Diffuse glioblastoma resembling acute hemorrhagic leukoencephalitis.
We report the case of a young man with sudden onset of diplopia after an upper respiratory tract infection. Based on the first radiological findings acute hemorrhagic leukoencephalitis, a variant of acute disseminated encephalomyelitis, was suspected and treatment with high dose intravenous dexamethasone was started but it was stopped for intolerance. The patient clinically worsened, developing gait instability, ataxia and ophthalmoplegia; brain MRI performed 20 days later showed severe progression of the disease with subependymal dissemination. After brain biopsy of the right temporal lesion the histological diagnosis was glioblastoma. These findings suggest that MRI features of acute hemorrhagic leukoencephalitis may dissimulate the diagnosis of diffuse glioma/glioblastoma. This case underscores the importance of considering diffuse glioma in the differential diagnosis of atypical signs and symptoms of acute hemorrhagic leukoencephalitis and underlines the relevant role of integrating neuroradiologic findings with neuropathology.


Trends on Axillary Surgery in Nondistant Metastatic Breast Cancer Patients Treated Between 2011 and 2015: A Dutch Population-based Study in the ACOSOG-Z0011 and AMAROS Era.
To evaluate patterns of care in axillary surgery for Dutch clinical T1-4N0M0 (cT1-4N0M0) breast cancer patients and to assess the effect of the American College for Surgeons Oncology Group (ACOSOG)-Z0011 and After Mapping of the Axilla: Radiotherapy Or Surgery (AMAROS) trial on axillary surgery patterns in Dutch cT1-2N0M0 sentinel node positive breast cancer patients. Since publication of the ACOSOG-Z0011 and AMAROS trial, omitting a completion axillary lymph node dissection (cALND) in sentinel node positive breast cancer patients is proposed in selected patients. Data were obtained from the nationwide Nationaal Borstkanker Overleg Nederland breast cancer audit. Descriptive analyses were used to demonstrate trends in axillary surgery. Multivariable logistic regression analyses were used to identify factors associated with the omission of cALND in cT1-2N0M0 sentinel node-positive breast cancer patients. Between 2011 and 2015 in cT1-4N0M0 breast cancer patients, the use of sentinel lymph node biopsy as definitive axillary staging increased from 72% to 93%, and (c)ALND as definitive axillary staging decreased from 24% to 6% (P < 0.001). The use of cALND decreased from 75% to 17% in cT1-2N0 sentinel node-positive patients (P < 0.001). Earlier year of diagnosis, lower age, primary mastectomy, invasive lobular subtype, increasing tumor grade, and treatment in a nonteaching hospital were associated with a lower probability of omitting cALND (P < 0.001). This study shows a trend towards less extensive axillary surgery in Dutch cT1-T4N0M0 breast cancer patients; illustrated by an overall increase of sentinel lymph node biopsy and decrease in cALND. Despite this trend, particularly noticed in cT1-2N0 sentinel node-positive patients after publication of the ACOSOG-Z0011 and AMAROS trial, variations in patterns of care in axillary surgery are still present.


[Sleep-wake patterns in Portuguese undergraduates].
Sleep habits of Portuguese undergraduates are almost unknown, and very few international published articles have addressed whether demographic and academic variables such as residence, university year and academic field, might be associated to the sleep-wake patterns of university students. The aims of the present work were thus to characterize perceived sleep habits, behaviours and problems of Portuguese undergraduates, and to examine them by gender, residence status, university year and academic field. The selected participants were 1654 undergraduates (55% female) of a public Portuguese university, aged 17-25 years (M = 19.98, SD = 1.65), at the 1st, 2nd a 3rd university years, studying Engineering, Management, Sciences, Languages and Education, in its majority living outside their parents/family home (<<moved>> students). Participants answered to a self-response questionnaire about sleep-wake patterns, developed for the main research. Compared to men, women showed more regular and earlier sleep-wake schedules, fewer sleeplessness nights, and less napping, but more troubles initiating/maintaining sleep and use of pills to fall asleep. <<Moved>> students had the latest sleep-wake schedules on week nights, and felt more disturbed by noise; <<moved>> men reported more sleeplessness nights to complete academic tasks and greater changes of sleep habits since high school. Across university years (1st-3rd), there was a rising of perceived change of sleep habits, a delay of bedtime on school nights, and a decrease, in men, of week-weekend irregularity of rise time and of sleeplessness nights. Engineering students had the fewest difficulties initiating/maintaining sleep and the lowest use of sleeping promoting pills but, together with Sciences and Management, later sleep-wake schedules, than Languages and Education students. Differences on sleep-wake patterns were found between men and women, in accordance to the sleep literature. On addition to gender, the present study highlights that university year and, most importantly, residence circumstances, are also important variables to be considered for a better understanding of sleep habits and behaviours in undergraduates. Thus, we hope our findings constitute a contribution for the improvement of health prevention and intervention strategies directed to university students.


PPI, paradoxes and Plato: who's sailing the ship?
Over the last decade, patient and public involvement (PPI) has become a requisite in applied health research. Some funding bodies demand explicit evidence of PPI, while others have made a commitment to developing PPI in the projects they fund. Despite being commonplace, there remains a dearth of engagement with the ethical and theoretical underpinnings of PPI processes and practices. More specifically, while there is a small (but growing) body of literature examining the effectiveness and impact of PPI, there has been relatively little reflection on whether the concept/practice of PPI is internally coherent. Here, the authors unpick a 'paradox' within PPI, which highlights a tension between its moral and pragmatic motivations and its implementation. The authors argue that this 'professionalisation paradox' means we need to rethink the practice, and purpose, of PPI in research.


Epistemology and experimentation: an examination of quality factors in research design.
Forty-four research articles published in the occupational therapy literature were examined to determine the effect of design quality on study outcome. All 44 of the studies examined involved a parallel-groups comparison design. Twenty-two of the studies included random assignment of subjects to various groups, and the remaining 22 investigations used some nonrandom method to determine subject allocation. A standardized metric (i.e., effect size) was used to determine the effect of the independent variable in the 44 studies. The data analysis revealed that effect-size values were not significantly different between studies that involved random assignment and those not involving random assignment. The argument is made that such design characteristics as random assignment should be examined as moderator variables in any attempt to synthesize findings from multiple studies. Such an approach would treat the design used in a study as one of many possible variables that could influence the outcome. This approach would modify the a priori assumption that one research design is inherently superior to another regardless of the research question or context.


Metabolic and cardiovascular outcomes in patients with Cushing's syndrome of different aetiologies during active disease and 1 year after remission.
Cushing's syndrome is associated with several comorbidities responsible for the increased cardiovascular risk, not only during the active phase but also after disease remission. In 29 patients with Cushing's syndrome (14 Cushing's diseases and 15 adrenal adenomas), waist circumference, fasting and 2-h glucose after oral glucose tolerance test (OGTT), lipid profile and blood pressure were evaluated during the active disease and 1 year after remission and compared with those in 29 sex-, age- and BMI-matched controls. During the active disease, waist circumference, 2-h glucose after OGTT, total and LDL cholesterol were higher in patients with Cushing's syndrome than in controls (P < 0·001) but similar in Cushing's disease and adrenal adenomas. The prevalence of impaired glucose tolerance (IGT), diabetes mellitus, dyslipidaemia and hypertension was higher (P < 0·001) in patients with Cushing's syndrome (27%, 24%, 59% and 72%) than in controls (10%, 0%, 21% and 10%), with no significant difference between Cushing's disease and adrenal adenomas. One year following hormonal remission, waist circumference persisted higher than in controls (P < 0·05) in both Cushing's disease and adrenal adenomas. Metabolic and cardiovascular abnormalities were still present in both groups, although with a lower prevalence, as well as with a more marked decrease in adrenal adenomas (P < 0·05 vs active disease for IGT, dyslipidaemia and hypertension). These results show that chronic hypercortisolism, independently of its aetiology, contributes to metabolic impairment and increased cardiovascular risk, while these abnormalities mostly persist in patients with previous Cushing's disease after hormonal remission. Pituitary hormonal deficiencies, hormonal replacement treatments and/or incomplete cure from Cushing's disease may account for these findings.


To embed or not to embed? A longitudinal study exploring the impact of curriculum design on the evidence-based practice profiles of UK pre-registration nursing students.
The use of Evidence-Based Practice (EBP) is increasingly emphasized within healthcare. However, little research has focused on nurses' pre-registration training; particularly regarding the impact of curriculum-design on learning EBP. This study compared the impact of embedding EBP throughout the curriculum, with modular-based teaching, on pre-registration nursing students' EBP profiles. A longitudinal panel study. A convenience sample of fifty-six pre-registration nursing students (55.4% studying an embedded EBP-curriculum and 44.6% studying a modular EBP-curriculum), were recruited from a UK University between 2011 and 2014. Participants completed the Student Evidence-Based Practice Questionnaire (S-EBPQ) in the first, second and third year of their course. This questionnaire measures four EBP domains: frequency of use, attitude, knowledge and skills in retrieving and reviewing evidence, and knowledge and skills in applying and sharing evidence. Two-way mixed between-within Analyses of Variance revealed significant improvements across all domains, except attitude (which remained broadly positive across all years), for both curriculum-groups. No significant differences in this improvement were identified between the two curricula overall. However, the direction and rate of change of scores on the retrieving and applying subscales (but not frequency of use) for the two groups differed across time; specifically those on the embedded curriculum showed a dip in scores on these subscales in year 2. This appeared to be related to associated features of the course such as the timing of placements and delivery of theory. Taking a modular or embedded approach to EBP may have little impact on students' final EBP profiles. However, careful consideration should be given to the timing of related course features which may play a key role in students' perceptions of their knowledge and skills in its application. Further research should explore how curriculum-design might build on students' initial positive attitudes towards EBP and its use in their practice.


Learning eigenfunctions links spectral embedding and kernel PCA.
In this letter, we show a direct relation between spectral embedding methods and kernel principal components analysis and how both are special cases of a more general learning problem: learning the principal eigenfunctions of an operator defined from a kernel and the unknown data-generating density. Whereas spectral embedding methods provided only coordinates for the training points, the analysis justifies a simple extension to out-of-sample examples (the Nyström formula) for multidimensional scaling (MDS), spectral clustering, Laplacian eigenmaps, locally linear embedding (LLE), and Isomap. The analysis provides, for all such spectral embedding methods, the definition of a loss function, whose empirical average is minimized by the traditional algorithms. The asymptotic expected value of that loss defines a generalization performance and clarifies what these algorithms are trying to learn. Experiments with LLE, Isomap, spectral clustering, and MDS show that this out-of-sample embedding formula generalizes well, with a level of error comparable to the effect of small perturbations of the training set on the embedding.


Psychological First Aid Intervention after Exposure to a Traumatic Event at Work among Emergency Medical Services Workers.
Psychological First Aid (PFA) is a promising early intervention for managing mental health symptoms and providing psychosocial support after exposure to a traumatic event (TE) among high-risk organizations such as Emergency Medical Service (EMS). However, recipients' experience with PFA remains understudied. This study aimed to explore the perception of EMS workers (n = 13) who received PFA administered by a peer helper using a qualitative inductive approach. Findings from a thematic analysis indicated that the PFA intervention addresses EMS workers' immediate needs in congruence with Hobfoll's five essential principles to enhance coping and recovery after a TE. Specific components of the intervention, such as its time-sensitive nature and the closeness with peers, were especially appreciated by EMS workers. The PFA intervention appeared to have a beneficial impact on recipients, regarding the reduction of stigma, the increase of help-seeking behaviors, and the decrease of organizational difficulties. In conclusion, the PFA intervention offered by peer helpers is appreciated by recipients and is a beneficial first step toward supporting EMS workers in the aftermath of workplace trauma. These qualitative findings contribute to the current literature by informing further research about PFA intervention in other high-risk organizations and quantitative studies aiming to test PFA's efficacy in such settings.


Visuospatial deficits in posterior cortical atrophy: structural and functional correlates.
To determine the neural substrates of biased spatial orienting in posterior cortical atrophy (PCA) by using a combined structural and functional neuroimaging approach. Patients with spatial neglect typically bisect horizontal long lines towards their brain lesions but the precise neural substrates of this spatial bias remain controversial and poorly explored in neurodegenerative disorders such as PCA. 15 patients with PCA underwent brain MRI and single photon emission computed tomography (SPECT) and were required to bisect five 20 cm long lines, each centred on an A4 horizontal sheet. Direct correlations between average deviations on the bisection task and both (1) the degree of grey matter density, as estimated by voxel based morphometry and (2) regional cerebral blood flow, as assessed by SPECT, were performed. Seven patients (47%) had pathological bias on the bisection task, deviating consistently towards the non-neglected side for each of the five lines. Rightward bias (sign of left-sided neglect) was more frequent and severe than leftward bias (sign of right-sided neglect). Correlation analyses showed that rightward deviations correlated with atrophy and hypoperfusion exclusively in the right hemisphere, involving a large scale fronto-parietal network; cortical atrophy was prominent in the parieto-temporal cortex but extended to the frontal region; hypoperfusion was substantial both in the middle frontal gyrus and in the postcentral region. No correlations emerged from leftward deviations. The results indicate that rightward bias (sign of left-sided neglect) in PCA depends on dysfunction of a large fronto-parietal network in the right hemisphere, related to both cortical atrophy and decreased cerebral perfusion.


Effects of Transobturator Midurethral Sling Surgery on Sexual Functions: One-Year Follow-Up.
To evaluate sexual functions of women having stress urinary incontinence (SUI) preoperatively and 6 months and 12 months after undergoing a transobturator tape (TOT) ± pelvic organ prolapse (POP) surgery. One hundred-ninety-five women with SUI ± POP were recruited and 150 sexually active women who had clinical ± urodynamic SUI and underwent TOT ± POP surgery were included in this prospective study. Urogynecologic symptoms were evaluated preoperatively, at 6 months, and 12 months by Female Sexual Function Index (FSFI). One hundred fifty women completed the study. Seventy-four underwent TOT-only and 76 underwent TOT + concomitant surgery. Mean total scores of FSFI were 21.7 ± 7.8, 22 ± 8.7, and 22.1 ± 8 in the preoperative period, postoperative 6, and 12 months, respectively. There was significant improvement in desire and total scores in the TOT-only group, whereas there was no significant difference in the TOT + concomitant surgery group except for significant worsening in the lubrication domain. The frequency of sexual intercourse increased while that of coital incontinence decreased after surgery. In our study, TOT was associated with decrease in coital incontinence and significant improvement in desire. In addition, there was significant improvement in FSFI desire and total scores in the TOT-only group, whereas no significant difference was observed in the TOT + concomitant surgery group except for the worsening of lubrication.


Heterozygosity for the mouse Apex gene results in phenotypes associated with oxidative stress.
Apurinic/apyrimidinic endonuclease is a key enzyme in the process of base excision repair, required for the repair of spontaneous base damage that arises as a result of oxidative damage to DNA. In mice, this endonuclease is coded by the Apex gene, disruption of which is incompatible with embryonic life. Here we confirm the embryonic lethality of Apex-null mice and report the phenotypic characterization of mice that are heterozygous mutants for the Apex gene (Apex+/-). We show that Apex heterozygous mutant cells and animals are abnormally sensitive to increased oxidative stress. Additionally, such animals manifest elevated levels of oxidative stress markers in serum, and we show that dietary supplementation with antioxidants restores these to normal levels. Apex+/- embryos and pups manifest reduced survival that can also be partially rescued by dietary supplementation with antioxidants. These results are consistent with a proposed role for this enzyme in protection against the deleterious effects of oxidative stress and raise the possibility that humans with heterozygous mutations in the homologous HAP1 gene may be at increased risk for the phenotypic consequences of oxidative stress in cells.


B-type natriuretic peptides and mortality after stroke: a systematic review and meta-analysis.
To measure the association of B-type natriuretic peptide (BNP) and N-terminal fragment of BNP (NT-proBNP) with all-cause mortality after stroke, and to evaluate the additional predictive value of BNP/NT-proBNP over clinical information. Suitable studies for meta-analysis were found by searching MEDLINE and EMBASE databases until October 26, 2012. Weighted mean differences measured effect size; meta-regression and publication bias were assessed. Individual participant data were used to estimate effects by logistic regression and to evaluate BNP/NT-proBNP additional predictive value by area under the receiver operating characteristic curves, and integrated discrimination improvement and categorical net reclassification improvement indexes. Literature-based meta-analysis included 3,498 stroke patients from 16 studies and revealed that BNP/NT-proBNP levels were 255.78 pg/mL (95% confidence interval [CI] 105.10-406.47, p = 0.001) higher in patients who died; publication bias entailed the loss of this association. Individual participant data analysis comprised 2,258 stroke patients. After normalization of the data, patients in the highest quartile had double the risk of death after adjustment for clinical variables (NIH Stroke Scale score, age, sex) (odds ratio 2.30, 95% CI 1.32-4.01 for BNP; and odds ratio 2.63, 95% CI 1.75-3.94 for NT-proBNP). Only NT-proBNP showed a slight added value to clinical prognostic variables, increasing discrimination by 0.028 points (integrated discrimination improvement index; p < 0.001) and reclassifying 8.1% of patients into correct risk mortality categories (net reclassification improvement index; p = 0.003). Neither etiology nor time from onset to death affected the association of BNP/NT-proBNP with mortality. BNPs are associated with poststroke mortality independent of NIH Stroke Scale score, age, and sex. However, their translation to clinical practice seems difficult because BNP/NT-proBNP add only minor predictive value to clinical information.


Documenting Routinely What Matters to People: Standardized Headings for Health Records of Patients with Chronic Health Conditions.
Specifying the content in electronic health records (EHRs) through standardized headings based on international reference classifications will facilitate their semantic interoperability. The objective of this study was to specify potential chapter headings for EHRs aligned with the World Health Organization's (WHO) International Classification of Functioning, Disability, and Health (ICF) based on the perspectives of people living with chronic health conditions, carers, and professionals. A multistage process was established including (1) a patient workshop, (2) an online survey of both patients and carers, and (3) an online consultation with patient and professional bodies. The ICF served as a starting point. Based on the first stage, a first draft of the headings was developed and further refined based on the feedback at each stage. We examined in a fourth step whether items from existing assessment tools support the operationalization of the identified headings. Therefore, we used the WHO Disability Assessment Schedule 2.0 (WHODAS2.0), a patient-reported instrument, and interRAI, a clinician-administered instrument. The first workshop was attended by eight people, the survey was completed by 250 persons, and the online consultation received detailed feedback by 18 professional bodies. This study resulted in 16 potential chapter headings for EHRs which capture aspects related to the body, such as emotions, motivation, sleep, and memory or thoughts, to being involved in social life, such as mobility, social activities, and finances, as well as to the care process, such as understanding of health issues and treatment or care priorities and goals. When using the WHODAS2.0 and interRAI together, they capture all except one of the proposed headings. The identified headings provide a high level structure for the standardized recording, use, and sharing of information. Once implemented, these headings have the potential to facilitate the delivery of personalized care planning for patients with long-term health problems.


Low-Rank Plus Sparse Decomposition of fMRI Data With Application to Alzheimer's Disease.
Studying functional brain connectivity plays an important role in understanding how human brain functions and neuropsychological diseases such as autism, attention-deficit hyperactivity disorder, and Alzheimer's disease (AD). Functional magnetic resonance imaging (fMRI) is one of the most popularly used tool to construct functional brain connectivity. However, the presence of noises and outliers in fMRI blood oxygen level dependent (BOLD) signals might lead to unreliable and unstable results in the construction of connectivity matrix. In this paper, we propose a pipeline that enables us to estimate robust and stable connectivity matrix, which increases the detectability of group differences. In particular, a low-rank plus sparse (L + S) matrix decomposition technique is adopted to decompose the original signals, where the low-rank matrix L recovers the essential common features from regions of interest, and the sparse matrix S catches the sparse individual variability and potential outliers. On the basis of decomposed signals, we construct connectivity matrix using the proposed novel concentration inequality-based sparse estimator. In order to facilitate the comparisons, we also consider correlation, partial correlation, and graphical Lasso-based methods. Hypothesis testing is then conducted to detect group differences. The proposed pipeline is applied to rs-fMRI data in Alzheimer's disease neuroimaging initiative to detect AD-related biomarkers, and we show that the proposed pipeline provides accurate yet more stable results than using the original BOLD signals.


Biomechanics in Paralympics: Implications for Performance.
To provide an overview of biomechanical studies in Paralympic research and their relevance for performance in Paralympic sports. The search terms paralympic biomechanics, paralympic sport performance, paralympic athlete performance, and paralympic athlete were entered into the electronic database PubMed. Thirty-four studies were found. Biomechanical studies in Paralympics mainly contributed to performance enhancement by technical optimization (n = 32) and/or injury prevention (n = 6). In addition, biomechanics was found to be important in understanding activity limitation caused by various impairments, which is relevant for evidence-based classification in Paralympic sports (n = 6). Distinctions were made between biomechanical studies in sitting (41%), standing (38%), and swimming athletes (21%). In sitting athletes, mostly kinematics and kinetics in wheelchair propulsion were studied, mainly in athletes with spinal-cord injuries. In addition, kinetics and/or kinematics in wheelchair basketball, seated discus throwing, stationary shot-putting, hand-cycling, sit-skiing, and ice sledge hockey received attention. In standing sports, primarily kinematics of athletes with amputations performing jump sports and running and the optimization of prosthetic devices were investigated. No studies were reported on other standing sports. In swimming, mainly kick rate and resistance training were studied. Biomechanical research is important for performance by gaining insight into technical optimization, injury prevention, and evidence-based classification in Paralympic sports. In future studies it is advised to also include physiological and biomechanical measures, allowing the assessment of the capability of the human body, as well as the resulting movement.


Evidence of gray matter reduction and dysfunction in chromosome 22q11.2 deletion syndrome.
Chromosome 22q11.2 deletion syndrome (22q11DS) is associated with cognitive deficits and morphometric brain abnormalities in childhood and a markedly elevated risk of schizophrenia in adolescence/early adulthood. Determining the relationship between neurocognition and neuroimaging findings would yield crucial information about childhood neurodevelopment and provide a basis for the study of the trajectory that occurs on the pathway to psychosis. We compared morphometric brain findings between non-psychotic children with 22q11DS (n = 22) and healthy controls (n = 16), and examined the association between neurocognitive functioning and morphometric brain findings. Volumetric regional gray matter differences between the 22q11DS and control subjects were measured, and correlations of the regional gray matter volumes and neurocognition were performed. Children with 22q11DS demonstrated reductions in gray matter in several brain regions, chiefly the frontal cortices, the cingulate gyrus and the cerebellum. The volumetric reductions in these salient areas were associated with poor performance in sustained attention, executive function and verbal memory; however, the relation of brain volume with cognitive performance did not differ between the patient and control groups. Thus, children with 22q11DS demonstrate gray matter reductions in multiple brain regions that are thought to be relevant to schizophrenia. The correlation of these volumetric reductions with poor neurocognition indicates that these brain regions may mediate higher neurocognitive functions implicated in schizophrenia.


Cholesterol granuloma of the maxillary sinus: six cases from the same region.
It is common to find cholesterol granuloma in the mastoid antrum and air cells of the temporal bone, but it is very rare in paranasal sinuses. In the development of this pathology, the key factor is the presence of a closed cavity containing exudate and blood. Six cases of cholesterol granuloma of the maxillary sinus are presented from six years' study in our hospital. According to the main symptoms, clinical findings, and radiological appearance (except the destruction of the antrum wall in some patients), the pathology was similar to chronic maxillary sinusitis. All the patients were treated with radical operative techniques. In this study, we reviewed the literature and our cases, and could not detect any findings to explain why this pathology had occurred frequently in our district. We strongly recommend that investigations should be carried out on all specimens obtained from paranasal sinus surgery, because the cholesterol granuloma in the maxillary antrum could be mistaken for chronic sinusitis.


Thyroid dysfunction and semen quality.
Thyroid hormones act on testis in multiple ways and exert their effect on different cell types, including Leydig and Sertoli cells, and germ cells. An excess or deficit of thyroid hormones results in alterations of testis function, including semen abnormalities. More frequently, hyperthyroidism has been associated with reduced semen volume and reduced sperm density, motility, and morphology, whereas hypothyroidism is associated with reduced sperm morphology. Therefore, thyroid function tests should be part of the diagnostic workup of the infertile man. This article is aimed at (1) elucidating how hyperthyroidism and hypothyroidism lead to a reduction in semen quality, briefly reviewing the current literature on murine models and humans, and (2) pinpointing the limitations of the studies carried out so far and identifying new perspectives for future research.


Using circulating tumor cells as a prognostic indicator in metastatic castration-resistant prostate cancer.
A more reliable tumor marker is needed as a prognostic indicator in metastatic castration-resistant prostate cancer. Circulating tumor cells (CTCs) are cells that have broken away from a tumor and flow in the bloodstream. Evidence has indicated that the presence of CTCs in the peripheral blood of men with solid malignancies correlates with clinical outcomes. When the CTC number is reduced to fewer than five cells per 7.5 ml of blood, survival outcomes often improve. The relationship between the number of CTCs and prognosis has the potential to influence treatment decisions. Therefore, oncology nurses and practitioners must evaluate the scientific evidence, understand the clinical implications, and realize the impact CTC counts may have on practice to effectively communicate the CTC results to a patient. In addition, oncology nurses and practitioners must know that although favorable changes in CTC count are associated with a better prognosis, that alone cannot be used to guide treatment decisions for an individual.


Immunochemical and single molecule force spectroscopy studies of specific interaction between the laminin binding protein and the West Nile virus surface glycoprotein E domain II.
ELISA and Western blot immunochemical data attest an effective and highly specific interaction of the surface glycoprotein E domain II (DII) of the tick born encephalitis and Dengue viruses with the laminin binding protein (LBP). Based on a highly conservative structure of the DII in different flaviviruses we propose a similarly effective interaction between the LBP and the DII of the surface glycoprotein E of the West Nile virus. We report the results of studies of this interaction by immunochemical and single molecule force spectroscopy methods. The specific binding between these species is confirmed by both methods.


A Novel Percutaneous Electrode Implant for Improving Robustness in Advanced Myoelectric Control.
Despite several decades of research, electrically powered hand and arm prostheses are still controlled with very simple algorithms that process the surface electromyogram (EMG) of remnant muscles to achieve control of one prosthetic function at a time. More advanced machine learning methods have shown promising results under laboratory conditions. However, limited robustness has largely prevented the transfer of these laboratory advances to clinical applications. In this paper, we introduce a novel percutaneous EMG electrode to be implanted chronically with the aim of improving the reliability of EMG detection in myoelectric control. The proposed electrode requires a minimally invasive procedure for its implantation, similar to a cosmetic micro-dermal implant. Moreover, being percutaneous, it does not require power and data telemetry modules. Four of these electrodes were chronically implanted in the forearm of an able-bodied human volunteer for testing their characteristics. The implants showed significantly lower impedance and greater robustness against mechanical interference than traditional surface EMG electrodes used for myoelectric control. Moreover, the EMG signals detected by the proposed systems allowed more stable control performance across sessions in different days than that achieved with classic EMG electrodes. In conclusion, the proposed implants may be a promising interface for clinically available prostheses.


Potentiation of thermal inactivation of glyceraldehyde-3-phosphate dehydrogenase by photodynamic treatment. A possible model for the synergistic interaction between photodynamic therapy and hyperthermia.
Thermal inactivation of glyceraldehyde-3-phosphate dehydrogenase appeared to be caused by a conformational mechanism, without involvement of covalent reactions. On the other hand, photodynamic inactivation of the enzyme (induced by illumination in the presence of Photofrin II) was caused by photo-oxidation of the essential thiol group in the active centre. A short photodynamic treatment of the enzyme, leading to only a limited inactivation, caused a pronounced potentiation of subsequent thermal inactivation, as measured over the temperature range 40-50 degrees C. Analysis of the experimental results according to the Arrhenius equation revealed that both the activation energy of thermal inactivation and the frequency factor (the proportionality constant) were significantly decreased by the preceding photodynamic treatment. The experimental results indicate a mechanism in which limited photodynamic treatment induced a conformational change of the protein molecule. This conformational change did not contribute to photodynamic enzyme inhibition, but was responsible for the decreased frequency factor and activation energy of subsequent thermal inactivation of the enzyme. The opposing effects of decreased activation energy and decreased frequency factor resulted in potentiation of thermal inactivation of the enzyme over the temperature range 40-50 degrees C. With other proteins, different results were obtained. With amylase the combined photodynamic and thermal effects were not synergistic, but additive, and photodynamic treatment had no effect on the frequency factor and the activation energy of thermal inactivation. With respect to myoglobin denaturation, the photodynamic and thermal effects were antagonistic over the whole practically applicable temperature range. Limited photodynamic treatment protected the protein against heat-induced precipitation, concomitantly increasing both the frequency factor and the activation energy of the process. These results offer a model for one of the possible mechanisms of synergistic interaction between photodynamic therapy and hyperthermia in cancer treatment.


Biology-inspired microphysiological systems to advance patient benefit and animal welfare in drug development
The first microfluidic microphysiological systems (MPS) entered the academic scene more than 15 years ago and were considered an enabling technology to human (patho)biology in vitro and, therefore, provide alternative approaches to laboratory animals in pharmaceutical drug development and academic research. Nowadays, the field generates more than a thousand scientific publications per year. Despite the MPS hype in academia and by platform providers, which says this technology is about to reshape the entire in vitro culture landscape in basic and applied research, MPS approaches have neither been widely adopted by the pharmaceutical industry yet nor reached regulated drug authorization processes at all. Here, 46 leading experts from all stakeholders - academia, MPS supplier industry, pharmaceutical and consumer products industries, and leading regulatory agencies - worldwide have analyzed existing challenges and hurdles along the MPS-based assay life cycle in a second workshop of this kind in June 2019. They identified that the level of qualification of MPS-based assays for a given context of use and a communication gap between stakeholders are the major challenges for industrial adoption by end-users. Finally, a regulatory acceptance dilemma exists against that background. This t4 report elaborates on these findings in detail and summarizes solutions how to overcome the roadblocks. It provides recommendations and a roadmap towards regulatory accepted MPS-based models and assays for patients' benefit and further laboratory animal reduction in drug development. Finally, experts highlighted the potential of MPS-based human disease models to feedback into laboratory animal replacement in basic life science research.


Radiofrequency ablation of early breast cancer followed by delayed surgical resection--a promising alternative to breast-conserving surgery.
To examine the radiofrequency ablation (RFA) reliability in early breast cancer, we performed RFA followed by delayed surgical resection on 41 patients with invasive or non-invasive breast carcinoma less than 2 cm. MRI scans were obtained before ablation and resection. Excised specimens were examined pathologically by haematoxylin-eosin and nicotinamide adenine dinucleotide-diaphorase staining. 40 patients completed 1 RFA session, which was sufficient to achieve complete tumour cell death. Overall complete ablation rate was 87.8% (36/41). There were no treatment-related complications other than that of a superficial burn in 1 case. After RFA, the tumour was no longer enhanced on MRI in 25/26 (96.2%) cases. Residual cancer, which was suspected on MRI in 1 case, was confirmed pathologically. MRI could be an applicable modality to evaluate therapeutic effect. RFA could be an alternate local treatment option to breast-conserving surgery for early breast cancer.


The Effect of Music on Exercise Intensity among Children with Autism Spectrum Disorder: A Pilot Study.
Children with autism spectrum disorder (ASD) are at risk for obesity, commonly have sleep disorders, and exhibit stereotypic behaviors that disrupt their learning. Vigorous levels of exercise have been shown to ameliorate these issues in children with ASD, but little research exists to provide techniques for motivating children with ASD to engage in exercise. The present study examined the effect of music on exercise intensity in a group of 13 elementary school students with ASD. Data were collected across six days during structured (e.g., verbal and physical prompts) and unstructured (e.g., minimal prompting) exercise periods. During these exercise periods, three music conditions were randomized: no music, slow-tempo music, and fast-tempo music. Exercise intensity, measured in Metabolic Equivalent of Tasks by triaxial accelerometers, was greatest during the structured exercise periods and during the slow music condition. Student characteristics moderated the impact of music condition on exercise intensity, such that students with high levels of adaptive behavior or lower levels of maladaptive behavior displayed greater exercise intensity during the fast music condition.


Multi-society guideline for reprocessing flexible gastrointestinal endoscopes. Society for Healthcare Epidemiology of America.
Flexible gastrointestinal endoscopy is a valuable diagnostic and therapeutic tool for the care of patients with gastrointestinal and pancreaticobiliary disorders. Compliance with accepted guidelines for the reprocessing of gastrointestinal endoscopes between patients is critical to the safety and success of their use. When these guidelines are followed, pathogen transmission can be effectively prevented. Increased efforts and resources should be directed to improve compliance with these guidelines. Further research in the area of gastrointestinal endoscope reprocessing should be encouraged. The organizations that endorsed this guideline are committed to assisting the FDA and manufacturers in addressing critical infection control issues in gastrointestinal device reprocessing.


Confounded carcinogenicity study of sodium fluoride in CD-1 mice.
To determine its carcinogenic potential, sodium fluoride (NaF) was fed to CD-1 mice for up to 97 weeks. Mice given NaF at a dose of 4, 10, or 25 mg/kg of body weight per day added to a low-fluoride diet were compared to controls given either an unsupplemented low-fluoride diet or laboratory chow. Nonneoplastic changes consistent with those previously recognized from fluoride toxicity were observed in teeth, bones, and joints. Unexpectedly, osteomas occurred in all groups. The incidence of osteomas was similar in groups given the low-fluoride control diet, laboratory chow, or NaF doses of 4 or 10 mg/kg per day. The incidence of osteomas in these groups was increased over that historically experienced at the laboratory and reported in the literature for CD-1 mice. The incidence of osteomas in the mice given 25 mg NaF/kg per day added to a low-fluoride diet was increased over that in the other groups. Osteomas were first observed at Week 55. No malignant bone tumors were observed during the course of the study. The locations, multiplicity, and morphologic features of the osteomas in all groups were similar to those associated with virus-induced bone tumors. Electron microscopic examination revealed abundant retrovirus particles in all osteomas examined from control and test mice. It was concluded that the study was confounded by a retrovirus which contributed to the induction of the osteomas. Because the study was confounded, it cannot be considered a valid bioassay to be used for risk assessment.


Management of smoking in pregnant women.
Smoking is the most important preventable cause of adverse outcomes in pregnancy. However, most smokers who become pregnant continue to smoke and most of those who quit relapse after delivery. This article explores the relationship between smoking and pregnancy, and reviews the evidence for best practice intervention by general practitioners. Continuing to smoke during pregnancy is strongly associated with socioeconomic disadvantage, mental illness and Aboriginal and Torres Strait Islander populations. Quitting is more difficult for these groups and interventions assist only sixin every 100 pregnant smokers to quit. Behavioural counselling is the first-line treatment. Nicotine replacement therapy (NRT) can be offered if the smoker is unable to quit without it, although its efficacy is uncertain. Adequate doses of nicotine and good adherance may be required for the best results. The use of NRT in pregnancy is likely to be less harmful than continuing to smoke. Women should be encouraged to quit smoking before becoming pregnant.


Clinical research priorities in emergency medicine: results of a consensus meeting and development of a weighting method for assessment of clinical research priorities.
There is limited evidence regarding clinical research priorities in emergency medicine outside of some special interest groups. The ACEM Clinical Trials Group undertook a consensus meeting with the aim of developing a reproducible weighting matrix for assessing clinical research priorities. A session at the ACEM annual scientific meeting was dedicated to this meeting. Results from a survey of the ACEM researcher database were presented, along with a proposed weighting matrix. After discussion and adjustment, consensus was achieved on the matrix. It was agreed that the following criteria be used in the matrix: research category and sub-category priority ranking from the ACEM researcher database survey, frequency of presentation of potentially eligible participants, the level of pre-existing evidence regarding the proposed research question and the likely clinical impact of the research. Each criterion was given a weighting, with clinical impact given the heaviest weighting. The weighting matrix was subsequently applied to the list of research questions that resulted from the researcher database survey and a list of research priorities determined. The weighting matrix allows reproducible comparison of research questions. The resultant list of research priorities will act as a guide for the ACEM Clinical Trials Group in determining future projects.


Microfluidic centrifugation assisted precipitation based DNA quantification.
Nucleic acid amplification methods are increasingly being used to detect trace quantities of DNA in samples for various diagnostic applications. However, quantifying the amount of DNA from such methods often requires time consuming purification, washing or labeling steps. Here, we report a novel microfluidic centrifugation assisted precipitation (μCAP) method for single-step DNA quantification. The method is based on formation of a visible precipitate, which can be quantified, when an intercalating dye (GelRed) is added to the DNA sample and centrifuged for a few seconds. We describe the mechanism leading to the precipitation phenomenon. We utilize centrifugal microfluidics to precisely control the formation of the visible and quantifiable mass. Using a standard CMOS sensor for imaging, we report a detection limit of 45 ng μl-1. Furthermore, using an integrated lab-on-DVD platform we recently developed, the detection limit is lowered to 10 ng μl-1, which is comparable to those of current commercially available instruments for DNA quantification. As a proof of principle, we demonstrate the quantification of LAMP products for a HIV-1B type genome containing plasmid on the lab-on-DVD platform. The simple DNA quantification system could facilitate advanced point of care molecular diagnostics.


An immune clock of human pregnancy.
The maintenance of pregnancy relies on finely tuned immune adaptations. We demonstrate that these adaptations are precisely timed, reflecting an immune clock of pregnancy in women delivering at term. Using mass cytometry, the abundance and functional responses of all major immune cell subsets were quantified in serial blood samples collected throughout pregnancy. Cell signaling-based Elastic Net, a regularized regression method adapted from the elastic net algorithm, was developed to infer and prospectively validate a predictive model of interrelated immune events that accurately captures the chronology of pregnancy. Model components highlighted existing knowledge and revealed previously unreported biology, including a critical role for the interleukin-2-dependent STAT5ab signaling pathway in modulating T cell function during pregnancy. These findings unravel the precise timing of immunological events occurring during a term pregnancy and provide the analytical framework to identify immunological deviations implicated in pregnancy-related pathologies.


A four-year trend in pulmonary bacteriologically confirmed tuberculosis case detection in Kampala-Uganda.
The management and control of pulmonary bacteriologically confirmed (PBC) tuberculosis (TB) also known as infectious TB is important not only to monitor for resistance but also to check for severity, treatment response and limit its spread. A retrospective analysis of diagnosis smear results of PBC TB patients in Kampala district registered between January 2012 and December 2015 at 65 TB diagnosis and treatment units (DTUs) was done. Of the 10,404 records; 6551 (63.0%) belonged to PBC TB patients, 3734 (57.0%) of whom were male. Sputum smear microscopy was the diagnostic test most commonly used 4905 (74.9%) followed by GeneXpert testing, 1023 (15.6%). Majority, 1951 (39.8%), of the PBC TB patients had a smear positivity grading of 3+ (> 10 acid-fast bacillus (AFB)/Fields). Public facilities diagnosed more PBC TB patients compared to private facilities, 3983 (60.8%) vs 2566 (39.2%). From 2012 through 2015, there was a statistically significant increase in PBC TB patients enrolled on anti-TB treatment from 1389 to 2194 (p = 0.000). The percentage of HIV positive co-infected PBC TB patients diagnosed decreased from 597(43%) to 890(40.6%) (p = 0.000) within same period. Linkage to HIV care improved from 229 (34.4%) in 2012 to 464 (52.1%) in 2015 (p = 0.000). The treatment success rate (TSR) for PBC TB patients improved from 69% in 2012 to 75.5% by end of 2015 (p = 0.001) with an improvement in cure rate from 52.3% to 62% (p = 0.000). There was an observed significant decrease in TB related mortality from 8.9 to 6.4% (p = 0.013). The proportion of diagnosed PBC TB patients increased from 2012 to 2015. PBC TB patients diagnosed with 3+ smear positivity grading results consistently contributed to the highest proportion of diagnosed PBC TB patients from 2012 to 2015. This could be due to the delay in diagnosis of TB patients because of late presentation of patients to clinics. A prospective study of PBC TB patients diagnosed with 3+ smear positivity grading may elucidate the reasons for the delay to diagnosis. Further, we propose a study of wider scope to estimate how many people a single PBC TB patient is likely to infect with TB before being diagnosed and treated.


Increase in susceptibility of Pseudomonas aeruginosa to carbapenem antibiotics in low-amino-acid media.
The in vitro susceptibility of Pseudomonas aeruginosa PAO1 to carbapenem antibiotics, such as CS-533, was influenced by various concentrations of basic amino acids, i.e., L-lysine, L-histidine, and L-arginine, in agar media. P. aeruginosa PAO1 showed higher susceptibility to carbapenems in minimal medium than it did in rich media such as Mueller-Hinton II agar. The susceptibility was decreased by the addition of a basic amino acid to the minimal medium, whereas it was influenced less by other amino acids. The susceptibility of PAO1 to cephalosporins, piperacillin, quinolones, and gentamicin was not influenced by the addition of a basic amino acid to the minimal medium. A significant change in susceptibility to carbapenems by the addition of a basic amino acid was not observed with D2 protein-deficient mutants of PAO1. Clinical isolates of P. aeruginosa also showed an increase in susceptibility in minimal medium. L-Lysine in minimal medium did not have any influence on the production of D2 protein, beta-lactamases, or penicillin-binding proteins of PAO1 or on the chemical degradation of CS-533. These results strongly indicate that the increase in susceptibility of P. aeruginosa to carbapenems relates to less competition with basic amino acids for permeation through the D2 protein channel of P. aeruginosa.


Vulvodynia: diagnostic techniques and treatment modalities.
Vulvodynia is a chronic vulvar discomfort often characterized by the patient's complaint of burning, stinging, irritation, or rawness. Vulvodynia has been recorded for centuries. Successful diagnostic techniques and treatment modalities, however, have come about only in the last decade. An accurate diagnosis is based on an exhaustive history and detailed physical examination. Highly technical and costly diagnostics provide little supplemental information. Differential diagnosis, previously called subsets of vulvodynia, includes infections (Candida, human papillomavirus, and herpes simplex virus), dermatoses (lichen sclerosus and inflammatory dermatoses), vulvar vestibulitis, iatrogenic causes, and dysesthesias (pudendal neuralgia and reflex sympathetic dystrophy). Primary care providers are fully capable of accurately diagnosing and managing vulvodynia patients, relying on subspecialty referral only for surgical intervention in selected cases.


The source of respiratory syncytial virus infection in infants: a household cohort study in rural Kenya.
Respiratory syncytial virus (RSV) vaccine development for direct protection of young infants faces substantial obstacles. Assessing the potential of indirect protection using different strategies, such as targeting older children or mothers, requires knowledge of the source of infection to the infants. We undertook a prospective study in rural Kenya. Households with a child born after the preceding RSV epidemic and ≥ 1 elder sibling were recruited. Nasopharyngeal swab samples were collected every 3-4 days irrespective of symptoms from all household members throughout the RSV season of 2009-2010 and tested for RSV using molecular techniques. From 451 participants in 44 households a total of 15 396 nasopharyngeal swab samples were samples were collected, representing 86% of planned sampling. RSV was detected in 37 households (84%) and 173 participants (38%) and 28 study infants (64%). The infants acquired infection from within (15 infants; 54%) or outside (9 infants; 32%) the household; in 4 households the source of infant infection was inconclusive. Older children were index case patients for 11 (73%) of the within-household infant infections, and 10 of these 11 children were attending school. We demonstrate that school-going siblings frequently introduce RSV into households, leading to infection in infants.


Accumulation of p53 tumor suppressor gene protein: an independent marker of prognosis in breast cancers.
Mutations of the tumor suppressor gene p53 have been identified in breast cancer cell lines, and some breast carcinomas are detectable by immunohistochemical assay because of p53 protein accumulation. This study was designed to determine whether p53 protein accumulation in breast cancers correlates with p53 gene mutation, with survival, and with five pathobiologic factors associated with prognosis. IgG1 monoclonal antibody to human p53 protein (PAb 1801) and immunohistochemical methods were used to detect p53 protein accumulation in archival formalin-fixed, paraffin-embedded, randomly selected carcinomas. We studied 295 invasive ductal carcinomas from the Massachusetts General Hospital; 151 were determined to be sporadic (not hereditary). We also studied 97 invasive ductal carcinomas--21 sporadic and 76 familial (hereditary)--from Creighton University. In addition, we examined 31 archival in situ carcinomas, 15 snap-frozen invasive ductal carcinomas, primary cell cultures from three benign breast tissue samples, and breast carcinoma cell lines MDA-MB-231 and MDA-MB-468. Nuclear p53 protein was observed in 16% of the 31 in situ carcinomas, 22% of the 172 sporadic carcinomas, 34% of the 50 tumors from patients with familial breast cancer, 52% of the 23 tumors from patients with the familial breast and ovarian cancer syndrome, and all three tumors from two patients with the Li-Fraumeni syndrome. There was complete concordance between p53 gene mutation and p53 protein accumulation in the 15 snap-frozen carcinomas and in both breast carcinoma cell lines. Statistically significant associations of p53 protein accumulation with estrogen receptor negativity and with high nuclear grade were found. There were statistically significant associations, independent of other prognostic factors, between p53 protein accumulation and metastasis-free and overall survival, for randomly accrued and for both sporadic and familial tumors. Immunohistochemically detected p53 protein accumulation was an independent marker of shortened survival and was seen more often in familial than in sporadic carcinomas. Our findings also suggest a correlation between p53 protein accumulation and p53 gene mutation.


Complete crystallographic analysis of the dynamics of CCA sequence addition.
CCA-adding polymerase matures the essential 3'-CCA terminus of transfer RNA without any nucleic-acid template. However, it remains unclear how the correct nucleotide triphosphate is selected in each reaction step and how the polymerization is driven by the protein and RNA dynamics. Here we present complete sequential snapshots of six complex structures of CCA-adding enzyme and four distinct RNA substrates with and without CTP (cytosine triphosphate) or ATP (adenosine triphosphate). The CCA-lacking RNA stem extends by one base pair to force the discriminator nucleoside into the active-site pocket, and then tracks back after incorporation of the first cytosine monophosphate (CMP). Accommodation of the second CTP clamps the catalytic cleft, inducing a reorientation of the turn, which flips C74 to allow CMP to be accepted. In contrast, after the second CMP is added, the polymerase and RNA primer are locked in the closed state, which directs the subsequent A addition. Between the CTP- and ATP-binding stages, the side-chain conformation of Arg 224 changes markedly; this is controlled by the global motion of the enzyme and position of the primer terminus, and is likely to achieve the CTP/ATP discrimination, depending on the polymerization stage. Throughout the CCA-adding reaction, the enzyme tail domain firmly anchors the TPsiC-loop of the tRNA, which ensures accurate polymerization and termination.


Flavonoid inhibition of sodium-dependent vitamin C transporter 1 (SVCT1) and glucose transporter isoform 2 (GLUT2), intestinal transporters for vitamin C and Glucose.
Vitamin C and flavonoids, polyphenols with uncertain function, are abundant in fruits and vegetables. We postulated that flavonoids have a novel regulatory action of delaying or inhibiting absorption of vitamin C and glucose, which are structurally similar. From six structural classes of flavonoids, at least 12 compounds were chosen for studies. We investigated the effects of selected flavonoids on the intestinal vitamin C transporter SVCT1(h) by transfecting and overexpressing SVCT1(h) in Chinese hamster ovary cells. Flavonoids reversibly inhibited vitamin C transport in transfected cells with IC(50) values of 10-50 microm, concentrations expected to have physiologic consequences. The most potent inhibitor class was flavonols, of which quercetin is most abundant in foods. Because Chinese hamster ovary cells have endogenous vitamin C transport, we expressed SVCT1(h) in Xenopus laevis oocytes to study the mechanism of transport inhibition. Quercetin was a reversible and non-competitive inhibitor of ascorbate transport; K(i) 17.8 microm. Quercetin was a potent non-competitive inhibitor of GLUT2 expressed in Xenopus oocytes; K(i) 22.8 microm. When diabetic rats were administered glucose with quercetin, hyperglycemia was significantly decreased compared with administration of glucose alone. Quercetin also significantly decreased ascorbate absorption in normal rats given ascorbate plus quercetin compared with rats given ascorbate alone. Quercetin was a specific transport inhibitor, because it did not inhibit intestinal sugar transporters GLUT5 and SGLT1 that were injected and expressed in Xenopus oocytes. Quercetin inhibited but was not transported by SVCT1(h). Considered together, these data show that flavonoids modulate vitamin C and glucose transport by their respective intestinal transporters and suggest a new function for flavonoids.


A marker of biological age explains individual variation in the strength of the adult stress response.
The acute stress response functions to prioritize behavioural and physiological processes that maximize survival in the face of immediate threat. There is variation between individuals in the strength of the adult stress response that is of interest in both evolutionary biology and medicine. Age is an established source of this variation-stress responsiveness diminishes with increasing age in a range of species-but unexplained variation remains. Since individuals of the same chronological age may differ markedly in their pace of biological ageing, we asked whether biological age-measured here via erythrocyte telomere length-predicts variation in stress responsiveness in adult animals of the same chronological age. We studied two cohorts of European starlings in which we had previously manipulated the rate of biological ageing by experimentally altering the competition experienced by chicks in the fortnight following hatching. We predicted that individuals with greater developmental telomere attrition, and hence greater biological age, would show an attenuated corticosterone (CORT) response to an acute stressor when tested as adults. In both cohorts, we found that birds with greater developmental telomere attrition had lower peak CORT levels and a more negative change in CORT levels between 15 and 30 min following stress exposure. Our results, therefore, provide strong evidence that a measure of biological age explains individual variation in stress responsiveness: birds that were biologically older were less stress responsive. Our results provide a novel explanation for the phenomenon of developmental programming of the stress response: observed changes in stress physiology as a result of exposure to early-life adversity may reflect changes in ageing.


Functional connexin "hemichannels": a critical appraisal.
"Hemichannels" are defined as the halves of gap junction channels (also termed connexons) that are contributed by one cell; "hemichannels" are considered to be functional if they are open in nonjunctional membranes in the absence of pairing with partners from adjacent cells. Several recent reviews have summarized the blossoming literature regarding functional "hemichannels", in some cases encyclopedically. However, most of these previous reviews have been written with the assumption that all data reporting "hemichannel" involvement really have studied phenomena in which connexons actually form the permeability or conductance pathway. In this review, we have taken a slightly different approach. We review the concept of "hemichannels", summarize properties that might be expected of half gap junctions and evaluate the extent to which the properties of presumptive "hemichannels" match expectations. Then we consider functions attributed to hemichannels, provide an overview of other channel types that might fulfill similar roles and provide sets of criteria that might be applied to verify involvement of connexin hemichannels in cell and tissue function. One firm conclusion is reached. The study of hemichannels is technically challenging and fraught with opportunities for misinterpretation, so that future studies must apply rigorous standards for detection of hemichannel expression and function. At the same time there are reasons to expect surprises, including the possibility that some time honored techniques for studying gap junctions may prove unsuitable for detecting hemichannels. We advise hemichannel researchers to proceed with caution and an open mind.


High-dose bicalutamide monotherapy for the treatment of prostate cancer.
Bicalutamide is a nonsteroidal competitive inhibitor of androgens at the androgen receptor. The level of blockade that can be achieved is dependent on the relative numbers of molecules of the agonist and the competitive antagonist around the receptor. Increasing the dose of a competitive inhibitor, therefore, should potentially increase the level of blockade. Bicalutamide has been investigated extensively at daily doses up to 150 mg, and there is evidence of increasing blockade at doses up to this point, as evidenced by increasing suppression of prostate-specific antigen (PSA) and also improvement in response rate, both subjective and objective. At doses of up to 150 mg, increases in plasma concentration of bicalutamide were approximately linear, and all doses were equally well tolerated. It was thought, therefore, that there was a case for investigating higher doses of bicalutamide to determine whether increased androgen blockade could be achieved with the use of bicalutamide as monotherapy. A number of studies have now been carried out evaluating bicalutamide in daily doses of 200 mg, 300 mg, and 450 mg. The 200-mg dose has been evaluated as a primary treatment for advanced prostate cancer and also as a second-line treatment option for patients who have demonstrated a flutamide withdrawal response. In noncomparative trials, the decline in PSA value associated with daily doses of 200 mg bicalutamide was greater than that observed with daily doses of 150 mg, and there was also a slightly higher response rate. When 200 mg daily doses were used as therapy following failure of flutamide in combination with castration, and also following evidence of a flutamide withdrawal response, further responses were seen, perhaps suggesting the theory that in some prostate cancer cell mutations, bicalutamide acts as a pure antagonist rather than as a partial agonist. More recently, bicalutamide has been evaluated at higher doses: 20 patients have been exposed for periods up to 6 months at daily doses of 300 mg. This dose was well tolerated, and evidence of PSA suppression and responses were seen that were at least equivalent to those observed at lower doses. Pharmacokinetics evaluation has been carried out at this dose, and there is now evidence of nonlinearity of plasma concentrations, suggesting that further dose escalation is unlikely to confer major additional benefit over the 150- and 200-mg doses. To confirm the evidence of nonlinearity of plasma concentrations at doses > 200 mg, a randomization between 450 mg bicalutamide and medical castration is currently being carried out. Patients are still being recruited into this trial, but there has been no evidence of any change in the tolerability profile of bicalutamide at any dose > 150 mg. In summary, bicalutamide has shown increasing evidence of activity as a competitive blocker of the androgen receptor at daily doses of up to 200 mg. At daily doses > 200 mg, there is evidence of nonlinearity of plasma concentrations, and therefore further benefit is unlikely to be seen as a result of further escalating the dose of bicalutamide.


Ocean acidification erodes crucial auditory behaviour in a marine fish.
Ocean acidification is predicted to affect marine ecosystems in many ways, including modification of fish behaviour. Previous studies have identified effects of CO(2)-enriched conditions on the sensory behaviour of fishes, including the loss of natural responses to odours resulting in ecologically deleterious decisions. Many fishes also rely on hearing for orientation, habitat selection, predator avoidance and communication. We used an auditory choice chamber to study the influence of CO(2)-enriched conditions on directional responses of juvenile clownfish (Amphiprion percula) to daytime reef noise. Rearing and test conditions were based on Intergovernmental Panel on Climate Change predictions for the twenty-first century: current-day ambient, 600, 700 and 900 µatm pCO(2). Juveniles from ambient CO(2)-conditions significantly avoided the reef noise, as expected, but this behaviour was absent in juveniles from CO(2)-enriched conditions. This study provides, to our knowledge, the first evidence that ocean acidification affects the auditory response of fishes, with potentially detrimental impacts on early survival.


Prevalence of psychiatric disorders in preschoolers.
Many disorders in childhood and adolescence were already present in the preschool years. However, there is little empirical research on the prevalence of psychiatric disorders in young children. A true community study using structured diagnostic tools has yet to be published. All children born in 2003 or 2004 in the city of Trondheim, Norway, who attended the regular community health check-up for 4-year-olds (97.2% of eligible children) whose parents consented to take part in the study (N = 2,475, 82.0%) were screened for behavioral and emotional problems with the Strengths and Difficulties Questionnaire (SDQ). A screen-stratified subsample of 1,250 children took part in a furthermore comprehensive study including a structured diagnostic interview (the Preschool Age Psychiatric Assessment, PAPA), which 995 parents (79.6%) completed. The estimated population rate for any psychiatric disorder (excluding encopresis - 6.4%) was 7.1%. The most common disorders were attention deficit hyperactivity disorder (1.9%), oppositional defiant disorder (1.8%), conduct disorder (0.7%), anxiety disorders (1.5%), and depressive disorders (2.0%). Comorbidity among disorders was common. More emotional and behavioral disorders were seen in children whose parents did not live together and in those of low socioeconomic status. Boys more often had attention-deficit/hyperactivity disorder (ADHD) and depressive disorders than girls. The prevalence of disorders among preschoolers was lower than in previous studies from the USA. Comorbidity was frequent and there was a male preponderance in ADHD and depression at this early age. These results underscore the fact that the most common disorders of childhood can already be diagnosed in preschoolers. However, rates of disorder in Norway may be lower than in the USA.


Treating chronic fatigue syndrome - a study into the scientific evidence for pharmacological treatments.
Chronic fatigue syndrome, or myalgic encephalomyelitis (CFS), is a severe disabling condition. Patients with CFS usually trial many different medicines, both conventional and complementary. An overview of the pharmacological treatments used by CFS patients and the available evidence underpinning the use of these treatments would be of great value to both patients and their healthcare providers. Ninety-four CFS patients recruited into an Australian study investigating immunological biomarkers filled out a questionnaire assessing the medicines they were taking. Evidence from randomised clinical trials was sought in biomedical databases. The 94 CFS patients used 474 different medicines and supplements. The most commonly used medicines were antidepressants, analgesics, sedatives, and B vitamins. We identified 20 randomised controlled trials studying these medicines in CFS patients. While conventional and complementary medicines are widely used by CFS patients, the evidence for effectiveness in CFS is very limited.


Prototype semantic infrastructure for automated small molecule classification and annotation in lipidomics.
The development of high-throughput experimentation has led to astronomical growth in biologically relevant lipids and lipid derivatives identified, screened, and deposited in numerous online databases. Unfortunately, efforts to annotate, classify, and analyze these chemical entities have largely remained in the hands of human curators using manual or semi-automated protocols, leaving many novel entities unclassified. Since chemical function is often closely linked to structure, accurate structure-based classification and annotation of chemical entities is imperative to understanding their functionality. As part of an exploratory study, we have investigated the utility of semantic web technologies in automated chemical classification and annotation of lipids. Our prototype framework consists of two components: an ontology and a set of federated web services that operate upon it. The formal lipid ontology we use here extends a part of the LiPrO ontology and draws on the lipid hierarchy in the LIPID MAPS database, as well as literature-derived knowledge. The federated semantic web services that operate upon this ontology are deployed within the Semantic Annotation, Discovery, and Integration (SADI) framework. Structure-based lipid classification is enacted by two core services. Firstly, a structural annotation service detects and enumerates relevant functional groups for a specified chemical structure. A second service reasons over lipid ontology class descriptions using the attributes obtained from the annotation service and identifies the appropriate lipid classification. We extend the utility of these core services by combining them with additional SADI services that retrieve associations between lipids and proteins and identify publications related to specified lipid types. We analyze the performance of SADI-enabled eicosanoid classification relative to the LIPID MAPS classification and reflect on the contribution of our integrative methodology in the context of high-throughput lipidomics. Our prototype framework is capable of accurate automated classification of lipids and facile integration of lipid class information with additional data obtained with SADI web services. The potential of programming-free integration of external web services through the SADI framework offers an opportunity for development of powerful novel applications in lipidomics. We conclude that semantic web technologies can provide an accurate and versatile means of classification and annotation of lipids.


Prevalence of lumbar facet joint pain in chronic low back pain.
This prospective study was designed to determine the prevalence of lumbar facet joint pain in a consecutive series of patients with chronic low back pain treated at an interventional, multidisciplinary private pain management practice utilizing double diagnostic blocks, to determine the prevalence of false positive rate of uncontrolled facet joint blocks, and to determine the relationship of clinical features of responders and non-responders to double diagnostic blocks. One hundred and twenty patients with low back pain with or without lower extremity pain were selected. The procedure consisted of diagnostic blocks using lidocaine and bupivacaine on separate occasions, usually two weeks apart. Each facet joint nerve was infiltrated with either 0.4 to 0.6 ml of 1% lidocaine (Xylocaine(R)) or 1% lidocaine (Xylocaine(R)) and 0.25% bupivacaine (Marcaine(R)). A definite response was defined as substantial with at least 75% relief of pain in the symptomatic area following local anesthetic block. Confirmatory blocks using bupivacaine 0.25% were performed at the same levels as the first injection if definite relief was obtained. The response to bupivacaine blocks which lasted longer than the lidocaine blocks was accepted as a positive response. All blocks were performed under fluoroscopic guidance. Eighty-one patients (67.5%) reported a definite response to lidocaine blocks. Confirmatory blocks with bupivacaine were performed in all 81 patients with 54 patients, i.e. 45% of total sample or 66.6% of lidocaine positive group reporting definite response with a false positive rate of 41%. Prevalence and relationship of pain referral pattern in patients with and without facet joint pain confirmed by double blocks showed no significant correlation. We found no relationship between the history, physical findings, age, gender, trauma, duration of pain, and diagnostic blocks. However, history of previous surgery showed a negative correlation as only 29% of the patients after previous surgery were positive in contrast to 51% of the nonsurgical population. The results of this study echo previous concerns of reliability of uncontrolled single blocks, history, and clinical features. This study demonstrated that the facet joint is a source of pain in 45% of the patients suffering with chronic low back pain in an interventional pain management setting in a private practice.


Self-Assembling PCL-PAMAM Linear Dendritic Block Copolymers (LDBCs) for Bioimaging and Phototherapeutic Applications.
This study represents a successful approach toward employing polycaprolactone-polyamidoamine (PCL-PAMAM) linear dendritic block copolymer (LDBC) nanoparticles as small-molecule carriers in NIR imaging and photothermal therapy. A feasible and robust synthetic strategy was used to synthesize a library of amphiphilic LDBCs with well-controlled hydrophobic-to-hydrophilic weight ratios. Systems with a hydrophobic weight ratio higher than 70% formed nanoparticles in aqueous media, which show hydrodynamic diameters of 51.6 and 96.4 nm. These nanoparticles exhibited loading efficiencies up to 21% for a hydrophobic molecule and 64% for a hydrophilic molecule. Furthermore, successful cellular uptake was observed via trafficking into endosomal and lysosomal compartments with an encapsulated NIR theranostic agent (C3) without inducing cell death. A preliminary photothermal assessment resulted in cell death after treating the cells with encapsulated C3 and exposing them to NIR light. The results of this work confirm the potential of these polymeric materials as promising candidates in theranostic nanomedicine.


Immunochemical identification of the ADP-ribosyltransferase in botulinum C1 neurotoxin as C3 exoenzyme-like molecule.
Botulinum C1 neurotoxin and C3 exoenzyme were purified to apparent homogeneity from the culture filtrate of Clostridium botulinum type C strain 003-9. Both preparations catalyzed ADP-ribosylation of the same substrate, the Mr 22,000 rho gene product (Gb). When the light and heavy chains of C1 toxin were separated, ADP-ribosyltransferase activity in the toxin was quantitatively recovered in the light chain fraction. Anti-C1 toxin antiserum precipitated the ADP-ribosyltransferase activity and the neurotoxicity of C1 toxin in parallel, whereas it had no effect on C3 exoenzyme. On the other hand, anti-C3 exoenzyme antiserum precipitated the ADP-ribosyltransferase activities of both C3 exoenzyme and C1 toxin. This antibody, however, did not precipitate the neurotoxicity of C1 toxin. The ADP-ribosyltransferase in C1 toxin was quantitatively adsorbed onto the anti-C3 antibody column and separated from the majority of C1 toxin protein. The enzyme was then eluted with acidic urea and Western blotting analysis of this eluate revealed the appearance of a protein band positively stained with anti-C3 antibody at a position similar to that of C3 exoenzyme. Quantitative determination by enzyme-linked immunosorbent assay showed that the C3-like immunoreactivity is present in the C1 toxin molecules at the molecular ratio of 1 to 1,000. These results suggest that the ADP-ribosyltransferase activity in C1 toxin is expressed by a C3-like molecule which is present in a small amount in the toxin preparation and appears to bind to the toxin component(s). The above results also indicate that the ADP-ribosyltransferase in C1 toxin is not related to its neurotoxin action.


Variable expressivity of autosomal dominant microcornea with cataract.
Autosomal dominant microcornea with a cataract, previously described in four families, was documented in a seven-generation family. Eighteen family members had microcornea and a cataract, and an additional six had sclerocornea or Peters' anomaly. Most individuals with microcornea had a corneal diameter of less than 11 mm in both meridians, with moderately steep corneal curvatures. The inherited cataract progressed to form a total cataract after visual maturity had been achieved. In the four affected children who had not undergone cataract extraction, the common abnormality was a posterior polar lens opacity. The variability of expressivity of the dominant gene would suggest that the embryological origins of microcornea and sclerocornea are similar.


Job strain, social support in the workplace, and haemoglobin A1c in Japanese men.
To examine the association between job strain (defined in the model of job demands and job control) and social support at the workplace with levels of glycosylated haemoglobin A1c (HbA1c) All male employees aged 40-60 in a manufacturing firm, Japan, were invited to take part in the study. A blood sample was taken from the participants and HbA1c (%) was measured. Job strain and social support at the workplace were assessed with the job content questionnaire (JCQ). After excluding those who had a history of diabetes mellitus or other chronic diseases, data from 268 male day workers were analyzed. Age adjusted average concentrations of HbA1c were significantly higher in the highest quartile group of job strain or the lowest quartile group of social support at the workplace (p<0.05). Multiple linear regression analysis indicated that job strain was significantly and positively related to HbA1c (p<0.05), whereas social support at the workplace was significantly and negatively related to HbA1c (p<0.05), both after controlling for other covariates. Greater job strain and lower social support at the workplace may be associated with increased concentrations of HbA1c. Increased blood glucose may be a physiological mediator between job strain or social support at the workplace and coronary heart disease.


Lmx1a is required for segregation of sensory epithelia and normal ear histogenesis and morphogenesis.
At embryonic day 8.5, the LIM-homeodomain factor Lmx1a is expressed throughout the otic placode but becomes developmentally restricted to non-sensory epithelia of the ear (endolymphatic duct, ductus reuniens, cochlea lateral wall). We confirm here that the ears of newborn dreher (Lmx1a (dr)) mutants are dysmorphic. Hair cell markers such as Atoh1 and Myo7 reveal, for the first time, that newborn Lmx1a mutants have only three sensory epithelia: two enlarged canal cristae and one fused epithelium comprising an amalgamation of the cochlea, saccule, and utricle (a "cochlear-gravistatic" endorgan). The enlarged anterior canal crista develops by fusion of horizontal and anterior crista, whereas the posterior crista fuses with an enlarged papilla neglecta that may extend into the cochlear lateral wall. In the fused endorgan, the cochlear region is distinguished from the vestibular region by markers such as Gata3, the presence of a tectorial membrane, and cochlea-specific innervation. The cochlea-like apex displays minor disorganization of the hair and supporting cells. This contrasts with the basal half of the cochlear region, which shows a vestibular epithelium-like organization of hair cells and supporting cells. The dismorphic features of the cochlea are also reflected in altered gene expression patterns. Fgf8 expression expands from inner hair cells in the apex to most hair cells in the base. Two supporting cell marker proteins, Sox2 and Prox1, also differ in their cellular distribution between the base and the apex. Sox2 expression expands in mutant canal cristae prior to their enlargement and fusion and displays a more diffuse and widespread expression in the base of the cochlear region, whereas Prox1 is not detected in the base. These changes in Sox2 and Prox1 expression suggest that Lmx1a expression restricts and sharpens Sox2 expression, thereby defining non-sensory and sensory epithelium. The adult Lmx1a mutant organ of Corti shows a loss of cochlear hair cells, suggesting that the long-term maintenance of hair cells is also disrupted in these mutants.


Adaptive Quantum Optics with Spatially Entangled Photon Pairs.
Light shaping facilitates the preparation and detection of optical states and underlies many applications in communications, computing, and imaging. In this Letter, we generalize light shaping to the quantum domain. We show that patterns of phase modulation for classical laser light can also shape higher orders of spatial coherence, allowing deterministic tailoring of high-dimensional quantum entanglement. By modulating spatially entangled photon pairs, we create periodic, topological, and random patterns of quantum illumination, without effect on intensity. We then structure the quantum illumination to simultaneously compensate for entanglement that has been randomized by a scattering medium and to characterize the medium's properties via a quantum measurement of the optical memory effect. The results demonstrate fundamental aspects of spatial coherence and open the field of adaptive quantum optics.


The CrP operon of Chlamydia psittaci and Chlamydia pneumoniae.
One of the critical developmental events during the unique intracellular life cycle of Chlamydiae is their differentiation from a metabolically active, replicative form or reticulate body (RB) to an infectious extracellular form of the organism (elementary body or EB). This process is characterized by the expression of two extraordinarily cysteine-rich envelope proteins of molecular masses 9 kDa and 60 kDa. We describe the molecular cloning and sequence determination of the 9 kDa cysteine-rich proteins (CrPs) of C. pneumoniae and C. psittaci. Comparison of these 9 kDa CrP amino acid sequences with those of C. trachomatis showed regions of structural variation and conservation. Transcription of the 9 kDa CrP genes occurred as both a monocistronic message and as a bicistronic message which included the 60 kDa CrP gene. Transcription of the 9 kDa and 60 kDa CrP genes was tightly linked to the chlamydial growth cycle with synthesis of their mRNAs and consequent translation of the 60 kDa CrPs occurring as RBs differentiated to form EBs. The maximal rate of transcription occurred late in the growth cycle from a single but highly conserved promoter which had close similarity with the Escherichia coli consensus promoter sequences. A stem and loop structure which could be involved in regulating translation of mRNA occurred in all three species between the transcriptional start point and the ribosome binding site. Although transcription is initiated from a single promoter in all three chlamydial species, transcriptional termination points for the monocistronic and bicistronic mRNAs differ in both number and position.


Origins and genetic legacy of Neolithic farmers and hunter-gatherers in Europe.
The farming way of life originated in the Near East some 11,000 years ago and had reached most of the European continent 5000 years later. However, the impact of the agricultural revolution on demography and patterns of genomic variation in Europe remains unknown. We obtained 249 million base pairs of genomic DNA from ~5000-year-old remains of three hunter-gatherers and one farmer excavated in Scandinavia and find that the farmer is genetically most similar to extant southern Europeans, contrasting sharply to the hunter-gatherers, whose distinct genetic signature is most similar to that of extant northern Europeans. Our results suggest that migration from southern Europe catalyzed the spread of agriculture and that admixture in the wake of this expansion eventually shaped the genomic landscape of modern-day Europe.


Preliminary investigation of visual attention to complex AAC visual scene displays in individuals with and without developmental disabilities.
Visual scene displays (VSDs) are one type of augmentative and alternative communication (AAC) display in which an integrated scene (typically a photograph) presents people engaged in shared activities, with "hotspots" for the concepts embedded within. Most AAC displays are more complex than a single VSD, and also contain a navigation bar. This preliminary study examined visual attention to these more complex AAC displays by participants with autism spectrum disorder (ASD) (n = 13), Down syndrome (n = 13), intellectual and developmental disabilities other than Down syndrome or ASD (n = 9), and preschoolers with typical development (n = 20). Participants viewed images that simulated complex AAC displays containing a main VSD and a navigation bar with thumbnail VSDs arranged in one of four locations (top, bottom, left, or right). Both the main VSD and the navigation bar attracted attention, with participants across groups looking at both elements more than expected based on the space those elements occupied within the display. Within the main VSD, participants spent more time fixating on the meaningful elements (i.e., children and shared activity) compared to the background. Results suggested that gaze patterns to the meaningful elements of the main VSD were influenced by the location of the navigation bar. The finding that bar location may influence visual attention patterns makes it an important AAC system design factor that warrants additional research.


Cost efficiency of institutional incentives for promoting cooperation in finite populations.
Institutions can provide incentives to enhance cooperation in a population where this behaviour is infrequent. This process is costly, and it is thus important to optimize the overall spending. This problem can be mathematically formulated as a multi-objective optimization problem where one wishes to minimize the cost of providing incentives while ensuring a minimum level of cooperation, sustained over time. Prior works that consider this question usually omit the stochastic effects that drive population dynamics. In this paper, we provide a rigorous analysis of this optimization problem, in a finite population and stochastic setting, studying both pairwise and multi-player cooperation dilemmas. We prove the regularity of the cost functions for providing incentives over time, characterize their asymptotic limits (infinite population size, weak selection and large selection) and show exactly when reward or punishment is more cost efficient. We show that these cost functions exhibit a phase transition phenomenon when the intensity of selection varies. By determining the critical threshold of this phase transition, we provide exact calculations for the optimal cost of the incentive, for any given intensity of selection. Numerical simulations are also provided to demonstrate analytical observations. Overall, our analysis provides for the first time a selection-dependent calculation of the optimal cost of institutional incentives (for both reward and punishment) that guarantees a minimum level of cooperation over time. It is of crucial importance for real-world applications of institutional incentives since the intensity of selection is often found to be non-extreme and specific for a given population.


Charts of fetal size: 3. Abdominal measurements.
To construct new size charts for fetal abdominal circumference and area. A prospective, cross sectional study. The routine ultrasound department of a London teaching hospital. The fetuses of 663 women seen in the routine antenatal booking clinic whose ultrasound and menstrual dates agreed within 10 days. Fetuses were scanned once only for the purpose of the study at gestations between 12 and 42 weeks, when up to 20 dimensions were measured. Separate regression models were fitted to estimate the mean and standard deviation as functions of gestational age. Centiles were derived by combining these two regression models, assuming that the measurements have a Normal distribution at each gestation. A total of 610 fetuses had their abdominal circumference measured directly. Abdominal diameters were recorded for 425 fetuses and the circumference was also derived from these, as was the abdominal area. New charts for abdominal circumference (directly measured and derived from diameters) are presented. The directly measured circumferences were consistently (by about 3.5%) greater than those derived from measurement of the abdominal diameters. The new charts are compared with previously published charts that are in wide use. A chart for abdominal area is also presented. We have constructed new size charts for the fetal abdominal circumference, both measured directly and derived from abdominal diameters. We have demonstrated the difference between the size charts constructed from these two sets of values and hence the importance of using the appropriately derived chart when assessing the abdominal circumference. The differences between the new charts and previous ones may be largely due to methodological differences.


Connected line drawing extraction from a perspective view of a polyhedron.
To extract line drawings with positional information from perspective veiws of three-dimensional objects is essential in image analysis and understanding. A new heuristic-search algorithm driven by a priori knowledge contained in a world model is presented which extracts a connected line drawing from a perspective view of a polyhedron. A main feature of our algorithm is that the search is concentrated on local areas centered at corners found with a corner finder. Therefore, the search time is significantly reduced and so are the positional errors in the extracted line drawing. An iterative process removes the false corners and lines and thus guarantees that our algorithm will work stably and reliably even in a noisy environment. Experimental results are presented.


Phylogeny and androgenesis in the invasive Corbicula clams (Bivalvia, Corbiculidae) in Western Europe.
The genus Corbicula is one of the most invasive groups of molluscs. It includes both sexual and androgenetic lineages. The present study re-assessed the different morphotypes and haplotypes of West European Corbicula in order to clarify their taxonomic identification and phylogenetic relationships with American and Asian Corbicula clams. We studied several populations from West European river basins (Meuse, Seine, Rhine and Rhône) through an "integrative taxonomy" approach. We combined morphology, partial mitochondrial COI and cyt b sequences and eleven microsatellite loci. Furthermore, we looked for discrepancies between mtDNA and nrDNA/morphology, indicative of androgenesis between lineages. There are three Corbicula morphotypes in Western Europe associated to three mitochondrial lineages and three genotypes. Form R shares the same COI haplotype as the American form A and the Japanese C. leana. Form S and the American form C have the same haplotype, although their morphologies seem divergent. The European form Rlc belongs to the same mitochondrial lineage as both the American form B and the Asian C. fluminea.Interestingly, within each haplotype/genotype or lineage, no genetic diversity was found although their invasive success is high. Moreover, we detected rare mismatches between mtDNA and nrDNA/morphology, indicative of androgenesis and mitochondrial capture between form R and form S and therefore challenging the phylogenetic relatedness and the species status within this genus. The global phylogenetic analysis revealed that the sexual Corbicula lineages seem restricted to the native areas while their androgenetic relatives are widespread and highly invasive. We clarified the discrepancies and incongruent results found in the literature about the European morphotypes of Corbicula and associated mitochondrial lineages. The three West European morphotypes belong to three distinct nuclear and mitochondrial lineages. However mitochondrial capture occurs in sympatric populations of forms R and S. The species status of the morphotypes therefore remains doubtful. Moreover the androgenetic lineages seem widely distributed compared to their sexual relatives, suggesting that androgenesis and invasive success may be linked in the genus Corbicula.


Animal-assisted therapy with farm animals for persons with psychiatric disorders.
Animal-assisted therapy (AAT) with farm animals for humans with psychiatric disorders may reduce depression and state anxiety, and increase self-efficacy, in many participants. Social support by the farmer appears to be important. Positive effects are best documented for persons with affective disorders or clinical depression. Effects may sometimes take a long time to be detectable, but may occur earlier if the participants are encouraged to perform more complex working skills. Progress must however be individually adapted allowing for flexibility, also between days. Therapists involved with mental health show a pronounced belief in the effects of AAT with farm animals, variation being related to type of disorder, therapist's sex and his/her experience with AAT. Research is still scarce and further research is required to optimize and individually adapt the design of farm animal-assisted interventions.


Contact-free Measurement of Heart Rate Variability via a Microwave Sensor.
Measures of heart rate variability (HRV) are widely used to assess autonomic nervous system (ANS) function. HRV can be recorded via electrocardiography (ECG), which is both non-invasive and widely available. However, ECG needs three electrodes touching the body of the subjects, which makes them feel nervous and uncomfortable, thus potentially affecting the recording. Contact-free detection of the heartbeat via a microwave sensor constitutes another means of determining the timing of cardiac cycles by continuous monitoring of mechanical contraction of the heart. This technique can measure the heartbeat without any electrodes touching human body and penetrate the clothes at some distances, which in some instances may prove a practical basis for HRV analysis. Comparison of 5-minute recordings demonstrated that there were no significant differences in the temporal, frequency domains and in non-linear dynamic analysis of HRV measures derived from heartbeat and ECG, which suggested this technique may prove a practical alternative to ECG for HRV analysis.


Novel Mitochondrial Cationic Uncoupler C4R1 Is an Effective Treatment for Combating Obesity in Mice.
Obesity is associated with premature mortality, impaired quality of life, and large healthcare costs. However, treatment options remain quite limited. Here we studied potential anti-obesity effects of a novel cationic mitochondrial uncoupler, C4R1 (derivative of rhodamine 19) in C57Bl/6 mice. Obesity was induced by long-term (eight weeks) high fat diet feeding at thermoneutrality. The treated group of mice received consecutively two doses of C4R1 in drinking water (30 and 12-14 µmol/kg daily) during 30 days. Effects of C4R1 were dose-dependent. After six days of C4R1 treatment at dose 30 µmol/kg daily, food intake was reduced by 68%, body weight by 19%, and fat mass by 21%. Body weight decrease was explained partly by reduced food intake and partly by increased metabolism, likely resulting from uncoupling. Body fat reduction upon C4R1 treatment was associated with improved lipid utilization estimated from decrease in respiratory quotient to the minimal level (0.7). Interestingly, the classical uncoupler 2,4-dinitrophenol at similar dose (27 µmol/kg daily) did not have any effect. Our results are relevant to the search for substances causing mild uncoupling of mitochondria that could be a promising therapeutic strategy to treat obesity.