma virus and its associated helper virus.
Closed circular viral DNA of simian sarcoma virus (SSV) and simian sarcoma-associated virus (SSAV) obtained from acutely infected dog cells was purified on preparative agarose gels, cleaved with EcoRI, and cloned in the phage lambda vector Charon 21A. The cloned 9-kilobase SSAV genome (B11) has the same restriction map as the bulk of the unintegrated linear SSAV DNA intermediate. Heteroduplex analysis between an SSV clone (lambda-C60) and an SSAV clone (lambda-B11) showed two substitution loops and one deletion loop. By using detailed restriction enzyme mapping and electron microscopic analysis, we showed that one of the substitution loops corresponds to an inversion of one of the two long terminal repeat units and adjacent cellular sequences in C60. The other substitution loop mapped close to the 3' long terminal repeat. At least part of this region was shown to contain SSV-specific sequences not shared by SSAV. The 1.9-kilobase deletion mapped at 3.5-5.5 kilobases of the linear SSAV genome, corresponding to most, if not all, of the pol gene.


AudioChip: A Deep Phenotyping Approach for Deconstructing and Quantifying Audiological Phenotypes of Self-Reported Speech Perception Difficulties.
About 15% of U.S. adults report speech perception difficulties despite showing normal audiograms. Recent research suggests that genetic factors might influence the phenotypic spectrum of speech perception difficulties. The primary objective of the present study was to describe a conceptual framework of a deep phenotyping method, referred to as AudioChipping, for deconstructing and quantifying complex audiometric phenotypes. In a sample of 70 females 18 to 35 years of age with normal audiograms (from 250 to 8000 Hz), the study measured behavioral hearing thresholds (250 to 16,000 Hz), distortion product otoacoustic emissions (1000 to 16,000 Hz), click-evoked auditory brainstem responses (ABR), complex ABR (cABR), QuickSIN, dichotic digit test score, loudness discomfort level, and noise exposure background. The speech perception difficulties were evaluated using the Speech, Spatial, and Quality of Hearing Scale-12-item version (SSQ). A multiple linear regression model was used to determine the relationship between SSQ scores and audiometric measures. Participants were categorized into three groups (i.e., high, mid, and low) using the SSQ scores before performing the clustering analysis. Audiometric measures were normalized and standardized before performing unsupervised k-means clustering to generate AudioChip. The results showed that SSQ and noise exposure background exhibited a significant negative correlation. ABR wave I amplitude, cABR offset latency, cABR response morphology, and loudness discomfort level were significant predictors for SSQ scores. These predictors explained about 18% of the variance in the SSQ score. The k-means clustering was used to split the participants into three major groups; one of these clusters revealed 53% of participants with low SSQ. Our study highlighted the relationship between SSQ and auditory coding precision in the auditory brainstem in normal-hearing young females. AudioChip was useful in delineating and quantifying internal homogeneity and heterogeneity in audiometric measures among individuals with a range of SSQ scores. AudioChip could help identify the genotype-phenotype relationship, document longitudinal changes in auditory phenotypes, and pair individuals in case-control groups for the genetic association analysis.


Darwin's "Mr. Arthrobalanus": Sexual Differentiation, Evolutionary Destiny and the Expert Eye of the Beholder.
Darwin's Cirripedia project was an exacting exercise in systematics, as well as an encrypted study of evolution in action. Darwin had a long-standing interest and expertise in marine invertebrates and their sexual arrangements. The surprising and revealing sexual differentiation he would uncover amongst barnacles represented an important step in his understanding of the origins of sexual reproduction. But it would prove difficult to reconcile these findings with his later theorizing. Moreover, the road to discovery was hardly straightforward. Darwin was both helped and hindered by the tacit expectations generated by his transformist theorizing, and had to overcome culturally-embedded assumptions about gender and reproductive roles. Significant observational backtracking was required to correct several oversights and misapprehensions, none more so than those relating to the chronically misunderstood "Mr. Arthrobalanus." With careful attention to chronology, this paper highlights some curious and overlooked aspects of Darwin's epic project.


Dopaminergic innervation of the human subventricular zone: a comparison between Huntington's chorea and Parkinson's disease.
The subventricular zone retains its neurogenic capacity throughout life and, as such, is often considered a potential source for endogenous repair in neurodegenerative disorders. Because dopamine is believed to stimulate adult neurogenesis, we looked for possible variations in the dopaminergic innervation of the subventricular zone between cases of Huntington's chorea and Parkinson's diseases. Antibodies against tyrosine hydroxylase (TH) and proliferating cell nuclear antigen (PCNA) were used as specific markers of dopaminergic axons and cell proliferating activity, respectively. The immunohistochemical approach was applied to postmortem tissue from 2 Parkinson's disease cases, 4 Huntington's disease cases, along with age-matched controls. The immunostaining was revealed with either diaminobenzidine or fluorescent-conjugated secondary antibodies. Optical density measurements were made along the entire dorso-ventral extent of the caudate nucleus. An intense TH+ zone was detected along the ventricular border of the caudate nucleus in Huntington's disease cases, but not in patients with Parkinson's disease or age-matched controls. This thin (287±38 μm) paraventricular zone was composed of numerous small and densely packed dopamine axon varicosities and overlapped the deep layers of the subventricular zone. Its immunoreactivity was 47±8% more intense than that of adjacent striatal areas. The dopamine innervation of the subventricular zone is strikingly massive in Huntington's chorea compared to Parkinson's disease, a finding that concurs with the marked increase in neurogenesis noted in the subventricular zone of Huntington's disease patients. This finding suggests that dopamine plays a crucial role in mechanisms designed to compensate for the massive striatal neuronal losses that occur in Huntington's disease.


Vitamin D receptor amounts across different segments of the gastrointestinal tract in Brown Swiss and Holstein Frisean cows of different age.
During different stages of lactation, different requirements of calcium have to be met depending on the milk amount. Vitamin D receptors (VDR) regulate calcium homeostasis by increasing the entry of Ca into blood from bone stores and dietary sources. The purpose of this study was to investigate if age and breed of cows influence VDR amounts across different segments of the gastrointestinal tract. Thirty-six cows were used (18 Brown Swiss, 18 Holstein Friesan, both > 5.5 years or < 4.5 years). Tissue specimens of the intestines were collected from the cows. Formaldehyde-fixed and microwave-treated paraffin sections were used for VDR immunohistochemistry employing a biotinylated monoclonal rat antibody and streptavidin peroxidase technique. The results showed that nuclei and cytoplasm of enterocytes stained positively for VDRs. Strongest immunoreactions were observed in intermediate and basal glandular cells. No significant differences were observed between the different groups. Vitamin D receptors immunoreactivities were prominent in duodenal mucosa, lower in jejunum and in colon, decreased further in ileum and were lowest in caecum. Decreases in number of positively marked cells and staining intensities resulted in reduced immunoreactions. The results of this study indicate that VDR are highly expressed at the site of maximal intestinal calcium absorption. No significant influence of age and breed was observed. The animals used were not in a negative Ca balance. The cows were all in the stage of late or mid lactation. During these periods, the Ca requirements are low and the diets are high in Ca concentration; and the animals are adapted to these circumstances. Passive absorption in adult animals seems to dominate when Ca intake is adequate or high. The active absorption may play a considerably more significant role during the peripartal period, when Ca homeostatic mechanisms are challenged because of tremendous Ca demand at the initiation of lactation.


Restriction of Nonpermissive RUNX3 Protein Expression in T Lymphocytes by the Kozak Sequence.
The transcription factor Runx3 promotes differentiation of naive CD4(+) T cells into type-1 effector T (TH1) cells at the expense of TH2. TH1 cells as well as CD8(+) T cells express a subset-specific Runx3 transcript from a distal promoter, which is necessary for high protein expression. However, all T cell subsets, including naive CD4(+) T cells and TH2 cells, express a distinct transcript of Runx3 that is derived from a proximal promoter and that produces functional protein in neurons. Therefore, accumulation of RUNX3 protein generated from the proximal transcript needs to be repressed at the posttranscriptional level to preserve CD4(+) T cell capability of differentiating into TH2 cells. In this article, we show that expression of RUNX3 protein from the proximal Runx3 transcript is blocked at the level of translational initiation in T cells. A coding sequence for the proximal Runx3 mRNA is preceded by a nonoptimal context sequence for translational initiation, known as the Kozak sequence, and thus generates protein at low efficiencies and with multiple alternative translational initiations. Editing the endogenous initiation context to an "optimal" Kozak sequence in a human T cell line resulted in enhanced translation of a single RUNX3 protein derived from the proximal transcript. Furthermore, RUNX3 protein represses transcription from the proximal promoter in T cells. These results suggest that nonpermissive expression of RUNX3 protein is restricted at the translational level, and that the repression is further enforced by a transcriptional regulation for maintenance of diverse developmental plasticity of T cells for different effector subsets.


Blocking of fimbria-mediated adherence of Haemophilus influenzae by sialyl gangliosides.
The structure of the receptor for the fimbriae of Haemophilus influenzae on human oropharyngeal epithelial cells and erythrocytes was determined in inhibition experiments with various sugars, glycolipids, and glycoproteins. Of 30 monosaccharides and disaccharides at a concentration of 0.1 M and of 3 polysaccharides at a concentration of 1 mg/ml, none inhibited fimbria-specific adherence and hemagglutination. Inhibition was obtained with gangliosides GM1, GM2, GM3, and GD1a in nanomolar concentrations, whereas the asialo derivative of GM1, sialyl-lactose, and sialoglycoproteins were poor inhibitors. These findings indicate that sialyl-lactosylceramide (GM3) is the minimal structure for the fimbria-dependent binding of H. influenzae to its receptor on oropharyngeal epithelial cells and erythrocytes. As is the case with GM2, substitution of GM3 with N-acetylgalactosamine makes the molecule a 10-fold-better receptor analog.


SAR pattern perturbations from resonance effects in water bolus layers used with superficial microwave hyperthermia applicators.
This study examines the effect of various thickness water bolus coupling layers on the SAR (Specific Absorption Rate) patterns from Dual Concentric Conductor (DCC) based Conformal Microwave Array (CMA) superficial hyperthermia applicators. Previous theory has suggested that water bolus coupling layers can be considered as a dielectric resonator; therefore, it is possible for the impinging electric field to stimulate volume oscillations and surface wave oscillations inside the water bolus. These spurious oscillations will destructively or constructively interact with the impinging electric field to cause a perturbation of the applicator SAR pattern. An experiment was designed which consisted of mapping the electric field produced by a four element DCC CMA applicator in liquid muscle phantom at depths of 5 and 10mm in front of four different thickness water boli; 0 (no bolus) 4, 9 and 13mm. Using the Finite Difference Time Domain (FDTD) method, SAR distributions were calculated for similar test cases. It was found that for water bolus thicknesses of 9mm or greater, there is a marked perturbation of both experimental and theoretical SAR distributions. It is believed that this perturbation is experimental confirmation of the volume and surface wave oscillation theory described by previous investigators.


Does routine symptom screening with ESAS decrease ED visits in breast cancer patients undergoing adjuvant chemotherapy?
In 2007, the provincial cancer agency in Ontario, Canada initiated a wide-scale program to screen for symptoms in the cancer population using the Edmonton Symptom Assessment Scale (ESAS). The purpose of this study is to evaluate the impact of screening with ESAS on emergency department (ED) visit rates in women with breast cancer receiving adjuvant chemotherapy. This retrospective cohort study used linked administrative health care data from across the province of Ontario, Canada. The cohort included all women aged ≥18 who were diagnosed with stage I-III breast cancer between January 2007 and December 2009 and received adjuvant chemotherapy within 6 months of diagnosis. Using an adjusted recurrent event model, we examined the association of screening with ESAS at a clinic visit on the ED visit rate. The relative rate of ED visits was 0.57 when prior ESAS screening occurred compared to when it did not. The relative rate of ED visits was 0.83 when the prior number of ESAS screens was modeled as a continuous variable. Alternatively stated, the rate of ED visits was 43 % lower among patients previously screened with ESAS compared to those not previously screened. For each additional prior ESAS assessment, there was a 17 % decreased rate of ED visits. Our results demonstrate that screening with ESAS is associated with decreased ED visits. To our knowledge, this is the first report on the effectiveness of routinely documenting a patient reported outcome on ED visits, in a real-world setting.


[Justification for subtotal esophagectomy in late spontaneous esophageal rupture].
A patient is presented who was operated for an intestinal obstruction and developed in the immediate postoperative period Boerhaave's syndrome. Subtotal esophagectomy with bipolar exclusion was performed. We discuss the advantages of radical surgery, even in advanced cases, if the size of the lesion justifies it, as compared to more conservative therapeutic attitudes.


Aged garlic extract retards progression of coronary artery calcification.
Prospective epidemiologic studies have identified several risk factors for heart disease, and most can be the target of risk reduction interventions. The most widely recognized risk factors for atherosclerotic cardiovascular disease (ASCVD) include age, gender, cigarette smoking, sedentary lifestyle, elevated LDL, reduced HDL, hypertension, and diabetes. The consistency of associations between these factors and ASCVD risk across populations is substantial. Our understanding of the pathogenesis and etiology of coronary ASCVD, as well as its clinical implications, has grown tremendously over the past 20 y. The role garlic might play in treating ASCVD has been postulated for many years, but until recently no studies on garlic's ability to inhibit the atherosclerotic process have been reported. A pilot study evaluating coronary artery calcification and the effect of garlic therapy in a group of patients who were also on statin therapy suggested incremental benefits. The implications of this study must be put in context of the potential importance of early atherosclerosis detection and prevention.


Skeletal abnormalities in humpback whales Megaptera novaeangliae stranded in the Brazilian breeding ground.
Skeletal tissues of 49 humpback whales Megaptera novaeangliae that stranded between 2002 and 2011 along the Abrolhos Bank seashore and its adjacent waters in Brazil were studied. Twelve (24.5%) animals presented pathological changes in one or more bones. Degenerative changes and developmental malformations were most frequent (10.2% each), followed by inflammatory/infectious and traumatic lesions (8.2% each). Infectious diseases led to severe lesions of the caudal vertebrae of 2 whales. In one of these individuals, the lesions involved 6 caudal vertebrae, leading to ankylosis of 3 vertebrae. Degenerative changes were observed in the vertebral columns of 3 animals, involving the joints of 13 ribs of 1 individual, and in the humerus of 1 whale. Traumatic lesions, such as osseous callus in the ribs, were observed in 4 animals. In 1 whale, the rib showed severe osteomyelitis, possibly resulting from the infection of multiple fractures. Developmental abnormalities such as spina bifida on 3 cervical vertebrae of 1 whale, fusion of spinal processes on thoracic vertebrae of 1 individual and fusion of the first 2 ribs unilaterally or bilaterally in 4 animals were found. Chronic infectious conditions found in the axial skeleton may have restrained spinal mobility and had detrimental effects on the general health of the animals, contributing to stranding and death. To our knowledge, this is the first systematic study on skeletal lesions in stranded humpback whales.


Impact of human MLL/COMPASS and polycomb complexes on the DNA methylome.
The correlation between DNA methylation and a subset of histone post-translational modifications (positive and negative) has hinted at an underlying regulatory crosstalk between histone marks and DNA methylation in patterning the human DNA methylome, an idea further supported by corresponding alterations to both histone marks and DNA methylation during malignant transformation. This study investigated the framework by which histone marks influence DNA methylation at a genome-wide level. Using RNAi in a pluripotent human embryonic carcinoma cell line we depleted essential components of the MLL/COMPASS, polycomb repressive complex 2 (PRC2), and PRC1 histone modifying complexes that establish, respectively, the post-translational modifications H3K4me3, H3K27me3, and H2AK119ub, and assayed the impact of the subsequent depletion of these marks on the DNA methylome. Absence of H2AK119ub resulted predominantly in hypomethylation across the genome. Depletion of H3K4me3 and, surprisingly, H3K27me3 caused CpG island hypermethylation at a subset of loci. Intriguingly, many promoters were co-regulated by all three histone marks, becoming hypermethylated with loss of H3K4me3 or H3K27me3 and hypomethylated with depletion of H2AK119ub, and many of these co-regulated loci were among those commonly targeted for aberrant hypermethylation in cancer. Taken together, our results elucidate novel roles for polycomb and MLL/COMPASS in regulating DNA methylation and define targets of this regulation.


Targeted overexpression of ornithine decarboxylase enhances beta-adrenergic agonist-induced cardiac hypertrophy.
These studies were designed to determine the consequences of constitutive overexpression of ornithine decarboxylase (ODC) in the heart. Induction of ODC is known to occur in response to agents that induce cardiac hypertrophy. However, it is not known whether high ODC levels are sufficient for the development of a hypertrophic phenotype. Transgenic mice were generated with cardiac-specific expression of a stable ODC protein using the alpha-myosin heavy-chain promoter. Founder lines with >1000-fold overexpression of ODC in the heart were established, resulting in a 50-fold overaccumulation of putrescine, 4-fold elevation in spermidine, a slight increase in spermine and accumulation of large amounts of cadaverine compared with littermate controls. Despite these significant alterations in polyamines, myocardial hypertrophy, as measured by ratio of heart to body weight, did not develop, although atrial natriuretic factor RNA was slightly elevated in transgenic ventricles. However, stimulation of beta-adrenergic signalling by isoproterenol resulted in severe hypertrophy and even death in ODC-overexpressing mice without further altering polyamine levels, compared with only a mild hypertrophy in littermates. When beta1-adrenergic stimulation was blocked by simultaneous treatment with isoproterenol and the beta1 antagonist atenolol, a significant, although reduced, hypertrophy was still present in the hearts of transgenic mice, suggesting that both beta1 and beta2 adrenergic receptors contribute to the hypertrophic phenotype. Therefore these mice provide a model to study the in vivo co-operativity between high ODC activity and activation of other pathways leading to hypertrophy in the heart.


Natural history of drusenoid pigment epithelial detachment in age-related macular degeneration: Age-Related Eye Disease Study Report No. 28.
To describe the natural history of eyes with drusenoid pigment epithelial detachments (DPEDs) associated with age-related macular degeneration (AMD). Multicenter, clinic-based, prospective cohort study. Among 4757 participants enrolled in the Age-Related Eye Disease Study (AREDS), 255 were identified as having DPED in at least 1 eye and having 5 or more years of follow-up after the initial detection of the DPED. Baseline and annual fundus photographs were evaluated for the evolution of the fundus features and the development of advanced AMD in the forms of central geographic atrophy (CGA) or neovascular (NV) AMD. Kaplan-Meier analyses of progression to advanced AMD and of moderate vision loss (> or =15 letters compared with baseline) were performed. Rate of progression to advanced AMD and change in visual acuity from baseline (in terms of mean letters lost and proportion losing > or =15 letters). A total of 311 eyes (from 255 participants) with DPED were followed for a median follow-up time of 8 years subsequent to the initial detection of a DPED. Of the 282 eyes that did not have advanced AMD at baseline, advanced AMD developed within 5 years in 119 eyes (42%) (19% progressing to CGA and 23% progressing to NV-AMD). In the remaining eyes that did not develop advanced AMD (n=163), progressive fundus changes, typified by the development of calcified drusen and pigmentary changes, were detected. Visual decline was prominent among study eyes, with approximately 40% of all eyes decreasing in visual acuity by > or =15 letters at 5 years follow-up. Mean visual acuity decreased from 76 letters ( approximately 20/30) at baseline to 61 letters ( approximately 20/60) at 5 years. Five-year decreases in mean visual acuity averaged 26 letters for eyes progressing to advanced AMD and 8 letters for non-progressing eyes. The natural history of eyes containing DPED is characterized by a high rate of progression to both CGA and NV-AMD. Among eyes not progressing to advanced AMD, progressive development of pigmentary changes and calcified drusen were observed. Decline of visual acuity is a common outcome, with or without progression to advanced forms of AMD.


Genomic counter-stress changes induced by the relaxation response.
Mind-body practices that elicit the relaxation response (RR) have been used worldwide for millennia to prevent and treat disease. The RR is characterized by decreased oxygen consumption, increased exhaled nitric oxide, and reduced psychological distress. It is believed to be the counterpart of the stress response that exhibits a distinct pattern of physiology and transcriptional profile. We hypothesized that RR elicitation results in characteristic gene expression changes that can be used to measure physiological responses elicited by the RR in an unbiased fashion. We assessed whole blood transcriptional profiles in 19 healthy, long-term practitioners of daily RR practice (group M), 19 healthy controls (group N(1)), and 20 N(1) individuals who completed 8 weeks of RR training (group N(2)). 2209 genes were differentially expressed in group M relative to group N(1) (p<0.05) and 1561 genes in group N(2) compared to group N(1) (p<0.05). Importantly, 433 (p<10(-10)) of 2209 and 1561 differentially expressed genes were shared among long-term (M) and short-term practitioners (N(2)). Gene ontology and gene set enrichment analyses revealed significant alterations in cellular metabolism, oxidative phosphorylation, generation of reactive oxygen species and response to oxidative stress in long-term and short-term practitioners of daily RR practice that may counteract cellular damage related to chronic psychological stress. A significant number of genes and pathways were confirmed in an independent validation set containing 5 N(1) controls, 5 N(2) short-term and 6 M long-term practitioners. This study provides the first compelling evidence that the RR elicits specific gene expression changes in short-term and long-term practitioners. Our results suggest consistent and constitutive changes in gene expression resulting from RR may relate to long term physiological effects. Our study may stimulate new investigations into applying transcriptional profiling for accurately measuring RR and stress related responses in multiple disease settings.


Dynamics of marine sessile organisms with space-limited growth and recruitment: application to corals.
We study a model for the community dynamics of marine sessile organisms with space limitation both in recruitment and in growth. We consider an open population in which recruits are supplied from a pelagic pool of larvae produced by adults in distant habitats. Assumptions are: the larval settlement rate is proportional to the amount of free space and to the abundance of larvae in the water column. The growth rate of settled individuals increases with the fraction of free space within the local habitat. We study the competition between two morphotypes with different rates of recruitment, growth, and mortality. When adult mortality is low, following a major disturbance that creates bare patch, the space is quickly filled by larval recruitment and adult growth. Then the morphotype composition changes slowly and converges to the equilibrium that is strongly affected by mortality. We also examine several other limiting cases in which one of the three demographic processes occurs either very slowly or very quickly. Based on the model behavior, we discuss the possible factors responsible for the spatial variation in the morphotype composition observed in coral communities. The dominance of branching corals in protected sites can be explained by their faster growth than tabular corals. The dominance of tabular corals in exposed sites can be explained either by lower mortality or by faster recruitment than branching corals.


Quality control of routine sampling in chemical analysis.
In sampling terminology, the 'target' is the mass of material that the customer needs to characterise, usually to support a decision about its acceptability or price. For most such materials there is an established sampling protocol regarded as fit for purpose. This is mainly because all targets are actually or potentially heterogeneous. But even when a protocol is followed exactly, repeat samples differ in composition from each other and from the target. Moreover, there is a distinct possibility that the target may be atypically heterogeneous. These circumstances, particularly the last, mean that a sample may not be fit for purpose, even when the sampling is executed strictly according to the protocol. And, of course, there is always the possibility that the sample was not collected according to the protocol! As either of these conditions might give rise to a suboptimal decision, it would be helpful to know when such an event occurred. That would call for some form of quality control on the sampling process.


European ancestry decreases the risk of early onset, severe lupus nephritis in a single center, multiethnic pediatric lupus inception cohort.
To determine whether pediatric SLE patients without European ancestry are at higher risk for development of severe lupus nephritis (ISN/RPS class III, IV or V). Ninety-eight of 101 patients with pediatric SLE (age <18 years at diagnosis) were enrolled. Race/ethnicity of four grandparents, socioeconomic status (SES) and language proficiency were collected. The primary outcome was time to development of severe lupus nephritis. Based on patient report of four grandparent ancestry, 29% had at least one grandparent of European ancestry (14% had all four grandparents of European ancestry). Patients without European ancestry were 46% Hispanic, 47% Asian, and 3% African American. In the entire 98 patient cohort, 12% had ≥3 different ancestries. Patients without European ancestry had significantly lower SES levels and English proficiency. There was no significant difference between patients with or without European ancestry in duration of SLE, age of onset, and lag time between symptoms and diagnosis. Patients with at least one grandparent of European ancestry had a decreased risk of developing severe lupus nephritis, which remained significant after controlling for age, gender, SES and English proficiency (hazard ratio 0.4, 95% confidence interval 0.2-0.9). This study demonstrates that presence of at least one grandparent of European ancestry decreases the risk of severe lupus nephritis, a finding that is not explained by measurable socioeconomic differences and language barriers.


Antibody-modified conduits for highly selective cytokine elimination from blood.
Cytokines play an important role in dysregulated immune responses to infection, pancreatitis, ischemia/reperfusion injury, burns, hemorrhage, cardiopulmonary bypass, trauma, and many other diseases. Moreover, the imbalance between inflammatory and antiinflammatory cytokines can have deleterious effects. Here, we demonstrated highly selective blood-filtering devices - antibody-modified conduits (AMCs) - that selectively eliminate multiple specific deleterious cytokines in vitro. AMCs functionalized with antibodies against human vascular endothelial growth factor A or tumor necrosis factor α (TNF-α) selectively eliminated the target cytokines from human blood in vitro and maintained them in reduced states even in the face of ongoing infusion at supraphysiologic rates. We characterized the variables that determine AMC performance, using anti-human TNF-α AMCs to eliminate recombinant human TNF-α. Finally, we demonstrated selective cytokine elimination in vivo by filtering interleukin 1 β from rats with lipopolysaccharide-induced hypercytokinemia.


Composition of phospholipid fatty acids in erythrocyte membranes of children with chronic juvenile arthritis: clinical and biochemical correlations.
Systemic diseases of connective tissue, including chronic juvenile arthritis are associated with a number of metabolic disorders such as e.g. lipid disturbances. The purpose of the present work was to analyse the composition of fatty acids in erythrocyte phospholipids of children with juvenile chronic arthritis and to determine a correlation between the composition of these acids and patients' clinical status. The study was conducted on 47 children with juvenile chronic arthritis (jca) and 29 healthy subjects. The following fractions of phospholipids were obtained with the help of thin-layer chromatography: phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidyloinositol, cardiolipin, sphingolipin. Fatty acids were analysed with the use of gas chromatograph (Hewlett-Packard 5890). Saturated fatty acids as well as mono- and polyunsaturated (n-3 and n-6) fatty acids were identified. The decrease in the percentage of linolenic acid, PUFA n-6 and PUFA n-3 was found in all the phospholipid fractions in children with jca when compared with control group. There was a concurrent increase in saturated fatty acids, mainly stearic and palmitic acids. The differences in the distribution of fatty acids in erythrocyte phospholipids were observed at early stage of the disease and they became more conspicuous as inflammatory process proceeded.


Emerging and resistant infections.
The lungs are a major target for infection and a key battleground in the fight against the development of antimicrobial drug-resistant pathogens. Ventilator-associated pneumonia (VAP) is associated with mortality rates of 24-50%. The optimal duration of antibiotic therapy against VAP is unknown, but prolonged courses are associated with the emergence of bacterial resistance. De-escalation strategies in which treatment is discontinued based on signs of clinical resolution, fixed durations of therapy (generally 7-8 d), or serum procalcitonin responses have been shown to decrease antibiotic consumption. Outcomes are comparable to longer treatment courses, with the possible exception of VAP due to nonfermenting, gram-negative bacilli such as Pseudomonas aeruginosa. Staphylococcus aureus is a leading cause of VAP and other infections. Outcomes after S. aureus infection are shaped by the interplay between environmental, bacterial, and host genetic factors. It is increasingly clear that mechanisms of pathogenesis vary in different types of S. aureus infections. Genome-scale studies of S. aureus strains, host responses, and host genetics are redefining our understanding of the pathogenic mechanisms underlying VAP. Genome-sequencing technologies are also revolutionizing our understanding of the molecular epidemiology, evolution, and transmission of influenza. Deep sequencing using next-generation technology platforms is defining the remarkable genetic diversity of influenza strains within infected hosts. Investigators have demonstrated that antiviral drug-resistant influenza may be present prior to the initiation of treatment. Moreover, drug-resistant minor variant influenza strains can be transmitted from person to person in the absence of selection pressure. Studies of lung infections and the causative pathogens will remain at the cutting edge of clinical and basic medical research.


Management of severe stifle trauma: 1. Stifle luxation.
Traumatic stifle joint luxation is an uncommon but severe injury. There is usually rupture of several stabilising structures of the joint including the cruciate ligaments, collateral ligaments, joint capsule and menisci. Successful management of this condition requires good anatomical knowledge and repair or replacement of all damaged structures to achieve adequate joint reduction and stability. Better understanding of the treatment options available will aid clinical decision-making. Due to the significant joint instability associated with these injuries, surgical repair is challenging. The use of a temporary transarticular pin to hold the stifle joint in anatomic reduction greatly aids ligament repair or replacement. Postoperative joint immobilisation has traditionally been recommended to protect the primary repair and aid periarticular fibrosis, but prolonged immobilisation can have deleterious long-term effects on the joint. Thus recommendations for the duration of postoperative immobilisation vary between 2 and 6 weeks. Also, due to their independent, outdoor lifestyle, affected cats may have been involved in a significant trauma with important concurrent injuries that need to be addressed prior to the orthopaedic repair. Published data is limited, with reports including only a small number of cats. The information and recommendations in this article have therefore been drawn from the available literature, the authors' experience and preliminary data from an ongoing multicentre retrospective study (unpublished). The aims of this article are to give the reader as thorough a summary as possible of the diagnosis, treatment, outcome and complications of traumatic stifle luxation.


Nonconvulsive seizures are common in children treated with extracorporeal cardiac life support.
The prevalence of electrographic seizures or nonconvulsive status epilepticus and the effect of such seizures in children treated with extracorporeal cardiac life support are not known. We investigated the occurrence of electrographic abnormalities, including asymmetries in amplitude or frequency of the background rhythm and interictal activity in children undergoing extracorporeal cardiac life support and their association with seizures. We compared mortality and radiologic evidence of neurologic injury between patients with seizures and those without seizures. Retrospective review of medical records and the Extracorporeal Life Support Organization database. PICU at a single institution. All pediatric patients up to 18 years old, who had extracorporeal cardiac life support and continuous electroencephalography monitoring between the years 2006 and 2011. None. Nineteen patients treated with extracorporeal cardiac life support underwent continuous electroencephalography monitoring. Seizures occurred in four patients (21%) and were exclusively nonconvulsive in three patients. Two of these four patients had nonconvulsive status epilepticus. Interictal discharges on electroencephalography were associated with seizures (odds ratio, 19.5 [95% CI, 1.29-292.75]; p = 0.03). Only 50% of the seizures were detected in the first hour of monitoring, whereas all seizures were detected within 24 hours. All patients with seizures had structural abnormalities seen on neuroimaging. Seizures were not significantly associated with increased mortality. To evaluate for ascertainment bias, we compared outcomes between patients who underwent extracorporeal cardiac life support and received continuous electroencephalography monitoring and those patients who underwent extracorporeal cardiac life support during the study period but did not receive electroencephalography (n = 30). Seizures are common in children during extracorporeal cardiac life support, and most seizures are nonconvulsive. In patients undergoing extracorporeal cardiac life support, clinical features are unreliable indicators of the presence of seizures. The presence of seizures is suggestive of CNS injury. This study is limited by the exclusion of neonates, a feature of the clinical use of electroencephalography at our institution. Although seizures were not associated with increased mortality, further prospective studies in larger populations are needed to assess the long-term morbidity associated with seizures during extracorporeal cardiac life support.


Incidence of lung cancer by histological type among asbestos cement workers in Denmark.
A significant twofold increased risk of lung cancer was found among 8000 men employed in the Danish asbestos cement industry between 1928 and 1984. The histological pattern of 104 lung cancer cases was studied with the aim of evaluating a relation between specific morphological types, duration of employment, and time since first employment. Age, sex, and calendar time specific incidence of morphological subtypes of lung cancer (adenocarcinoma, squamous cell carcinoma, anaplastic carcinoma, and unspecified malignant tumour) for all Danish men were computed from 1943 to 1984, from data routinely collected by the Danish Cancer Registry. Person-years of observation were counted from 15 years after the date of first employment until date of diagnosis of cancer, death, emigration, or the end of follow up on 31 December 1984. Expected numbers of cases were computed by applying person-years at risk to the appropriate incidence rates. Observed numbers were distributed accordingly and the relative risk calculated. The relative risk for adenocarcinoma was 3.31 (observed (O) 24, expected (E) 7.26), for squamous cell carcinoma 1.67 (O, 37, E, 22.12), for anaplastic carcinoma 1.58 (O, 23, E, 14.53), and for unspecified malignant tumour 1.57 (O, 18, E, 11.46). An increased risk by duration of employment and time since first employment was most pronounced for adenocarcinoma. The link between adenocarcinoma and asbestos was confirmed in this, the first study of risk of lung cancer by histological category based on incident cancer cases for a whole population during a 50 year period.


Mortality among asbestos-exposed workers in a railroad workshop.
The mortality experience of a cohort of 3 297 railroad maintenance shopworkers exposed to asbestos was investigated. The study period was 1951-1980, and the vital status was assessed for 99.6% of the men. Individual estimates of cumulative asbestos exposure were based on detailed records on work tasks and divisions. Dust measurements were scanty in earlier decades, and estimates of average fiber levels were therefore based on information on the amount and kind of asbestos used, job descriptions, and interviews with older workers. The overall mortality was lower than expected from the national death rates (standardized mortality ratio = 82). The mortality from lung cancer increased as cumulative exposure increased in consistent dose-response relationships. Employment times of less than 30 years in workplaces with moderate levels of mainly chrysotile asbestos was not associated with any apparent increase in the risk of lung cancer. A subgroup exposed for more than 30 years in workplaces repairing steam engines, where amphiboles were used as well, had a standardized mortality ratio of 192 for lung cancer. This figure may be an underestimation due to healthy worker selection and fewer smokers than normal. The "true" standardized mortality ratio was estimated to be about 300. Five cases of mesothelioma were observed.


Translating Co-Design from Face-to-Face to Online: An Australian Primary Producer Project Conducted during COVID-19.
Primary producers face considerable risks for poor mental health. While this population can be difficult to engage in programs to prevent poor mental health, approaches tailored to reflect the context of primary producers' life and work have been successful. This paper reports on the co-design phase of a project designed to prevent poor mental health for primary producers-specifically, the advantages, challenges and considerations of translating face-to-face co-design methods to an online environment in response to COVID-19 restrictions. The co-design phase drew upon the existing seven-step co-design framework developed by Trischler and colleagues. Online methods were adopted for all steps of the process. This paper models how this co-design approach can work in an online, primary producer context and details key considerations for future initiatives of this type. The development of online co-design methods is an important additional research method for use not only during a pandemic but also when operating with limited resources or geographic constraints. Results demonstrate the following: (i) co-designing online is possible given adequate preparation, training and resource allocation; (ii) "hard to reach" populations can be engaged using online methods providing there is adequate early-stage relationship building; (iii) co-design quality need not be compromised and may be improved when translating to online; and (iv) saved costs and resources associated with online methods can be realigned towards intervention/service creation, promotion and user engagement. Suggestions for extending Trischler and colleagues' model are incorporated.