Strongly Participatory Science and Knowledge Justice in an Environmentally Contested Region.
This article draws insights from a case study examining unanswered health questions of residents in two polluted towns in an industrial region in southern France. A participatory health study, as conducted by the author, is presented as a way to address undone science by providing the residents with relevant data supporting their illness claims. Local residents were included in the health survey process, from the formulation of the questions to the final data analysis. Through this strongly participatory science (SPS) process, the townspeople offered many creative ideas in the final report for how the data could be used to assist in improving their health and environment and policy work is already in evidence, resulting from the study. Drawing from the literature on participatory science and expertise as well as from the initial outcomes of the local health study, I propose that SPS produces a form of knowledge justice. Understanding knowledge and its making as part of a social justice agenda aligns well with environmental justice frames. Through SPS, local residents have a hermeneutical resource to make sense of their embodied lives and augment their claims with strong data supporting actions for improving their health and environment.


UK guidelines for the management of bone sarcomas.
This document is an update of the British Sarcoma Group guidelines published in 2010. The aim is to provide a reference standard for the clinical care of patients in the UK with bone sarcomas. Recent recommendations by the European Society of Medical Oncology, The National Comprehensive Cancer Network and The National Institute for Health and Care Excellence have been incorporated, and the literature since 2010 reviewed. The standards represent a consensus amongst British Sarcoma Group members in 2015. It is acknowledged that these guidelines will need further updates as care evolves. The key recommendations are that bone pain or a palpable mass should always lead to further investigation and that patients with clinico-radiological findings suggestive of a primary bone tumour at any site in the skeleton should be referred to a specialist centre and managed by a fully accredited bone sarcoma multidisciplinary team. Treatment recommendations are provided for the major tumour types and for localised, metastatic and recurrent disease. Follow up schedules are suggested.


Carnivorous diving beetles of the genus Desmopachria (Coleoptera: Dytiscidae) from Brazil: new species, new records, and a checklist.
Eight new species of Desmopachria Babington, 1841 are described and illustrated from Brazil: D. dicrophallica sp nov., D. disticta sp nov., D. grammosticta sp nov., D. grandinigra sp nov., D. itamontensis sp nov., D. leptophallica sp nov., D. stethothrix sp nov., and D. ukuki sp nov. The species D. amyae Miller, 2001, D. chei Miller, 1999, D. margarita Young, 1990, and D. volatidisca Miller, 2001 are recorded for the first time from Brazil. From species of the Desmopachria reported in Brazil, D. aldessa Young, 1980 has a new record from Pará state and D. fossulata Zimmermann, 1928, D. granoides Young, 1986, and D. laevis Sharp, 1882 have new records from Rio de Janeiro State. A checklist of all Desmopachria recorded from Brazil is presented with notes about some of the localities.


Construct validity of PROMIS® Cognitive Function in cancer patients and noncancer controls.
The Patient-Reported Outcomes Measurement Information System Cognitive Function-Concerns® (PROMIS®-CF-Concerns) assesses self-reported cognitive complaints. Construct validity data for the CF-Concerns are few. To add to the literature, an analysis of criterion validity for cognitive complaints (European Organisation for Research and Treatment of Cancer-Cognitive Functioning subscale [EORTC-CF]) and cognitive performance (neuropsychological tests of memory [NIH Toolbox Auditory Verbal Learning Test] and verbal fluency [Controlled Oral Word Association Test]) and discriminant validity (self-reports of negative emotions of anxiety, depression, negative mood) are provided. A two-group comparison design was used. Forty-four patients with chronic lymphocytic leukemia (CLL) and 44 age- and gender-matched noncancer controls completed self-report measures and neuropsychological tests. Spearman's rank correlations (rs) and independent-samples t tests were used. Regarding criterion validity, PROMIS®-CF-Concerns significantly correlated with the EORTC-CF (rs = 0.77, p < .001), although not with tests of memory (-0.19) or verbal fluency (0.16). As expected, patients with CLL performed lower than did controls on neuropsychological tests (ps < .05) yet did not differ from controls on PROMIS®-CF-Concerns. PROMIS®-CF-Concerns was reliably and significantly correlated with negative emotions, with rs ranges across measures of -0.42 to -0.69 for the CLL group and -0.53 to -0.78 for controls. PROMIS®-CF-Concerns exhibited high internal consistency. Criterion validity was evidenced for cognitive complaints though not for cognitive performance as assessed here. In summary, the analysis supports the criterion validity of PROMIS®-CF-Concerns for cognitive complaints. It also covaries with self-reports of co-occurring anxiety, depression, and negative mood. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


Quality of life in a prospective, multicenter phase 2 trial of neoadjuvant full-dose gemcitabine, oxaliplatin, and radiation in patients with resectable or borderline resectable pancreatic adenocarcinoma.
To determine the health-related quality of life (QOL) during and after neoadjuvant chemoradiation therapy and surgery for patients with pancreatic adenocarcinoma. Participants of a prospective, phase 2 multi-institutional trial treated with neoadjuvant chemoradiation followed by surgery completed QOL questionnaires (European Organization for Research and Treatment in Cancer Quality of Life Questionnaire version 3.0 [EORTC-QLQ C30], EORTC-Pancreatic Cancer module [EORTC-PAN 26], and Functional Assessment of Cancer Therapy Hepatobiliary and Pancreatic subscale [FACT-Hep]) at baseline, after 2 cycles of neoadjuvant therapy, after surgery, at 6 months from initiation of therapy, and at 6-month intervals for 2 years. Mean scores were compared with baseline. A change >10% was considered a minimal clinically important difference. Of 71 participants in the trial, 55 were eligible for QOL analysis. Compliance ranged from 32% to 74%. The EORTC-QLQ C30 global QOL did not significantly decline after neoadjuvant therapy, whereas the Functional Assessment of Cancer Therapy global health measure showed a statistically, but not clinically significant decline (-8, P=.02). This was in parallel with deterioration in physical functioning (-14.1, P=.001), increase in diarrhea (+16.7, P=.044), and an improvement in pancreatic pain (-13, P=.01) as per EORTC-PAN 26. Because of poor patient compliance in the nonsurgical group, long-term analysis was performed only from surgically resected participants (n=36). Among those, global QOL returned to baseline levels after 6 months, remaining near baseline through the 24-month visit. The study regimen consisting of 2 cycles of neoadjuvant therapy was completed without a clinically significant QOL deterioration. A transient increase in gastrointestinal symptoms and a decrease in physical functioning were seen after neoadjuvant chemoradiation. In those patients who underwent surgical resection, most domains returned back to baseline levels by 6 months.


Soft modes and strain redistribution in continuous models of amorphous plasticity: the Eshelby paradigm, and beyond?
The deformation of disordered solids relies on swift and localised rearrangements of particles. The inspection of soft vibrational modes can help predict the locations of these rearrangements, while the strain that they actually redistribute mediates collective effects. Here, we study soft modes and strain redistribution in a two-dimensional continuous mesoscopic model based on a Ginzburg-Landau free energy for perfect solids, supplemented with a plastic disorder potential that accounts for shear softening and rearrangements. Regardless of the disorder strength, our numerical simulations show soft modes that are always sharply peaked at the softest point of the material (unlike what happens for the depinning of an elastic interface). Contrary to widespread views, the deformation halo around this peak does not always have a quadrupolar (Eshelby-like) shape. Instead, for finite and narrowly-distributed disorder, it looks like a fracture, with a strain field that concentrates along some easy directions. These findings are rationalised with analytical calculations in the case where the plastic disorder is confined to a point-like 'impurity'. In this case, we unveil a continuous family of elastic propagators, which are identical for the soft modes and for the equilibrium configurations. This family interpolates between the standard quadrupolar propagator and the fracture-like one as the anisotropy of the elastic medium is increased. Therefore, we expect to see a fracture-like propagator when extended regions on the brink of failure have already softened along the shear direction and thus rendered the material anisotropic, but not failed yet. We speculate that this might be the case in carefully aged glasses just before macroscopic failure.


Comorbid symptoms of depression and musculoskeletal pain and risk of long term sickness absence.
Symptoms of depression and musculoskeletal pain have both been found to be associated with increased risk of long term sickness absence (LTSA). The comorbidity between depression and pain i.e. simultaneous presence of both symptoms, is well established in the literature. The aim for the current investigation was to investigate whether the presence of comorbid pain influences the associations between depressive symptoms and LTSA or if the presence of comorbid depressive symptoms influences associations between musculoskeletal pain and LTSA. A sample of 6572 Danish female health care workers responding to a questionnaire about health and working conditions were followed up in a national register of social transfer payments (DREAM) for 550 days. We estimated the risk for LTSA of four weeks or more, associated with depressive symptoms and number of musculoskeletal pain locations using a Cox proportional hazards model allowing multiple observations per individual. We conducted a test for multiplicative interaction between musculoskeletal pain locations and depressive symptoms, and presented stratified regression models to facilitate the interpretation of the results. The severity of depressive symptoms was correlated with the number of pain locations reported (Spearman's rho = .24, p < 0.001). We found a significant multiplicative interaction between depressive symptoms and musculoskeletal pain in predicting the risk of LTSA. Depressive symptoms and number of musculoskeletal pain locations were associated with increased risk of LTSA for individuals who did not have comorbid symptoms. However, we found no significant associations between the two predictors and LTSA among participants who reported comorbid symptoms. The risk of LTSA associated with depressive symptoms and musculoskeletal pain appears to be moderated by the presence of comorbid symptoms. The modified risk for LTSA among workers with comorbid symptoms requires further investigation.


ATP-sensitive potassium (K(ATP)) channel openers diazoxide and nicorandil lower intraocular pressure in vivo.
To evaluate the expression of ATP-sensitive potassium (K(ATP)) channel subunits and study the effect of K(ATP) channel openers diazoxide and nicorandil on intraocular pressure (IOP) in an in vivo mouse model. Expression of K(ATP) channel subunits in normal C57BL/6 mouse eyes was studied by immunohistochemistry and confocal microscopy. Wild-type C57BL/6 mice were treated with K(ATP) channel openers diazoxide (n = 10) and nicorandil (n = 10) for 14 days. Similar treatments with diazoxide were performed on K(ir)6.2((-/-)) mice (n = 10). IOP was recorded with a handheld tonometer 1 hour, 4 hours, and 23 hours following daily treatment. Posttreatment histology was examined by light and transmission electron microscopy. The K(ATP) channel subunits SUR2B, K(ir)6.1, and K(ir)6.2 were identified in all tissues within mouse eyes. Treatment with diazoxide in wild-type mice decreased IOP by 21.5 ± 3.2% with an absolute IOP reduction of 3.9 ± 0.6 mm Hg (P = 0.002). Nicorandil also decreased IOP (18.9 ± 1.8%) with an absolute IOP reduction of 3.4 ± 0.4 mm Hg (P = 0.002). Treatment with diazoxide in K(ir)6.2((-/-)) mice had no effect on IOP. No morphological abnormalities were observed in diazoxide- or nicorandil-treated eyes. K(ATP) channel openers diazoxide and nicorandil are effective regulators of IOP in mouse eyes. K(ir)6.2 appears to be a major K(ATP) channel subunit through which IOP is lowered following treatment with diazoxide.


Protective effects of pine bark extract against cisplatin-induced hepatotoxicity and oxidative stress in rats.
We investigated the protective effects of pine bark extract (pycnogenol®, PYC) against cisplatin-induced hepatotoxicity and oxidative stress in rats. Twenty-four male rats were divided into the following four groups: (1) vehicle control, (2) cisplatin (7.5 mg/kg), (3) cisplatin & PYC 10 (10 mg/kg/day), and (4) cisplatin & PYC 20 (20 mg/kg/day). A single intraperitoneal injection of cisplatin induced hepatotoxicity, as evidenced by an increase in serum aminotransferase and histopathological alterations, including degeneration/necrosis of hepatocytes, vacuolation, and sinusoidal dilation. In addition, an increase in the malondialdehyde (MDA) concentration and a decrease in the reduced glutathione (GSH) content and catalase (CAT), superoxide dismutase (SOD), and glutathione S-transferase (GST) activities were observed in the cisplatin-treated rat hepatic tissues. In contrast, PYC treatment effectively prevented cisplatin-induced hepatotoxicity, including the elevation of aminotransferase and histopathological lesions, in a dosedependent manner. Moreover, PYC treatment also induced antioxidant activity by decreasing MDA level and increasing GSH content and SOD and GST activities in liver tissues. These results indicate that PYC has a protective effect against acute hepatotoxicity induced by cisplatin in rats, and that the protective effects of PYC may be due to inhibiting lipid peroxidation and increasing antioxidant activity.


Well-being, health, and productivity improvement after an employee well-being intervention in large retail distribution centers.
To evaluate changes in well-being, biometric, and productivity indicators after a well-being intervention. Biometric and self-reported outcomes were assessed among 677 retail distribution center employees before and after a 6-month well-being intervention. Despite lower well-being at baseline compared to an independent random sample of workers, program participants' well-being, productivity, body mass index, systolic blood pressure, and total cholesterol improved significantly after the intervention, whereas the decline in diastolic blood pressure was not significant. Moreover, participants' specific transition across well-being segments over the intervention period demonstrated more improvement than decline. There is evidence that programs designed to improve well-being within a workforce can be used to significantly and positively impact employee health and productivity, which should result in reduced health care costs, improved employee productivity, and increased overall profitability.


Transcriptional regulation of lipid homeostasis in mycobacteria.
Mycolic acids are major components of the cell envelope of mycobacteria, such as Mycobacterium tuberculosis, and play an important role in its architecture, impermeability and interaction with the environment. Synthesis of mycolic acids is carried out by two types of fatty acid synthases (FAS) working in concert: type I FAS, a multifunctional enzyme capable of de novo synthesis of medium-chain fatty acids, and type II FAS, responsible for their elongation. In this article we report the identification and characterization of a transcriptional regulator (MabR), whose binding to the FAS-II promoter region was demonstrated in vitro and in vivo. Overexpression and knock-down studies in Mycobacterium smegmatis revealed the repressor nature of MabR, with reduced amounts of FAS-II transcripts and fatty acids in the overproducing strain. Under these conditions, downregulation of fas transcription was also observed, thereby suggesting the existence of cross-talk between the two FAS, mediated by MabR. Finally, the finding that a mabR knock-out mutant could only be obtained in a merodiploid strain of M. smegmatis, confirmed the predicted essentiality, thus implying an essential role for MabR in mycobacterial fatty acid metabolism.


Bacterial symbionts and natural products.
The study of bacterial symbionts of eukaryotic hosts has become a powerful discovery engine for chemistry. This highlight looks at four case studies that exemplify the range of chemistry and biology involved in these symbioses: a bacterial symbiont of a fungus and a marine invertebrate that produce compounds with significant anticancer activity, and bacterial symbionts of insects and nematodes that produce compounds that regulate multilateral symbioses.


Burrowing and nest building activity in mice after exposure to grid floor, isoflurane or ip injections.
Burrowing and nest building are examples of highly motivated innate behaviours in rodents. Assessments based on these behaviours can be used as non-invasive indicators of pain, distress and suffering. In this study, we investigated the effect of three stressful procedures, namely grid floor housing for 24 h, 15 min of isoflurane anaesthesia and an intraperitoneal saline injection daily for three days, on nest building and burrowing in female C57BL/6NTac mice. For burrowing, we also investigated the effect of the presence of a shelter and nesting material (standard home cage enrichment) versus no shelter and nesting material, and whether the test can be performed during normal working hours. Alongside this, we investigated the effect of grid floor, isoflurane anaesthesia and intraperitoneal injections on stress hormone level, body weight, fur status and sucrose preference. The burrowing test was found to be sensitive to 24 h grid floor housing when no shelter but only a cardboard tube was present during testing. The mice burrowed a mean of 21 g less after grid floor housing (P < .01). This change was accompanied by decreased sucrose preference (P < .01) and body weight (P < .01). 15 min of anaesthesia with isoflurane induced changes in the nest building activity test. After exposure to isoflurane the mice built less complex nests (P = .04). This was accompanied by a decrease in sucrose preference (P < .01), a decrease in body weight (P < .01), and elevated stress hormone levels (P < .01). One daily intraperitoneal injection of saline for three days did not result in changes in nest building activity (P > .01). We also found that the mice burrowed equal amount during normal working hours and prior to the dark phase, indicating that the burrowing test can be performed during normal working hours instead of prior to the dark phase (P = .62).


Impact of Microscope-Integrated OCT on Ophthalmology Resident Performance of Anterior Segment Surgical Maneuvers in Model Eyes.
The integration of swept-source optical coherence tomography (SS-OCT) into the operating microscope enables real-time, tissue-level three-dimensional (3D) imaging to aid in ophthalmic microsurgery. In this prospective randomized controlled study, we evaluated the impact of SS microscope-integrated OCT (MI-OCT) on ophthalmology residents' performance of ophthalmic microsurgical maneuvers. Fourteen ophthalmology residents from a single institution were stratified by year of training and randomized to perform four anterior segment surgical maneuvers on porcine eyes with (MI-OCT+) or without (MI-OCT-) direct intraoperative OCT guidance. Subsequently, both groups repeated the same maneuvers without MI-OCT feedback to test whether initial MI-OCT experience affected subsequent surgical performance. Finally, the MI-OCT- group was crossed over and allowed to repeat the same maneuvers with direct MI-OCT guidance. Each resident completed a survey at the completion of the study. With direct MI-OCT feedback, residents demonstrated enhanced performance in depth-based anterior segment maneuvers (corneal suture passes at 50% and 90% depth and corneal laceration repair) compared with the residents operating without MI-OCT. Microscope-integrated OCT+ residents continued to outperform the controls when both groups subsequently operated without MI-OCT. For clear corneal wound geometry, there was no statistically significant effect of MI-OCT as applied in this study. Overall, the resident surgeons rated their subjective experience of using MI-OCT very favorably. Microscope-integrated OCT feedback enhances performance of ophthalmology residents in select anterior segment surgical maneuvers. Microscope-integrated OCT represents a valuable tool in the surgical education of ophthalmology residents.


Programme sensitivity and effectiveness of mammography service screening in Helsinki, Finland.
To evaluate the effectiveness of mammography service screening. Helsinki (population 0.5 million), the capital of Finland, the breast cancer service screening programme was started gradually in 1986. The study was based on the data from the breast cancer screening programme in Helsinki. All incident cases of breast cancer and rates in the female population in Helsinki during the period 1970-97, and information on the subsequent breast cancer mortality were derived from the files of the Finnish Cancer Registry. To estimate the sensitivity of the programme, the number of screen detected cancers were compared with the overall number of breast cancers at the targeted age groups. Effects of screening were estimated for cumulative incidence and for the refined mortalities among the birth cohorts screened. Altogether 144 400 invitations had been sent during 1986-97 among the 50-9 year old women as targeted in Helsinki. The average attendance rate was 82%; and 545 breast cancers were detected by screening, with a detection rate of 0.46%. In the birth cohort of women born between the start of 1935 and the end of 1939-namely, those subjected to most complete screening and long follow up time since the onset of the programme-there was an increase in the cumulative incidence of breast cancer (relative risk (RR) 1.18, 95% confidence interval (95% CI) 1.09 to 1.27). The estimated sensitivity of the screening programme was 58%; and 53% if corrected for overdiagnosis. There was also a decrease of 19% (RR 0.81, 95% CI 0.62 to 1.05) in the refined mortality within this screened birth cohort, compared with the death rate of women of comparable ages in the non-screened reference cohort. The study provides further support to the hypothesis that service screening with mammography reduces the risk of breast cancer mortality.


A NWB-based dataset and processing pipeline of human single-neuron activity during a declarative memory task.
A challenge for data sharing in systems neuroscience is the multitude of different data formats used. Neurodata Without Borders: Neurophysiology 2.0 (NWB:N) has emerged as a standardized data format for the storage of cellular-level data together with meta-data, stimulus information, and behavior. A key next step to facilitate NWB:N adoption is to provide easy to use processing pipelines to import/export data from/to NWB:N. Here, we present a NWB-formatted dataset of 1863 single neurons recorded from the medial temporal lobes of 59 human subjects undergoing intracranial monitoring while they performed a recognition memory task. We provide code to analyze and export/import stimuli, behavior, and electrophysiological recordings to/from NWB in both MATLAB and Python. The data files are NWB:N compliant, which affords interoperability between programming languages and operating systems. This combined data and code release is a case study for how to utilize NWB:N for human single-neuron recordings and enables easy re-use of this hard-to-obtain data for both teaching and research on the mechanisms of human memory.


Intravenous magnesium for pediatric sickle cell vaso-occlusive crisis: methodological issues of a randomized controlled trial.
Multiple recent Sickle Cell Disease studies have been terminated due to poor enrollment. We developed methods to overcome past barriers and utilized these to study the efficacy and safety of intravenous magnesium for vaso-occlusive crisis (VOC). We describe the methods of the Intravenous Magnesium in Sickle Vaso-occlusive Crisis (MAGiC) trial and discuss methods used to overcome past barriers. MAGiC was a multi-center randomized double-blind placebo-controlled trial of intravenous magnesium versus normal saline for treatment of VOC. The study was a collaboration between Pediatric Hematologists and Emergency Physicians in the Pediatric Emergency Care Applied Research Network (PECARN). Eligible patients were randomized within 12 hours of receiving intravenous opioids in the Emergency Department (ED) and administered study medication every 8 hours. The primary outcome was hospital length of stay. Associated plasma studies elucidated magnesium's mechanism of action and the pathophysiology of VOC. Health-related quality of life was measured. Site-, protocol-, and patient-related barriers from prior studies were identified and addressed. Limited study staff availability, lack of collaboration with the ED, and difficulty obtaining consent were previously identified barriers. Leveraging PECARN resources, forging close collaborations between Sickle Cell Centers and EDs of participating sites, and approaching eligible patients for prior consent helped overcome these barriers. Participation in the PECARN network and establishment of collaborative arrangements between Sickle Cell Centers and their affiliated EDs are major innovative features of the MAGiC study that allowed improved subject capture. These methods could serve as a model for future studies of VOCs.


Arabidopsis gls mutants and distinct Fd-GOGAT genes. Implications for photorespiration and primary nitrogen assimilation.
Ferredoxin-dependent glutamate synthase (Fd-GOGAT) plays a major role in photorespiration in Arabidopsis, as has been determined by the characterization of mutants deficient in Fd-GOGAT enzyme activity (gls). Despite genetic evidence for a single Fd-GOGAT locus and gene, we discovered that Arabidopsis contains two expressed genes for Fd-GOGAT (GLU1 and GLU2). Physical and genetic mapping of the gls1 locus and GLU genes indicates that GLU1 is linked to the gls1 locus, whereas GLU2 maps to a different chromosome. Contrasting patterns of GLU1 and GLU2 expression explain why a mutation in only one of the two genes for Fd-GOGAT leads to a photorespiratory phenotype in the gls1 mutants. GLU1 mRNA was expressed at the highest levels in leaves, and its mRNA levels were specifically induced by light or sucrose. In contrast, GLU2 mRNA was expressed at lower constitutive levels in leaves and preferentially accumulated in roots. Although these results suggest a major role for GLU1 in photorespiration, the sucrose induction of GLU1 mRNA in leaves also suggests a role in primary nitrogen assimilation. This possibility is supported by the finding that chlorophyll levels of a gls mutant are significantly lower than those of the wild type when grown under conditions that suppress photorespiration. Both the mutant analysis and gene regulation studies suggest that GLU1 plays a major role in photorespiration and also plays a role in primary nitrogen assimilation in leaves, whereas the GLU2 gene may play a major role in primary nitrogen assimilation in roots.


The brain and its main anatomical subdivisions in living hominoids using magnetic resonance imaging.
Primary comparative data on the hominoid brain are scarce and major neuroanatomical differences between humans and apes have not yet been described satisfactorily, even at the gross level. Basic questions that involve the evolution of the human brain cannot be addressed adequately unless the brains of all extant hominoid species are analyzed. Contrary to the scarcity of original data, there is a rich literature on the topic of human brain evolution and several debates exist on the size of particular sectors of the brain, e.g., the frontal lobe. In this study we applied a non-invasive imaging technique (magnetic resonance) on living human, great ape and lesser ape subjects in order to investigate the overall size of the hominoid brain. The images were reconstructed in three dimensions and volumetric estimates were obtained for the brain and its main anatomical sectors, including the frontal and temporal lobes, the insula, the parieto-occipital sector and the cerebellum.A remarkable homogeneity is present in the relative size of many of the large sectors of the hominoid brain, but interspecific and intraspecific variation exists in certain parts of the brain. The human cerebellum is smaller than expected for an ape brain of human size. It is suggested that the cerebellum increased less than the cerebrum after the split of the human lineage from the African ancestral hominoid stock. In contrast, humans have a slightly larger temporal lobe and insula than expected, but differences are not statistically significant. Humans do not have a larger frontal lobe than expected for an ape brain of human size and gibbons have a relatively smaller frontal lobe than the rest of the hominoids. Given the fact that the frontal lobe in humans and great apes has similar relative size, it is parsimonious to suggest that the relative size of the whole of the frontal lobe has not changed significantly during hominid evolution in the Plio-Pleistocene.


Photometric Stereo in a Scattering Medium.
Photometric stereo is widely used for 3D reconstruction. However, its use in scattering media such as water, biological tissue and fog has been limited until now, because of forward scattered light from both the source and object, as well as light scattered back from the medium (backscatter). Here we make three contributions to address the key modes of light propagation, under the common single scattering assumption for dilute media. First, we show through extensive simulations that single-scattered light from a source can be approximated by a point light source with a single direction. This alleviates the need to handle light source blur explicitly. Next, we model the blur due to scattering of light from the object. We measure the object point-spread function and introduce a simple deconvolution method. Finally, we show how imaging fluorescence emission where available, eliminates the backscatter component and increases the signal-to-noise ratio. Experimental results in a water tank, with different concentrations of scattering media added, show that deconvolution produces higher-quality 3D reconstructions than previous techniques, and that when combined with fluorescence, can produce results similar to that in clear water even for highly turbid media.


Cluster Analysis of Presolar Silicon Carbide Grains: Evaluation of Their Classification and Astrophysical Implications.
Cluster analysis of presolar silicon carbide grains based on literature data for 12C/13C, 14N/15N, δ 30Si/28Si, and δ 29Si/28Si including or not inferred initial 26Al/27Al data, reveals nine clusters agreeing with previously defined grain types but also highlighting new divisions. Mainstream grains reside in three clusters probably representing different parent star metallicities. One of these clusters has a compact core, with a narrow range of composition, pointing to an enhanced production of SiC grains in asymptotic giant branch (AGB) stars with a narrow range of masses and metallicities. The addition of 26Al/27Al data highlights a cluster of mainstream grains, enriched in 15N and 26Al, which cannot be explained by current AGB models. We defined two AB grain clusters, one with 15N and 26Al excesses, and the other with 14N and smaller 26Al excesses, in agreement with recent studies. Their definition does not use the solar N isotopic ratio as a divider, and the contour of the 26Al-rich AB cluster identified in this study is in better agreement with core-collapse supernova models. We also found a cluster with a mixture of putative nova and AB grains, which may have formed in supernova or nova environments. X grains make up two clusters, having either strongly correlated Si isotopic ratios or deviating from the 2/3 slope line in the Si 3-isotope plot. Finally, most Y and Z grains are jointly clustered, suggesting that the previous use of 12C/13C = 100 as a divider for Y grains was arbitrary. Our results show that cluster analysis is a powerful tool to interpret the data in light of stellar evolution and nucleosynthesis modeling and highlight the need of more multi-element isotopic data for better classification.


Superresolving the kidney-a practical comparison of fluorescence nanoscopy of the glomerular filtration barrier.
Immunofluorescence microscopy is routinely used in the diagnosis of and research on renal impairments. However, this highly specific technique is restricted in its maximum resolution to about 250 nm in the lateral and 700 nm in the axial directions and thus not sufficient to investigate the fine subcellular structure of the kidney's glomerular filtration barrier. In contrast, electron microscopy offers high resolution, but this comes at the cost of poor preservation of immunogenic epitopes and antibody penetration alongside a low throughput. Many of these drawbacks were overcome with the advent of super-resolution microscopy methods. So far, four different super-resolution approaches have been used to study the kidney: single-molecule localization microscopy (SMLM), stimulated emission depletion (STED) microscopy, structured illumination microscopy (SIM), and expansion microscopy (ExM), however, using different preservation methods and widely varying labelling strategies. In this work, all four methods were applied and critically compared on kidney slices obtained from samples treated with the most commonly used preservation technique: fixation by formalin and embedding in paraffin (FFPE). Strengths and weaknesses, as well as the practicalities of each method, are discussed to enable users of super-resolution microscopy in renal research make an informed decision on the best choice of technique. The methods discussed enable the efficient investigation of biopsies stored in kidney banks around the world. Graphical abstract.


[Correlation between psychopathological symptoms, coping style in adolescent and childhood repeated physical, emotional maltreatment].
To study possible relationship between psychopathological symptoms, positive and negative coping styles in adolescents who experienced repeated serious childhood physical abuse (CPA), moderate CPA, and childhood emotional abuse (CEA). A total of 5453 students were recruited as subjects from 9 middle schools at grades 7, 8, 10, and 11. They provided informed consent and participated in the self-administered anonymous survey on their frequencies of serious or moderate physical abuse and emotional abuse by his/her parents or other caregivers about average times of experiencing maltreatment every year during primary school. The Symptoms Checklist 90 (SCL-90) was used to rate general mental problem and 9 special psychopathological symptoms. The trait positive and negative coping styles were assessed with the Trait Coping Style Questionnaire (TCSQ). Totally 5141 respondents substantially completed surveys. It was defined as repeating childhood maltreatment that the adolescent reported he/she had suffered 3 or more episodes of one or more forms of serious CPA, moderate CPA, and CEA. Multinomial logistic regression model was used to analyze the effect of the types and quantities of repeating childhood experiences on mental health when the positive, negative coping styles, and both of them entered the statistics model, taking the demographic variables as covariates. Of respondents, 9.1 percent were rated as having general mental health problem. The rates of somatization, obsession, interpersonal susceptivity, depression, anxiety, phobia, paranoia, and psychotic symptoms were 1.3%, 3.6%, 3.6%, 2.8%, 2.2%, 4.0%, 2.1%, 2.8% and 1.6%, respectively. Dose-response trend existed between the number of items of repeating serious CPA, moderate CPA, CEA, and rates of general mental problems, 9 kinds of psychopathological symptoms, number of positive items of psychopathological symptoms. Compared with the respondents without serious CPA, moderate CPA or CEA, those with repeating childhood maltreatment had higher scores of negative coping styles. In the respondents with repeating childhood maltreatments, the prevalence of general mental problems and number of positive psychopathological symptoms increased with the rising of scores of negative coping styles. The results from multinomial logistic regression analysis showed that negative coping style decreased the odds ratio (OR) of repeating serious CPA, moderate CPA, and CEA with general mental health problems, but positive coping style did not. The experiences of repeating childhood physical or emotional maltreatment are associated with a wide variety of psychopathological symptoms and general mental health problems. Negative coping strategies may moderate the links of childhood abusive experiences and mental problems.


Gadolinium contrast agents - are they really safe?
Gadolinium-based contrast agents (GBCA) are used worldwide for enhanced MRI examinations, including heart and vessels. Gadolinium is a highly toxic heavy metal. If used in GBCA it must be tightly bound to ligands. The configuration of ligands influences the stability of the GBCA and two types of chelates have been used. Macrocyclic chelates offer better protection and binding of gadolinium ion than linear chelates with a flexible open chain - gadolinium could be more easily released from the latter ones. GBCAs are excreted from the body mostly by the kidneys, which is of importance in chronic kidney disease.Two states are related to gadolinium: nephrogenic systemic fibrosis (NSF) and gadolinium body storage. NSF is a severe and debilitating disease, directly connected to gadolinium toxicity, proven after the use of linear chelates. Due to strict recommendations of radiology societies, NSF was practically eradicated. Gadolinium deposition was observed especially in bones and in some brain areas: in dentate nucleus and in globus pallidus, even years after the GBCA administration. The form of the storage (chelated or free), as well as their clinical impact, are not clear, but first observations of "gadolinium deposition disease" have been reported.


Age and disease related changes in intestinal bacterial populations assessed by cell culture, 16S rRNA abundance, and community cellular fatty acid profiles.
The normal intestinal microflora plays an important role in host metabolism and provides a natural defence mechanism against invading pathogens. Although the microbiota in adults has been extensively studied, little is known of the changes that occur in the microflora with aging. These may have important consequences in elderly people, many of whom are receiving antibiotic therapy and who are most susceptible to intestinal dysbiosis. To characterise the major groups of faecal bacteria in subjects of different ages using a combination of cultural, molecular, and chemotaxonomic approaches. Comparative microbiological studies were made on four different subject groups: children (16 months to seven years, n=10), adults (21-34 years, n=7), healthy elderly subjects (67-88 years, n=5), and geriatric patients (68-73 years, n=4) diagnosed with Clostridium difficile diarrhoea. Selected faecal bacteria were investigated using viable counting procedures, 16S ribosomal RNA (rRNA) abundance measurements, and the occurrence of specific signature fatty acids in whole community fatty acid methyl ester profiles. The principal microbiological difference between adults and children was the occurrence of higher numbers of enterobacteria in the latter group, as determined by viable counts (p<0.05) and 16S rRNA (p<0.01) measurements. Moreover, a greater proportion of children's faecal rRNA was hybridised by the three probes (bifidobacteria, enterobacteria, bacteroides-porphyromonas-prevotella) used in the study, indicating a less developed gut microbiota. Species diversity was also markedly lower in the Clostridium difficile associated diarrhoea group, which was characterised by high numbers of facultative anaerobes and low levels of bifidobacteria and bacteroides. Although it was a considerably less sensitive diagnostic tool, cellular fatty acid analysis correlated with viable bacterial counts and 16S rRNA measurements in a number of bacteria, including bacteroides. Polyphasic analysis of faecal bacteria showed that significant structural changes occur in the microbiota with aging, and this was especially evident with respect to putatively protective bifidobacteria. Reductions in these organisms in the large bowel may be related to increased disease risk in elderly people.


The dynamics of post-operative plasma ACTH values following transsphenoidal surgery for Cushing's disease.
Rapid assessment of adrenal function is critical following transsphenoidal surgery (TSS) for Cushing's disease (CD) in order to determine surgical efficacy. We hypothesize that there may be a role for ACTH measurement as a rapid indicator of adrenal function. Following surgery for CD, glucocorticoids were withheld and paired plasma ACTH and serum cortisol levels were measured every 6 h. Post-operative hypocortisolemia was defined as serum cortisol <2 mcg/dl or a serum cortisol <5 mcg/dl with the onset of symptoms of adrenal insufficiency within 72 h. We studied 12 subjects, all female, mean age 44.6 years (range 25-55), including 13 surgeries: nine subjects attained hypocortisolemia. Plasma ACTH levels decreased more in subjects with hypocortisolemia (0.9 pg/ml/hr, P = 0.0028) versus those with persistent disease (0 0.2 pg/ml/hr, P = 0.26) within the first 48 h after surgery. In contrast to subjects with persistent disease, all subjects with hypocortisolemia achieved a plasma ACTH <20 pg/ml by 19 h (range 1-19 h). Four of the nine subjects with hypocortisolemia achieved plasma ACTH <20 pg/ml by 13 h and the remaining five subjects by 19 h. Hypocortisolemia occurred between 3-36 h following achievement of a plasma ACTH <20 pg/ml. In CD, a reduction in postoperative plasma ACTH levels differentiates subjects with surgical remission versus subjects with persistent disease. The utility of plasma ACTH measurements in the postoperative management of CD remains to be determined.


The spectrum of giant cell arteritis and polymyalgia rheumatica: revisiting the concept of the disease.
GCA and PMR are conditions of older persons that frequently overlap. The traditional concept of GCA has focused on cranial symptoms such as headache and visual disturbance, but extra-cranial manifestations such as constitutional symptoms, polymyalgia and limb claudication have also long been recognized. These symptoms may coincide with cranial GCA, occur as an independent clinical subset [large-vessel (LV) GCA] or overlap with PMR. Imaging studies have demonstrated that up to one-third of patients with PMR have subclinical LV inflammation at disease outset. The implication of this finding for PMR management is unclear. Pathophysiological studies have emphasized the pivotal role of dendritic cells (DCs) and T cells in the pathogenesis of GCA, and the activation of certain pattern recognition receptors on DCs may determine the clinical subset of GCA. In patients with only PMR clinically, it is conceivable that transmural arterial inflammation has either not yet started or is prevented by unexplored regulatory pathways. This concept is supported by vasculitis of peri-adventitial small-vessels and activated DCs in the adventitia of temporal arteries, in the absence of media-infiltrating T cells. This review examines the clinical and pathophysiological spectrum of GCA and its subsets with PMR, the role of newer imaging techniques for GCA diagnosis and the management of these diseases.


Identification and clinical implications of a novel pathogenic variant in the GJB2 gene causes autosomal recessive non-syndromic hearing loss in a consanguineous Iranian family.
Mutations in the GJB2 gene, which encodes the connexin26 protein and is involved in inner ear homeostasis, are the most common cause of autosomal recessive non-syndromic hearing loss (ARNSHL) in many populations. This study was aimed to determine the molecular etiology in a consanguineous Iranian family affected by profound ARNSHL. A comprehensive family history was obtained, and clinical evaluations and pedigree analysis were performed in the family with 4 affected members. After extraction of genomic DNA, the entire coding region of GJB2 was directly sequenced in all family members. In silico analyses were also performed using available software tools. Sanger sequencing results showed a novel rare homozygous variant (c.109_110insG) in the GJB2 gene. This frameshift variant in exon 2 of the GJB2 gene fulfills the criteria of being categorized as pathogenic according to the American College of Medical Genetics and Genomics (ACMG) guideline. Confirmation was done with the co-segregation study and checking the frequency of the novel variant in 100 ethnically matched normal control subjects. The present study suggests that investigation of GJB2 mutations may still be useful to determine the etiology of HL in Iran.


Army Physician Career Satisfaction Based on a Medical Corps Survey.
It is critical the U.S. Army retains skilled physicians in the Medical Corps (MC) to ensure direct support to military operations and medical readiness. The purpose of this study was to examine U.S. Army physicians' opinions concerning: readiness to perform required duties, work environment, support and recognition they receive, military career intentions, and how these factors may relate to Army physician job satisfaction. A cross-sectional study of Army physicians was conducted using a 45-item web-based survey tool, "Army Medicine Medical Corps (MC) Engagement/Satisfaction Survey 2018." The survey used a combination of multiple choice (Likert-scaled and categorical) and open text statements and questions. Satisfaction with their Army physician career was measured using a 5-point unipolar Likert scale response on level of satisfaction. Chi-square tests of independence were conducted on all demographic characteristics to examine if levels of satisfaction with Army physician career were associated with a particular demographic profile. Agreement opinions expressed on 20 statements about professional readiness, work environment, and job recognition were summarized and rank-ordered by percentage of "strongly agree" responses. Categorical responses to several questions related to career intentions were summarized overall and by career satisfaction level. Multivariate logistic regression was performed to identify demographic factors, which may influence career satisfaction as an Army physician. Approximately 47% (2,050/4,334) of U.S. Army physicians participated in the MC 2018 survey. Career satisfaction percentages overall were: "extremely satisfied" (10.0%), "quite satisfied" (24.8%), "moderately satisfied" (33.9%), "slightly satisfied" (22.6%), and "not at all satisfied" (8.3%). Respondents were in least agreement to statements about sufficient administrative support and recognition of doing good work. Logistic regression results showed military rank as a significant predictor of negative career satisfaction as an Army physician. For Captains, the odds for being "not at all satisfied" with their military career were almost nine times that of Colonels. Also, compared to their baseline group, physicians who completed their graduate medical education training, mission critical surgeons, and physicians who worked in military treatment facilities that were either a hospital (not a medical center) or a clinic-ambulatory surgery center had a greater risk of being "not at all satisfied" with their career as an Army physician. There is significant room for improvement in MC officer career satisfaction. The drivers of satisfaction are multiple and apply differently among MC officers of varied ranks and experience. Senior officers are the ones who are the most satisfied with their military career. Results of this novel MC officer study may serve as an impetus to identify existing shortcomings and make necessary changes to retain skilled Army physicians. Army leaders should invest resources to develop and sustain initiatives that improve military career satisfaction and retention of MC officers.


Compound activity prediction using models of binding pockets or ligand properties in 3D.
Transient interactions of endogenous and exogenous small molecules with flexible binding sites in proteins or macromolecular assemblies play a critical role in all biological processes. Current advances in high-resolution protein structure determination, database development, and docking methodology make it possible to design three-dimensional models for prediction of such interactions with increasing accuracy and specificity. Using the data collected in the Pocketome encyclopedia, we here provide an overview of two types of the three-dimensional ligand activity models, pocketbased and ligand property-based, for two important classes of proteins, nuclear and G-protein coupled receptors. For half the targets, the pocket models discriminate actives from property matched decoys with acceptable accuracy (the area under ROC curve, AUC, exceeding 84%) and for about one fifth of the targets with high accuracy (AUC > 95%). The 3D ligand property field models performed better than 95% in half of the cases. The high performance models can already become a basis of activity predictions for new chemicals. Family-wide benchmarking of the models highlights strengths of both approaches and helps identify their inherent bottlenecks and challenges.


Ornithine decarboxylase regulates M1 macrophage activation and mucosal inflammation via histone modifications.
Macrophage activation is a critical step in host responses during bacterial infections. Ornithine decarboxylase (ODC), the rate-limiting enzyme in polyamine metabolism, has been well studied in epithelial cells and is known to have essential roles in many different cellular functions. However, its role in regulating macrophage function during bacterial infections is not well characterized. We demonstrate that macrophage-derived ODC is a critical regulator of M1 macrophage activation during both Helicobacter pylori and Citrobacter rodentium infection. Myeloid-specific Odc deletion significantly increased gastric and colonic inflammation, respectively, and enhanced M1 activation. Add-back of putrescine, the product of ODC, reversed the increased macrophage activation, indicating that ODC and putrescine are regulators of macrophage function. Odc-deficient macrophages had increased histone 3, lysine 4 (H3K4) monomethylation, and H3K9 acetylation, accompanied by decreased H3K9 di/trimethylation both in vivo and ex vivo in primary macrophages. These alterations in chromatin structure directly resulted in up-regulated gene transcription, especially M1 gene expression. Thus, ODC in macrophages tempers antimicrobial, M1 macrophage responses during bacterial infections through histone modifications and altered euchromatin formation, leading to the persistence and pathogenesis of these organisms.


Cotrimoxazole prophylaxis for opportunistic infections in adults with HIV.
The prevention and early treatment of infections are the mainstay of the medical management of the majority of people with HIV infection, who live in low income countries without access to antiretroviral drugs. Cotrimoxazole is cheap and effective against a wide range of organisms. However, routine prophylactic treatment is difficult to deliver in low-resource settings, and could also lead to increased resistance to the drug. To assess the effects of routinely administered cotrimoxazole on death and illness episodes in HIV infected adults. We searched the Cochrane HIV/AIDS Group register, the Cochrane Controlled Trials Register, MEDLINE, LILACS, AIDSLINE, AIDSTRIALS and AIDSDRUGS databases, and proceedings and abstracts from AIDS and tuberculosis (TB) conferences (search date July 2001). We checked reference lists for trials and other pertinent articles, and contacted pharmaceutical companies and experts in the field. Randomised or quasi randomised trials comparing routinely administered cotrimoxazole versus placebo or no treatment in adults (age greater than 13 years). Two reviewers independently assessed trial eligibility and quality, and extracted data. Where data were incomplete or unclear trial authors were contacted for further details. Four trials involving 1476 people were identified. Three trials (1416 people) studied heterosexual men and women in West Africa. A fourth trial was of homosexual men on chemotherapy for Kaposi's sarcoma, in the United States. Meta-analysis of the three African trials showed a significant beneficial effect of cotrimoxazole for death: relative risk 0.69 (95% confidence interval 0.55 to 0.87); for morbid events: 0.76 (0.64 to 0.9); and for hospitalisation: 0.66 (0.48 to 0.92). There was no significantly greater risk of adverse effects: relative risk 1.28 (0.47 to 3.51). Effects were similar in people with early and advanced HIV disease. Insufficient evidence was found on effects in areas with higher bacterial resistance or in people on antiretroviral therapy. In the trials included in the review, cotrimoxazole prophylaxis had a beneficial effect in preventing death and illness episodes in adults with both early and advanced HIV disease. However, the wider applicability of these findings is unclear, in particular to areas with higher background bacterial resistance to cotrimoxazole. Further trials would be required in differing settings to widen applicability.


Outcome of dogs with high-grade soft tissue sarcomas treated with and without adjuvant doxorubicin chemotherapy: 39 cases (1996-2004).
To examine the effect of adjuvant doxorubicin chemotherapy on outcome in dogs with high-grade (grade 3) soft tissue sarcomas (HGSTSs). Retrospective case series. 39 dogs. Medical records of dogs with HGSTSs were reviewed. Dogs treated with surgery alone or receiving single-agent doxorubicin chemotherapy postoperatively were included in the study. Owners and referring veterinarians were contacted for follow-up information. Slides from histologic sections were reviewed to confirm the diagnosis of HGSTSs. Cases in which follow-up examination was not performed and radiation therapy or chemotherapy other than doxorubicin was administered were excluded. 39 dogs met inclusion criteria. Twenty-one dogs received adjuvant doxorubicin. Tumor-, patient-, and treatment-related variables were not significantly associated with measured outcomes including local, metastatic, and overall disease-free intervals as well as survival time. Overall median disease-free interval was 724 days with a median survival time of 856 days for all dogs. Adjuvant doxorubicin-based chemotherapy did not benefit this population of dogs with HGSTSs. Outcome for visceral HGSTSs was similar to that of nonvisceral HGSTSs in these cases.


Poster - Thurs Eve-30: Investigation of a patient immobilization system for breast tomotherapy.
Using tomotherapy to deliver adjuvant radiation therapy for breast cancer treatment requires more precise immobilization than can be achieved using gravity alone. We evaluated the use of a thermoplastic shell to immobilize the patient's torso during breast cancer treatment. To measure intrafraction breathing motion, 4DCT scans were performed for eight post-lumpectomy or post-mastectomy breast cancer patients with the thermoplastic shell in place. The 4DCT scans were then analyzed to determine the magnitude of motion of the breast surface, chest wall, and heart over the breathing cycle. Maximum surface motion was typically less than 2mm, with a maximum of 4mm. Maximum displacement of the chest wall was less than 3mm with a maximum of 5mm in a single patient. Comparison with the setup errors recorded prior to repositioning the patients suggests that, with the thermoplastic shell in place, patient setup error will be a more significant source of uncertainty in patient position than breathing motion.


Traditional Uses, Phytochemistry, and Bioactivities of Cananga odorata (Ylang-Ylang).
Ylang-ylang (Cananga odorata Hook. F. & Thomson) is one of the plants that are exploited at a large scale for its essential oil which is an important raw material for the fragrance industry. The essential oils extracted via steam distillation from the plant have been used mainly in cosmetic industry but also in food industry. Traditionally, C. odorata is used to treat malaria, stomach ailments, asthma, gout, and rheumatism. The essential oils or ylang-ylang oil is used in aromatherapy and is believed to be effective in treating depression, high blood pressure, and anxiety. Many phytochemical studies have identified the constituents present in the essential oils of C. odorata. A wide range of chemical compounds including monoterpene, sesquiterpenes, and phenylpropanoids have been isolated from this plant. Recent studies have shown a wide variety of bioactivities exhibited by the essential oils and the extracts of C. odorata including antimicrobial, antibiofilm, anti-inflammatory, antivector, insect-repellent, antidiabetic, antifertility and antimelanogenesis activities. Thus, the present review summarizes the information concerning the traditional uses, phytochemistry, and biological activities of C. odorata. This review is aimed at demonstrating that C. odorata not only is an important raw material for perfume industry but also considered as a prospective useful plant to agriculture and medicine.


Isolation of single human hematopoietic stem cells capable of long-term multilineage engraftment.
Lifelong blood cell production is dependent on rare hematopoietic stem cells (HSCs) to perpetually replenish mature cells via a series of lineage-restricted intermediates. Investigating the molecular state of HSCs is contingent on the ability to purify HSCs away from transiently engrafting cells. We demonstrated that human HSCs remain infrequent, using current purification strategies based on Thy1 (CD90) expression. By tracking the expression of several adhesion molecules in HSC-enriched subsets, we revealed CD49f as a specific HSC marker. Single CD49f(+) cells were highly efficient in generating long-term multilineage grafts, and the loss of CD49f expression identified transiently engrafting multipotent progenitors (MPPs). The demarcation of human HSCs and MPPs will enable the investigation of the molecular determinants of HSCs, with a goal of developing stem cell-based therapeutics.


Ultraviolet A1 phototherapy: a British Photodermatology Group workshop report.
Whole-body ultraviolet (UV)A1 (340-400 nm) phototherapy was first introduced 30 years ago, but is currently available in the UK in only three dermatology departments. A workshop to discuss UVA1 was held by the British Photodermatology Group in May 2009, the aim of which was to provide an overview of UVA1 phototherapy and its role in practice, and to identify areas in which further studies are required. The conclusions were that UVA1 phototherapy is an effective treatment in several inflammatory skin diseases, including localized scleroderma and atopic eczema (AE); however, deficiencies and limitations exist in the published evidence base. For most diseases, such as AE, other treatments also exist, which are generally more effective than UVA1. However, for some diseases, particularly morphoea, the evidence of efficacy is stronger for UVA1 than for other treatments. Acute adverse effects of UVA1 are minimal. The risk of long-term adverse effects, particularly skin cancer, is unknown. Medium to high doses of UVA1 are needed for efficacy in most situations, but the equipment to deliver such doses is large, expensive and difficult to install. UVA1 is currently underprovided, and the recommendation of the workshop is that more tertiary centres should have access to UVA1 phototherapy in the UK.


Human microglial cell isolation from adult autopsy brain: brain pH, regional variation, and infection with human immunodeficiency virus type 1.
Microglia are the main source of productive infection by human immunodeficiency virus type 1 (HIV-1) in the central nervous system (CNS). Infection of microglia is difficult to study because nonhuman microglia are not infected by HIV-1, adult human microglia from surgically removed brain tissues are scarce, and fetal human microglial cells differ from adult cells in potentially important ways. Adult autopsies are a potential source of brain tissue for HIV-1 research, but the technique of isolating and infecting cells postmortem is not completely standardized. The authors determined optimal conditions for isolating and infecting adult microglial cells using 18 adult autopsy brain specimens from HIV-1-infected and noninfected decedents. The yield of mixed glial cells overall was on average 0.5 x 10(6) cells per gram of wet tissue. There was no correlation between the number of microglia isolated and the postmortem interval (PMI), HIV seropositivity, age, or gender. Brain pH accounted for about 41% of yield variability; a pH of less than 6.0 generally was not compatible with adequate cell recovery. The highest microglial cell yields were derived from anterior brain sectors (frontal lobe and temporal lobe) versus occipital lobe and cerebellum. A PMI of up to 25.5 h produced excellent cell yields in frontal lobe samples with high brain pH. HIV-1 infection of frontal lobe microglia was 100% successful using both CXCR4- and CCR5-tropic strains of HIV-1. With proper selection of cases and brain region, autopsy brain specimens are a dependable source of viable microglial cells to study CNS HIV-1 infection.


Distribution of the invA, -B, -C, and -D genes of Salmonella typhimurium among other Salmonella serovars: invA mutants of Salmonella typhi are deficient for entry into mammalian cells.
Invasion of intestinal epithelial cells is an essential virulence factor of salmonellae. A group of genes, invABC and invD, that allow Salmonella typhimurium to penetrate cultured epithelial cells have previously been characterized (J. E. Galán and R. Curtiss III, Proc. Natl. Acad. Sci. USA 86:6383-6387, 1989). The distribution of these genes among Salmonella isolates belonging to 37 different species or serovars was investigated by Southern and colony blot hybridization analyses. Regions of high sequence similarity to the invABC genes were present in all Salonella isolates examined, while regions of sequence similarity to the invD gene were present in all but one (S. arizonae) of the isolates tested, with little restriction fragment length polymorphism. Sequences similar to these genes were not detected in strains of Escherichia coli, Yersinia spp., or Shigella spp. invA mutants (unable to express the invABC genes) of several Salmonella species or serovars, including S. typhi, were constructed and examined for their ability to penetrate Henle-407 cells. All mutants were deficient for entry into cultured epithelial cells, indicating that the invABC genes were not only present in these strains but also functional.


Synaptophysin gene expression in human brain: a quantitative in situ hybridization and immunocytochemical study.
Synaptophysin is a presynaptic vesicle protein. Its quantitative detection has become established as a molecular marker of synaptic density. We have studied synaptophysin messenger RNA in the neocortex, hippocampus and cerebellum using in situ hybridization histochemistry to see if the encoding transcript can be detected in post mortem human brain and to investigate factors which might influence its abundance. Synaptophysin was also measured immunocytochemically in the hippocampus. The level of synaptophysin messenger RNA expression was uniform in all neocortical areas examined. Strong correlations were found for the amount of synaptophysin messenger RNA between individual regions and between homologous areas in the two hemispheres. Synaptophysin messenger RNA declined with increasing age and prolonged post mortem interval. Synaptophysin immunoreactivity also reduced with age, as well as with duration of formalin fixation but not post mortem interval. Synaptophysin immunoreactivity correlated with the abundance of the messenger RNA in neurons within, and projecting to, each hippocampal subfield. Significantly greater synaptophysin immunoreactivity was seen in the left than the right CA4 and CA1 regions. These data show that quantitative detection of synaptophysin messenger RNA as well as synaptophysin itself can reliably be carried out in post mortem human brain sections. They are in keeping with other findings that synaptic density is relatively uniform through the neocortex and decreases with age. They also suggest a possible asymmetry of hippocampal synaptophysin expression. The level of synaptophysin messenger RNA paralleled that of synaptophysin immunoreactivity, indicating that changes in gene expression contribute to variations in the latter observed in aging and other situations. Detection of synaptophysin messenger RNA broadens the range of methods by which synaptic protein gene products can be studied and used as markers of synaptic density and synaptic involvement during physiological and pathological processes in human brain.


End-of-life care in a COPD patient awaiting lung transplantation: a case report.
COPD is nowadays the main indication for lung transplantation. In appropriately selected patients with end stage COPD, lung transplantation may improve quality of life and prognosis of survival. However, patients with end stage COPD may die while waiting for lung transplantation. Palliative care is important to address the needs of patients with end stage COPD. This case report shows that in a patient with end stage COPD listed for lung transplantation offering palliative care and curative-restorative care concurrently may be problematic. If the requirements to remain a transplantation candidate need to be met, the possibilities for palliative care may be limited. Discussing the possibilities of palliative care and the patient's treatment preferences is necessary to prevent that end-of-life care needs of COPD patients dying while listed for lung transplantation are not optimally addressed. The patient's end-of-life care preferences may ask for a clear distinction between the period in which palliative and curative-restorative care are offered concurrently and the end-of-life care period. This may be necessary to allow a patient to spend the last stage of life according to his or her wishes, even when this implicates that lung transplantation is not possible anymore and the patient will die because of end stage COPD.


Knowledge, attitude and oral care practices for preventing ventilator-associated pneumonia among critical care nurses - A questionnaire study.
A cross-sectional study was conducted among intensive care unit (ICU) nurses in private hospitals in India to identify knowledge and practice of ICU nurses in the prevention of ventilator-associated pneumonia (VAP). Knowledge of 135 nurses working in ICU was tested using a questionnaire consisting of 18 questions. Fourteen forms were excluded from the statistical analysis due to incomplete data entry by the participants. The data of 121 filled questionnaires were analyzed. The information letters, consent forms, and questionnaires were handed to ICU nurses by Research assistant. Data were coded and entered into SPSS version for descriptive and inferential statistics. A majority of the participants perceived oral care as a necessity in all critically ill patients. Nurses were generally aware of the most likely mechanism of acquiring pneumonia. The type and frequency of oral care varied widely. Many of them stated that they had adequate supplies to provide oral care. Although a majority of nurses had some formal training in oral care, they would appreciate an opportunity to enhance and improve their knowledge and skills. The methods of oral care provided vary widely. In summary, randomized controlled trial to date has demonstrated that tooth brushing is associated with a trend toward lower rates of VAP in intubated mechanically ventilated critically ill patients. But it is also to be noted that there was no clear difference between electric and manual tooth brushing. In-house training and workshop can provide required skills needed for the betterment of the treatment provided.


A soybean 101-kD heat shock protein complements a yeast HSP104 deletion mutant in acquiring thermotolerance.
A cDNA clone encoding a 101-kD heat shock protein (HSP101) of soybean was isolated and sequenced. Genomic DNA gel blot analysis indicated that the corresponding gene is a member of a multigene family. The mRNA for HSP101 was not detected in 2-day-old etiolated soybean seedlings grown at 28 degrees C but was induced by elevated temperatures. DNA sequence comparison has shown that the corresponding gene belongs to the Clp (caseinolytic protease) (or Hsp100) gene family, which is evolutionarily conserved and found in both prokaryotes and eukaryotes. On the basis of the spacer length between the two conserved ATP binding regions, this gene has been identified as a member of the ClpB subfamily. Unlike other Clp genes previously isolated from higher plants, the expression of this soybean Hsp101 gene is heat inducible, and it does not have an N-terminal signal peptide for targeting to chloroplasts. Transformation of the soybean Hsp101 gene into a yeast HSP104 deletion mutant complemented restoration of acquired thermotolerance, a process in which cells survive an otherwise lethal heat stress after they are given a permissive heat treatment.


Purification and characterization of a hyperthermostable Mn-superoxide dismutase from Thermus thermophilus HB27.
Thermostable Mn-dependent catalases are promising enzymes in biotechnological applications. In the present study, a Mn-containing superoxide dismutase of the hyperthermophilic Thermus thermophilus HB27 had been purified and characterized by a two-stage ultrafiltration process after being expressed in E. coli. The enzyme was highly stable at 90°C and retained 57% activity after heat treatment at 100°C for 1 h. The native form of the enzyme was determined as a homotetramer by analytical size exclusion chromatography and sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The final purified enzyme had an isoelectric point of 6.2 and a high α-helical content of 70%, consistent with the theoretical values. This showed that the purified SOD folded with a reasonable secondary structure.


The compositional and evolutionary logic of metabolism.
Metabolism is built on a foundation of organic chemistry, and employs structures and interactions at many scales. Despite these sources of complexity, metabolism also displays striking and robust regularities in the forms of modularity and hierarchy, which may be described compactly in terms of relatively few principles of composition. These regularities render metabolic architecture comprehensible as a system, and also suggests the order in which layers of that system came into existence. In addition metabolism also serves as a foundational layer in other hierarchies, up to at least the levels of cellular integration including bioenergetics and molecular replication, and trophic ecology. The recapitulation of patterns first seen in metabolism, in these higher levels, motivates us to interpret metabolism as a source of causation or constraint on many forms of organization in the biosphere. Many of the forms of modularity and hierarchy exhibited by metabolism are readily interpreted as stages in the emergence of catalytic control by living systems over organic chemistry, sometimes recapitulating or incorporating geochemical mechanisms.We identify as modules, either subsets of chemicals and reactions, or subsets of functions, that are re-used in many contexts with a conserved internal structure. At the small molecule substrate level, module boundaries are often associated with the most complex reaction mechanisms, catalyzed by highly conserved enzymes. Cofactors form a biosynthetically and functionally distinctive control layer over the small-molecule substrate. The most complex members among the cofactors are often associated with the reactions at module boundaries in the substrate networks, while simpler cofactors participate in widely generalized reactions. The highly tuned chemical structures of cofactors (sometimes exploiting distinctive properties of the elements of the periodic table) thereby act as 'keys' that incorporate classes of organic reactions within biochemistry.Module boundaries provide the interfaces where change is concentrated, when we catalogue extant diversity of metabolic phenotypes. The same modules that organize the compositional diversity of metabolism are argued, with many explicit examples, to have governed long-term evolution. Early evolution of core metabolism, and especially of carbon-fixation, appears to have required very few innovations, and to have used few rules of composition of conserved modules, to produce adaptations to simple chemical or energetic differences of environment without diverse solutions and without historical contingency. We demonstrate these features of metabolism at each of several levels of hierarchy, beginning with the small-molecule metabolic substrate and network architecture, continuing with cofactors and key conserved reactions, and culminating in the aggregation of multiple diverse physical and biochemical processes in cells.


The Diagnostic Value of FibroScan in Assessing Significant Liver Fibrosis in Patients with Chronic Hepatitis B.
Significant liver fibrosis is recognized as the key link of therapy and prognosis in patients with chronic hepatitis B infection (CHB). The present study is designed to estimate the benefits of FibroScan (FS) in diagnosing significant fibrosis in patients with CHB. Two hundred and eight consecutive CHB patients, who underwent liver biopsy, FS and laboratory tests, were recruited. The receiver operating characteristic (ROC) curves were generated to assess the performance of non-invasive models. Liver stiffness measurement (LSM) and aspartate transaminase (AST) to platelet (PLT) ratio index (APRI), but not age-platelet index (API) or AST to alanine aminotransferase (ALT) ratio (AAR), were closely correlated with significant fibrosis; areas under ROC curves (AUROC) were 0.817 (p < 0.001), 0.705 (p = 0.003), 0.626 (p = 0.065) and 0.631 (p = 0.055), respectively. When combining LSM with APRI, the AUROC was 0.813, p < 0.001. FibroScan can predict the presence of significant liver fibrosis, so as to avoid liver biopsy. It seems that the combination of FS and APRI does not significantly improve the ability to predict significant fibrosis.


Comparison of three different prehospital wrapping methods for preventing hypothermia--a crossover study in humans.
Accidental hypothermia increases mortality and morbidity in trauma patients. Various methods for insulating and wrapping hypothermic patients are used worldwide. The aim of this study was to compare the thermal insulating effects and comfort of bubble wrap, ambulance blankets / quilts, and Hibler's method, a low-cost method combining a plastic outer layer with an insulating layer. Eight volunteers were dressed in moistened clothing, exposed to a cold and windy environment then wrapped using one of the three different insulation methods in random order on three different days. They were rested quietly on their back for 60 minutes in a cold climatic chamber. Skin temperature, rectal temperature, oxygen consumption were measured, and metabolic heat production was calculated. A questionnaire was used for a subjective evaluation of comfort, thermal sensation, and shivering. Skin temperature was significantly higher 15 minutes after wrapping using Hibler's method compared with wrapping with ambulance blankets / quilts or bubble wrap. There were no differences in core temperature between the three insulating methods. The subjects reported more shivering, they felt colder, were more uncomfortable, and had an increased heat production when using bubble wrap compared with the other two methods. Hibler's method was the volunteers preferred method for preventing hypothermia. Bubble wrap was the least effective insulating method, and seemed to require significantly higher heat production to compensate for increased heat loss. This study demonstrated that a combination of vapour tight layer and an additional dry insulating layer (Hibler's method) is the most efficient wrapping method to prevent heat loss, as shown by increased skin temperatures, lower metabolic rate and better thermal comfort. This should then be the method of choice when wrapping a wet patient at risk of developing hypothermia in prehospital environments.


Cholinergic stimulation of phosphatidylinositol hydrolysis by rat corneal epithelium in vitro.
Phosphatidic acid (PA) is an obligate intermediate in the phosphatidylinositol (PI) cycle and may serve as a sensitive marker for this pathway of reactions. Previously, we have shown that acetylcholine (ACh) stimulates formation of labeled PA in whole rat corneas whose phospholipids were prelabeled with [14C]arachidonate. To determine which layer of the cornea exhibits the ACh effect, intact epithelium was isolated from the rest of the corneal tissue (designated "stroma/endothelium") by incubating rat corneas with neutral protease and then stripping off the epithelium using forceps. The epithelium was ultrastructurally normal and avidly incorporated [14C]arachidonate into phospholipids; the stroma/endothelium had only trace incorporation. [14C]Arachidonyl-PA formation by the epithelium was significantly increased after a 37 second (+58%) and was maximal after a 5.0 minute (+188%) incubation in the presence of 1 mM ACh. The stimulation by ACh was blocked by atropine and scopolamine but not by d-tubocurarine. The epithelium also incorporated significant quantities of [3H]inositol into phosphatidylinositol (PI), phosphatidylinositol monophosphate (PIP), and phosphatidyl-inositol bisphosphate (PIP 2). When [3H]inositol-labeled epithelia were incubated for 5 minutes with 1 mM ACh, [3H]inositol monophosphate (IP) was increased 200%, [3H]inositol bisphosphate (IP2) was increased 225%, and [3H]inositol 2 trisphosphate (IP3) was increased 74%. These results suggest that muscarinic cholinergic receptors may be an important regulator of the PI cycle in corneal epithelium and thus may affect intracellular calcium mobilization and epithelial proliferation and regeneration.


Hyaluronan (HA) interacting proteins RHAMM and hyaluronidase impact prostate cancer cell behavior and invadopodia formation in 3D HA-based hydrogels.
To study the individual functions of hyaluronan interacting proteins in prostate cancer (PCa) motility through connective tissues, we developed a novel three-dimensional (3D) hyaluronic acid (HA) hydrogel assay that provides a flexible, quantifiable, and physiologically relevant alternative to current methods. Invasion in this system reflects the prevalence of HA in connective tissues and its role in the promotion of cancer cell motility and tissue invasion, making the system ideal to study invasion through bone marrow or other HA-rich connective tissues. The bio-compatible cross-linking process we used allows for direct encapsulation of cancer cells within the gel where they adopt a distinct, cluster-like morphology. Metastatic PCa cells in these hydrogels develop fingerlike structures, "invadopodia", consistent with their invasive properties. The number of invadopodia, as well as cluster size, shape, and convergence, can provide a quantifiable measure of invasive potential. Among candidate hyaluronan interacting proteins that could be responsible for the behavior we observed, we found that culture in the HA hydrogel triggers invasive PCa cells to differentially express and localize receptor for hyaluronan mediated motility (RHAMM)/CD168 which, in the absence of CD44, appears to contribute to PCa motility and invasion by interacting with the HA hydrogel components. PCa cell invasion through the HA hydrogel also was found to depend on the activity of hyaluronidases. Studies shown here reveal that while hyaluronidase activity is necessary for invadopodia and inter-connecting cluster formation, activity alone is not sufficient for acquisition of invasiveness to occur. We therefore suggest that development of invasive behavior in 3D HA-based systems requires development of additional cellular features, such as activation of motility associated pathways that regulate formation of invadopodia. Thus, we report development of a 3D system amenable to dissection of biological processes associated with cancer cell motility through HA-rich connective tissues.


Cytokines in rheumatoid arthritis - shaping the immunological landscape.
Cytokine-mediated pathways are central to the pathogenesis of rheumatoid arthritis (RA). The purpose of this short Opinion article is to briefly overview the roles of cytokine families in the various phases and tissue compartments of this disease. In particular, we consider the combinatorial role played by cytokines in mediating the overlapping innate and adaptive immune responses associated with disease onset and persistence, and also those cytokine pathways that, in turn, drive the stromal response that is critical for tissue localization and associated articular damage. The success of cytokine inhibition in the clinic is also considerable, not only in offering remarkable therapeutic advances, but also in defining the hierarchical position of distinct cytokines in RA pathogenesis, especially IL-6 and TNF. This hierarchy, in turn, promises to lead to the description of meaningful clinical endotypes and the consequent possibility of therapeutic stratification in future.


Surgical ventricular restoration and other surgical approaches to heart failure.
Historically, few patients with ischemic congestive heart failure (CHF) have been considered for cardiac surgical intervention unless there was an obvious need for coronary revascularization or valve repair. New surgical procedures and non-mechanical assist devices are being used and tested in patients with end-stage CHF. We report on The Ohio State University Medical Center's early involvement in the international and multi-institutional Surgical Treatment for Ischemic Heart Failure (STICH) trial, which is evaluating the value of coronary artery bypass in patients with ischemic CHF as compared to medical therapies alone, and whether surgical ventricular restoration (SVR) offers additional benefit to patients with dilated hearts undergoing revascularization. Beyond standard coronary revascularization and SVR, new surgically deployed devices that attempt to augment ventricular performance by direct restraint of left ventricular dilatation or by reducing ventricular wall stress through altering ventricular shape are reviewed. The growing clinical and experimental experience with cellular cardiomyoplasty (in particular, autologous skeletal myoblast and adult-derived stem transplantation) also is reviewed. This review is intended to express the institutional insights of the authors, who have been involved in clinical trials and basic science research in each of these areas.


Impact of venography on the diagnosis and management of deep vein thrombosis.
In general medical patients presenting with suspected deep vein thrombosis routine use of x ray venography was associated with a large fall in the proportion of patients with a final diagnosis of deep vein thrombosis, from 83% to 25% (p less than 0.001), and with an appreciable shortening of hospital stay, from 13.6 to 7.2 days. The diagnosis of deep vein thrombosis was rejected in only 4% of patients when a venogram was not performed, and it is estimated that two patients were treated with anticoagulants unnecessarily for every patient treated correctly. The risk, expense, and inconvenience of unnecessary anticoagulant treatment far exceeds the risk, expense, and inconvenience of performing venograms routinely. The common practice of misdiagnosing deep vein thrombosis clinically should be abandoned.


A characterization of DNA release in Pseudomonas aeruginosa cultures and biofilms.
Pseudomonas aeruginosa produces extracellular DNA which functions as a cell-to-cell interconnecting matrix component in biofilms. Comparison of extracellular DNA and chromosomal DNA by the use of polymerase chain reaction and Southern analysis suggested that the extracellular DNA is similar to whole-genome DNA. Evidence that the extracellular DNA in P. aeruginosa biofilms and cultures is generated via lysis of a subpopulation of the bacteria was obtained through experiments where extracellular beta-galactosidase released from lacZ-containing P. aeruginosa strains was assessed. Experiments with the wild type and lasIrhlI, pqsA, pqsL and fliMpilA mutants indicated that the extracellular DNA is generated via a mechanism which is dependent on acyl homoserine lactone and Pseudomonas quinolone signalling, as well as on flagella and type IV pili. Microscopic investigation of flow chamber-grown wild-type P. aeruginosa biofilms stained with different DNA stains suggested that the extracellular DNA is located primarily in the stalks of mushroom-shaped multicellular structures, with a high concentration especially in the outer part of the stalks forming a border between the stalk-forming bacteria and the cap-forming bacteria. Biofilms formed by lasIrhlI, pqsA and fliMpilA mutants contained less extracellular DNA than biofilms formed by the wild type, and the mutant biofilms were more susceptible to treatment with sodium dodecyl sulphate than the wild-type biofilm.


Fast localization of the optic disc using projection of image features.
Optic Disc (OD) localization is an important pre-processing step that significantly simplifies subsequent segmentation of the OD and other retinal structures. Current OD localization techniques suffer from impractically-high computation times (few minutes per image). In this work, we present a fast technique that requires less than a second to localize the OD. The technique is based upon obtaining two projections of certain image features that encode the x- and y- coordinates of the OD. The resulting 1-D projections are then searched to determine the location of the OD. This avoids searching the 2-D image space and, thus, enhances the speed of the OD localization process. Image features such as retinal vessels orientation and the OD brightness are used in the current method. Four publicly-available databases, including STARE and DRIVE, are used to evaluate the proposed technique. The OD was successfully located in 330 images out of 340 images (97%) with an average computation time of 0.65 s.


The contribution of quantitative trait loci and neutral marker loci to the genetic variances and covariances among quantitative traits in random mating populations.
Using Cockerham's approach of orthogonal scales, we develop genetic models for the effect of an arbitrary number of multiallelic quantitative trait loci (QTLs) or neutral marker loci (NMLs) upon any number of quantitative traits. These models allow the unbiased estimation of the contributions of a set of marker loci to the additive and dominance variances and covariances among traits in a random mating population. The method has been applied to an analysis of allozyme and quantitative data from the European oyster. The contribution of a set marker loci may either be real, when the markers are actually QTLs, or apparent, when they are NMLs that are in linkage disequilibrium with hidden QTLs. Our results show that the additive and dominance variances contributed by a set of NMLs are always minimum estimates of the corresponding variances contributed by the associated QTLs. In contrast, the apparent contribution of the NMLs to the additive and dominance covariances between two traits may be larger than, equal to or lower than the actual contributions of the QTLs. We also derive an expression for the expected variance explained by the correlation between a quantitative trait and multilocus heterozygosity. This correlation explains only a part of the genetic variance contributed by the markers, i.e., in general, a combination of additive and dominance variances and, thus, provides only very limited information relative to the method supplied here.


Analytical goals for coagulation tests based on biological variation.
Allowable imprecision and bias reference limits for laboratory data can be calculated based on measurements of biological variation. Although biological variation of clinical chemical data has been reported from many laboratories, there have been few reports of biological variation in coagulation tests. In this study, we calculated the biological variation of 13 coagulation tests in the clinical laboratory of Kyushu University Hospital and determined allowable imprecision and bias limits of variation. The participating subjects were 17 healthy individuals: three males and two females in their 20s, two males and two females in their 30s, one male and four females in their 40s, and two males and one female in their 50s. Monthly measurements were performed before breakfast 12 times from June 2001 to May 2002 and allowable imprecision and bias limits were calculated. Taken together with coefficient of variation of control plasma used in daily laboratory work at the hospital, the allowable imprecision limits of intra-laboratory variation determined in this study appear to be in attainable ranges.


Dietary patterns and the risk of colorectal cancer and adenomas.
The association of colorectal cancer risk with select foods has been evaluated by dietary pattern analysis. This review of the literature was conducted to thoroughly examine the available evidence for the association between dietary patterns and colorectal cancers and adenomas. A total of 32 articles based on worldwide epidemiological studies were identified. Pattern identification was achieved by exploratory data analyses (principal component, factor, and cluster analyses) in most articles, and only a few used a priori-defined scores. Dietary patterns named as healthy, prudent, fruit and vegetables, fat-reduced/diet foods, vegetable/fish/poultry, fruit/whole grain/dairy, and healthy eating index-2005, recommended food and Mediterranean diet scores were all associated with reduced risk of colorectal cancer and the risk estimates varied from 0.45 to 0.90. In contrast, diets named Western, pork-processed meat-potatoes, meat-eaters, meat and potatoes, traditional patterns, and dietary risk and life summary scores were associated with increased risk of colorectal cancer with risk estimates varying from 1.18 to 11.7. Dietary patterns for adenomas were consistent with those identified for colorectal cancer.


Daily iron supplementation for improving anaemia, iron status and health in menstruating women.
Iron-deficiency anaemia is highly prevalent among non-pregnant women of reproductive age (menstruating women) worldwide, although the prevalence is highest in lower-income settings. Iron-deficiency anaemia has been associated with a range of adverse health outcomes, which restitution of iron stores using iron supplementation has been considered likely to resolve. Although there have been many trials reporting effects of iron in non-pregnant women, these trials have never been synthesised in a systematic review. To establish the evidence for effects of daily supplementation with iron on anaemia and iron status, as well as on physical, psychological and neurocognitive health, in menstruating women. In November 2015 we searched CENTRAL, Ovid MEDLINE, EMBASE, and nine other databases, as well as four digital thesis repositories. In addition, we searched the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP) and reference lists of relevant reviews. We included randomised controlled trials (RCTs) and quasi-RCTs comparing daily oral iron supplementation with or without a cointervention (folic acid or vitamin C), for at least five days per week at any dose, to control or placebo using either individual- or cluster-randomisation. Inclusion criteria were menstruating women (or women aged 12 to 50 years) reporting on predefined primary (anaemia, haemoglobin concentration, iron deficiency, iron-deficiency anaemia, all-cause mortality, adverse effects, and cognitive function) or secondary (iron status measured by iron indices, physical exercise performance, psychological health, adherence, anthropometric measures, serum/plasma zinc levels, vitamin A status, and red cell folate) outcomes. We used the standard methodological procedures of Cochrane. The search strategy identified 31,767 records; after screening, 90 full-text reports were assessed for eligibility. We included 67 trials (from 76 reports), recruiting 8506 women; the number of women included in analyses varied greatly between outcomes, with endpoint haemoglobin concentration being the outcome with the largest number of participants analysed (6861 women). Only 10 studies were considered at low overall risk of bias, with most studies presenting insufficient details about trial quality.Women receiving iron were significantly less likely to be anaemic at the end of intervention compared to women receiving control (risk ratio (RR) 0.39 (95% confidence interval (CI) 0.25 to 0.60, 10 studies, 3273 women, moderate quality evidence). Women receiving iron had a higher haemoglobin concentration at the end of intervention compared to women receiving control (mean difference (MD) 5.30, 95% CI 4.14 to 6.45, 51 studies, 6861 women, high quality evidence). Women receiving iron had a reduced risk of iron deficiency compared to women receiving control (RR 0.62, 95% CI 0.50 to 0.76, 7 studies, 1088 women, moderate quality evidence). Only one study (55 women) specifically reported iron-deficiency anaemia and no studies reported mortality. Seven trials recruiting 901 women reported on 'any side effect' and did not identify an overall increased prevalence of side effects from iron supplements (RR 2.14, 95% CI 0.94 to 4.86, low quality evidence). Five studies recruiting 521 women identified an increased prevalence of gastrointestinal side effects in women taking iron (RR 1.99, 95% CI 1.26 to 3.12, low quality evidence). Six studies recruiting 604 women identified an increased prevalence of loose stools/diarrhoea (RR 2.13, 95% CI 1.10, 4.11, high quality evidence); eight studies recruiting 1036 women identified an increased prevalence of hard stools/constipation (RR 2.07, 95% CI 1.35 to 3.17, high quality evidence). Seven studies recruiting 1190 women identified evidence of an increased prevalence of abdominal pain among women randomised to iron (RR 1.55, 95% CI 0.99 to 2.41, low quality evidence). Eight studies recruiting 1214 women did not find any evidence of an increased prevalence of nausea among women randomised to iron (RR 1.19, 95% CI 0.78 to 1.82). Evidence that iron supplementation improves cognitive performance in women is uncertain, as studies could not be meta-analysed and individual studies reported conflicting results. Iron supplementation improved maximal and submaximal exercise performance, and appears to reduce symptomatic fatigue. Although adherence could not be formally meta-analysed due to differences in reporting, there was no evident difference in adherence between women randomised to iron and control. Daily iron supplementation effectively reduces the prevalence of anaemia and iron deficiency, raises haemoglobin and iron stores, improves exercise performance and reduces symptomatic fatigue. These benefits come at the expense of increased gastrointestinal symptomatic side effects.


Curvature- and fluid-stress-driven tissue growth in a tissue-engineering scaffold pore.
Cell proliferation within a fluid-filled porous tissue-engineering scaffold depends on a sensitive choice of pore geometry and flow rates: regions of high curvature encourage cell proliferation, while a critical flow rate is required to promote growth for certain cell types. When the flow rate is too slow, the nutrient supply is limited; when it is too fast, cells may be damaged by the high fluid shear stress. As a result, determining appropriate tissue-engineering-construct geometries and operating regimes poses a significant challenge that cannot be addressed by experimentation alone. In this paper, we present a mathematical theory for the fluid flow within a pore of a tissue-engineering scaffold, which is coupled to the growth of cells on the pore walls. We exploit the slenderness of a pore that is typical in such a scenario, to derive a reduced model that enables a comprehensive analysis of the system to be performed. We derive analytical solutions in a particular case of a nearly piecewise constant growth law and compare these with numerical solutions of the reduced model. Qualitative comparisons of tissue morphologies predicted by our model, with those observed experimentally, are also made. We demonstrate how the simplified system may be used to make predictions on the design of a tissue-engineering scaffold and the appropriate operating regime that ensures a desired level of tissue growth.