Proton Beam Therapy for Early Breast Cancer: A Systematic Review and Meta-analysis of Clinical Outcomes.
Adjuvant proton beam therapy (PBT) is increasingly available to patients with breast cancer. It achieves better planned dose distributions than standard photon radiation therapy and therefore may reduce the risks. However, clinical evidence is lacking. A systematic review of clinical outcomes from studies of adjuvant PBT for early breast cancer published in 2000 to 2022 was undertaken. Early breast cancer was defined as when all detected invasive cancer cells are in the breast or nearby lymph nodes and can be removed surgically. Adverse outcomes were summarized quantitatively, and the prevalence of the most common ones were estimated using meta-analysis. Thirty-two studies (1452 patients) reported clinical outcomes after adjuvant PBT for early breast cancer. Median follow-up ranged from 2 to 59 months. There were no published randomized trials comparing PBT with photon radiation therapy. Scattering PBT was delivered in 7 studies (258 patients) starting 2003 to 2015 and scanning PBT in 22 studies (1041 patients) starting 2000 to 2019. Two studies (123 patients) starting 2011 used both PBT types. For 1 study (30 patients), PBT type was unspecified. Adverse events were less severe after scanning than after scattering PBT. They also varied by clinical target. For partial breast PBT, 498 adverse events were reported (8 studies, 358 patients). None were categorized as severe after scanning PBT. For whole breast or chest wall ± regional lymph nodes PBT, 1344 adverse events were reported (19 studies, 933 patients). After scanning PBT, 4% (44/1026) of events were severe. The most prevalent severe outcome after scanning PBT was dermatitis, which occurred in 5.7% (95% confidence interval, 4.2-7.6) of patients. Other severe adverse outcomes included infection, pain, and pneumonitis (each ≤1%). Of the 141 reconstruction events reported (13 studies, 459 patients), the most prevalent after scanning PBT was prosthetic implant removal (34/181, 19%). This is a quantitative summary of all published clinical outcomes after adjuvant PBT for early breast cancer. Ongoing randomized trials will provide information on its longer-term safety compared with standard photon radiation therapy.


Recent advances in transformation optics.
Within the past a few years, transformation optics has emerged as a new research area, since it provides a general methodology and design tool for manipulating electromagnetic waves in a prescribed manner. Using transformation optics, researchers have demonstrated a host of striking phenomena and devices; many of which were only thought possible in science fiction. In this paper, we review the most recent advances in transformation optics. We focus on the theory, design, fabrication and characterization of transformation devices such as the carpet cloak, "Janus" lens and plasmonic cloak at optical frequencies, which allow routing light at the nanoscale. We also provide an outlook of the challenges and future directions in this fascinating area of transformation optics.


Comparative analysis of carbohydrate active enzymes in Clostridium termitidis CT1112 reveals complex carbohydrate degradation ability.
Clostridium termitidis strain CT1112 is an anaerobic, gram positive, mesophilic, cellulolytic bacillus isolated from the gut of the wood-feeding termite, Nasutitermes lujae. It produces biofuels such as hydrogen and ethanol from cellulose, cellobiose, xylan, xylose, glucose, and other sugars, and therefore could be used for biofuel production from biomass through consolidated bioprocessing. The first step in the production of biofuel from biomass by microorganisms is the hydrolysis of complex carbohydrates present in biomass. This is achieved through the presence of a repertoire of secreted or complexed carbohydrate active enzymes (CAZymes), sometimes organized in an extracellular organelle called cellulosome. To assess the ability and understand the mechanism of polysaccharide hydrolysis in C. termitidis, the recently sequenced strain CT1112 of C. termitidis was analyzed for both CAZymes and cellulosomal components, and compared to other cellulolytic bacteria. A total of 355 CAZyme sequences were identified in C. termitidis, significantly higher than other Clostridial species. Of these, high numbers of glycoside hydrolases (199) and carbohydrate binding modules (95) were identified. The presence of a variety of CAZymes involved with polysaccharide utilization/degradation ability suggests hydrolysis potential for a wide range of polysaccharides. In addition, dockerin-bearing enzymes, cohesion domains and a cellulosomal gene cluster were identified, indicating the presence of potential cellulosome assembly.


Efficacy of a multimodal rehabilitation program in a dental hygienist with upper quadrant disorders. Description of a case report with one-year follow-up.
Many musculoskeletal disorders are work-related. For the success of treatment, it is essential to promptly recognize these cases and introduce a specific intervention able to act on the causes. In Literature many activities predisposing workers to incorrect posture and long maintained attitudes are highlighted. The professionals involved in dental hygiene are among these. For these patients it is not sufficient to just reduce pain, but it is necessary to have a broader approach to rehabilitation, which can also act on neuromuscular imbalances induced by work. The article describes the case of a dental hygienist with upper quadrant disorders treated by physiotherapy and education. Particular importance during treatment was given to postural re-education. The treatment lasted two months (8 sessions, 1 session per week). The outcomes introduced were Visual Analogue Scale, VAS (70/100 at the beginning and 0/100 at the end of treatment) and Neck Pain and Disability Scale, NPDS (62.5/100 at the beginning and 3/100 at the end of treatment); at 12-month follow-up, VAS was 10/100 and NPDS was 19/100. A multimodal rehabilitation, with emphasis to musculoskeletal imbalance correction, proved to be useful in a patient who maintained prolonged flexion and rotation of the spine, front shoulder closure, and arm suspension due to occupational daily activities. The improvements lasted over time.


Increased expression of the cyclin D1 gene in Barrett's esophagus.
Previous studies have found a 3-10-fold amplification and overexpression of the cyclin D1 gene in about 32% of human esophageal squamous cell carcinoma. The purpose of this study was to evaluate the prevalence of increased expression of the cyclin D1 protein in Barrett's esophagus. Using 69 formalin-fixed and paraffin-embedded human esophageal specimens, which had been removed endoscopically or obtained at surgery during 1993 and 1994, all immunohistochemical analyses were performed using an avidin-biotin complex immunoperoxidase technique. Increased nuclear expression of the cyclin D1 protein was noted in 32 of 69 samples (46%; 44% of the samples from males and 50% of the samples from females). Positive nuclear staining for the cyclin D1 protein in Barrett's disease with intestinal metaplasia was found in 38% of the male cases and 25% of the female cases, whereas in gastric metaplasia it was positive in 33% of men and 48% of women. Nuclear accumulation of the cyclin D1 protein was also found in both dysplastic and nondysplastic lesions, and it was not associated with sex, age, or cigarette or alcohol consumption. Samples from patients taking proton pump inhibitors tended to be less frequently positive (32%) for cyclin D1 nuclear staining when compared to patients taking H2 antagonists (45%) or antacids (55%). These studies suggest that increased expression of cyclin D1 is an early event in the tumorigenic process of esophageal adenocarcinomas and that the increased expression of this gene might predispose the epithelium to malignant transformation.


Pharmacokinetics of fluoride in man and its clinical relevance.
A large number of parameters will influence and mediate the activity and the pharmacological response of dental fluoride products after systemic or topical treatment. This report reviews some aspects of the pharmacokinetics of fluoride in man, fluoride bio-availability, plasma kinetics, and kinetics of fluoride in saliva and plaque fluid. Pharmacokinetic studies in growing dogs show that 90% of a single injected fluoride dose is retained shortly after birth, but at maturity it decreases to about 50%. The degree of fluoride accumulating in calcifying tissues seems to be strongly related to age. The bio-availability of fluoride from swallowed fluoride toothpaste is shown to be decreased if the toothpaste is ingested close to a meal. Several studies show that fluoride exerts its cariostatic effects through the liquid phase surrounding the enamel. The importance of fluoride in the fluid environment of the teeth and the kinetics of fluoride in saliva are discussed. Clinical studies using different slow-release fluoride systems indicate that they are promising cariostatic agents--in particular intra-oral slow-release devices and lozenges. A new micro-analytical method to study the kinetics of fluoride in plaque fluid collected from single tooth sites has been developed. Preliminary studies show that the clearance of fluoride from plaque fluid is slowest in the upper incisor region, followed by the molar region, and faster in the lower incisor region. A site-by-site study of the concentration of fluoride in plaque fluid after topical fluoride administration could be extremely beneficial in optimization of the methods and recommended safety regimens for fluoride therapy.


Assessment of a national voucher scheme to deliver insecticide-treated mosquito nets to pregnant women.
The benefits of a health-related intervention may be compromised by the challenges of delivering the intervention on a large scale. We analyzed the process involved in the Tanzania National Voucher Scheme, a system for delivering insecticide-treated mosquito nets to pregnant women. We aimed to identify potential ways to equitably improve overall coverage of the intervention. We defined five steps in the process. We collected data from a multistage cluster survey of nationally representative households conducted in 2007 across 21 districts in Tanzania. Using these data, we multiplied the rate of success of each step cumulatively to estimate the overall success of the system. The rate of coverage for use of insecticide-treated nets among pregnant women was 23% (95% confidence interval [CI] 19%-27%). We observed large differences in coverage by socio-economic status, from 7% (95% CI 4%-13%) among participants in the poorest households to 48% (95% CI 38%-59%) among those in the richest households. The rate of success of each step in the process was high (60%-98%). However, the cumulative rate of success for the process as a whole was low (30%). The largest and most inequitable reduction in coverage occurred in the step involving treatment of nets with insecticide. The cumulative effect of modest attrition at several steps in the process substantially diminished the overall rate of coverage for all women, but most markedly among the poorest participants. Analysis of the process suggests that delivery of nets treated with long-lasting insecticide rather than untreated nets packaged with an insecticide-treatment kit could result in an improvement in coverage of 22 percentage points, from 30% to 52%.


Exercise tolerance and alcohol intake. Blood pressure relation.
The relations of systolic and diastolic blood pressures to alcohol intake and exercise tolerance levels in 15,612 men and 3,855 women were investigated. Alcohol intake was assessed by questionnaire and stratified into seven levels for men and six for women according to the ounces of ethanol consumed per week. Exercise tolerance was determined by maximal treadmill exercise testing and was categorized into six age-specific by sex-specific levels. Both systolic and diastolic blood pressure were significantly related to both alcohol intake and exercise tolerance levels in both men and women. These relations, which were positive for alcohol and negative for exercise tolerance, remained after covariance adjustment for age, body mass index, and cigarette smoking. Alcohol intake was not significantly correlated with exercise tolerance. The relation of blood pressure to alcohol was not linear because the blood pressure of moderate consumers of alcohol tended to be slightly lower than that of nondrinkers. Higher blood pressure was found only in drinkers whose ethanol intake exceeded 9.5 ounces (approximately 285 ml or 19 drinks) per week. However, heavy drinkers in high exercise tolerance categories had no higher blood pressure than nondrinkers in low exercise tolerance groups. Exercise tolerance or physiological fitness appears to be important in quantifying the relation between alcohol intake and blood pressure and should be considered in describing this relation.


Does Ulipristal Acetate Affect Surgical Experience at Laparoscopic Myomectomy?
To compare surgical experience of laparoscopic/robotic myomectomy in premenopausal patients pretreated with ulipristal acetate (UPA) with women not hormonally pretreated. A retrospective, multicenter cohort study of laparoscopic/robotic myomectomy procedure videos (Canadian Task Force Classification III). Multiple university-affiliated tertiary care hospitals. Fifty-five premenopausal women who underwent laparoscopic/robotic myomectomy for intramural myomas and were either pretreated with 3 months of UPA or had no hormonal pretreatment. Laparoscopic/robotic myomectomy surgical videos were independently reviewed by 2 gynecologists blinded to whether or not patients received pretreatment with UPA. Each procedure was scored using a novel 22-point surgical global rating tool containing 6 subscales: depth of myometrial incision, ease of myoma-myometrium cleavage plane identification, ease of myoma detachment, blood loss during myoma detachment, myometrial blood loss after myoma detachment, and myoma consistency. Participating surgeons submitted 55 videos of laparoscopic/robotic myomectomy procedures recorded over a 3-year period (2012-2015). Fifty met the inclusion criteria (25 UPA-treated patients and 25 patients without hormonal pretreatment). Patients treated with UPA were more likely to be older than patients with no medical pretreatment (mean age = 33.5 vs 38.3 years, p = .002). There were no statistically significant differences regarding other baseline characteristics such as the largest diameter of myoma removed, the number of myomas removed, or the estimated blood loss. There was no difference in the physician assessors' mean global rating score for patients with UPA pretreatment versus no pretreatment (12.4 vs 13.4, p = .23). Within the 6 subscales, no differences were observed between the 2 groups. Each video was graded independently by 2 assessors, and there was high inter-rater agreement for the total score and each subscale. There was no difference in surgical experience for myomectomies of patients pretreated with UPA versus those without medical pretreatment.


Municipal return to work management in cancer survivors undergoing cancer treatment: a protocol on a controlled intervention study.
Cancer survivors are often left on their own to deal with the challenges of resuming work during or after cancer treatment, mainly due to unclear agreements between stakeholders responsible for occupational rehabilitation. Social inequality exists in cancer risk, survival probability and continues with regard to the chance of being able to return to work. The aim is to apply an early, individually tailored occupational rehabilitation intervention to cancer survivors in two municipalities parallel with cancer treatment focusing on enhancing readiness for return to work. In a controlled trial municipal job consultants use acceptance and commitment therapy dialogue and individual-placement-and-support-inspired tools with cancer survivors to engage them in behaviour changes toward readiness for return to work. The workplace is involved in the return to work process. Patients referred to surgery, radiotherapy or chemotherapy at the Oncology Department, Aarhus University Hospital, Denmark for the diagnoses; breast, colon-rectal, head and neck, thyroid gland, testicular, ovarian or cervix cancer are eligible for the study. Patients must be residents in the municipalities of Silkeborg or Randers, 18-60 years of age and have a permanent or temporary employment (with at least 6 months left of their contract) at inclusion. Patients, for whom the treating physician considers occupational rehabilitation to be unethical, or who are not reading or talking Danish are excluded. The control group has identical inclusion and exclusion criteria except for municipality of residence. Return to work is the primary outcome and is indentified in a social transfer payment register. Effect is assessed as relative cumulative incidences within 52 weeks and will be analysed in generalised linear regression models using the pseudo values method. As a secondary outcome; co-morbidity and socio-economic status is analysed as effect modifiers of the intervention effect on return to work. The innovative element of this intervention is the timing of the occupational rehabilitation which is much earlier initiated than usual and the active involvement of the workplace. We anticipate that vulnerable cancer survivors will benefit from this approach and reduce the effects of social inequality on workability. Current Controlled Trials ISRCTN50753764 . Registered August 21(st), 2014.


Ytterbium fiber laser based on first-order fiber Bragg gratings written with 400 nm femtosecond pulses and a phase-mask.
A Fiber Bragg grating of 369 nm pitch was inscribed in a germanium-free double-clad ytterbium doped silica fiber using a femto-second pulse train at 400 nm wavelength and a phase mask. The photo-induced refractive index modulation of higher than 4 x 10(-3) was obtained and the accompanying photo-induced losses were subsequently removed by thermal annealing, resulting in a low loss (<0.1 dB), stable and high reflectivity (>40 dB) FBG. Based on this FBG, a monolithic Ytterbium fiber laser operating at 1073 nm with slope efficiency of 71% and output power of 13 W was demonstrated.


Effect of infant immunisation with meningococcus serogroup C-CRM(197) conjugate vaccine on diphtheria immunity and reactogenicity in pre-school aged children.
The majority of Men C conjugate vaccines given in the UK use CRM(197), a mutant diphtheria toxoid, as their protein carrier. We studied the effects of prior immunisation with Men C-CRM(197) conjugate vaccine on immunity to diphtheria in 193 children before and after a booster dose of Men C at 4 years. Baseline diphtheria antibodies were higher in children given four previous doses of Men C (P<0.0001) and tended to be higher following boosting in those who had received three or four doses. This enhanced immunity was not associated with increased reactogenicity.


Use of electronic medical records in oncology outcomes research.
Oncology outcomes research could benefit from the use of an oncology-specific electronic medical record (EMR) network. The benefits and challenges of using EMR in general health research have been investigated; however, the utility of EMR for oncology outcomes research has not been explored. Compared to current available oncology databases and registries, an oncology-specific EMR could provide comprehensive and accurate information on clinical diagnoses, personal and medical histories, planned and actual treatment regimens, and post-treatment outcomes, to address research questions from patients, policy makers, the pharmaceutical industry, and clinicians/researchers. Specific challenges related to structural (eg, interoperability, data format/entry), clinical (eg, maintenance and continuity of records, variety of coding schemes), and research-related (eg, missing data, generalizability, privacy) issues must be addressed when building an oncology-specific EMR system. Researchers should engage with medical professional groups to guide development of EMR systems that would ultimately help improve the quality of cancer care through oncology outcomes research.


A gamma camera count rate saturation correction method for whole-body planar imaging.
Whole-body (WB) planar imaging has long been one of the staple methods of dosimetry, and its quantification has been formalized by the MIRD Committee in pamphlet no 16. One of the issues not specifically addressed in the formalism occurs when the count rates reaching the detector are sufficiently high to result in camera count saturation. Camera dead-time effects have been extensively studied, but all of the developed correction methods assume static acquisitions. However, during WB planar (sweep) imaging, a variable amount of imaged activity exists in the detector's field of view as a function of time and therefore the camera saturation is time dependent. A new time-dependent algorithm was developed to correct for dead-time effects during WB planar acquisitions that accounts for relative motion between detector heads and imaged object. Static camera dead-time parameters were acquired by imaging decaying activity in a phantom and obtaining a saturation curve. Using these parameters, an iterative algorithm akin to Newton's method was developed, which takes into account the variable count rate seen by the detector as a function of time. The algorithm was tested on simulated data as well as on a whole-body scan of high activity Samarium-153 in an ellipsoid phantom. A complete set of parameters from unsaturated phantom data necessary for count rate to activity conversion was also obtained, including build-up and attenuation coefficients, in order to convert corrected count rate values to activity. The algorithm proved successful in accounting for motion- and time-dependent saturation effects in both the simulated and measured data and converged to any desired degree of precision. The clearance half-life calculated from the ellipsoid phantom data was calculated to be 45.1 h after dead-time correction and 51.4 h with no correction; the physical decay half-life of Samarium-153 is 46.3 h. Accurate WB planar dosimetry of high activities relies on successfully compensating for camera saturation which takes into account the variable activity in the field of view, i.e. time-dependent dead-time effects. The algorithm presented here accomplishes this task.


DNA polymorphisms and haplotype patterns of transcription factors involved in barley endosperm development are associated with key agronomic traits.
Association mapping is receiving considerable attention in plant genetics for its potential to fine map quantitative trait loci (QTL), validate candidate genes, and identify alleles of interest. In the present study association mapping in barley (Hordeum vulgare L.) is investigated by associating DNA polymorphisms with variation in grain quality traits, plant height, and flowering time to gain further understanding of gene functions involved in the control of these traits. We focused on the four loci BLZ1, BLZ2, BPBF and HvGAMYB that play a role in the regulation of B-hordein expression, the major fraction of the barley storage protein. The association was tested in a collection of 224 spring barley accessions using a two-stage mixed model approach. Within the sequenced fragments of four candidate genes we observed different levels of nucleotide diversity. The effect of selection on the candidate genes was tested by Tajima's D which revealed significant values for BLZ1, BLZ2, and BPBF in the subset of two-rowed barleys. Pair-wise LD estimates between the detected SNPs within each candidate gene revealed different intra-genic linkage patterns. On the basis of a more extensive examination of genomic regions surrounding the four candidate genes we found a sharp decrease of LD (r2<0.2 within 1 cM) in all but one flanking regions.Significant marker-trait associations between SNP sites within BLZ1 and flowering time, BPBF and crude protein content and BPBF and starch content were detected. Most haplotypes occurred at frequencies <0.05 and therefore were rejected from the association analysis. Based on haplotype information, BPBF was associated to crude protein content and starch content, BLZ2 showed association to thousand-grain weight and BLZ1 was found to be associated with flowering time and plant height. Differences in nucleotide diversity and LD pattern within the candidate genes BLZ1, BLZ2, BPBF, and HvGAMYB reflect the impact of selection on the nucleotide sequence of the four candidate loci.Despite significant associations, the analysed candidate genes only explained a minor part of the total genetic variation although they are known to be important factors influencing the expression of seed quality traits. Therefore, we assume that grain quality as well as plant height and flowering time are influenced by many factors each contributing a small part to the expression of the phenotype. A genome-wide association analysis could provide a more comprehensive picture of loci involved in the regulation of grain quality, thousand grain weight and the other agronomic traits that were analyzed in this study. However, despite available high-throughput genotyping arrays the marker density along the barely genome is still insufficient to cover all associations in a whole genome scan. Therefore, the candidate gene-based approach will further play an important role in barley association studies.


Optogenetic inhibition of Delta reveals digital Notch signalling output during tissue differentiation.
Spatio-temporal regulation of signalling pathways plays a key role in generating diverse responses during the development of multicellular organisms. The role of signal dynamics in transferring signalling information in vivo is incompletely understood. Here, we employ genome engineering in Drosophila melanogaster to generate a functional optogenetic allele of the Notch ligand Delta (opto-Delta), which replaces both copies of the endogenous wild-type locus. Using clonal analysis, we show that optogenetic activation blocks Notch activation through cis-inhibition in signal-receiving cells. Signal perturbation in combination with quantitative analysis of a live transcriptional reporter of Notch pathway activity reveals differential tissue- and cell-scale regulatory modes. While at the tissue-level the duration of Notch signalling determines the probability with which a cellular response will occur, in individual cells Notch activation acts through a switch-like mechanism. Thus, time confers regulatory properties to Notch signalling that exhibit integrative digital behaviours during tissue differentiation.


KPNA2 is overexpressed in human and mouse endometrial cancers and promotes cellular proliferation.
Endometrial cancer is the most frequently occurring malignancy of the female genital tract in Western countries. Although in many cases surgically curable, about 30% of the tumours represent an aggressive and untreatable disease. In an attempt to establish a reliable prognostic marker for endometrial carcinomas disregarding their histological diversity, we investigated the expression of KPNA2, a mediator of nucleocytoplasmic transport, and other cell proliferation-associated proteins and their correlation with cancer progression. We analysed patient tissue microarrays (TMAs) assembled from 527 endometrial cancer tissue specimens and uterus samples from a Trp53 knockout mouse model of endometrial cancer. Our data show that KPNA2 expression was significantly up-regulated in human endometrial carcinomas and associated with higher tumour grade (p = 0.026), higher FIGO stage (p = 0.027), p53 overexpression (p < 0.001), activation of the PI3K/AKT pathway, and epithelial-mesenchymal transition. Increased nuclear KPNA2 immunoreactivity was identified as a novel predictor of overall survival, independent of well-established prognostic factors in Cox regression analyses (hazard ratio 1.7, 95% CI 1.13-2.56, p = 0.01). No significant association between KPNA2 expression and endometrial cancer subtype was detected. In the mouse model, KPNA2 showed increased expression levels from precancerous (EmgD, EIC) to far-advanced invasive lesions. We further investigated the cell proliferation capacity after siRNA-mediated KPNA2 knockdown in the human endometrial cancer cell line MFE-296. KPNA2 silencing led to decreased proliferation of the cancer cells, suggesting interplay of the protein with the cell cycle. Taken together, increased expression of KPNA2 is an independent prognostic marker for poor survival. The mechanism of enhanced nucleocytoplasmic transport by KPNA2 overexpression seems a common event in aggressive cancers since we have shown a significant correlation of KPNA2 expression and tumour aggressiveness in a large variety of other solid tumour entities. Introducing KPNA2 immunohistochemistry in routine diagnostics may allow for the identification of patients who need more aggressive treatment regimens.


Exome sequencing identifies a missense mutation in Isl1 associated with low penetrance otitis media in dearisch mice.
Inflammation of the middle ear (otitis media) is very common and can lead to serious complications if not resolved. Genetic studies suggest an inherited component, but few of the genes that contribute to this condition are known. Mouse mutants have contributed significantly to the identification of genes predisposing to otitis media The dearisch mouse mutant is an ENU-induced mutant detected by its impaired Preyer reflex (ear flick in response to sound). Auditory brainstem responses revealed raised thresholds from as early as three weeks old. Pedigree analysis suggested a dominant but partially penetrant mode of inheritance. The middle ear of dearisch mutants shows a thickened mucosa and cellular effusion suggesting chronic otitis media with effusion with superimposed acute infection. The inner ear, including the sensory hair cells, appears normal. Due to the low penetrance of the phenotype, normal backcross mapping of the mutation was not possible. Exome sequencing was therefore employed to identify a non-conservative tyrosine to cysteine (Y71C) missense mutation in the Islet1 gene, Isl1(Drsh). Isl1 is expressed in the normal middle ear mucosa. The findings suggest the Isl1(Drsh) mutation is likely to predispose carriers to otitis media. Dearisch, Isl1(Drsh), represents the first point mutation in the mouse Isl1 gene and suggests a previously unrecognized role for this gene. It is also the first recorded exome sequencing of the C3HeB/FeJ background relevant to many ENU-induced mutants. Most importantly, the power of exome resequencing to identify ENU-induced mutations without a mapped gene locus is illustrated.


Predictive Relationship Between Parental Beliefs and Accommodation of Pediatric Anxiety.
Behavior performed by parents to assist a youth in avoiding or alleviating anxiety, known as accommodation, is ubiquitous among pediatric anxiety disorders and strongly related to poor treatment outcome. According to cognitive-behavioral theory, the beliefs parents hold regarding accommodation should predict parental accommodating behavior. Unfortunately, little is known about the beliefs parents hold regarding accommodation, as there exists no validated measure of this construct. First, the psychometric properties were examined for the Parental Accommodation Scale (PAS), a novel measure of parental accommodating behavior frequency (PAS-Behavior scale) and parental beliefs about accommodation (PAS-Belief scale). Second, the relationship between parental beliefs about accommodation and accommodation frequency was examined. Results provide preliminary evidence of the internal consistency and convergent validity of the PAS. Stronger positive beliefs about accommodation significantly predicted accommodation frequency, even after controlling for youth anxiety severity. Specifically, beliefs that accommodation prevents youth from losing behavioral and emotional control significantly predicted accommodation frequency. Therefore, efforts to decrease accommodation in clinical settings should involve correcting maladaptive parental beliefs about accommodation, with a particular emphasis on beliefs regarding the necessity of accommodation in preventing a youth from losing behavioral and emotional control.


Dose of jogging and long-term mortality: the Copenhagen City Heart Study.
People who are physically active have at least a 30% lower risk of death during follow-up compared with those who are inactive. However, the ideal dose of exercise for improving longevity is uncertain. The aim of this study was to investigate the association between jogging and long-term, all-cause mortality by focusing specifically on the effects of pace, quantity, and frequency of jogging. As part of the Copenhagen City Heart Study, 1,098 healthy joggers and 3,950 healthy nonjoggers have been prospectively followed up since 2001. Cox proportional hazards regression analysis was performed with age as the underlying time scale and delayed entry. Compared with sedentary nonjoggers, 1 to 2.4 h of jogging per week was associated with the lowest mortality (multivariable hazard ratio [HR]: 0.29; 95% confidence interval [CI]: 0.11 to 0.80). The optimal frequency of jogging was 2 to 3 times per week (HR: 0.32; 95% CI: 0.15 to 0.69) or ≤1 time per week (HR: 0.29; 95% CI: 0.12 to 0.72). The optimal pace was slow (HR: 0.51; 95% CI: 0.24 to 1.10) or average (HR: 0.38; 95% CI: 0.22 to 0.66). The joggers were divided into light, moderate, and strenuous joggers. The lowest HR for mortality was found in light joggers (HR: 0.22; 95% CI: 0.10 to 0.47), followed by moderate joggers (HR: 0.66; 95% CI: 0.32 to 1.38) and strenuous joggers (HR: 1.97; 95% CI: 0.48 to 8.14). The findings suggest a U-shaped association between all-cause mortality and dose of jogging as calibrated by pace, quantity, and frequency of jogging. Light and moderate joggers have lower mortality than sedentary nonjoggers, whereas strenuous joggers have a mortality rate not statistically different from that of the sedentary group.


A Biomarker for Alzheimer's Disease Based on Patterns of Regional Brain Atrophy.
Introduction: It has been shown that Alzheimer's disease (AD) is accompanied by marked structural brain changes that can be detected several years before clinical diagnosis via structural magnetic resonance (MR) imaging. In this study, we developed a structural MR-based biomarker for in vivo detection of AD using a supervised machine learning approach. Based on an individual's pattern of brain atrophy a continuous AD score is assigned which measures the similarity with brain atrophy patterns seen in clinical cases of AD. Methods: The underlying statistical model was trained with MR scans of patients and healthy controls from the Alzheimer's Disease Neuroimaging Initiative (ADNI-1 screening). Validation was performed within ADNI-1 and in an independent patient sample from the Open Access Series of Imaging Studies (OASIS-1). In addition, our analyses included data from a large general population sample of the Study of Health in Pomerania (SHIP-Trend). Results: Based on the proposed AD score we were able to differentiate patients from healthy controls in ADNI-1 and OASIS-1 with an accuracy of 89% (AUC = 95%) and 87% (AUC = 93%), respectively. Moreover, we found the AD score to be significantly associated with cognitive functioning as assessed by the Mini-Mental State Examination in the OASIS-1 sample after correcting for diagnosis, age, sex, age·sex, and total intracranial volume (Cohen's f2 = 0.13). Additional analyses showed that the prediction accuracy of AD status based on both the AD score and the MMSE score is significantly higher than when using just one of them. In SHIP-Trend we found the AD score to be weakly but significantly associated with a test of verbal memory consisting of an immediate and a delayed word list recall (again after correcting for age, sex, age·sex, and total intracranial volume, Cohen's f2 = 0.009). This association was mainly driven by the immediate recall performance. Discussion: In summary, our proposed biomarker well differentiated between patients and healthy controls in an independent test sample. It was associated with measures of cognitive functioning both in a patient sample and a general population sample. Our approach might be useful for defining robust MR-based biomarkers for other neurodegenerative diseases, too.


Restoration of Spinal Motion: Conversion of Anterior Cervical Fusion With Pseudarthrosis to Artificial Disc Replacement.
Describe the technique and outcomes of the conversion of prior anterior cervical discectomy and fusion (ACDF) with pseudarthrosis to an artificial disc replacement (ADR). Case report. Five patients completed the following pain and function questionnaires at baseline and postoperatively: visual analog pain scale (VAS), Neck Disability Index (NDI), PROMIS Emotional Distress-Depression Short Form-4a (P-EDD), PROMIS Pain Interference Short Form 6b (P-PI), and PROMIS Physical Function Short Form-10a (P-SF). Pseudarthrosis was diagnosed using computed tomography imaging of the cervical spine. The level of prior fusion with pseudarthrosis was remobilized after a standard anterior approach was made, and an artificial disc replacement was performed after revision discectomy. The conversion of fusion to ADR was successful in all 5 patients without intraoperative or postoperative complication or the need to perform revision fusion. The average follow-up duration was 12.4 months (range 6-24months). VAS improved on average (median) from 6 (6.0) to 2 (2.2), NDI improved from 23 (21) to 15 (17), P-EDD 4a improved from 11 (11) to 4 (4), and P-PI and P-SF improved from 23 (22) to 16 (19) and from 37 (35) to 41 (39.5), respectively. Radiographic range of motion increased at the fusion conversion level from an average of 1° ± 1.2° to 8.1° ± 4.6° after the insertion of the artificial disc replacement. The reversal of ACDF and conversion to an artificial disc replacement is feasible and achieves postoperative range of motion that is similar to that achieved when performed in a segment not previously fused.


Top 10 Research Priorities in Spatial Lifecourse Epidemiology.
The International Initiative on Spatial Lifecourse Epidemiology (ISLE) convened its first International Symposium on Lifecourse Epidemiology and Spatial Science at the Lorentz Center in Leiden, Netherlands, 16–20 July 2018. Its aim was to further an emerging transdisciplinary field: Spatial Lifecourse Epidemiology. This field draws from a broad perspective of scientific disciplines including lifecourse epidemiology, environmental epidemiology, community health, spatial science, health geography, biostatistics, spatial statistics, environmental science, climate change, exposure science, health economics, evidence-based public health, and landscape ecology. The participants, spanning 30 institutions in 10 countries, sought to identify the key issues and research priorities in spatial lifecourse epidemiology. The results published here are a synthesis of the top 10 list that emerged out of the discussion by a panel of leading experts, reflecting a set of grand challenges for spatial lifecourse epidemiology in the coming years. https://doi.org/10.1289/EHP4868.


Equity and the financial costs of informal caregiving in palliative care: a critical debate.
Informal caregivers represent the foundation of the palliative care workforce and are the main providers of end of life care. Financial pressures are among the most serious concerns for many carers and the financial burden of end of life caregiving can be substantial. The aim of this critical debate paper was to review and critique some of the key evidence on the financial costs of informal caregiving and describe how these costs represent an equity issue in palliative care. The financial costs of informal caregiving at the end of life can be significant and include carer time costs, out of pocket costs and employment related costs. Financial burden is associated with a range of negative outcomes for both patient and carer. Evidence suggests that the financial costs of caring are not distributed equitably. Sources of inequity are reflective of those influencing access to specialist palliative care and include diagnosis (cancer vs non-cancer), socio-economic status, gender, cultural and ethnic identity, and employment status. Effects of intersectionality and the cumulative effect of multiple risk factors are also a consideration. Various groups of informal end of life carers are systematically disadvantaged financially. Addressing these, and other, determinants of end of life care is central to a public health approach to palliative care that fully recognises the value of carers. Further research exploring these areas of inequity in more depth and gaining a more detailed understanding of what influences financial burden is required to take the next steps towards meeting this aspiration. We will address the conclusions and recommendations we have made in this paper through the work of our recently established European Association of Palliative Care (EAPC) Taskforce on the financial costs of family caregiving.


Primary infection of dogs with Echinococcus granulosus: systemic and local (Peyer's patches) immune responses.
Local and systemic lymphocyte proliferation and antibody production were tested in five dogs 35 days after primary experimental infection with Echinococcus granulosus. A significant cell proliferation was demonstrated by [3H] thymidine incorporation in mesenteric, popliteal and/or Peyer's patches (PPs) cells in response to E. granulosus protoscolex or adult worm antigen in three of five infected dogs, but not in five control animals. In contrast, blood mononuclear cells responded very weakly in only two of the infected dogs to parasite antigens. Elevated levels (compared with preinfection status) of protoscolex- and adult worm antigen-specific serum IgG were detected (ELISA) in four of the five dogs 35 days after infection. Furthermore, slightly elevated levels of parasite-specific IgE and IgA were observed in the sera of three and four in four infected dogs, respectively. Specific serum IgM was not significantly higher 35 days after infection than before infection. Local antibody production was studied in vitro using PPs, mesenteric and popliteal cells isolated from three infected and three uninfected dogs by ELISA using adult worm antigen. In two of three cultures of unstimulated PPs cells of infected dogs, parasite-specific IgG was detectable. Parasite-specific IgA and IgM were detected in one of the unstimulated PPs cell culture derived from an infected dog. Following in vitro stimulation with parasite antigen, PPs cells from two infected dogs showed increased parasite-specific IgG and PPs cells of all three infected dogs produced parasite-specific IgA. PPs cells from uninfected dogs did not produce significant quantities of parasite-specific antibodies and cells from mesenteric and popliteal lymph nodes of infected or uninfected dogs neither produced antibodies whilst in in vitro cultures.


Terson syndrome in subarachnoid hemorrhage, intracerebral hemorrhage, and traumatic brain injury.
This prospective trial was designed to evaluate the incidence of Terson syndrome in patients suffering from subarachnoid hemorrhage, intracerebral hemorrhage, or traumatic brain injury and whether consequences necessarily derive from the intraocular hemorrhage itself. Two ophthalmologic examinations were performed to identify patients with Terson syndrome. Data on initial Glasgow Coma Scale, Hunt and Hess and Fisher grades, aneurysm site and diameter, and volume of hemorrhage in intracerebral hemorrhage patients were correlated to the location and course of Terson syndrome. Follow-up was performed after 3 months, including clinical and ophthalmologic investigations. The data showed that 16 of 83 subarachnoid hemorrhage patients (19.3%), 2 of 22 intracerebral hemorrhage patients (9.1%), and 1 of 32 traumatic brain injury patients (3.1%) suffered from Terson syndrome. Low Glasgow Coma Scale (p = 0.002), high Hunt and Hess grade (p < 0.001), and high Fisher grade (p = 0.002) were found to be associated with a higher incidence of Terson syndrome. The neurological outcome in subarachnoid hemorrhage patients suffering from Terson syndrome was worse compared with that of subarachnoid hemorrhage patients without Terson syndrome (p = 0.005), and vitrectomy was performed in seven eyes of six patients due to poor visual acuity. Terson syndrome is underestimated in patients with subarachnoid hemorrhage and a rare pathology in intracerebral hemorrhage as well as in traumatic brain injury patients. Spontaneous regression of the intraocular hemorrhage may be seen, but in half of the patients, vitrectomy is necessary to prevent permanent visual deterioration.


Gratefully received, gratefully repaid: the role of perceived fairness in cooperative interactions.
It is well documented that people would remunerate fair behaviours and penalize unfair behaviours. It is argued that individuals' reactions following the receipt of a gift depend on the perceived intentions of the donors. Fair intentions should prompt positive affect, like gratitude, triggering cooperative behaviours; while intended unfairness should trigger negative affect, like anger, fostering anti-social actions. It is, however, contended that when people lack information to infer others' intention they may use 'normative' beliefs about fairness - what a typical fair individual 'should' do in these circumstances - to guide their behaviour. In this experiment we examined this assertion. We had 122 participants play a one-shot, double-anonymous game with half playing as potential helpers (P1s) and half as recipients (P2s). Whether a participant was a P1 or P2 was chance-determined and all participants knew this. P1s decided whether to help P2s and whether to make their help unconditional (no repayment needed) or conditional (full or 'taxed' repayment). P2s decided whether to accept the offer and whatever conditions attached but were blind to the list of helping options available to P1s. We anticipated that recipients would refer to the 'injunctive norm' that 'fair people should help "for free" when it is only by chance that they are in a position to help'. Therefore, without knowing P1s' different helping options, unconditional offers should be rated by recipients as fairer than conditional offers, and this should be linked to greater gratitude with greater gratitude linked to greater reciprocation. Path analyses confirmed this serial mediation. The results showed that recipients of unconditional offers, compared to conditional ones, interpreted the helpers' motives as more helpful, experienced greater gratitude and were more eager to reciprocate. The behavioural data further revealed that, when given a latter option to default, 38% of recipients of conditional offers did so.


Lung function and blood levels of copper, selenium, vitamin C and vitamin E in the general population.
Increased dietary intake of antioxidants has been associated with higher lung function, but few studies have used biological markers of antioxidant intake. This study aimed to determine if antioxidant status, as measured by blood levels, influences lung function. Using a random subsample of 479 participants, aged 18-65 y old, from a larger cross-sectional observational study, the association of forced expiratory volume in 1 s (FEV1) with plasma copper, vitamin C, vitamin E and serum selenium was assessed. An s.d. increase in blood copper level was associated with a difference in FEV1 of -48 ml (95% confidence intervals: -95, -2 ml, P = 0.04), vitamin C +49 ml (+4, +94, P = 0.03), vitamin E -15 ml (-62, +32, P = 0.53) and selenium +52 ml (+7, +96, P = 0.02). The sizes of association were not appreciably altered in a mutually adjusted model. Higher levels of serum vitamin C and selenium appear to be associated with higher FEV1. The association between higher serum copper and lower FEV1 requires further study in view of the ubiquitous exposure to this mineral.


Synthesis, antimicrobial evaluation, QSAR and in Silico ADMET studies of decanoic acid derivatives.
Various derivatives of decanoic acid (CD) have been synthesized and evaluated against Gram positive B. subtilis, S. aureus and Gram negative E. coli bacteria as well a sagainst fungi C. albicans and A. niger. Quantitative structure activity relationship (QSAR) models for antimicrobial activities were developed using multiple linear regression and cross validated by leave one out (LOO) approach. QSAR studies indicated that activity against Gram positive bacteria was governed by lipophilicity of the compounds while topologicalsteric nature of the molecule was deciding factor for antifungal activity. Further, in silico ADMET studies showed that compounds CD12, 19, 20 and 23 could be explored further for other activities.


Study of different spectral regions and delay bandwidth relation in slow light photonic crystal waveguides.
We investigate slow light propagation in monomode photonic crystal waveguides with different spectral features such as constant group index, high bandwidth and low group velocity dispersion. The form of the waveguide mode alters dramatically and spans three different spectral intervals by tuning the size of the boundary holes. Namely, slope of the band gap guided mode changes sign from negative to positive toward the Brillouin zone edge. In between there is a transition region where modes have nearly zero slopes. Maximum group index occurs at these turning points at the expense of high dispersion and narrow bandwidth. The apparent trade-off relationship between group index and bandwidth is revealed systematically. We show that as the radius of the innermost hole is increased above a certain value, the former one decreases and the latter one increases both exponentially but with a different ratio. The product of average group index and bandwidth is defined as a figure of merit which reaches up to a value of approximately 0.30 after a detailed parametric search. The findings of the frequency domain analysis obtained by plane wave expansion method are confirmed via finite-difference time-domain study.


The ultrastructure of adult vertebrate peripheral myelinated nerve fibers in relation to myelinogenesis.
Adult chameleon myelinated peripheral nerve fibers have been studied with the electron microscope in thin sections. The outer lamella of the myelin sheath has been found to be connected as a double membrane to the surface of the Schwann cell. The inner lamella is connected as a similar double membrane with the double axon-Schwann membrane. The relations of these double connecting membranes suggest that the layered myelin structure is composed of a double membrane which is closely wound about the axon as a helix. These findings support the new theory of myelinogenesis proposed recently by Geren. The possible significance of these results with respect to cell surface membranes and cytoplasmic double membranes is discussed.


[Implantable devices for central venous access in cancer patients. Our experience in 217 cases].
The need of having a venous via available for infusion of chemotherapy treatment along with the difficulty of repeated venous access in oncological patients has lead to the ever more frequent placement of central venous access systems (CVAS) implanted into subcutaneous tissue. From February 1985 to December 1990 217 CVAS were implanted in 205 oncological patients. Twenty-six were Port-a-Cath and 191 were Implantofix. The average of complications was 0.08/100 days of implantation with an incidence of catheter thrombosis obstruction of 0.03/100 days and system infection of 0.02/100 days. Currently 81 devices continue functioning with 23 having been withdrawn due to complications and 17 for completion of the treatment to which they had been submitted. Ninety-one patients died during this follow up. The CVAS are devices which are of easy placement, simple handling, requiring minimum care and few complications. Their efficacy is confirmed by the analysis of the data presented in the present study.


Swi2/Snf2 remodelers: hybrid views on hybrid molecular machines.
Swi2/Snf2 (switch/sucrose non-fermentable) enzymes form a large and diverse class of proteins and multiprotein assemblies that remodel nucleic acid:protein complexes, using the energy of ATP hydrolysis. The core Swi2/Snf2 type ATPase domain belongs to the 'helicase and NTP driven nucleic acid translocase' superfamily 2 (SF2). It serves as a motor that functionally and structurally interacts with different targeting domains and functional modules to drive a plethora of remodeling activities in chromatin structure and dynamics, transcription regulation and DNA repair. Recent progress on the interaction of Swi2/Snf2 enzymes and multiprotein assemblies with their substrate nucleic acids and proteins, using hybrid structural biology methods, illuminates mechanisms for complex chemo-mechanical remodeling reactions. For Mot1, a hybrid mechanism of remodeler and chaperone emerged.


Grape seed-derived procyanidins alleviate gout pain via NLRP3 inflammasome suppression.
Gout is one of the common inflammatory arthritis which affects many people for inflicting unbearable pain. Macrophage-mediated inflammation plays an important role in gout. The uptake of monosodium urate (MSU) crystals by macrophages can lead to activation of NOD-like receptors containing a PYD 3 (NLRP3) inflammasome, thus accelerating interleukin (IL)-1β production. Reactive oxygen species (ROS) promoted development of the inflammatory process through NLRP3 inflammasome. Our study aimed to find a food-derived compound to attenuate gout pain via the specific inhibition of the NLRP3 inflammasome in macrophages. CD-1 mice were used to evaluate the degree of pain and the swelling dimension of joints after an intra-articular (IA) MSU injection in the ankle. The murine macrophage cell line Raw 264.7 was used to investigate the effects of procyanidins and the mechanism underlying such effects. Histological analysis was used to measure the infiltration of inflammatory cells. ROS produced from Raw 264.7 cells were evaluated by flow cytometry. Cell signaling was measured by Western blot assay and immunofluorescence. Procyanidins significantly attenuated gout pain and suppressed ankle swelling. Procyanidins also inhibited MSU-induced activation of the NLRP3 inflammasome and increase of IL-1β. Furthermore, procyanidins decreased ROS levels in Raw 264.7 cells. Suppression of the NLRP3 inflammasome in macrophages contributes to the amelioration of gout pain by procyanidins.


Direct and correlated responses to selection in two lines of rabbits selected for feed efficiency under ad libitum and restricted feeding: III. Digestion and excretion of nitrogen and minerals.
Two rabbit lines have been created to result in better feed efficiency: the ConsoResidual line was selected for a lower residual feed intake under ad libitum feeding, and the ADGrestrict line was selected for higher ADG under restricted feeding (-20% of ad libitum). The present study aimed to analyze the digestion and excretion of N and minerals from 29 to 63 d of age of these 2 lines compared with an unselected control line (G0) under 2 feeding levels (ad libitum or restricted). The ADGrestrict line had greater digestibility compared with G0 (+1.3% for OM and N; < 0.05), and the ConsoResidual line had intermediate values. There was no genetic line effect on the digestibility of N and P and on minerals concentrations (P, Zn, and Cu) in the feces and in the urine. The N balance was improved for the 2 selected lines (+5%; < 0.05), leading to a reduced N output through the feces (0.06 g/d compared with G0; < 0.001) and the urine (-0.07 g/d; < 0.05) and to an improved N retention ratio (+3% compared with G0). Over the whole fattening period (d 29-63), significant differences were observed among lines only when fed ad libitum, with 13% greater DM fecal output and 5% greater N fecal output for G0. The N excretion in urine was 2 g less in the 2 selected lines, leading to a reduction of total N release of 4.4 g (compared with G0). The P excretion in feces (12 g) or urine (0.1 g) did not differ among the 3 lines. Over the whole fattening period and for ad libitum-fed rabbits, the 5% improvement in feed efficiency ( < 0.01) for the 2 selected lines corresponded to 400 g less feed intake (-8%) and to 20 g less N intake. The fecal excretion of the ADGrestrict and ConsoResidual lines were reduced by 200 g DM ( < 0.01), corresponding to 417 g fresh matter and 5 g of N. The excretion in minerals (P, Zn, and Cu) was not affected by the line. The feeding level strongly reduced the fecal and urine outputs (-50 and -60%, respectively; < 0.001). Higher digestibility coefficients ( < 0.001) were found in restricted-fed rabbits for OM (+6%), N (+8%), and P (+11%). The N balance was substantially improved by the restriction, with 40% less total (feces + urine) N excretion ( < 0.001). The P balance was improved by the restriction (0.469 vs. 0.360). Over the fattening period, the P fecal output was 37% less (-6 g) with 24% less feed intake and the Zn and Cu outputs were reduced by 27 (-130 mg) and 29% (-30 mg), respectively.


Evidence for a frontoparietal control system revealed by intrinsic functional connectivity.
Two functionally distinct, and potentially competing, brain networks have been recently identified that can be broadly distinguished by their contrasting roles in attention to the external world versus internally directed mentation involving long-term memory. At the core of these two networks are the dorsal attention system and the hippocampal-cortical memory system, a component of the brain's default network. Here spontaneous blood-oxygenation-level-dependent (BOLD) signal correlations were used in three separate functional magnetic resonance imaging data sets (n = 105) to define a third system, the frontoparietal control system, which is spatially interposed between these two previously defined systems. The frontoparietal control system includes many regions identified as supporting cognitive control and decision-making processes including lateral prefrontal cortex, anterior cingulate cortex, and inferior parietal lobule. Detailed analysis of frontal and parietal cortex, including use of high-resolution data, revealed clear evidence for contiguous but distinct regions: in general, the regions associated with the frontoparietal control system are situated between components of the dorsal attention and hippocampal-cortical memory systems. The frontoparietal control system is therefore anatomically positioned to integrate information from these two opposing brain systems.


Metabolic Regulation of Cell Fate and Function.
Increasing evidence implicates metabolic pathways as key regulators of cell fate and function. Although the metabolism of glucose, amino acids, and fatty acids is essential to maintain overall energy homeostasis, the choice of a given metabolic pathway and the levels of particular substrates and intermediates increasingly appear to modulate specific cellular activities. This connection is likely related to the growing appreciation that molecules such as acetyl-CoA act as a shared currency between metabolic flux and chromatin modification. We review recent evidence for a role of metabolism in modulating cellular function in four distinct contexts. These areas include the immune system, the tumor microenvironment, the fibrotic response, and stem cell function. Together, these examples suggest that metabolic pathways do not simply provide the fuel that powers cellular activities but instead help to shape and determine cellular identity.


Arthroscopically detected intra-articular lesions associated with acute ankle fractures.
Anatomic surgical realignment of ankle fractures may still be associated with poor clinical outcomes, possibly as a result of occult intra-articular injury. The aim of this study was to determine if the severity of an acute ankle fracture is correlated with an increased number of arthroscopically detected intra-articular chondral lesions. We conducted a retrospective review of the medical charts on 283 ankle fractures that had been treated with open reduction and internal fixation and for which ankle arthroscopy had been routinely performed. The severity of the ankle fractures was categorized, with use of the arthroscopic findings derived from the operative reports as well as the findings on preoperative radiographs, according to the Lauge-Hansen criteria. Of the 283 patients, eighty-four (forty-four female and forty male) met our inclusion criteria. Chondral lesions were found in sixty-one patients (73%). Of seventeen fractures graded as pronation-external rotation or supination-external rotation type I according to the Lauge-Hansen classification, fifteen were associated with one or no chondral lesion and two, with two or more chondral lesions. Of ten fractures graded as pronation-external rotation or supination-external rotation type II, nine were associated with one or no chondral lesion and one, with two or more chondral lesions. Of fifty-six fractures graded as pronation-external rotation or supination-external rotation type IV, twenty-seven were associated with one or no chondral lesion and twenty-nine, with two or more chondral lesions. Type-IV pronation-external rotation and supination-external rotation ankle fractures were more likely to be associated with two or more chondral lesions than type-I fractures (odds ratio = 8.1, 95% confidence interval = 1.7 to 38.6; p = 0.0044) or type-II fractures (odds ratio = 9.7, 95% confidence interval = 1.1 to 81.5; p = 0.0172). Chondral lesions are commonly found after an acute ankle fracture. This retrospective study demonstrated that the number of intra-articular chondral lesions associated with the more severe ankle fracture patterns (pronation-external rotation and supination-external rotation type-IV fractures) was greater than the number associated with the less severe ankle fracture patterns.


High-dose alpha-tocopherol therapy does not affect HDL subfractions in patients with coronary artery disease on statin therapy.
Subfractions of HDL, particularly large HDL (HDL2), are inversely correlated with the severity of coronary artery disease (CAD). alpha-Tocopherol (AT) is the main lipid-soluble antioxidant in plasma. Results of a previous small study (n = 44) suggested that either a combination of an antioxidant cocktail [800 IU/day 2R,4'R,8'R-(RRR)-AT plus 1 g vitamin C, 25 mg beta-carotene, and 100 microg selenium] or individual antioxidant vitamins combined with simvastatin-niacin (S-N) therapy attenuated the protective increase in HDL2 seen with S-N alone. Few data are available on the effect of AT therapy alone on HDL subfractions, which we addressed in this study. In a prospective placebo-controlled study, we randomized 127 patients with stable CAD to receive high-dose RRR-AT (1200 IU/day for 2 years) or placebo. HDL subfractions (small, medium, and large HDL particles) were analyzed by nuclear magnetic resonance spectroscopy. AT concentrations significantly increased in the AT arm but not with placebo. No differences were noted between AT and placebo groups in concentrations of total cholesterol, triglyceride, LDL-cholesterol, or HDL-cholesterol. AT therapy did not affect total, small, medium, or large HDL particles compared with baseline or placebo. Furthermore, serum apolipoprotein A1 concentrations did not change after 2 years AT therapy as compared with baseline. High-dose AT therapy administered for a 2-year period does not negatively affect either HDL subfractions or apolipoprotein A1 in patients with CAD on statin therapy. Thus the negative interaction previously proposed between antioxidant cocktail and statin therapy cannot be attributed to AT.


Using intervention mapping to develop a culturally appropriate intervention to prevent childhood obesity: the HAPPY (Healthy and Active Parenting Programme for Early Years) study.
Interventions that make extensive use of theory tend to have larger effects on behaviour. The Intervention Mapping (IM) framework incorporates theory into intervention design, implementation and evaluation, and was applied to the development of a community-based childhood obesity prevention intervention for a multi-ethnic population. IM was applied as follows: 1) Needs assessment of the community and culture; consideration of evidence-base, policy and practice; 2) Identification of desired outcomes and change objectives following identification of barriers to behaviour change mapped alongside psychological determinants (e.g. knowledge, self-efficacy, intention); 3) Selection of theory-based methods and practical applications to address barriers to behaviour change (e.g., strategies for responsive feeding); 4) Design of the intervention by developing evidence-based interactive activities and resources (e.g., visual aids to show babies stomach size). The activities were integrated into an existing parenting programme; 5) Adoption and implementation: parenting practitioners were trained by healthcare professionals to deliver the programme within Children Centres. HAPPY (Healthy and Active Parenting Programme for Early Years) is aimed at overweight and obese pregnant women (BMI > 25); consists of 12 × 2.5 hr. sessions (6 ante-natal from 24 weeks; 6 postnatal up to 9 months); it addresses mother's diet and physical activity, breast or bottle feeding, infant diet and parental feeding practices, and infant physical activity. We have demonstrated that IM is a feasible and helpful method for providing an evidence based and theoretical structure to a complex health behaviour change intervention. The next stage will be to assess the impact of the intervention on behaviour change and clinical factors associated with childhood obesity. The HAPPY programme is currently being tested as part of a randomised controlled feasibility trial.


Discovery of SNPs for individual identification by reduced representation sequencing of moose (Alces alces).
Monitoring of wild animal populations is challenging, yet reliable information about population processes is important for both management and conservation efforts. Access to molecular markers, such as SNPs, enables population monitoring through genotyping of various DNA sources. We have developed 96 high quality SNP markers for individual identification of moose (Alces alces), an economically and ecologically important top-herbivore in boreal regions. Reduced representation libraries constructed from 34 moose were high-throughput de novo sequenced, generating nearly 50 million read pairs. About 50 000 stacks of aligned reads containing one or more SNPs were discovered with the Stacks pipeline. Several quality criteria were applied on the candidate SNPs to find markers informative on the individual level and well representative for the population. An empirical validation by genotyping of sequenced individuals and additional moose, resulted in the selection of a final panel of 86 high quality autosomal SNPs. Additionally, five sex-specific SNPs and five SNPs for sympatric species diagnostics are included in the panel. The genotyping error rate was 0.002 for the total panel and probability of identities were low enough to separate individuals with high confidence. Moreover, the autosomal SNPs were highly informative also for population level analyses. The potential applications of this SNP panel are thus many including investigations of population size, sex ratios, relatedness, reproductive success and population structure. Ideally, SNP-based studies could improve today's population monitoring and increase our knowledge about moose population dynamics.


First Report of a Wilt Disease of Hiemalis Begonias Caused by Fusarium foetens in the United States.
During 2003, 10% of the Hiemalis begonias (Begonia × hiemalis Fotsch) developed wilt symptoms in a commercial greenhouse in Connecticut. Foliage turned a dull green, and stems developed a dark watersoaked discoloration near the soil line and had vascular discoloration. Stems, petioles, and leaves collapsed and became covered with sporodochia of a Fusarium spp. Single conidia were isolated from sporodochia and cultured on carnation leaf agar (CLA) and potato dextrose agar for 10 days. Isolates resembled Fusarium oxysporum, but the profuse sporulation with minimal aerial mycelium and the rare occurrence of polyphialides was consistent with the description of F. foetens (2). A comparison of a partial sequence of the 1-α elongation factor gene showed a 100% match with F. foetens. Inocula from five isolates were grown on CLA, washed from the plate, and adjusted to 106 conidia per ml. Suspension (50 μl) was injected into stems of healthy 6-week-old Hiemalis begonias cv. Barkos (one plant per isolate). Controls received distilled water. After 4 weeks, all inoculated plants turned dark and collapsed, and the same fungus was reisolated from these plants. Control stems remained healthy. An isolate (O-2348) has been deposited at the Fusarium Research Center at Pennsylvania State University, University Park. F. foetens has recently been described in association with a new disease of Hiemalis begonias in Europe (1). References: (1) R. Schrage, Phytomedizinischen Gesellschaft 33:68, 2003. (2) H.-J. Schroers et al. Mycologia 96:393, 2004.


Discriminating mild parkinsonism: methods for epidemiological research.
Methods for the efficient and accurate detection of parkinsonism are essential for epidemiological studies. We sought to determine whether parkinsonism could be detected by a neurologist from a videotaped assessment and whether neurobehavioral methods (motor, cognitive, and sensory) discriminated between patients with Parkinson's disease (PD) and controls. Fifteen patients with mild PD (Hoehn and Yahr I-III) were compared to 15 age-, sex-, and education- matched controls. Each participant underwent a videotaped neurological examination (based on the Unified Parkinson's Disease Rating Scale, UPDRS), administered by a trained technician, and reviewed by a neurologist, as well as a series of neurobehavioral tests. The neurologist identified PD patients with 86% sensitivity and 100% specificity. Among the neurobehavioral tests, finger tapping, combined with one or more among olfaction, visual contrast sensitivity, or Paired Associates Learning, correctly classified 90%, or more, of subjects. Individual psychological tests did not discriminate reliably between groups. We conclude that videotaped assessments of parkinsonism or objective tests of motor and sensory function can accurately detect patients with PD. Both approaches have potential for identifying PD cases, but the latter may be more efficient for screening.


Peoniflorin suppresses tumor necrosis factor-α induced chemokine production in human dermal microvascular endothelial cells by blocking nuclear factor-κB and ERK pathway.
Peoniflorin (PF) extracted from the root of Paeonia lactiflora pall displays anti-inflammation and antioxidant properties in several animal models. Chemokines are vital for directing the movement of circulating leukocytes to the sites of inflammation and are involved in the pathogenesis of various inflammatory skin diseases. Herein, we investigated the effects and potential mechanisms of PF on tumor necrosis factor-α (TNF-α) induced chemokine production in human dermal microvascular endothelial cells. Human dermal microvascular endothelial cell line (HMEC-1) was treated by TNF-α with or without PF. PF markedly attenuated TNF-α-induced chemokines (including CCL2, CCL5, CCL20, CXCL8, CXCL16 and CX3CL1) mRNA expression in HMEC-1. PF also reduced the secretion of these chemokines in culture supernatants. In addition, endothelial activation in the presence of PF markedly blocked the chemotactic activities of TNF-α-stimulated HMEC-1 supernatant on promyelocytic leukemia cell line (HL-60) or the acute mature monocytic leukemia cell line (THP-1) cell migration. Furthermore, Western blot data revealed TNF-α upregulated phosphorylation of inhibitor of κB-α (IκBα) and phosphorylation of extracellular signal-regulated kinase (ERK)1/2, which was almost completely reversed by PF. Finally, PF inhibited nuclear factor-κB (NF-κB) nuclear translocation to the nucleus. Taken together, our data provide the first evidence that PF has an anti-inflammatory ability against TNF-α-induced chemokine production and leukocyte migration, which may be at least partly related to the inhibition of NF-κB and ERK pathway. PF may be a candidate medicine for the treatment of inflammatory skin diseases.


Interaction of 125I-labeled botulinum neurotoxins with nerve terminals. II. Autoradiographic evidence for its uptake into motor nerves by acceptor-mediated endocytosis.
Using pharmacological (Simpson, L.L., 1980, J. Pharmacol. Exp. Ther. 212:16-21) and autoradiographic techniques (Black, J.D., and J.O. Dolly, 1986, J. Cell Biol., 103:521-534), it has been shown that botulinum neurotoxin (BoNT) is translocated across the motor nerve terminal membrane to reach a postulated intraterminal target. In the present study, the nature of this uptake process was investigated using electron microscopic autoradiography. It was found that internalization is acceptor-mediated and that binding to specific cell surface acceptors involves the heavier chain of the toxin. In addition, uptake was shown to be energy and temperature-dependent and to be accelerated by nerve stimulation, a treatment which also shortens the time course of the toxin-induced neuroparalysis. These results, together with the observation that silver grains were often associated with endocytic structures within the nerve terminal, suggested that acceptor-mediated endocytosis is responsible for toxin uptake. This proposal is supported further by the fact that lysosomotropic agents, which are known to interfere with the endocytic pathway, retard the onset of BoNT-induced neuroparalysis and also affect the distribution of silver grains at nerve terminals treated with 125I-BoNT. Possible recycling of BoNT acceptors (an important aspect of acceptor-mediated endocytosis of toxins) at motor nerve terminals was indicated by comparing the extent of labeling in the presence and absence of metabolic inhibitors. On the basis of these collective results, it is concluded that BoNT is internalized by acceptor-mediated endocytosis and, hence, the data support the proposal that this toxin inhibits release of acetylcholine by interaction with an intracellular target.


Classification of steel materials by laser-induced breakdown spectroscopy coupled with support vector machines.
The feasibility of steel materials classification by support vector machines (SVMs), in combination with laser-induced breakdown spectroscopy (LIBS) technology, was investigated. Multi-classification methods based on SVM, the one-against-all and the one-against-one models, and a combination model, are applied to classify nine types of round steel. Due to the inhomogeneity of steel composition, the data obtained using the one-against-all and one-against-one models were ambiguous and difficult to discriminate; whereas, the combination model, was able to successfully distinguish most of the ambiguous data and control the computation cost within an acceptable range. The studies presented here demonstrate that LIBS-SVM is a useful technique for the identification and discrimination of steel materials, and would be very well-suited for process analysis in the steelmaking industry.


Macrocrystals of Colloidal Quantum Dots in Anthracene: Exciton Transfer and Polarized Emission.
In this work, centimeter-scale macrocrystals of nonpolar colloidal quantum dots (QDs) incorporated into anthracene were grown for the first time. The exciton transfer from the anthracene host to acceptor QDs was systematically investigated, and anisotropic emission from the isotropic QDs in the anthracene macrocrystals was discovered. Results showed a decreasing photoluminescence lifetime of the donor anthracene, indicating a strengthening energy transfer with increasing QD concentration in the macrocrystals. With the anisotropy study, QDs inside the anthracene host acquired a polarization ratio of ~1.5 at 0° collection angle, and this increases to ~2.5 at the collection angle of 60°. A proof-of-concept application of these excitonic macrocrystals as tunable color converters on light-emitting diodes was also demonstrated.


Medicine-based evidence: reverse translational ear research recommendations.
Presented here is a first-person account of the evolution of the practice of surgical neurootology to that of medical neurootology shaped mainly by results of treatment directed at underlying otosclerosis-like lesions of the otic capsule and metabolic factors. With new technologies and rapidly evolving concepts, the changing treatment algorithms did not remain constant to provide the usual evidence-based outcome analyses. However, the majority of the patients presenting with neurootological symptoms had undergone previous medical or surgical treatment before undergoing the medical management herein described. The underlying ongoing basic science findings over this period were linked to the clinical observations. On the basis of the more effective results of treating neurootological disorders, recommendations are made for future areas of investigation-mostly basic science-into developing an investigative foundation for future effective management of patients with a variety of neurootological disorders.


The Impact of Heterogeneity and Awareness in Modeling Epidemic Spreading on Multiplex Networks.
In the real world, dynamic processes involving human beings are not disjoint. To capture the real complexity of such dynamics, we propose a novel model of the coevolution of epidemic and awareness spreading processes on a multiplex network, also introducing a preventive isolation strategy. Our aim is to evaluate and quantify the joint impact of heterogeneity and awareness, under different socioeconomic conditions. Considering, as case study, an emerging public health threat, Zika virus, we introduce a data-driven analysis by exploiting multiple sources and different types of data, ranging from Big Five personality traits to Google Trends, related to different world countries where there is an ongoing epidemic outbreak. Our findings demonstrate how the proposed model allows delaying the epidemic outbreak and increasing the resilience of nodes, especially under critical economic conditions. Simulation results, using data-driven approach on Zika virus, which has a growing scientific research interest, are coherent with the proposed analytic model.


Dynamics of Asymmetric and Symmetric Divisions of Muscle Stem Cells In Vivo and on Artificial Niches.
Stem cells can be maintained through symmetric cell divisions (SCDs) and asymmetric cell divisions (ACDs). How and when these divisions occur in vivo in vertebrates is poorly understood. Here, we developed a clonogenic cell tracing method that demonstrates the asymmetric distribution of transcription factors along with old and new DNA in mouse muscle stem cells during skeletal muscle regeneration. Combining single-cell tracking and artificial niches ex vivo, we show how cells switch from ACDs to SCDs, suggesting that they are not engaged in an obligate mode of cell division. Further, we generated SNAP-tagged histone H3-reporter mice and find that, unlike fly germline stem cells, differential fate outcomes are associated with a symmetric distribution of the H3.1 and H3.3 histone variants in mouse muscle stem cells. This versatile and efficient H3-SNAP labeling system will allow an investigation of mechanisms underlying the maintenance of epigenomic identity and plasticity in a variety of tissues.


A randomized controlled trial on the immediate and long-term effects of arm slings on shoulder subluxation in stroke patients.
Arm slings are often used in clinical practice to support the hemiplegic arm aiming to prevent or treat glenohumeral subluxation. Evidence supporting the corrective effect of slings on subluxation is scarce and long-term studies are lacking. The aim of this study was to determine both the immediate and long-term effect on acromiohumeral distance using the Actimove® sling and Shoulderlift and to determine the effect of slings on pain and passive range of motion of the shoulder in stroke patients with glenohumeral subluxation. Randomized control trial. Hospital inpatients. Stroke patients. Twenty-eight stroke patients, with severe upper limb impairments, were randomly allocated to 3 groups (Actimove, Shoulderlift, No sling). Patients wore their supportive device for 6 weeks and no sling in the control group. Immediate and postinterventional effect on acromiohumeral distance was measured using sonography. Pain (VAS), ROM (goniometry), spasticity (Modified Ashworth Scale), Fugl-Meyer Assessment and trunk stability (TIS) were also assessed before and after the intervention. The level of immediate correction of both slings was different at baseline and after 6 weeks (0 weeks: Shoulderlift 63%, Actimove 36%; 6 weeks: Shoulderlift 28%, Actimove 24%). Comparing the level of subluxation over time shows a distinct decrease in subluxation but only for the control group (-37.59% or 3.30 mm). Subluxation remained the same in the Actimove group (-2.77% or 0.27 mm) but increased in the Shoulderlift group (+12.44% or 1.03 mm). After 6 weeks, the Actimove group reported more pain at rest (P=0.036). ROM for abduction and external rotation decreased in 2 groups and remained un-altered in the Shoulderlift group. Results of immediate correction varied. Subluxation seemed to reduce in patients that did not wear a sling. The (assumed) presence of subluxation may not benefit from wearing an arm sling which may itself inhibit active correction. If a sling is indicated the Shoulderlift may be preferable to the Actimove sling.


Improved Automated Detection of Diabetic Retinopathy on a Publicly Available Dataset Through Integration of Deep Learning.
To compare performance of a deep-learning enhanced algorithm for automated detection of diabetic retinopathy (DR), to the previously published performance of that algorithm, the Iowa Detection Program (IDP)-without deep learning components-on the same publicly available set of fundus images and previously reported consensus reference standard set, by three US Board certified retinal specialists. We used the previously reported consensus reference standard of referable DR (rDR), defined as International Clinical Classification of Diabetic Retinopathy moderate, severe nonproliferative (NPDR), proliferative DR, and/or macular edema (ME). Neither Messidor-2 images, nor the three retinal specialists setting the Messidor-2 reference standard were used for training IDx-DR version X2.1. Sensitivity, specificity, negative predictive value, area under the curve (AUC), and their confidence intervals (CIs) were calculated. Sensitivity was 96.8% (95% CI: 93.3%-98.8%), specificity was 87.0% (95% CI: 84.2%-89.4%), with 6/874 false negatives, resulting in a negative predictive value of 99.0% (95% CI: 97.8%-99.6%). No cases of severe NPDR, PDR, or ME were missed. The AUC was 0.980 (95% CI: 0.968-0.992). Sensitivity was not statistically different from published IDP sensitivity, which had a CI of 94.4% to 99.3%, but specificity was significantly better than the published IDP specificity CI of 55.7% to 63.0%. A deep-learning enhanced algorithm for the automated detection of DR, achieves significantly better performance than a previously reported, otherwise essentially identical, algorithm that does not employ deep learning. Deep learning enhanced algorithms have the potential to improve the efficiency of DR screening, and thereby to prevent visual loss and blindness from this devastating disease.


Diosgenin stimulates osteogenic activity by increasing bone matrix protein synthesis and bone-specific transcription factor Runx2 in osteoblastic MC3T3-E1 cells.
Diosgenin, a steroid saponin extracted from the root of wild yam (Dioscorea villossa) is claimed to have osteogenic property. However, detailed studies providing evidence to this claim have not been fully undertaken. In this study, we investigated the effect of diosgenin on the osteogenesis of murine MC3T3-E1 osteoblastic cells. Cells were cultured with varying levels of diosgenin (0-10 μM) within 25 days of bone formation period. Diosgenin was found to stimulate proliferation within the range of 0.01-5 μM using MTT assay. The medium and cellular levels of Type 1 collagen and alkaline phosphatase (ALP), both of which are major bone matrix proteins, increased within the low range of diosgenin concentration (>0-3 μM), and this pattern was further confirmed by collagen and ALP staining of the extracellular matrix (ECM). The cellular protein expression of ALP and collagen Type 1 was also increased at 0.1-1 μM diosgenin treatment as analyzed by Western blot. Calcium deposition within the ECM also showed the same pattern as assessed by Alizarin Red S and Von Kossa staining. Bone-specific transcription factor runt-related transcription factor 2 (Runx2) and Runx2-regulated osteopontin protein expressions were induced at low concentration (0.1-1 μM) and again decreased with high diosgenin concentrations. Based on our findings, our study suggests that diosgenin can enhance bone formation by stimulating the synthesis and secretion of Type 1 collagen and ALP and bone marker proteins Runx2 and osteopontin expression. The increased levels of these marker proteins, in turn, can increase the formation of calcium deposits within the ECM thereby increasing bone formation.


Gender and age interact to affect early outcome after intracerebral hemorrhage.
Intracerebral hemorrhage (ICH) is a common and devastating form of cerebrovascular disease. In ICH, gender differences in outcomes remain relatively understudied but have been examined in other neurological emergencies. Further, a potential effect of age and gender on outcomes after ICH has not been explored. This study was designed to test the hypothesis that age and gender interact to modify neurological outcomes after ICH. Adult patients admitted with spontaneous primary supratentorial ICH from July 2007 through April 2010 were assessed via retrospective analysis of an existing stroke database at Duke University. Univariate analysis of collected variables was used to compare gender and outcome. Unfavorable outcome was defined as discharge to hospice or death. Using multivariate regression, the combined effect of age and gender on outcome after ICH was analyzed. In this study population, women were younger (61.1+14.5 versus 65.8+17.3 years, p=0.03) and more likely to have a history of substance abuse (35% versus 8.9%, p<0.0001) compared to men. Multivariable models demonstrated that advancing age had a greater effect on predicting discharge outcome in women compared to men (p=0.02). For younger patients, female sex was protective; however, at ages greater than 60 years, female sex was a risk factor for discharge to hospice or death. While independently associated with discharge to hospice or death after ICH, the interaction effect between gender and age demonstrated significantly stronger correlation with early outcome after ICH in a single center cohort. Prospective study is required to verify these findings.


An empirical study of the traditional Mach card effect.
The traditional achromatic Mach card effect is an example of lightness inconstancy and a demonstration of how shape and lightness perception interact. We present a quantitative study of this phenomenon and explore the conditions under which it occurs. The results demonstrate that observers show lightness constancy only when sufficient information is available about the light-source position, and the perceptual task required of them is surface identification rather than direct colour-appearance matching. An analysis and comparison of these results with the chromatic Mach card effect (Bloj et al 1999 Nature 402 877-879) demonstrate that the luminance effects of mutual illumination do not account for the change in lightness perception in the traditional Mach card.


Are morphologic features of recent small subcortical infarcts related to specific etiologic aspects?
Recent small subcortical infarcts (RSSIs) mostly result from the occlusion of a single, small, brain artery due to intrinsic cerebral small-vessel disease (CSVD). Some RSSIs may be attributable to other causes such as cardiac embolism or large-artery disease, and their association with coexisting CSVD and vascular risk factors may vary with morphological magnetic resonance imaging (MRI) features. We retrospectively identified all inpatients with a single symptomatic MRI-confirmed RSSI between 2008 and 2013. RSSIs were rated for size, shape, location (i.e. anterior: basal ganglia and centrum semiovale posterior cerebral circulation: thalamus and pons) and MRI signs of concomitant CSVD. In a further step, clinical data, including detailed diagnostic workup and vascular risk factors, were analyzed with regard to RSSI features. Among 335 RSSI patients (mean age 71.1 ± 12.1 years), 131 (39%) RSSIs were >15 mm in axial diameter and 66 (20%) were tubular shaped. Atrial fibrillation (AF) was present in 44 (13.1%) and an ipsilateral vessel stenosis > 50% in 30 (9%) patients. Arterial hypertension and CSVD MRI markers were more frequent in patients with anterior-circulation RSSIs, whereas diabetes was more prevalent in posterior-circulation RSSIs. Larger RSSIs occurred more frequently in the basal ganglia and pons, and the latter were associated with signs of large-artery atherosclerosis. Patients with concomitant AF had no specific MRI profile. Our findings suggest the contribution of different pathophysiological mechanisms to the occurrence of RSSIs in the anterior and posterior cerebral circulation. While there appears to be some general association of larger infarcts in the pons with large-artery disease, we found no pattern suggestive of AF in RSSIs.


Periplasmic superoxide dismutase in meningococcal pathogenicity.
Meningococcal sodC encodes periplasmic copper- and zinc-cofactored superoxide dismutase (Cu,Zn SOD) which catalyzes the conversion of the superoxide radical anion to hydrogen peroxide, preventing a sequence of reactions leading to production of toxic hydroxyl free radicals. From its periplasmic location, Cu,Zn SOD was inferred to acquire its substrate from outside the bacterial cell and was speculated to play a role in preserving meningococci from the action of microbicidal oxygen free radicals produced in the context of host defense. A sodC mutant was constructed by allelic exchange and was used to investigate the role of Cu,Zn SOD in pathogenicity. Wild-type and mutant meningococci grew at comparable rates and survived equally long in aerobic liquid culture. The mutant showed no increased sensitivity to paraquat, which generates superoxide within the cytosol, but was approximately 1,000-fold more sensitive to the toxicity of superoxide generated in solution by the xanthine/xanthine oxidase system. These data support a role for meningococcal Cu,Zn SOD in protection against exogenous superoxide. In experiments to translate this into a role in pathogenicity, wild-type and mutant organisms were used in an intraperitoneal mouse infection model. The sodC mutant was significantly less virulent. We conclude that periplasmic Cu,Zn SOD contributes to the virulence of Neisseria meningitidis, most likely by reducing the effectiveness of toxic oxygen host defenses.


Acute lower respiratory infections in childhood: opportunities for reducing the global burden through nutritional interventions.
Inadequate nutrition and acute lower respiratory infection (ALRI) are overlapping and interrelated health problems affecting children in developing countries. Based on a critical review of randomized trials of the effect of nutritional interventions on ALRI morbidity and mortality, we concluded that: (1) zinc supplementation in zinc-deficient populations prevents about one-quarter of episodes of ALRI, which may translate into a modest reduction in ALRI mortality; (2) breastfeeding promotion reduces ALRI morbidity; (3) iron supplementation alone does not reduce ALRI incidence; and (4) vitamin A supplementation beyond the neonatal period does not reduce ALRI incidence or mortality. There was insufficient evidence regarding other potentially beneficial nutritional interventions. For strategies with a strong theoretical rationale and probable operational feasibility, rigorous trials with active clinical case-finding and adequate sample sizes should be undertaken. At present, a reduction in the burden of ALRI can be expected from the continued promotion of breastfeeding and scale-up of zinc supplementation or fortification strategies in target populations.


All cause and disease specific mortality in patients with knee or hip osteoarthritis: population based cohort study.
To examine all cause and disease specific mortality in patients with osteoarthritis of the knee or hip. Population based cohort study. General practices in the southwest of England. 1163 patients aged 35 years or over with symptoms and radiological confirmation of osteoarthritis of the knee or hip. Age and sex standardised mortality ratios and multivariable hazard ratios of death after a median of 14 years' follow-up. Patients with osteoarthritis had excess all cause mortality compared with the general population (standardised mortality ratio 1.55, 95% confidence interval 1.41 to 1.70). Excess mortality was observed for all disease specific causes of death but was particularly pronounced for cardiovascular (standardised mortality ratio 1.71, 1.49 to 1.98) and dementia associated mortality (1.99, 1.22 to 3.25). Mortality increased with increasing age (P for trend <0.001), male sex (adjusted hazard ratio 1.59, 1.30 to 1.96), self reported history of diabetes (1.95, 1.31 to 2.90), cancer (2.28, 1.50 to 3.47), cardiovascular disease (1.38, 1.12 to 1.71), and walking disability (1.48, 1.17 to 1.86). However, little evidence existed for increased mortality associated with previous joint replacement, obesity, depression, chronic inflammatory disease, eye disease, or presence of pain at baseline. The more severe the walking disability, the higher was the risk of death (P for trend <0.001). Patients with osteoarthritis are at higher risk of death compared with the general population. History of diabetes, cancer, or cardiovascular disease and the presence of walking disability are major risk factors. Management of patients with osteoarthritis and walking disability should focus on effective treatment of cardiovascular risk factors and comorbidities, as well as on increasing physical activity.


Preferential expression of an alpha-tubulin gene of Arabidopsis in pollen.
The pool of tubulin protein in tissues of Arabidopsis is provided by the expression of multiple alpha-tubulin (TUA) and beta-tubulin genes. Whereas most tubulin genes are expressed in many tissues, previous evidence suggested that the TUA1 gene might be expressed primarily in pollen. We now report a detailed analysis of TUA1 expression during Arabidopsis development. In RNA from tissues of dissected flowers, TUA1 transcripts were detected only in stamens and mature pollen. Chimeric genes containing TUA1 5' flanking DNA fused to the beta-glucuronidase (GUS) coding region were used to create transgenic Arabidopsis plants. Plants containing a chimeric gene with 533 bp of 5' flanking sequence were analyzed by histochemical assay to localize GUS expression within the plant. The blue product of GUS enzyme activity accumulated very rapidly in postmitotic pollen grains. Much lower levels of GUS activity were detected in anthers with uninucleate pollen grains, in flower receptacles, and in a few vegetative tissues. Analysis of 5' deletions of the TUA1 promoter suggested that 97 bp of 5' flanking DNA is sufficient to drive GUS expression in pollen and young anthers, whereas at least 380 bp is required to detect GUS expression in the receptacle. Examination of the TUA1 promoter sequence revealed several motifs that are repeated within the TUA1 promoter and are similar to sequences in other pollen-specific promoters.


Platanus hispanica-inspired design of Co-carbon nanotube frameworks through chemical vapor deposition: a highly integrated hierarchical electrocatalyst for oxygen reduction reactions.
In this communication, a novel platanus hispanica-like, highly integrated hierarchical electrocatalyst, with Co-carbon nanotubes anchored through porous Co embedded carbon sphere frameworks (Co-CNTFs), was fabricated using a chemical vapor deposition (CVD) method. More importantly, the prepared Co-CNTFs demonstrate even better activity than commercial Pt electrocatalysts in an alkaline medium. This presented CVD approach provides an effective way to grow metal-CNTs in situ through various metal-complex-derived functional nanomaterials and can be expanded to metallic oxide, metallic sulfide, and metallic phosphide, among others, to introduce carbon nanotube frameworks with a multitude of potential applications.


The noncustodial parent and medical treatment.
Despite the frequency of divorce, there are no comprehensive guidelines for the relative rights of custodial and noncustodial parents. Since there are no definite rules for the parties to follow, divorced parents receive conflicting advice and are more likely to engage in bitter misunderstandings. This paper creates a framework for defining whether the noncustodial parent has a right to authorize emergency medical care, routine medical care, serious nonemergency medical care, psychiatric evaluation, and psychiatric treatment. The author suggests that the noncustodial parent should be able to authorize routine medical treatment, but not routine psychiatric treatment.