A hybrid machine learning model to predict and visualize nitrate concentration throughout the Central Valley aquifer, California, USA.
Intense demand for water in the Central Valley of California and related increases in groundwater nitrate concentration threaten the sustainability of the groundwater resource. To assess contamination risk in the region, we developed a hybrid, non-linear, machine learning model within a statistical learning framework to predict nitrate contamination of groundwater to depths of approximately 500m below ground surface. A database of 145 predictor variables representing well characteristics, historical and current field and landscape-scale nitrogen mass balances, historical and current land use, oxidation/reduction conditions, groundwater flow, climate, soil characteristics, depth to groundwater, and groundwater age were assigned to over 6000 private supply and public supply wells measured previously for nitrate and located throughout the study area. The boosted regression tree (BRT) method was used to screen and rank variables to predict nitrate concentration at the depths of domestic and public well supplies. The novel approach included as predictor variables outputs from existing physically based models of the Central Valley. The top five most important predictor variables included two oxidation/reduction variables (probability of manganese concentration to exceed 50ppb and probability of dissolved oxygen concentration to be below 0.5ppm), field-scale adjusted unsaturated zone nitrogen input for the 1975 time period, average difference between precipitation and evapotranspiration during the years 1971-2000, and 1992 total landscape nitrogen input. Twenty-five variables were selected for the final model for log-transformed nitrate. In general, increasing probability of anoxic conditions and increasing precipitation relative to potential evapotranspiration had a corresponding decrease in nitrate concentration predictions. Conversely, increasing 1975 unsaturated zone nitrogen leaching flux and 1992 total landscape nitrogen input had an increasing relative impact on nitrate predictions. Three-dimensional visualization indicates that nitrate predictions depend on the probability of anoxic conditions and other factors, and that nitrate predictions generally decreased with increasing groundwater age.


Campus Information Sharing and Responses to Sexual Misconduct Violations: An Exploratory Study.
Recent years have seen growing public interest in how college and university administrators respond to sexual misconduct. Despite policy changes in this area, minimal research exists on how institutions of higher education (IHEs) are sharing and processing information about students found responsible for sexual misconduct. Aiming to establish some of the key questions and parameters in this line of research, this practitioner-researcher collaboration offers a first look at how IHEs share information about students who have been found responsible both within their campus and between campuses, as well as how IHEs respond when that information is shared (e.g., admitting a student applicant who has been previously sanctioned for a sexual misconduct violation). Practitioners designed and disseminated a questionnaire to campus administrators, including Title IX coordinators and student conduct administrators, via higher education association listservs. Exploratory results from 176 participants showed that 80% reported having some form of policy regarding sharing information within their institution, while approximately half have policies regarding sharing information to other IHEs regarding students found responsible of sexual misconduct. Nearly one-third of participants reported that their IHEs are engaging in campus information sharing through the use of transcript notation. In terms of IHEs receiving information about student applicants having been previously sanctioned for a sexual misconduct violation, approximately one-fourth of participants indicated their IHE has chosen not to accept a student for this reason within the past 5 years, and a quarter of IHEs have accepted such students. For those IHEs that have accepted a student previously found responsible, the majority of IHEs are not following the outcomes of these students, indicating an unknown in terms of whether information sharing policies were effective. As a result, preliminary findings suggest that more evaluation research is needed before any further policies are mandated.


Microarray analysis of human leucocyte subsets: the advantages of positive selection and rapid purification.
For expression profiling to have a practical impact in the management of immune-related disease it is essential that it can be applied to peripheral blood cells. Early studies have used total peripheral blood mononuclear cells, and as a consequence the majority of the disease-related signatures identified have simply reflected differences in the relative abundance of individual cell types between patients and controls. To identify cell-specific changes in transcription it would be necessary to profile purified leucocyte subsets. We have used sequential rounds of positive selection to isolate CD4 and CD8 T cells, CD19 B cells, CD14 monocytes and CD16 neutrophils for microarray analysis from a single blood sample. We compared gene expression in cells isolated in parallel using either positive or negative selection and demonstrate that there are no significant consistent changes due to positive selection, and that the far inferior results obtained by negative selection are largely due to reduced purity. Finally, we demonstrate that storing cells prior to separation leads to profound changes in expression, predominantly in cells of the myeloid lineage. Leukocyte subsets should be prepared for microarray analysis by rapid positive selection.


Aflatoxin Exposure from Milk in Rural Kenya and the Contribution to the Risk of Liver Cancer.
Milk is an important commodity in Kenya; the country has the largest dairy herd and highest per capita milk consumption in East Africa. As such, hazards in milk are of concern. Aflatoxin M1 (AFM1) is a toxic metabolite of aflatoxin B1 (AFB1) excreted in milk by lactating animals after ingesting AFB1-contaminated feeds. This metabolite is injurious to human health, but there is little information on the risk to human health posed by AFM1 in milk in rural Kenya. To fill this gap, a quantitative risk assessment (QRA) applying probabilistic statistical tools to quantify risks was conducted. This assessed the risk of liver cancer posed by AFM1 in milk, assuming 10-fold lower carcinogenicity than AFB1. Data from four agro-ecological zones in Kenya (semi-arid, temperate, sub-humid and humid) were used. We estimated that people were exposed to between 0.3 and 1 ng AFM1 per kg body weight per day through the consumption of milk. The annual incidence rates of cancer attributed to the consumption of AFM1 in milk were 3.5 × 10-3 (95% CI: 3 × 10-3-3.9 × 10-3), 2.9 × 10-3 (95% CI: 2.5 × 10-3-3.3 × 10-3), 1.4 × 10-3 (95% CI: 1.2 × 10-3-1.5 × 10-3) and 2.7 × 10-3 (95% CI: 2.3 × 10-3-3 × 10-3) cancers per 100,000 in adult females, adult males, children 6-18 years old, and in children less than five years old, respectively. Our results show that aflatoxin exposure from milk contributes relatively little to the incidence of liver cancer. Nonetheless, risk managers should take action based on cumulative exposure from all sources of aflatoxins.


Usage Patterns and Beliefs about Therapeutic Ultrasound by Canadian Physical Therapists: An Exploratory Population-Based Cross-Sectional Survey.
To explore the frequency and patterns of ultrasound (US) usage among physical therapists, to describe the most common purposes for using therapeutic US, and to investigate beliefs about therapeutic US. A survey was sent to 95% of physical therapists licensed to practise in the province of Alberta, Canada. Of 2,269 physical therapists to whom email invitations were sent, 438 (19.3%) provided full responses. RESULTS indicate that US is still frequently incorporated into treatment regimens and is widely believed to be effective; however, the study also found a decrease in US usage over the past 15 years. While physical therapists recognize the lack of evidence for the effectiveness of US, many consider it clinically useful. Physical therapists using US rely largely on their clinical experience when making decisions about its use, but this depends on level of education: clinicians with an MScPT degree tended to base more of their US decisions on research evidence, likely because of the increasing emphasis on research evidence in graduate education. Despite the questionable effectiveness of therapeutic US, physical therapists still commonly use this treatment modality, largely because of a belief that US is clinically useful. However, US usage has decreased over the past 15 years.


Identification and Treatment of Pathophysiological Comorbidities of Autism Spectrum Disorder to Achieve Optimal Outcomes.
Despite the fact that the prevalence of autism spectrum disorder (ASD) continues to rise, no effective medical treatments have become standard of care. In this paper we review some of the pathophysiological abnormalities associated with ASD and their potential associated treatments. Overall, there is evidence for some children with ASD being affected by seizure and epilepsy, neurotransmitter dysfunction, sleep disorders, metabolic abnormalities, including abnormalities in folate, cobalamin, tetrahydrobiopterin, carnitine, redox and mitochondrial metabolism, and immune and gastrointestinal disorders. Although evidence for an association between these pathophysiological abnormalities and ASD exists, the exact relationship to the etiology of ASD and its associated symptoms remains to be further defined in many cases. Despite these limitations, treatments targeting some of these pathophysiological abnormalities have been studied in some cases with high-quality studies, whereas treatments for other pathophysiological abnormalities have not been well studied in many cases. There are some areas of more promising treatments specific for ASD including neurotransmitter abnormalities, particularly imbalances in glutamate and acetylcholine, sleep onset disorder (with behavioral therapy and melatonin), and metabolic abnormalities in folate, cobalamin, tetrahydrobiopterin, carnitine, and redox pathways. There is some evidence for treatments of epilepsy and seizures, mitochondrial and immune disorders, and gastrointestinal abnormalities, particularly imbalances in the enteric microbiome, but further clinical studies are needed in these areas to better define treatments specific to children with ASD. Clearly, there are some promising areas of ASD research that could lead to novel treatments that could become standard of care in the future, but more research is needed to better define subgroups of children with ASD who are affected by specific pathophysiological abnormalities and the optimal treatments for these abnormalities.


Why are some spatial discriminations independent of contrast?
The accuracy of some spatial discriminations, including spatial frequency and orientation, is independent of the contrasts of the stimuli discriminated except when contrasts are near the detection threshold. This fact is surprising because higher contrasts should improve signal-to-noise ratios and performance. Two alternative explanations of this puzzle are examined, using a signal-detection-theory vector model: (1) noise increases with stimulus contrast in such a way that signal-to-noise ratios remain constant; (2) noise is constant, but the difference signal generated by each individual tuned mechanism is independent of contrast because the response function of the mechanism becomes compressive (approximately logarithmic) at a low contrast. The alternative explanations generate different predictions, which have been tested in several experiments. The results reject alternative (1) as a model of suprathreshold discrimination and give mixed support to alternative (2).


Perioperative management of the patient with rheumatoid arthritis.
A multidisciplinary approach is required to care for patients with rheumatoid arthritis (RA) in the perioperative period. In preparation for surgery, patients must have a cardiovascular risk assessment performed due to the high risk of heart disease in patients with RA. Treatment of RA is with immunomodulatory medications, which present unique challenges for the perioperative period. Currently, there is no consensus on how to manage disease modifying antirheumatic drug (DMARD) therapy in the perioperative setting. Much of the data to guide therapy is based on retrospective cohort data. Choices regarding DMARDs require an individualized approach with collaboration between surgeons and rheumatologists. Consensus regarding biologic therapy is to hold the therapy in the perioperative period with the length of time dictated by the half-life of the medication. Special attention is required at the time of surgery for potential need for stress dose steroids. Further, there must be close communication with anesthesiologists in terms of airway management particularly in light of the risk for cervical spine disease. There are no consensus guidelines regarding the requirement for cervical spine radiographs prior to surgery. However, history and exam alone cannot be relied upon to identify cervical spine disease. Patients with RA who undergo joint replacement arthroplasty are at higher risk for infection and dislocation compared to patients with osteoarthritis, necessitating particular vigilance in postoperative follow up. This review summarizes available evidence regarding perioperative management of patients with RA.


The New Equivocal: Changes to HER2 FISH Results When Applying the 2013 ASCO/CAP Guidelines.
Human epidermal growth factor receptor 2 (HER2, ERBB2) testing is an important prognostic/predictive marker in breast cancer management, especially in selecting HER2-targeted treatment. American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines address HER2 status and were recently revised in 2013, replacing the 2007 version. For in situ hybridization interpretation, 2013 guidelines return to the prior threshold of a HER2/CEP17 ratio of 2.0 or greater for positive and eliminate 1.8 to 2.2 as the equivocal range. Also, the HER2 signal/nucleus ratio is accounted for, with 6.0 or greater for positive and 4.0 to less than 6.0 for equivocal, even in cases with a HER2/CEP17 ratio less than 2.0. With institutional review board approval, we reviewed our 2006 to 2012 HER2 fluorescence in situ hybridization (FISH) results and classified them according to both the 2007 and 2013 guidelines as negative, positive, or equivocal. Of 717 HER2 FISH results, 55 (7.7%) changed category when reassessed by 2013 guidelines. Nineteen of 25 results in the 2007 equivocal category were reassigned as positive (n = 13) or negative (n = 6). Thirty-five previously negative cases became equivocal in the 2013 scheme, 12 of these with 1+ immunohistochemistry. The positive category increased from 71 to 85. The 2013 ASCO/CAP guidelines increased the number of HER2 FISH positive and equivocal results. The equivocal group is substantially different, posing a dilemma for clinical management.


Shifts of spatial attention in perceived 3-D space.
Previous studies have shown that spatial attention can shift in three-dimensional (3-D) space determined by binocular disparity. Using Posner's precueing paradigm, the current work examined whether attentional selection occurs in perceived 3-D space defined by occlusion. Experiment 1 showed that shifts of spatial attention induced by central cues between two surfaces in the left and right visual fields did not differ between the conditions when the two surfaces were located at the same or different perceptual depth. In contrast, Experiment 2 found that peripheral cues generated a stronger cue validity effect when the two surfaces were perceived at a different rather than at the same perceptual depth. The results suggest that exogenous but not endogenous attention operates in perceived 3-D space.


Cerebral blood flow is reduced in ME/CFS during head-up tilt testing even in the absence of hypotension or tachycardia: A quantitative, controlled study using Doppler echography.
The underlying hypothesis in orthostatic intolerance (OI) syndromes is that symptoms are associated with cerebral blood flow (CBF) reduction. Indirect CBF measurements (transcranial Doppler flow velocities), provide inconsistent support of this hypothesis. The aim of the study was to measure CBF during a 30 min head-up tilt test (HUT), using Doppler flow imaging of carotid and vertebral arteries, in individuals with chronic fatigue syndrome/myalgic encephalomyelitis (ME/CFS), a condition with a high prevalence of OI. 429 ME/CFS patients were studied: 247 had a normal heart rate (HR) and blood pressure (BP) response to HUT, 62 had delayed orthostatic hypotension (dOH), and 120 had postural orthostatic tachycardia syndrome (POTS). We also studied 44 healthy controls (HC). CBF measurements were made at mid-tilt and end-tilt. Before mid-tilt, we administered a verbal questionnaire to ascertain for 15 OI symptoms. End-tilt CBF reduction was 7% in HC versus 26% in the overall ME/CFS group, 24% in patients with a normal HR/BP response, 28% in those with dOH, and 29% in POTS patients (all P < .0005). Using a lower limit of normal of 2SD of CBF reduction in HC (13% reduction), 82% of patients with normal HR/BP response, 98% with dOH and 100% with POTS showed an abnormal CBF reduction. There was a linear correlation of summed OI symptoms with the degree of CBF reduction at mid-tilt (P < .0005). During HUT, extracranial Doppler measurements demonstrate that CBF is reduced in ME/CFS patients with POTS, dOH, and even in those without HR/BP abnormalities. This study shows that orthostatic intolerance symptoms are related to CBF reduction, and that the majority of ME/CFS patients (90%) show an abnormal cerebral flow reduction during orthostatic stress testing. This may have implications for the diagnosis and treatment of ME/CFS patients.


Bone response to titanium alloy implants placed in diabetic rats.
Although dental implants continue to provide consistent and predictable treatment options for most patients, some people with uncontrolled systemic disease may be denied implant treatment. Diabetes is one such disease. According to the U.S. Centers for Disease Control and Prevention, diabetes is a leading cause of blindness, kidney failure, and amputations of the lower extremities. These complications result from microvascular disturbances associated with diabetes. The effect of diabetes on the healing of titanium implants has not been well established. In this study of 32 rats, diabetes was induced in 16 animals by injection of streptozotocin (65 mg/kg); the remaining 16 animals served as controls. Titanium alloy implants were placed in the tibiae of all 32 rats using standard surgical techniques. Implants healed for 14 days. Blood samples were obtained for serum glucose, osteocalcin, and alkaline phosphatase analyses. Implants were retrieved and processed for histomorphometric analyses. Three quantities were measured using light microscopy, video capture, and computer analysis: percent osseointegration (i.e., linear bone interface), associated bone volume percent, and contact frequency. Diabetic animals demonstrated significantly less osseointegration than controls. However, bone volume percent in diabetic animals was about 4 times greater than controls. Biochemical analyses were mixed; diabetic animals demonstrated increased serum osteocalcin levels compared to controls but decreased alkaline phosphatase. Based on the results of this study, it was concluded that the bone response associated with titanium alloy implants in the tibiae of diabetic rats is uniquely different from controls.


Adipokines, adiposity, and bone marrow adipocytes: Dangerous accomplices in multiple myeloma.
Obesity has become a global epidemic influencing the establishment and progression of a wide range of diseases, such as diabetes, cardiovascular disease, and cancer. In 2016, International Agency for Research on Cancer reported that obesity is now associated with 13 different cancers, one of which is multiple myeloma (MM), a destructive cancer of plasma cells that predominantly reside in the bone marrow. Obesity is the accumulation of excess body fat, which causes metabolic, endocrine, immunologic, and inflammatory-like changes. Obesity is usually associated with an increase in visceral and/or subcutaneous fat; however, an additional fat depot that also responds to diet-induced changes is bone marrow adipose tissue (BMAT). There have been several studies over the past few decades that have identified BMAT as a key driver in MM progression. Adipocytes secrete numerous adipokines, such as leptin, adiponectin, resistin, adipsin, and visfatin, which when secreted at normal controlled levels have protective properties. However, in obesity these levels of secretion change, coupled with an increase in adipocyte number and size causing a profound and lasting effect on the bone microenvironment, contributing to MM cell growth, survival, and migration as well as potentially fueling bone destruction. Obesity is a modifiable risk factor making it an attractive option for targeted therapy. This review discusses the link between obesity, monoclonal gammopathy of undetermined significance (a benign condition that precedes MM), and myeloma, and the contribution of key adipokines to disease establishment and progression.


Malignancy in coeliac disease--effect of a gluten free diet.
Two hundred and ten patients with coeliac disease previously reported from this unit were reviewed at the end of 1985 after a further 11 years of follow up. The initial review at the end of 1974 could not demonstrate that a gluten free diet (GFD) prevented these complications, probably because the time on diet was relatively short. The same series has therefore been kept under surveillance with the particular aim of assessing the effects of diet on malignancy after a further prolonged follow up period. Twelve new cancers have occurred: of which one was a carcinoma of the oesophagus and two lymphomas. Thirty nine cancers developed in 38 patients and of 69 deaths, 33 were the result of malignancy. A two-fold relative risk (RR) of cancer was found and was because of an increased risk of cancer of the mouth and pharynx (RR = 9.7, p less than 0.01, 95% confidence interval (CI) = 2.0-28.3), oesophagus (RR = 12.3, p less than 0.01, CI = 2.5-36.5), and of non-Hodgkin's lymphoma (RR = 42.7, p less than 0.001, CI = 19.6-81.4). The results indicate that for coeliac patients who have taken a GFD for five years or more the risk of developing cancer over all sites is not increased when compared with the general population. The risk is increased, however, in those taking a reduced gluten, or a normal diet, with an excess of cancers of the mouth, pharynx and oesophagus (RR = 22.7, p < 0.001), and also of lymphoma (RR = 77.8, p < 0.001). A significant decreasing trend in the excess morbidity rate over increasing use of a GFD was found. The results are suggestive of a protective role for a GFD against malignancy in coeliac disease and give further support for advising all patients to adhere to a strict GFD for life.


Conservation of an intricate circuit for crucial modifications of the tRNAPhe anticodon loop in eukaryotes.
Post-transcriptional tRNA modifications are critical for efficient and accurate translation, and have multiple different roles. Lack of modifications often leads to different biological consequences in different organisms, and in humans is frequently associated with neurological disorders. We investigate here the conservation of a unique circuitry for anticodon loop modification required for healthy growth in the yeast Saccharomyces cerevisiae. S. cerevisiae Trm7 interacts separately with Trm732 and Trm734 to 2'-O-methylate three substrate tRNAs at anticodon loop residues C₃₂ and N₃₄, and these modifications are required for efficient wybutosine formation at m(1)G₃₇ of tRNA(Phe). Moreover, trm7Δ and trm732Δ trm734Δ mutants grow poorly due to lack of functional tRNA(Phe). It is unknown if this circuitry is conserved and important for tRNA(Phe) modification in other eukaryotes, but a likely human TRM7 ortholog is implicated in nonsyndromic X-linked intellectual disability. We find that the distantly related yeast Schizosaccharomyces pombe has retained this circuitry for anticodon loop modification, that S. pombe trm7Δ and trm734Δ mutants have more severe phenotypes than the S. cerevisiae mutants, and that tRNA(Phe) is the major biological target. Furthermore, we provide evidence that Trm7 and Trm732 function is widely conserved throughout eukaryotes, since human FTSJ1 and THADA, respectively, complement growth defects of S. cerevisiae trm7Δ and trm732Δ trm734Δ mutants by modifying C₃₂ of tRNA(Phe), each working with the corresponding S. cerevisiae partner protein. These results suggest widespread importance of 2'-O-methylation of the tRNA anticodon loop, implicate tRNA(Phe) as the crucial substrate, and suggest that this modification circuitry is important for human neuronal development.


Tranexamic acid: a review of its use in the treatment of hyperfibrinolysis.
Tranexamic acid, a synthetic derivative of the amino acid lysine, is an antifibrinolytic agent that acts by binding to plasminogen and blocking the interaction of plasmin(ogen) with fibrin, thereby preventing dissolution of the fibrin clot. Tranexamic acid (Transamin®) is indicated in Japan for use in certain conditions with abnormal bleeding or bleeding tendencies in which local or systemic hyperfibrinolysis is considered to be involved. This article reviews the efficacy and tolerability of tranexamic acid in conditions amenable to antifibrinolytic therapy and briefly overviews the pharmacological properties of the drug. In large, randomized controlled trials, tranexamic acid generally significantly reduced perioperative blood loss compared with placebo in a variety of surgical procedures, including cardiac surgery with or without cardiopulmonary bypass, total hip and knee replacement and prostatectomy. In many instances, tranexamic acid also reduced transfusion requirements associated with surgery. It also reduced blood loss in gynaecological bleeding disorders, such as heavy menstrual bleeding, postpartum haemorrhage and bleeding irregularities caused by contraceptive implants. Tranexamic acid significantly reduced all-cause mortality and death due to bleeding in trauma patients with significant bleeding, particularly when administered early after injury. It was also effective in traumatic hyphaema, gastrointestinal bleeding and hereditary angioneurotic oedema. While it reduces rebleeding in subarachnoid haemorrhage, it may increase ischaemic complications. Pharmacoeconomic analyses predicted that tranexamic acid use in surgery and trauma would be very cost effective and potentially life saving. In direct comparisons with other marketed agents, tranexamic acid was at least as effective as ε-aminocaproic acid and more effective than desmopressin in surgical procedures. It was more effective than desmopressin, etamsylate, flurbiprofen, mefenamic acid and norethisterone, but less effective than the levonorgestrel-releasing intra-uterine device in heavy menstrual bleeding and was as effective as prednisolone in traumatic hyphaema. Tranexamic acid was generally well tolerated. Most adverse events in clinical trials were of mild or moderate severity; severe or serious events were rare. Therefore, while high-quality published evidence is limited for some approved indications, tranexamic acid is an effective and well tolerated antifibrinolytic agent.


Excretion of dengue virus RNA by Aedes aegypti allows non-destructive monitoring of viral dissemination in individual mosquitoes.
Successful transmission of a vector-borne pathogen relies on a complex life cycle in the arthropod vector that requires initial infection of the digestive tract followed by systemic viral dissemination. The time interval between acquisition and subsequent transmission of the pathogen, called the extrinsic incubation period, is one of the most influential parameters of vector-borne pathogen transmission. However, the dynamic nature of this process is often ignored because vector competence assays are sacrificial and rely on end-point measurements. Here, we report that individual Aedes aegypti mosquitoes release large amounts of dengue virus (DENV) RNA in their excreta that can be non-sacrificially detected over time following oral virus exposure. Further, we demonstrate that detection of DENV RNA in excreta from individual mosquitoes is correlated to systemic viral dissemination with high specificity (0.9-1) albeit moderate sensitivity (0.64-0.89). Finally, we illustrate the potential of our finding to detect biological differences in the dynamics of DENV dissemination in a proof-of-concept experiment. Individual measurements of the time required for systemic viral dissemination, a prerequisite for transmission, will be valuable to monitor the dynamics of DENV vector competence, to carry out quantitative genetics studies, and to evaluate the risk of DENV transmission in field settings.


Anastomosing hemangioma of the kidney: radiologic and pathologic distinctions of a kidney cancer mimic.
Anastomosing hemangioma (ah) is a rare subtype of primary vascular tumour that can, clinically and radiologically, present similarly to malignant renal tumours such as renal cell carcinoma (rcc) and angiosarcoma. Rarely seen in the genitourinary system, the ah we report here occurred in a 40-year-old male patient diagnosed initially with rcc based on imaging and successfully treated by laparoscopic left radical nephrectomy, with adrenal sparing and perihilar lymph node dissection. The pathologic diagnosis of ah can be challenging on small biopsy specimens; we therefore opine that it is appropriate to excise these lesions to facilitate diagnosis and definitively exclude common renal cancers. However, in this review, we describe some radiologic and pathologic distinctions between ah and malignant tumours.


Leukosialin (CD43, sialophorin) redistribution in uropods of polarized neutrophils is induced by CD43 cross-linking by antibodies, by colchicine or by chemotactic peptides.
We investigated a possible association of leukosialin (CD43), the major surface sialoglycoprotein of leukocytes, with neutrophil cytoskeleton. We first analysed the solubility of CD43 in Triton X-100 and observed that CD43 of resting neutrophils was mostly soluble. The small proportion of CD43 molecules, which 'spontaneously' precipitated in Triton, appeared associated with F-actin, as demonstrated by the fact that this insolubility did not occur when cells were incubated with cytochalasin B or when F-actin was depolymerized with DNase I in the Triton precipitate. Cell stimulation with anti-CD43 mAb (MEM59) enhanced this CD43-cytoskeleton association. By immunofluorescence as well as by electron microscopy, we observed a redistribution of CD43 on the neutrophil membrane, initially in patches followed by caps, during anti-CD43 cross-linking at 37 degrees C. This capping did not occur at 4 degrees C and was inhibited by cytochalasin B and by a myosin disrupting drug butanedione monoxime, thus providing evidence that the actomyosin contracile sytem is involved in the capping and further suggesting an association of CD43 with the cytoskeleton. Some of the capped cells exhibited a front-tail polarization with CD43 caps located in the uropod at the rear of the cell. Surprisingly, colchicine and the chemotactic factor fNLPNTL which induce neutrophil polarization associated with cell motility, also resulted in a clustering of CD43 in the uropod, independently of a cross-linking of the molecule by mAbs. An intracellular redistribution of F-actin, mainly at the leading front and of myosin in the tail, was observed during CD43 clustering induced by colchicine and in cells polarized by anti-CD43 mAbs cross-linking. We conclude that neutrophil CD43 interacts with the cytoskeleton, either directly or indirectly, to redistribute in the cell uropod under antibodies stimulation or during cell polarization by colchicine, thus highly suggesting that CD43 may be involved in cell polarization.


Update of the Texaco mortality study 1947-93: Part II. Analyses of specific causes of death for white men employed in refining, research, and petrochemicals.
To examine patterns of mortality for specific causes of death with increases in the Texaco mortality study to determine if the patterns are related to employment in the petroleum industry. Mortality patterns by duration of employment in various job groups were examined for mesothelioma, non-Hodgkin's lymphoma, multiple myeloma, cell type specific leukaemia, and brain tumours. Mortality from mesothelioma was examined for the total cohort and for two maintenance groups with the greatest potential for exposure to asbestos. The insulator group had a standardised mortality ratio (SMR) of 3029, and a larger group consisting of insulators, carpenters, labourers, electricians, pipefitters, boiler-makers, and welders had an SMR of 411. The mortalities from mesothelioma increased with increasing duration of employment. Mortality was lower for those first employed after 1950. An analysis of all brain tumours for the total cohort and some job and unit subgroups resulted in an SMR of 178 for those employed on the units related to motor oil and 166 for those employed as laboratory workers. Mortality from brain tumours in both of these job groups was higher for those employed > or = 5 years in the group. An analysis of non-Hodgkin's lymphoma showed no consistent patterns among the various employment groups. Mortality from multiple myeloma was non-significantly increased among people employed on the crude (SMR = 155) and fluid catalytic cracking units (SMR = 198). Leukaemia mortality was not increased for the total cohort, and a cell type analysis of leukaemia mortality for the total cohort showed no significant increases for the major cell types. However, there were significant increases for acute unspecified leukaemia (SMR = 276) and leukaemia of unknown cell type (SMR = 231). Analyses of specific causes of death by duration of employment in various job and process units did not show any patterns which suggest that, other than for mesothelioma, any of these increases in mortalities were likely to have resulted from workplace exposures or from employment at one of the places included in the Texaco mortality study.


Hawaiian skirt: an F-box gene that regulates organ fusion and growth in Arabidopsis.
A fast neutron-mutagenized population of Arabidopsis (Arabidopsis thaliana) Columbia-0 wild-type plants was screened for floral phenotypes and a novel mutant, termed hawaiian skirt (hws), was identified that failed to shed its reproductive organs. The mutation is the consequence of a 28 bp deletion that introduces a premature amber termination codon into the open reading frame of a putative F-box protein (At3g61590). The most striking anatomical characteristic of hws plants is seen in flowers where individual sepals are fused along the lower part of their margins. Crossing of the abscission marker, Pro(PGAZAT):beta-glucuronidase, into the mutant reveals that while floral organs are retained it is not the consequence of a failure of abscission zone cells to differentiate. Anatomical analysis indicates that the fusion of sepal margins precludes shedding even though abscission, albeit delayed, does occur. Spatial and temporal characterization, using Pro(HWS):beta-glucuronidase or Pro(HWS):green fluorescent protein fusions, has identified HWS expression to be restricted to the stele and lateral root cap, cotyledonary margins, tip of the stigma, pollen, abscission zones, and developing seeds. Comparative phenotypic analyses performed on the hws mutant, Columbia-0 wild type, and Pro(35S):HWS ectopically expressing lines has revealed that loss of HWS results in greater growth of both aerial and below-ground organs while overexpressing the gene brings about a converse effect. These observations are consistent with HWS playing an important role in regulating plant growth and development.


Reciprocal analysis of Francisella novicida infections of a Drosophila melanogaster model reveal host-pathogen conflicts mediated by reactive oxygen and imd-regulated innate immune response.
The survival of a bacterial pathogen within a host depends upon its ability to outmaneuver the host immune response. Thus, mutant pathogens provide a useful tool for dissecting host-pathogen relationships, as the strategies the microbe has evolved to counteract immunity reveal a host's immune mechanisms. In this study, we examined the pathogen Francisella novicida and identified new bacterial virulence factors that interact with different parts of the Drosophila melanogaster innate immune system. We performed a genome-wide screen to identify F. novicida genes required for growth and survival within the fly and identified a set of 149 negatively selected mutants. Among these, we identified a class of genes including the transcription factor oxyR, and the DNA repair proteins uvrB, recB, and ruvC that help F. novicida resist oxidative stress. We determined that these bacterial genes are virulence factors that allow F. novicida to counteract the fly melanization immune response. We then performed a second in vivo screen to identify an additional subset of bacterial genes that interact specifically with the imd signaling pathway. Most of these mutants have decreased resistance to the antimicrobial peptide polymyxin B. Characterization of a mutation in the putative transglutaminase FTN_0869 produced a curious result that could not easily be explained using known Drosophila immune responses. By using an unbiased genetic screen, these studies provide a new view of the Drosophila immune response from the perspective of a pathogen. We show that two branches of the fly's immunity are important for fighting F. novicida infections in a model host: melanization and an imd-regulated immune response, and identify bacterial genes that specifically counteract these host responses. Our work suggests that there may be more to learn about the fly immune system, as not all of the phenotypes we observe can be readily explained by its interactions with known immune responses.


MicroRNAs and Targeted Therapies in Non-small Cell Lung Cancer: Minireview.
The discovery of driver oncogene alterations in non-small cell lung cancer (NSCLC), such as EGFR, EML4-ALK, MET and RAS, as well as the identification of their specific targeted inhibitors have led to new opportunities for treatment of this tumor. Drug resistance, intrinsic or acquired, represents the major cause of failure of novel biological agents. MicroRNAs (miRNAs) are a family of small non-coding RNAs that can silence their cognate target genes by specifically binding mRNAs or inhibiting their translation. The recent evidences that several micro-RNAs can modulate the oncogenic driver pathways in NSCLC and that they are involved in drug resistance of their targeted inhibitors, have paved the way for new therapeutic strategies. This minireview aims 1) to explore the potential mechanisms by which key miRNAs may up-regulate or down-regulate specific oncogenic driver pathways; 2) highlight the role of microRNAs in the mechanisms of resistance to targeted therapies; 3) discuss the therapeutic potential by using short-interfering RNAs or artificial miRNAs as anti-cancer therapies.


Sepsis trends: increasing incidence and decreasing mortality, or changing denominator?
Numerous studies suggest that the incidence of sepsis has been steadily increasing over the past several decades while mortality rates are falling. However, reliably assessing trends in sepsis epidemiology is challenging due to changing diagnosis and coding practices over time. Ongoing efforts by clinicians, administrators, policy makers, and patient advocates to increase sepsis awareness, screening, and recognition are leading to more patients being labeled with sepsis. Subjective clinical definitions and heterogeneous presentations also allow for wide discretion in diagnosing sepsis rather than specific infections alone or non-specific syndromes. These factors create a potential ascertainment bias whereby the inclusion of less severely ill patients in sepsis case counts over time leads to a perceived increase in sepsis incidence and decrease in sepsis mortality rates. Analyses that rely on administrative data alone are further confounded by changing coding practices in response to new policies, financial incentives, and efforts to improve documentation. An alternate strategy for measuring sepsis incidence, outcomes, and trends is to use objective and consistent clinical criteria rather than administrative codes or registries to identify sepsis. This is feasible using data routinely found in electronic health record systems, such as blood culture draws and sustained courses of antibiotics to identify infection and laboratory values, vasopressors, and mechanical ventilation to measure acute organ dysfunction. Recent surveillance studies using this approach suggest that sepsis incidence and mortality rates have been essentially stable over the past decade. In this review, we summarize the major epidemiologic studies of sepsis trends, potential biases in these analyses, and the recent change in the surveillance paradigm toward using objective clinical data from electronic health records to more accurately characterize sepsis trends.


Caffeine Use among Active Duty Navy and Marine Corps Personnel.
Data from the National Health and Nutrition Examination Survey (NHANES) indicate 89% of Americans regularly consume caffeine, but these data do not include military personnel. This cross-sectional study examined caffeine use in Navy and Marine Corps personnel, including prevalence, amount of daily consumption, and factors associated with use. A random sample of Navy and Marine Corps personnel was contacted and asked to complete a detailed questionnaire describing their use of caffeine-containing substances, in addition to their demographic, military, and lifestyle characteristics. A total of 1708 service members (SMs) completed the questionnaire. Overall, 87% reported using caffeinated beverages ≥1 time/week, with caffeine users consuming a mean ± standard error of 226 ± 5 mg/day (242 ± 7 mg/day for men, 183 ± 8 mg/day for women). The most commonly consumed caffeinated beverages (% users) were coffee (65%), colas (54%), teas (40%), and energy drinks (28%). Multivariable logistic regression modeling indicated that characteristics independently associated with caffeine use (≥1 time/week) included older age, white race/ethnicity, higher alcohol consumption, and participating in less resistance training. Prevalence of caffeine use in these SMs was similar to that reported in civilian investigations, but daily consumption (mg/day) was higher.


Estimating patient-specific and anatomically correct reference model for craniomaxillofacial deformity via sparse representation.
A significant number of patients suffer from craniomaxillofacial (CMF) deformity and require CMF surgery in the United States. The success of CMF surgery depends on not only the surgical techniques but also an accurate surgical planning. However, surgical planning for CMF surgery is challenging due to the absence of a patient-specific reference model. Currently, the outcome of the surgery is often subjective and highly dependent on surgeon's experience. In this paper, the authors present an automatic method to estimate an anatomically correct reference shape of jaws for orthognathic surgery, a common type of CMF surgery. To estimate a patient-specific jaw reference model, the authors use a data-driven method based on sparse shape composition. Given a dictionary of normal subjects, the authors first use the sparse representation to represent the midface of a patient by the midfaces of the normal subjects in the dictionary. Then, the derived sparse coefficients are used to reconstruct a patient-specific reference jaw shape. The authors have validated the proposed method on both synthetic and real patient data. Experimental results show that the authors' method can effectively reconstruct the normal shape of jaw for patients. The authors have presented a novel method to automatically estimate a patient-specific reference model for the patient suffering from CMF deformity.


How do people think about interdependence? A multidimensional model of subjective outcome interdependence.
Interdependence is a fundamental characteristic of social interactions. Interdependence Theory states that 6 dimensions describe differences between social situations. Here we examine if these 6 dimensions describe how people think about their interdependence with others in a situation. We find that people (in situ and ex situ) can reliably differentiate situations according to 5, but not 6, dimensions of interdependence: (a) mutual dependence, (b) power, (c) conflict, (d) future interdependence, and (e) information certainty. This model offers a unique framework for understanding how people think about social situations compared to another recent model of situation construal (DIAMONDS). Furthermore, we examine factors that are theorized to shape perceptions of interdependence, such as situational cues (e.g., nonverbal behavior) and personality (e.g., HEXACO and Social Value Orientation). We also study the implications of subjective interdependence for emotions and cooperative behavior during social interactions. This model of subjective interdependence explains substantial variation in the emotions people experience in situations (i.e., happiness, sadness, anger, and disgust), and explains 24% of the variance in cooperation, above and beyond the DIAMONDS model. Throughout these studies, we develop and validate a multidimensional measure of subjective outcome interdependence that can be used in diverse situations and relationships-the Situational Interdependence Scale (SIS). We discuss how this model of interdependence can be used to better understand how people think about social situations encountered in close relationships, organizations, and society. (PsycINFO Database Record


Cardioprotective and anti-oxidant effects of the terpenoid constituents of Ginkgo biloba extract (EGb 761).
Hemodynamic and electron spin resonance analyses were used to assess the in vivo and in vitro cardioprotective and antioxidant effects of therapeutically relevant doses of Ginkgo biloba extract (EGb 761) and its terpenoid constituents (ginkgolides A and B, bilobalide) in the rat. Significant anti-ischemic effects, indicating improved myocardial functional recovery, were observed after repeated (15-day) oral treatments with both EGb 761 (60 mg/kg/day) and ginkgolide A (4 mg/kg/day), as compared to placebo. In vitro pre- and post-ischemic perfusion of hearts in the presence of the ginkgolides A and B (both at 0.05 microgram/ml) or bilobalide (0.15 microgram/ml), but not EGb 761 (5 micrograms/ml), significantly improved all hemodynamic parameters. Post-ischemic levels of the 5,5-dimethyl-1-pyrroline N-oxide (DMPO)/hydroxyl radical spin-adduct (DMPO-OH) in coronary effluents were significantly decreased after in vivo oral treatments or after in vitro perfusion with EGb 761 or the terpenes, the most effective compound being ginkgolide A. As the presence of the terpenes did not influence the formation of the superoxide/DMPO adduct or DMPO-OH in acellular tests with superoxide and hydroxyl radical generators, their cardioprotective effects appear to involve an inhibition of free radical formation rather than direct free radical scavenging.


Small-Format Drug Conjugates: A Viable Alternative to ADCs for Solid Tumours?
Antibody-Drug Conjugates (ADCs) have been through multiple cycles of technological innovation since the concept was first practically demonstrated ~40 years ago. Current technology is focusing on large, whole immunoglobulin formats (of which there are approaching 100 in clinical development), many with site-specifically conjugated payloads numbering 2 or 4. Despite the success of trastuzumab-emtansine in breast cancer, ADCs have generally failed to have an impact in solid tumours, leading many to explore alternative, smaller formats which have better penetrating properties as well as more rapid pharmacokinetics (PK). This review describes research and development progress over the last ~10 years obtained from the primary literature or conferences covering over a dozen different smaller format-drug conjugates from 80 kDa to around 1 kDa in total size. In general, these agents are potent in vitro, particularly more recent ones incorporating ultra-potent payloads such as auristatins or maytansinoids, but this potency profile changes when testing in vivo due to the more rapid clearance. Strategies to manipulate the PK properties, whilst retaining the more effective tumour penetrating properties could at last make small-format drug conjugates viable alternative therapeutics to the more established ADCs.


Inhibitor of apoptosis-stimulating protein of p53 (iASPP) prevents senescence and is required for epithelial stratification.
Inhibitor of apoptosis-stimulating protein of p53 (iASPP) is the most ancient member of the ASPP family of proteins and an evolutionarily conserved inhibitor of p53. iASPP is also a binding partner and negative regulator of p65RelA. Because p65RelA and the p53 family members often have opposite effects in controlling cell fate, it is important to understand the cellular context in which iASPP can regulate their activities. To address this question and to study the biological importance of iASPP in vivo, we generated a transgenic mouse in which iASPP expression is controlled by the Cre/loxP recombination system. We observed that iASPP is able to prevent premature cellular senescence in mouse embryonic fibroblasts. iASPP loss resulted in increased differentiation of primary keratinocytes both in vitro and in vivo. In stratified epithelia, nuclear iASPP often colocalized with p63 in the nuclei of basal keratinocytes. Consistent with this, iASPP bound p63 and inhibited the transcriptional activity of both TAp63α and ΔNp63α in vitro and influenced the expression level of p63-regulated genes such as loricrin and involucrin in vivo. In contrast, under the same conditions, p65RelA was frequently expressed as a cytoplasmic protein in the suprabasal layers of stratified epithelia and rarely colocalized with nuclear iASPP. Thus, iASPP is likely to control epithelial stratification by regulating p63's transcriptional activity, rather than p65RelA's. This study identifies iASPP as an inhibitor of senescence and a key player in controlling epithelial stratification.


Seroprevalence and HIV-associated factors among adults with severe mental illness - a vulnerable population.
BACKGROUND: Adults with severe mental illness (SMI) display an increased prevalence of HIV compared with the general population. Recommendations for provider-initiated testing in South Africa lack robust evidence because the studies - mainly from low-prevalence regions - overestimate the risk of HIV among adults with SMI. OBJECTIVE: We aimed to assess whether the mentally ill are a vulnerable population in South Africa. METHODS: All new admissions to an acute psychiatric ward from July to December 2000 were tested for HIV anonymously and the results linked with socio-demographic and clinical data. We did a restricted analysis of black females from a population-based survey of black females with SMI. RESULTS: There were 216 admissions, of whom 206 were included in the analysis. The seroprevalence of HIV-1 was 29.1% (confidence interval 27.8 - 32.4); seroprevalence of HIV among the women was 40%. The following predicted HIV positivity: female (odds ratio (OR) 3.5 (1.7 - 6.9)), infections of the chest or central nervous system (OR 3.2 (1.4 - 7.5)), age group 30 - 39 years (OR 2.3 (1.1 - 4.8)) and aggression on admission. The age and sex ratios among the SMI group were similar to the general population. Adults with SMI have an almost three times greater prevalence of HIV than the general population, after controlling for age and gender. CONCLUSIONS: Adults with SMI are a vulnerable population; therefore, provider-initiated HIV testing and other prevention and treatment programmes must be tailored to their needs.


The role of metals in mammalian olfaction of low molecular weight organosulfur compounds.
Covering: up to the end of 2017While suggestions concerning the possible role of metals in olfaction and taste date back 50 years, only recently has it been possible to confirm these proposals with experiments involving individual olfactory receptors (ORs). A detailed discussion of recent experimental results demonstrating the key role of metals in enhancing the response of human and other vertebrate ORs to specific odorants is presented against the backdrop of our knowledge of how the sense of smell functions both at the molecular and whole animal levels. This review emphasizes the role of metals in the detection of low molecular weight thiols, sulfides, and other organosulfur compounds, including those found in strong-smelling animal excretions and plant volatiles, and those used in gas odorization. Alternative theories of olfaction are described, with evidence favoring the modified "shape" theory. The use of quantum mechanical/molecular modeling (QM/MM), site-directed mutagenesis and saturation-transfer-difference (STD) NMR is discussed, providing support for biological studies of mouse and human receptors, MOR244-3 and OR OR2T11, respectively. Copper is bound at the active site of MOR244-3 by cysteine and histidine, while cysteine, histidine and methionine are involved with OR2T11. The binding pockets of these two receptors are found in different locations in the three-dimensional seven transmembrane models. Another recently deorphaned human olfactory receptor, OR2M3, highly selective for a thiol from onions, and a broadly-tuned thiol receptor, OR1A1, are also discussed. Other topics covered include the effects of nanoparticles and heavy metal toxicants on vertebrate and fish ORs, intranasal zinc products and the loss of smell (anosmia).


Cognitive Recovery by Decade in Healthy 40- to 80-Year-Old Volunteers After Anesthesia Without Surgery.
Postoperative delirium and postoperative cognitive dysfunction are the most common complications for older surgical patients. General anesthesia may contribute to the development of these conditions, but there are little data on the association of age with cognitive recovery from anesthesia in the absence of surgery or underlying medical condition. We performed a single-center cohort study of healthy adult volunteers 40 to 80 years old (N = 71, mean age 58.5 years, and 44% women) with no underlying cognitive dysfunction. Volunteers underwent cognitive testing before and at multiple time points after 2 hours of general anesthesia consisting of propofol induction and sevoflurane maintenance, akin to a general anesthetic for a surgical procedure, although no procedure was performed. The primary outcome was time to recovery to cognitive baseline on the Postoperative Quality of Recovery Scale (PQRS) within 30 days of anesthesia. Secondary cognitive outcomes were time to recovery on in-depth neuropsychological batteries, including the National Institutes of Health Toolbox and well-validated paper-and-pencil tests. The primary hypothesis is that time to recovery of cognitive function after general anesthesia increases across decades from 40 to 80 years of age. We examined this with discrete-time logit regression (for the primary outcome) and linear mixed models for interactions of age decade with time postanesthesia (for secondary outcomes). There was no association between age group and recovery to baseline on the PQRS; 36 of 69 (52%) recovered within 60-minute postanesthesia and 63 of 69 (91%) by day 1. Hazard ratios (95% confidence interval) for each decade compared to 40- to 49-year olds were: 50 to 59 years, 1.41 (0.50-4.03); 60 to 69 years, 1.03 (0.35-3.00); and 70 to 80 years, 0.69 (0.25-1.88). There were no significant differences between older decades relative to the 40- to 49-year reference decade in recovery to baseline on secondary cognitive measures. Recovery of cognitive function to baseline was rapid and did not differ between age decades of participants, although the number in each decade was small. These results suggest that anesthesia alone may not be associated with cognitive recovery in healthy adults of any age decade.


Pavlovian-to-instrumental transfer effects in the nucleus accumbens relate to relapse in alcohol dependence.
In detoxified alcohol-dependent patients, alcohol-related stimuli can promote relapse. However, to date, the mechanisms by which contextual stimuli promote relapse have not been elucidated in detail. One hypothesis is that such contextual stimuli directly stimulate the motivation to drink via associated brain regions like the ventral striatum and thus promote alcohol seeking, intake and relapse. Pavlovian-to-Instrumental-Transfer (PIT) may be one of those behavioral phenomena contributing to relapse, capturing how Pavlovian conditioned (contextual) cues determine instrumental behavior (e.g. alcohol seeking and intake). We used a PIT paradigm during functional magnetic resonance imaging to examine the effects of classically conditioned Pavlovian stimuli on instrumental choices in n = 31 detoxified patients diagnosed with alcohol dependence and n = 24 healthy controls matched for age and gender. Patients were followed up over a period of 3 months. We observed that (1) there was a significant behavioral PIT effect for all participants, which was significantly more pronounced in alcohol-dependent patients; (2) PIT was significantly associated with blood oxygen level-dependent (BOLD) signals in the nucleus accumbens (NAcc) in subsequent relapsers only; and (3) PIT-related NAcc activation was associated with, and predictive of, critical outcomes (amount of alcohol intake and relapse during a 3 months follow-up period) in alcohol-dependent patients. These observations show for the first time that PIT-related BOLD signals, as a measure of the influence of Pavlovian cues on instrumental behavior, predict alcohol intake and relapse in alcohol dependence.


Coupling of photoactivatable glycolipid probes to apolipoproteins A-I and A-II in human high density lipoproteins 2 and 3.
High density lipoprotein (HDL) from human serum was subfractionated into HDL2 and HDL3 by rate-zonal density gradient ultracentrifugation. The orientation of apoproteins (apo) A-I and A-II in these subfractions was investigated by use of the photosensitive glycolipid probes, 2-(4-azido-2-nitrophenoxy)-palmitoyl[1-14C]glucosamine (compound A) and 12-(4-azido-2-nitrophenoxy)-stearoyl[1-14C]glucosamine (compound B). Both probes were added to the HDL-structures in a ratio of two or three probe molecules per particle and were photoactivated by irradiation at a wavelength above 340 nm. After delipidation the probe-apoprotein adducts were analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Both the "shallow" probe (compound A) and the "depth" probe (compound B) were coupled for 10-14% (of the label added) to apoA-I and apoA-II from HDL3 and for about 6% to apoA-I and apoA-II from HDL2. By taking into account the relative amounts of apoA-I and apoA-II, it was estimated that the "shallow" probe labeled apoA-I 40% more effectively than apoA-II in both HDL2 and HDL3; the "depth" probe labeled apoA-I and apoA-II equally well in both subfractions. The data suggest that towards the surface HDL2 and HDL3 contain a relatively larger portion of apoA-I than apoA-II, whilst towards the core both subfractions are occupied by an equal portion of apoA-I and apoA-II. Application of these photolabels has failed to point out differences in the structural organization of HDL2 and HDL3.


Quantification and analysis of intramolecular interactions.
Non-covalent interactions play a prominent role in chemistry and biology. While a myriad of theoretical methods have been devised to quantify and analyze intermolecular interactions, the theoretical toolbox for the intramolecular analogues is much scarcer. Yet interactions within molecules govern fundamental phenomena as illustrated by the energetic differences between structural isomers. Their accurate quantification is of utmost importance. This paper gives an overview of the most common approaches able to probe intramolecular interactions and stresses both their characteristics and limitations. We finally introduce our recent theoretical approach, which represents the first step towards the development of an intramolecular version of Symmetry-Adapted Perturbation Theory (SAPT).


Gamma-Diketone central neuropathy: quantitative analyses of cytoskeletal components in myelinated axons of the rat rubrospinal tract.
Loss of axon caliber is a primary component of gamma-diketone neuropathy [LoPachin RM, DeCaprio AP. gamma-Diketone central neuropathy: axon atrophy and the role of cytoskeletal protein adduction. Toxicol Appl Pharmacol 2004;199:20-34]. It is possible that this effect is mediated by changes in the density of cytoskeletal components and corresponding spatial relationships. To examine this possibility, morphometric methods were used to quantify the effects of 2,5-hexanedione (HD) intoxication on neurofilament-microtubule densities and nearest neighbor distances in myelinated rubrospinal axons. Rats were exposed to HD at one of two daily dose-rates (175 or 400 mg/kg per day, gavage) until a moderate level of neurotoxicity was achieved (99 or 21 days of intoxication, respectively) as determined by gait analysis and measurements of hindlimb grip strength. Results indicate that, regardless of dose-rate, HD intoxication did not cause changes in axonal neurofilament (NF) density, but did significantly increase microtubule (MT) density. No consistent alterations in interneurofilament or NF-MT distances were detected by ultrastructural morphometric analyses. These data suggest that the axon atrophy induced by HD was not mediated by major disruptions of stationary cytoskeletal organization. Recent biochemical studies of spinal cord from HD intoxicated rats showed that, although the NF protein content in the stationary cytoskeleton (polymer fraction) was not affected, the mobile subunit pool was depleted substantially [LoPachin RM, He D, Reid ML, Opanashuk LA. 2,5-Hexanedione-induced changes in the monomeric neurofilament protein content of rat spinal cord fractions. Toxicol Appl Pharmacol 2004;198:61-73]. The stability of the polymer fraction during HD intoxication is consistent with the absence of significant ultrastructural modifications noted in the present study. Together, these findings implicate loss of mobile NF proteins as the primary mechanism of axon atrophy.


Accelerated Electrons Observed Down to <7 keV in a NuSTAR Solar Microflare.
We report the detection of emission from a nonthermal electron distribution in a small solar microflare (GOES class A5.7) observed by the Nuclear Spectroscopic Telescope Array, with supporting observation by the Reuven Ramaty High Energy Solar Spectroscopic Imager (RHESSI). The flaring plasma is well accounted for by a thick-target model of accelerated electrons collisionally thermalizing within the loop, akin to the "coronal thick-target" behavior occasionally observed in larger flares. This is the first positive detection of nonthermal hard X-rays from the Sun using a direct imager (as opposed to indirectly imaging instruments). The accelerated electron distribution has a spectral index of 6.3 ± 0.7, extends down to at least 6.5 keV, and deposits energy at a rate of ~2 × 1027 erg s-1, heating the flare loop to at least 10 MK. The existence of dominant nonthermal emission in X-rays down to <5 keV means that RHESSI emission is almost entirely nonthermal, contrary to what is usually assumed in RHESSI spectroscopy. The ratio of nonthermal to thermal energies is similar to that of large flares, in contrast to what has been found in previous studies of small RHESSI flares. We suggest that a coronal thick target may be a common property of many small microflares based on the average electron energy and collisional mean free path. Future observations of this kind will enable understanding of how flare particle acceleration changes across energy scales, and will aid the push toward the observational regime of nanoflares, which are a possible source of significant coronal heating.


Frequency and Management of Hemorrhagic Malignant Wounds: A Retrospective, Single-Center, Observational Study.
The prevalence of bleeding episodes in malignant wounds (MW) is poorly documented, with no distinction between minor and potentially severe bleedings. This affects the quality of care. Assessing the frequency and management of hemorrhagic malignant wounds at Institut Curie hospital, an anti cancer center. Retrospective study conducted from the medical records of patients followed up by the Research and Wound Care Unit from Curie Institute (Paris, France), between 2017 and 2018. Patients >18 years of age, seen at least once by the Unit, and with an MW > 10 cm2 were included. Ninety patients were included, 74.4% female and 25.6% male, with a median age of 64 years (32-92). The most frequent etiologies were breast cancer (52.2%), sarcomas (12.2%), squamous cell carcinoma ear, nose and throat (11%), and pelvic cancer (8.9%). The median survival of patients after their first consultation was 5.6 months (95% CI: 4.6-8.4). Minor bleedings were observed in 38.9% of situations. Bleedings were significantly higher in malignant fungating wounds (P < 0.01). They were treated by the application of alginate or nonadherent dressings. The presence of at least one minor bleeding significantly increased the risk of more severe bleedings (P < 0.001). Hemorrhagic episodes were reported in 18.9% of patients, and 2.2% of patients died as a result of these bleeding episodes. Hemorrhages were fully controlled by hemostatic dressings in 70.6% of cases. The appearance of bleeding (minor or hemorrhagic) was significantly associated with survival (P < 0.001). MWs with bleedings appear to be associated with a poor prognosis and could be a reason for early palliative care even if the patient's general condition is preserved. Palliative care must incorporate wound care skills to provide the most appropriate solutions to this anxiety-provoking symptom.


Adaptation to sensory loss.
The human brain has the remarkable ability to adapt to changes in its environment by benefiting from its 'plastic' properties. Following brain injury, the amputation of a limb, or the loss of a sensory input such as peripheral blindness, brain circuitry often seems to be able to reorganize itself in order to compensate for the handicap by being recruited to carry out tasks not associated with their prior 'default' functioning. The purpose of this review is to illustrate the brain's remarkable ability to adapt to changes in its environment, particularly when it is faced with a sensory loss. Two excellent models to study this phenomenon are provided by blind and deaf individuals. In both cases, studies have shown that they appear to compensate for the loss of sensory input with enhanced abilities in their remaining senses. These behavioral modifications are often coupled with changes in cerebral processing, generally in the form of crossmodal recruitment of deaffarented primary and secondary sensory areas. We will also discuss the possible mechanisms underlying these changes and whether the functional topography of these regions present in unimpaired individuals is preserved in blindness and deafness. The notion of a critical period for plastic changes will also be discussed and its importance will be shown to be twofold. On the one hand, the functional relevance of crossmodal processing appears to decrease as a function of the age of onset of the deficiency. On the other hand, the more cortical reorganization takes place, the less likely brain areas will be able to process input from its original sensory modality. This is especially important for deaf individuals as auditory input can now be restored thanks to cochlear implants. Copyright © 2010 John Wiley & Sons, Ltd. For further resources related to this article, please visit the WIREs website.


Evidence for medium chain triglycerides in the treatment of primary intestinal lymphangiectasia.
Primary intestinal lymphangiectasia is an uncommon congenital anomaly. It is an intrinsic abnormality of the intestinal lymphatics system. Over the years, various treatment options such as diuretics, albumin transfusions and a medium chain triglycerides (MCT) diet as well as surgical options such as resection of isolated segments and peritoneal-venous shunts have been used. An MCT diet, which is a low fat, high protein diet, is increasingly used in the management of this anomaly. The aim was to review the evidence for medium chain triglycerides as a therapeutic option in patients with primary intestinal lymphangiectasia. A literature search was performed and individual case details were extracted. We found 55 cases, of which 3 were from our own institute. The cases were divided in 2 groups: Group A (n=27) consisted of patients treated with MCT, and Group B (n=28) consisted patients not treated with MCT. Cases were analysed for symptomatic response to MCT as well as mortality. 17 of 27 cases (63%) treated with MCT had complete resolution of symptoms while only 10 of 28 (35.7%) patients in group B showed complete resolution. Mortality for Group A was 1 out of 27 (3.7%), while mortality in group B was 5 of 28 (17.85%) patients. We conclude that, although an MCT diet is not completely curative in all cases, it does improve the symptoms of primary intestinal lymphangiectasia and reduces mortality. Hence it is a valid option in the paediatric age group.


Involvement of 90-kuD ribosomal S6 kinase in collagen type I expression in rat hepatic fibrosis.
To investigate the relationship between 90-kuD ribosomal S6 kinase (p90RSK) and collagen type I expression during the development of hepatic fibrosis in vivo and in vitro. Rat hepatic fibrosis was induced by intraperitoneal injection of dimethylnitrosamine. The protein expression and cell location of p90RSK and their relationship with collagen type I were determined by co-immunofluoresence and confocal microscopy. Subsequently, RNAi strategy was employed to silence p90RSK mRNA expression in HSC-T6, an activated hepatic stellate cell (HSC) line. The expression of collagen type I in HSC-T6 cells was assessed by Western blotting and real-time polymerase chain reaction. Furthermore, HSCs were transfected with expression vectors or RNAi constructs of p90RSK to increase or decrease the p90RSK expression, then collagen type I promoter activity in the transfected HSCs was examined by reporter assay. Lastly HSC-T6 cells transfected with p90RSK siRNA was treated with or without platelet-derived growth factor (PDGF)-BB at a final concentration of 20 microg/L and the cell growth was determined by MTS conversion. In fibrotic liver tissues, p90RSK was over-expressed in activated HSCs and had a significant positive correlation with collagen type I levels. In HSC-T6 cells transfected with RNAi targeted to p90RSK, the expression of collagen type I was down-regulated (61.8% in mRNA, P < 0.01, 89.1% in protein, P < 0.01). However, collagen type I promoter activity was not increased with over-expression of p90RSK and not decreased with low expression either, compared with controls in the same cell line (P = 0.076). Furthermore, p90RSK siRNA exerted the inhibition of HSC proliferation, and also abolished the effect of PDGF on the HSC proliferation. p90RSK is over-expressed in activated HSCs and involved in regulating the abnormal expression of collagen type I through initiating the proliferation of HSCs.


Genome-wide association study identifies loci at ATF7IP and KLK2 associated with percentage of circulating free PSA.
Percentage of free-to-total prostate-specific antigen (%fPSA) is an independent predictor of risk for prostate cancer among men with modestly elevated level of total PSA (tPSA) in blood. Physiological and pathological factors have been shown to influence the %fPSA value and diagnostic accuracy. To evaluate genetic determinants of %fPSA, we conducted a genome-wide association study of serum %fPSA by genotyping 642,584 single nucleotide polymorphisms (SNPs) in 3192 men of European ancestry, each with a tPSA level of 2.5 to 10 ng/ml, that were recruited in the REduction by DUtasteride of Prostate Cancer Events study. Single nucleotide polymorphisms (SNPs) with P < 10(-5) were further evaluated among the controls of a population-based case-control study in Sweden (2899 prostate cancer cases and 1722 male controls), including 464 controls having tPSA levels of 2.5 to 10 ng/ml. We identified two loci that were associated with %fPSA at a genome-wide significance level (P <5 x 10(-8)). The first associated SNP was rs3213764 (P = 6.45 x 10(-10)), a nonsynonymous variant (K530R) in the ATF7IP gene at 12p13. This variant was also nominally associated with tPSA (P = .015). The second locus was rs1354774 (P = 1.25 x 10(-12)), near KLK2 at 19q13, which was not associated with tPSA levels, and is separate from the rs17632542 locus at KLK3 that was previously associated with tPSA levels and prostate cancer risk. Neither rs3213764 nor rs1354774 was associated with prostate cancer risk or aggressiveness. These findings demonstrate that genetic variants at ATF7IP and KLK2 contribute to the variance of %fPSA.


In Vitro High-Content Imaging-Based Phenotypic Analysis of Bronchial 3D Organotypic Air-Liquid Interface Cultures.
High-content imaging (HCI) is a powerful method for quantifying biological effects in vitro. Historically, HCI has been applied to adherent cells growing in monolayers. With the advent of confocal versions of HCI devices, researchers now have the option of performing analyses on 3D cell cultures. However, some obstacles remain in integrating the third dimension, such as limited light penetration and less sophisticated image analysis. Here, we report the development of an HCI technique for imaging human bronchial 3D organotypic air-liquid interface (ALI) cultures (hBR-ALI). In this method, we monitored differentiation status through HCI evaluation markers representative of ciliated epithelial cells and goblet cells (Muc5AC [mucin 5AC]). As a second use case for demonstrating the utility of this technique, we induced goblet cell hyperplasia in hBR-ALI by using interleukin (IL)-13. Our results demonstrate the utility of the HCI technique for imaging hBR-ALI grown on Transwell inserts. This technique may be expanded to other cell culture systems, such as skin epithelia and 3D intestinal systems.


A quick assay for monitoring recombinant hirudin during cardiopulmonary bypass in patients with heparin-induced thrombocytopenia type II : adaptation of the ecarin clotting time to the act II device.
Recombinant hirudin is increasingly advocated as a promising alternative anticoagulation for patients with heparin-induced thrombocytopenia type II during cardiopulmonary bypass. This requires monitoring of the ecarin clotting time. No commercial ecarin clotting time assay is available for clinical use. We adapted the ecarin clotting time to the easy-to-handle ACT II device. Three different concentrations of the ecarin reagent (20, 10, 5 U/mL) were investigated as preliminary studies. Standard calibration curves were constructed for concentrations of recombinant hirudin ranging from 0 to 5 microgram/mL. In vivo samples were collected from patients with heparin-induced thrombocytopenia type II who underwent cardiopulmonary bypass, and the values were compared with the values obtained by the chromogenic method. The final concentration for the assay of 5 IU/mL ecarin was further assessed in vitro for reproducibility and the influence of variations in hematocrit, platelet count, and procoagulants. All three concentrations of ecarin revealed linearity to 5 microgram/mL concentrations of recombinant hirudin. The ecarin concentration of 5 U/mL revealed the best correlation (0.87) to the laboratory method, was reproducible over the whole recombinant hirudin range, and was not influenced by the variations in the in vitro setup. The ACT II/ecarin clotting time with an ecarin concentration of 5 U/mL is a simple and reliable assay for monitoring recombinant hirudin during cardiopulmonary bypass. Use of this assay allows a wider use of recombinant hirudin in patients with heparin-induced thrombocytopenia type II during bypass and thereby may contribute to the safer management of these patients.


Subxiphoid pericardiastomy in the management of pericardial effusions.
Subxiphoid pericardiostomy for diagnosis and treatment of pericardial effusion was used in 21 patients. Total evacuation of the pericardial contents, direct inspection to break down loculations, simultaneous biopsies of the pericardium and pericardial fluid samples for diagnostic tests were achieved while avoiding the need for repeated pericardiocentesis and more invasive and difficult open drainage methods. Complete drainage without recurrence was obtained in 19 patients with one death and recurrence of effusion in another one. Two of these 19 cases developed constrictive pericarditis on follow-up and required a pericardiectomy. No other complications were encountered. The procedure can be done safely under local anaesthesia for all types of pericardial effusions providing prompt and long term relief of the abnormal haemodynamics.


Intravenous Iron Dosing and Infection Risk in Patients on Hemodialysis: A Prespecified Secondary Analysis of the PIVOTAL Trial.
Experimental and observational studies have raised concerns that giving intravenous (IV) iron to patients, such as individuals receiving maintenance hemodialysis, might increase the risk of infections. The Proactive IV Iron Therapy in Haemodialysis Patients (PIVOTAL) trial randomized 2141 patients undergoing maintenance hemodialysis for ESKD to a high-dose or a low-dose IV iron regimen, with a primary composite outcome of all-cause death, heart attack, stroke, or hospitalization for heart failure. Comparison of infection rates between the two groups was a prespecified secondary analysis. Secondary end points included any infection, hospitalization for infection, and death from infection; we calculated cumulative event rates for these end points. We also interrogated the interaction between iron dose and vascular access (fistula versus catheter). We found no significant difference between the high-dose IV iron group compared with the lose-dose group in event rates for all infections (46.5% versus 45.5%, respectively, which represented incidences of 63.3 versus 69.4 per 100 patient years, respectively); rates of hospitalization for infection (29.6% versus 29.3%, respectively) also did not differ. We did find a significant association between risk of a first cardiovascular event and any infection in the previous 30 days. Compared with patients undergoing dialysis with an arteriovenous fistula, those doing so via a catheter had a higher incidence of having any infection, hospitalization for infection, or fatal infection, but IV iron dosing had no effect on these outcomes. The high-dose and low-dose IV iron groups exhibited identical infection rates. Risk of a first cardiovascular event strongly associated with a recent infection.


Urine carcinoembryonic antigen levels are more useful than serum levels for early detection of Bilharzial and non-Bilharzial urinary bladder carcinoma: observations of 43 Egyptian cases.
Both urinary bilharziasis and urothelial neoplasia are associated with increased production of tissue carcinoembryonic antigen (CEA). Urine and serum CEA were determined in 43 patients with urinary bladder carcinoma including 22 post bilharzial and 21 nonbiharzial cases, in addition to 10 normal control cases. A significant increase was detected in both urine and serum CEA levels with bladder carcinoma compared to control cases. Urinary CEA was significantly elevated in 86% of bilharzial, versus 62% in nonbilharzial bladder carcinoma. Only 10.5% of control cases had urinary CEA elevation. The mean urinary CEA in bilharzial, was higher than that of nonbilharzial carcinoma, but the difference was not statistically significant. There was a definite relationship between urine CEA and the stage of malignancy; the higher the stage, the higher the level of urine CEA. No relationship could be detected between the stage of malignancy and serum CEA, or between the grades of malignancy and urine or serum CEA levels. Urinary CEA is more useful than serum CEA in the early detection of urotherlial carcinoma particularly if provoked by bilharziasis. Its level is also correlated with the tumor stage.


Retrospective data collection and analytical techniques for patient safety studies.
To enhance patient safety, data about actual clinical events must be collected and scrutinized. This paper has two purposes. First, it provides an overview of some of the methods available to collect and analyze retrospective data about medical errors, near misses, and other relevant patient safety events. Second, it introduces a methodological approach that focuses on non-routine events (NRE), defined as all events that deviate from optimal clinical care. In intermittent in-person surveys of anesthesia providers, 75 of 277 (27%) recently completed anesthetic cases contained a non-routine event (98 total NRE). Forty-six of the cases (17%) had patient impact while only 20 (7%) led to patient injury. In contrast, in the same hospitals over a two-year period, we collected event data on 135 cases identified with traditional quality improvement processes (event incidence of 0.7-2.7%). In these quality improvement cases, 120 (89%) had patient impact and 74 (55%) led to patient injury. Preliminary analyses not only illustrate some of the analytical methods applicable to safety data but also provide insight into the potential value of the non-routine event approach for the early detection of risks to patient safety before serious patient harm occurs.


Four chromosome scale genomes and a pan-genome annotation to accelerate pecan tree breeding.
Genome-enabled biotechnologies have the potential to accelerate breeding efforts in long-lived perennial crop species. Despite the transformative potential of molecular tools in pecan and other outcrossing tree species, highly heterozygous genomes, significant presence-absence gene content variation, and histories of interspecific hybridization have constrained breeding efforts. To overcome these challenges, here, we present diploid genome assemblies and annotations of four outbred pecan genotypes, including a PacBio HiFi chromosome-scale assembly of both haplotypes of the 'Pawnee' cultivar. Comparative analysis and pan-genome integration reveal substantial and likely adaptive interspecific genomic introgressions, including an over-retained haplotype introgressed from bitternut hickory into pecan breeding pedigrees. Further, by leveraging our pan-genome presence-absence and functional annotation database among genomes and within the two outbred haplotypes of the 'Lakota' genome, we identify candidate genes for pest and pathogen resistance. Combined, these analyses and resources highlight significant progress towards functional and quantitative genomics in highly diverse and outbred crops.


Principal stratification designs to estimate input data missing due to death.
We consider studies of cohorts of individuals after a critical event, such as an injury, with the following characteristics. First, the studies are designed to measure "input" variables, which describe the period before the critical event, and to characterize the distribution of the input variables in the cohort. Second, the studies are designed to measure "output" variables, primarily mortality after the critical event, and to characterize the predictive (conditional) distribution of mortality given the input variables in the cohort. Such studies often possess the complication that the input data are missing for those who die shortly after the critical event because the data collection takes place after the event. Standard methods of dealing with the missing inputs, such as imputation or weighting methods based on an assumption of ignorable missingness, are known to be generally invalid when the missingness of inputs is nonignorable, that is, when the distribution of the inputs is different between those who die and those who live. To address this issue, we propose a novel design that obtains and uses information on an additional key variable-a treatment or externally controlled variable, which if set at its "effective" level, could have prevented the death of those who died. We show that the new design can be used to draw valid inferences for the marginal distribution of inputs in the entire cohort, and for the conditional distribution of mortality given the inputs, also in the entire cohort, even under nonignorable missingness. The crucial framework that we use is principal stratification based on the potential outcomes, here mortality under both levels of treatment. We also show using illustrative preliminary injury data that our approach can reveal results that are more reasonable than the results of standard methods, in relatively dramatic ways. Thus, our approach suggests that the routine collection of data on variables that could be used as possible treatments in such studies of inputs and mortality should become common.


A glimpse into the past and predictions for the future: the molecular evolution of the tuberculosis agent.
Recent advances in genomics and molecular biology are providing an excellent opportunity to get a glimpse into the past, to examine the present, and to predict the future evolution of pathogenic mycobacteria, and in particular that of Mycobacterium tuberculosis, the agent of human tuberculosis. The recent availability of genome sequences of several Mycobacterium canettii strains, representing evolutionary early-branching tubercle bacilli, has allowed the genomic and molecular features of the putative ancestor of the M. tuberculosis complex (MTBC) to be reconstituted. Analyses have identified extensive lateral gene transfer and recombination events in M. canettii and/or the MTBC, leading to suggestions of a past environmental reservoir where the ancestor(s) of the tubercle bacilli might have adapted to an intracellular lifestyle. The daily increases in M. tuberculosis genome data and the remaining urgent Public Health problem of tuberculosis make it more important than ever to try and understand the origins and the future evolution of the MTBC. Here we critically discuss a series of questions on gene-loss, acquisition, recombination, mutation and conservation that have recently arisen and which are key to better understand the outstanding evolutionary success of one of the most widespread and most deadly bacterial pathogens in the history of humankind.


Understanding the Static Interfacial Polymer Layer by Exploring the Dispersion States of Nanocomposites.
The dynamic and static properties of the interfacial region between polymer and nanoparticles have wide-ranging consequences on performances of nanomaterials. The thickness and density of the static layer are particularly difficult to assess experimentally due to superimposing nanoparticle interactions. Here, we tune the dispersion of silica nanoparticles in nanocomposites by preadsorption of polymer layers in the precursor solutions, and by varying the molecular weight of the matrix chains. Nanocomposite structures ranging from ideal dispersion to repulsive order or various degrees of aggregation are generated and observed by small-angle scattering. Preadsorbed chains are found to promote ideal dispersion, before desorption in the late stages of nanocomposite formation. The microstructure of the interfacial polymer layer is characterized by detailed modeling of X-ray and neutron scattering. Only in ideally well-dispersed systems a static interfacial layer of reduced polymer density over a thickness of ca. 2 nm is evidenced based on the analysis with a form-free density profile optimized using numerical simulations. This interfacial gradient layer is found to be independent of the thickness of the initially adsorbed polymer, but appears to be generated by out-of-equilibrium packing and folding of the preadsorbed layer. The impact of annealing is investigated to study the approach of equilibrium, showing that initially ideally well-dispersed systems adopt a repulsive hard-sphere structure, while the static interfacial layer disappears. This study thus promotes the fundamental understanding of the interplay between effects which are decisive for macroscopic material properties: polymer-mediated interparticle interactions, and particle interfacial effects on the surrounding polymer.


The effects of deformation, ischemia, and reperfusion on the development of muscle damage during prolonged loading.
Deep tissue injury (DTI) is a severe form of pressure ulcer where tissue damage starts in deep tissues underneath intact skin. In the present study, the contributions of deformation, ischemia, and reperfusion to skeletal muscle damage development were examined in a rat model during a 6-h period. Magnetic resonance imaging (MRI) was used to study perfusion (contrast-enhanced MRI) and tissue integrity (T2-weighted MRI). The levels of tissue deformation were estimated using finite element models. Complete ischemia caused a gradual homogeneous increase in T2 (∼20% during the 6-h period). The effect of reperfusion on T2 was highly variable, depending on the anatomical location. In experiments involving deformation, inevitably associated with partial ischemia, a variable T2 increase (17-66% during the 6-h period) was observed reflecting the significant variation in deformation (with two-dimensional strain energies of 0.60-1.51 J/mm) and ischemia (50.8-99.8% of the leg) between experiments. These results imply that deformation, ischemia, and reperfusion all contribute to the damage process during prolonged loading, although their importance varies with time. The critical deformation threshold and period of ischemia that cause muscle damage will certainly vary between individuals. These variations are related to intrinsic factors, such as pathological state, which partly explain the individual susceptibility to the development of DTI and highlight the need for regular assessments of individual subjects.


Tied up and isolated in the schoolhouse.
In 1999, the United States General Accountability Office (USGAO) investigated restraints and seclusion use in mental health settings and found patterns of misuse and abuse. A decade later, it found the same misuse and abuse in schools. Restraints and seclusion are traumatizing and dangerous procedures that have caused injury and death. In the past decade, restraints and seclusion have gone from being considered an essential part of the psychiatric mental health toolkit to being viewed as a symptom of treatment failure. In most mental health settings, the use of restraints and seclusion has plummeted due to federal regulations, staff education, and concerted effort of psychiatric national and local leadership. The purpose of this article is to provide a background to and an overview of the present imbroglio over restraints and seclusion in public and private schools, articulate their dangers, dispel myths and misinformation about them, and suggest a leadership role for school nurses in reducing the use of these procedures.


Facilitators and Barriers to Health-Seeking Behaviours among Filipino Migrants: Inductive Analysis to Inform Health Promotion.
Understanding factors that influence health-seeking behaviour of migrants is necessary to intervene for behaviour change. This paper explores Filipino migrants' perceptions of facilitators and barriers to maintaining health in Australia. Open-ended survey item responses reflecting factors that assisted and hindered health following migration to Australia were inductively analysed. Three hundred and thirty-seven of the 552 survey respondents (61%) provided open-ended responses. Responses were grouped into two major categories: individual factors, including personal resources and cultural influences, and environmental factors encompassing both the physical conditions in the host country and health service access. Awareness of practices that enhance health was a major personal facilitator of health-seeking behaviour; however, competing priorities of daily living were perceived as barriers. Cultural beliefs and practices influenced health-seeking behaviour. Despite high self-rated English language skills in this population, new migrants and the elderly cited communication difficulties as barriers to accessing health services. Insight into facilitators and barriers to health-seeking behaviour in this less researched migrant population revealed tools for enhancing engagement in health promotion programs addressing healthy lifestyle.


Adverse effects to quality of life arising from treatment can recover with intermittent androgen suppression in men with prostate cancer.
Health-related quality of life (HQOL) research is a means of broadening the assessment of treatment effects. This longitudinal study investigated the dynamic change to quality of life (QOL) and testosterone dependant physiology in men commencing an intermittent maximal androgen blockade program (IMAB). Two hundred and fifty men were accrued to the multi-centre study of IMAB (Flutamide 250 mg TDS, Leuprolide 22.5 mg depot) ceasing treatment after 9 months if PSA <4 ng/ml, and restarting when PSA >20 ng/ml. QOL was assessed every 3 months for 30 months using the EORTC QLQ-C30 and EORTC QLQ-PR25 module. Data completion for the whole study was 90%. At baseline, our cohort was less symptomatic and had better function than the EORTC reference cohort, which may be related to a shift in clinical practice with time. Testosterone suppression (AS) lead to a significant reduction in global HQOL and deterioration in most function and symptom scales. During the off period, there was a trend of progressive improvement in HQOL that paralleled testosterone recovery but was slower than the rate of deterioration during the treatment phase. Maximum recovery of HQOL occurred most frequently by months 9-12. Testosterone recovery was slower and less complete in older men, and lead to concomitant poorer HOQL recovery. Whilst the magnitude of mean change to scale scores was small, there was a consistent and simultaneous deterioration during maximal androgen blockade (MAB) and improvement during androgen recovery. Older men are more likely to show an impaired testosterone recovery, and this was paralleled by a slower HQOL recovery. Newer methods of analysis to describe results in a way that has meaning to the individual patient are warranted.


"Well it's like someone at the other end cares about you." A qualitative study exploring the views of users and providers of care of contact-based interventions following self-harm.
We investigated the views of service users and staff regarding contact-based interventions (e.g., letters, telephone calls or crisis cards) following self-harm. Self-harm patients recently discharged from an emergency department were selected using purposive sampling (n=11). Clinical staff from relevant service areas and voluntary staff took part in a focus group and individual interviews (n=10). Interviews were transcribed and thematic analyses were conducted using methods of constant comparison to ensure that emergent themes remained grounded in the data. Most service users and staff participants identified the period of time directly after discharge as the time of greatest need. A contact-based intervention was viewed by service users as a gesture of caring, which counteracted feelings of loneliness. Delivery by mental health specialists was preferred, initially by phone, but letters were considered helpful later. The intervention should be both genuine in delivery and linked to current services. Potential barriers included means of accessing the service and threats to privacy. The findings suggest that an appropriate design for an intervention might be the provision of an information leaflet, telephone calls (soon after discharge), then letters (offering continuity of contact). Aspects of value and concern expressed by service users should be helpful to clinicians and service providers.


Activation of the mesostriatal reward pathway with exposure to ultraviolet radiation (UVR) vs. sham UVR in frequent tanners: a pilot study.
Frequent and excessive tanning persists despite a growing understanding of its associated morbidity and mortality, suggesting that ultraviolet radiation may impart rewarding effects beyond the assumed cosmetic benefits. To empirically measure putative centrally rewarding properties of ultraviolet radiation (UVR), we assessed the effects of a commercially available tanning bed upon regional cerebral blood flow (rCBF), a measure of brain activity, using single-photon emission computed tomography (SPECT). Seven frequent salon bed tanners were placed under a UVA/UVB tanning light during two sessions; one session with UVR and the other with filtered UVR (sham UVR). Session order was randomized and subjects were blinded to study order. During the UVR session, relative to sham UVR session, subjects demonstrated a relative increase in rCBF of the dorsal striatum, anterior insula and medial orbitofrontal cortex, brain regions associated with the experience of reward. These changes were accompanied by a decrease in the subjective desire to tan. These findings suggest that UVR may have centrally rewarding properties that encourage excessive tanning.