Volumetric spectroscopic imaging of glioblastoma multiforme radiation treatment volumes.
Magnetic resonance (MR) imaging and computed tomography (CT) are used almost exclusively in radiation therapy planning of glioblastoma multiforme (GBM), despite their well-recognized limitations. MR spectroscopic imaging (MRSI) can identify biochemical patterns associated with normal brain and tumor, predominantly by observation of choline (Cho) and N-acetylaspartate (NAA) distributions. In this study, volumetric 3-dimensional MRSI was used to map these compounds over a wide region of the brain and to evaluate metabolite-defined treatment targets (metabolic tumor volumes [MTV]). Volumetric MRSI with effective voxel size of ∼1.0 mL and standard clinical MR images were obtained from 19 GBM patients. Gross tumor volumes and edema were manually outlined, and clinical target volumes (CTVs) receiving 46 and 60 Gy were defined (CTV46 and CTV60, respectively). MTVCho and MTVNAA were constructed based on volumes with high Cho and low NAA relative to values estimated from normal-appearing tissue. The MRSI coverage of the brain was between 70% and 76%. The MTVNAA were almost entirely contained within the edema, and the correlation between the 2 volumes was significant (r=0.68, P=.001). In contrast, a considerable fraction of MTVCho was outside of the edema (median, 33%) and for some patients it was also outside of the CTV46 and CTV60. These untreated volumes were greater than 10% for 7 patients (37%) in the study, and on average more than one-third (34.3%) of the MTVCho for these patients were outside of CTV60. This study demonstrates the potential usefulness of whole-brain MRSI for radiation therapy planning of GBM and revealed that areas of metabolically active tumor are not covered by standard RT volumes. The described integration of MTV into the RT system will pave the way to future clinical trials investigating outcomes in patients treated based on metabolic information.


Bufo arenarum egg jelly coat: purification and characterization of two highly glycosylated proteins.
Egg jelly coats from Bufo arenarum are formed by components secreted along the oviduct. These secretion products overlay the oocytes as they transit along the different oviductal portions. In this study, we have isolated two highly glycosylated proteins of the jelly coat, which are secreted almost all the way along the oviduct. Both glycoproteins [designated as highly glycosylated protein (HGP) and low-molecular-mass highly glycosylated protein (L-HGP)] were purified to homogeneity, from the secretion of the caudal oviduct portion, by CsCl density gradient ultracentrifugation. HGP is a high-molecular-mass protein with mucin-like characteristics: high viscosity, a high content of serine and threonine, about 70% carbohydrate by weight, and a protease-resistant domain. Cleavage of disulphide bridges with reducing agents resulted in the release of a single subunit (300000 Da). L-HGP is also a disulphide-cross-linked protein with lower apparent monomeric molecular mass, in the range 100-120 kDa and containing 50% carbohydrate by weight. HGP contains galactose, fucose, N-acetylgalactosamine and sialic acid, but no mannose, suggesting the presence of O-linked oligosaccharides exclusively. The secretion ratio of HGP increases from cephalic (16% of total protein in pars preconvoluta) to caudal (40% of total protein in pars convoluta) oviductal portions. It appears to be the major structural component of the jelly coat. Our purification data suggest that HGP is non-covalently linked to the other egg jelly proteins. Polyclonal antiserum to each purified glycoprotein from secretion was raised in rabbits and used to localize both glycoproteins in the different oviductal portions, total egg jelly and the aqueous medium where oocyte strings were incubated. HGP forms a stable fibre matrix around the oocyte. L-HGP is present in the jelly coat and is released into the incubation medium.


A pharmacological evidence for the presence of antihistaminic and anticholinergic activities in Equisetum debile Roxb.
The study was designed to evaluate possible antihistaminic and anticholinergic activities of Equisetum debile. Effects of crude ethanolic (Ed.Eth) and effects of crude aqueous (Ed.Aq) extracts of E. debile were studied using isolated guinea pig ileum, rabbit jejunum, and rabbit trachea. Tissue responses were recorded using isotonic and isometric transducers, connected with PowerLab data acquisition system. A dose-dependent (0.1-0.3 mg/ml) rightward shift was demonstrated in histamine concentration-response curves. Whereas a complete relaxation of carbachol (1 μM)-induced contractions in isolated rabbit jejunum (3 mg/ml) and tracheal (10 mg/ml) preparations was observed, similar to dicyclomine at 1 and 3 μM, respectively. However, no significant difference between the effects of Ed.Eth and Ed.Aq was observed. Study provides pharmacological evidence for the presence of antihistaminic and anticholinergic activities in crude extracts of E. debile and also highlight its medicinal significance in the management of airway and gastrointestinal disorders.


False memories and normal aging: Links between inhibitory capacities and monitoring processes.
Empirical evidence suggests an increased production of false memories with advancing age. The activation-monitoring theory proposes that strategic monitoring processes influence the probability of false recall in the DRM paradigm. In the present study, we examined the hypothesis that a low level of inhibition may impair the efficient use of monitoring processes during information retrieval and thus increase the production of false memories in aging. Accordingly, we conducted a study in which older adults with low or high levels of inhibition performed a standard DRM task or an inclusion DRM task that disables monitoring processes. The results indicated that low inhibitory capacities were associated with fewer correct recalls and increased production of critical lures (false memories), suggesting difficulties in using monitoring processes at the time of retrieval. Our findings also showed that the relationship between Age and the production of critical lures in a standard DRM task is mediated by Inhibition. These results are interpreted as suggesting that inhibitory abilities may partly be linked to the impairment of monitoring processes in the elderly. (PsycINFO Database Record


Defining Scholarship in Physician Assistant Education.
The goal of educational scholarship is to establish evidence that identifies excellence in teaching, curriculum design, student assessment, mentoring, advising, leadership, and administration. Our challenge as faculty is to determine what best defines this within our profession. Responsibilities of physician assistant (PA) educators include not only increasing evidence supporting quality in PA education but also outlining strategies that lead us to this success. As innovative scholars, we should focus on expanding the definition of educational scholarship by reevaluating criteria that define it. We then can explore new opportunities for faculty to develop a portfolio that endorses their academic advancement. The outcomes of this scholarship can be used to further advance PA education and clinical practice. Educational scholarship should satisfy the following: address a need, expand existing research, and be provocative, measurable, and reproducible. As innovative scholars, we should also consider analyzing existing evidence and determine whether what has been defined as best practices in the general areas of health care education are also effective in PA education. The outcomes of this research can be used to establish best practices within PA education. Cultivating a collaborative environment among programs will enable our profession to gather robust evidence supporting a quality education.


Response of renal allograft recipients to pneumococcal vaccine.
Antibody responses to pneumococcal polysaccharide vaccine were compared in a control group of 17 normal adults and in a group of 27 adult patients with stable renal function (serum creatinine 0.8--2.1 mg/dl) seven months to nine years following renal transplantation. Using the indirect hemagglutination technique, antibody titers to 13 of the 14 capsular antigens contained in the vaccine were determined for each patient just prior to and again three weeks following immunization. There was no significant difference between the two groups in the proportion of patients responding with a fourfold rise in titer to 12 of the 13 antigens tested. The response rate to antigen type 3 was reduced in the transplant group (p less than 0.05). Mean fold increase in indirect hemagglutination titers was likewise determined for each antigen, and a reduced response in the transplant group was noted only to antigen type 23 (p = 0.037). Immunosuppressed renal allograft recipients appear capable of mounting a nearly normal antibody response to pneumococcal vaccine.


With or without us? An audit of disability research in the southern African region.
Disability research in the global South has not received significant critical consideration as to how it can be used to challenge the oppression and marginalisation of people with disabilities in low-income and middle-income countries. The Southern Africa Federation of the Disabled (SAFOD) embarked on a programme to use research to influence policy and practice relating to people with disabilities in Southern Africa, and commissioned an audit on research expertise in the region. In this article, a research audit is reported on and situated in a framework of emancipatory research. This article sets out to describe a preliminary audit of disability research in the southern African region and to draw conclusions about the current state of disability research in the region and make recommendations. The research method entailed working with disability researchers in the ten SAFOD member countries and utilising African disability networks hosted on electronic media. Disability researchers working in the region completed 87 questionnaires, which were reviewed through a thematic analysis. The discussion of results provides a consideration of definitions of disability; the understanding of disability rights, research topics and methodologies; the participation of people with disabilities in research; and the challenges and opportunities for using research to inform disability activism. The conclusion highlights critical issues for future research in the region, and considers how a disability researcher database can be used as a tool for disability organisations to prioritise research that serves a disability rights agenda.


The use of actor-based immersive health and safety inductions: Lessons from the Thames Tideway Tunnel megaproject.
Health and safety inductions are ubiquitous in construction but tend to be poorly designed and suffer low levels of worker engagement. In this paper we report on the evaluation of an innovative, full day, actor-based health and safety induction called EPIC, currently being used on London's Thames Tideway Tunnel megaproject. As of March 2019, more than 14,000 individuals had attended EPIC. This evaluation examines the impact of EPIC from the perspective of participants and other stakeholders, and considers the utility of actor-based immersive health and safety inductions for use more widely, in both construction and other sectors. Using a mixed-method, longitudinal approach to data collection, EPIC is evaluated against Kirkpatrick's (1959) 'four levels' framework of reactions, learning, behaviour change and results. This paper discusses factors which support and hinder actor-based inductions, and the challenges involved in assessing the impact of inductions on subsequent behaviour and health and safety outcomes.


Prevalence and Clinical Import of Thoracic Injury Identified by Chest Computed Tomography but Not Chest Radiography in Blunt Trauma: Multicenter Prospective Cohort Study.
Chest computed tomography (CT) diagnoses more injuries than chest radiography, so-called occult injuries. Wide availability of chest CT has driven substantial increase in emergency department use, although the incidence and clinical significance of chest CT findings have not been fully described. We determine the frequency, severity, and clinical import of occult injury, as determined by changes in management. These data will better inform clinical decisions, need for chest CT, and odds of intervention. Our sample included prospective data (2009 to 2013) on 5,912 patients at 10 Level I trauma center EDs with both chest radiography and chest CT at physician discretion. These patients were 40.6% of 14,553 enrolled in the parent study who had either chest radiography or chest CT. Occult injuries were pneumothorax, hemothorax, sternal or greater than 2 rib fractures, pulmonary contusion, thoracic spine or scapula fracture, and diaphragm or great vessel injury found on chest CT but not on preceding chest radiography. A priori, we categorized thoracic injuries as major (having invasive procedures), minor (observation or inpatient pain control >24 hours), or of no clinical significance. Primary outcome was prevalence and proportion of occult injury with major interventions of chest tube, mechanical ventilation, or surgery. Secondary outcome was minor interventions of admission rate or observation hours because of occult injury. Two thousand forty-eight patients (34.6%) had chest injury on chest radiography or chest CT, whereas 1,454 of these patients (71.0%, 24.6% of all patients) had occult injury. Of these, in 954 patients (46.6% of injured, 16.1% of total), chest CT found injuries not observed on immediately preceding chest radiography. In 500 more patients (24.4% of injured patients, 8.5% of all patients), chest radiography found some injury, but chest CT found occult injury. Chest radiography found all injuries in only 29.0% of injured patients. Two hundred and two patients with occult injury (of 1,454, 13.9%) had major interventions, 343 of 1,454 (23.6%) had minor interventions, and 909 (62.5%) had no intervention. Patients with occult injury included 514 with pulmonary contusions (of 682 total, 75.4% occult), 405 with pneumothorax (of 597 total, 67.8% occult), 184 with hemothorax (of 230 total, 80.0% occult), those with greater than 2 rib fractures (n=672/1,120, 60.0% occult) or sternal fracture (n=269/281, 95.7% occult), 12 with great vessel injury (of 18 total, 66.7% occult), 5 with diaphragm injury (of 6, 83.3% occult), and 537 with multiple occult injuries. Interventions for patients with occult injury included mechanical ventilation for 31 of 514 patients with pulmonary contusion (6.0%), chest tube for 118 of 405 patients with pneumothorax (29.1%), and 75 of 184 patients with hemothorax (40.8%). Inpatient pain control or observation greater than 24 hours was conducted for 183 of 672 patients with rib fractures (27.2%) and 79 of 269 with sternal fractures (29.4%). Three of 12 (25%) patients with occult great vessel injuries had surgery. Repeated imaging was conducted for 50.6% of patients with occult injury (88.1% chest radiography, 11.9% chest CT, 7.5% both). For patients with occult injury, 90.9% (1,321/1,454) were admitted, with 9.1% observed in the ED for median 6.9 hours. Forty-four percent of observed patients were then admitted (4.0% of patients with occult injury). In a more seriously injured subset of patients with blunt trauma who had both chest radiography and chest CT, occult injuries were found by chest CT in 71% of those with thoracic injuries and one fourth of all those with blunt chest trauma. More than one third of occult injury had intervention (37.5%). Chest tubes composed 76.2% of occult injury major interventions, with observation or inpatient pain control greater than 24 hours in 32.4% of occult fractures. Only 1 in 20 patients with occult injury was discharged home from the ED. For these patients with blunt trauma, chest CT is useful to identify otherwise occult injuries.


A flexible template boundary element in the RNA subunit of fission yeast telomerase.
Telomerase adds telomeric repeat sequences to chromosome ends using a short region of its RNA subunit as a template. Telomerase RNA subunits are phylogenetically highly divergent, and different strategies have evolved to demarcate the boundary of the template region. The recent identification of the gene encoding telomerase RNA in the fission yeast Schizosaccharomyces pombe (ter1+) has opened the door for structure-function analyses in a model that shares many features with the telomere maintenance machinery of higher eukaryotes. Here we describe a structural element in TER1 that defines the 5' boundary of the template. Disruption of a predicted long range base pairing interaction between template-adjacent nucleotides and a sequence further upstream resulted in reverse transcription beyond the template region and caused telomere shortening. Normal telomere length was restored by combining complementary nucleotide substitutions in both elements, showing that base pairing, not a specific sequence, limits reverse transcription beyond the template. The template boundary described here resembles that of budding yeasts and some mammalian telomerases. However, unlike any previously characterized boundary element, part of the paired region overlaps with the template itself, thus necessitating disruption of these interactions during most reverse transcription cycles. We show that changes in the paired region directly affect the length of individual telomeric repeat units. Our data further illustrate that marginal alignment of the telomeric 3' end with RNA sequences downstream of the template is responsible for primer slippage, causing incorporation of strings of guanosines at the start of a subset of repeats.


Genetic Mapping of Loci for Resistance to Stem Rust in a Tetraploid Wheat Collection.
Stem rust, caused by Puccinia graminis f. sp. tritici (Pgt), is a major biotic constraint to wheat production worldwide. Disease resistant cultivars are a sustainable means for the efficient control of this disease. To identify quantitative trait loci (QTLs) conferring resistance to stem rust at the seedling stage, an association mapping panel consisting of 230 tetraploid wheat accessions were evaluated for reaction to five Pgt races under greenhouse conditions. A high level of phenotypic variation was observed in the panel in response to all of the races, allowing for genome-wide association mapping of resistance QTLs in wild, landrace, and cultivated tetraploid wheats. Twenty-two resistance QTLs were identified, which were characterized by at least two marker-trait associations. Most of the identified resistance loci were coincident with previously identified rust resistance genes/QTLs; however, six regions detected on chromosomes 1B, 5A, 5B, 6B, and 7B may be novel. Availability of the reference genome sequence of wild emmer wheat accession Zavitan facilitated the search for candidate resistance genes in the regions where QTLs were identified, and many of them were annotated as NOD (nucleotide binding oligomerization domain)-like receptor (NLR) genes or genes related to broad spectrum resistance.


Agarose gel shift assay reveals that calreticulin favors substrates with a quaternary structure in solution.
Here we present an agarose gel shift assay that, in contrast to other electrophoresis approaches, is loaded in the center of the gel. This allows proteins to migrate in either direction according to their isoelectric points. Therefore, the presented assay enables a direct visualization, separation, and prefractionation of protein interactions in solution independent of isoelectric point. We demonstrate that this assay is compatible with immunochemical methods and mass spectrometry. The assay was used to investigate interactions with several potential substrates for calreticulin, a chaperone that is involved in different biological aspects through interaction with other proteins. The current analytical assays used to investigate these interactions are mainly spectroscopic aggregation assays or solid phase assays that do not provide a direct visualization of the stable protein complex but rather provide an indirect measure of interactions. Therefore, no interaction studies between calreticulin and substrates in solution have been investigated previously. The results presented here indicate that calreticulin has a preference for substrates with a quaternary structure and primarily β-sheets in their secondary structure. It is also demonstrated that the agarose gel shift assay is useful in the study of other protein interactions and can be used as an alternative method to native polyacrylamide gel electrophoresis.


Adaptive evolution of a novel Drosophila lectin induced by parasitic wasp attack.
Drosophila melanogaster has long been used as a model for the molecular genetics of innate immunity. Such work has uncovered several immune receptors that recognize bacterial and fungal pathogens by binding unique components of their cell walls and membranes. Drosophila also act as hosts to metazoan pathogens such as parasitic wasps, which can infect a majority of individuals in natural populations, but many aspects of their immune responses against these more closely related pathogens are poorly understood. Here, we present data describing the transcriptional induction and molecular evolution of a candidate Drosophila anti-wasp immunity gene, lectin-24A. Lectin-24A has a secretion signal sequence and its lectin domain suggests a function in sugar group binding. Transcript levels of lectin-24A were induced significantly stronger and faster following wasp attack than following wounding or bacterial infection, demonstrating lectin-24A is not a general stress response or defense response gene but is instead part of a specific response against wasps. The major site of lectin-24A transcript production is the fat body, the main humoral immune tissue of flies. Interestingly, lectin-24A is a new gene of the D. melanogaster/Drosophila simulans clade, displaying very little homology to any other Drosophila lectins. Population genetic analyses of lectin-24A DNA sequence data from African and North American populations of D. melanogaster and D. simulans revealed gene length polymorphisms segregating at high frequencies as well as strong evidence of repeated and recent selective sweeps. Thus, lectin-24A is a rapidly evolving new gene that has seemingly developed functional importance for fly resistance against infection by parasitic wasps.


Incidence and outcome of Kaposi sarcoma after hematopoietic stem cell transplantation: a retrospective analysis and a review of the literature, on behalf of infectious diseases working party of EBMT.
The incidence, the clinical characteristics, and the outcome of Kaposi sarcoma (KS) in patients after hematopoietic stem cell transplantation (HSCT) were assessed. During the period 1987-2018, 13 cases of KS were diagnosed, 3 females and 10 males, median age of 50 years, median time from HSCT of 7 months. KS had an incidence of 0.17% in allogeneic and 0.05% in autologous HSCT. HHV-8 was documented in eight of nine tumor tissue samples assessed. The organ involvement was: skin in nine, lymph nodes in six, oral cavity in four, and visceral in three patients, respectively; seven patients had >1 organ involved. Five patients had immunosuppression withdrawn, whereas four and three patients received radiotherapy and chemotherapy, respectively. Eight patients are alive (median follow-up 48 months, range 5-128), whereas five patients died after a median time of 8 months from the diagnosis of KS. However, no death was caused by KS. We conclude that the incidence of KS after HSCT is very low. Although KS can be managed with the reduction of immunosuppression, visceral forms may require chemotherapy and/or radiotherapy. The low prevalence of KS indicates that screening for HHV-8 serology and surveillance for HHV-8 viremia are not indicated in HSCT patients.


A cell cycle-associated change in Ca2+ releasing activity leads to the generation of Ca2+ transients in mouse embryos during the first mitotic division.
We have used Ca2+-sensitive fluorescent dyes to monitor intracellular Ca2+ during mitosis in one-cell mouse embryos. We find that fertilized embryos generate Ca2+ transients at nuclear envelope breakdown (NEBD) and during mitosis. In addition, fertilized embryos arrested in metaphase using colcemid continue to generate Ca2+ transients. In contrast, parthenogenetic embryos produced by a 2-h exposure to strontium containing medium do not generate detectable Ca2+ transients at NEBD or in mitosis. However, when parthenogenetic embryos are cultured continuously in strontium containing medium Ca2+ transients are detected in mitosis but not in interphase. This suggests that mitotic Ca2+ transients are detected in the presence of an appropriate stimulus such as fertilization or strontium. The Ca2+ transient detected in fertilized embryos is not necessary for inducing NEBD since parthenogenetic embryos undergo nuclear envelope breakdown (NEBD). Also the first sign that NEBD is imminent occurs several minutes before the Ca2+ transient. The Ca2+ transient at NEBD appears to be associated with the nucleus since nuclear transfer experiments show that the presence of a karyoplast from a fertilized embryo is essential. Finally, we show that the intracellular Ca2+ chelator Bapta inhibits NEBD in fertilized and parthenogenetic embryos in a dose-dependent manner. These studies show that during mitosis there is an endogenous increase in Ca2+ releasing activity that leads to the generation of Ca2+ transients specifically during mitosis. The ability of Ca2+ buffers to inhibit NEBD regardless of the presence of global Ca2+ transients suggests that the underlying cell cycle-associated Ca2+ releasing activity may take the form of localized Ca2+ transients.


Interleukin-1 production and antigen presentation by normal human peritoneal macrophages.
Human peritoneal macrophages from healthy females have been investigated for their capability to produce interleukin-1 (IL-1), their expression of HLA-DR and -DQ, and for their antigen-presenting capacity in concanavalin A, tetanus toxoid (TT), and autologous T-cell proliferative responses. Fifteen out of thirty macrophage populations produced IL-1 but the activity was 1/5 to 1/10 that of peripheral blood mononuclear cells stimulated under similar conditions. High levels of HLA-DR were expressed on all macrophages while lower and more variable levels of DQ were found. All macrophages induced mitogen-dependent T-cell proliferation while the ability to induce a proliferative response to TT was variable, 12/23 tests were positive. In five samples stimulatory capacity of macrophages in the absence of TT was as strong as in the presence of the stimulus, suggesting that in vivo processed immunogen could be responsible for the proliferative response. The surface density of HLA-D-region-determined antigens was not indicative of the macrophages' ability to induce antigen-specific proliferation. IL-1 production, however, correlated with this function. Antigen presentation was not confined exclusively to peritoneal populations consisting of recently immigrant monocyte-like cells, nor were all young macrophages able to present antigen. This may reflect on the diversion of macrophage function by the local environment.


Polyethylene Glycol and Caspase Inhibitor Emricasan Alleviates Cold Injury in Primary Rat Hepatocytes.
Current methods of storing explanted donor livers at 4°C in University of Wisconsin (UW) solution result in loss of graft function and ultimately leads to less-than-ideal outcomes post transplantation. Our lab has previously shown that supplementing UW solution with 35-kilodalton polyethylene glycol (PEG) has membrane stabilizing effects for cold stored primary rat hepatocytes in suspension. Expanding on past studies, we here investigate if PEG has the same beneficial effects in an adherent primary rat hepatocyte cold storage model. In addition, we investigated the extent of cold-induced apoptosis through treating cold-stored hepatocytes with pan caspase inhibitor emricasan. In parallel to storage at the current cold storage standard of 4°C, we investigated the effects of lowering the storage temperature to -4°C, at which the storage solution remains ice-free due to the supercooling phenomenon. We show the addition of 5% PEG to the storage medium significantly reduced the release of lactate dehydrogenase (LDH) in plated rat hepatocytes and a combinatorial treatment with emricasan maintains hepatocyte viability and morphology following recovery from cold storage. These results show that cold-stored hepatocytes undergo multiple mechanisms of cold-induced injury and that PEG and emricasan treatment in combination with supercooling may improve cell and organ preservation.


Assessing the risk of attack in the management of asthma: a review and proposal for revision of the current control-centred paradigm.
Asthma guidelines focus on day-to-day control of symptoms. However, asthma attacks remain common. They continue to cause mortality and considerable morbidity, and are a major financial burden to the UK National Health Service (NHS) and the wider community. Asthma attacks have chronic consequences, being associated with loss of lung function and significant psychological morbidity. In this article we argue that addressing daily symptom control is only one aspect of asthma treatment, and that there should be a more explicit focus on reducing the risk of asthma attacks. Management of future risk by general practitioners is already central to other conditions such as ischaemic heart disease and chronic renal impairment. We therefore propose a revised approach that separately considers the related domains of daily control and future risk of asthma attack. We believe this approach will have advantages over the current 'stepwise' approach to asthma management. It should encourage individualised treatment, including non-pharmacological measures, and thus may lead to more efficacious and less harmful management strategies. We speculate that this type of approach has the potential to reduce morbidity and healthcare costs related to asthma attacks.


Androgen-androgen receptor system protects against angiotensin II-induced vascular remodeling.
Age-related andropause promotes cardiovascular disease in males. Although we had previously reported that the androgen-androgen receptor (AR) system plays important roles in cardiac growth and remodeling, the system's involvement in vascular remodeling remains unclear. To clarify this role, 25-wk-old male AR knockout (ARKO) mice and littermate male wild-type (WT) mice were divided into two groups with and without angiotensin II (Ang II) administration (2.0 mg/kg . d) for 14 d, respectively. No morphological differences in the coronary artery and thoracic aorta were observed between the groups without Ang II. Ang II stimulation markedly increased medial thickness and perivascular fibrosis in ARKO mice, with enhanced TGF-beta1, collagen type I, and collagen type III gene expression in the aorta. Ang II stimulation also prominently increased superoxide production, lipid peroxidation, and gene expression of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase components in ARKO mice compared with WT mice. In addition, phosphorylation of c-Jun N-terminal kinase (JNK) and phosphorylated (Smad2/3) was remarkably enhanced in Ang II-treated ARKO mice compared with Ang II-treated WT mice. Notably, daily urinary nitric oxide (NO) metabolites excretion as a marker of NO bioavailability, aortic endothelial NO synthase expression and phosphorylation, and Akt phosphorylation were significantly reduced in ARKO mice compared with WT mice, regardless of Ang II stimulation. In conclusion, the androgen-AR system is required for the preservation of NO bioavailability through Akt-endothelial NO synthase system activation and exerts protective effects against Ang II-induced vascular remodeling by regulating oxidative stress, c-Jun N-terminal kinase (JNK) signaling, and the TGF-beta-phosphorylated Smad pathway.


Advance in Targeted Cancer Therapy and Mechanisms of Resistance.
Drug resistance remains one of the important clinical challenges, making cancer one of the leading causes of death worldwide [...].


Assessing Clinical Faculty Understanding of Statistical Terms Used to Measure Treatment Effects and Their Application to Teaching.
Understanding of statistical terms used to measure treatment effect is important for evidence-informed medical teaching and practice. We explored knowledge of these terms among clinical faculty who instruct and mentor a continuum of medical learners to inform medical faculty learning needs. This was a mixed methods study that used a questionnaire to measure a health professional's understanding of measures of treatment effect and a focus group to explore perspectives on learning, applying, and teaching these terms. We analyzed questionnaire data using descriptive statistics and focus group data using thematic analysis. We analyzed responses from clinical faculty who were physicians and completed all sections of the questionnaire (n = 137). Overall, approximately 55% were highly confident in their understanding of statistical terms; self-reported understanding was highest for number needed to treat (77%). Only 26% of respondents correctly responded to all comprehension questions; however, 80% correctly responded to at least one of these questions. There was a significant association among self-reported understanding and ability to correctly calculate terms. A focus group with clinical/medical faculty (n = 4) revealed themes of mentorship, support and resources, and beliefs about the value of statistical literacy. We found that half of clinical faculty members are highly confident in their understanding of relative and absolute terms. Despite the limitations of self-assessment data, our study provides some evidence that self-assessment can be reliable. Recognizing that faculty development is not mandatory for clinical faculty in many centers, and the notion that faculty may benefit from mentorship in critical appraisal topics, it may be appropriate to first engage and support influential clinical faculty rather than using a broad strategy to achieve universal statistical literacy. Second, senior leadership in medical education should support continuous learning by providing paid, protected time for faculty to incorporate evidence in their teaching.


The impact of gender and NASH on chronic kidney disease before and after liver transplantation.
Chronic kidney disease (CKD) after liver transplant (LT) is associated with increased long-term mortality. The impact of gender on CKD before and after LT is unknown. To further define risk factors and analyse gender differences in the incidence and progression of CKD after liver transplant. Four hundred and fifty-five consecutive adult primary solitary LT recipients were included. Iothalamate clearance tests performed over time were analysed. Mean age was 51.4 ± 10.4 years with 63% males. A percentage of 29.1% of females and 21.1% of males had a GFR<60 ml/min/1.73 m(2) and 10.2% of females and 5.9% of males had GFR<30 ml/min/1.73 m(2) prior to transplant. At 1 year, 52.6% of recipients tested (69.6% females, 43.0% males) had GFR<60 ml/min/1.73 m(2) and 7.3% (11.6% females, 4.9% males) had GFR<30 ml/min/1.73 m(2) . Pre-LT GFR<60 ml/min/1.73 m(2) [OR 3.28, (1.76-6.10), P ≤ 0.001], female gender (OR 2.96, (1.72-5.10), P < 0.001) and age [OR 1.09, (1.05-1.12), P < 0.001] were independently predictive of stage ≥3 CKD at 1 year post-LT. Female gender [OR 2.52, (1.25-4.71), P = 0.004], age [OR 1.05, (1.02-1.08), P = 0.003] and NASH [OR 2.95, (1.06-8.21), P = 0.039] were independently predictive of ≥stage 3 CKD at 5 years post-LT. Pre-LT diabetes was associated with stage 4 CKD at 5 years [OR 2.91, (1.33-6.36), P = 0.008] post-LT. In addition to age and pre-LT CKD, female gender and NASH are independent predictors of ≥stage 3 CKD post-LT. Gender-based approaches to optimize modifiable risk factors are needed to improved post-transplant renal function.


Population genomic analyses from low-coverage RAD-Seq data: a case study on the non-model cucurbit bottle gourd.
Restriction site-associated DNA sequencing (RAD-Seq), a next-generation sequencing-based genome 'complexity reduction' protocol, has been useful in population genomics in species with a reference genome. However, the application of this protocol to natural populations of genomically underinvestigated species, particularly under low-to-medium sequencing depth, has not been well justified. In this study, a Bayesian method was developed for calling genotypes from an F₂ population of bottle gourd [Lagenaria siceraria (Mol.) Standl.] to construct a high-density genetic map. Low-depth genome shotgun sequencing allowed the assembly of scaffolds/contigs comprising approximately 50% of the estimated genome, of which 922 were anchored for identifying syntenic regions between species. RAD-Seq genotyping of a natural population comprising 80 accessions identified 3226 single nuclear polymorphisms (SNPs), based on which two sub-gene pools were suggested for association with fruit shape. The two sub-gene pools were moderately differentiated, as reflected by the Hudson's F(ST) value of 0.14, and they represent regions on LG7 with strikingly elevated F(ST) values. Seven-fold reduction in heterozygosity and two times increase in LD (r²) were observed in the same region for the round-fruited sub-gene pool. Outlier test suggested the locus LX3405 on LG7 to be a candidate site under selection. Comparative genomic analysis revealed that the cucumber genome region syntenic to the high FST island on LG7 harbors an ortholog of the tomato fruit shape gene OVATE. Our results point to a bright future of applying RAD-Seq to population genomic studies for non-model species even under low-to-medium sequencing efforts. The genomic resources provide valuable information for cucurbit genome research.


Reproducibility of occlusal contacts utilizing a computerized instrument.
This study was designed to examine clinically the accuracy and reproducibility of occlusal contacts made by a computerized device (the T-scan) in ten asymptomatic subjects. The results showed 100% accuracy and reproducibility for all contacts in all subjects. A great advantage of this instrument over silk marking ribbon is that it not only records contacts but can also analyze the timing and force of each contact.


Long-term results after pulmonary resection of renal cell carcinoma metastases.
Until now no conclusive data exist regarding the factors influencing long-term survival after pulmonary resection of renal cell carcinoma metastases. The aim of the present study, therefore, was to discover definitive prognostic factors for survival using a large and homogeneous single center patient cohort. Between 1980 and 2000, 105 patients, after curative resection of lung metastases from renal cell carcinoma, were followed in this long-term study. These patients underwent a total of 150 surgical procedures. Survival analysis was done using the Kaplan-Meier method and the log-rank test. Multivariate analysis of prognostic factors was performed using the Cox multivariate proportional hazard model. Median survival after curative resection reached 43 months (range, 1 to 218 months). Survival at 3, 5, and 10 years was 54%, 40%, and 33%, respectively. Univariate analysis revealed that a complete resection, a less than 4-cm diameter of the metastases and tumor-free lymph nodes at the time of primary operation, were highly significant dependent prognostic factors (p < 0.001). These factors were also shown to be independent prognostic factors as suggested by multivariate analysis (p < 0.05). The size of the metastatic nodule, the completeness of pulmonary resection, and the lymph node status at the time of nephrectomy are the most important prognostic factors that influence survival after resection of pulmonary metastases. Recurrence of resectable pulmonary metastases does not impair survival, thus favoring repeated resection in patients with recurrent disease.


[Acute vascular occlusion of the eye fundus: ocular and general evaluation. General treatment plan].
Occlusion of retinal arterioles and veins and acute papillitis are often local manifestations of systemic disease. Treatment should start as soon as the diagnosis is made. At the same time the ocular lesions should be assessed and the local and systemic risk factors sought. Identified risk factors should be treated immediately if possible. The primary aim is to reestablish perfusion in the occluded vessels in order to limit the extent of lesions and to restore function. In practice, intervention is often too late. Subsequent treatment aims at consolidating the result, and may take a year; relapse should be avoided by treatment of the risk factors.


Hippocampal synaptic transmission and plasticity are preserved in myosin Va mutant mice.
Recent studies have identified myosin Va as an organelle motor that may have important functions in neurons. Abundantly expressed at the hippocampal postsynaptic density, it interacts with protein complexes involved in synaptic plasticity. It is also located in presynaptic terminals and may function to recruit vesicles in the reserve pool to the active zone. Dilute-lethal mice are spontaneous myosin Va mutants and have severe neurological symptoms. We studied hippocampal physiology at CA3-CA1 excitatory synapses in dilute-lethal mutant mice to test the hypothesis that myosin Va plays a role in pre- or postsynaptic elements of synaptic transmission. In all assays performed, the mutant synapses appeared to be functioning normally, both pre- and postsynaptically. These data suggest that myosin Va is not essential for the synaptic release machinery, postsynaptic receptor composition, or plasticity at this synapse, but does not exclude significant roles for myosin Va in other cell types nor potential compensation by other myosin V isoforms.


Thalidomide Exerts Anti-Inflammatory Effects in Cutaneous Lupus by Inhibiting the IRF4/NF-ҡB and AMPK1/mTOR Pathways.
Thalidomide is effective in patients with refractory cutaneous lupus erythematosus (CLE). However, the mechanism of action is not completely understood, and its use is limited by its potential, severe side-effects. Immune cell subset analysis in thalidomide's CLE responder patients showed a reduction of circulating and tissue cytotoxic T-cells with an increase of iNKT cells and a shift towards a Th2 response. We conducted an RNA-sequencing study using CLE skin biopsies performing a Therapeutic Performance Mapping System (TMPS) analysis in order to generate a predictive model of its mechanism of action and to identify new potential therapeutic targets. Integrating RNA-seq data, public databases, and literature, TMPS analysis generated mathematical models which predicted that thalidomide acts via two CRBN-CRL4A- (CRL4CRBN) dependent pathways: IRF4/NF-ҡB and AMPK1/mTOR. Skin biopsies showed a significant reduction of IRF4 and mTOR in post-treatment samples by immunofluorescence. In vitro experiments confirmed the effect of thalidomide downregulating IRF4 in PBMCs and mTOR in keratinocytes, which converged in an NF-ҡB reduction that led to a resolution of the inflammatory lesion. These results emphasize the anti-inflammatory role of thalidomide in CLE treatment, providing novel molecular targets for the development of new therapies that could avoid thalidomide's side effects while maintaining its efficacy.


[Proton magnetic relaxation and thermodynamic parameters of ribonuclease solutions during thermal denaturation].
Heat denaturation of ribonuclease in diluted water solutions was studied by means of proton magnetic relaxation, microcalorimetry and viscosity. It has been shown that heat denaturation of ribonuclease is a one stage process; it involves the whole globule and is accompanied by changes in the state of salvated (water) molecules. A redistribution of water molecules in the hydrate "envelope" of protein changes the character of proton magnetic relaxation of the whole solvent.


Nursing intervention to enhance acceptance of pregnancy in first-time mothers: focusing on the comfortable experiences of pregnant women.
The purpose of the present study was to describe effective nursing care through evaluation of a nursing intervention that enhanced acceptance of pregnancy and focused on a comfortable experience for pregnant women. Thirty-two subjects who were expected to have a normal pregnancy were assigned into either the intervention or the control group. The nursing intervention consisted of the use of a pregnancy diary and four interviews, two of which were held in the first trimester, one in the second and one in the third trimester. The nursing care given was recorded in tapes and field notes. The data were analyzed using a qualitative content analysis method. As a result of analyzing the nursing care of 13 women pregnant for the first time who were provided with nursing intervention, the following seven categories of nursing care were extracted for the intervention: encouragement of women to record their experiences using a pregnancy diary; recognizing and acknowledging negative feelings; reducing the negative aspects of pregnancy and reframing; expression and reinforcement of positive feelings; clarification and reinforcement of positive meanings; awareness of own comfortable experiences; promotion of diverse comfortable aspects and continuation of comfortable experiences. The seven nursing care interventions were effective in increasing the comfortable experiences of pregnant women and enhancing a positive attitude towards pregnancy. Nursing intervention can aid in enhancing positivity and comfort in pregnant women. Furthermore, this nursing intervention can be applied to adolescents, socially disadvantaged pregnant women, and hospitalized women.


A Comparison of Physical Activity Between Home-Based and Centre-Based Pulmonary Rehabilitation: A Randomised Controlled Secondary Analysis.
Background: Pulmonary rehabilitation (PR) is a highly effective intervention for individuals with chronic obstructive pulmonary disease (COPD). Physical activity (PA) has been shown to increase after a centre-based programme, yet it is not clear if a home-based programme can offer the same benefit. This study aimed to evaluate the effect of home-based PR compared with the centre-based PR on the PA levels post 7 weeks of PR and 6 months follow-up. Method: In this study, 51 participants with COPD, of them, 36 (71%) men completed physical activity monitoring with a SenseWear Armband, at three time points (baseline, 7 weeks, and 6 months). The participants were randomly assigned to either centre-based supervised PR (n = 25; 69 ± 6 years; FEV1 55 ± 20% predicted) or home-based PR (n = 26; 68 ± 7 years; FEV1 42 ± 19% predicted) programmes lasting 7 weeks. The home-based programme includes one hospital visit, a self-management manual, and two telephone calls. The PA was measured as step count, time in moderate PA (3-6 metabolic equivalent of tasks [METs]) in bouts of more than 10 min and sedentary time (<2 METs). Results: Home-based PR increased step count significantly more than the centre-based PR after 7 weeks (mean difference 1,463 steps: 95% CI 280-2,645, p = 0.02). There was no difference in time spent in moderate PA was observed (mean difference 62 min: 95% CI -56 to 248, p = 0.24). Sedentary behaviour was also significantly different between the centre and home-based groups. The home group spent 52 min less time sedentary compared with the centre-based (CI -106 to 2, p = 0.039). However, after 6 months, the step count and time spent in moderate PA returned to baseline in both the groups. Conclusion: This study provides an important insight into the role of home-based PR which has the potential to be offered as an alternative to the centre-based PR. Understanding who may best respond from the centre or home-based PR warrants further exploration and how to maintain these initial benefits for the long-term. Trial Registry: ISRCTN: No.: ISRCTN81189044; URL: isrctn.com.


Oxidized guanine lesions and hOgg1 activity in lung cancer.
In humans, the oxidatively induced DNA lesion 8-hydroxyguanine (8-oxoG) is removed from DNA by hOgg1, a DNA glycosylase/AP lyase that specifically incises 8-oxoG opposite cytosine. We analysed the expression of hOGG1 mRNA in 18 lung cancer and three normal cell lines. Although hOGG1 was overexpressed in most cell lines, 2/18 (11.1%) showed a lower hOGG1 mRNA and protein expression (approximately 80% decrease) relative to normal cell lines. Liquid chromatography/mass spectrometry analysis showed increased levels of 8-oxoG in the two cell lines with the lowest hOGG1 mRNA expression. We examined the ability of nuclear and mitochondrial extracts to incise 8-oxoG lesion in cell lines H1650 and H226 expressing lower hOGG1 mRNA and H1915 and H1975 with higher than normal hOGG1 mRNA expression. Both nuclear and mitochondrial extracts from H1915 and H1975 cells were proficient in 8-oxoG removal. However, both cell lines with the lowest hOGG1 mRNA expression exhibited a severe reduction in 8-oxoG incision in both nuclear and mitochondrial extracts. Under-expression of hOGG1 mRNA and hOgg1 protein was associated with a decrease in mitochondrial DNA repair in response to oxidative damaging agents. These results provide evidence for defective incision of 8-oxoG in both nuclear and mitochondria of H1650 and H226 lung cancer cell lines. These results may implicate 8-oxoG repair defects in certain lung cancers.


Water supply emergency preparedness and response in health care facilities: A systematic review on international evidence.
Enabling health care facilities to deal with impairments or outages of water supply and sewage systems is essential and particularly important in the face of growing risk levels due to climate change and natural hazards. Yet, comprehensive assessments of the existing preparedness and response measures, both in theory and practice, are lacking. The objective of this review is to assess water supply and wastewater management in health care facilities in emergency settings and low-resource contexts. It thereby is a first step toward knowledge transfer across different world regions and/or contexts. A systematic review was performed to identify published articles on the subject using online MEDLINE and Web of Science. The initial searches yielded a total of 1,845 records. Two independent reviewers screened identified records using selection criteria. A total of 39 relevant studies were identified. Descriptive analyses were used to summarize evidence of included studies. Overall, water supply was far more discussed than wastewater management. Studies on emergency preparedness identified back-up water storage tank, additional pipelines, and underground wells as key sources to supply health care facilities with water during an emergency. In emergency response, bottled of water, followed by in-situ back-up water storage tanks previously installed as part of disaster preparedness measures, and tanker trucks to complete were most used. Questions on how to improve existing technologies, their uptake, but also the supplementation by alternative measures remain unanswered. Only few guidelines and tools on emergency preparedness were identified, while multiple studies formulated theoretical recommendations to guide preparedness. Recovery planning was rarely discussed, despite many studies mentioning the importance of the reconstruction and restoration phases. Literature focus on recovery is mostly on technical aspects, while organizational ones are largely absent. Despite their key role for preparedness and response, citizens and patients' perspectives are hugely underrepresented. This fits into the bigger picture as communication, awareness raising and actor cooperation in general is addressed comparatively little. Combining organizational and technical aspects, and intersecting theory and practice will be necessary to address existing gaps. Improving both, preparedness and response, is key to maintaining public health and providing primary care.


The Role of 18F Fluorodeoxyglucose Positron Emission Tomography Scanning in the Diagnosis and Management of Systemic Vasculitis.
Primary systemic vasculitis is a group of heterogeneous disorders, characterized by inflammation of blood vessels causing end organ damage from ischemia, aneurysm formation or dissection. Delay in the early diagnosis owing to non-specific symptoms, lack of definitive serological tests, limited availability of biopsy and standard imaging tests pose significant challenge in the management of these diseases. 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) scanning is being increasingly used in the management of systemic vasculitis, especially the large vessel vasculitides: giant cell arteritis (GCA) and Takayasu arteritis (TAK). FDG-PET involves detection of positron rays emitted by FDG, a fluorinated glucose analogue which is avidly taken up by metabolically active inflammatory cells in the walls of involved blood vessels. 18F-FDG-PET scan, especially when combined with computed tomography or magnetic resonance imaging (MRI) can give information about active inflammation as well as structural damage associated with vasculitis. In patients with GCA, FDG-PET has acceptable sensitivity and specificity for the early diagnosis in non-cranial GCA, cranial GCA with negative biopsy, assessment of immediate response to treatment, predicting prognosis, but has limited value in serial follow-up and prediction of relapses. In TAK, FDG-PET can be useful for early diagnosis and probably for serial assessment of disease activity. FDG-PET has a limited role in medium and small vessel vasculitis.


Original antigenic sin responses to Betacoronavirus spike proteins are observed in a mouse model, but are not apparent in children following SARS-CoV-2 infection.
The effects of pre-existing endemic human coronavirus (HCoV) immunity on SARS-CoV-2 serologic and clinical responses are incompletely understood. We sought to determine the effects of prior exposure to HCoV Betacoronavirus HKU1 spike protein on serologic responses to SARS-CoV-2 spike protein after intramuscular administration in mice. We also sought to understand the baseline seroprevalence of HKU1 spike antibodies in healthy children and to measure their correlation with SARS-CoV-2 binding and neutralizing antibodies in children hospitalized with acute coronavirus disease 2019 (COVID-19) or multisystem inflammatory syndrome (MIS-C). Groups of 5 mice were injected intramuscularly with two doses of alum-adjuvanted HKU1 spike followed by SARS-CoV-2 spike; or the reciprocal regimen of SARS-Cov-2 spike followed by HKU1 spike. Sera collected 21 days following each injection was analyzed for IgG antibodies to HKU1 spike, SARS-CoV-2 spike, and SARS-CoV-2 neutralization. Sera from children hospitalized with acute COVID-19, MIS-C or healthy controls (n = 14 per group) were analyzed for these same antibodies. Mice primed with SARS-CoV-2 spike and boosted with HKU1 spike developed high titers of SARS-CoV-2 binding and neutralizing antibodies; however, mice primed with HKU1 spike and boosted with SARS-CoV-2 spike were unable to mount neutralizing antibodies to SARS-CoV-2. HKU1 spike antibodies were detected in all children with acute COVID-19, MIS-C, and healthy controls. Although children with MIS-C had significantly higher HKU1 spike titers than healthy children (GMT 37239 vs. 7551, P = 0.012), these titers correlated positively with both SARS-CoV-2 binding (r = 0.7577, P<0.001) and neutralizing (r = 0.6201, P = 0.001) antibodies. Prior murine exposure to HKU1 spike protein completely impeded the development of neutralizing antibodies to SARS-CoV-2, consistent with original antigenic sin. In contrast, the presence of HKU1 spike IgG antibodies in children with acute COVID-19 or MIS-C was not associated with diminished neutralizing antibody responses to SARS-CoV-2.


Using evidence from different sources: an example using paracetamol 1000 mg plus codeine 60 mg.
Meta-analysis usually restricts the information pooled, for instance using only randomised, double-blind, placebo-controlled trials. This neglects other types of high quality information. This review explores using different information for the combination of paracetamol 1000 mg and codeine 60 mg in acute postoperative pain. Randomised, double-blind, placebo-controlled trials of paracetamol 1000 mg and codeine 60 mg had an NNT of 2.2 (95% confidence interval 1.7 to 2.9) for at least 50% pain relief over four to six hours in three trials with 197 patients. Computer simulation of randomised trials demonstrated 92% confidence that the simulated NNT was within +/- 0.5 of the underlying value of 2.2 with this number of patients. The result was supported a rational dose-response relationship for different doses of paracetamol and codeine in 17 additional trials with 1,195 patients. Three controlled trials lacking a placebo and with 117 patients treated with of paracetamol 1000 mg and codeine 60 mg had 73% (95%CI 56% to 81%) of patients with at least 50% pain relief, compared with 57% (48% to 66%) in placebo controlled trials. Six trials in acute pain were omitted because of design issues, like the use of different pain measures or multiple dosing regimens. In each paracetamol 1000 mg and codeine 60 mg was shown to be better than placebo or comparators for at least one measure. Different designs of high quality trials can be used to support limited information used in meta-analysis without recourse to low quality trials that might be biased.


Dysfunctional immunometabolic effects of vitamin D deficiency, increased cardiometabolic risk. Potential epidemiological alert in America?
Vitamin D deficiency is a serious public health problem worldwide that affects not only skeletal health, but also a wide range of acute and chronic diseases. However, there is still skepticism because of the lack of randomized, controlled trials to support association studies on the benefits of vitamin D for non-skeletal health. This review was based on articles published during the 1980-2015 obtained from the Cochrane Central Register of controlled trials, MEDLINE and PubMed, and focuses on recent challenges with regard to the definition of vitamin D deficiency and how to achieve optimal serum 25-hydroxyvitamin D levels from dietary sources, supplements, and sun exposure. The effect of vitamin D on epigenetic fetal programming and regulation of genes that may potentially explain why vitamin D could have such lifelong comprehensive health benefits is reviewed. Optimization of vitamin D levels in children and adults around the world has potential benefits to improve skeletal health and to reduce the risk of chronic diseases, including some types of cancer, autoimmune diseases, infectious diseases, type 2 diabetes mellitus, and severe cardiovascular disorders such as atherothrombosis, neurocognitive disorders, and mortality.


Entrainment of circadian phase in developing gray short-tailed opossums: mother vs. environment.
In a marsupial species, the gray short-tailed opossum (Monodelphis domestica), the suprachiasmatic nuclei (SCN), the site of a circadian clock, are formed postnatally and begin oscillating as a circadian clock on day 20. In this study, we examined how the timing (phase) of the SCN clock in the developing opossum is coordinated to the environmental light-dark cycle. When pups were reared from birth in darkness by intact dams, the circadian phases in SCN metabolic activity (monitored by 2-deoxy-D-[14C]glucose autoradiography) in 27-day-old pups were desynchronized. When pups were reared in a light-dark cycle that was 12 h out of phase with the circadian time of blinded dams, the pattern of SCN metabolic activity on day 20 was rhythmic and in phase with the light-dark cycle but out of phase with the circadian time of the dam. On day 20, retina-mediated light activation of SCN metabolic activity was also demonstrated, and anterograde tract-tracing studies revealed the presence of the retinohypothalamic tract within the SCN. These results show there is no influence of the opossum dam on the timing of the pup's biological clock. Instead, from the inception of the daily rhythm in SCN metabolic activity, its timing is regulated by retina-mediated light-dark entrainment.


[Cardioprotective effect of taurine].
The review analyses data which had been accumulated in the recent years on the pharmacological properties of the inhibiting amino acid taurine concerning its cardiotropic action. The results of experimental and clinical studies of the beneficial effect of this compound on pathologically changed function of the heart are shown, and the mechanisms of this effect both on the cellular and systemic level are discussed.


The value of azygography in carcinoma of the esophagus.
A method of azygography has been used in a study of patients with carcinoma of the esophagus prior to thoracotomy. Total blockage or progressive reduction of venous caliber at the actual level of the lesion with contralateral filling of the azygos vein or back pressure signs on the azygogram indicates that the growth is not resectable at operation.


Impact of clinical leadership development on the clinical leader, nursing team and care-giving process: a case study.
This study explored the dynamics related to a leadership development programme and their impact on the clinical leader, the nursing team and the care-giving process. While there is a growing conviction about the need to invest in transformational leadership in nursing, further insight into the true complexity of leadership development and, more specifically, how leadership can make a difference in nursing and patient outcomes is essential. A single instrumental case study was conducted in a unit of a large academic hospital where a Clinical Leadership development Project (CLP) was implemented successfully. We used mixed methods with multiple sources of data to capture the complexity of leadership development. Data were collected through individual interviews, focus groups and observation of participants. A purposive sample of 17 participants representing a wide variety of team members has permitted data saturation. The data were categorized and conceptualized and finally organized into a framework describing leadership development on the unit and its impact on the leader, the nursing team and the care-giving process. Leadership development is an ongoing, interactive process between the clinical leader and the co-workers. The head nurse became more effective in areas of self-awareness, communication skills, performance and vision. The nursing team benefited because more effective leadership promoted effective communication, greater responsibility, empowerment and job clarity. Improved clinical leadership seemed also to influence patient-centred communication, continuity of care and interdisciplinary collaboration. The results of the study give more insight into the processes underlying the leader's progress towards attaining a transformational leadership style and its impact on the team members. The impact of leadership on the care-giving process, however, remains difficult to describe. The interactive nature of leadership development makes CLP a challenge for the leader as well for the team members. Through its impact on the leader and the nursing team, CLP is a valuable instrument for improving work environments of nurses, contributing positively to patient-centred care.


Seeking help from health and welfare services among elderly single women.
The current research is a pilot study that included 87 single women who responded to an announcement placed in one of the national newspapers and then filled out interview questionnaires. The study hypothesized three groups of variables for predicting elderly single women's appeals for help from health and welfare services: (a) demographic variables, (b) intrapersonal variables, and (c) interpersonal variables. The research tools were (a) a demographics questionnaire constructed specifically for this study; (b) a personal assessment of single life: chosen or unchosen, including a question regarding what single people think about bachelorhood/spinsterhood; (c) an approach to the institution of bachelorhood/spinsterhood; (d) self-evaluation questionnaire; (e) a sense of mastery over life questionnaire; (f) informal support networks questionnaire; and (g) an assessment of the appeal to health and welfare services for help. A special questionnaire was constructed, which included a list of health and welfare services. The research findings indicate connections among all the research variables. All the research hypotheses were confirmed. Special attention should be given to this one tenth and more of the elder population. It might improve the lives of those women and save Western governments a lot of money.


A contribution to the incidence of nucleoli in normal human blood monocytes.
Normal blood monocytes were studied in blood donors to provide more information on the presence of nucleoli and nucleolar types in these cells. Nucleoli in monocytes were visualized using cytochemical procedures that detect RNA and characteristic nucleolar proteins, i.e. nucleophosmin, nucleolin, fibrillarin and AgNOR proteins, in peripheral blood smears. Nucleoli were detected in all blood monocytes. The nucleolar coefficient (number of nucleoli per cell) was 2.6 and no differences were found between men and women. Concerning the incidence of nucleolar types, monocytes from both male and female blood donors possessed mainly only inactive micronucleoli characteristic of mature or advanced maturation stages of blood cells; however, 16-20% of monocytes also contained functionally dominant ring-shaped nucleoli, which reflect a reversible decrease of rRNA transcription and in blood cells are intermediate stages between actively transcribing large nucleoli in highly immature cells and inactive micronucleoli in terminal nucleolated maturation stages. Monocytes containing large nucleoli with a relatively uniform distribution of RNA characteristic of immature or stimulated blood cells were rare (< 2%). Nucleoli are present in all normal blood monocytes. The incidence of the main nucleolar types represents a very convenient complementary marker for evaluating the maturation and possibly the stimulated state of these cells.


Is intramedullary nailing more effective than non-operative treatment in adults with displaced middle-third clavicle fractures?
Clavicle fractures are common, accounting for 5-12 % of all fractures. Traditionally, displaced middle-third clavicle fractures have been managed non-operatively but the associated displacement often leads to mal-union with shortening, cosmetic deformity and occasionally non-union, with clinicians looking towards alternative operative methods such as intramedullary nailing (IMN). However, such methods have their own complications. In order to ascertain the effectiveness of IMN in the management of middle-third clavicle fractures compared with non-operative treatment, analysis of recent evidence is required and this review aims to achieve that, focusing on relevant, contemporary randomised-control trials. Essential search-terms identified from the research question were used to formulate a search strategy. A systematic search of multiple databases was then performed from 1966 until present and appropriate papers for appraisal identified. Thirteen papers were identified, with 10 excluded using appropriate eligibility criteria. The remaining papers were then critically appraised. With regards shoulder function, all papers demonstrated an association between IMN and a significantly (P < 0.05) superior shoulder function score, but no consensus with regards to complication rates. However, all have identified limitations; therefore, their overall findings must be considered conservatively. Further, high-quality research, ideally in the form of well-designed, multi-centre RCTs is required to allow acceptable implementation of IMN of middle-third clavicle fractures into widespread practice. However, early results demonstrate that in young patients with displaced middle-third clavicle fractures, who are motivated to return to work, IMN provides superior functional results and should be considered. However, the importance of considering each patient individually as to their suitability for each management option, before coming to an informed decision with the patient rather than having a blanket approach to MTCF is essential. Level 1.


The natural history of osteoarthritis after a slipped capital femoral epiphysis/the pistol grip deformity.
The presence of femoroacetabular impingement (FAI) after a slipped capital femoral epiphysis is thought to predispose the subsequent development of osteoarthritis (OA); however, there is a lack of evidence to support this hypothesis. One hundred twenty-one patients with stable slipped capital femoral epiphysis treated with in situ fixation were reviewed at a minimum of 20-year follow-up; the presence of a pistol grip deformity and FAI was determined. The Harris Hip Score (HHS) was used to measure clinical outcome, and the Tönnis grade for qualifying the presence of OA was determined. One hundred twenty-one patients were followed up at a mean of 22.3 years (range, 20.1 to 32.5 y); the slip was considered grade 1 in 34 hips, grade 2 in 65 hips, and grade 3 in 22 hips. Ninety-six patients had clinical and radiographic signs of FAI. The mean HHS for the entire cohort was 75.6; however, for the 25 patients without FAI it was 89.3 and for the 96 patients with FAI it was 75.4 (P=0.004). We found radiographic signs of OA in all 121 patients: considered grade 1 in 14 hips, grade 2 in 32 hips, and grade 3 in 75 hips. The mean Tönnis grade of OA was 2.5. A direct relationship between the radiographic grade of OA and the HHS was observed. The occurrence of FAI (or a pistol grip deformity) after even a low-grade slip is common. We found clinical and radiographic signs of FAI in most of our patients, and also found that the degree of deformity is directly related to the presence of OA in early adulthood.


Fall or shaken: traumatic brain injury in children caused by falls or abuse at home - a review on biomechanics and diagnosis.
In cases of traumatic brain injuries in children it may be difficult to differentiate between physical abuse and accidental occurrence. This review will shed light on discriminating epidemiological as well as biomechanical data, morphological findings, and clinical features. As a basic principle, simple injuries are caused by simple mechanisms like falls whereas life-threatening injuries should be attributed to abuse until proven otherwise. Implausibilities between reported events and mechanisms by caregivers as well as more than one explanation of injury indicate suspicion of child abuse. From reviewing the literature, it can be stated that falls from less than 1.5 m lead only in few cases to severe brain injuries. Children who experienced a fall at home seldom exhibit fractures of the skull but just minor intracranial injuries without neurological deficits. Regarding biomechanical aspects, multiple or complex skull fractures, depression fractures, additional fractures of the body, and intracranial hemorrhages as a consequence of an impact are the most important findings in child abuse. Moreover, additional specific morphological criteria give evidence of clinical and/or post-mortem diagnosis of the shaken baby syndrome. These include subdural hemorrhage and laceration of the brain and retinal bleeding, epidural hemorrhage of the cervical cord, gripping marks (bruises) on chest and/or shoulders, and tearing injuries of the throat and neck muscles. Post-mortem signs of recurrent shaken baby syndrome are indicated by iron-positive cells or microglial cells in neuronal or retinal tissue. A clinical diagnosis will be dependent on the one hand on the exclusion of coagulation diseases, on the other hand on the demonstration of a subdural hemorrhage by means of neuroimaging techniques, i.e., CT and MRI, as well as retinal hemorrhage. The shaken baby syndrome will usually be observed within the first year of life. The doctor has to manifest his diagnosis to the caregivers and - before informing the caregivers - he must be sure of his diagnosis.


Can colonic migrating motor complexes occur in mice lacking the endothelin-3 gene?
In mammals, colonic migrating motor complexes (CMMC) are a major propulsive contraction responsible for the expulsion of faecal content. Mice with a mutation of the endothelin-3 gene raised on a 129SL background strain have ~70% colonic aganglionosis, lack CMMC, and are lethal within 12 days postpartum. In contrast, endothelin-3 mutant mice raised and maintained on a C57BL6 background strain (lethal-spotted (ls/ls) mice) can live for much longer, but it is unclear whether CMMC generation is preserved in these mice also lacking the endothelin-3 gene. The aim of this study was to determine whether CMMC exist in ls/ls mouse colon and, if so, whether their existence and frequency are related to the length of aganglionosis. Spatiotemporal mapping and mechanical recordings of colonic wall movements were made from isolated whole colons obtained from wild-type and ls/ls mice. Although ls/ls mice had a megacolon, they still generated CMMC in the ganglionic segment, which on some occasions could propagate short distances into the aganglionic region. There was large variability in aganglionosis length, which showed a weak correlation with the existence or frequency of CMMC. Interestingly, CMMC propagation velocity was slower in ls/ls mice when evoked by intraluminal fluid. A myogenic motor pattern was identified in the aganglionic region that was maintained under tonic inhibition. We show that despite megacolon, ls/ls mice still generate CMMC in the ganglionic region. These offspring have sufficient propulsive motility in the ganglionic segment to live a normal murine lifespan and rarely die of bowel obstruction.


Energy interconversion by the sarcoplasmic reticulum Ca2+-ATPase: ATP hydrolysis, Ca2+ transport, ATP synthesis and heat production.
The sarcoplasmic reticulum of skeletal muscle retains a membrane bound Ca2+-ATPase which is able to interconvert different forms of energy. A part of the chemical energy released during ATP hydrolysis is converted into heat and in the bibliography it is assumed that the amount of heat produced during the hydrolysis of an ATP molecule is always the same, as if the energy released during ATP cleavage were divided in two non-interchangeable parts: one would be converted into heat, and the other used for Ca2+ transport. Data obtained in our laboratory during the past three years indicate that the amount of heat released during the hydrolysis of ATP may vary between 7 and 32 Kcal/mol depending on whether or not a transmembrane Ca2+ gradient is formed across the sarcoplasmic reticulum membrane. Drugs such as heparin and dimethyl sulfoxide are able to modify the fraction of the chemical energy released during ATP hydrolysis which is used for Ca2+ transport and the fraction which is dissipated in the surrounding medium as heat.


Lack of hepatitis C virus reinfection in lifetime of Japanese general population with previous hepatitis C virus (HCV) infection successfully treated with anti-HCV therapy.
Achieving sustained virologic response (SVR) to antiviral therapy for hepatitis C virus (HCV) infection is an important step for eliminating HCV infection worldwide. However, recurrence of HCV viremia may occur due to HCV reinfection and confirmation of the long-term absence of HCV viremia, i.e., the absence of HCV reinfection, is necessary in post-SVR patients. In this report, we studied the long-term results of serum HCV RNA measurements in patients with SVR in whom serum HCV RNA was monitored over decades. Serum HCV RNA was measured at every visit in a total of 1,392 SVR patients who underwent regular visits to the hospital after SVR, of whom 434 patients (31.2%) had continued regular visits for more than 10 years. No patients demonstrated positive serum HCV RNA during follow-up after SVR with a total of 23,187 HCV RNA tests. This study confirmed the absence of reinfection with HCV in Japanese general population with SVR for decades. Once HCV had been eradicated by anti-HCV therapy, HCV infection rarely recurs even in a lifetime in Japan, unless patients are in high risk group of HCV infection and drop out for follow-up.


Glycerol hypersensitivity in a Drosophila model for glycerol kinase deficiency is affected by mutations in eye pigmentation genes.
Glycerol kinase plays a critical role in metabolism by converting glycerol to glycerol 3-phosphate in an ATP dependent reaction. In humans, glycerol kinase deficiency results in a wide range of phenotypic variability; patients can have severe metabolic and CNS abnormalities, while others possess hyperglycerolemia and glyceroluria with no other apparent phenotype. In an effort to help understand the pathogenic mechanisms underlying the phenotypic variation, we have created a Drosophila model for glycerol kinase deficiency by RNAi targeting of dGyk (CG18374) and dGK (CG7995). As expected, RNAi flies have reduced glycerol kinase RNA expression, reduced phosphorylation activity and elevated glycerol levels. Further investigation revealed these flies to be hypersensitive to fly food supplemented with glycerol. Due to the hygroscopic nature of glycerol, we predict glycerol hypersensitivity is a result of greater susceptibility to desiccation, suggesting glycerol kinase to play an important role in desiccation resistance in insects. To evaluate a role for genetic modifier loci in determining severity of the glycerol hypersensitivity observed in knockdown flies, we performed a preliminary screen of lethal transposon insertion mutant flies using a glycerol hypersensitive survivorship assay. We demonstrate that this type of screen can identify both enhancer and suppressor genetic loci of glycerol hypersensitivity. Furthermore, we found that the glycerol hypersensitivity phenotype can be enhanced or suppressed by null mutations in eye pigmentation genes. Taken together, our data suggest proteins encoded by eye pigmentation genes play an important role in desiccation resistance and that eye pigmentation genes are strong modifiers of the glycerol hypersensitive phenotype identified in our Drosophila model for glycerol kinase deficiency.


Building Embodied Spaces for Spatial Memory Neurorehabilitation with Virtual Reality in Normal and Pathological Aging.
Along with deficits in spatial cognition, a decline in body-related information is observed in aging and is thought to contribute to impairments in navigation, memory, and space perception. According to the embodied cognition theories, bodily and environmental information play a crucial role in defining cognitive representations. Thanks to the possibility to involve body-related information, manipulate environmental stimuli, and add multisensory cues, virtual reality is one of the best candidates for spatial memory rehabilitation in aging for its embodied potential. However, current virtual neurorehabilitation solutions for aging and neurodegenerative diseases are in their infancy. Here, we discuss three concepts that could be used to improve embodied representations of the space with virtual reality. The virtual bodily representation is the combination of idiothetic information involved during virtual navigation thanks to input/output devices; the spatial affordances are environmental or symbolic elements used by the individual to act in the virtual environment; finally, the virtual enactment effect is the enhancement on spatial memory provided by actively (cognitively and/or bodily) interacting with the virtual space and its elements. Theoretical and empirical findings will be presented to propose innovative rehabilitative solutions in aging for spatial memory and navigation.


Evaluation of silicon based microdosimetry for Boron Neutron Capture Therapy Quality Assurance.
The shift from reactor to accelerator based neutron production has created a renewed interested in Boron Neutron Capture Therapy (BNCT). BNCT is reliant upon the favourable uptake of 10B by tumour cells along with the interaction with neutrons to produce high LET fragments (He and Li nuclei) that deposit energy locally within the tumour cells. As with any radiation based treatment, Quality Assurance (QA) is crucial. In particular, Geant4 was used to model and optimise the geometry and packaging of Silicon on Insulator (SOI) microdosimeters for BNCT Quality Assurance purposes in view of experimental measurements at the KUR research reactor, in Japan. In this context, design optimisation pertains to the sensitive volume size and probability of neutron activation. This study has shown conclusively that whilst the materials currently used in the fabrication of silicon based microdosimeters are appropriate, there are changes with respect to the sensitive volume thickness that should be addressed to reduce the number of 'stoppers' in the microdosimeter.


Adjunctive phototherapies for oral manifestation of HIV-related histoplasmosis and leishmaniasis: An unusual case report.
Secondary infections of leishmaniasis and histoplasmosis in patients with advanced HIV are still a concern in low- and middle-income countries. The most common drugs for the treatment of both infections may be problematic mainly due to their toxicity. The present study aimed to report a case in which a concurrent oral manifestation of leishmaniasis and histoplasmosis in a hospitalized patient with HIV was managed with a combination of photobiomodulation therapy (PBMT) and antimicrobial photodynamic therapy (aPDT) as an adjuvant treatment. In addition to the use of conventional systemic oral drugs, a single aPDT session followed by two PBMT sessions was proposed, which resulted in complete wound healing within four days. Given the complexity of the current case, PBMT in combination with aPDT may be considered as an effective adjuvant option for managing oral infectious lesions of histoplasmosis and leishmaniasis in immunocompromised patients.


HIV care provider perceptions and approaches to managing unhealthy alcohol use in primary HIV care settings: a qualitative study.
HIV care providers often serve as the specialist and the primary care point-of-contact for persons living with HIV (PLWH) and unhealthy alcohol use. The purpose of the present qualitative study was to understand HIV care provider perceptions and approaches to managing unhealthy alcohol use in HIV primary care settings. Using a semi-structured interview guide, in-depth interviews were conducted among 14 HIV care providers (5 medical doctors, 5 nurse practitioners/physician assistants, 2 medical assistants, 2 clinical administrative staff) in private and public HIV clinics, across urban and rural areas of Florida. Interviews were coded using a grounded theory approach with inter-rater consensus. Six themes were identified. In summary, providers reported (1) inconsistent assessment of alcohol consumption, as well as (2) varying levels of confidence in self-report of alcohol use which may be affected by patient provider rapport and trust. While providers (3) acknowledge potential negative impacts of alcohol use on health outcomes and HIV treatment, providers reported (4) inconsistent recommendations regarding alcohol use among their patients. Lastly, providers reported (5) limited resources for patients with unhealthy alcohol use and (6) low confidence in their ability to help patients reduce use. Results from our study suggest salient differences in provider approaches to the assessment and management of unhealthy alcohol use in HIV primary care settings. Implementation of care for unhealthy alcohol use in these settings may be facilitated through use of clinically useful, validated alcohol use assessments and use of evidence-based recommendations of alcohol use/non-use among PLWH. Training in brief intervention techniques for alcohol reduction may increase provider confidence and support in the management of unhealthy alcohol use among PLWH.


T cell adhesion to intercellular adhesion molecule-1 (ICAM-1) is controlled by cell spreading and the activation of integrin LFA-1.
Many leukocyte integrins require activation before they can adhere to their ligands. For example, stimulation of T cells enables the integrin LFA-1 to bind to ligand. This study compares two well known protocols for inducing T cell LFA-1 mediated adhesion to intercellular adhesion molecule-1 (ICAM)-1. We how that treatment with high concentrations of the divalent cation Mg2+ induces a high affinity state of LFA-1, which is reflected in the binding of soluble ICAM-1 and correlates with the expression of the epitope recognized by mAb 24. The second stimulation protocol with the phorbol ester phorbol-12,13-dibutyrate (PDBu) does not induce a high affinity state of LFA-1, and in this situation, adhesion is dependent on cell spreading and intracellular events involving protein kinase C, [Ca2+]i, and actin polymerization. These low affinity LFA-1 receptors are responsible for the initial contact with immobilized ligand because, unlike the Mg2+-stimulated receptors, adhesion is not blocked by soluble ICAM-1. Finally, we used a third method of inducing LFA-1-mediated adhesion by stimulation of T cells through the TCR/CD3 complex. This procedure, which is considered to be a more physiologic trigger for LFA-1 activation, resembles the phorbol ester protocol in that high affinity LFA-1 receptors are not induced and cell adhesion depends on involvement of the cytoskeleton and cell spreading.


Kratom (Mitragyna speciosa) Validation: Quantitative Analysis of Indole and Oxindole Alkaloids Reveals Chemotypes of Plants and Products.
Many consumers are turning to kratom (Mitragyna speciosa) to self-manage pain and opioid addiction. In the United States, an array of capsules, powders, and loose-leaf kratom products are readily available. Additionally, several online sites supply live kratom plants. A prerequisite to establishing quality control and quality assurance standards for the kratom industry, or understanding how alkaloid levels effect clinical outcomes, is the identification and quantitation of major and minor alkaloid constituents within available products and preparations. To this end, an ultra-high performance liquid chromatography-high resolution mass spectrometry method was developed for the analysis of 8 indole alkaloids (7-hydroxymitragynine, ajmalicine, paynantheine, mitragynine, speciogynine, isopaynantheine, speciociliatine, and mitraciliatine) and 6 oxindole alkaloids (isomitraphylline, isospeciofoleine, speciofoline, corynoxine A, corynoxeine, and rhynchophylline) in US-grown kratom plants and commercial products. These commercial products shared a qualitatively similar alkaloid profile, with 12 - 13 detected alkaloids and high levels of the indole alkaloid mitragynine (13.9 ± 1.1 - 270 ± 24 mg/g). The levels of the other major alkaloids (paynantheine, speciociliatine, speciogynine, mitraciliatine, and isopaynantheine) and the minor alkaloids varied in concentration from product to product. The alkaloid profile of US-grown M. speciosa "Rifat" showed high levels of the indole alkaloid speciogynine (7.94 ± 0.83 - 11.55 ± 0.18 mg/g) and quantifiable levels of isomitraphylline (0.943 ± 0.033 - 1.47 ± 0.18 mg/g). Notably, the alkaloid profile of a US-grown M. speciosa seedling was comparable to the commercial products with a high level of mitragynine (15.01 ± 0.20 mg/g). This work suggests that there are several M. speciosa chemotypes.


Deep Learning Algorithm for Fully Automated Detection of Small (≤4 cm) Renal Cell Carcinoma in Contrast-Enhanced Computed Tomography Using a Multicenter Database.
Renal cell carcinoma (RCC) is often found incidentally in asymptomatic individuals undergoing abdominal computed tomography (CT) examinations. The purpose of our study is to develop a deep learning-based algorithm for fully automated detection of small (≤4 cm) RCCs in contrast-enhanced CT images using a multicenter database and to evaluate its performance. For the algorithmic detection of RCC, we retrospectively selected contrast-enhanced CT images of patients with histologically confirmed single RCC with a tumor diameter of 4 cm or less between January 2005 and May 2020 from 7 centers in the Japan Medical Image Database. A total of 453 patients from 6 centers were selected as dataset A, and 132 patients from 1 center were selected as dataset B. Dataset A was used for training and internal validation. Dataset B was used only for external validation. Nephrogenic phase images of multiphase CT or single-phase postcontrast CT images were used. Our algorithm consisted of 2-step segmentation models, kidney segmentation and tumor segmentation. For internal validation with dataset A, 10-fold cross-validation was applied. For external validation, the models trained with dataset A were tested on dataset B. The detection performance of the models was evaluated using accuracy, sensitivity, specificity, and the area under the curve (AUC). The mean ± SD diameters of RCCs in dataset A and dataset B were 2.67 ± 0.77 cm and 2.64 ± 0.78 cm, respectively. Our algorithm yielded an accuracy, sensitivity, and specificity of 88.3%, 84.3%, and 92.3%, respectively, with dataset A and 87.5%, 84.8%, and 90.2%, respectively, with dataset B. The AUC of the algorithm with dataset A and dataset B was 0.930 and 0.933, respectively. The proposed deep learning-based algorithm achieved high accuracy, sensitivity, specificity, and AUC for the detection of small RCCs with both internal and external validations, suggesting that this algorithm could contribute to the early detection of small RCCs.


Multiple micronutrient deficiencies persist during early childhood in Mongolia.
Data on the prevalence of micronutrient deficiencies in children in Mongolia is limited. We therefore determined the prevalence of anaemia, iron deficiency anaemia (IDA), and deficiencies of iron, folate, vitamin A, zinc, selenium, and vitamin D among young Mongolian children. Anthropometry and non-fasting morning blood samples were collected from 243 children aged 6-36 months from 4 districts in Ulaanbaatar and 4 rural capitols for haemoglobin (Hb), serum ferritin, folate, retinol, zinc, selenium, and 25-hydroxyvitamin D (25-OHD) assays. Children with alpha-1-glycoprotein >1.2mg/L (n=27) indicative of chronic infection were excluded, except for folate, selenium, and 25-hydroxyvitamin D assays. Of the children 14.5% were stunted and none were wasted. Zn deficiency (serum Zn <9.9 micromol/L) had the highest prevalence (74%), followed by vitamin D deficiency 61% (serum 25-OHD<25 nmol/L). The prevalence of anaemia (24%) and iron deficiency anaemia (IDA) (16%) was lower, with the oldest children (24-36 mos) at lowest risk. Twenty one percent of the children had low iron stores, and 33% had vitamin A deficiencies (serum retinol < 0.70 micromol/L), even though two thirds had received vitamin A supplements. Serum selenium values were low, perhaps associated with low soil selenium concentrations. In contrast, no children in Ulaanbaatar and only 4% in the provincial capitols had low serum folate values (<6.8 nmol/L). Regional differences (p<0.05) existed for anaemia, deficiencies of vitamin A, folate, and selenium, but not for zinc or IDA. Of the children, 78% were at risk of > or = two coexisting micronutrient deficiencies emphasizing the need for multimicronutrient interventions in Mongolia.


Megestrol acetate treatment of growth failure in children infected with human immunodeficiency virus.
To evaluate the effect of megestrol acetate on weight gain and linear growth in human immunodeficiency virus-infected children with growth failure. All human immunodeficiency virus-infected children with growth failure treated with megestrol acetate at our institution were evaluated retrospectively. Weight, height, and weight:height ratio were documented from 6 months before initiation of megestrol acetate until 6 months after treatment was discontinued. Measurements were corrected for age and sex by conversion to z-scores. Incremental growth was determined before, during, and after treatment. The potential effects of CD4+ T-lymphocyte count and percentage, antiretroviral therapy, and intercurrent illnesses on growth were evaluated. Nineteen patients were treated with a total of 27 courses of megestrol acetate. The median duration of therapy was 7 months (range, 3 to 11 months), and the median megestrol acetate dose was 7.91 mg/kg/day (range, 4.06 to 8.56 mg/kg/day). From 6 months and 3 months before treatment to the onset of therapy, median changes in weight z-scores were -.27 and -.15, respectively. During megestrol acetate treatment, median changes in weight z-scores were +.29 after 1 month of therapy, +.40 after 3 months, and +.57 after 6 months. After megestrol acetate therapy was discontinued, poor weight gain and weight loss resumed. Median 6-month growth velocities for weight were less than the 10th percentile before megestrol acetate, greater than the 97th percentile during treatment, and less than the 3rd percentile after treatment was discontinued. Megestrol acetate therapy was not associated with changes in linear growth. Antiretroviral therapy, CD4+ T-lymphocyte count or percentage, or intercurrent illnesses were not associated with statistically significant differences in response to megestrol acetate therapy. Megestrol acetate treatment of growth failure in pediatric human immunodeficiency virus disease is associated with weight gain, without affecting linear growth.


Chronic sinusitis.
Sinusitis is a very common chronic illness with a substantial health care impact. This review focuses on factors contributing to sinusitis pathogenesis and chronicity, including anatomic factors, disturbances in mucociliary clearance, microbial pathogens, and inflammatory factors. A distinction is made between "infectious" and "noninfectious" types of inflammation in chronic sinusitis. The inflammatory characteristics of noninfectious inflammation are reviewed primarily in the context of chronic hyperplastic sinusitis with nasal polyposis. Key features of this type of inflammation include the presence of chronic inflammatory cells, large numbers of eosinophils, and IL-5-producing T lymphocytes. Allergic fungal sinusitis is discussed as a special type of chronic sinusitis. Published studies on the outcomes of medical management are reviewed. Finally, algorithms for medical management of chronic sinusitis and allergic fungal sinusitis are presented.


Regulatory Considerations for Physiological Closed-Loop Controlled Medical Devices Used for Automated Critical Care: Food and Drug Administration Workshop Discussion Topics.
Part of the mission of the Center for Devices and Radiological Health (CDRH) at the US Food and Drug Administration is to facilitate medical device innovation. Therefore, CDRH plays an important role in helping its stakeholders such as manufacturers, health care professionals, patients, patient advocates, academia, and other government agencies navigate the regulatory landscape for medical devices. This is particularly important for innovative physiological closed-loop controlled (PCLC) devices used in critical care environments, such as intensive care units, emergency settings, and battlefield environments. CDRH's current working definition of a PCLC medical device is a medical device that incorporates physiological sensor(s) for automatic manipulation of a physiological variable through actuation of therapy that is conventionally made by a clinician. These emerging devices enable automatic therapy delivery and may have the potential to revolutionize the standard of care by ensuring adequate and timely therapy delivery with improved performance in high workload and high-stress environments. For emergency response and military applications, automatic PCLC devices may play an important role in reducing cognitive overload, minimizing human error, and enhancing medical care during surge scenarios (ie, events that exceed the capability of the normal medical infrastructure). CDRH held an open public workshop on October 13 and 14, 2015 with the aim of fostering an open discussion on design, implementation, and evaluation considerations associated with PCLC devices used in critical care environments. CDRH is currently developing regulatory recommendations and guidelines that will facilitate innovation for PCLC devices. This article highlights the contents of the white paper that was central to the workshop and focuses on the ensuing discussions regarding the engineering, clinical, and human factors considerations.


Hindered diffusion in microporous membranes with known pore geometry.
The hindrance effect on the aqueous diffusion rate of solutes within membrane pores of molecular size has been accurately determined. Mica membranes, 3 to 5 micrometers thick, were prepared with uniform, straight pores from 90 to 600 angstroms in diameter. With these membranes a direct estimation was possible of the interaction between pore size and molecular diffusion rates. There were no uncertainties due to wide pore size distributions or nonuniform tortuous channels as in previously used model microporous materials such as dialysis tubing or gels. Aqueous diffusion rates through these mica membranes were measured for a series of compounds with molecular diameters from 5.2 to 43 angstroms and were corrected for "liquid film resistances" adjacent to the membrane-solution interface to obtain estimates of molecular diffusivities within the micropores of the membrane. Definite evidence is presented showing that, even when molecular size is a small fraction of pore size, diffusion rates decrease markedly. The apparent reduction in solute diffusivity in the microporous membrane can be quantitatively estimated by means of the Renkin equation for hindered diffusion.