The Effect of Medical Cannabis on Pain Level and Quality of Sleep among Rheumatology Clinic Outpatients.
Medical cannabis (MC) is becoming increasingly popular for the treatment of chronic pain conditions. In this study, we evaluated the effect of MC treatment on pain level and quality of sleep of patients with different medical conditions at the rheumatology clinic. Patients licensed for the use of MC at the rheumatology clinics at different settings were located and contacted. Their demographic and clinical parameters were documented, including type of medical cannabis consumed, way of consumption, and current monthly consumed amount. These patients were contacted by phone and asked about the effect on pain level and quality of sleep. A total of 351 patients were located, and 319 completed the questionnaire. Mean age was 46 ± 12 years, 76% were female, 82% had fibromyalgia, ∼9% had mechanical problems, ∼4% had inflammatory problems, ∼4% had neurological problems, and ∼1% had other problems. The average monthly consumed dose of MC was 31, 35, 36, and 32 g, with mean pain level reduction of 77%, 82%, 83%, and 57%, and mean sleep quality improvement of 78%, 71%, 87%, and 76% among patients with fibromyalgia, mechanical, neuropathic, and inflammatory problems, respectively. Mean THC and CBD contents were 18.38% ± 4.96 and 2.62% ± 4.87, respectively. The THC concentration, duration of MC consumption, and MC consumption dose had independent significant correlations with pain reduction while only the duration of MC consumption had an independent significant correlation with sleep quality improvement. MC had a favorable effect on pain level and quality of sleep among all spectrums of problems at the rheumatology clinic.


Screening and interventions for childhood overweight: a summary of evidence for the US Preventive Services Task Force.
Childhood and adolescent overweight and obesity are related to health risks, medical conditions, and increased risk of adult obesity, with its attendant effects on morbidity and mortality rates. The prevalence of childhood overweight and obesity has more than doubled in the past 25 years. Purpose. This evidence synthesis examines the evidence for the benefits and harms of screening and early treatment of overweight among children and adolescents in clinical settings. We developed an analytic framework and 7 key questions representing the logical evidence connecting screening and weight control interventions with changes in overweight and behavioral, physiologic, and health outcomes in childhood or adulthood. We searched the Cochrane Library from 1996 to April 2004. We searched Medline, PsycINFO, DARE, and CINAHL from 1966 to April 2004. One reviewer abstracted relevant information from each included article into standardized evidence tables, and a second reviewer checked key elements. Two reviewers quality-graded each article with US Preventive Services Task Force criteria. Although BMI is a measure of relative weight rather than adiposity, it is recommended widely for use among children and adolescents to determine overweight and is the currently preferred measure. The risk of adult overweight from childhood overweight provides the best available evidence to judge the clinical validity of BMI as an overweight criterion for children and adolescents. BMI measures in childhood track to adulthood moderately or very well, with stronger tracking seen for children with >or=1 obese parent and children who are more overweight or older. The probability of adult obesity (BMI of >30 kg/m(2)) is >or=50% among children >13 years of age whose BMI percentiles meet or exceed the 95th percentile for age and gender. BMI-based overweight categorization for individuals, particularly for racial/ethnic minorities with differences in body composition, may have limited validity because BMI measures cannot differentiate between increased weight for height attributable to relatively greater fat-free mass (muscle, bone, and fluids) and that attributable to greater fat. No trials of screening programs to identify and to treat childhood overweight have been reported. Limited research is available on effective, generalizable interventions for overweight children and adolescents that can be conducted in primary care settings or through primary care referrals. BMI measurements of overweight among older adolescents identify those at increased risk of developing adult obesity. Interventions to treat overweight adolescents in clinical settings have not been shown to have clinically significant benefits, and they are not widely available. Screening to categorize overweight among children under age 12 or 13 who are not clearly overweight may not provide reliable risk categorization for adult obesity. Screening in this age group is compromised by the fact that there is little generalizable evidence for primary care interventions. Because existing trials report modest short- to medium-term improvements (approximately 10-20% decrease in percentage of overweight or a few units of change in BMI), however, overweight improvements among children and adolescents seem possible.


Informed constrained spherical deconvolution (iCSD).
Diffusion-weighted (DW) magnetic resonance imaging (MRI) is a noninvasive imaging method, which can be used to investigate neural tracts in the white matter (WM) of the brain. However, the voxel sizes used in DW-MRI are relatively large, making DW-MRI prone to significant partial volume effects (PVE). These PVEs can be caused both by complex (e.g. crossing) WM fiber configurations and non-WM tissue, such as gray matter (GM) and cerebrospinal fluid. High angular resolution diffusion imaging methods have been developed to correctly characterize complex WM fiber configurations, but significant non-WM PVEs are also present in a large proportion of WM voxels. In constrained spherical deconvolution (CSD), the full fiber orientation distribution function (fODF) is deconvolved from clinically feasible DW data using a response function (RF) representing the signal of a single coherently oriented population of fibers. Non-WM PVEs cause a loss of precision in the detected fiber orientations and an emergence of false peaks in CSD, more prominently in voxels with GM PVEs. We propose a method, informed CSD (iCSD), to improve the estimation of fODFs under non-WM PVEs by modifying the RF to account for non-WM PVEs locally. In practice, the RF is modified based on tissue fractions estimated from high-resolution anatomical data. Results from simulation and in-vivo bootstrapping experiments demonstrate a significant improvement in the precision of the identified fiber orientations and in the number of false peaks detected under GM PVEs. Probabilistic whole brain tractography shows fiber density is increased in the major WM tracts and decreased in subcortical GM regions. The iCSD method significantly improves the fiber orientation estimation at the WM-GM interface, which is especially important in connectomics, where the connectivity between GM regions is analyzed.


Wavelength dependence of pyrimidine dimer formation in DNA of human skin irradiated in situ with ultraviolet light.
The UV components of sunlight are believed to be a major cause of human skin cancer, and DNA is thought to be the principal molecular target. Alterations of the intensity and wavelength distribution of solar UV radiation reaching the surface of the earth, for example by depletion of stratospheric ozone, will change the effectiveness of solar radiation in damaging DNA in human skin. Evaluation of the magnitude of such effects requires knowledge of the altered sunlight spectrum and of the action spectrum for damaging DNA in human skin. We have determined an action spectrum for the frequency of pyrimidine dimer formation induced in the DNA of human skin per unit dose of UV incident on the skin surface. The peak of this action spectrum is near 300 nm and decreases rapidly at both longer and shorter wavelengths. The decrease in our action spectrum for wavelengths less than 300 nm is attributed to the absorption of the upper layers of the skin, an in situ effect that is inherently included in our measurements. Convolution of the dimer action spectrum with the solar spectra corresponding to a solar angle of 40 degrees under current levels of stratospheric ozone (0.32-cm O3 layer) and those for 50% ozone depletion (0.16-cm O3 layer), indicate about a 2.5-fold increase in dimer formation. If the action spectrum for DNA damage that results in skin cancer resembles that for dimer induction in skin, our results, combined with epidemiological data, suggest that a 50% decrease in stratospheric ozone would increase the incidence of nonmelanoma skin cancers among white males in Seattle, Washington, by 7.5- to 8-fold, to a higher incidence than is presently seen in the corresponding population of Albuquerque, New Mexico.


Expression of GRIM-19 in missed abortion and possible pathogenesis.
To study the expression of a gene associated with retinoid-interferon (IFN)-induced mortality 19 (GRIM-19) in the villi of patients with missed abortion and possible pathogenesis. Case-control study. University hospital. Villous samples were collected from a total of 50 women with missed abortion and 50 women with normal pregnancies. Villous samples from the missed-abortion group were collected by curettage or manual vacuum aspiration. The control villous samples were obtained by vacuum aspiration. Protein and messenger RNA levels of GRIM-19 in villous samples were measured by Western blot and real-time polymerase chain reaction, and the location of GRIM-19 in trophoblasts was detected by immunohistochemistry. Apoptotic cells and microvessel density in villous sample were assayed by TUNEL and immunostaining. Mitochondrial membrane potential and apoptotic changes of the HTR-8/SVneo cell line in response to down-regulation of GRIM-19 were evaluated by 5,5',6,6'-Tetrachloro-1,1',3,3'-tetraethyl-imidacarbocyanine iodide and annexin V/propidium iodide. Vascular endothelial growth factor production was measured by ELISA. GRIM-19 protein and messenger RNA levels in the villi from women with missed abortion were found to be significantly lower than in women who had normal pregnancies. Many more apoptotic cells and lower microvessel density were detected in villi from patients with missed abortion. Knockdown of GRIM-19 in HTR-8/SVneo cells gave rise to a collapse of mitochondrial membrane potential and increase in apoptosis. Simultaneously, the vascular endothelial growth factor secretion in the HTR-8/SVneo cells culture medium decreased as GRIM-19 became down-regulated. The GRIM-19 deficiency in the villus may be associated with missed abortion via increasing apoptosis and affecting angiogenesis.


Reduced hypothalamic blood flow after radiation treatment of nasopharyngeal cancer: SPECT studies in 34 patients.
To determine the effect of cranial irradiation on hypothalamic blood flow, we performed 44 regional cerebral blood flow studies with 99mTc hexamethyl propyleneamine oxime (HMPAO) single-photon emission CT (SPECT) on four normal volunteers and 34 patients with pathologically proved nasopharyngeal cancer. Twenty-three men and 15 women, 30-65 years old, were divided into four study groups: group 1 served as a control and consisted of four normal volunteers and six patients studied prior to cranial irradiation; group 2 patients had cranial irradiation half a year before the SPECT study (n = 12, one from group 1); group 3 patients were irradiated 1 year before the study (n = 13, three from group 1 and two from group 2); and group 4 patients were irradiated at least 5 years before SPECT imaging (n = 9). Six patients were studied twice. Quantification of the 99mTc-HMPAO brain SPECT studies was done separately by three radiologists to obtain the hypothalamus/occipital (H/O) and hypothalamus/parasagittal (H/P) ratios. Endocrinologic studies were performed in all cases and the hypothalamus-thyrotroph-thyroid, hypothalamus-gonadotroph-testis (ovary), hypothalamus-lactotroph, hypothalamus-somatotroph, and hypothalamus-corticotroph-adrenal axes were evaluated separately. We determined that regional hypothalamic blood flow was reduced after cranial irradiation in patients with nasopharyngeal cancer. The H/O ratio of groups 3 and 4 did not differ from that of group 2 (one-half year after cranial irradiation). The H/O ratio was significantly reduced 6 months and 1 year after cranial irradiation; mean +/- SD = 0.5801 +/- 0.0829 (p less than .025), 0.5725 +/- 0.0791 (p less than .01) versus 0.6477 +/- 0.0458 before cranial irradiation, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)


Different Brain Regions are Infected with Fungi in Alzheimer's Disease.
The possibility that Alzheimer's disease (AD) has a microbial aetiology has been proposed by several researchers. Here, we provide evidence that tissue from the central nervous system (CNS) of AD patients contain fungal cells and hyphae. Fungal material can be detected both intra- and extracellularly using specific antibodies against several fungi. Different brain regions including external frontal cortex, cerebellar hemisphere, entorhinal cortex/hippocampus and choroid plexus contain fungal material, which is absent in brain tissue from control individuals. Analysis of brain sections from ten additional AD patients reveals that all are infected with fungi. Fungal infection is also observed in blood vessels, which may explain the vascular pathology frequently detected in AD patients. Sequencing of fungal DNA extracted from frozen CNS samples identifies several fungal species. Collectively, our findings provide compelling evidence for the existence of fungal infection in the CNS from AD patients, but not in control individuals.


Pro-sterol carrier protein-2: role of the N-terminal presequence in structure, function, and peroxisomal targeting.
Although the 20-amino acid presequence present in 15-kDa pro-sterol carrier protein-2 (pro-SCP-2, the precursor of the mature 13-kDa SCP-2) alters the function of SCP-2 in lipid metabolism, the molecular basis for this effect is unresolved. The presequence dramatically altered SCP-2 structure as determined by circular dichroism, mass spectroscopy, and antibody accessibility such that pro-SCP-2 had 3-fold less alpha-helix, 7-fold more beta-structure, 6-fold more reactive C terminus to carboxypeptidase A, 2-fold less binding of anti-SCP-2, and did not enhance sterol transfer from plasma membranes. These differences were not due to protein stability since (i) the same concentration of guanidine hydrochloride was required for 50% unfolding, and (ii) the ligand binding sites displayed the same high affinity (nanomolar K(d) values) in the order: cholesterol straight chain fatty acid > kinked chain fatty acid. Laser scanning confocal microscopy and double immunofluorescence demonstrated that pro-SCP-2 was more efficiently targeted to peroxisomes. Transfection of l-cells or McAR7777 hepatoma cells with cDNA encoding pro-SCP-2 resulted in 45% and 59% of SCP-2, respectively, colocalizing with the peroxisomal marker PMP70. In contrast, l-cells transfected with cDNA encoding SCP-2 exhibited 3-fold lower colocalization of SCP-2 with PMP70. In summary, the data suggest for the first time that the 20-amino acid presequence of pro-SCP-2 alters SCP-2 structure to facilitate peroxisomal targeting mediated by the C-terminal SKL peroxisomal targeting sequence.


Transcutaneous Auricular Vagus Nerve Stimulation at 20 Hz Improves Depression-Like Behaviors and Down-Regulates the Hyperactivity of HPA Axis in Chronic Unpredictable Mild Stress Model Rats.
Transcutaneous auricular vagus nerve stimulation (taVNS) has gained growing interest as a non-invasive and non-pharmacologic treatment option in various neurological and psychiatric disorders. Animal experiments and clinical trials confirm that taVNS at the auricular concha region has beneficial effects on depression. However, stimulation frequencies are selected empirically, and there is no evidence showing that any frequency is superior to the others. This study explores antidepressant-like effects of three frequencies of taVNS on rats subjected to chronic unpredictable mild stress (CUMS). Sprague-Dawley rats were randomly divided into five groups, i.e., the control, CUMS, 5 Hz-taVNS, 20 Hz-taVNS, and 100 Hz-taVNS groups. The three different frequencies were administered during the 30-min taVNS procedure once a day for 28 consecutive days. Rats exposed to CUMS showed signs of depression-like behaviors, including reduction in sucrose preference and increased immobility time in forced swimming and open field tests as well as significant dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis as detected by plasma corticosterone and adrenocorticotropic hormone concentration. The 28 days' taVNS sessions with three frequencies elicited quite different consequences. Although 20 Hz taVNS significantly reversed the depression-like behaviors and downregulated the hyperactivity of the HPA axis, neither 5 nor 100 Hz showed any antidepressant-like effect on CUMS-induced rat behavior. Based on these results, we propose that, out of the three frequencies for taVNS intervention on depression, 20 Hz may be the optimized frequency to have a better modulation effect on HPA axis function by activating the auricular vagus nerve.


B cell insensitivity in a rat model of non-insulin-dependent diabetes. Evidence for a rapidly reversible effect of previous hyperglycemia.
In perfused pancreas of rats rendered diabetic by streptozotocin injection (STZ) during neonatal age the insulin response to 27 mM glucose was significant but impaired. It was unaffected by the alpha adrenergic blocker phentolamine. When 27 mM mannoheptulose was added simultaneously with 27 mM glucose, insulin release was inhibited, but less promptly than in pancreases from non-diabetic rats. When mannoheptulose was introduced 15 min after starting perfusion with 27 mM glucose, inhibition was apparent in non-diabetic rats, but not in STZ. In non-diabetic rats perfusion without glucose for 40 min failed to affect the subsequent response to 27 mM glucose. Conversely, in STZ, glucose omission enhanced 3.7-fold the response to 27 mM glucose. Insulin release in response to 3-isobutyl-1-methylxanthine (IBMX) was more marked in STZ than in non-diabetic rats. After glucose omission the IBMX-induced response was, however, reduced (67%) in STZ, but not significantly (7%) in non-diabetic rats. Thus, glucopenia in vitro sensitizes B cells of STZ to glucose, but desensitizes them to IBMX. Abnormal responsiveness may be linked to metabolic consequences of B cell fuel abundance.


Effect of dry needling of gluteal muscles on straight leg raise: a randomised, placebo controlled, double blind trial.
To use a randomised, double blind, placebo controlled trial to establish the effect on straight leg raise, hip internal rotation, and muscle pain of dry needling treatment to the gluteal muscles in athletes with posterior thigh pain referred from gluteal trigger points. A randomised, double blind, placebo controlled trial of 59 male runners was performed during the 2002 Australian Rules football season. Subjects were thoroughly screened and had magnetic resonance imaging of their hamstring muscles to exclude local pathology. The inclusion criterion was reproduction of recognisable posterior thigh pain with the application of digital pressure to the gluteal trigger points. Subjects randomly received either therapeutic or placebo needle treatment on one occasion at their gluteal trigger points. Range of motion and visual analogue scale data were collected immediately before, immediately after, 24 hours after, and 72 hours after the intervention. Range of motion was measured with passive straight leg raise and hip internal rotation. Visual analogue scales were completed for hamstring and gluteal pain and tightness at rest and during a running task. Magnetic resonance imaging scans revealed normal hamstring musculature in most subjects. Straight leg raise and hip internal rotation remained unchanged in both groups at all times. Visual analogue scale assessment of hamstring pain and tightness and gluteal tightness after running showed improvements immediately after the intervention in both groups (p = 0.001), which were maintained at 24 and 72 hours. The magnitude of this improvement was the same for therapeutic and placebo interventions. Resting muscle pain and tightness were unaffected. Neither dry needling nor placebo needling of the gluteal muscles resulted in any change in straight leg raise or hip internal rotation. Both interventions resulted in subjective improvement in activity related muscle pain and tightness. Despite being commonly used clinical tests in this situation, straight leg raise and hip internal rotation are not likely to help the therapist assess response to treatment. Patient reports of response to such treatment are better indicators of its success. The mechanisms by which these responses occur and the reasons for the success of the placebo needling treatment are areas for further investigation.


Heart rate detection from single-foot plantar bioimpedance measurements in a weighing scale.
Electronic bathroom scales are an easy-to-use, affordable mean to measure physiological parameters in addition to body weight. They have been proposed to obtain the ballistocardiogram (BCG) and derive from it the heart rate, cardiac output and systolic blood pressure. Therefore, weighing scales may suit intermittent monitoring in e-health and patient screening. Scales intended for bioelectrical impedance analysis (BIA) have also been proposed to estimate the heart rate by amplifying the pulsatile impedance component superimposed on the basal impedance. However, electronic weighing scales cannot easily obtain the BCG from people that have a single leg neither are bioimpedance measurements between both feet recommended for people wearing a pacemaker or other electronic implants, neither for pregnant women. We propose a method to detect the heart rate (HR) from bioimpedance measured in a single foot while standing on an bathroom weighting scale intended for BIA. The electrodes built in the weighing scale are used to apply a 50 kHz voltage between the outer electrode pair and to measure the drop in voltage across the inner electrode pair. The agreement with the HR simultaneously obtained from the ECG is excellent. We have also compared the drop in voltage across the waist and the thorax with that obtained when measuring bioimpedance between both feet to compare the possible risk of the proposed method to that of existing BIA scales.


Diesel Exhaust Particles Upregulate Interleukins IL-6 and IL-8 in Nasal Fibroblasts.
Diesel exhaust particles (DEP) are a major source of air pollution. Nasal fibroblasts are known to produce various cytokines and chemokines. The aim of this study was to evaluate DEP-induced cytokines and chemokines in nasal fibroblasts and to identify the signaling pathway involved. A cytokine and chemokine array performed after stimulation of nasal fibroblasts with DEP revealed that levels of IL-6 and IL-8 were increased most significantly among various cytokines and chemokines. RT-PCR and ELISA were used to determine the mRNA and protein expression levels of IL-6 and IL-8. Signaling pathways of p-38, Akt, and NF-κB were analyzed by western blotting, luciferase assay, and ELISA. Organ cultures of nasal interior turbinate were also developed to demonstrate the ex vivo effect of DEP on the expression of IL-6 and IL-8 and the associated signaling pathway. DEP increased the expressions of IL-6 and IL-8 in nasal fibroblasts at mRNA and protein levels. DEP induced phosphorylation of p38, Akt, and NF-κB, whereas inhibitors of p38, Akt, and NF-κB blocked these phophorylations and the expressions of IL-6 and IL-8. These findings were also observed in ex vivo organ culture of nasal inferior turbinate. DEP induces expression of IL-6 and IL-8 via p38, Akt, and NF-κB signaling pathways in nasal fibroblasts. This finding suggests that air pollution might induce or aggravate allergic rhinitis or chronic rhinosinusitis.


Local and systemic changes in expression of resistance genes, NB-LRR genes and their putative microRNAs in Norway spruce after wounding and inoculation with the pathogen Ceratocystis polonica.
NB-LRR resistance proteins are involved in recognizing pathogens and other exogenous stressors in plants. Resistance proteins are the first step in induced defence responses and a better understanding of their regulation is important to understand the mechanisms of plant defence. Much of the post-transcriptional regulation in plants is controlled by microRNAs (miRNA). We examined the expression of five Norway spruce miRNA that may regulate NB-LRR related transcripts in secondary phloem (bark) of resistant Norway spruce after wounding and inoculation with the necrotrophic blue stain fungus Ceratocystis polonica. The plants of this clone recovered from both the pathogen inoculations and wounding alone. We found local and systemic induction of the resistance marker genes PaChi4, PaPAL and PaPX3 indicative of an effective induced host defence response. There were minor local and systemic changes in the expression of five miRNAs and 21 NB-LRRs between healthy and treated plants. Only five putative NB-LRRs (PaLRR1, PaLRR3, PaLRR14, PaLRR15 and PaLRR16) showed significant increases greater than two-fold as a local response to C. polonica. Of all NB-LRRs only PaLRR3, the most highly differentially regulated NB-LRR, showed a significant increase also due to wounding. The five miRNAs showed indications of an initial local and systemic down-regulation at day 1, followed by a later increase up to and beyond the constitutive levels at day 6. However, the initial down-regulation was significant only for miR3693 and miR3705. Overall, local and systemic expression changes were evident only for the established resistance marker genes and PaLRR3. The minor expression changes observed both for the followed miRNAs and their predicted NB-LRR targets suggest that the expression of most NB-LRR genes are maintained close to their constitutive levels in stressed and healthy Norway spruce plants.


Busulfan plus cyclophosphamide versus busulfan plus fludarabine as a preparative regimen for allogeneic haemopoietic stem-cell transplantation in patients with acute myeloid leukaemia: an open-label, multicentre, randomised, phase 3 trial.
The standard busulfan-cyclophosphamide myeloablative conditioning regimen is associated with substantial non-relapse mortality in patients older than 40 years with acute myeloid leukaemia who are undergoing allogeneic stem-cell transplantation. Because the combination of busulfan plus fludarabine has been proposed to reduce non-relapse mortality, we aimed to compare this treatment with busulfan plus cyclophosphamide as a preparative regimen in these patients. We did an open-label, multicentre, randomised, phase 3 trial for patients with acute myeloid leukaemia at 25 hospital transplant centres in Italy and one in Israel. Eligible patients were aged 40-65 years, had an Eastern Cooperative Oncology Group performance status less than 3, and were in complete remission. Patients were randomly assigned 1:1 to receive intravenous busulfan plus cyclophosphamide or busulfan plus fludarabine. Treatment allocations were not masked to investigators or patients. Randomisation was done centrally via a dedicated web-based system using remote data entry, with patients stratified by donor type and complete remission status. Patients allocated to busulfan plus cyclophosphamide received intravenous busulfan 0·8 mg/kg four times per day during 2 h infusions for four consecutive days (16 doses from days -9 through -6; total dose 12·8 mg/kg) and cyclophosphamide at 60 mg/kg per day for two consecutive days (on days -4 and -3; total dose 120 mg/kg). Patients allocated to busulfan plus fludarabine received the same dose of intravenous busulfan (from days -6 through -3) and fludarabine at 40 mg/m(2) per day for four consecutive days (from days -6 through -3; total dose 160 mg/m(2)). The primary endpoint was 1-year non-relapse mortality, which was assessed on an intention-to-treat basis; safety outcomes were assessed in the per-protocol population. This trial has been completed and is registered with ClinicalTrials.gov, number NCT01191957. Between Jan 3, 2008, and Dec 20, 2012, we enrolled and randomly assigned 252 patients to receive busulfan plus cyclophosphamide (n=125) or busulfan plus fludarabine (n=127). Median follow-up was 27·5 months (IQR 9·8-44·3). 1-year non-relapse mortality was 17·2% (95% CI 11·6-25·4) in the busulfan plus cyclophosphamide group and 7·9% (4·3-14·3) in the busulfan plus fludarabine group (Gray's test p=0·026). The most frequently reported grade 3 or higher adverse events were gastrointestinal events (28 [23%] of 121 patients in the busulfan plus cyclophosphamide group and 26 [21%] of 124 patients in the busulfan plus fludarabine group) and infections (21 [17%] patients in the busulfan plus cyclophosphamide group and 13 [10%] patients in the busulfan plus fludarabine group had at least one such event). In older patients with acute myeloid leukaemia, the myeloablative busulfan plus fludarabine conditioning regimen is associated with lower transplant-related mortality than busulfan plus cyclophosphamide, but retains potent antileukaemic activity. Accordingly, this regimen should be regarded as standard of care during the planning of allogeneic transplants for such patients. Agenzia Italiana del Farmaco.


Hippocampal sparing radiotherapy for pediatric medulloblastoma: impact of treatment margins and treatment technique.
We investigated how varying the treatment margin and applying hippocampal sparing and proton therapy impact the risk of neurocognitive impairment in pediatric medulloblastoma patients compared with current standard 3D conformal radiotherapy. We included 17 pediatric medulloblastoma patients to represent the variability in tumor location relative to the hippocampal region. Treatment plans were generated using 3D conformal radiotherapy, hippocampal sparing intensity-modulated radiotherapy, and spot-scanned proton therapy, using 3 different treatment margins for the conformal tumor boost. Neurocognitive impairment risk was estimated based on dose-response models from pediatric CNS malignancy survivors and compared among different margins and treatment techniques. Mean hippocampal dose and corresponding risk of cognitive impairment were decreased with decreasing treatment margins (P < .05). The largest risk reduction, however, was seen when applying hippocampal sparing proton therapy-the estimated risk of impaired task efficiency (95% confidence interval) was 92% (66%-98%), 81% (51%-95%), and 50% (30%-70%) for 3D conformal radiotherapy, intensity-modulated radiotherapy, and proton therapy, respectively, for the smallest boost margin and 98% (78%-100%), 90% (60%-98%), and 70% (39%-90%) if boosting the whole posterior fossa. Also, the distance between the closest point of the planning target volume and the center of the hippocampus can be used to predict mean hippocampal dose for a given treatment technique. We estimate a considerable clinical benefit of hippocampal sparing radiotherapy. In choosing treatment margins, the tradeoff between margin size and risk of neurocognitive impairment quantified here should be considered.


Physical fitness and anthropometrical profile of the Brazilian male judo team.
The present study had as objectives (1) to compare the morphological and functional characteristics of the male judo players of the Brazilian Team A (n=7) with the judo players of Teams B and C (reserves; n=15), and (2) to verify the association between the variables measured. Thus, 22 athletes from the seven Olympic weight categories were submitted to: a body composition evaluation (body mass, height, ten skinfolds, eight circumferences, three bone diameters and percent body fat estimation); the Special Judo Fitness Test (SJFT); maximal strength tests (one repetition-maximum, 1 RM, in bench press, row, and squat); and the Cooper test. One-way analysis of covariance was used to compare the groups. The relationships between variables were determined by the Pearson coefficient correlation. The significance level was fixed at 5%. No significant difference was found in any variable between them. The main significant correlations observed were between the following variables: VO2max and number of throws in the SJFT (r=0.79); percent body fat and estimated VO2max (r=-0.83) and number of throws in the SJFT (r=-0.70); chest circumference and bench press 1 RM (r=0.90) and in the row (r=0.80); and thigh circumference and squat 1 RM (r=0.86). However, there was no significant correlation between circumferences and 1 RM/kg of body mass. According to these results the main conclusions are: (1) the physical variables measured do not discriminate performance when analysis is directed to the best athletes; (2) a higher percent body fat is negatively correlated with performance in activities with body mass locomotion (Cooper test and the SJFT); (3) judo players with higher aerobic power performed better in high-intensity intermittent exercise; (4) judo players with bigger circumferences present bigger absolute maximal strength.


A human polymorphism affects NEDD4L subcellular targeting by leading to two isoforms that contain or lack a C2 domain.
Ubiquitination serves multiple cellular functions, including proteasomal degradation and the control of stability, function, and intracellular localization of a wide variety of proteins. NEDD4L is a member of the HECT class of E3 ubiquitin ligases. A defining feature of NEDD4L protein isoforms is the presence or absence of an amino-terminal C2 domain, a class of subcellular, calcium-dependent targeting domains. We previously identified a common variant in human NEDD4L that generates isoforms that contain or lack a C2 domain. To address the potential functional significance of the NEDD4L common variant on NEDD4L subcellular localization, NEDD4L isoforms that either contained or lacked a C2 domain were tagged with enhanced green fluorescent protein, transfected into Xenopus laevis kidney epithelial cells, and imaged by performing confocal microscopy on live cells. We report that the presence or absence of this C2 domain exerts differential effects on the subcellular distribution of NEDD4L, the ability of C2 containing and lacking NEDD4L isoforms to mobilize in response to a calcium stimulus, and the intracellular transport of subunits of the NEDD4L substrate, ENaC. Furthermore, the ability of the C2-containing isoform to influence beta-ENaC mobilization from intracellular pools involves the NEDD4L active site for ubiquitination. We propose a model to account for the potential impact of this common genetic variant on protein function at the cellular level. NEDD4L isoforms that contain or lack a C2 domain target different intracellular locations. Additionally, whereas the C2-containing NEDD4L isoform is capable of shuttling between the plasma membrane and intracellular compartments in response to calcium stimulus the C2-lacking isoform can not. The C2-containing isoform differentially affects the mobilization of ENaC subunits from intracellular pools and this trafficking step requires NEDD4L ubiquitin ligase activity. This observation suggests a new mechanism for the requirement for the PY motif in cAMP-mediated exocytosis of ENaC. We have elucidated how a common genetic variant can underlie significant functional diversity in NEDD4L at the cellular level. We propose a model that describes how that functional variation may influence blood pressure. Moreover, our observations regarding differential function of the NEDD4L isoforms may impact other aspects of physiology that involve this ubiquitin ligase.


Search for heavy neutrinos and W(R) bosons with right-handed couplings in a left-right symmetric model in pp collisions at sqrt[s]=7 TeV.
Results are presented from a search for heavy, right-handed muon neutrinos, N(μ), and right-handed W(R) bosons, which arise in the left-right symmetric extensions of the standard model. The analysis is based on a 5.0 fb(-1) sample of proton-proton collisions at a center-of-mass energy of 7 TeV, collected by the CMS detector at the Large Hadron Collider. No evidence is observed for an excess of events over the standard model expectation. For models with exact left-right symmetry, heavy right-handed neutrinos are excluded at 95% confidence level for a range of neutrino masses below the W(R) mass, dependent on the value of M(W(R)). The excluded region in the two-dimensional (M(W(R)), M(N(μ)) mass plane extends to M(W(R))=2.5 TeV.


Conceptualizing the integration of HIV treatment and prevention: findings from a process evaluation of a community-based, national capacity-building intervention.
This paper responds to a gap in knowledge about the conceptualization of integration in community-based AIDS organizations (CBAOs). A community-based process evaluation was conducted of a national intervention, developed by the Canadian AIDS Treatment Information Exchange (CATIE), to enhance treatment information provision in CBAOs and encourage its integration with prevention services. Our study involved 13 interviews with intervention participants in 6 CBAOs across Canada, CATIE staff, and funders, as well as a 25-person verification exercise. Intervention participants conceptualized integration as linking front-line HIV treatment, health promotion and prevention services, emphasizing mediation between scientific and lay knowledge, the political context of integration and the role of social determinants in clients' health and access to services. Challenges to integration include high staff turnover and inflexible funding structures. Complex health education related to the relationship between viral load and HIV transmission is a critical area of integrated service delivery. Study findings help distinguish a community-based concept of HIV-related integration from alternative uses of the term while pointing out key tensions associated with efforts to integrate HIV prevention and treatment in a community-based context.


The honeybee (Apis mellifera) developmental state shapes the genetic composition of the deformed wing virus-A quasispecies during serial transmission.
The main biological threat to the western honeybee (Apis mellifera) is the parasitic mite Varroa destructor, largely because it vectors lethal epidemics of honeybee viruses that, in the absence of this mite, are relatively innocuous. The severe pathology is a direct consequence of excessive virus titres caused by this novel transmission route. However, little is known about how the virus adapts genetically during transmission and whether this influences the pathology. Here, we show that upon injection into honeybee pupae, the deformed wing virus type-A (DWV-A) quasispecies undergoes a rapid, extensive expansion of its sequence space, followed by strong negative selection towards a uniform, common shape by the time the pupae have completed their development, with no difference between symptomatic and asymptomatic adults in either DWV titre or genetic composition. This suggests that the physiological and molecular environment during pupal development has a strong, conservative influence on shaping the DWV-A quasispecies in emerging adults. There was furthermore no evidence of any progressive adaptation of the DWV-A quasispecies to serial intra-abdominal injection, simulating mite transmission, despite the generation of ample variation immediately following each transmission, suggesting that the virus either had already adapted to transmission by injection, or was unaffected by it.


Clinical grand rounds: atypical hemolytic uremic syndrome.
Atypical hemolytic uremic syndrome (aHUS) is a rare, lifethreatening, chronic, genetic disease of uncontrolled alternative pathway complement activation. The understanding of the pathophysiology and genetics of this disease has expanded over recent decades and promising new developments in the management of aHUS have emerged. Regardless of the cause of aHUS, with or without a demonstrated mutation or autoantibody, blockade of terminal complement activation through C5 is of high interest as a mechanism to ameliorate the disease. Eculizumab, an existing monoclonal antibody directed against C5 with high affinity, prevents the perpetuation of the downstream activation of the complement cascade and the damage caused by generation of the anaphylotoxin C5a and the membrane attack complex C5b-9, by blocking C5 cleavage. We report the successful use of eculizumab in a patient after kidney transplantation and discuss the disease aHUS.


Promoting deceased organ and tissue donation registration in family physician waiting rooms (RegisterNow-1 trial): study protocol for a pragmatic, stepped-wedge, cluster randomized controlled registry.
There is a worldwide shortage of organs available for transplant, leading to preventable mortality associated with end-stage organ disease. While most citizens in many countries with an intent-to-donate "opt-in" system support organ donation, registration rates remain low. In Canada, most Canadians support organ donation but less than 25% in most provinces have registered their desire to donate their organs when they die. The family physician office is a promising yet underused setting in which to promote organ donor registration and address known barriers and enablers to registering for deceased organ and tissue donation. We developed a protocol to evaluate an intervention to promote registration for organ and tissue donation in family physician waiting rooms. This protocol describes a planned, stepped-wedge, cluster randomized registry trial in six family physician offices in Ontario, Canada to evaluate the effectiveness of reception staff providing patients with a pamphlet that addresses barriers and enablers to registration including a description of how to register for organ donation. An Internet-enabled tablet will also be provided in waiting rooms so that interested patients can register while waiting for their appointments. Family physicians and reception staff will be provided with training and/or materials to support any conversations about organ donation with their patients. Following a 2-week control period, the six offices will cross sequentially into the intervention arm in randomized sequence at 2-week intervals until all offices deliver the intervention. The primary outcome will be the proportion of patients visiting the office who are registered organ donors 7 days following their office visit. We will evaluate this outcome using routinely collected registry data from provincial administrative databases. A post-trial qualitative evaluation process will assess the experiences of reception staff and family physicians with the intervention and the stepped-wedge trial design. Promoting registration for organ donation in family physician offices is a potentially useful strategy for increasing registration for organ donation. Increased registration may ultimately help to increase the number of organs available for transplant. The results of this trial will provide important preliminary data on the effectiveness of using family physician offices to promote registration for organ donation. ClinicalTrials.gov, ID: NCT03213171 . Registered on 11 July 2017.


Commentary on "common genetic polymorphisms modify the effect of smoking on absolute risk of bladder cancer." Garcia-Closas M, Rothman N, Figueroa JD, Prokunina-Olsson L, Han SS, Baris D, Jacobs EJ, Malats N, De Vivo I, Albanes D, Purdue MP, Sharma S, Fu YP, Kogevinas M, Wang Z, Tang W, Tardón A, Serra C, Carrato A, García-Closas R, Lloreta J, Johnson A, Schwenn M, Karagas MR, Schned A, Andriole G Jr., Grubb R 3rd, Black A, Gapstur SM, Thun M, Diver WR, Weinstein SJ, Virtamo J, Hunter DJ, Caporaso N, Landi MT, Hutchinson A, Burdett L, Jacobs KB, Yeager M, Fraumeni JF Jr., Chanock SJ, Silverman DT, Chatterjee N, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.: Cancer Res 2013;73(7):2211-20 [Epub 2013 Mar 27].
Bladder cancer results from the combined effects of environmental and genetic factors, smoking being the strongest risk factor. Evaluating absolute risks resulting from the joint effects of smoking and genetic factors is critical to assess the public health relevance of genetic information. Analyses included up to 3,942 cases and 5,680 controls of European background in seven studies. We tested for multiplicative and additive interactions between smoking and 12 susceptibility loci, individually and combined as a polygenic risk score (PRS). Thirty-year absolute risks and risk differences by levels of the PRS were estimated for U.S. males aged 50 years. Six of 12 variants showed significant additive gene-environment interactions, most notably NAT2 (P = 7×10(-4)) and UGT1A6 (P = 8×10(-4)). The 30-year absolute risk of bladder cancer in U.S. males was 6.2% for all current smokers. This risk ranged from 2.9% for current smokers in the lowest quartile of the PRS to 9.9% for current smokers in the upper quartile. Risk difference estimates indicated that 8,200 cases would be prevented if elimination of smoking occurred in 100,000 men in the upper PRS quartile compared with 2,000 cases prevented by a similar effort in the lowest PRS quartile (P(additive) = 1×10(-4)). Thus, the potential impact of eliminating smoking on the number of bladder cancer cases prevented is larger for individuals at higher than lower genetic risk. Our findings could have implications for targeted prevention strategies. However, other smoking-related diseases, as well as practical and ethical considerations, need to be considered before any recommendations could be made.


Colchicine poisoning: the dark side of an ancient drug.
Colchicine is used mainly for the treatment and prevention of gout and for familial Mediterranean fever (FMF). It has a narrow therapeutic index, with no clear-cut distinction between nontoxic, toxic, and lethal doses, causing substantial confusion among clinicians. Although colchicine poisoning is sometimes intentional, unintentional toxicity is common and often associated with a poor outcome. We performed a systematic review by searching OVID MEDLINE between 1966 and January 2010. The search strategy included "colchicine" and "poisoning" or "overdose" or "toxicity" or "intoxication." Colchicine is readily absorbed after oral administration, but undergoes extensive first-pass metabolism. It is widely distributed and binds to intracellular elements. Colchicine is primarily metabolized by the liver, undergoes significant enterohepatic re-circulation, and is also excreted by the kidneys. THERAPEUTIC AND TOXIC DOSES: The usual adult oral doses for FMF is 1.2-2.4 mg/day; in acute gout 1.2 mg/day and for gout prophylaxis 0.5-0.6 mg/day three to four times a week. High fatality rate was reported after acute ingestions exceeding 0.5 mg/kg. The lowest reported lethal doses of oral colchicine are 7-26 mg. CYP 3A4 and P-glycoprotein inhibitors, such as clarithromycin, erythromycin, ketoconazole, ciclosporin, and natural grapefruit juice can increase colchicine concentrations. Co-administration with statins may increase the risk of myopathy. Colchicine's toxicity is an extension of its mechanism of action - binding to tubulin and disrupting the microtubular network. As a result, affected cells experience impaired protein assembly, decreased endocytosis and exocytosis, altered cell morphology, decreased cellular motility, arrest of mitosis, and interrupted cardiac myocyte conduction and contractility. The culmination of these mechanisms leads to multi-organ dysfunction and failure. REPRODUCTIVE TOXICOLOGY AND LACTATION: Colchicine was not shown to adversely affect reproductive potential in males or females. It crosses the placenta but there is no evidence of fetal toxicity. Colchicine is excreted into breast milk and considered compatible with lactation. Colchicine poisoning presents in three sequential and usually overlapping phases: 1) 10-24 h after ingestion - gastrointestinal phase mimicking gastroenteritis may be absent after intravenous administration; 2) 24 h to 7 days after ingestion - multi-organ dysfunction. Death results from rapidly progressive multi-organ failure and sepsis. Delayed presentation, pre-existing renal or liver impairment are associated with poor prognosis. 3) Recovery typically occurs within a few weeks of ingestion, and is generally a complete recovery barring complications of the acute illness. History of ingestion of tablets, parenteral administration, or consumption of colchicine-containing plants suggest the diagnosis. Colchicine poisoning should be suspected in patients with access to the drug and the typical toxidrome (gastroenteritis, hypotension, lactic acidosis, and prerenal azotemia). Timely gastrointestinal decontamination should be considered with activated charcoal, and very large, recent (<60 min) ingestions may warrant gastric lavage. Supportive treatments including administration of granulocyte colony-stimulating factor are the mainstay of treatment. Although a specific experimental treatment (Fab fragment antibodies) for colchicine poisoning has been used, it is not commercially available. Although colchicine poisoning is relatively uncommon, it is imperative to recognize its features as it is associated with a high mortality rate when missed.


Optimizing the diagnosis of hippocampal sclerosis using MR imaging.
To establish the optimal imaging parameters and MR features of hippocampal sclerosis. Twenty-five outpatients with intractable temporal lobe epilepsy and 10 control subjects were studied at 1.5T. Four features of hippocampal abnormality were specifically evaluated; increased hippocampal signal on T2-weighted images, decreased signal on T1-weighted images, hippocampal atrophy, and disruption of the internal hippocampal structure. Hippocampal sclerosis was diagnosed alone in 64% of patients and with ipsilateral pathology in a further 8%. In these 18 cases, increased hippocampal signal on T2-weighted images was seen in 77%, hippocampal atrophy in 83%, decreases signal on T1-weighted images in 83%, and disruption of the internal hippocampal structure in 89%. No abnormality was reported in any of the 10 control cases. Four MR features diagnostic of hippocampal sclerosis are reported. Inversion recovery images are very useful for identifying decreased signal in the hippocampus and loss of internal structure within the hippocampus. Based on an appreciation of these four features in optimized images, hippocampal sclerosis can be diagnosed with a high degree of accuracy and sensitivity.


Dysregulation of MS risk genes and pathways at distinct stages of disease.
To perform systematic transcriptomic analysis of multiple sclerosis (MS) risk genes in peripheral blood mononuclear cells (PBMCs) of subjects with distinct MS stages and describe the pathways characterized by dysregulated gene expressions. We monitored gene expression levels in PBMCs from 3 independent cohorts for a total of 297 cases (including clinically isolated syndromes (CIS), relapsing-remitting MS, primary and secondary progressive MS) and 96 healthy controls by distinct microarray platforms and quantitative PCR. Differential expression and pathway analyses for distinct MS stages were defined and validated by literature mining. Genes located in the vicinity of MS risk variants displayed altered expression in peripheral blood at distinct stages of MS compared with the healthy population. The frequency of dysregulation was significantly higher than expected in CIS and progressive forms of MS. Pathway analysis for each MS stage-specific gene list showed that dysregulated genes contributed to pathogenic processes with scientific evidence in MS. Systematic gene expression analysis in PBMCs highlighted selective dysregulation of MS susceptibility genes playing a role in novel and well-known pathogenic pathways.


Residual cancer burden after neoadjuvant chemotherapy and long-term survival outcomes in breast cancer: a multicentre pooled analysis of 5161 patients.
Previous studies have independently validated the prognostic relevance of residual cancer burden (RCB) after neoadjuvant chemotherapy. We used results from several independent cohorts in a pooled patient-level analysis to evaluate the relationship of RCB with long-term prognosis across different phenotypic subtypes of breast cancer, to assess generalisability in a broad range of practice settings. In this pooled analysis, 12 institutes and trials in Europe and the USA were identified by personal communications with site investigators. We obtained participant-level RCB results, and data on clinical and pathological stage, tumour subtype and grade, and treatment and follow-up in November, 2019, from patients (aged ≥18 years) with primary stage I-III breast cancer treated with neoadjuvant chemotherapy followed by surgery. We assessed the association between the continuous RCB score and the primary study outcome, event-free survival, using mixed-effects Cox models with the incorporation of random RCB and cohort effects to account for between-study heterogeneity, and stratification to account for differences in baseline hazard across cancer subtypes defined by hormone receptor status and HER2 status. The association was further evaluated within each breast cancer subtype in multivariable analyses incorporating random RCB and cohort effects and adjustments for age and pretreatment clinical T category, nodal status, and tumour grade. Kaplan-Meier estimates of event-free survival at 3, 5, and 10 years were computed for each RCB class within each subtype. We analysed participant-level data from 5161 patients treated with neoadjuvant chemotherapy between Sept 12, 1994, and Feb 11, 2019. Median age was 49 years (IQR 20-80). 1164 event-free survival events occurred during follow-up (median follow-up 56 months [IQR 0-186]). RCB score was prognostic within each breast cancer subtype, with higher RCB score significantly associated with worse event-free survival. The univariable hazard ratio (HR) associated with one unit increase in RCB ranged from 1·55 (95% CI 1·41-1·71) for hormone receptor-positive, HER2-negative patients to 2·16 (1·79-2·61) for the hormone receptor-negative, HER2-positive group (with or without HER2-targeted therapy; p<0·0001 for all subtypes). RCB score remained prognostic for event-free survival in multivariable models adjusted for age, grade, T category, and nodal status at baseline: the adjusted HR ranged from 1·52 (1·36-1·69) in the hormone receptor-positive, HER2-negative group to 2·09 (1·73-2·53) in the hormone receptor-negative, HER2-positive group (p<0·0001 for all subtypes). RCB score and class were independently prognostic in all subtypes of breast cancer, and generalisable to multiple practice settings. Although variability in hormone receptor subtype definitions and treatment across patients are likely to affect prognostic performance, the association we observed between RCB and a patient's residual risk suggests that prospective evaluation of RCB could be considered to become part of standard pathology reporting after neoadjuvant therapy. National Cancer Institute at the US National Institutes of Health.


Ectomesenchymoma: case report and review of the literature.
Ectomesenchymoma (EMCH) is a rare tumor that may arise in the brain or soft tissue. This tumor type is defined as a form including ectodermal components represented by neuroblasts or ganglion cells and differentiated mesenchymal structures of various types. The mesenchymal component is most often a rhabdomyosarcoma, but liposarcoma, malignant fibrous histiocytoma, leiomyosarcoma, chondrosarcoma, malignant schwannoma, and osseous elements have also been recorded. We report a case of an abdominal malignant ectomesenchymoma, containing three components, schwannoma, embryonal rhabdomyosarcoma, and ganglion cells, in a four-month-old infant. We also review 43 previously reported cases.


The relationship between diabetes and carotid artery calcifications detected via dental cone-beam computed tomography in patients undergoing implant treatment planning.
The authors investigated the association between carotid artery calcifications (CACs) detected incidentally on dental cone-beam computed tomographic scans and positive diabetes status. Two patient groups were identified retrospectively from a patient database: positive for CACs based on cone-beam computed tomographic scans and positive diabetes status. In addition to demographic characteristics, data including diabetes status and presence, type, and absence of CACs were obtained. A χ2 statistical analysis was completed by means of dividing the data into sets of known CAC and known history of diabetes; significance level was P < .05. To satisfy the a priori power analysis, records from 2010 through 2021 were used. For the positive CAC group, data were obtained from 288 patients (171 men, 117 women) and 68 patients (24%) had a positive diabetes status at the time of cone-beam computed tomography (P < .001). There were significantly more male patients (n = 47) than female patients (n = 21) with diabetes (χ2 = 9.9; P = .002). For the positive diabetes group, data were obtained from 225 patients (149 men, 76 women), and 100 patients (44%) had an identifiable CAC. There were significantly more male patients (n = 73) than female patients (n = 27) with CAC (χ2 = 21.2; P < .001). There was a significant relationship to diabetes for patients with CACs, indicating potential undiagnosed diabetes. Male patients with diabetes are significantly more at risk of developing CACs. People with CAC may be at risk of having undiagnosed diabetes and require heightened awareness during implant treatment planning.


Hepatitis B virus genotypes and extrahepatic manifestations.
This study aimed at correlating the presence of extrahepatic manifestations with hepatitis B virus (HBV) genotypes in patients with chronic HBV infection. This was a national (France), multicenter, retrospective, cross-sectional study. HBV genotypes were determined in 190 patients HBsAg-positive for at least 6 months and documented before any treatment. Patients were aged 42+/-15 years and mainly male (77%). Alcohol intake was high in 6% of them, ALT elevated in 73%; 27% were cirrhotic. All HBV genotypes were found, mainly A (24%), D (29%), C (11%), and E (10%). Thirty (16%) patients had clinical extrahepatic manifestations, mainly sensory-motor deficiency, sicca syndrome, myalgia, glomerulonephritis, and arthralgia-arthritis. Their presence was not related to any epidemiologic, viral (including genotypes) or hepatic factor, but to a higher platelet count (P=0.004). Twenty-nine (15%) patients had biological extrahepatic manifestations, mainly anti-smooth muscle, antinuclear, and anti-nucleosome antibodies. Their presence was related only to anti-HBe antibodies positivity (P=0.007) or elevated platelet count (P=0.003). Carrying precore mutant HBV increased by 2.8 folds the risk to have at least one extrahepatic biological manifestation. No relationships between HBV genotypes and the presence of extrahepatic manifestations were evidenced in patients with chronic HBV infection.


Cyclometalated titanium and zirconium complexes stabilised by a new silylmethylene-linked tetradentate triamidophosphine.
The silylmethylene-linked triamidophosphine P(CH2SiMe2NHPh)3 was isolated in form of its tri-lithium salt Li3[P(CH2SiMe2NPh)3]·2.5Et2O (1·2.5Et2O) and employed for the synthesis of titanium and zirconium complexes. Starting from 1·2.5Et2O, the chlorido complexes [κ(4)-N,N,N,P-PN3]MCl (4-M, M = Ti, Zr) were prepared and examined with respect to alkylation. Upon reaction of 4-Ti with (trimethylsilyl)methyl lithium, intra-ligand cyclometalation at one of the ortho-N-phenyl positions was observed and the resulting thermally stable titanazetidine [κ(5)-N,N,N,P,C-N2P(NC)]Ti (5-Ti) isolated. Similarly, the related zirconazetidine [κ(5)-N,N,N,P,C-N2P(NC)]Zr(THF) (5-Zr) was isolated upon reaction of 4-Zr with Bn2Mg(THF)2. Using LiCH2PMe2 as alkyl transfer reagent, both complexes 4-M were converted to the corresponding phosphametallacyclopropanes [κ(4)-N,N,N,P-PN3]M(κ(2)-C,P-CH2PMe2) (7-M, M = Ti, Zr). Upon gentle heating, complexes 7-M were cleanly converted to the cyclometalated species 5-M and trimethylphosphine. These results are discussed in the context of related amidophosphine and triamidoamine complexes.


Impact of a 3-year multi-centre community-based intervention on risk factors for chronic disease and obesity among free-living adults: the Healthy Alberta Communities study.
Healthy Alberta Communities (HAC) was a 3-year community-based intervention to reduce lifestyle-related risk factors for chronic disease and obesity at a population-level. The current paper examines changes in blood pressure (BP) and anthropometric indicators within HAC communities compared to secular trends. Between 2006 and 2009, this community-academic partnership sought to create environments supportive of healthier dietary and physical activity behaviours within four diverse communities in Alberta, Canada. Height, weight, waist and hip circumference and BP were measured among 1554 and 1808 community residents at baseline (2006) and follow-up (2009), respectively. A comparison sample was drawn from a representative national survey. Samples were stratified by age and change between pre- and post-intervention was assessed using t-tests. Changes in parameters over time between groups were compared using meta-analysis. The net difference in change in outcomes (change in intervention communities minus change in comparison group) represented the effect of the intervention. Adjusted systolic (SBP) and diastolic (DBP) BP declined within most age groups in HAC communities from pre- to post-intervention. The net decline in SBP was 1 mmHg in 20-39 year olds (p = 0.006) and 2 mmHg in 40-59 year olds (p = 0.001), while the net decline in DBP was 3 mmHg in 20-39 year olds (p < 0.001), 2 mmHg in 40-59 year olds (p < 0.001) and 3 mmHg in 60-79 year olds (p < 0.001). The net increase in the proportion of individuals with normal BP was 5.9 % (p < 0.001), while the net decline in the proportion of individuals with stage 1 hypertension was 4.5 % (p < 0.001). BMI and body weight were unchanged. There was a significant net increase in waist and hip circumference among 20-39 year olds within intervention communities. Findings suggest HAC succeeded in shifting the population distribution of BP in a leftward direction. By contrast, anthropometric parameters remained unchanged or worsened within intervention communities. Therefore, while improvements in some clinical risk factors can be achieved through relatively diffuse and shorter-term community-level environmental changes, improvements in others may require interventions of greater intensity and duration. Evaluating the success of community-based interventions based on their efficacy in changing individual-level clinical indicators may, however, underestimate their potential.


Trust, trustworthiness and health.
Trust is an essential component of good healthcare. If patients trust their physicians, then the relationship between them can be a richer and more meaningful one. The patient is more likely to feel confident and able to disclose symptoms, helping diagnosis and future care. If public health and community workers are trusted, not only is it likely that their work will be easier, in that their actions will be respected and accepted, but their advice will also be sought spontaneously. Trust, can, therefore, be thought of as something that is of benefit to all: healthcare workers, individuals and communities. Trust is, generally, something to be prized and we need to do anything we can to strengthen it.


Effects of Heating Season on Residential Indoor and Outdoor Polycyclic Aromatic Hydrocarbons, Black Carbon, and Particulate Matter in an Urban Birth Cohort.
Exposure to air pollutants has been associated with adverse health effects. However, analyses of the effects of season and ambient parameters such as ozone have not been fully conducted. Residential indoor and outdoor air levels of polycyclic aromatic hydrocarbons (PAH), black carbon (measured as absorption coefficient [Abs]), and fine particulate matter <2.5 μm (PM)(2.5) were measured over two-weeks in a cohort of 5-6 year old children (n=334) living in New York City's Northern Manhattan and the Bronx between October 2005 and April 2010. The objectives were to: 1) characterize seasonal changes in indoor and outdoor levels and indoor/outdoor (I/O) ratios of PAH (gas + particulate phase; dichotomized into Σ(8)PAH(semivolatile) (MW 178-206), and Σ(8)PAH(nonvolatile) (MW 228-278)), Abs, and PM(2.5); and 2) assess the relationship between PAH and ozone. Results showed that heating compared to nonheating season was associated with greater Σ(8)PAH(nonvolatile) (p<0.001) and Abs (p<0.05), and lower levels of Σ(8)PAH(semivolatile) (p<0.001). In addition, the heating season was associated with lower I/O ratios of Σ(8)PAH(nonvolatile) and higher I/O ratios of Σ(8)PAH(semivolatile) (p<0.001) compared to the nonheating season. In outdoor air, Σ(8)PAH(nonvolatile) was correlated negatively with community-wide ozone concentration (p<0.001). Seasonal changes in emission sources, air exchanges, meteorological conditions and photochemical/chemical degradation reactions are discussed in relationship to the observed seasonal trends.


The role of the chronic care model in promoting the management of the patient with rare liver disease.
The chronic care model (CCM) provides a holistic approach for managing chronic illnesses. Patients with rare liver diseases (RLD) have complex needs, impaired quality of life and often life-threatening complications. Most RLD meet the criteria for a long-term chronic condition and should be viewed through the prism of CCM. We aimed to ascertain whether the CCM has been considered for the frequently-encountered RLD. MEDLINE®/PubMed®/Cochrane/EMBASE were searched to identify publications relating to the use of the CCM for the management of six RLD. We identified 33 articles eligible for inclusion. Six, eleven, one, thirteen, two and zero studies, discussed individual components of the CCM for autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), primary sclerosing cirrhosis (PSC), Wilsons disease (WD), alpha-1 antitrypsin deficiency (A1AD) and lysosomal acid lipase deficiency (LALd) respectively. We have not identified studies using the full CCM for any of the aforementioned RLD. Unlike in common chronic conditions e.g. diabetes, there has been limited consideration of the use of CCM (or its components) for the management of RLD. This may reflect a reluctance of the clinical community to view these diseases as chronic or lack of healthcare policy investment in rare diseases in general.


Noninfectious penile lesions.
Family physicians commonly diagnose and manage penile cutaneous lesions. Noninfectious lesions may be classified as inflammatory and papulosquamous (e.g., psoriasis, lichen sclerosus, angiokeratomas, lichen nitidus, lichen planus), or as neoplastic (e.g., carcinoma in situ, invasive squamous cell carcinoma). The clinical presentation and appearance of the lesions guide the diagnosis. Psoriasis presents as red or salmon-colored plaques with overlying scales, often with systemic lesions. Lichen sclerosus presents as a phimotic, hypopigmented prepuce or glans penis with a cellophane-like texture. Angiokeratomas are typically asymptomatic, well-circumscribed, red or blue papules, whereas lichen nitidus usually produces asymptomatic pinhead-sized, hypopigmented papules. The lesions of lichen planus are pruritic, violaceous, polygonal papules that are typically systemic. Carcinoma in situ should be suspected if the patient has velvety red or keratotic plaques of the glans penis or prepuce, whereas invasive squamous cell carcinoma presents as a painless lump, ulcer, or fungating irregular mass. Some benign lesions, such as psoriasis and lichen planus, can mimic carcinoma in situ or squamous cell carcinoma. Biopsy is indicated if the diagnosis is in doubt or neoplasm cannot be excluded. The management of benign penile lesions usually involves observation or topical corticosteroids; however, neoplastic lesions generally require surgery.


Sex-specific developmental changes in muscle size and bone geometry at the femoral shaft.
When expressed as a percentage of the average result in young adults, bone mineral content lags behind bone length before puberty. Even though this observation has led to speculation about bone fragility in children, such relationships could simply be due to scaling effects when measures with different geometrical dimensions are compared. The study population comprised 145 healthy subjects (6-25 years, 94 females). Magnetic resonance imaging and dual-energy X-ray absorptiometry were used to determine femur length, bone mineral content, cortical bone mineral density, cross-sectional bone geometry (bone diameter; cortical thickness; total, cortical and medullary areas; cross-sectional and polar moments of area; bone strength index) and muscle area at the proximal one-third site of the femur. Results were dimensionally scaled by raising two-, three- and four-dimensional variables to the power of 1/2, 1/3 and 1/4, respectively. Sex-differences were also assessed before and after functionally adjusting variables for femur length and weight or muscle size. In prepubertal children, unscaled results expressed as percentages of adult values were lowest for variables with the highest dimensions (e.g., moments of area<bone mineral content<cross-sectional areas<femur length). However, when dimensionally scaled, results in children represented similar percentages of the respective average adult values, even after functional adjustments. Before puberty, there was no sex-difference in adjusted bone or muscle variables. After puberty, males had greater total and cortical bone area, bone diameter, moments of area, bone strength index and muscle area than women, both in absolute terms as well as adjusted for femur length and weight. The largest sex-difference was found for muscle area. When compared relative to muscle size, young adult women attained greater total and cortical bone area than men. Growth in femoral length, diameter, mass and strength appears well coordinated before puberty. Postpubertal females have narrower femora, less bone strength and muscle size than males. However, when muscle size is taken into account, females have a larger femoral bone cross-section and more cortical bone. These sex-differences likely result from a combination of mechanical and hormonal effects occurring during puberty.


Decisions to Transfer Nursing Home Residents to Emergency Departments: A Scoping Review of Contributing Factors and Staff Perspectives.
Nursing home (NH) residents are a frail and vulnerable population often faced with iatrogenic effects of hospital stays when transferred to emergency departments for acute changes in health status. Avoidable or unnecessary transfers of care need to be identified and defined to prevent unintended harm. The aim of this scoping review was to identify characteristics of avoidable or unnecessary transitions of NH residents to emergency departments, and examine factors influencing decision-making by NH staff, residents, and their family members to transfer nursing home residents to emergency departments. The search strategy began with 5 electronic databases, and a hand search of gray literature. Published qualitative and quantitative studies were included that examined the definition of avoidable or unnecessary transfers, and/or reported factors associated with decision-making to transfer NH residents to emergency departments. Methods included quality assessments, data extraction, and synthesis using content analysis. A total of 783 titles and abstracts were retrieved and screened resulting in 19 included studies. Results describing "avoidable" or "unnecessary" transfers were grouped into 3 dimensions of factors: management of early-acute or low-acuity symptoms and chronic disease management in NHs, ambulatory care-sensitive indicators, and use of post hoc assessments. Five categories of factors contributing to decision-making to transfer were identified: nursing factors, physician factors, facility/resource factors, NH resident/family factors, and health system factors. A consensus on the definition of "avoidable" or "unnecessary" transfers was not found. Findings suggest that transfers of NH residents to emergency departments may be avoided with increased care capacity within NHs. The decision-making process involved in the transfer is influenced by many factors, with intentions of both improving clinical outcomes and maintaining quality of life for the NH resident. Acute changes in health status are contextually specific and decisions must consider not only the resident's acute condition, but also resources available in the NH, and resident and family members' preferences for care. A definition of "avoidable" or "unnecessary" transfer must include reliable measurement, yet remain flexible enough to be generalizable to various care facilities to meet the needs of NH residents and manage required care safely within the NH. Robust research aimed at improving the primary care of NH residents is essential to informing health policy reform and education of those providing care in NHs.


Source of the great A.D. 1257 mystery eruption unveiled, Samalas volcano, Rinjani Volcanic Complex, Indonesia.
Polar ice core records attest to a colossal volcanic eruption that took place ca. A.D. 1257 or 1258, most probably in the tropics. Estimates based on sulfate deposition in these records suggest that it yielded the largest volcanic sulfur release to the stratosphere of the past 7,000 y. Tree rings, medieval chronicles, and computational models corroborate the expected worldwide atmospheric and climatic effects of this eruption. However, until now there has been no convincing candidate for the mid-13th century "mystery eruption." Drawing upon compelling evidence from stratigraphic and geomorphic data, physical volcanology, radiocarbon dating, tephra geochemistry, and chronicles, we argue the source of this long-sought eruption is the Samalas volcano, adjacent to Mount Rinjani on Lombok Island, Indonesia. At least 40 km(3) (dense-rock equivalent) of tephra were deposited and the eruption column reached an altitude of up to 43 km. Three principal pumice fallout deposits mantle the region and thick pyroclastic flow deposits are found at the coast, 25 km from source. With an estimated magnitude of 7, this event ranks among the largest Holocene explosive eruptions. Radiocarbon dates on charcoal are consistent with a mid-13th century eruption. In addition, glass geochemistry of the associated pumice deposits matches that of shards found in both Arctic and Antarctic ice cores, providing compelling evidence to link the prominent A.D. 1258/1259 ice core sulfate spike to Samalas. We further constrain the timing of the mystery eruption based on tephra dispersal and historical records, suggesting it occurred between May and October A.D. 1257.


Is REST a regulator of pluripotency?
Establishment and maintenance of the pluripotent state of ESCs is a key issue in stem cell biology and regenerative medicine, and consequently identification of transcription factors that regulate ESC pluripotency is an important goal. Singh et al. claim that the transcriptional repressor REST is such a regulator and that a 50% reduction of REST in ESCs leads to activation of a specific microRNA, miR-21, and that this subsequently results in loss of pluripotency markers and a reciprocal gain in some lineage-specific differentiation markers. In contrast, we show that, in haplodeficient Rest(+/-) ESCs, we detected no change in pluripotency markers, no precocious expression of differentiated neuronal markers and no interaction of REST with miR-21. It is vital that identification of factors that regulate pluripotency is based on robust, consistent data, and the contrast in data reported here undermines the claim by Singh et al. that REST is such a regulator.


Postweaning and feedlot growth and carcass characteristics of Angus-, gray Brahman-, Gir-, Indu-Brazil-, Nellore-, and red Brahman-sired F1 calves.
Postweaning, feedlot, and carcass data from crossbred calves sired by five Bos indicus breeds and one Bos taurus breed were evaluated. Data included records from F1 calves out of multiparous Hereford cows sired by Angus, Gray Brahman, Gir, Indu-Brazil, Nellore, and Red Brahman bulls. The Zebu crosses grew faster postweaning and were heavier and taller as yearlings than the Angus crosses (P < .05). Among the Zebu-sired calves, the Red and Gray Brahman crosses were faster gaining and were heavier at a year of age than the Gir, Indu-Brazil, and Nellore. The Nellore crosses were significantly taller than the Gray Brahman- and Gir-sired crosses; the Indu-Brazil and Red Brahman were intermediate. Angus crosses were lightest on and off feed but were not significantly different from Gir, and Red and Gray Brahman were heaviest (P < .05). The Nellore and Indu-Brazil were similar in initial weight, but Indu-Brazil calves were similar to Red and Gray Brahman for final weight. The Angus cross was more desirable (P < .05) in marbling score and quality grade although the Nellore crosses had the most desirable score and grade of the Zebu crosses. Gir crosses had higher skeletal maturity scores (P < .05) than Nellore, Gray Brahman, Indu-Brazil, and Angus crosses; Red Brahman crosses were intermediate Angus crosses had the lightest carcasses but not significantly lighter than the Indu-Brazil, Gir, or Nellore. Red Brahman-cross carcasses were heaviest and Gray Brahman-cross carcasses were intermediate.(ABSTRACT TRUNCATED AT 250 WORDS)


Does informed consent influence therapeutic outcome? A clinical trial of the hypnotic activity of placebo in patients admitted to hospital.
To examine whether written informed consent might influence the results of clinical trials the effect of placebo when given with or without informed consent to patients suffering from insomnia was studied. The study was a single blind observer blinded trial, and patients were paired according to sex, age, and hospital environment. Randomisation assigned the first patient of each pair to the control group (without informed consent) or the group to give informed consent. Of the 56 patients, 26 refused to give informed consent, and the age and sex distribution of these differed significantly (p less than 0.02) from the 30 pairs of patients ultimately enrolled into the study. In this "biased" sample, the hypnotic activity of placebo was significantly higher in the control group (p less than 0.05). It is concluded that the informed consent procedure biases the results of clinical trials and might affect their general applicability.


Antigen retrieval technique utilizing citrate buffer or urea solution for immunohistochemical demonstration of androgen receptor in formalin-fixed paraffin sections.
We developed a staining protocol for demonstration of androgen receptor (AR) in formalin-fixed, paraffin-embedded tissue sections. The method is based on the antigen retrieval microwave (MW) heating technique. Results are compared with different types of enzyme digestion pre-treatments. The strongest immunostaining signal and clearest background were obtained by MW heating of dewaxed paraffin sections in 5% urea or citrate buffer solution (pH 6); pure distilled water gave less consistent results. Enzymatic digestion with pepsin (0.05% in 2 N HCl) for 30 min at room temperature, or trypsin followed by pronase, or pronase digestion alone, also produced enhanced staining of AR in some cases, but there was more nonspecific background, and specific reactivity was less intense. The antigen retrieval MW method can be used to demonstrate AR epitope in prostate tissue after fixation in formalin for as long as 7 days. AR immunolocalization was also compared in frozen and paraffin sections processed from the same specimen of prostate carcinoma tissue and was found to be qualitatively and quantitatively similar. This study also provided new information concerning the basic principles of the antigen retrieval MW method that may be helpful in further development of this technique.


Application of identified QTL-marker associations in rice quality improvement through a design-breeding approach.
A permanent mapping population of rice consisting of 65 non-idealized chromosome segment substitution lines (denoted as CSSL1 to CSSL65) and 82 donor parent chromosome segments (denoted as M1 to M82) was used to identify QTL with additive effects for two rice quality traits, area of chalky endosperm (ACE) and amylose content (AC), by a likelihood ratio test based on stepwise regression. Subsequently, the genetics and breeding simulation tool QuLine was employed to demonstrate the application of the identified QTL in rice quality improvement. When a LOD threshold of 2.0 was used, a total of 16 chromosome segments were associated with QTL for ACE, and a total of 15 segments with QTL for AC in at least one environment. Four target genotypes denoted as DG1 to DG4 were designed based on the identified QTL, and according to low ACE and high AC breeding objectives. Target genotypes DG1 and DG2 can be achieved via a topcross (TC) among the three lines CSSL4, CSSL28, and CSSL49. Results revealed that TC2: (CSSL4 x CSSL49) x CSSL28 and TC3: (CSSL28 x CSSL49) x CSSL4 resulted in higher DG1 frequency in their doubled haploid populations, whereas TC1: (CSSL4 x CSSL28) x CSSL49 resulted in the highest DG2 frequency. Target genotypes DG3 and DG4 can be developed by a double cross among the four lines CSSL4, CSSL28, CSSL49, and CSSL52. In a double cross, the order of parents affects the frequency of target genotype to be selected. Results suggested that the double cross between the two single crosses (CSSL4 x CSSL28) and (CSSL49 x CSSL52) resulted in the highest frequency for DG3 and DG4 genotypes in its derived doubled haploid derivatives. Using an enhancement selection methodology, alternative ways were investigated to increase the target genotype frequency without significantly increasing the total cost of breeding operations.


Role of ureteric stents in relieving obstruction in patients with obstructive uropathy.
The aim of this study is to evaluate the role of ureteric stents in relieving obstruction and improvement of kidney function in patients with obstructive uropathy. This study involved 138 patients with obstructive uropathy with age ranged from 2 months to 73 years. Patients classified into two groups: Group (I): Includes 57 patients (41.3%), ureteric stents fixed to them; and Group (II): Includes 81 patients (58.6%) managed by other treatment modalities. All patients underwent clinical assessment, Laboratory and radiologic investigations: At presentation and postoperative. These included: Complete urine analysis, urine culture and sensitivity, serum creatinine, serum urea nitrogen, serum uric acid, serum sodium (Na), serum potassium (K), Fasting blood glucose level and blood picture and plain X-ray (KUB), abdominal ultrasonography (US), diuretic renography and retrograde pyelography. Renal glomerular filtration rate (GFR) was used as an indicator for improvement of renal function after fixation of ureteric stent. In group I: 56 (71.8%) kidneys showed significant recovery compared to 61 kidneys (66.3%). In group II, there is statistically significant relation between renal perfusion and renal recovery (P < 0.004), statistically significant relation between parenchymal thickness and recovery in both groups (P < 0.0002), statistically significant relation between degree of corticomedullary differentiation and recovery (P < 0.0003) and statistically significant relationship between hemoglobin levels at presentation and the recoverability (P < 0.002). The predictors of renal recoverability revealed that ureteral stents alone can help in regaining renal function and significant improvement of clinical condition in patients with obstructive uropathy.


Visual Representation of Cultural and Collegial Collaboration.
Description Our colleagues are those on whom we not only rely to help us with patient care and advocacy but also to establish a meaningful and collaborative relationship. The connection between comrades of different departments and specialties facilitates a deep understanding of the intricacies involved in treating a variety of maladies, and we quickly find ourselves ardently discussing our own life struggles, achievements, woes, and joys with those whom we once considered strangers, which only demonstrates the steadfastness of our professional and collegial relationships. However, for a holistic approach to the discipline of healing, the interconnectedness of other subdisciplines needs to be recognized. Therefore, in an attempt to bridge the perceptual disciplinary gaps, the commonalities of approach, and affinities of cultural traditions need to be integrated. In this painting, one can appreciate a central stained-glass pattern that mimics those seen in ancient Persian forts and buildings of old. The medium used is acrylic paint, embellished with glitter and sparkling rhinestones to add an element of elegance and regality. Surrounding the central pattern are intricate and brightly colored South Asian henna designs, which often decorate the palms of individuals celebrating auspicious occasions. This combination of elements reflects how different cultures and backgrounds can intermingle and enhance both the technique as well as the visual beauty of mutual interactions and the awareness of interconnectedness.


Decrease in self-esteem mediates the association between symptoms of social phobia and depression in middle adolescence in a sex-specific manner: a 2-year follow-up of a prospective population cohort study.
Social phobia and depression are common, highly comorbid disorders in middle adolescence. The mechanism underlying this comorbidity, however, is unclear. Decrease in self-esteem caused by the initial disorder might play a decisive role in the development of the subsequent disorder. The present study aimed to determine whether the association between symptoms of social phobia and depression is mediated by decrease in self-esteem in mid-adolescent girls and boys. As a part of the prospective Adolescent Mental Health Cohort (AMCH), subjects of this study were 9th grade pupils (mean age, 15.5) responding to a survey conducted in 2002-2003 (T1) and to a 2-year follow-up survey in 2004-2005 (T2) (N = 2070, mean age 17.6 years, 54.5% girls). Symptoms of social phobia without symptoms of depression at age 15 and symptoms of depression at age 17 were associated only among boys, and this association was mediated by decrease in self-esteem. Symptoms of depression without symptoms of social phobia at age 15 and symptoms of social phobia at age 17 were associated only among girls, and this association was partially mediated by decrease in self-esteem. Decrease in self-esteem plays a decisive role in the association between social phobia and depression. Self-esteem should be a key focus in interventions for adolescents suffering from social phobia or depression. Efficient intervention for the first disorder might help to prevent the decline in self-esteem and thus the incidence of the subsequent disorder. These findings are based on a sample of Finnish adolescents and should be confirmed in other jurisdictions or in more ethnically diverse samples.


Function of the heater: the dead horse arum revisited.
The dead horse arum, Helicodiceros muscivorus, is a conspicuous, foul smelling and thermogenic plant of the Araceae family. This Mediterranean arum lily copies several aspects of a carcass in order to attract carrion blowflies, which are subsequently exploited as unrewarded pollinators. We have previously shown that this plant exhibits a highly accurate olfactory carrion mimicry, which serves to attract the blowflies. In this study, we have investigated the role of thermogeny in the arum. We show that the thermogeny has a direct effect on the pollinators, altering their behaviour. By manipulating heat and odour release of the plant, we can show that the heat, produced along the appendix, is important to lure the flies to this structure, which is vital as the flies from the appendix are more prone to enter the trap chamber that houses the female and male florets. This study provides rare evidence for a direct functional role of thermogeny.


Diagnostic efficacy of 18F-FDG PET/CT in patients with adrenal incidentaloma.
The management of adrenal incidentaloma is still a challenge with respect to determining its functionality (hormone secretion) and malignancy. In this light, we performed 18F-FDG PET/CT scan to assess the SUVmax values in different adrenal masses including Cushing syndrome, pheochromocytoma, primary hyperaldosteronism and non-functional adrenal adenomas. Total 109 (73 F, 36 M) patients with adrenal mass (incidentaloma), mean age of 53.3 ± 10.2 years (range, 24-70) were screened by 18F-FDG PET/CT. Data of 18F-FDG PET/CT imaging of the patients were assessed by the same specialist. Adrenal masses were identified according to the calculated standardized uptake values (SUVs). Clinical examination, 24-h urine cortisol, catecholamine metabolites, 1-mg dexamethasone suppression test, aldosterone/renin ratio and serum electrolytes were analyzed. Based on the clinical and hormonal evaluations, there were 100 patients with non-functional adrenal mass, four with cortisol-secreting, four with pheochromocytomas and one with aldosterone-secreting adenoma. Mean adrenal mass diameter of 109 patients was 2.1 ± 4.3 (range, 1-6.5 cm). The 18F-FDG PET/CT imaging of the patients revealed that lower SUVmax values were found in non-functional adrenal masses (SUVmax 3.2) when compared to the functional adrenal masses including four with cortisol-secreting adenoma (SUVmax 10.1); four with pheochromcytoma (SUVmax 8.7) and one with aldosterone-secreting adenomas (SUVmax 3.30). Cortisol-secreting (Cushing syndrome) adrenal masses showed the highest SUVmax value (10.1), and a cut-off SUVmax of 4.135 was found with an 84.6% sensitivity and 75.6% specificity cortisol-secreting adrenal adenoma. Consistent with the similar studies, non-functional adrenal adenomas typically do not show increased FDG uptake and a certain form of functional adenoma could present various FDG uptake in FDG PET/CT. Especially functional adrenal adenomas (cortisol secreting was the highest) showed increased FDG uptake in comparison to the non-functional adrenal masses. Therefore, setting a specific SUVmax value in the differentiation of malignant adrenal lesion from the benign one is risky and further studies, including a high number of functional adrenal mass are needed.


Altered Sympathoadrenal Activity Following Cold-Water Diving.
Little data exist on the effect of extremely cold-water diving on thermo-metabolic hormone secretion. Moreover, the impact of repetitive dives on the stress response is unknown. The purpose of this study was to determine the effects of two daily bouts of cold-water diving on the hormonal and metabolic profile of elite military personnel and to measure the stress response. Healthy, male, Norwegian Special Forces operators (n = 5) volunteered for this study. Physiological and hormone data were analyzed prior to and following twice-daily Arctic dives (3.3°C). Core temperature was maintained (p > .05), whereas skin temperature was significantly reduced over the course of each dive (p < .01). Pairwise comparisons revealed adrenocorticotropic hormone (ACTH) and cortisol concentration significantly decreased across both dives and days (p < .001). Adrenaline and noradrenaline significantly increased across both time and day (p < .001). Leptin, testosterone, and IGF-1 significantly decreased over time but recovered between days. The main findings of this effort are that there is a rapid sympathetic-adreno-medullary (SAM/SNS) response to cold-water diving and a suppression of the hypothalamic-pituitary-adrenal (HPA) axis and hormones related to repair and recovery. While the sample size was too small to determine the role of SAM/SNS, HPA, and thyroid hormone effect on thermoregulation, it addresses a gap in our understanding of physiological adaptions that occurs in extreme environments.


Mitogenesis, cell migration, and loss of focal adhesions induced by tenascin-C interacting with its cell surface receptor, annexin II.
In a previous study we demonstrated that the alternatively spliced region of tenascin-C, TNfnA-D, bound with high affinity to a cell surface receptor, annexin II. In the present study we demonstrate three changes in cellular activity that are produced by adding intact tenascin-C or TNfnA-D to cells, and we show that all three activities are blocked by antibodies against annexin II. 1) TNfnA-D added to confluent endothelial cells induced loss of focal adhesions. 2) TNfnA-D produced a mitogenic response of confluent, growth-arrested endothelial cells in 1% serum. TNfnA-D stimulated mitogenesis only when it was added to cells before or during exposure to other mitogens, such as basic fibroblast growth factor or serum. Thus the effect of TNfnA-D seems to be to facilitate the subsequent response to growth factors. 3) TNfnA-D enhanced cell migration in a cell culture wound assay. Antibodies to annexin II blocked all three cellular responses to TNfnA-D. These data show that annexin II receptors on endothelial cells mediate several cell regulatory functions attributed to tenascin-C, potentially through modulation of intracellular signalling pathways.


Updated efficacy of avelumab in patients with previously treated metastatic Merkel cell carcinoma after ≥1 year of follow-up: JAVELIN Merkel 200, a phase 2 clinical trial.
Merkel cell carcinoma (MCC) is a rare, aggressive skin cancer associated with poor survival outcomes in patients with distant metastatic disease (mMCC). In an initial analysis from JAVELIN Merkel 200, a phase 2, prospective, open-label, single-arm trial in mMCC, avelumab-a human anti-programmed death-ligand 1 (PD-L1) monoclonal antibody-showed promising efficacy and a safety profile that was generally manageable and tolerable. Here, we report the efficacy of avelumab after ≥1 year of follow-up in patients with distant mMCC that had progressed following prior chemotherapy for metastatic disease. Patients received avelumab 10 mg/kg by 1-h intravenous infusion every 2 weeks until confirmed disease progression, unacceptable toxicity, or withdrawal. The primary endpoint was best overall response. Secondary endpoints included duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Patients (N = 88) were followed for a minimum of 12 months. The confirmed objective response rate was 33.0% (95% CI, 23.3%-43.8%; complete response: 11.4%). An estimated 74% of responses lasted ≥1 year, and 72.4% of responses were ongoing at data cutoff. Responses were durable, with the median DOR not yet reached (95% CI, 18.0 months-not estimable), and PFS was prolonged; 1-year PFS and OS rates were 30% (95% CI, 21%-41%) and 52% (95% CI, 41%-62%), respectively. Median OS was 12.9 months (95% CI, 7.5-not estimable). Subgroup analyses suggested a higher probability of response in patients receiving fewer prior lines of systemic therapy, with a lower baseline disease burden, and with PD-L1-positive tumors; however, durable responses occurred irrespective of baseline factors, including tumor Merkel cell polyomavirus status. With longer follow-up, avelumab continues to show durable responses and promising survival outcomes in patients with distant mMCC whose disease had progressed after chemotherapy. Clinicaltrials.gov identifier: NCT02155647.


Monoaminergic activity at the level of the hypothalamus and striatum: relationship to anticipated feeding and pancreatic insulin responses.
The present study examined monoaminergic activity at the level of the lateral hypothalamus (LH), ventromedial hypothalamus (VMH) and ventral striatum associated with the conditioned cephalic phase insulin release. Partially food-deprived male Wistar rats were divided into 3 groups. Two of the groups were conditioned to drink a 50% glucose solution each morning for 3 weeks; the control group received an amount of glucose equal to the amount drunk by the experimental animals with their afternoon meal. On test day, conditioned animals were sacrificed either just prior to glucose presentation or 2 min following consumption of the solution; control animals were sacrificed at the same time. Gas chromatography/mass spectrometry was used to determine the levels of the monoamines noradrenaline (NA), dopamine (DA) and serotonin (5-HT), as well as their principal metabolites dihydroxyphenylethyleneglycol, 3,4-dihydroxyphenylacetic acid (DOPAC) and 5-hydroxyindoleacetic acid (5-HIAA) in the LH and VMH. DA and DOPAC levels were assayed in the striatum. Although serum glucose levels were unchanged, animals conditioned to drink glucose had significantly higher serum insulin levels. This increased insulin was associated with increased content of 5-HT and 5-HIAA at the level of the LH and VMH, increased NA content in the LH, increased DOPAC levels in the VMH as well as increases in the ratio of DOPAC to DA in the striatum. A regression analysis showed that 5-HIAA at the level of the LH related closely to serum insulin levels.(ABSTRACT TRUNCATED AT 250 WORDS)