Expression of the Mr 67,000 laminin receptor is an adverse prognostic indicator in human thyroid cancer: an immunohistochemical study.
Increased expression of the Mr 67,000 laminin receptor (LR) is a consistent event which appears as cancer cells acquire an invasive and metastatic phenotype. The Mr 67,000 LR is one of the many laminin-binding proteins able to interact with the major glycoprotein of basement membranes, laminin. The recent development of a specific monoclonal antibody directed against the Mr 67,000 LR MLuC5 has allowed us to study large retrospective groups of human cancers with the aim of correlating the Mr 67,000 LR expression to the clinical, pathological, and survival data of the patients. A significant correlation has already been established between the increased expression of Mr 67,000 LR and survival of patients with breast, colon, ovary, lung, and endometrial cancers. In this study, we investigated the possibility that the detection of Mr 67,000 LR in thyroid human cancers could also be of prognostic value. We analyzed the expression of Mr 67,000 LR with immunohistochemistry using MLuC5 antibodies in paraffin sections of 40 benign and 170 malignant thyroid human tumors. We found that Mr 67,000 LR was not usually detectable in normal thyroid tissues adjacent to the lesion. Only 3 of the 40 thyroid adenomas examined (7.5%) presented cells positive for Mr 67,000 LR. For the malignant thyroid tumors examined, we found that 22.3% of papillary thyroid carcinomas, 38% of follicular thyroid carcinomas, 40% of poorly differentiated carcinomas, 25% of medullary carcinomas, and 58.3% of anaplastic carcinomas expressed a high level of Mr 67,000 LR. Although no correlation between the Mr 67,000 LR expression and survival was found in patients with follicular thyroid carcinomas, papillary thyroid carcinomas, anaplastic carcinomas, and medullary carcinomas, there was a significant correlation in primary thyroid cancers. Our data represent the first extensive study of the Mr 67,000 LR expression in human thyroid cancers and strongly suggest that its detection could be of prognostic value in the investigation of primary thyroid cancers.


Spatial irregularities of sensitivity along the organ of Corti of the cochlea.
Fine structures of spatial profiles were computed from existing records of cat and chinchilla auditory-nerve fibers on the basis of their characteristic frequencies and cochlear maps. The spatial fine structures of characteristic-frequency thresholds and of "spontaneous" and driven firing rates were mutually correlated, implying the presence of sensitivity fluctuations due to spatial irregularities of presynaptic structures or processes of the inner hair cells and their input. These findings suggest that activity that appears spontaneous is not actually spontaneous and may indicate irregularities of tonotopic mapping in cochlear mechanics.


Molecular localization of variable and conserved regions of pspA and identification of additional pspA homologous sequences in Streptococcus pneumoniae.
PspA is anchored to the surface of all pneumococci by the C-terminal end of the molecule. The N-terminal half of PspA is known to be serologically variable and to be able to elicit protective immune responses. Molecular analysis with DNA probes spanning different regions of pspA was carried out to identify homologous sequences among pneumococcal isolates. At high stringency, DNA probes derived from the 3'-half of pspA (encoding the C-terminal half of PspA) hybridized to all of 37 pneumococcal isolates tested, representing 20 capsular serotypes and 12 PspA serotypes. Most strains had two sequences highly homologous to this region of pspA. Using derivatives of strain Rx1, with insertion mutations in pspA, it was possible to identify the functional pspA sequence. At 50% stringency, the 3' pspA probes also detected lytA and additional sequences. lytA encodes autolysin and shares homology with the 3' portion of pspA. A probe derived from the 5'-half of pspA (encoding the N-terminal half of PspA) hybridized with only 75% of strains and generally detected only one of the two sequences recognized by the 3' probes. Thus, the 3'-half of pspA appears to contain more highly conserved sequences than the 5'-half of pspA and shares homology with several additional sequences, suggesting that the pneumococcus might make several proteins that interact with the surface by the same mechanism as PspA.


Is a compromise possible in Russia between animal advocates and researchers who use animals in harmful experiments?
The current situation relating to the use of laboratory animals in Russia, which is primarily characterised by the complete absence of legislation for their protection, is examined and discussed. This lack of regulation causes well-founded protests by animal protection organisations and a number of reputable politicians. It also has a negative influence on the quality of medical and biological research results that are obtained through the use of experimental animals in Russia. The opinion is expressed that the Russian scientific community should be able to build upon the experience of other countries - in particular, members of the European Union, where there is an effective system of self-control over the ethical and legislative regulation of animal-based research. It is suggested that, in Russia, the basic animal protection principles of the Three Rs should be introduced, when the decision on whether to finance scientific projects involving the use of animals is being made.


Validated SNPs for eGFR and their associations with albuminuria.
Albuminuria and reduced glomerular filtration rate are manifestations of chronic kidney disease (CKD) that predict end-stage renal disease, acute kidney injury, cardiovascular disease and death. We hypothesized that SNPs identified in association with the estimated glomerular filtration rate (eGFR) would also be associated with albuminuria. Within the CKDGen Consortium cohort (n= 31 580, European ancestry), we tested 16 eGFR-associated SNPs for association with the urinary albumin-to-creatinine ratio (UACR) and albuminuria [UACR >25 mg/g (women); 17 mg/g (men)]. In parallel, within the CARe Renal Consortium (n= 5569, African ancestry), we tested seven eGFR-associated SNPs for association with the UACR. We used a Bonferroni-corrected P-value of 0.003 (0.05/16) in CKDGen and 0.007 (0.05/7) in CARe. We also assessed whether the 16 eGFR SNPs were associated with the UACR in aggregate using a beta-weighted genotype score. In the CKDGen Consortium, the minor A allele of rs17319721 in the SHROOM3 gene, known to be associated with a lower eGFR, was associated with lower ln(UACR) levels (beta = -0.034, P-value = 0.0002). No additional eGFR-associated SNPs met the Bonferroni-corrected P-value threshold of 0.003 for either UACR or albuminuria. In the CARe Renal Consortium, there were no associations between SNPs and UACR with a P< 0.007. Although we found the genotype score to be associated with albuminuria (P= 0.0006), this result was driven almost entirely by the known SHROOM3 variant, rs17319721. Removal of rs17319721 resulted in a P-value 0.03, indicating a weak residual aggregate signal. No alleles, previously demonstrated to be associated with a lower eGFR, were associated with the UACR or albuminuria, suggesting that there may be distinct genetic components for these traits.


Diabetic Driving Studies-Part 3: A Comparison of Mean Brake Response Time Between Neuropathic Diabetic Drivers With and Without Foot Pathology.
We have previously demonstrated an abnormally delayed mean brake response time and an increased frequency of abnormally delayed brake responses in a group of neuropathic diabetic drivers compared with a control group of drivers with neither diabetes nor lower extremity neuropathy. The objective of the present case-control study was to compare the mean brake response time between neuropathic diabetic drivers with and without specific diabetic foot pathology. The braking performances of the participants were evaluated using a computerized driving simulator with specific measurement of the mean brake response time and the frequency of abnormally delayed brake responses. We analyzed a control group of 20 active drivers with type 2 diabetes, lower extremity neuropathy, and no history of diabetic foot pathology and an experimental group of 20 active drivers with type 2 diabetes, lower extremity neuropathy, and a history of diabetic foot pathology (ulceration, amputation, and/or Charcot neuroarthropathy) from an urban U.S. podiatric medical clinic. Neuropathic diabetic drivers without a history of specific foot pathology demonstrated an 11.11% slower mean brake response time (0.790 ± 0.223 versus 0.711 ± 0.135 second; p < .001), with abnormally delayed reactions occurring at a similar frequency (58.13% versus 48.13%; p = .0927). Both groups demonstrated a mean brake response time slower than a suggested threshold of 0.70 second. The results of the present investigation provide evidence that diabetic patients across a spectrum of lower extremity sensorimotor neuropathy and foot pathology demonstrate abnormal automobile brake responses and might be at risk of impaired driving function.


Effective interventions to facilitate the uptake of breast, cervical and colorectal cancer screening: an implementation guideline.
Appropriate screening may reduce the mortality and morbidity of colorectal, breast, and cervical cancers. Several high-quality systematic reviews and practice guidelines exist to inform the most effective screening options. However, effective implementation strategies are warranted if the full benefits of screening are to be realized. We developed an implementation guideline to answer the question: What interventions have been shown to increase the uptake of cancer screening by individuals, specifically for breast, cervical, and colorectal cancers? A guideline panel was established as part of Cancer Care Ontario's Program in Evidence-based Care, and a systematic review of the published literature was conducted. It yielded three foundational systematic reviews and an existing guidance document. We conducted updates of these reviews and searched the literature published between 2004 and 2010. A draft guideline was written that went through two rounds of review. Revisions were made resulting in a final set of guideline recommendations. Sixty-six new studies reflecting 74 comparisons met eligibility criteria. They were generally of poor to moderate quality. Using these and the foundational documents, the panel developed a draft guideline. The draft report was well received in the two rounds of review with mean quality scores above four (on a five-point scale) for each of the items. For most of the interventions considered, there was insufficient evidence to support or refute their effectiveness. However, client reminders, reduction of structural barriers, and provision of provider assessment and feedback were recommended interventions to increase screening for at least two of three cancer sites studied. The final guidelines also provide advice on how the recommendations can be used and future areas for research. Using established guideline development methodologies and the AGREE II as our methodological frameworks, we developed an implementation guideline to advise on interventions to increase the rate of breast, cervical and colorectal cancer screening. While advancements have been made in these areas of implementation science, more investigations are warranted.


A Randomized, Placebo-controlled Trial of Fidaxomicin for Prophylaxis of Clostridium difficile-associated Diarrhea in Adults Undergoing Hematopoietic Stem Cell Transplantation.
Clostridium difficile-associated diarrhea (CDAD) is common during hematopoietic stem-cell transplantation (HSCT) and is associated with increased morbidity and mortality. We evaluated fidaxomicin for prevention of CDAD in HSCT patients. In this double-blind study, subjects undergoing HSCT with fluoroquinolone prophylaxis stratified by transplant type (autologous/allogeneic) were randomized to once-daily oral fidaxomicin (200 mg) or a matching placebo. Dosing began within 2 days of starting conditioning or fluoroquinolone prophylaxis and continued until 7 days after neutrophil engraftment or completion of fluoroquinolone prophylaxis/clinically-indicated antimicrobials for up to 40 days. The primary endpoint was CDAD incidence through 30 days after study medication. The primary endpoint analysis counted confirmed CDAD, receipt of CDAD-effective medications (for any indication), and missing CDAD assessment (for any reason, including death) as failures; this composite analysis is referred to as "prophylaxis failure" to distinguish from the pre-specified sensitivity analysis, which counted only confirmed CDAD (by toxin immunoassay or nucleic acid amplification test) as failure. Of 611 subjects enrolled, 600 were treated and analyzed. Prophylaxis failure was similar in fidaxomicin and placebo recipients (28.6% vs 30.8%; difference 2.2% [-5.1, 9.5], P = .278). However, most failures were due to non-CDAD events. Confirmed CDAD was lower in fidaxomicin vs placebo recipients (4.3% vs 10.7%; difference 6.4% [2.2, 10.6], P = .0014). Drug-related adverse events occurred in 15.0% of fidaxomicin recipients and 20.0% of placebo recipients. While no difference was demonstrated between arms in the primary analysis, results of the sensitivity analysis demonstrated that fidaxomicin significantly reduced the incidence of CDAD in HSCT recipients. NCT01691248.


Touching my face with my supernumerary hand: a cheeky illusion.
A self-touch paradigm elicits a surprising illusion. With the participant's eyes closed, the examiner guides the participant's right index finger to administer strokes and taps to the right side of the participant's face. At the same time, the examiner strokes and taps the corresponding location on the left side of the participant's face. Although the participant administered touch to only the right side of the face, this paradigm elicited the illusion of self-touch to both sides of the face, and the illusion often implicated a third, disconnected or disembodied, hand. We propose an explanation, and draw parallels with the phenomenon of supernumerary phantom limb.


BRONCO: Biomedical entity Relation ONcology COrpus for extracting gene-variant-disease-drug relations.
Comprehensive knowledge of genomic variants in a biological context is key for precision medicine. As next-generation sequencing technologies improve, the amount of literature containing genomic variant data, such as new functions or related phenotypes, rapidly increases. Because numerous articles are published every day, it is almost impossible to manually curate all the variant information from the literature. Many researchers focus on creating an improved automated biomedical natural language processing (BioNLP) method that extracts useful variants and their functional information from the literature. However, there is no gold-standard data set that contains texts annotated with variants and their related functions. To overcome these limitations, we introduce a Biomedical entity Relation ONcology COrpus (BRONCO) that contains more than 400 variants and their relations with genes, diseases, drugs and cell lines in the context of cancer and anti-tumor drug screening research. The variants and their relations were manually extracted from 108 full-text articles. BRONCO can be utilized to evaluate and train new methods used for extracting biomedical entity relations from full-text publications, and thus be a valuable resource to the biomedical text mining research community. Using BRONCO, we quantitatively and qualitatively evaluated the performance of three state-of-the-art BioNLP methods. We also identified their shortcomings, and suggested remedies for each method. We implemented post-processing modules for the three BioNLP methods, which improved their performance.Database URL:http://infos.korea.ac.kr/bronco.


The promises of big data and small data for travel behavior (aka human mobility) analysis.
The last decade has witnessed very active development in two broad, but separate fields, both involving understanding and modeling of how individuals move in time and space (hereafter called "travel behavior analysis" or "human mobility analysis"). One field comprises transportation researchers who have been working in the field for decades and the other involves new comers from a wide range of disciplines, but primarily computer scientists and physicists. Researchers in these two fields work with different datasets, apply different methodologies, and answer different but overlapping questions. It is our view that there is much, hidden synergy between the two fields that needs to be brought out. It is thus the purpose of this paper to introduce datasets, concepts, knowledge and methods used in these two fields, and most importantly raise cross-discipline ideas for conversations and collaborations between the two. It is our hope that this paper will stimulate many future cross-cutting studies that involve researchers from both fields.


Cerebral microenvironment influences expression of the vitronectin gene in astrocytic tumors.
Expression of the vitronectin gene was detected in advanced human astrocytoma by in situ hybridization, whereas vitronectin mRNA was undetectable in low grade tumors or in normal adult brain, indicating that vitronectin is a marker of malignant astrocytoma. We established a model of human astrocytoma by transplanting U-251MG human astrocytoma cells intracerebrally into acid mice (C.B.17 severe combined immunodeficient mice). In this model, tumors progressed rapidly and vitronectin mRNA was preferentially detected at the invading tumor margins, i.e. where tumor cells were adjacent to the normal brain tissue. Surprisingly, when U-251MG cells were injected subcutaneously into scid mice, vitronectin mRNA was undetectable throughout the tumor. Moreover, vitronectin mRNA or protein could not be detected among these cells in culture under a wide variety of growth conditions. These findings demonstrate that the cerebral microenvironment influences the expression of the vitronectin gene in malignant astrocytoma. Importantly, the vitronectin binding integrins alpha v beta 3 and alpha v beta 5 localized to distinct sites within these tumors, with beta 3 mRNA synthesized among invading cells, and alpha v and beta 5 mRNAs detected throughout the tumor. In vitro, both of these receptors were capable of promoting adhesion and invasion of astrocytoma cells on a vitronectin substratum. These findings implicate the expression of the vitronectin gene as a contributing factor to the biological behavior of astrocytomas within the cerebral microenvironment.


Does stopping smoking delay onset of angina after infarction?
This study was designed to determine the relation between stopping smoking and angina after infarction in survivors of an acute coronary attack. The study population comprised 408 men aged under 60 who survived a first attack of unstable angina or myocardial infarction by 28 days and were smoking cigarettes at the time of their attack. These patients were followed up for an average of nine years. Three hundred and eighty four were alive at the one year follow up examination, when the presence or absence of angina together with habits of smoking were recorded. The prevalence of angina at one year was 19.5% in the 241 who had stopped smoking cigarettes compared with 32.2% in those who had continued (p less than 0.01). Six years later, however, the prevalence of angina after infarction was the same in the two groups. It is concluded that the onset of angina after infarction can be delayed by stopping smoking cigarettes but that this effect is not maintained in the long term.


Factors associated with mental health in Peruvian medical students during the COVID-19 pandemic: a multicentre quantitative study.
To assess the mental health status and associated factors of Peruvian medical students during the COVID-19 pandemic. Descriptive, multicentre, correlational study that used the "Patient Health Questionnaire-9 (PHQ-9)", the "Generalized Anxiety Disorder-7 (GAD-7)" and the "Impact of Event Scale-Revised (IES-R)" questionnaires to evaluate mental health problems. A total of 1,238 students from 8 Peruvian medical schools participated in the study. Of these, 68.5% were women, and the mean age was 21.4 years. Depressive symptoms were found in 74% of the participants, anxiety symptoms in 57% and distress symptoms in 65%. The variables associated with the development of symptoms of moderate-severe depression, anxiety and distress were: not having family economic stability, being in the first years of medical training, being female, and fearing that their medical training would be delayed and impaired. In a sample of medical students surveyed during the COVID-19 pandemic, mental health problems were common. The factors associated with mental health reported in this study could be useful in identifying vulnerable medical students who require timely psychosocial support and/or psychiatric care.


Accelerating research on biological aging and mental health: Current challenges and future directions.
Aging is associated with complex biological changes that can be accelerated, slowed, or even temporarily reversed by biological and non-biological factors. This article focuses on the link between biological aging, psychological stressors, and mental illness. Rather than comprehensively reviewing this rapidly expanding field, we highlight challenges in this area of research and propose potential strategies to accelerate progress in this field. This effort requires the interaction of scientists across disciplines - including biology, psychiatry, psychology, and epidemiology; and across levels of analysis that emphasize different outcome measures - functional capacity, physiological, cellular, and molecular. Dialogues across disciplines and levels of analysis naturally lead to new opportunities for discovery but also to stimulating challenges. Some important challenges consist of 1) establishing the best objective and predictive biological age indicators or combinations of indicators, 2) identifying the basis for inter-individual differences in the rate of biological aging, and 3) examining to what extent interventions can delay, halt or temporarily reverse aging trajectories. Discovering how psychological states influence biological aging, and vice versa, has the potential to create novel and exciting opportunities for healthcare and possibly yield insights into the fundamental mechanisms that drive human aging.


Two Automated Techniques for Carotid Lumen Diameter Measurement: Regional versus Boundary Approaches.
The degree of stenosis in the carotid artery can be predicted using automated carotid lumen diameter (LD) measured from B-mode ultrasound images. Systolic velocity-based methods for measurement of LD are subjective. With the advancement of high resolution imaging, image-based methods have started to emerge. However, they require robust image analysis for accurate LD measurement. This paper presents two different algorithms for automated segmentation of the lumen borders in carotid ultrasound images. Both algorithms are modeled as a two stage process. Stage one consists of a global-based model using scale-space framework for the extraction of the region of interest. This stage is common to both algorithms. Stage two is modeled using a local-based strategy that extracts the lumen interfaces. At this stage, the algorithm-1 is modeled as a region-based strategy using a classification framework, whereas the algorithm-2 is modeled as a boundary-based approach that uses the level set framework. Two sets of databases (DB), Japan DB (JDB) (202 patients, 404 images) and Hong Kong DB (HKDB) (50 patients, 300 images) were used in this study. Two trained neuroradiologists performed manual LD tracings. The mean automated LD measured was 6.35 ± 0.95 mm for JDB and 6.20 ± 1.35 mm for HKDB. The precision-of-merit was: 97.4 % and 98.0 % w.r.t to two manual tracings for JDB and 99.7 % and 97.9 % w.r.t to two manual tracings for HKDB. Statistical tests such as ANOVA, Chi-Squared, T-test, and Mann-Whitney test were conducted to show the stability and reliability of the automated techniques.


Life shocks and crime: a test of the "turning point" hypothesis.
Other researchers have posited that important events in men's lives-such as employment, marriage, and parenthood-strengthen their social ties and lead them to refrain from crime. A challenge in empirically testing this hypothesis has been the issue of self-selection into life transitions. This study contributes to this literature by estimating the effects of an exogenous life shock on crime. We use data from the Fragile Families and Child Wellbeing Study, augmented with information from hospital medical records, to estimate the effects of the birth of a child with a severe health problem on the likelihood that the infant's father engages in illegal activities. We conduct a number of auxiliary analyses to examine exogeneity assumptions. We find that having an infant born with a severe health condition increases the likelihood that the father is convicted of a crime in the three-year period following the birth of the child, and at least part of the effect appears to operate through work and changes in parental relationships. These results provide evidence that life events can cause crime and, as such, support the "turning point" hypothesis.


Effects of cadmium on structure and enzymatic activity of Cu,Zn-SOD and oxidative status in neural cells.
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder disease. Ten percent of the ALS patients are congenital (familial ALS), and the other 90% are sporadic ALS (SALS). It has been shown that mutations found in the Cu,Zn-SOD cause 20% of the familial ALS due to its low enzyme activity. We hypothesized that heavy metals may interfere the structure of Cu,Zn-SOD protein to suppress its activity in some of the SALS. In this study, we expressed and characterized the recombinant human Cu,Zn-SOD under various concentrations of Cu(2+), Zn(2+), and Cd(2+). By atomic absorption spectrophotometry, we demonstrated that adding of cadmium significantly increased the content of cadmium ion, but reduced its Zn(2+) content and enzyme activity of the Cu,Zn-SOD protein. The data of circular dichroism spectra demonstrated that the secondary structure of Cu,Zn-SOD/Cd is different from Cu,Zn-SOD, but close to apo-SOD. In addition to the effect of cadmium on Cu,Zn-SOD, cadmium was also shown to induce neural cell apoptosis. To further investigate the mechanism of neural cell apoptosis induced by cadmium, we used proteomics to analyze the altered protein expressions in neural cells treated with cadmium. The altered proteins include cellular structural proteins, stress-related and chaperone proteins, proteins involved in reactive oxygen species (ROS), enzyme proteins, and proteins that mediated cell death and survival signaling. Taken together, in this paper, we demonstrate that cadmium decreases the content of Zn(2+), changes the conformation of Cu,Zn-SOD protein to decrease its enzyme activity, and causes oxidative stress-induced neural cell apoptosis.


Infant feeding and later obesity risk.
Some 30 years ago, Günter Dörner proposed that exposure to hormones, metabolites and neurotransmitters during limited, sensitive periods of early development exert programming effects on disease risk in human adults. Early programming of long term health has since received broad scientific support and attention. For example, evidence increases for programming effects of infant feeding choices on later obesity risk. Meta-analyses of observational studies indicate that breast feeding reduces the odds ratio for obesity at school age by about 20%, relative to formula feeding, even after adjustment for biological and sociodemographic confounding variables. We hypothesized that breast feeding protects against later obesity by reducing the likelihood of high weight gain in infancy, and that this protection is caused at least partly by the lower protein supply with breast milk relative to standard infant formulae (the "Early Protein Hypothesis"). These hypotheses are tested in the European Childhood Obesity Project, a randomized double blind intervention trial in more than 1,000 infants in five European countries (Belgium, Germany, Italy, Poland, Spain). Formula fed infants were randomized to receive during the first year of life infant formulae and follow-on-formulae with higher or lower protein contents. Follow-up at 2 years of age shows that lower protein supply with formula normalizes early growth relative to a breast fed reference group and to the WHO growth reference. These results demonstrate that modification of infant feeding practice has an important potential for long-term health promotion and should prompt a review of the recommendations and policies for infant formula composition.


Waste management requirements of community i.v. therapy services.
Healthcare professionals carry a legal and professional responsibility for the safe disposal of clinical wastes. Sharps safety is paramount, and though this is a well-recognized hazard there remains an unacceptably high incidence of sharps injury and of blood and body fluid exposures that are particularly frequent among ancillary and support staff and waste handlers. Statutory Local Authority waste collection and disposal services generally provide the most convenient and cost-effective approach to community-generated clinical wastes though there remains much room for improvement. Special arrangements will be necessary for the careful collection, packaging and disposal of not only cytotoxic and cytostatic drug wastes, and of items contaminated with these drug substances, and of controlled drugs, but of all other prescription and many non-prescription pharmaceutical products.


Protein acetylation in metabolism - metabolites and cofactors.
Reversible acetylation was initially described as an epigenetic mechanism regulating DNA accessibility. Since then, this process has emerged as a controller of histone and nonhistone acetylation that integrates key physiological processes such as metabolism, circadian rhythm and cell cycle, along with gene regulation in various organisms. The widespread and reversible nature of acetylation also revitalized interest in the mechanisms that regulate lysine acetyltransferases (KATs) and deacetylases (KDACs) in health and disease. Changes in protein or histone acetylation are especially relevant for many common diseases including obesity, diabetes mellitus, neurodegenerative diseases and cancer, as well as for some rare diseases such as mitochondrial diseases and lipodystrophies. In this Review, we examine the role of reversible acetylation in metabolic control and how changes in levels of metabolites or cofactors, including nicotinamide adenine dinucleotide, nicotinamide, coenzyme A, acetyl coenzyme A, zinc and butyrate and/or β-hydroxybutyrate, directly alter KAT or KDAC activity to link energy status to adaptive cellular and organismal homeostasis.


Presurgical language fMRI: Technical practices in epilepsy surgical planning.
Little is known about how language functional MRI (fMRI) is executed in clinical practice in spite of its widespread use. Here we comprehensively documented its execution in surgical planning in epilepsy. A questionnaire focusing on cognitive design, image acquisition, analysis and interpretation, and practical considerations was developed. Individuals responsible for collecting, analyzing, and interpreting clinical language fMRI data at 63 epilepsy surgical programs responded. The central finding was of marked heterogeneity in all aspects of fMRI. Most programs use multiple tasks, with a fifth routinely using 2, 3, 4, or 5 tasks with a modal run duration of 5 min. Variants of over 15 protocols are in routine use with forms of noun-verb generation, verbal fluency, and semantic decision-making used most often. Nearly all aspects of data acquisition and analysis vary markedly. Neither of the two best-validated protocols was used by more than 10% of respondents. Preprocessing steps are broadly consistent across sites, language-related blood flow is most often identified using general linear modeling (76% of respondents), and statistical thresholding typically varies by patient (79%). The software SPM is most often used. fMRI programs inconsistently include input from experts with all required skills (imaging, cognitive assessment, MR physics, statistical analysis, and brain-behavior relationships). These data highlight marked gaps between the evidence supporting fMRI and its clinical application. Teams performing language fMRI may benefit from evaluating practice with reference to the best-validated protocols to date and ensuring individuals trained in all aspects of fMRI are involved to optimize patient care.


Oxygen transport in children on maintenance haemodialysis.
1. Adaptive mechanisms of oxygen transport by blood have been studied in severely anaemic young patients on maintenance haemodialysis, in conditions of hyperphosphataemia (Pi greater than or equal to 2.2 mmol/l) or normophosphataemia. 2. In hyperphosphataemia whole-blood affinity for oxygen was slightly decreased, as measured by an increase in P50 (the partial pressure of oxygen necessary to half saturate haemoglobin). 2,3-Diphosphoglycerate was increased by 10% (P less than 0.10) whereas Pi, total erythrocyte phosphate and ATP were increased by 100%, 47% and 36% respectively, compared with control values. 3. After correction of hyperphosphataemia a small but significant decrease in P50 and 2,3-diphosphoglycerate, to normal values, was observed whereas the other variables, although significantly lowered, remained above control values. 4. In these severely anaemic and hyperphosphataemic patients P50 and 2,3-diphosphoglycerate are only slightly increased. ATP synthesis appears to be favoured over that of 2,3-diphosphoglycerate. This is possibly due to alterations in the erythrocyte membrane elicited by bi-weekly extracorporeal circulation. Adequate oxygen transport can be achieved only through a drastic increase in blood flow. Correction of hyperphosphataemia adds further to the abnormality. It is concluded that this condition could induce a long-term myocardial fatigue, which might be prevented with occasional small blood transfusions.


Implications for neurobiological research of cognitive models of psychosis: a theoretical paper.
Cognitive models of the positive symptoms of psychosis specify the cognitive, social and emotional processes hypothesized to contribute to their occurrence and persistence, and propose that vulnerable individuals make characteristic appraisals that result in specific positive symptoms. We describe cognitive models of positive psychotic symptoms and use this as the basis of discussing recent relevant empirical investigations and reviews that integrate cognitive approaches into neurobiological frameworks. Evidence increasingly supports a number of the hypotheses proposed by cognitive models. These are that: psychosis is on a continuum; specific cognitive processes are risk factors for the transition from subclinical experiences to clinical disorder; social adversity and trauma are associated with psychosis and with negative emotional processes; and these emotional processes contribute to the occurrence and persistence of psychotic symptoms. There is also evidence that reasoning biases contribute to the occurrence of delusions. The benefits of incorporating cognitive processes into neurobiological research include more sophisticated, bidirectional and interactive causal models, the amplification of phenotypes in neurobiological investigations by including emotional processes, and the adoption of more specific clinical phenotypes. For example, there is potential value in studying gene x environment x cognition/emotion interactions. Cognitive models and their derived phenotypes constitute the missing link in the chain between genetic or acquired biological vulnerability, the social environment and the expression of individual positive symptoms.


Short-Term Exposure to Nitrogen Dioxide Provides Basal Pathogen Resistance.
Nitrogen dioxide (NO2) forms in plants under stress conditions, but little is known about its physiological functions. Here, we explored the physiological functions of NO2 in plant cells using short-term fumigation of Arabidopsis (Arabidopsis thaliana) for 1 h with 10 µL L-1 NO2. Although leaf symptoms were absent, the expression of genes related to pathogen resistance was induced. Fumigated plants developed basal disease resistance, or pattern-triggered immunity, against the necrotrophic fungus Botrytis cinerea and the hemibiotrophic bacterium Pseudomonas syringae Functional salicylic acid and jasmonic acid (JA) signaling pathways were both required for the full expression of NO2-induced resistance against B. cinerea An early peak of salicylic acid accumulation immediately after NO2 exposure was followed by a transient accumulation of oxophytodienoic acid. The simultaneous NO2-induced expression of genes involved in jasmonate biosynthesis and jasmonate catabolism resulted in the complete suppression of JA and JA-isoleucine (JA-Ile) accumulation, which was accompanied by a rise in the levels of their catabolic intermediates 12-OH-JA, 12-OH-JA-Ile, and 12-COOH-JA-Ile. NO2-treated plants emitted the volatile monoterpene α-pinene and the sesquiterpene longifolene (syn. junipene), which could function in signaling or direct defense against pathogens. NO2-triggered B. cinerea resistance was dependent on enhanced early callose deposition and CYTOCHROME P450 79B2 (CYP79B2), CYP79B3, and PHYTOALEXIN DEFICIENT3 gene functions but independent of camalexin, CYP81F2, and 4-OH-indol-3-ylmethylglucosinolate derivatives. In sum, exogenous NO2 triggers basal pathogen resistance, pointing to a possible role for endogenous NO2 in defense signaling. Additionally, this study revealed the involvement of jasmonate catabolism and volatiles in pathogen immunity.


The association of single-nucleotide polymorphisms in the oxytocin receptor and G protein-coupled receptor kinase 6 (GRK6) genes with oxytocin dosing requirements and labor outcomes.
Oxytocin is a potent uterotonic agent that is widely used for induction and augmentation of labor. Oxytocin has a narrow therapeutic index and the optimal dosing for any individual woman varies widely. The objective of this study was to determine whether genetic variation in the oxytocin receptor (OXTR) or in the gene encoding G protein-coupled receptor kinase 6 (GRK6), which regulates desensitization of the oxytocin receptor, could explain variation in oxytocin dosing and labor outcomes among women being induced near term. Pregnant women with a singleton gestation residing in Durham County, NC, were prospectively enrolled as part of the Healthy Pregnancy, Healthy Baby cohort study. Those women undergoing an induction of labor at 36 weeks or greater were genotyped for 18 haplotype-tagging single-nucleotide polymorphisms in OXTR and 7 haplotype-tagging single-nucleotide polymorphisms in GRK6 using TaqMan assays. Linear regression was used to examine the relationship between maternal genotype and maximal oxytocin infusion rate, total oxytocin dose received, and duration of labor. Logistic regression was used to test for the association of maternal genotype with mode of delivery. For each outcome, backward selection techniques were utilized to control for important confounding variables and additive genetic models were used. Race/ethnicity was included in all models because of differences in allele frequencies across populations, and Bonferroni correction for multiple testing was used. DNA was available from 482 women undergoing induction of labor at 36 weeks or greater. Eighteen haplotype-tagging single-nucleotide polymorphisms within OXTR and 7 haplotype-tagging single-nucleotide polymorphisms within GRK6 were examined. Five single-nucleotide polymorphisms in OXTR showed nominal significance with maximal infusion rate of oxytocin, and two single-nucleotide polymorphisms in OXTR were associated with total oxytocin dose received. One single-nucleotide polymorphism in OXTR and two single-nucleotide polymorphisms in GRK6 were associated with duration of labor, one of which met the multiple testing threshold (P = .0014, rs2731664 [GRK6], mean duration of labor, 17.7 hours vs 20.2 hours vs 23.5 hours for AA, AC, and CC genotypes, respectively). Three single-nucleotide polymorphisms, two in OXTR and one in GRK6, showed nominal significance with mode of delivery. Genetic variation in OXTR and GRK6 is associated with the amount of oxytocin required as well as the duration of labor and risk for cesarean delivery among women undergoing induction of labor near term. With further research, pharmacogenomic approaches may potentially be utilized to develop personalized treatment to improve safety and efficacy outcomes among women undergoing induction of labor.


Prevalence of Cryptosporidium species in recreational versus non-recreational water sources.
Cryptosporidiosis, caused by the protozoan parasite Cryptosporidium, represents the major public health concern of water utilities in developed nations due to its small size, resistance to disinfection and ability to be shed in large numbers in faeces. In Australia, recreational access is not allowed on direct supply sources, however, in Western Australia, limited recreational access to drinking water catchments has been allowed, although only in the outer catchment. Recreational activities within 2 km of the drinking water body is prohibited. The present study compared the amount, prevalence and species of Cryptosporidium in recreational versus non-recreational water catchments in the south west of Western Australia (WA). Recreational water catchments, which allowed swimming and camping had a higher prevalence of Cryptosporidium and the majority of samples were the human-associated C. hominis. Non-recreational catchments had a lower prevalence and all the samples genotyped were C. parvum. Risk analysis identified increasing population as strongly correlated with an increase in the prevalence of Cryptosporidium in recreational catchments. This suggests that recreational access to drinking water catchments is a serious public health risk and government policy limiting activities to the outer catchment should be supported.


Ethnic variation in the correlation between random serum glucose concentration and glycated haemoglobin.
To determine if the relationship between serum glucose concentration and glycated haemoglobin is different between African-Americans and whites. Retrospective cross-sectional study comparing the association between glycated haemoglobin and serum glucose levels, based upon ethnicity. Two databases were evaluated: (i) 4215 African-American and 6359 white outpatients who had simultaneous glycated haemoglobin, random serum glucose and creatinine concentration measurements between 2000 and 2007 at the North Carolina Baptist Hospital and (ii) 1021 white and 312 African-American Diabetes Heart Study (DHS) participants. In North Carolina Baptist Hospital clinic attendees, a given glycated haemoglobin was associated with higher serum glucose concentrations in African-Americans compared with whites. In a multivariate model with glycated haemoglobin as the outcome variable, racial differences remained significant after adjustment for serum glucose, age, gender and kidney function. For individuals with a serum glucose between 5.6 and 8.3 mmol/l, the glucose : glycated haemoglobin ratio was 1.03 +/- 0.16 mmol/l/% in white individuals and 0.99 +/- 0.17 mmol/l/% in African-Americans (P < 0.0001). For a glycated haemoglobin value of 7.0%, there was a 0.98-mmol/l difference in predicted serum glucose concentration in 50-year-old African-American men, relative to white. Results were replicated in the DHS, where in a best-fit linear model, after adjustment for glucose, African-American race was a significant predictor of glycated haemoglobin (P < 0.0001). African-Americans have higher glycated haemoglobin values at given serum glucose concentrations relative to whites. This finding may contribute to the observed difference in glycated haemoglobin values reported between these race groups.


An investigation of the inflammatory cytokine and chemokine network in systemic sclerosis.
Systemic sclerosis (SSc) is characterised by vasculopathy, an aberrantly activated immune system and excessive extracellular matrix deposition. Inflammatory chemokines control migration of cells to sites of tissue damage; their removal from inflamed sites is essential for resolution of the inflammatory response. The atypical chemokine receptor D6 has a critical role in this physiological balance. To explore potential deregulation of this system in SSc, inflammatory chemokine and D6 expression were compared with that in healthy controls (HC). Serum levels of inflammatory mediators were assessed by luminex analysis. Peripheral blood mononuclear cells (PBMCs) were used in molecular and immunocytochemical analysis. Platelet-rich plasma was collected and assessed by western blotting for D6 expression levels. Sex-matched HC were used for comparison. 72 patients with SSc and 30 HC were enrolled in the study. The chemokines MCP-1/CCL2, MIP-1α/CCL3, MIP-1β/CCL4 and IL-8/CXCL8 were significantly increased in patients with SSc, regardless of disease subtype and phase. Quantitative PCR analysis revealed a significant 10-fold upregulation of D6 transcripts in patients with SSc compared with controls, and this was paralleled by increased D6 protein expression in the PBMCs of patients with SSc. Platelet lysates also showed strong D6 expression in patients with SSc but not in controls. Importantly, high levels of D6 expression correlated with reduced levels of its ligands in serum. Inflammatory chemokines and the regulatory receptor D6 are significantly upregulated in SSc and high D6 levels are associated with lower systemic chemokine levels, indicating that some patients control systemic chemokine levels using D6. These results suggest that chemokines may represent a therapeutic target in SSc.


Gut microbiota-bile acid-interleukin-22 axis orchestrates polycystic ovary syndrome.
Polycystic ovary syndrome (PCOS) is characterized by androgen excess, ovulatory dysfunction and polycystic ovaries1, and is often accompanied by insulin resistance2. The mechanism of ovulatory dysfunction and insulin resistance in PCOS remains elusive, thus limiting the development of therapeutics. Improved metabolic health is associated with a relatively high microbiota gene content and increased microbial diversity3,4. This study aimed to investigate the impact of the gut microbiota and its metabolites on the regulation of PCOS-associated ovarian dysfunction and insulin resistance. Here, we report that Bacteroides vulgatus was markedly elevated in the gut microbiota of individuals with PCOS, accompanied by reduced glycodeoxycholic acid and tauroursodeoxycholic acid levels. Transplantation of fecal microbiota from women with PCOS or B. vulgatus-colonized recipient mice resulted in increased disruption of ovarian functions, insulin resistance, altered bile acid metabolism, reduced interleukin-22 secretion and infertility. Mechanistically, glycodeoxycholic acid induced intestinal group 3 innate lymphoid cell IL-22 secretion through GATA binding protein 3, and IL-22 in turn improved the PCOS phenotype. This finding is consistent with the reduced levels of IL-22 in individuals with PCOS. This study suggests that modifying the gut microbiota, altering bile acid metabolism and/or increasing IL-22 levels may be of value for the treatment of PCOS.


Adsorption and growth of palladium clusters on graphdiyne.
The density functional formalism has been used to investigate the stability and the properties of small palladium clusters supported on graphdiyne layers. The large triangular holes existing on the graphdiyne structure provide efficient sites to hold the clusters at small distances from the plane of the graphdiyne layer. The cluster adsorption energies, between 3 and 4 eV, are large enough to maintain the clusters tightly bound to the triangular holes. The competition between dispersion of Pd atoms on graphdiyne and growth of Pd clusters in the triangular holes of the layer is also discussed. In addition, the triangular holes can be simultaneously decorated with clusters on both sides. This indicates that palladium clusters could be used to build nanostructures formed by stacked graphdiyne layers with tailored interlayer distances controlled by the size of the clusters. The size of the clusters also controls the electronic HOMO-LUMO gap of the material.


Band 3 Cape Town (E90K) causes severe hereditary spherocytosis in combination with band 3 Prague III.
Hereditary spherocytosis (HS) is an inherited haemolytic anaemia, characterized by spheroidal, osmotically fragile red blood cells. This disorder exhibits heterogeneity in terms of both clinical severity and underlying molecular defect. We have studied a South African Cape Coloured individual with severe HS owing to a band 3 deficiency caused by two mutations, occurring in trans, in the band 3 gene: a novel variant that we have designated band 3 Cape Town and a previously described mutation, band 3 Prague III. Analysis of erythrocyte membrane proteins indicated a deficiency of both band 3 and protein 4.2, as well as a decreased functional capacity of band 3 to transport anions. Band 3 Cape Town is defined by a GAG-->AAG point mutation at codon 90, substituting a glutamic acid with a lysine in the cytoplasmic domain of the molecule, while band 3 Prague III is a codon 870 CGG-->TGG point mutation, replacing an arginine with a tryptophan in the transmembrane region of band 3. mRNA is transcribed from both mutant alleles, implying that mutant proteins are synthesized, but are either degraded prior to membrane incorporation or insertion is impaired. We conclude that the combination of these two mutations exacerbated the clinical presentation of the proband.


Down-regulation of LXR/RXR activation and negative acute phase response pathways in colon adenocarcinoma revealed by proteomics and bioinformatics analysis.
Deficiency of vitamin D could be a major cause of colon cancer as suggested as early as 1980 by Drs. Cedric and Frank Garland of the University of California and has recently been underscored by a large European case control study. Whether vitamin D deficiency is because of inadequate intake (food and sunshine) or because of vitamin D metabolism disorder in the patient body is unknown. A proteomics approach to identify protein pathways associated with vitamin D transportation and metabolism pathways will help us understand better the pathology of the colon cancer. Lysates of colon adenocarcinoma tissues and their matched healthy tissues, from seven colon cancer patients, have been evaluated by quantitative proteomics and bioinformatics analysis to determine protein expression profiles. Unsupervised hierarchical clustering and principle component analysis (PCA) were utilized for protein expression profiling and biomarker identification, while the reporter ion ratios from tandem-mass-tagging (TMT) labeled peptides were used for quantification. Ingenuity Pathway Analysis (IPA) was used to analyze protein pathways. Proteomics analyses demonstrated that the proteins involved in vitamin D/E binding, heme/iron binding and transportation, and lipid/steroid transportation/metabolic systems were down-regulated in colon cancer and the same set of proteins were down-regulated in the LXR/RXR activation and acute-phase response pathways, revealing a plausible mechanistic connection between vitamin D deficiency, iron homeostasis, and colon cancer.


Functional, biochemical, and chromatographic characterization of the complete [Ca2+]i oscillation-inducing activity of porcine sperm.
A cytosolic sperm protein(s), referred to as sperm factor (SF), is delivered into eggs by the sperm during mammalian fertilization to induce repetitive increases in the intracellular concentration of free Ca2+ ([Ca2+]i) that are referred to as [Ca2+]i oscillations. [Ca2+]i oscillations are essential for egg activation and early embryonic development. Recent evidence shows that the novel sperm-specific phospholipase C (PLC), PLCzeta, may be the long sought after [Ca2+]i oscillation-inducing SF. Here, we demonstrate the complete extraction of SF from porcine sperm and show that regardless of the method of extraction a single molecule/complex appears to be responsible for the [Ca2+]i oscillation-inducing activity of these extracts. Consistent with this notion, all sperm fractions that induced [Ca2+]i oscillations, including FPLC-purified fractions, exhibited high in vitro PLC activity at basal Ca2+ levels (0.1-5 microM), a hallmark of PLCzeta. Notably, we detected immunoreactive 72-kDa PLCzeta in an inactive fraction, and several fractions capable of inducing oscillations were devoid of 72-kDa PLCzeta. Nonetheless, in the latter fractions, proteolytic fragments, presumably corresponding to cleaved forms of PLCzeta, were detected by immunoblotting. Therefore, our findings corroborate the hypothesis that a sperm-specific PLC is the main component of the [Ca2+]i oscillation-inducing activity of sperm but provide evidence that the presence of 72-kDa PLCzeta does not precisely correspond with the Ca2+ releasing activity of porcine sperm fractions.


Effects of body size and change in body size from infancy through childhood on body mass index in adulthood.
Weight and weight gain throughout infancy are related to later obesity, but whether the strength of the associations varies during the infancy period is uncertain. Our aims were to identify the period of infancy when change in body weight has the strongest association with adult body mass index (BMI) and also the extent to which these associations during infancy are mediated through childhood BMI. The Copenhagen Perinatal Cohort, in which participants were followed from birth through 42 years of age, provided information on weight at 12 months and BMI at 42 years for 1633 individuals. Information on weight at birth, 2 weeks, 1, 2, 3, 4 and 6 months was retrieved from health visitors' records and information on BMI at ages 7 and 13 years from school health records. The associations of infant weight and weight gain standard deviation scores (SDS) with adult BMI-SDS were analyzed using multiple linear regression and path analysis. Higher-weight-SDS at all ages from birth to an age 12 months were associated with higher-BMI-SDS at 42 years (regression coefficients 0.08-0.12). Infant weight gain-SDS was associated with greater BMI-SDS at 42 years only between birth and 3 months (0.09, 95% confidence intervals (CI) 0.04, 0.15) driven by an association between 2 and 3 months (0.12, 95% CI: 0.04, 0.20). The latter was partly mediated through later BMI in the path analysis. Infant weight gain-SDS between 3 and 12 months was not associated with greater BMI-SDS at 42 years. Faster weight gain during only the first 3 months of infancy was associated with increased adult BMI, although not in a consistent monthly pattern. Adult BMI is more sensitive to high weight gain during early infancy than late infancy, but not specifically to the first month of life.


Abnormal Cannabidiol Modulates Vitamin A Metabolism by Acting as a Competitive Inhibitor of CRBP1.
Cellular retinol-binding proteins (CRBPs) facilitate the uptake and intracellular transport of vitamin A. They integrate retinoid metabolism, playing an important role in regulating the synthesis of bioactive vitamin A metabolites. Thus, CRBPs constitute potential pharmacological targets to modulate cellular retinoid status that in turn may have applications in the treatment of certain immunological, metabolic, and ocular disorders. Here we identify abnormal cannabidiol (abn-CBD) as a nonretinoid inhibitor of cellular retinol-binding protein 1 (CRBP1). X-ray crystal structures of CRBP1 in complex with abn-CBD and its derivatives revealed a distinctive mode of protein-ligand interaction and provided a molecular basis for the high affinity and selectivity of this compound. We demonstrated that abn-CBD modulates the flux of retinoids via the retinoid cycle in vivo. Furthermore, the biological activity of abn-CBD was evidenced by its ability to protect against light-induced retinal damage in Balb/cJ mice. Altogether, our findings indicate that targeting selected CRBPs with a small-molecule inhibitor can potentially lead to the development of new therapeutic agents to counteract diseases with etiologies involving imbalance in retinoid metabolism or signaling.


Topical meeting on optical interference coatings (OIC'2001): manufacturing problem.
Measurements are presented of the experimental filters submitted to the first optical thin-film manufacturing problem posed in conjunction with the Topical Meeting on Optical Interference Coatings, in which the object was to produce multilayers with spectral transmittance and reflectance curves that were as close as possible to the target values that were specified in the 400- to 600-nm spectral region. No limit was set on the overall thickness of the solutions or the number of layers used in their construction. The participants were free to use the coating materials of their choice. Six different groups submitted a total of 11 different filters for evaluation. Three different physical vapor deposition processes were used for the manufacture of the coatings: magnetron sputtering, ion-beam sputtering, and plasma-ion-assisted, electron-beam gun evaporation. The solutions ranged in metric thickness from 758 to 4226 nm and consisted of between 8 and 27 layers. For all but two of the samples submitted, the average rms departure of the measured transmittances and reflectances from the target values in the spectral region of interest was between 0.98% and 1.55%.


The impact of chemo- and radiotherapy treatments on selfish de novo FGFR2 mutations in sperm of cancer survivors.
What effect does cancer treatment have on levels of spontaneous selfish fibroblast growth factor receptor 2 (FGFR2) point mutations in human sperm? Chemotherapy and radiotherapy do not increase levels of spontaneous FGFR2 mutations in sperm but, unexpectedly, highly-sterilizing treatments dramatically reduce the levels of the disease-associated c.755C > G (Apert syndrome) mutation in sperm. Cancer treatments lead to short-term increases in gross DNA damage (chromosomal abnormalities and DNA fragmentation) but the long-term effects, particularly at the single nucleotide resolution level, are poorly understood. We have exploited an ultra-sensitive assay to directly quantify point mutation levels at the FGFR2 locus. 'Selfish' mutations are disease-associated mutations that occur spontaneously in the sperm of most men and their levels typically increase with age. Levels of mutations at c.752-755 of FGFR2 (including c.755C > G and c.755C > T associated with Apert and Crouzon syndromes, respectively) in semen post-cancer treatment from 18 men were compared to levels in pre-treatment samples from the same individuals (n = 4) or levels in previously screened population controls (n = 99). Cancer patients were stratified into four different groups based on the treatments they received and the length of time for spermatogenesis recovery. DNA extracted from semen samples was analysed using a previously established highly sensitive assay to identify mutations at positions c.752-755 of FGFR2. Five to ten micrograms of semen genomic DNA was spiked with internal controls for quantification purposes, digested with MboI restriction enzyme and gel extracted. Following PCR amplification, further MboI digestion and a nested PCR with barcoding primers, samples were sequenced on Illumina MiSeq. Mutation levels were determined relative to the spiked internal control; in individuals heterozygous for a nearby common single nucleotide polymorphism (SNP), mutations were phased to their respective alleles. Patients treated with moderately-sterilizing alkylating regimens and who recovered spermatogenesis within <3 years after therapy (Group 3, n = 4) or non - alkylating chemotherapy and/or low gonadal radiation doses (Group 1, n = 4) had mutation levels similar to untreated controls. However, patients who had highly-sterilizing alkylating treatments (i.e. >5 years to spermatogenesis recovery) (Group 2, n = 7) or pelvic radiotherapy (Group 4, n = 3) exhibited c.755C > G mutation levels at or below background. Two patients (A and B) treated with highly-sterilizing alkylating agents demonstrated a clear reduction from pre-treatment levels; however pre-treatment samples were not available for the other patients with low mutation levels. Therefore, although based on their age we would expect detectable levels of mutations, we cannot exclude the possibility that these patients also had low mutation levels pre-treatment. In three patients with low c.755C > G levels at the first timepoint post-treatment, we observed increasing mutation levels over time. For two such patients we could phase the mutation to a nearby polymorphism (SNP) and determine that the mutation counts likely originated from a single or a small number of mutational events. This study was limited to 18 patients with different treatment regimens; for nine of the 18 patients, samples from only one timepoint were available. Only 12 different de novo substitutions at the FGFR2 c.752-755 locus were assessed, two of which are known to be disease associated. Our data add to the body of evidence from epidemiological studies and experimental data in humans suggesting that male germline stem cells are resilient to the accumulation of spontaneous mutations. Collectively, these data should provide physicians and health-care professionals with reassuring experimental-based evidence for counselling of male cancer patients contemplating their reproductive options several years after treatment. This work was primarily supported by grants from the Wellcome (grant 091182 to AG and AOMW; grant 102 731 to AOMW), the University of Oxford Medical Sciences Division Internal Fund (grant 0005128 to GJM and AG), the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre Programme (to AG) and the US National Institutes of Health (to MLM). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. None of the authors has any conflicts of interest to declare. NA.


Integrating EDDS-enhanced washing with low-cost stabilization of metal-contaminated soil from an e-waste recycling site.
While chelant-enhanced soil washing has been widely studied for metal extraction from contaminated soils, there are concerns about destabilization and leaching of residual metals after remediation. This study integrated 2-h soil washing enhanced by biodegradable ethylenediaminedisuccinic acid (EDDS) and 2-month stabilization using agricultural waste product (soybean stover biochar pyrolyzed at 300 and 700 °C), industrial by-product (coal fly ash (CFA)), and their mixture. After integration with 2-month stabilization, the leachability and mobility of residual metals (Cu, Zn, and Pb) in the field-contaminated soil were significantly reduced, especially for Cu, in comparison with 2-h EDDS washing alone. This suggested that the metals destabilized by EDDS-washing could be immobilized by subsequent stabilization with biochar and CFA. Moreover, when the remediation performance was evaluated for phytoavailability and bioaccessibility, prior EDDS washing helped to achieve a greater reduction in the bioavailable fraction of metals than sole stabilization treatment. This was probably because the weakly-bound metals were first removed by EDDS washing before stabilization. Both individual and combined applications of biochar and CFA showed comparable effectiveness regardless of the difference in material properties, possibly due to the high level of amendments (150 ton ha(-1)). Based on the mobility and bioaccessibility results, the estimated human health risk (primarily resulting from Pb) could be mitigated to an acceptable level in water consumption pathway or reduced by half in soil ingestion pathway. These results suggest that an integration of EDDS washing with soil stabilization can alleviate post-remediation impacts of residual metals in the treated soil.


GPDPLQ1237-A Type II Collagen Neo-Epitope Biomarker of Osteoclast- and Inflammation-Derived Cartilage Degradation in vitro.
C-telopeptide of type II collagen (CTX-II) has been shown to be a highly relevant biomarker of cartilage degradation in human rheumatic diseases, if measured in synovial fluid or urine. However, serum or plasma CTX-II have not been demonstrated to have any clinical utility to date. Here, we describe the GPDPLQ1237 ELISA which targets the EKGPDPLQ↓ neo-epitope, an elongated version of the CTX-II neo-epitope (EKGPDP↓), speculated to be a blood-precursor of CTX-II generated by the cysteine protease cathepsin K. Human osteoclast cartilage resorption cultures as well as oncostatin M and tumour necrosis factor α-stimulated bovine cartilage explant cultures were used to validate GPDPLQ1237 biologically by treating the cultures with the cysteine protease inhibitor E-64 and/or the matrix metalloproteinase (MMP) inhibitor GM6001 to assess the potential contributions of these two protease classes to GPDPLQ1237 release. Cartilage resorption-derived GPDPLQ1237 release was inhibited by E-64 (72.1% inhibition), GM6001 (75.5%), and E-64/GM6001 (91.5%), whereas CTX-II release was inhibited by GM6001 (87.0%) but not by E-64 (5.5%). Cartilage explant GPDPLQ1237 and CTX-II release were both fully inhibited by GM6001 but were not inhibited by E-64. No clinically relevant GPDPLQ1237 reactivity was identified in human serum, plasma, or urine from healthy donors or arthritis patients. In conclusion, the GPDPLQ1237 biomarker is released during osteoclast-derived cysteine protease- and MMP-mediated cartilage degradation in vitro, whereas CTX-II release is mediated by MMPs and not by cysteine proteases, as well as from MMP-mediated cartilage degradation under a pro-inflammatory stimulus. These findings suggest that GPDPLQ1237 may be relevant in diseases with pathological osteoclast activity and cartilage degradation. Further studies are required to validate the neo-epitope in human samples.


Maternal and Child Health Services in the Context of the Ebola Virus Disease: Health Care Workers' Knowledge, Attitudes and Practices in Rural Guinea.
The objective of this study was to document maternal and child health care workers' knowledge, attitudes and practices on service delivery before, during and after the 2014 EVD outbreak in rural Guinea. We conducted a descriptive cross-sectional study in ten health districts between October and December 2015, using a standardized self-administered questionnaire. Overall 299 CHWs (94% response rate) participated in the study, including nurses/health technicians (49%), midwives (23%), managers (16%) and physicians (12%). Prior to the EVD outbreak, 87% of CHWs directly engaged in managing febrile cases within the facility, while the majority (89% and 63%) referred such cases to another facility and/or EVD treatment centre during and after the EVD outbreak, respectively. Compared to the period before the EVD outbreak when approximately half of CHWs (49%) reported systematically measuring body temperature prior to providing any care to patients, most CHWs reported doing so during (98%) and after the EVD outbreak (88%). The main challenges encountered were the lack of capacity to screen for EVD cases within the facility (39%) and the lack of relevant equipment (10%). The majority (91%) of HCWs reported a decrease in the use of services during the EVD outbreak while an increase was reported by 72% of respondents in the period following the EVD outbreak. Infection prevention and control measures established during the EVD outbreak have substantially improved self-reported provider practices for maternal and child health services in rural Guinea. However, more efforts are needed to maintain and sustain the gain achieved.


Attention-dependent coupling between beta activities recorded in the cat's thalamic and cortical representations of the central visual field.
We have previously proposed that enhanced 16-24 Hz (beta) local field potential activity in the primary visual cortex and lateral geniculate nucleus may be an electrophysiological correlate of the attentional mechanism that increases the gain of afferent visual information flow to the cortex. In this study, we measured coupling between beta signals recorded in the thalamic (i.e. lateral geniculate or perigeniculate) and cortical representations of the central visual field (within 5 degrees from area centralis), during visual and auditory attentive situations. Signal coupling was calculated in two ways: (i) by means of crosscorrelation between raw beta activities, which depends primarily on phase coherence, and (ii) by phase-independent crosscorrelation between amplitude envelopes of beta activities. Mean amplitudes of raw signal cross correlations obtained for thalamo-cortical recording pairs were not significantly different when calculated during behavioural demands for either visual or auditory attention. In contrast, amplitudes of envelope cross correlations obtained during behaviour requiring visual attention were, on average, two times higher than those calculated during the auditory task. This attention-related coupling emerged from synchronized amplitude modulation of beta oscillatory activity that occurs within the cortico-thalamic circuit involved in central vision.


Historical Persistence of Alcohol-Induced Mortality in the Russian Federations: Legacy of Early Industrialization.
The study aims to investigate insofar regional differences in alcohol-induced mortality in Russia, which emerged during the early industrialization of the country, persisted over a prolonged period of time (from late nineteenth to early twenty-first century), surviving fundamental political and social changes Russia experienced. Multivariate regression models with historical and contemporary data on alcohol-induced mortality in Russian regions were estimated to document the persistence of spatial patterns of mortality, as well as to identify the possible mediating variables. Numerous robustness checks were used to corroborate the results. Alcohol-induced male mortality in Russian regions in 1880s-1890s is significantly and strongly correlated with male mortality due to accidental alcohol poisoning in Russian regions in 2010-2012. For female mortality, no robust correlation was established. The results for male mortality do not change if one controls for a variety of other determinants of alcohol-induced mortality and are not driven by outlier regions. Consumption of strong alcohol (in particular vodka) appears to be the mediator variable explaining this persistence. Hazardous drinking behavioral patterns, once they emerge and crystalize during the periods of fragmentation of the traditional society and the early onsets of modernization and urbanization, can be extremely persistent. Even highly intrusive policy interventions at a later stage (like those of the Soviet government) may turn out to be insufficient to change the path-dependent outcomes.


Challenges in launching multinational oncology clinical trials in India.
In the recent past, there has been an impressive growth in the number of clinical trials launched worldwide, including India. Participation in well-designed oncology clinical trials is of advantage to Indian healthcare system in general, and cancer patients in particular. However, the number of clinical trials being run in India is not commensurate with the cancer burden prevailing in the country. In this article, the authors investigate the reasons for this discrepancy, highlight critical bottlenecks, and propose ways to ameliorate the situation.


Translational pain research: evaluating analgesic effect in experimental visceral pain models.
Deep visceral pain is frequent and presents major challenges in pain management, since its pathophysiology is still poorly understood. One way to optimize treatment of visceral pain is to improve knowledge of the mechanisms behind the pain and the mode of action of analgesic substances. This can be achieved through standardized experimental human pain models. Experimental pain models in healthy volunteers are advantageous for evaluation of analgesic action, as this is often difficult to assess in the clinic because of confounding factors such as sedation, nausea and general malaise. These pain models facilitate minimizing the gap between knowledge gained in animal and human clinical studies. Combining experimental pain studies and pharmacokinetic studies can improve understanding of the pharmacokinetic-pharmacodynamic relationship of analgesics and, thus, provide valuable insight into optimal clinical treatment of visceral pain. To improve treatment of visceral pain, it is important to study the underlying mechanisms of pain and the action of analgesics used for its treatment. An experimental pain model activates different modalities and can be used to investigate the mechanism of action of different analgesics in detail. In combination with pharmacokinetic studies and objective assessment such as electroencephalography, new information regarding a given drug substance and its effects can be obtained. Results from experimental human visceral pain research can bridge the gap in knowledge between animal studies and clinical condition in patients suffering from visceral pain, and thus constitute the missing link in translational pain research.


A high-salt/high fat diet alters circadian locomotor activity and glucocorticoid synthesis in mice.
Salt is an essential nutrient; however, excessive salt intake is a prominent public health concern worldwide. Various physiological functions are associated with circadian rhythms, and disruption of circadian rhythms is a prominent risk factor for cardiovascular diseases, cancer, and immune disease. Certain nutrients are vital regulators of peripheral circadian clocks. However, the role of a high-fat and high-salt (HFS) diet in the regulation of circadian gene expression is unclear. This study aimed to investigate the effect of an HFS diet on rhythms of locomotor activity, caecum glucocorticoid secretion, and clock gene expression in mice. Mice administered an HFS diet displayed reduced locomotor activity under normal light/dark and constant dark conditions in comparison with those administered a normal diet. The diurnal rhythm of caecum glucocorticoid secretion and the expression levels of glucocorticoid-related genes and clock genes in the adrenal gland were disrupted with an HFS diet. These results suggest that an HFS diet alters locomotor activity, disrupts circadian rhythms of glucocorticoid secretion, and downregulates peripheral adrenal gland circadian clock genes.


Inhaled corticosteroids and the treatment of lymphocytic bronchiolitis following lung transplantation.
Airway rejection after lung transplantation is recognized histologically as lymphocytic bronchiolitis (LB). We hypothesized that inhaled steroids could control LB and that changes in exhaled nitric oxide (eNO) would correlate with the development of LB and also have a role in monitoring response to treatment. A cohort of 120 lung transplant (LT) recipients attending for review and biopsy had eNO measurements, FEV1, lavage microbiology, and biopsy histology performed prospectively. Wilcoxon signed-rank test was used to assess the significance of changes in eNO and FEV1. The coefficient of reproducibility of eNO measurement in stable recipients was 2.36 ppb. Fourteen developed graft dysfunction owing to isolated LB and were treated with inhaled budesonide 800 microg twice daily. They showed significant increases in eNO at diagnosis, median (range) 10.9 ppb (4.6 to 48) ppb compared with baseline, 4.33 (1.0 to 10.76), p = 0.008, and a decrease in FEV1. After inhaled treatment, both eNO and FEV1 returned to baseline values. Seven developed acute vascular rejection (with or without LB) and were treated with oral corticosteroids; no changes in eNO occurred at diagnosis or after treatment. Serial eNO measurements provide a useful noninvasive method of identifying airway inflammation in LT recipients. Inhaled budesonide may be a useful addition to systemic immunosuppressants in controlling airway inflammation posttransplant.


Patient safety in surgery.
Improving patient safety is an increasing priority for surgeons and hospitals since sentinel events can be catastrophic for patients, caregivers, and institutions. Patient safety initiatives aimed at creating a safe operating room (OR) culture are increasingly being adopted, but a reliable means of measuring their impact on front-line providers does not exist. We developed a surgery-specific safety questionnaire (SAQ) and administered it to 2769 eligible caregivers at 60 hospitals. Survey questions included the appropriateness of handling medical errors, knowledge of reporting systems, and perceptions of safety in the operating room. MANOVA and ANOVA were performed to compare safety results by hospital and by an individual's position in the OR using a composite score. Multilevel confirmatory factor analysis was performed to validate the structure of the scale at the operating room level of analysis. The overall response rate was 77.1% (2135 of 2769), with a range of 57% to 100%. Factor analysis of the survey items demonstrated high face validity and internal consistency (alpha = 0.76). The safety climate scale was robust and internally consistent overall and across positions. Scores varied widely by hospital [MANOVA omnibus F (59, 1910) = 3.85, P < 0.001], but not position [ANOVA F (4, 1910) = 1.64, P = 0.16], surgeon (mean = 73.91), technician (mean = 70.26), anesthesiologist (mean = 71.57), CRNA (mean = 71.03), and nurse (mean = 70.40). The percent of respondents reporting good safety climate in each hospital ranged from 16.3% to 100%. Safety climate in surgical departments can be validly measured and varies widely among hospitals, providing the opportunity to benchmark performance. Scores on the SAQ can serve to evaluate interventions to improve patient safety.


Assessing vegetation recovery in reclaimed opencast mines of the Teruel coalfield (Spain) using Landsat time series and boosted regression trees.
Opencast mining is an activity that caters to many economic sectors; however, it has a large impact on society and the environment. After mining, the major concern is to restore the previous land cover, which was generally a natural vegetation cover. Establishing permanent vegetation cover can restore landscape connectivity and previous ecosystem functions, enhance aesthetic values and prevent off-side effects associated with post-mining landscapes. Opencast mining reclamation deals with these issues with several strategies that aim to develop a vegetation cover after mining activity has stopped. However, not all reclamation actions are effective, and assessing their efficiency by monitoring vegetation development at reclaimed sites is a time-consuming task because it usually involves extensive field work. In this study, we present a semi-automatic approach based on analysing satellite data (Landsat) time series and using a machine learning technique to identify suitable conditions for vegetation development at reclaimed opencast mines. We analysed the Teruel coalfield (Aragón, central-eastern Spain). This area is a representative Mediterranean-Continental region that is of particular interest due the diversity of reclamation actions that have been applied and the increase in drier conditions during the last decades. Conditions were described with topography derived variables, technical reclamation features and drought-occurrence variables as potential explanatory factors. The implemented approach allowed us to identify the main abiotic filters for vegetation of this geographic region: the water availability and soil retention (both controlled by the topographic slope), and the proximity to seed sources. The analysis evidenced the negative influence of drought occurrence on vegetation development, and different responses were found depending on the timescale at which drought is calculated. Our results indicate that the reclamation landform model is the main key factor influencing vegetation development. A model such as the smooth berm-slope increases water availability and controls soil erosion, and hence, improves vegetation development. In addition, we found that further than 500-600 m from the mine, the effect of seed source declines dramatically. Therefore, all these issues should be considered in future reclamation designs in a Mediterranean-Continental environment. Our methodology could be adapted to other geographic regions where spatial environmental data are available.


Tube fusion: making connections in branched tubular networks.
Organs like the vertebrate vascular system and the insect tracheal system develop from separate primordia that undergo fusion events to form interconnected tubular networks. Although the correct pattern of tubular connections (anastomoses) in these organs is crucial for their normal function, the cellular and molecular mechanisms that govern tube fusion are only beginning to be understood. The process of tube fusion involves tip cell specification, cell-cell recognition and contact formation, self-avoidance, changes in cell shape and topology, lumen formation, and luminal membrane fusion. Significant insights into the underlying cellular machinery have been provided by genetic studies of tracheal tube fusion in Drosophila. Here, we summarize these findings and we highlight similarities and differences between tube fusion processes in the Drosophila tracheae and in the vertebrate vascular system. We integrate the findings from studies in vivo with the important mechanistic insights that have been gained from the analysis of tubulogenesis in cultured cells to propose a mechanistic model of tube fusion, aspects of which are likely to apply to diverse organs and organisms.


Accelerated brain aging towards transcriptional inversion in a zebrafish model of the K115fs mutation of human PSEN2.
The molecular changes involved in Alzheimer's disease (AD) progression remain unclear since we cannot easily access antemortem human brains. Some non-mammalian vertebrates such as the zebrafish preserve AD-relevant transcript isoforms of the PRESENILIN genes lost from mice and rats. One example is PS2V, the alternative transcript isoform of the PSEN2 gene. PS2V is induced by hypoxia/oxidative stress and shows increased expression in late onset, sporadic AD brains. A unique, early onset familial AD mutation of PSEN2, K115fs, mimics the PS2V coding sequence suggesting that forced, early expression of PS2V-like isoforms may contribute to AD pathogenesis. Here we use zebrafish to model the K115fs mutation to investigate the effects of forced PS2V-like expression on the transcriptomes of young adult and aged adult brains. We edited the zebrafish genome to model the K115fs mutation. To explore its effects at the molecular level, we analysed the brain transcriptome and proteome of young (6-month-old) and aged (24-month-old) wild type and heterozygous mutant female sibling zebrafish. Finally, we used gene co-expression network analysis (WGCNA) to compare molecular changes in the brains of these fish to human AD. Young heterozygous mutant fish show transcriptional changes suggesting accelerated brain aging and increased glucocorticoid signalling. These early changes precede a transcriptional 'inversion' that leads to glucocorticoid resistance and other likely pathological changes in aged heterozygous mutant fish. Notably, microglia-associated immune responses regulated by the ETS transcription factor family are altered in both our zebrafish mutant model and in human AD. The molecular changes we observe in aged heterozygous mutant fish occur without obvious histopathology and possibly in the absence of Aβ. Our results suggest that forced expression of a PS2V-like isoform contributes to immune and stress responses favouring AD pathogenesis. This highlights the value of our zebrafish genetic model for exploring molecular mechanisms involved in AD pathogenesis.


Cost-effectiveness of using high-sensitivity C-reactive protein to identify intermediate- and low-cardiovascular-risk individuals for statin therapy.
Many myocardial infarctions and strokes occur in individuals with low-density lipoprotein cholesterol levels below recommended treatment thresholds. High sensitivity C-reactive protein (hs-CRP) testing has been advocated to identify low- and intermediate-risk individuals who may benefit from statin therapy. A decision analytic Markov model was used to follow hypothetical cohorts of individuals with normal lipid levels but without coronary artery disease, peripheral arterial disease, or diabetes mellitus. The model compared current Adult Treatment Panel III practice guidelines, a strategy of hs-CRP screening in those without an indication for statin treatment by current practice guidelines followed by treatment only in those with elevated hs-CRP levels, and a strategy of statin therapy at specified predicted risk thresholds without hs-CRP testing. Risk-based treatment without hs-CRP testing was the most cost-effective strategy, assuming that statins were equally effective regardless of hs-CRP status. However, if normal hs-CRP levels identified a subgroup with little or no benefit from statin therapy (<20% relative risk reduction), then hs-CRP screening would be the optimal strategy. If harms from statin use were greater than generally recognized, then use of current clinical guidelines would be the optimal strategy. Risk-based statin treatment without hs-CRP testing is more cost-effective than hs-CRP screening, assuming that statins have good long-term safety and provide benefits among low-risk people with normal hs-CRP.


Genital and oral mucosal immune response against HIV-1 in exposed uninfected individuals.
Epidemiologic reports routinely indicate that the high rate of HIV-1 transmission via mucosal exposure has been relatively stable since the epidemic began. Unfortunately, research on mucosal immune responses to HIV-1 has not been done in proportion to its importance. Most knowledge about immune responses against HIV-1 in humans comes from studies limited to the use of peripheral blood cells and plasma. Consequently, T-cell-based HIV-1 vaccines have long been considered a primary end point of preventive therapeutic strategies. The interest in HIV-1 exposed uninfected individuals has intensified because of the lessons to be learned about a natural immunologic response that promotes opposition to the infection. Such information has useful applications in the clinical setting. This review describes the current status of research on mucosal immune responses to HIV-1 from examining mucosal fluids and tissues of sexually exposed uninfected adults.


The visual pigment xenopsin is widespread in protostome eyes and impacts the view on eye evolution.
Photoreceptor cells in the eyes of Bilateria are often classified into microvillar cells with rhabdomeric opsin and ciliary cells with ciliary opsin, each type having specialized molecular components and physiology. First data on the recently discovered xenopsin point towards a more complex situation in protostomes. In this study, we provide clear evidence that xenopsin enters cilia in the eye of the larval bryozoan Tricellaria inopinata and triggers phototaxis. As reported from a mollusc, we find xenopsin coexpressed with rhabdomeric-opsin in eye photoreceptor cells bearing both microvilli and cilia in larva of the annelid Malacoceros fuliginosus. This is the first organism known to have both xenopsin and ciliary opsin, showing that these opsins are not necessarily mutually exclusive. Compiling existing data, we propose that xenopsin may play an important role in many protostome eyes and provides new insights into the function, evolution, and possible plasticity of animal eye photoreceptor cells.


[Social companies and solidary economy: perspectives for the work inclusion of individuals with mental disorders].
The psychiatric reform process requires the implementation of public policies that guarantee the work inclusion of individuals with mental disorders. To do this, work must be understood as a promoter of autonomy, emancipation and citizenship. The objective of this study is to reflect on the theoretical concepts related to social insertion through work, with the purpose of exploring the inclusion of individuals with mental disorders in the work market. The concepts social company and solidary economy where selected as fundamental for the study. In the social company, the subject is considered to be a social being, focusing on the development process towards emancipation. In solidary economy, the objective is to develop an economy that is more just, equal and solidary. Further discussions on these concepts should be developed to support the implementation of projects for social inclusion through work.


Human-Like Neutralizing Antibodies Protect Mice from Aerosol Exposure with Western Equine Encephalitis Virus.
Western equine encephalitis virus (WEEV) causes symptoms in humans ranging from mild febrile illness to life-threatening encephalitis, and no human medical countermeasures are licensed. A previous study demonstrated that immune serum from vaccinated mice protected against lethal WEEV infection, suggesting the utility of antibodies for pre- and post-exposure treatment. Here, three neutralizing and one binding human-like monoclonal antibodies were evaluated against WEEV aerosol challenge. Dose-dependent protection was observed with two antibodies administered individually, ToR69-3A2 and ToR68-2C3. In vitro neutralization was not a critical factor for protection in this murine model, as ToR69-3A2 is a strong neutralizing antibody, and ToR68-2C3 is a non-neutralizing antibody. This result highlights the importance of both neutralizing and non-neutralizing antibodies in the protection of mice from WEEV lethality.


A New Vessel-Based Method to Estimate Automatically the Position of the Nonfunctional Fovea on Altered Retinography From Maculopathies.
The purpose of this study was to validate a new automated method to locate the fovea on normal and pathological fundus images. Compared to the normative anatomic measures (NAMs), our vessel-based fovea localization (VBFL) approach relies on the retina's vessel structure to make predictions. The spatial relationship between the fovea location and vessel characteristics is learnt from healthy fundus images and then used to predict fovea location in new images. We evaluate the VBFL method on three categories of fundus images: healthy images acquired with different head orientations and fixation locations, healthy images with simulated macular lesions, and pathological images from age-related macular degeneration (AMD). For healthy images taken with the head tilted to the side, the NAM estimation error is significantly multiplied by 4, whereas VBFL yields no significant increase, representing a 73% reduction in prediction error. With simulated lesions, VBFL performance decreases significantly as lesion size increases and remains better than NAM until lesion size reaches 200 degrees2. For pathological images, average prediction error was 2.8 degrees, with 64% of the images yielding an error of 2.5 degrees or less. VBFL was not robust for images showing darker regions and/or incomplete representation of the optic disk. The vascular structure provides enough information to precisely locate the fovea in fundus images in a way that is robust to head tilt, eccentric fixation location, missing vessels, and actual macular lesions. The VBFL method should allow researchers and clinicians to assess automatically the eccentricity of a newly developed area of fixation in fundus images with macular lesions.


The eukaryotic translation initiation factor eIF4E is a direct transcriptional target of NF-κB and is aberrantly regulated in acute myeloid leukemia.
The eukaryotic translation initiation factor eIF4E is a potent oncogene elevated in many cancers, including the M4 and M5 subtypes of acute myeloid leukemia (AML). Although eIF4E RNA levels are elevated 3- to 10-fold in M4/M5 AML, the molecular underpinnings of this dysregulation were unknown. Here, we demonstrate that EIF4E is a direct transcriptional target of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) that is dysregulated preferentially in M4 and M5 AML. In primary hematopoietic cells and in cell lines, eIF4E levels are induced by NF-κB activating stimuli. Pharmacological or genetic inhibition of NF-κB represses this activation. The endogenous human EIF4E promoter recruits p65 and cRel to evolutionarily conserved κB sites in vitro and in vivo following NF-κB activation. Transcriptional activation is demonstrated by recruitment of p300 to the κB sites and phosphorylated Pol II to the coding region. In primary AML specimens, generally we observe that substantially more NF-κB complexes associate with eIF4E promoter elements in M4 and M5 AML specimens examined than in other subtypes or unstimulated normal primary hematopoietic cells. Consistently, genetic inhibition of NF-κB abrogates eIF4E RNA levels in this same population. These findings provide novel insights into the transcriptional control of eIF4E and a novel molecular basis for its dysregulation in at least a subset of M4/M5 AML specimens.


Cognitive and clinical outcomes of homocysteine-lowering B-vitamin treatment in mild cognitive impairment: a randomized controlled trial.
Homocysteine is a risk factor for Alzheimer's disease. In the first report on the VITACOG trial, we showed that homocysteine-lowering treatment with B vitamins slows the rate of brain atrophy in mild cognitive impairment (MCI). Here we report the effect of B vitamins on cognitive and clinical decline (secondary outcomes) in the same study. This was a double-blind, single-centre study, which included participants with MCI, aged ≥ 70 y, randomly assigned to receive a daily dose of 0.8 mg folic acid, 0.5 mg vitamin B(12) and 20 mg vitamin B(6) (133 participants) or placebo (133 participants) for 2 y. Changes in cognitive or clinical function were analysed by generalized linear models or mixed-effects models. The mean plasma total homocysteine was 30% lower in those treated with B vitamins relative to placebo. B vitamins stabilized executive function (CLOX) relative to placebo (P = 0.015). There was significant benefit of B-vitamin treatment among participants with baseline homocysteine above the median (11.3 µmol/L) in global cognition (Mini Mental State Examination, P < 0.001), episodic memory (Hopkins Verbal Learning Test-delayed recall, P = 0.001) and semantic memory (category fluency, P = 0.037). Clinical benefit occurred in the B-vitamin group for those in the upper quartile of homocysteine at baseline in global clinical dementia rating score (P = 0.02) and IQCODE score (P = 0.01). In this small intervention trial, B vitamins appear to slow cognitive and clinical decline in people with MCI, in particular in those with elevated homocysteine. Further trials are needed to see if this treatment will slow or prevent conversion from MCI to dementia.


Randomized trial on the effects of a combined physical/cognitive training in aged MCI subjects: the Train the Brain study.
Age-related cognitive impairment and dementia are an increasing societal burden. Epidemiological studies indicate that lifestyle factors, e.g. physical, cognitive and social activities, correlate with reduced dementia risk; moreover, positive effects on cognition of physical/cognitive training have been found in cognitively unimpaired elders. Less is known about effectiveness and action mechanisms of physical/cognitive training in elders already suffering from Mild Cognitive Impairment (MCI), a population at high risk for dementia. We assessed in 113 MCI subjects aged 65-89 years, the efficacy of combined physical-cognitive training on cognitive decline, Gray Matter (GM) volume loss and Cerebral Blood Flow (CBF) in hippocampus and parahippocampal areas, and on brain-blood-oxygenation-level-dependent (BOLD) activity elicited by a cognitive task, measured by ADAS-Cog scale, Magnetic Resonance Imaging (MRI), Arterial Spin Labeling (ASL) and fMRI, respectively, before and after 7 months of training vs. usual life. Cognitive status significantly decreased in MCI-no training and significantly increased in MCI-training subjects; training increased parahippocampal CBF, but no effect on GM volume loss was evident; BOLD activity increase, indicative of neural efficiency decline, was found only in MCI-no training subjects. These results show that a non pharmacological, multicomponent intervention improves cognitive status and indicators of brain health in MCI subjects.