Determinants of HIV-1 Late Presentation in Patients Followed in Europe.
To control the Human Immunodeficiency Virus (HIV) pandemic, the World Health Organization (WHO) set the 90-90-90 target to be reached by 2020. One major threat to those goals is late presentation, which is defined as an individual presenting a TCD4+ count lower than 350 cells/mm3 or an AIDS-defining event. The present study aims to identify determinants of late presentation in Europe based on the EuResist database with HIV-1 infected patients followed-up between 1981 and 2019. Our study includes clinical and socio-demographic information from 89851 HIV-1 infected patients. Statistical analysis was performed using RStudio and SPSS and a Bayesian network was constructed with the WEKA software to analyze the association between all variables. Among 89,851 HIV-1 infected patients included in the analysis, the median age was 33 (IQR: 27.0-41.0) years and 74.4% were males. Of those, 28,889 patients (50.4%) were late presenters. Older patients (>56), heterosexuals, patients originated from Africa and patients presenting with log VL >4.1 had a higher probability of being late presenters (p < 0.001). Bayesian networks indicated VL, mode of transmission, age and recentness of infection as variables that were directly associated with LP. This study highlights the major determinants associated with late presentation in Europe. This study helps to direct prevention measures for this population.


Segmentation of dual-axis swallowing accelerometry signals in healthy subjects with analysis of anthropometric effects on duration of swallowing activities.
Dysphagia (swallowing difficulty) is a serious and debilitating condition that often accompanies stroke, acquired brain injury, and neurodegenerative illnesses. Individuals with dysphagia are prone to aspiration (the entry of foreign material into the airway), which directly increases the risk of serious respiratory consequences such as pneumonia. Swallowing accelerometry is a promising noninvasive tool for the detection of aspiration and the evaluation of swallowing. In this paper, dual-axis accelerometry was implemented since the motion of the hyolaryngeal complex occurs in both anterior-posterior and superior-inferior directions during swallowing. Dual-axis cervical accelerometry signals were acquired from 408 healthy subjects during dry, wet, and wet chin tuck swallowing tasks. The proposed segmentation algorithm is based on the idea of sequential fuzzy partitioning of the signal and is well suited for long signals with nonstationary variance. The algorithm was validated with simulated signals with known swallowing locations and a subset of 295 real swallows manually segmented by an experienced speech language pathologist. In both cases, the algorithm extracted individual swallows with over 90% accuracy. The time duration analysis was carried out with respect to gender, body mass index (BMI), and age. Demographic and anthropometric variables influenced the duration of these segmented signals. Male participants exhibited longer swallows than female participants (p=0.05). Older participants and participants with higher BMIs exhibited swallows with significantly longer (p=0.05) duration than younger participants and those with lower BMIs, respectively.


The size of cycle-to-cycle variability in biomechanical exposure among butchers performing a standardised cutting task.
The effects of employment duration and pain development on motor variability were investigated during repetitive work. Electromyographic (EMG) and kinematics data from two previous studies were re-analysed. Newly employed butchers were followed prospectively in relation to employment duration and pain development. Healthy butchers with long-term experience were compared with novices. The variability of the cycle time, EMG ratio and arm and trunk movement was expressed as cycle-to-cycle standard deviations. During the first 6 months of employment, cycle time variability decreased, while posture and movement variability increased (p < 0.05). In presence of pain, the variability of the initial arm position decreased while it increased for the trunk (p < 0.05). Experienced butchers showed a larger variability than novices for work cycle and several kinematic variables, but a smaller EMG ratio variability (p < 0.05). These findings indicate that the variability of motor patterns in repetitive work changes with experience and pain. A change towards a more variable motor strategy may protect workers from work-related musculoskeletal disorders.


Differential effect of steady versus oscillating flow on bone cells.
Loading induced fluid flow has recently been proposed as an important biophysical signal in bone mechanotransduction. Fluid flow resulting from activities which load the skeleton such as standing, locomotion, or postural muscle activity are predicted to be dynamic in nature and include a relatively small static component. However, in vitro fluid flow experiments with bone cells to date have been conducted using steady or pulsing flow profiles only. In this study we exposed osteoblast-like hFOB 1.19 cells (immortalized human fetal osteoblasts) to precisely controlled dynamic fluid flow profiles of saline supplemented with 2% fetal bovine serum while monitoring intracellular calcium concentration with the fluorescent dye fura-2. Applied flows included steady flow resulting in a wall shear stress of 2 N m(-2), oscillating flow (+/-2 Nm(-2)), and pulsing flow (0 to 2 N m(-2)). The dynamic flows were applied with sinusoidal profiles of 0.5, 1.0, and 2.0 Hz. We found that oscillating flow was a much less potent stimulator of bone cells than either steady or pulsing flow. Furthermore, a decrease in responsiveness with increasing frequency was observed for the dynamic flows. In both cases a reduction in responsiveness coincides with a reduction in the net fluid transport of the flow profile. Thus. these findings support the hypothesis that the response of bone cells to fluid flow is dependent on chemotransport effects.


Ibuprofen: from invention to an OTC therapeutic mainstay.
The discovery of ibuprofen's anti-inflammatory activity by Dr (now Professor) Stewart Adams and colleagues (Boots Pure Chemical Company Ltd, Nottingham, UK) 50 years ago represented a milestone in the development of anti-inflammatory analgesics. Subsequent clinical studies were the basis for ibuprofen being widely accepted for treating painful conditions at high anti-rheumatic doses (≤ 2400 mg/d), with lower doses (≤ 1200 mg/d for ≤ 10 days) for mild-moderate acute pain (e.g. dental pain, headache, dysmenorrhoea, respiratory symptoms and acute injury). The early observations have since been verified in studies comparing ibuprofen with newer cyclo-oxygenase-2 selective inhibitors ('coxibs'), paracetamol and other non-steroidal anti-inflammatory drugs (NSAIDs). The use of the low-dose, non-prescription, over-the-counter (OTC) drug was based on marketing approval in 1983 (UK) and 1984 (USA); and it is now available in over 80 countries. The relative safety of OTC ibuprofen has been supported by large-scale controlled studies. It has the same low gastro-intestinal (GI) effects as paracetamol (acetaminophen) and fewer GI effects than aspirin. Ibuprofen is a racemate. Its physicochemical properties and the short plasma-elimination half-life of the R(-) isomer, together with its limited ability to inhibit cyclo-oxygenase-1 (COX-1) and thus prostaglandin (PG) synthesis, compared with that of S(+)-ibuprofen, are responsible for the relatively low GI toxicity. The R(-) isomer is then converted in the body to the S(+) isomer after absorption in the GI tract. Ex vivo inhibition of COX-1 (thromboxane A(2)) and COX-2 (PGE(2)) at the plasma concentrations of S(+)-ibuprofen corresponding to those found in the plasma following ingestion of 400 mg ibuprofen in dental and other inflammatory pain models provides evidence of the anti-inflammatory mechanism at OTC dosages. R(-)-ibuprofen has effects on leucocytes, suggesting that ibuprofen has anti-leucocyte effects, which underlie its anti-inflammatory actions. Future developments include novel gastro-tolerant forms for 'at risk' patients, and uses in the prevention of neuro-inflammatory states and cancers.


Towards integrated care for chronic conditions: Dutch policy developments to overcome the (financial) barriers.
Chronic non-communicable diseases are a major threat to population health and have a major economic impact on health care systems. Worldwide, integrated chronic care delivery systems have been developed to tackle this challenge. In the Netherlands, the recently introduced integrated payment system--the chain-DTC--is seen as the cornerstone of a policy stimulating the development of a well-functioning integrated chronic care system. The purpose of this paper is to describe the recent attempts in the Netherlands to stimulate the delivery of integrated chronic care, focusing specifically on the new integrated payment scheme and the barriers to introducing this scheme. We also highlight possible threats and identify necessary conditions to the success of the system. This paper is based on a combination of methods and sources including literature, government documents, personal communications and site visits to disease management programs (DMPs). The most important conditions for the success of the new payment system are: complete care protocols describing both general (e.g. smoking cessation, physical activity) and disease-specific chronic care modules, coverage of all components of a DMP by basic health care insurance, adequate information systems that facilitate communication between caregivers, explicit links between the quality and the price of a DMP, expansion of the amount of specialized care included in the chain-DTC, inclusion of a multi-morbidity factor in the risk equalization formula of insurers, and thorough economic evaluation of DMPs.


Leptospira ainlahdjerensis sp. nov., Leptospira ainazelensis sp. nov., Leptospira abararensis sp. nov. and Leptospira chreensis sp. nov., four new species isolated from water sources in Algeria.
Leptospira strains were isolated from freshwater sampled at four sites in Algeria and characterized by whole-genome sequencing and matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS). The cells were spiral-shaped and motile. Phylogenetic and MALDI-TOF MS analyses showed that the strains can be clearly distinguished from the other described species in the genus Leptospira, therefore representing two novel species of the pathogen subclade P1 and two novel species of the saprophyte subclade S1. The names Leptospira ainlahdjerensis sp. nov. (type strain 201903070T=KIT0297T=CIP111912T), Leptospira ainazelensis sp. nov. (201903071T=KIT0298T=CIP111913T), Leptospira abararensis sp. nov. (201903074T=KIT0299T=CIP111914T) and Leptospira chreensis (201903075T=KIT0300T=CIP111915T) are proposed.


Temperatures of desert plants: another perspective on the adaptability of leaf size.
Surface temperatures of perennial plants in the Sonoran Desert of California ranged from 20 degrees C above air temperature to over 18 degrees C below air temperature during rapid growth periods following rain. Desert cactus with large photosynthetic stem surfaces had the highest temperatures and lowest transpiration rates. Perennial plants with relatively small leaves had moderate transpiration rates and leaf temperatures close to air temperature. Desert perennials with relatively large leaves had leaf temperatures well below air temperature along with the greatest accompanying transpiration rates of over 20 micrograms per square centimeter per second, but also had correspondingly low temperatures for maximum photosynthesis. The low leaf temperatures measured for these large-leafed species are an exception to the more common pattern for desert plants whereby a smaller leaf size prevents overheating and leads to reductions in transpiration and increased water-use efficiency. The contribution of a larger leaf size to a lower leaf temperature, and thus higher rate of photosynthesis for these large-leafed species, may represent an adaptive pattern previously unrecognized for desert plants.


Cross-orientation suppression in human visual cortex.
Cross-orientation suppression was measured in human primary visual cortex (V1) to test the normalization model. Subjects viewed vertical target gratings (of varying contrasts) with or without a superimposed horizontal mask grating (fixed contrast). We used functional magnetic resonance imaging (fMRI) to measure the activity in each of several hypothetical channels (corresponding to subpopulations of neurons) with different orientation tunings and fit these orientation-selective responses with the normalization model. For the V1 channel maximally tuned to the target orientation, responses increased with target contrast but were suppressed when the horizontal mask was added, evident as a shift in the contrast gain of this channel's responses. For the channel maximally tuned to the mask orientation, a constant baseline response was evoked for all target contrasts when the mask was absent; responses decreased with increasing target contrast when the mask was present. The normalization model provided a good fit to the contrast-response functions with and without the mask. In a control experiment, the target and mask presentations were temporally interleaved, and we found no shift in contrast gain, i.e., no evidence for suppression. We conclude that the normalization model can explain cross-orientation suppression in human visual cortex. The approach adopted here can be applied broadly to infer, simultaneously, the responses of several subpopulations of neurons in the human brain that span particular stimulus or feature spaces, and characterize their interactions. In addition, it allows us to investigate how stimuli are represented by the inferred activity of entire neural populations.


Recipes for creating animal models of diabetic cardiovascular disease.
For more than 50 years, investigators have unsuccessfully tried to recreate in experimental animals the cardiovascular complications of diabetes seen in humans. In particular, accelerated atherosclerosis and dilated cardiomyopathy, the major causes of mortality in patients with diabetes, have been conspicuously absent in many mouse models of the disease. Under the auspices of the NIH, the Animal Models of Diabetic Complications Consortium has worked to address this issue. This effort has focused on the development of mouse models because of the high level of genomic information available and the many well-developed genetic manipulations that may be performed in mice. Importantly, the consortium has also worked to standardize many methods to assess metabolic and cardiovascular end points for measurement of the diabetic state and its macrovascular complications. Finally, for maximum benefits from these animal models in the study of atherosclerosis and of other diabetic complications, the consortium has created a system for sharing both the animal models and the accumulated phenotypic data with the greater scientific community.


Performance of small cluster surveys and the clustered LQAS design to estimate local-level vaccination coverage in Mali.
Estimation of vaccination coverage at the local level is essential to identify communities that may require additional support. Cluster surveys can be used in resource-poor settings, when population figures are inaccurate. To be feasible, cluster samples need to be small, without losing robustness of results. The clustered LQAS (CLQAS) approach has been proposed as an alternative, as smaller sample sizes are required. We explored (i) the efficiency of cluster surveys of decreasing sample size through bootstrapping analysis and (ii) the performance of CLQAS under three alternative sampling plans to classify local VC, using data from a survey carried out in Mali after mass vaccination against meningococcal meningitis group A. VC estimates provided by a 10 × 15 cluster survey design were reasonably robust. We used them to classify health areas in three categories and guide mop-up activities: i) health areas not requiring supplemental activities; ii) health areas requiring additional vaccination; iii) health areas requiring further evaluation. As sample size decreased (from 10 × 15 to 10 × 3), standard error of VC and ICC estimates were increasingly unstable. Results of CLQAS simulations were not accurate for most health areas, with an overall risk of misclassification greater than 0.25 in one health area out of three. It was greater than 0.50 in one health area out of two under two of the three sampling plans. Small sample cluster surveys (10 × 15) are acceptably robust for classification of VC at local level. We do not recommend the CLQAS method as currently formulated for evaluating vaccination programmes.


Short-range and long-range context effects on coliphage T4 endonuclease II-dependent restriction.
Synthetic sites inserted into a plasmid were used to analyze the sequence requirements for in vivo DNA cleavage dependent on bacteriophage T4 endonuclease II. A 16-bp variable sequence surrounding the cleavage site was sufficient for cleavage, although context both within and around this sequence influenced cleavage efficiency. The most efficiently cleaved sites matched the sequence CGRCCGCNTTGGCNGC, in which the strongly conserved bases to the left were essential for cleavage. The less-conserved bases in the center and in the right half determined cleavage efficiency in a manner not directly correlated with the apparent base preference at each position; a sequence carrying, in each of the 16 positions, the base most preferred in natural sites in pBR322 was cleaved infrequently. This, along with the effects of substitutions at one or two of the less-conserved positions, suggests that several combinations of bases can fulfill the requirements for recognition of the right part of this sequence. The replacements that improve cleavage frequency are predicted to influence helical twist and roll, suggesting that recognition of sequence-dependent DNA structure and recognition of specific bases are both important. Upon introduction of a synthetic site, cleavage at natural sites within 800 to 1,500 bp from the synthetic site was significantly reduced. This suggests that the enzyme may engage more DNA than its cleavage site and cleaves the best site within this region. Cleavage frequency at sites which do not conform closely to the consensus is, therefore, highly context dependent. Models and possible biological implications of these findings are discussed.


Evidence for Optimal Integration of Visual Feature Representations across Saccades.
We explore the visual world through saccadic eye movements, but saccades also present a challenge to visual processing by shifting externally stable objects from one retinal location to another. The brain could solve this problem in two ways: by overwriting preceding input and starting afresh with each fixation or by maintaining a representation of presaccadic visual features in working memory and updating it with new information from the remapped location. Crucially, when multiple objects are present in a scene the planning of eye movements profoundly affects the precision of their working memory representations, transferring limited memory resources from fixation toward the saccade target. Here we show that when humans make saccades, it results in an update of not just the precision of representations but also their contents. When multiple item colors are shifted imperceptibly during a saccade the perceived colors are found to fall between presaccadic and postsaccadic values, with the weight given to each input varying continuously with item location, and fixed relative to saccade parameters. Increasing sensory uncertainty, by adding color noise, biases updating toward the more reliable input, which is consistent with an optimal integration of presaccadic working memory with a postsaccadic updating signal. We recover this update signal and show it to be tightly focused on the vicinity of the saccade target. These results reveal how the nervous system accumulates detailed visual information from multiple views of the same object or scene. This study examines the consequences of saccadic eye movements for the internal representation of visual objects. A saccade shifts the image of a stable visual object from one part of the retina to another. We show that visual representations are built up over these different views of the same object, by combining information obtained before and after each saccade. The weights given to presaccadic and postsaccadic information are determined by the relative reliability of each input. This provides evidence that the visual system combines inputs over time in a statistically optimal way.


Functional insights into human HMG-CoA lyase from structures of Acyl-CoA-containing ternary complexes.
HMG-CoA lyase (HMGCL) is crucial to ketogenesis, and inherited human mutations are potentially lethal. Detailed understanding of the HMGCL reaction mechanism and the molecular basis for correlating human mutations with enzyme deficiency have been limited by the lack of structural information for enzyme liganded to an acyl-CoA substrate or inhibitor. Crystal structures of ternary complexes of WT HMGCL with the competitive inhibitor 3-hydroxyglutaryl-CoA and of the catalytically deficient HMGCL R41M mutant with substrate HMG-CoA have been determined to 2.4 and 2.2 A, respectively. Comparison of these beta/alpha-barrel structures with those of unliganded HMGCL and R41M reveals substantial differences for Mg(2+) coordination and positioning of the flexible loop containing the conserved HMGCL "signature" sequence. In the R41M-Mg(2+)-substrate ternary complex, loop residue Cys(266) (implicated in active-site function by mechanistic and mutagenesis observations) is more closely juxtaposed to the catalytic site than in the case of unliganded enzyme or the WT enzyme-Mg(2+)-3-hydroxyglutaryl-CoA inhibitor complex. In both ternary complexes, the S-stereoisomer of substrate or inhibitor is specifically bound, in accord with the observed Mg(2+) liganding of both C3 hydroxyl and C5 carboxyl oxygens. In addition to His(233) and His(235) imidazoles, other Mg(2+) ligands are the Asp(42) carboxyl oxygen and an ordered water molecule. This water, positioned between Asp(42) and the C3 hydroxyl of bound substrate/inhibitor, may function as a proton shuttle. The observed interaction of Arg(41) with the acyl-CoA C1 carbonyl oxygen explains the effects of Arg(41) mutation on reaction product enolization and explains why human Arg(41) mutations cause drastic enzyme deficiency.


Initial experience with percutaneous edge-to-edge transcatheter mitral valve repair in a tertiary medical center in Taiwan.
The transcatheter edge-to-edge mitral valve repair, using MitraClip, has been a safe and effective treatment for severe mitral regurgitation (SMR) in the westerners. However, the therapeutic results of the MitralClip in Taiwan remained elucidated. Patients with symptomatic SMR were evaluated by the heart team. For those with high or prohibitive surgical risks, transcatheter mitral valve repair was performed in hybrid operation room. During procedure, continuous hemodynamic monitoring was conducted. Transthoracic echocardiography (TTE), blood tests, and six-minute walk test (6MWT) were performed before and 1-month after surgery. A total of 20 patients (73.4 ± 11.1 years, 85% male) with a mean Euroscore II of 13.2 ± 17.7% and a mean STS score of 8.7 ± 9.0% for mortality were enrolled. After a mean procedural time of 239 ± 95 min, an average of 1.8 ± 0.7 clips were used in each procedure. The procedural successful rate was 95% to achieve mild residual mitral regurgitation. Cardiac output was increased from 3.6 ± 0.9 to 4.6 ± 1.4 (p = 0.008) and V-wave of left atrial pressure declined from 24.4 ± 9.8 to 19.3 ± 7.1 (p = 0.030) immediately during the index procedure. There was no peri-procedural death, myocardial infarction, stroke or any events requiring emergent cardiac surgery. All patients experienced significant improvement in heart failure symptoms. The 6-min walk distance increased from 219.6 ± 118.4 m to 279.1 ± 111.6 (p = 0.04) at 1 month. The echocardiogram further showed significant improvements of mitral regurgitation, pulmonary artery systolic pressure, and the left ventricular end-diastolic volume. Trans-catheter edge-to-edge mitral valve repairs are safe and effective in Asians with symptomatic SMR, regarding the improvements of clinical symptoms and exercise capacities. MitraClips is also associated with reverse remodeling of pulmonary hypertension and left ventricular size in patients with SMR.


American Burn Association Guidelines on the Management of Acute Pain in the Adult Burn Patient: A Review of the Literature, a Compilation of Expert Opinion, and Next Steps.
The ABA pain guidelines were developed 14 years ago and have not been revised despite evolution in the practice of burn care. A sub-committee of the American Burn Association's Committee on the Organization and Delivery of Burn Care was created to revise the adult pain guidelines. A MEDLINE search of English-language publications from 1968 to 2018 was conducted using the keywords "burn pain," "treatment," and "assessment." Selected references were also used from the greater pain literature. Studies were graded by two members of the committee using Oxford Centre for Evidence-based Medicine-Levels of Evidence. We then met as a group to determine expert consensus on a variety of topics related to treating pain in burn patients. Finally, we assessed gaps in the current knowledge and determined research questions that would aid in providing better recommendations for optimal pain management of the burn patient. The literature search produced 189 papers, 95 were found to be relevant to the assessment and treatment of burn pain. From the greater pain literature 151 references were included, totaling 246 papers being analyzed. Following this literature review, a meeting to establish expert consensus was held and 20 guidelines established in the areas of pain assessment, opioid medications, nonopioid medications, regional anesthesia, and nonpharmacologic treatments. There is increasing research on pain management modalities, but available studies are inadequate to create a true standard of care. We call for more burn specific research into modalities for burn pain control as well as research on multimodal pain control.


Hypothermic machine perfusion ameliorates ischemia-reperfusion injury in rat lungs from non-heart-beating donors.
The use of non-heart-beating donors (NHBD) has come into practice to resolve the shortage of donor lungs. This study investigated whether hypothermic machine perfusion (HMP) can improve the quality of NHBD lungs. An uncontrolled NHBD model was achieved in male Lewis rats. Ninety minutes after cardiac arrest, HMP was performed for 60 min at 6°C to 10°C. The first study investigated the physiological lung functions during HMP and the lung tissue energy levels before and after HMP. The second study divided the rats into three groups (n=6 each): no ischemia group; 90-min warm ischemia+60-min HMP+120-min static cold storage (SCS) (HMP group); and 90-min warm ischemia+180-min SCS group. All lungs were reperfused for 60 min at 37°C. Lung functions were evaluated at given timings throughout the experiments. Oxidative damage during reperfusion was evaluated immunohistochemically with a monoclonal antibody against 8-hydroxy-2'-deoxyguanosine. The first study revealed that lung functions were stable during HMP. Lung tissue energy levels decreased during warm ischemia but were significantly increased by HMP (P<0.05). The second study confirmed that HMP significantly decreased pulmonary vascular resistance, increased pulmonary compliance, and improved pulmonary oxygenation. The ratio of 8-hydroxy-2'-deoxyguanosine positive cells to total cells significantly increased in the SCS group (P<0.01). Short-term HMP improved lung tissue energy levels that decreased during warm ischemia and ameliorated ischemia-reperfusion injury with decreased production of reactive oxygen species.


Coherent lidar airborne windshear sensor: performance evaluation.
National attention has focused on the critical problem of detecting and avoiding windshear since the crash on 2 Aug. 1985 of a Lockheed L-1011 at Dallas/Fort Worth International Airport. As part of the NASA/FAA National Integrated Windshear Program, we have defined a measurable windshear hazard index that can be remotely sensed from an aircraft, to give the pilot information about the wind conditions he will experience at some later time if he continues along the present flight path. A technology analysis and end-to-end performance simulation measuring signal-to-noise ratios and resulting wind velocity errors for competing coherent laser radar (lidar) systems have been carried out. The results show that a Ho:YAG lidar at a wavelength of 2.1 microm and a CO(2) lidar at 10.6 microm can give the pilot information about the line-of-sight component of a windshear threat from his present position to a region extending 2-4 km in front of the aircraft. This constitutes a warning time of 20-40 s, even in conditions of moderately heavy precipitation. Using these results, a Coherent Lidar Airborne Shear Sensor (CLASS) that uses a Q-switched CO(2) laser at 10.6 microm is being designed and developed for flight evaluation in the fall of 1991.


Body mass index is a stronger predictor of alanine aminotransaminase levels than alcohol consumption.
The relative effects of obesity compared to alcohol on liver injury are uncertain. We examined their effects on alanine aminotransferase (ALT) and gamma glutamyltransferase (GGT) levels in a population-based cohort. Adult residents (2610: 1326 males, 1284 females) from Busselton, Australia, participated in a cross-sectional survey determining alcohol intake as determined by a validated questionnaire, anthropometric measurements and serum analysis. Alcohol consumption was classified as never, light (<140 g/week), moderate (140-420 g/week) or heavy (>420 g/week). The majority of subjects were either overweight (41%) or obese (17%). A minority of subjects were moderate (25%) or heavy drinkers (4%). Body mass index (BMI) and waist circumference were strongly associated with ALT and GGT (P < 0.0001 for all tests). Alcohol consumption was modestly associated with ALT in females (P = 0.01) but not in males (P = 0.9). In contrast, GGT was significantly associated with alcohol in both genders (P < 0.0005). The risk of an elevated ALT was seven-fold higher with obesity but only two-fold higher with moderate or heavy alcohol use. Obesity accounted for half of all elevated ALT levels in the cohort, whereas alcohol excess was responsible for less than 10%. No synergistic effect was observed between BMI or waist circumference and alcohol on ALT or GGT (P > 0.2 for all tests). Excess weight is more common than excessive alcohol consumption in the community and confers a greater risk of elevated aminotransaminase levels.


High-density lipoproteins and adrenal steroidogenesis: A population-based study.
Cholesterol trafficked within plasma lipoproteins, in particular high-density lipoproteins (HDL), may represent an important source of cholesterol that is required for adrenal steroidogenesis. Based on a urinary gas chromatography method, compromised adrenal function has been suggested in men but not in women with (genetically determined) low plasma HDL-cholesterol (HDL-C). The objective of the article was to examine the extent to which glucocorticoid production relates to HDL-C in a population-based cohort. A total of 240 subjects (120 men and 120 women, aged 20-79 years) without relevant comorbidities were recruited from the general population. Glucocorticoid metabolites were measured by gas chromatography with tandem mass spectrometric detection in 24-hour urine collections to estimate total glucocorticoid production (TGP). Fasting plasma (apo)lipoproteins were assayed by routine methods. TGP was not decreased but tended to be increased in subjects with low HDL-C (NCEP-ATPIII criteria; P = .094). In univariate analysis, TPG was correlated inversely with HDL-C (r = -0.353, P < .001) and apoA-I (r = -0.263, P = .01). Multivariable linear regression analysis demonstrated that TGP was still inversely related to HDL-C (β = -0.145, P = .019) or alternatively to low HDL-C (β = -0.129, P = .013) taking age, sex, current smoking, and other metabolic syndrome components into account. In this population-based study, urinary glucocorticoid metabolite excretion was inversely associated with HDL-C. We found no evidence for an attenuated adrenal function in men and women with low HDL-C.


Genes and arthritis.
Familial clustering is a common feature of many different arthritic conditions which can be explained by shared genetic or environmental influences or a combination of these. The aetiology of some of these diseases (e.g. multiple epiphyseal dysplasia, Lesch-Nyan syndrome) is clearly monogenic but the majority of common rheumatic conditions, such as osteoarthritis (OA) and rheumatoid arthritis (RA) are complex and multi-factorial with a polygenic component. In the last 10 years there has been spectacular progress in unravelling the underlying genetic mechanisms of many monogenic disorders including many that affect the musculoskeletal system. Among these osteogenesis imperfecta (OI) and the Marfan syndrome are striking examples in which molecular defects of matrix protein components of the mesodermal tissues have been revealed. In particular, the power of modern molecular genetics both to test candidate genes (e.g. collagen in OI) and to identify genes where no prior knowledge of the protein defects exists (e.g. fibrillin in the Marfan syndrome) has proved quite remarkable. In the near future many of the techniques that have been applied successfully to these monogenic diseases can be expected to provide insights into the genetic component of common diseases, such as rheumatoid arthritis. However, it is important to realize before embarking on these studies that even monogenic diseases may provide significant problems of analysis and interpretation. Some of these problems are exemplified below (e.g. phenocopies, mosaicism, imprinting).


Quantitative measurement of quality outcome in malignant glioma patients using an independent living score (ILS). Assessment of a retrospective cohort.
Although a number of tools have been developed to measure 'quality of life' in patients with malignant glioma, there remains no completely satisfactory technique that incorporates a quality of life measure into survival analysis. We propose that a patient's ability to maintain independent activity offers a way to accomplish this goal. An independent living score (ILS) is generated by awarding points on a monthly basis based on Karnofsky score and weighing the score based on the particular month of the clinical course. The ILS has a large range for any given survival, and can discriminate important treatment effects to which standard survival analyses are completely insensitive. Using this score and several variations, we were able to retrospectively analyze a patient cohort to assess what correlated with ILS. We found a strong correlation with survival of all the measures tested. Interestingly, we found that patients for whom a total resection was performed and those who were most intensively treated had significantly higher ILS values, suggesting that not only did more aggressive treatment improve survival but that it did not simply increase survival at the expense of the time a patient remained independent. Since the general course for patients with malignant glioma is one of increasing disability and loss of independence, we feel that these measures can serve as a way to distinguish between those therapies that increase survival at the expense of quality of life versus those that do not. Consideration should be given to incorporating these measures into prospective trials.


The diagnosis and management of acute childhood illness: is there a role for health visitors?
Much of the published literature on nurse practitioners relates to nurses with backgrounds, training and nursing experience other than health visiting. Health visitors however may be ideally placed to develop their role in the identification and management of acute childhood illness, and such a development may benefit patients, the health service and health visitors themselves. This study examines the current practice and attitudes of heath visitors in identifying and managing acute childhood illness using a postal questionnaire survey in one community National Health Service (NHS) Trust. The majority of responding health visitors reported that they were already identifying and advising on a range of acute childhood illnesses. Their confidence in undertaking these activities varied by condition. They were less confident in identifying and advising on conditions requiring the use of diagnostic equipment, viral illnesses which are becoming increasingly rare, and those with potentially serious outcomes. More knowledge and more training were seen as methods for increasing confidence. Most health visitors could see advantages in taking on this role; almost two thirds felt it would become part of the role of the health visitor in the future and a high level of interest was expressed in developing such a role.


Potential benefits of scanned intensity-modulated proton therapy versus advanced photon therapy with regard to sparing of the salivary glands in oropharyngeal cancer.
To test the hypothesis that scanned intensity-modulated proton therapy (IMPT) results in a significant dose reduction to the parotid and submandibular glands as compared with intensity-modulated radiotherapy with photons (IMRT) and three-dimensional conformal radiotherapy (3D-CRT) for oropharyngeal cancer. In addition, we investigated whether the achieved dose reductions would theoretically translate into a reduction of salivary dysfunction and xerostomia. Ten patients with N0 oropharyngeal carcinoma were used. The intensity-modulated plans delivered simultaneously 70 Gy to the boost planning target volume (PTV2) and 54 Gy to the elective nodal areas (PTV1). The 3D-CRT technique delivered sequentially 70 Gy and 46 Gy to PTV2 and PTV1, respectively. Normal tissue complication probabilities were calculated for salivary dysfunction and xerostomia. Planning target volume coverage results were similar for IMPT and IMRT. Intensity-modulated proton therapy clearly improved the conformity. The 3D-CRT results were inferior to these results. The mean dose to the parotid glands by 3D-CRT (50.8 Gy), IMRT (25.5 Gy), and IMPT (16.8 Gy) differed significantly. For the submandibular glands no significant differences between IMRT and IMPT were found. The dose reductions obtained with IMPT theoretically translated into a significant reduction in normal tissue complication probability. Compared with IMRT and 3D-CRT, IMPT improved sparing of the organs at risk, while keeping similar target coverage results. The dose reductions obtained with IMPT vs. IMRT and 3D-CRT varied widely per individual patient. Intensity-modulated proton therapy theoretically translated into a clinical benefit for most cases, but this requires clinical validation.


Photochemical processes, carbon assimilation and RNA accumulation of sucrose transporter genes in tomato arbuscular mycorrhiza.
Arbuscular mycorrhizal fungi enhance CO₂ assimilation of their hosts which ensure the demand for carbohydrates of these obligate biotrophic microorganisms. Photosynthetic parameters were measured in tomato colonised or not by the arbuscular mycorrhizal fungus Glomus mosseae. In addition, carbohydrate contents and mRNA accumulation of three sucrose transporter genes were analysed. Mycorrhizal plants showed increased opening of stomata and assimilated significant more CO₂. A higher proportion of the absorbed light was used for photochemical processes, while non-photochemical quenching and the content of photoprotective pigments were lower. Analysis of sugar contents showed no significant differences in leaves but enhanced levels of sucrose and fructose in roots, while glucose amounts stayed constant. The three sucrose transporter encoding genes of tomato SlSUT1, SlSUT2 and SlSUT4 were up-regulated providing transport capacities to transfer sucrose into the roots. It is proposed that a significant proportion of sugars is used by the mycorrhizal fungus, because only amounts of fructose were increased, while levels of glucose, which is mainly transferred towards the fungus, were nearly constant.


Surviving hypopharynx-larynx carcinoma in the era of IMRT.
Outcome in locoregionally advanced laryngeal carcinoma and hypopharyngeal carcinoma after conventional radiation techniques is known for modest disease control and considerable late toxicity. Considering the lack of standardization in prescription dose for intensity-modulated radiotherapy (IMRT), we aimed to compare the results after our methods of simultaneously integrated boost IMRT with published results. Between March 2002 and December 2008, 65 hypopharyngeal, 31 supraglottic, and 27 locoregionally advanced glottic tumor patients underwent definitive IMRT (with simultaneous chemotherapy in 86%). Of these, 64% presented with locoregionally advanced disease. Mean follow-up was 26 months (range, 3-83 months), with a median of 21 months. Treatment (2.0-2.2 Gy per fraction, 66-72.6 Gy) followed a prospectively defined protocol. If the boost volume included more than half of the larynx or a substantial part of the pharynx, dose was limited to 2.0 Gy per fraction. The 2-year local, nodal, and locoregional control (LRC) rates for the entire cohort were 82%, 90%, and 77%, respectively; the disease-free and overall survival rates were 75% and 83%, respectively. The ultimate 2-year LRC rate, including salvage surgery, was 86%. Laryngectomy was required in 2 LRC patients needing tracheostoma already before; 2 further LRC patients needed tracheostomy before IMRT and remained tracheostoma dependent, and 3 patients remained feeding tube dependent after IMRT. Salvage laryngectomy was successful in 8 of 11. Of all 123 patients, 91 patients (74%) are locoregionally controlled and live with a functional laryngopharynx. Simultaneously integrated boost IMRT with limited acceptance of dose inhomogeneity resulted in very satisfactory disease control despite a slight left shift of planning target volume curves on the dose-volume histogram. Considering the treatment tolerance, a careful increase in dose in our patients seems possible. Dose-volume comparisons remain difficult because no international standards have been defined for contouring and volume-related dose distribution.


Emerging concepts: from coeliac disease to non-coeliac gluten sensitivity.
The rise in gluten consumption over time has led to the increasing recognition of coeliac disease (CD) with associated complications. However, only recently has there been an appreciation that the spectrum of gluten-related disorders is greater than just CD, which may explain the growing global popularity in gluten-free products. Current literature suggests that a newly recognised clinical entity in the form of non-coeliac gluten sensitivity (NCGS) may be the most common gluten-related disorder encountered by healthcare professionals, although its exact prevalence is as yet unknown. This article will review the historical relationship between mankind and gluten as well as the progressive recognition that it is possible for gluten to have a deleterious effect on our health. To this effect we discuss the prevalence, diagnosis and complications of CD including the benefits derived from a gluten-free diet (GFD). Finally, we discuss our current understanding of NCGS, in addition to highlighting the need for further research to determine the extent, clinicopathological features and serological biomarkers to help recognise this emerging condition in clinical practice.


SNPeffect 4.0: on-line prediction of molecular and structural effects of protein-coding variants.
Single nucleotide variants (SNVs) are, together with copy number variation, the primary source of variation in the human genome and are associated with phenotypic variation such as altered response to drug treatment and susceptibility to disease. Linking structural effects of non-synonymous SNVs to functional outcomes is a major issue in structural bioinformatics. The SNPeffect database (http://snpeffect.switchlab.org) uses sequence- and structure-based bioinformatics tools to predict the effect of protein-coding SNVs on the structural phenotype of proteins. It integrates aggregation prediction (TANGO), amyloid prediction (WALTZ), chaperone-binding prediction (LIMBO) and protein stability analysis (FoldX) for structural phenotyping. Additionally, SNPeffect holds information on affected catalytic sites and a number of post-translational modifications. The database contains all known human protein variants from UniProt, but users can now also submit custom protein variants for a SNPeffect analysis, including automated structure modeling. The new meta-analysis application allows plotting correlations between phenotypic features for a user-selected set of variants.


eFSM--a novel online neural-fuzzy semantic memory model.
Fuzzy rule-based systems (FRBSs) have been successfully applied to many areas. However, traditional fuzzy systems are often manually crafted, and their rule bases that represent the acquired knowledge are static and cannot be trained to improve the modeling performance. This subsequently leads to intensive research on the autonomous construction and tuning of a fuzzy system directly from the observed training data to address the knowledge acquisition bottleneck, resulting in well-established hybrids such as neural-fuzzy systems (NFSs) and genetic fuzzy systems (GFSs). However, the complex and dynamic nature of real-world problems demands that fuzzy rule-based systems and models be able to adapt their parameters and ultimately evolve their rule bases to address the nonstationary (time-varying) characteristics of their operating environments. Recently, considerable research efforts have been directed to the study of evolving Tagaki-Sugeno (T-S)-type NFSs based on the concept of incremental learning. In contrast, there are very few incremental learning Mamdani-type NFSs reported in the literature. Hence, this paper presents the evolving neural-fuzzy semantic memory (eFSM) model, a neural-fuzzy Mamdani architecture with a data-driven progressively adaptive structure (i.e., rule base) based on incremental learning. Issues related to the incremental learning of the eFSM rule base are carefully investigated, and a novel parameter learning approach is proposed for the tuning of the fuzzy set parameters in eFSM. The proposed eFSM model elicits highly interpretable semantic knowledge in the form of Mamdani-type if-then fuzzy rules from low-level numeric training data. These Mamdani fuzzy rules define the computing structure of eFSM and are incrementally learned with the arrival of each training data sample. New rules are constructed from the emergence of novel training data and obsolete fuzzy rules that no longer describe the recently observed data trends are pruned. This enables eFSM to maintain a current and compact set of Mamdani-type if-then fuzzy rules that collectively generalizes and describes the salient associative mappings between the inputs and outputs of the underlying process being modeled. The learning and modeling performances of the proposed eFSM are evaluated using several benchmark applications and the results are encouraging.


Healthier by precommitment.
We tested a voluntary self-control commitment device to help grocery shoppers make healthier food purchases. Participants, who were already enrolled in a large-scale incentive program that discounts the price of eligible groceries by 25%, were offered the chance to put their discount on the line. Agreeing households pledged that they would increase their purchases of healthy food by 5 percentage points above their household baseline for each of 6 months. If they reached that goal, their discount was awarded as usual; otherwise, their discount was forfeited for that month. Thirty-six percent of households that were offered the binding commitment agreed; they subsequently showed an average 3.5-percentage-point increase in healthy grocery items purchased in each of the 6 months; households that declined the commitment and control-group households that were given a hypothetical option to precommit did not show such an increase. These results suggest that self-aware consumers will seize opportunities to create restrictive choice environments for themselves, even at some risk of financial loss.


Vestibular dysfunction in Gulf War syndrome.
Vestibular complaints of Gulf War veterans were characterized by a nested case-control study of 23 veterans with 3 different Gulf War syndromes and 20 matched control subjects. All subjects completed a standardized symptom questionnaire and underwent standard audiovestibular tests administered by audiologists blinded to group identities. The prevalence of reported dizzy spells was higher in veterans with Gulf War syndromes 1 (100%), 2 (85%), and 3 (100%) than in controls (25%, P < 0.0001). Dizzy spells were more frequent, lasted longer, and involved a wider variety of accompanying symptoms in veterans with syndrome 2 than in those with syndromes 1 and 3. Audiovestibular testing showed greater interocular asymmetry of nystagmic velocity on sinusoidal harmonic acceleration in syndromes 1 (P = 0.015) and 2 (P = 0.002), greater asymmetry of saccadic velocity in syndrome 2 (P = 0.4), diminished nystagmic velocity after caloric stimulation bilaterally in syndrome 3 (P = 0.02 to 0.04), more subjects with pathologic nystagmus (P = 0. 09), and greater interside asymmetry of wave I to III interpeak latency on auditory brain stem response in syndromes 1 (P = 0.005) and 2 (P = 0.07). Asymmetry of gain on sinusoidal harmonic acceleration and pathologic nystagmus were most strongly associated with symptoms of paroxysmal vertigo (P = 0.002 and 0.07, respectively); asymmetry of saccadic velocity, with the severity of vertigo (P = 0.004); and abnormal caloric response, with chronic dysequilibrium (P = 0.006). The findings are compatible with a subtle neurologic injury from organophosphate-induced delayed neurotoxicity.


The Role of Auditory Features Within Slot-Themed Social Casino Games and Online Slot Machine Games.
Over the last few years playing social casino games has become a popular entertainment activity. Social casino games are offered via social media platforms and mobile apps and resemble gambling activities. However, social casino games are not classified as gambling as they can be played for free, outcomes may not be determined by chance, and players receive no monetary payouts. Social casino games appear to be somewhat similar to online gambling activities in terms of their visual and auditory features, but to date little research has investigated the cross over between these games. This study examines the auditory features of slot-themed social casino games and online slot machine games using a case study design. An example of each game type was played on three separate occasions during which, the auditory features (i.e., music, speech, sound effects, and the absence of sound) within the games were logged. The online slot-themed game was played in demo mode. This is the first study to provide a qualitative account of the role of auditory features within a slot-themed social casino game and an online slot machine game. Our results found many similarities between how sound is utilised within the two games. Therefore the sounds within these games may serve functions including: setting the scene for gaming, creating an image, demarcating space, interacting with visual features, prompting players to act, communicating achievements to players, providing reinforcement, heightening player emotions and the gaming experience. As a result this may reduce the ability of players to make a clear distinction between these two activities, which may facilitate migration between games.


Potential biomarkers associated with discrimination between latent and active pulmonary tuberculosis.
A third of the world's population has latent tuberculous infection (LTBI). Current TB diagnostics used in developing countries are ineffective and are unable to distinguish LTBI from active TB. Identifying biomarkers that could aid in the early detection of TB and in distinguishing TB states could be a major breakthrough in global TB control. To identify potential immune biomarkers to distinguish active TB from LTBI. A cross-sectional study was conducted among 19 active TB patients, 8 TB-negative individuals (controls) and 16 LTBI non-human immunodeficiency virus infected individuals in Nairobi, Kenya. Excess supernatants from the QuantiFERON®-TB Gold In-Tube test were used to measure immune analytes using a Th17-focused Milliplex® assay. Overall antigen-specific responses were higher in the LTBI group than in active TB patients and controls. Interleukin (IL) 17F, macrophage inflammatory protein 3 alpha (MIP-3α), IL-13, IL-17A, IL-5, interferon-gamma (IFN-γ), IL-9, IL-1β and IL-2 were significantly differentially produced by individuals with LTBI and active TB patients. Receiver operator curve analysis revealed good discriminative abilities of these analytes. Co-expression analysis highlighted uniquely co-expressed cytokine pairs between TB groups. These findings suggest that IL-17F, MIP-3α, IL-13, IL-17A, IL-5, IL-9, IL-1β and IL-2, in addition to IFN-γ, could identify and uniquely discriminate between TB states.


Overexpression of a panel of cancer stem cell markers enhances the predictive capability of the progression and recurrence in the early stage cholangiocarcinoma.
Cancer recurrence is the important problem of cholangiocarcinoma (CCA) patients, lead to a very high mortality rate. Therefore, the identification of candidate markers to predict CCA recurrence is needed in order to effectively manage the disease. This study aims to examine the predictive value of cancer stem cell (CSC) markers on the progression and recurrence of CCA patients. The expression of 6 putative CSC markers, cluster of differentiation 44 (CD44), CD44 variant 6 (CD44v6), CD44 variants 8-10 (CD44v8-10), cluster of differentiation 133 (CD133), epithelial cell adhesion molecule (EpCAM), and aldehyde dehydrogenase 1A1 (ALDH1A1), was investigated in 178 CCA tissue samples using immunohistochemistry (IHC) and analyzed with respect to clinicopathological data and patient outcome including recurrence-free survival (RFS) and overall survival (OS). The candidate CSC markers were also investigated in serum from CCA patients, and explored for their predictive ability on CCA recurrence. Elevated protein level of CD44 and positive expression of CD44v6 and CD44v8-10 were significantly associated with short RFS and OS, while high levels of ALDH1A1 were correlated with a favorable prognosis patient. The elevated CD44v6 level was also correlated with higher tumor staging, whereas a decreasing level of ALDH1A1 was correlated with lower tumor staging. The levels of CD44, CD44v6 and CD44v8-10 were also correlated and were associated with a poor outcome. Furthermore, soluble CD44, CD44v6, CD44v8-10 and EpCAM were significantly increased in the recurrence group for early stage CCA; they also correlated with high levels of the tumor marker CA19-9. Elevated levels of CD44, CD44v6, CD44v8-10 or EpCAM alone or in combination has the potential to predict CCA recurrence. The overexpression of CD44, CD44v6, CD44v8-10 and EpCAM increases predictability of post-operative CCA recurrence. Moreover, the overexpression of the panel of CSC markers combined with CA19-9 could improve our predictive ability for tumor recurrence in early stage CCA patients. This result may be beneficial for the patients in order to predict the outcome after treatment and may be useful for clinical intervention in order to improve patient survival.


Unconscious learning of likes and dislikes is persistent, resilient, and reconsolidates.
Preferences profoundly influence decision-making and are often acquired through experience, yet it is unclear what role conscious awareness plays in the formation and persistence of long-term preferences and to what extent they can be altered by new experiences. We paired visually masked cues with monetary gains or losses during a decision-making task. Despite being unaware of the cues, subjects were influenced by their predictive values over successive trials of the task, and also revealed a strong preference for the appetitive over the aversive cues in supraliminal choices made days after learning. Moreover, the preferences were resistant to an intervening procedure designed to abolish them by a change in reinforcement contingencies, revealing a surprising resilience once formed. Despite their power however, the preferences were abolished when this procedure took place shortly after reactivating the memories, indicating that the underlying affective associations undergo reconsolidation. These findings highlight the importance of initial experiences in the formation of long-lasting preferences even in the absence of consciousness, while suggesting a way to overcome them in spite of their resiliency.


What does real-world walking mean to people with stroke? An interpretive descriptive study.
Understanding personal experiences of real-world walking for stroke survivors could assist clinicians to tailor interventions to their clients' specific needs. We explored the research questions: "What does real-world walking mean to people after stroke and how do they think it can be better?" Using an Interpretive Descriptive methodology, we purposively sampled eight stroke survivors who reported difficulty walking in the real-world. We sought diversity on key participant characteristics. Participants were interviewed using a semi-structured guide. Data were analysed with thematic analysis. Many found real-world walking, particularly in the outdoors, created opportunities for freedom from dependence and a visible step by step progress, which generated hope for future recovery. Conversely, when participants did not experience sufficient progress, they expressed negative emotions. Participants strove to overcome challenges to their walking goals using everyday routines, planning skills, and confidence building experiences to motivate themselves. They also drew on, and extended, social resources highlighting the relational aspects of real-world walking. Walking in their real-world provided a meaningful, desirable, but challenging goal for participants that required significant emotional effort. Successful progress in real-world walking builds confidence and hope and can contribute to psychological wellbeing by providing opportunities for successful mastery and social connectedness.IMPLICATIONS FOR REHABILITATIONReal-world settings can be unpredictable which makes walking in the real-world after stroke demanding.Positive experiences of walking in the real-world can provide significant psychological benefits to stroke survivors.Many survivors need to carefully concentrate on the act of walking in outdoor settings.Pre-planning routes, confidence-building experiences and developing daily routines may help patients overcome these challenges.


The Value of Ultrasonography, Leukocyte Count and Clinical Results in Diagnosis of Acute Appendicitis and the Duration of Stay of the Patients in Emergency Department.
In this study, we aimed to compare the clinical data of patients diagnosed with acute appendicitis in our center with the literature. The patients who were diagnosed with acute appendicitis between 01.10.2010 and 01.10.2011 in Emergency Department of İzmir Bozyaka Training and Research Hospital were included in this study. Patient demographics, dates and times of emergency department application, dates and times of hospitalization in the general surgery ward, duration of stay in the emergency department, leukocyte count and its relationship with age, the perforation rate, the relationship of perforation with age and leukocyte count, and the final diagnosis and ultrasound findings were assessed in this study. A total of 482 patients who were diagnosed with acute appendicitis [300 (62.2%) male, mean age 30.7±12.03; 182 (37.8%) female, mean age 31.17±13.22)] were enrolled. The duration of stay in the emergency department was between 0-6 and 6-12 hours in 320 (66.4%) and 143 (29.7%) patients, respectively. The ultrasonography findings were consistent with acute appendicitis in 366 (75.9%) patients, and the mean leukocyte count of these patients was 13.141/mm(3). 46 (9.5%) of the patients were diagnosed with perforated appendicitis. The ultrasonography findings were not consistent with acute appendicitis in 36 (7.5%) patients and the leukocyte counts were less than 11.000/mm(3) in these patients. According to the present study results, acute appendicitis is commonly seen among the young adult male population. The coherence of ultrasonography findings with the diagnosis and its association with leukocytosis is significant and supportive. Additionally, the ultrasonography findings, leukocytosis, medical history and physical examination are important and essential factors for the diagnosis of acute appendicitis. A large number of patients with acute appendicitis were followed-up between 0-6 hours in the emergency department.


Intermediate filaments and the initiation of desmosome assembly.
The desmosome junction is an important component in the cohesion of epithelial cells, especially epidermal keratinocytes. To gain insight into the structure and function of desmosomes, their morphogenesis has been studied in a primary mouse epidermal (PME) cell culture system. When these cells are grown in approximately 0.1 mM Ca2+, they contain no desmosomes. They are induced to form desmosomes when the Ca2+ level in the culture medium is raised to approximately 1.2 mM Ca2+. PME cells in medium containing low levels of Ca2+, and then processed for indirect immunofluorescence using antibodies directed against desmoplakins (desmosomal plaque proteins), display a pattern of discrete fluorescent spots concentrated mainly in the perinuclear region. Double label immunofluorescence using keratin and desmoplakin antibodies reveals that the desmoplakin-containing spots and the cytoplasmic network of tonofibrils (bundles of intermediate filaments [IFB]) are in the same juxtanuclear region. Within 1 h after the switch to higher levels of Ca2+, the spots move toward the cell surface, primarily to areas of cell-cell contact and not to free cell surfaces. This reorganization occurs at the same time that tonofibrils also move toward cell surfaces in contact with neighboring cells. Once the desmoplakin spots have reached the cell surface, they appear to aggregate to form desmosomes. These immunofluorescence observations have been confirmed by immunogold ultrastructural localization. Preliminary biochemical and immunological studies indicate that desmoplakin appears in whole cell protein extracts and in Triton high salt insoluble residues (i.e., cytoskeletal preparations consisting primarily of IFB) prepared from PME cells maintained in medium containing both low and normal Ca2+ levels. These findings show that certain desmosome components are preformed in the cytoplasm of PME cells. These components undergo a dramatic reorganization, which parallels the changes in IFB redistribution, upon induction of desmosome formation. The reorganization depends upon both the extracellular Ca2+ level and the establishment of cell-to-cell contacts. Furthermore, the data suggests that desmosomes do not act as organizing centers for the elaboration of IFB. Indeed, we postulate that the movement of IFB and preformed desmosomal components to the cell surface is an important initiating event in desmosome morphogenesis.


Integrating intention and context: assessing social cognition in adults with Asperger syndrome.
Deficits in social cognition are an evident clinical feature of the Asperger syndrome (AS). Although many daily life problems of adults with AS are related to social cognition impairments, few studies have conducted comprehensive research in this area. The current study examined multiple domains of social cognition in adults with AS assessing the executive functions (EF) and exploring the intra and inter-individual variability. Fifteen adult's diagnosed with AS and 15 matched healthy controls completed a battery of social cognition tasks. This battery included measures of emotion recognition, theory of mind (ToM), empathy, moral judgment, social norms knowledge, and self-monitoring behavior in social settings. We controlled for the effect of EF and explored the individual variability. The results indicated that adults with AS had a fundamental deficit in several domains of social cognition. We also found high variability in the social cognition tasks. In these tasks, AS participants obtained mostly subnormal performance. EF did not seem to play a major role in the social cognition impairments. Our results suggest that adults with AS present a pattern of social cognition deficits characterized by the decreased ability to implicitly encode and integrate contextual information in order to access to the social meaning. Nevertheless, when social information is explicitly presented or the situation can be navigated with abstract rules, performance is improved. Our findings have implications for the diagnosis and treatment of individuals with AS as well as for the neurocognitive models of this syndrome.


Benefits of protected areas for nonbreeding waterbirds adjusting their distributions under climate warming.
Climate warming is driving changes in species distributions and community composition. Many species have a so-called climatic debt, that is, shifts in range lag behind shifts in temperature isoclines. Inside protected areas (PAs), community changes in response to climate warming can be facilitated by greater colonization rates by warm-dwelling species, but also mitigated by lowering extirpation rates of cold-dwelling species. An evaluation of the relative importance of colonization-extirpation processes is important to inform conservation strategies that aim for both climate debt reduction and species conservation. We assessed the colonization-extirpation dynamics involved in community changes in response to climate inside and outside PAs. To do so, we used 25 years of occurrence data of nonbreeding waterbirds in the western Palearctic (97 species, 7071 sites, 39 countries, 1993-2017). We used a community temperature index (CTI) framework based on species thermal affinities to investigate species turnover induced by temperature increase. We determined whether thermal community adjustment was associated with colonization by warm-dwelling species or extirpation of cold-dwelling species by modeling change in standard deviation of the CTI (CTISD ). Using linear mixed-effects models, we investigated whether communities in PAs had lower climatic debt and different patterns of community change than communities outside PAs. For CTI and CTISD combined, communities inside PAs had more species, higher colonization, lower extirpation, and lower climatic debt (16%) than communities outside PAs. Thus, our results suggest that PAs facilitate 2 independent processes that shape community dynamics and maintain biodiversity. The community adjustment was, however, not sufficiently fast to keep pace with the large temperature increases in the central and northeastern western Palearctic. Our results underline the potential of combining CTI and CTISD metrics to improve understanding of the colonization-extirpation patterns driven by climate warming.


Implant-based Breast Reconstruction Infections: The Importance of Recognizing Local Pathogens.
Implant-based breast reconstruction (IBR) is the most common method of reconstruction for breast cancer. Bacterial infection is a well-known risk with reported rates ranging from 1% to 43%. The most common pathogens of breast implant infection described in the literature are Staphylococcus aureus, Staphylococcus epidermidis, and coagulase-negative staphylococci. However, the prevalence of other pathogens and their antibiotic sensitivity profile differs profoundly in different parts of the world. To review the current literature and protocols with respect to our region and to determine a more accurate antibiotic protocol aimed at our specific local pathogens. A retrospective review was conducted of all cases of clinically infected implant-based breast reconstruction in our institution from June 2013 to June 2019, as well as review of microbiologic data from around the world based on current literature. A total of 28 patients representing 28 clinically infected implant-based breast reconstruction were identified during the studied period. Thirteen patients (46.4%) had a positive bacterial culture growth, with P. aeruginosa being the most common microorganism identified (46.1%). Review of international microbiological data demonstrated significant variation at different places and time periods. Microbiological data in cases of infected breast reconstructions should be collected and analyzed in every medical center and updated every few years due to the variations observed. These data will help to adjust the optimal empirical antibiotic regimens given to patients presenting with infections after breast reconstruction.


immunoClust--An automated analysis pipeline for the identification of immunophenotypic signatures in high-dimensional cytometric datasets.
Multiparametric fluorescence and mass cytometry offers new perspectives to disclose and to monitor the high diversity of cell populations in the peripheral blood for biomarker research. While high-end cytometric devices are currently available to detect theoretically up to 120 individual parameters at the single cell level, software tools are needed to analyze these complex datasets automatically in acceptable time and without operator bias or knowledge. We developed an automated analysis pipeline, immunoClust, for uncompensated fluorescence and mass cytometry data, which consists of two parts. First, cell events of each sample are grouped into individual clusters. Subsequently, a classification algorithm assorts these cell event clusters into populations comparable between different samples. The clustering of cell events is designed for datasets with large event counts in high dimensions as a global unsupervised method, sensitive to identify rare cell types even when next to large populations. Both parts use model-based clustering with an iterative expectation maximization algorithm and the integrated classification likelihood to obtain the clusters. A detailed description of both algorithms is presented. Testing and validation was performed using 1) blood cell samples of defined composition that were depleted of particular cell subsets by magnetic cell sorting, 2) datasets of the FlowCAP III challenges to identify populations of rare cell types and 3) high-dimensional fluorescence and mass-cytometry datasets for comparison with conventional manual gating procedures. In conclusion, the immunoClust-algorithm is a promising tool to standardize and automate the analysis of high-dimensional cytometric datasets. As a prerequisite for interpretation of such data, it will support our efforts in developing immunological biomarkers for chronic inflammatory disorders and therapy recommendations in personalized medicine. immunoClust is implemented as an R-package and is provided as source code from www.bioconductor.org.


Cycling to and from a stem cell niche: the temporal and spatial odyssey of mitotic male germ cells.
The development of male germ cells within the prenatal and prepubertal periods in mammals combines multiple biological events that integrate cell cycle regulation, epigenetic reprogramming, and cell migration along temporally and spatially dynamic lines. Germ cells arise from their precursor primordial germ cells in the mid-gestation embryo, forming gonocytes that enter G0 phase cell cycle arrest within the fetal testis. Cyclin-dependent kinase inhibitors, activated retinoblastoma 1 protein, and increased levels of transforming growth factor beta 2 collectively influence this cell cycle arrest. Gonocyte quiescence persists until shortly after birth, whereupon the cells concomitantly re-enter the cell cycle and migrate towards a niche that establishes and maintains self-renewing spermatogonial stem cells and balances them with differentiating spermatogonia. Platelet-derived growth factor signaling is one of the mechanisms that regulates both mitotic activation and migration in neonatal gonocytes, along with mitogens, 17β-estradiol and retinoic acid, and chemoattractants C-C-motif ligand 9 and members of the ADAM, integrin, and tetraspanin families. Numerous germ cell-intrinsic proteins have been identified that ensure the retention of germ cells within the spermatogonial stem cell niche. Sertoli cells are a significant component of this niche, contributing essential growth factors and chemokines to spermatogonia. This review focuses on the dynamic events that occur to mitotic male germ cells before and during their arrival at this niche, with an emphasis on the cell cycle and directed migration.


Objectively identifying landmark use and predicting flight trajectories of the homing pigeon using Gaussian processes.
Pigeons home along idiosyncratic habitual routes from familiar locations. It has been suggested that memorized visual landmarks underpin this route learning. However, the inability to experimentally alter the landscape on large scales has hindered the discovery of the particular features to which birds attend. Here, we present a method for objectively classifying the most informative regions of animal paths. We apply this method to flight trajectories from homing pigeons to identify probable locations of salient visual landmarks. We construct and apply a Gaussian process model of flight trajectory generation for pigeons trained to home from specific release sites. The model shows increasing predictive power as the birds become familiar with the sites, mirroring the animal's learning process. We subsequently find that the most informative elements of the flight trajectories coincide with landscape features that have previously been suggested as important components of the homing task.


A systematic review of the impact of sedation practice in the ICU on resource use, costs and patient safety.
Patients in intensive care units (ICUs) often receive sedation for prolonged periods. In order to better understand the impact of sub-optimal sedation practice on outcomes, we performed a systematic review, including observational studies and controlled trials which were conducted in sedated patients in the ICU and which compared the impact of changes in or different protocols for sedation management on economic and patient safety outcomes. We searched Medline, Embase and CINAHL online literature databases from 1988 to 15th May 2008 and hand searched conferences. English-language studies set in the ICU, in sedated adult humans on mechanical ventilation, which reported the impact of sedation practice on cost and resource use and patient safety outcomes, were included. All abstracts were reviewed twice by two independent reviewers, with all conflicts resolved by a third reviewer, to check that they met the review inclusion criteria. Full-text papers of all included studies were retrieved and again reviewed twice against inclusion criteria. Data were doubly extracted from studies. Study aims, design, population, and outcomes including duration of mechanical ventilation, length of stay in ICU and hospital, costs and rates of mortality and adverse events were extracted. Due to heterogeneity between study designs and outcomes reported, no quantitative data synthesis such as meta-analysis was possible. Included studies varied in design, patient population and aim, with the majority being before-after studies. Overall, studies showed that improvements in sedation practice, such as the introduction of guidelines and protocols, or daily interruption of sedation, were associated with improvements in outcomes including ICU and hospital length of stay, duration of mechanical ventilation, and costs. Mortality and the incidence of nosocomial infections were also reduced. Systematic interventions to improve sedation practice and maintain patients at an optimal sedation level in the ICU may improve patient outcomes and optimize resource usage.


Manual hyperinflation combined with expiratory rib cage compression for reduction of length of ICU stay in critically ill patients on mechanical ventilation.
Although manual hyperinflation (MH) is widely used for pulmonary secretion clearance, there is no evidence to support its routine use in clinical practice. Our objective was to evaluate the effect that MH combined with expiratory rib cage compression (ERCC) has on the length of ICU stay and duration of mechanical ventilation (MV). This was a prospective randomized controlled clinical trial involving ICU patients on MV at a tertiary care teaching hospital between January of 2004 and January of 2005. Among the 49 patients who met the study criteria, 24 and 25 were randomly assigned to the respiratory physiotherapy (RP) and control groups, respectively. Of those same patients, 6 and 8, respectively, were later withdrawn from the study. During the 5-day observation period, the RP patients received MH combined with ERCC, whereas the control patients received standard nursing care. The two groups were similar in terms of the baseline characteristics. The intervention had a positive effect on the duration of MV, as well as on the ICU discharge rate and Murray score. There were significant differences between the control and RP groups regarding the weaning success rate on days 2 (0.0% vs. 37.5%), 3 (0.0% vs. 37.5%), 4 (5.3% vs. 37.5%), and 5 (15.9% vs. 37.5%), as well as regarding the ICU discharge rate on days 3 (0% vs. 25%), 4 (0% vs. 31%), and 5 (0% vs. 31%). In the RP group, there was a significant improvement in the Murray score on day 5. Our results show that the use of MH combined with ERCC for 5 days accelerated the weaning process and ICU discharge.


Catalytic control over the formation of supramolecular materials.
In this Perspective, we will discuss how the rate of formation of supramolecular materials can be drastically enhanced by catalytically controlling the rate of formation of their molecular building blocks, resulting in the formation of out-of-equilibrium soft materials with enhanced mechanical properties. Also, the use of surface confined, patterned catalysts allows spatial control over self-assembly, which can be applied to the formation of regular, micrometer sized hydrogel patterns. Catalysis has been applied for decades as an indispensable tool in the synthesis of both simple and highly complex molecules and polymers, ranging from milligram lab-scale to multi-ton industrial processes. However, despite being widespread in nature, until recently the use of catalysis to control the formation of supramolecular materials has remained limited. We will demonstrate the large potential of using catalysis as a tool in the construction of soft materials, illustrated by recent developments.


Left ventricular mass independently associates with masked hypertension in young healthy adults: the African-PREDICT study.
Masked hypertension is reportedly common in young adults. However, it is unknown if these masked hypertensive individuals already present with organ damage. We determined whether a relationship exists between left ventricular structure and function, and masked hypertension in young healthy adults. In this cross-sectional study, we included 774 black and white men and women (aged 20-30 years) who had successful ambulatory blood pressure monitoring readings (>70% valid readings) and valid echocardiography done. We found that 16.4% had masked hypertension (60.6% whites; 67.7% men). When performing multivariable-adjusted logistic regression, we found masked hypertensive patients to have higher odds to present with increased left ventricular mass index (odds ratio 1.67, P = 0.031) compared to normotensive individuals. In multivariable-adjusted linear regression analyses, left ventricular mass index positively and independently associated with masked hypertension [adjusted R = 0.193, β = 0.08 (0.01; 0.16), P = 0.046]. However, we found no independent link between echocardiographic measures of left ventricular function and masked hypertension. This study highlights the importance of the early detection of masked hypertension as young apparently healthy adults already show an increased left ventricular mass index, thereby indicating increased risk for future cardiovascular disease.


The Effect of Metalinguistic Sentence Combining on Eighth-Grade Students' Understanding and Written Expression of Comparison and Contrast in Science.
Purpose The purpose of this study was to examine whether sentence combining with an explicit metalinguistic approach in comparison to typical science instruction was effective in improving written expression and understanding of comparison/contrast in science for eighth-grade students who struggle with literacy. Method Eighty-four eighth-grade students who struggle with literacy participated in this study. The experimental group (n = 36) received the writing intervention of metalinguistic sentence combining (MSC) during their science class for a total of 400 min (20 intervention sessions, 20 min each), while the comparison group (n = 48) participated in their typical science instruction. Total science instruction time was held constant for both groups. All students completed pretests and posttests to determine an increase in (a) syntactic factors of academic science text such as longer sentence length and use of syntactic forms of connectives, targeted connectives, left embeddedness, and agentless passive voice when responding to a science compare and contrast writing prompt; and (b) listing similarities and differences between two science concepts on a graphic organizer. Results Treatment was effective in improving the experimental group's score in listing similarities and differences between two science concepts on a graphic organizer. There were no significant differences between the two groups in their use of syntactic factors typical of academic text when responding to a science compare and contrast writing prompt. Conclusions MSC was effective in improving the experimental student's ability to demonstrate understanding of comparison and contrast in science. Modifications to the MSC intervention may yield better results in the experimental group's posttreatment writing in future studies. Supplemental Material https://doi.org/10.23641/asha.12735950.


Regulation of dendritic protein synthesis by miniature synaptic events.
We examined dendritic protein synthesis after a prolonged blockade of action potentials alone and after a blockade of both action potentials and miniature excitatory synaptic events (minis). Relative to controls, dendrites exposed to a prolonged blockade of action potentials showed diminished protein synthesis. Dendrites in which both action potentials and minis were blocked showed enhanced protein synthesis, suggesting that minis inhibit dendritic translation. When minis were acutely blocked or stimulated, an immediate increase or decrease, respectively, in dendritic translation was observed. Taken together, these results reveal a role for miniature synaptic events in the acute regulation of dendritic protein synthesis in neurons.


Cilia gene mutations cause atrioventricular septal defects by multiple mechanisms.
Atrioventricular septal defects (AVSDs) are a common severe form of congenital heart disease (CHD). In this study we identified deleterious non-synonymous mutations in two cilia genes, Dnah11 and Mks1, in independent N-ethyl-N-nitrosourea-induced mouse mutant lines with heritable recessive AVSDs by whole-exome sequencing. Cilia are required for left/right body axis determination and second heart field (SHF) Hedgehog (Hh) signaling, and we find that cilia mutations affect these requirements differentially. Dnah11avc4 did not disrupt SHF Hh signaling and caused AVSDs only concurrently with heterotaxy, a left/right axis abnormality. In contrast, Mks1avc6 disrupted SHF Hh signaling and caused AVSDs without heterotaxy. We performed unbiased whole-genome SHF transcriptional profiling and found that cilia motility genes were not expressed in the SHF whereas cilia structural and signaling genes were highly expressed. SHF cilia gene expression predicted the phenotypic concordance between AVSDs and heterotaxy in mice and humans with cilia gene mutations. A two-step model of cilia action accurately predicted the AVSD/heterotaxyu phenotypic expression pattern caused by cilia gene mutations. We speculate that cilia gene mutations contribute to both syndromic and non-syndromic AVSDs in humans and provide a model that predicts the phenotypic consequences of specific cilia gene mutations.


Screening for Wilms tumor and hepatoblastoma in children with Beckwith-Wiedemann syndromes: a cost-effective model.
We undertook a cost-benefit analysis of screening for Wilms tumor and hepatoblastoma in children with Beckwith-Wiedemann syndrome (BWS), a known cancer predisposition syndrome. The purpose of this analysis was twofold: first, to assess whether screening in children with BWS has the potential to be cost-effective; second, if screening appears to be cost-effective, to determine which parameters would be most important to assess if a screening trial were initiated. We used data from the BWS registry at the National Cancer Institute, the National Wilms Tumor Study (NWTS), and large published series to model events for two hypothetical cohorts of 1,000 infants born with BWS. One hypothetical cohort was screened for cancer until a predetermined age, representing the base case. The other cohort was unscreened. For our base case, we assumed: (a) sonography examinations three times yearly (triannually) from birth until 7 years of age; (b) screening would result in one stage shift downward at diagnosis for Wilms tumor and hepatoblastoma; (c) 100% sensitivity and 95% specificity for detecting clinical stage I Wilms tumor and hepatoblastoma; (d) a 3% discount rate; (e) a false positive result cost of $402. We estimated mortality rates based on published Wilms tumor and hepatoblastoma stage specific survival. Using the base case, screening a child with BWS from birth until 4 years of age results in a cost per life year saved of $9,642 while continuing until 7 years of age results in a cost per life-year saved of $14,740. When variables such as cost of screening examination, discount rate, and effectiveness of screening were varied based on high and low estimates, the incremental cost per life-year saved for screening up until age four remained comparable to acceptable population based cancer screening ranges (< $50,000 per life year saved). Under our model's assumptions, abdominal sonography examinations in children with BWS represent a reasonable strategy for a cancer screening program. A cancer screening trial is warranted to determine if, when, and how often children with BWS should be screened and to determine cost-effectiveness in clinical practice.


Fibromylagia, chronic fatigue, and adult attention deficit hyperactivity disorder in the adult: a case study.
Adult attention deficit hyperactivity disorder (ADHD) may share common features with fibromyalgia syndrome (FMS) and chronic fatigue syndrome (CFS). In an outpatient psychiatric clinic, a number of adult patients who presented primarily with symptoms of ADHD, predominately inattentive type, also reported unexplained fatigue, widespread musculoskeletal pain or a pre-existing diagnosis of CFS or FMS. As expected, ADHD pharmacotherapy usually attenuated the core ADHD symptoms of inattention, distractibility, hyperactivity, and impulsivity. Less expected was the observation that some patients also reported amelioration of pain and fatigue symptoms. The utility of ADHD medications in FMS and CFS states may be their innate arousal and enhanced filtering properties. This model supposes that FMS and CFS are central processing problems rather than peripheral disorders of muscles and joints.


Controllable color display induced by excitation-intensity-dependent competition between second and third harmonic generation in ZnO nanorods.
We investigated the second and third harmonic generation (SHG and THG) in ZnO nanorods (NRs) by using a femtosecond laser (optical parametric amplifier with tunable wavelengths) with a long excitation wavelength of 1350 nm and a low repetition rate of 1 kHz. The damage threshold for ZnO NRs in this case was sufficiently large, enabling us to observe the competition between SHG and THG. The transition from red to blue emission and the mixing of red and blue light with different ratios were successfully demonstrated by simply varying excitation intensity, implying the potential applications of ZnO NRs in all-optical display.


An antigen processing polymorphism revealed by HLA-B8-restricted cytotoxic T lymphocytes which does not correlate with TAP gene polymorphism.
In previous studies of antigen presentation through HLA-B27, we identified a healthy person whose lymphoblastoid cells do not present three B27-restricted viral epitopes to specific cytotoxic T lymphocytes (CTL), despite adequate cell surface expression of HLA-B2702 of normal sequence. Similar findings were observed in all members of his family sharing the HLA-A3-B2702 haplotype. The original donor, NW, carries HLA-B8 on his other class I haplotype, which his daughter, HW, has inherited. We now report a failure to present an HLA-B8-restricted epitope from influenza nucleoprotein following viral infection of NW cells, although exogenous added peptide is still presented normally. However, cells from HW, which do not carry the A3-B2702 haplotype, present the expected epitope after viral infection. Another B8-restricted epitope, from human immunodeficiency virus-gag, is presented equally well by both cell lines when infected with gag-vaccinia. This antigen processing phenotype does not correlate with any of the known human TAP-1 and TAP-2 polymorphisms.


Glucagon-like peptide-1 (GLP-1) raises blood-brain glucose transfer capacity and hexokinase activity in human brain.
In hyperglycemia, glucagon-like peptide-1 (GLP-1) lowers brain glucose concentration together with increased net blood-brain clearance and brain metabolism, but it is not known whether this effect depends on the prevailing plasma glucose (PG) concentration. In hypoglycemia, glucose depletion potentially impairs brain function. Here, we test the hypothesis that GLP-1 exacerbates the effect of hypoglycemia. To test the hypothesis, we determined glucose transport and consumption rates in seven healthy men in a randomized, double-blinded placebo-controlled cross-over experimental design. The acute effect of GLP-1 on glucose transfer in the brain was measured by positron emission tomography (PET) during a hypoglycemic clamp (3 mM plasma glucose) with (18)F-fluoro-2-deoxy-glucose (FDG) as tracer of glucose. In addition, we jointly analyzed cerebrometabolic effects of GLP-1 from the present hypoglycemia study and our previous hyperglycemia study to estimate the Michaelis-Menten constants of glucose transport and metabolism. The GLP-1 treatment lowered the vascular volume of brain tissue. Loading data from hypo- to hyperglycemia into the Michaelis-Menten equation, we found increased maximum phosphorylation velocity (V max) in the gray matter regions of cerebral cortex, thalamus, and cerebellum, as well as increased blood-brain glucose transport capacity (T max) in gray matter, white matter, cortex, thalamus, and cerebellum. In hypoglycemia, GLP-1 had no effects on net glucose metabolism, brain glucose concentration, or blood-brain glucose transport. Neither hexokinase nor transporter affinities varied significantly with treatment in any region. We conclude that GLP-1 changes blood-brain glucose transfer and brain glucose metabolic rates in a PG concentration-dependent manner. One consequence is that hypoglycemia eliminates these effects of GLP-1 on brain glucose homeostasis.


Association of Radiation and Procarbazine Dose With Risk of Colorectal Cancer Among Survivors of Hodgkin Lymphoma.
Hodgkin lymphoma (HL) survivors have higher rates of colorectal cancer, which may be associated with subdiaphragmatic radiation therapy and/or alkylating chemotherapy. Although radiation dose-response associations with breast, lung, stomach, pancreatic, and esophageal cancer after HL have been demonstrated, the association of radiation therapy with colorectal cancer remains unclear. To quantify the rate of colorectal cancer according to radiation dose to the large bowel and procarbazine dose among HL survivors. A nested case-control study examined 5-year HL survivors at 5 hospital centers in the Netherlands. Participants had been diagnosed with HL in 1964 to 2000, when they were 15 to 50 years of age, and were followed for a median of approximately 26 years. Survivors of HL who developed colorectal cancer and survivors who were selected as controls were individually matched on sex, age at HL diagnosis, and date of HL diagnosis. Data were analyzed from July 2021 to October 2022. Mean radiation doses to the large bowel were estimated by reconstructing individual radiation therapy treatments on representative computed tomography data sets. Excess rate ratios (ERRs) were modeled to evaluate the excess risk associated with each 1-gray increase in radiation dose, and potential effect modification by procarbazine was explored. The study population included 316 participants (mean [SD] age at HL diagnosis, 33.0 [9.8] years; 221 [69.9%] men), 78 of whom were HL survivors who developed colorectal cancer (cases) and 238 who did not (controls). The median (IQR) interval between HL and colorectal cancer was 25.7 (18.2-31.6) years. Increased colorectal cancer rates were seen for patients who received subdiaphragmatic radiation therapy (rate ratio [RR], 2.4; 95% CI, 1.4-4.1) and those who received more than 8.4 g/m2 procarbazine (RR, 2.5; 95% CI, 1.3-5.0). Overall, colorectal cancer rate increased linearly with mean radiation dose to the whole large bowel and dose to the affected bowel segment. The association between radiation dose and colorectal cancer rate became stronger with increasing procarbazine dose: the ERR per gray to the whole bowel was 3.5% (95% CI, 0.4%-12.6%) for patients who did not receive procarbazine, and increased 1.2-fold (95% CI, 1.1-1.3) for each 1-g/m2 increase in procarbazine dose. This nested case-control study of 5-year HL survivors found a dose-response association between radiation therapy and colorectal cancer risk, and modification of this association by procarbazine. These findings may enable individualized colorectal cancer risk estimations, identification of high-risk survivors for subsequent screening, and optimization of treatment strategies.


Angiotensin-(1-7) attenuates diabetic nephropathy in Zucker diabetic fatty rats.
Angiotensin (ANG)-(1-7) is known to attenuate diabetic nephropathy; however, its role in the modulation of renal inflammation and oxidative stress in type 2 diabetes is poorly understood. Thus in the present study we evaluated the renal effects of a chronic ANG-(1-7) treatment in Zucker diabetic fatty rats (ZDF), an animal model of type 2 diabetes and nephropathy. Sixteen-week-old male ZDF and their respective controls [lean Zucker rats (LZR)] were used for this study. The protocol involved three groups: 1) LZR + saline, 2) ZDF + saline, and 3) ZDF + ANG-(1-7). For 2 wk, animals were implanted with subcutaneous osmotic pumps that delivered either saline or ANG-(1-7) (100 ng·kg(-1)·min(-1)) (n = 4). Renal fibrosis and tissue parameters of oxidative stress were determined. Also, renal levels of interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), ED-1, hypoxia-inducible factor-1α (HIF-1α), and neutrophil gelatinase-associated lipocalin (NGAL) were determined by immunohistochemistry and immunoblotting. ANG-(1-7) induced a reduction in triglyceridemia, proteinuria, and systolic blood pressure (SBP) together with a restoration of creatinine clearance in ZDF. Additionally, ANG-(1-7) reduced renal fibrosis, decreased thiobarbituric acid-reactive substances, and restored the activity of both renal superoxide dismutase and catalase in ZDF. This attenuation of renal oxidative stress proceeded with decreased renal immunostaining of IL-6, TNF-α, ED-1, HIF-1α, and NGAL to values similar to those displayed by LZR. Angiotensin-converting enzyme type 2 (ACE2) and ANG II levels remained unchanged after treatment with ANG-(1-7). Chronic ANG-(1-7) treatment exerts a renoprotective effect in ZDF associated with a reduction of SBP, oxidative stress, and inflammatory markers. Thus ANG-(1-7) emerges as a novel target for treatment of diabetic nephropathy.