Which neuropsychiatric and behavioural features distinguish frontal and temporal variants of frontotemporal dementia from Alzheimer's disease?
To investigate the prevalence of changes in mood, personality, and behaviour in frontotemporal dementia (FTD) and Alzheimer's disease (AD) and hence, which features reliably distinguish between them. To establish whether the frontal and temporal variants of FTD are characterised by different behavioural changes. A questionnaire was designed to assess a wide range of neuropsychiatric changes; it incorporated features reported in previous studies of FTD and components of the neuropsychiatric inventory.(1) This was completed by 37 carers of patients with Alzheimer's disease (AD) and 33 patients with frontotemporal dementia (FTD), comprising 20 with temporal variant FTD (tv FTD) or semantic dementia and 13 with frontal variant FTD (fv FTD). An exploratory principal components factor analysis and discriminant function analysis was applied. Factor analysis showed four robust and meaningful symptom clusters: factor 1-stereotypic and eating behaviour; factor 2-executive dysfunction and self care; factor 3-mood changes; factor 4-loss of social awareness. Only stereotypic and altered eating behaviour and loss of social awareness reliably differentiated AD from FTD with no effect of disease severity. By contrast, executive dysfunction, poor self care, and restlessness showed a significant effect of disease severity only, with the more impaired patients scoring more highly. Changes in mood were found to be equally prevalent in the three patient groups. Analysis of individual symptoms showed increased rates of mental rigidity and depression in the patients with semantic dementia compared with those with fv FTD. Conversely, the latter group showed greater disinhibition. Discriminant function analysis correctly classified 71.4% overall and 86.5% of the patients with AD. This questionnaire disclosed striking differences between patients with FTD and AD, but only stereotypic behaviour, changes in eating preference, disinhibition, and features of poor social awareness reliably separated the groups. The patients with fv FTD and semantic dementia were behaviourally very similar, reflecting the involvement of a common network, the ventral frontal lobe, temporal pole, and amygdala. Dysexecutive symptoms and poor self care were found to be affected by the severity of the disease, reflecting perhaps spread to dorsolateral prefrontal areas relatively late in the course of both FTD and AD. This questionnaire may be of value in the diagnosis and the monitoring of therapies.


Coronary computed tomographic imaging in women: An expert consensus statement from the Society of Cardiovascular Computed Tomography.
This expert consensus statement from the Society of Cardiovascular Computed Tomography (SCCT) provides an evidence synthesis on the use of computed tomography (CT) imaging for diagnosis and risk stratification of coronary artery disease in women. From large patient and population cohorts of asymptomatic women, detection of any coronary artery calcium that identifies females with a 10-year atherosclerotic cardiovascular disease risk of >7.5% may more effectively triage women who may benefit from pharmacologic therapy. In addition to accurate detection of obstructive coronary artery disease (CAD), CT angiography (CTA) identifies nonobstructive atherosclerotic plaque extent and composition which is otherwise not detected by alternative stress testing modalities. Moreover, CTA has superior risk stratification when compared to stress testing in symptomatic women with stable chest pain (or equivalent) symptoms. For the evaluation of symptomatic women both in the emergency department and the outpatient setting, there is abundant evidence from large observational registries and multi-center randomized trials, that CT imaging is an effective procedure. Although radiation doses are far less for CT when compared to nuclear imaging, radiation dose reduction strategies should be applied in all women undergoing CT imaging. Effective and appropriate use of CT imaging can provide the means for improved detection of at-risk women and thereby focus preventive management resulting in long-term risk reduction and improved clinical outcomes.


GIP-induced vasodilation in human adipose tissue involves capillary recruitment.
Glucose-dependent insulinotropic polypeptide (GIP) in combination with hyperinsulinemia increase blood flow and triglyceride clearance in subcutaneous abdominal adipose tissue in lean humans. The present experiments were performed to determine whether the increase involves capillary recruitment. Eight lean healthy volunteers were studied before and after 1 h infusion of GIP or saline during a hyperglycemic-hyperinsulinemic clamp, raising plasma glucose and insulin to postprandial levels. Subcutaneous abdominal adipose tissue blood flow (ATBF) was measured by the 133Xenon clearance technique, and microvascular blood volume was determined by contrast-enhanced ultrasound imaging. During infusion of saline and the clamp, both ATBF (2.7 ± 0.5 mL/min 100 g/tissue) and microvascular blood volume remained unchanged throughout the experiments. During GIP infusion and the clamp, ATBF increased ~fourfold to 11.4 ± 1.9 mL/min 100 g/tissue, P < 0.001. Likewise, the contrast-enhanced ultrasound signal intensity, a measure of the microvascular blood volume, increased significantly 1 h after infusion of GIP and the clamp (P = 0.003), but not in the control experiments. In conclusion, the increase in ATBF during GIP infusion involves recruitment of capillaries in healthy lean subjects, which probably increases the interaction of circulating lipoproteins with lipoprotein lipase, thus promoting adipose tissue lipid uptake.


Melatonin downregulates nuclear receptor RZR/RORγ expression causing growth-inhibitory and anti-angiogenesis activity in human gastric cancer cells in vitro and in vivo.
An adequate supply of oxygen and nutrients, derived from the formation of novel blood vessels, is critical for the growth and expansion of tumor cells. It has been demonstrated that melatonin (MLT) exhibits marked in vitro and in vivo oncostatic activities. The primary purpose of the present study was to evaluate the in vitro and in vivo antitumor activity of MLT on the growth and angiogenesis of gastric cancer cells, and explore the underlying molecular mechanisms. The present results revealed that MLT inhibited the growth of gastric cancer SGC-7901 cells in a dose- and time-dependent manner. In addition, the present study demonstrated that low concentrations (0.01, 0.1 and 1 mM) of MLT had no clear effect on vascular endothelial growth factor (VEGF) secretion, whereas a high concentration (3 mM) of MLT suppressed VEGF secretion in SGC-7901 cells. Notably, administration of MLT caused suppression of gastric cancer growth and blockade of tumor angiogenesis in tumor-bearing nude mice. Furthermore, MLT treatment reduced the expression of the MLT nuclear receptor RZR/RORγ, SUMO-specific protease 1, hypoxia-inducible factor-1α and VEGF at transcriptional and translational levels within gastric cancer cells during tumorigenesis. In conclusion, MLT nuclear receptor RZR/RORγ may be of great importance in the MLT mediated anti-angiogenesis and growth-inhibitory effect in gastric cancer cells. Since RZR/RORγ is overexpressed in multiple human cancers, MLT may be a promising agent for the treatment of cancers.


Triterpenoids amplify anti-tumoral effects of mistletoe extracts on murine B16.f10 melanoma in vivo.
Mistletoe extracts are often used in complementary cancer therapy although the efficacy of that therapy is controversially discussed. Approved mistletoe extracts contain mainly water soluble compounds of the mistletoe plant, i.e. mistletoe lectins. However, mistletoe also contains water-insoluble triterpenoids (mainly oleanolic acid) that have anti-tumorigenic effects. To overcome their loss in watery extracts we have solubilized mistletoe triterpenoids with cyclodextrins, thus making them available for in vivo cancer experiments. B16.F10 subcutaneous melanoma bearing C57BL/6 mice were treated with new mistletoe extracts containing both water soluble compounds and solubilized triterpenoids. Tumor growth and survival was monitored. In addition, histological examinations of the tumor material and tumor surrounding tissue were performed. Addition of solubilized triterpenoids increased the anti-tumor effects of the mistletoe extracts, resulting in reduced tumor growth and prolonged survival of the mice. Histological examination of the treated tumors showed mainly tumor necrosis and some apoptotic cells with active caspase-3 and TUNEL staining. A significant decrease of CD31-positive tumor blood vessels was observed after treatment with solubilized triterpenoids and different mistletoe extracts. We conclude that the addition of solubilized mistletoe triterpenoids to conventional mistletoe extracts improves the efficacy of mistletoe treatment and may represent a novel treatment option for malignant melanoma.


Improving identification of differentially expressed genes by integrative analysis of Affymetrix and Illumina arrays.
Together with the widely used Affymetrix microarrays, the recently introduced Illumina platform has become a cost-effective alternative for genome-wide studies. To efficiently use data from both array platforms, there is a pressing need for methods that allow systematic integration of multiple datasets, especially when the number of samples is small. To address these needs, we introduce a meta-analytic procedure for combining Affymetrix and Illumina data in the context of detecting differentially expressed genes between the platforms. We first investigate the effect of different expression change estimation procedures within the platforms on the agreement of the most differentially expressed genes. Using the best estimation methods, we then show the benefits of the integrative analysis in producing reproducible results across bootstrap samples. In particular, we demonstrate its biological relevance in identifying small but consistent changes during T helper 2 cell differentiation.


Designation of type strains for seven species of the order Myxococcales and proposal for neotype strains of Cystobacter ferrugineus, Cystobacter minus and Polyangium fumosum.
Ten species of the order Myxococcales with validly published names are devoid of living type strains. Four species of the genus Chondromyces are represented by dead herbarium samples as the type material. For a species of the genus Melittangium and two species of the genus Polyangium, no physical type material was assigned at the time of validation of the names or later on. In accordance with rule 18f of the International Code of Nomenclature of Bacteria the following type strains are designated for these species: strain Cm a14(T) ( = DSM 14605(T) = JCM 12615(T)) as the type strain of Chondromyces apiculatus, strain Cm c5(T) ( = DSM 14714(T) = JCM 12616(T)) as the type strain of Chondromyces crocatus, strain Sy t2(T) ( = DSM 14631(T) = JCM 12617(T)) as the type strain of Chondromyces lanuginosus, strain Cm p51(T) ( = DSM 14607(T) = JCM 12618(T)) as the type strain of Chondromyces pediculatus, strain Me b8(T) ( = DSM 14713(T) = JCM 12633(T)) as the type strain of Melittangium boletus, strain Pl s12(T) ( = DSM 14670(T) = JCM 12637(T)) as the type strain of Polyangium sorediatum and strain Pl sm5(T) ( = DSM 14734(T) = JCM 12638(T)) as the type strain of Polyangium spumosum. Furthermore, the type strains given for three species of the genera Cystobacter and Polyangium had been kept at one university institute and have been lost according to our investigations. In accordance with Rule 18c of the Bacteriological Code, we propose the following neotype strains: strain Cb fe18 ( = DSM 14716 = JCM 12624) as the neotype strain of Cystobacter ferrugineus, strain Cb m2 ( = DSM 14751 = JCM 12627) as the neotype strain of Cystobacter minus and strain Pl fu5 ( = DSM 14668 = JCM 12636) as the neotype strain of Polyangium fumosum. The proposals of the strains are based on the descriptions and strain proposals given in the respective chapters of Bergey's Manual of Systematic Bacteriology (2005).


Use of Cannabidiol in the Management of Insomnia: A Systematic Review.
Background: Cannabidiol (CBD), one of the major cannabinoids derived from the cannabis plant, is available over the counter. CBD is often used by patients for the management of insomnia, yet research supporting CBDs effectiveness as a treatment for insomnia is inadequate. Objective: The objective of this review was to critically evaluate the literature regarding the therapeutic benefits of CBD in the management of insomnia. Methods: A comprehensive search of the following databases from inception to December 29, 2021, was conducted: Ovid MEDLINE® and Epub Ahead of Print, In-Process & Other Non-Indexed Citations and Daily, Ovid Embase, Ovid Cochrane Central Register of Controlled Trials, Ovid Cochrane Database of Systematic Reviews, and Scopus. The search included randomized controlled trials, nonrandomized experimental studies, cross-sectional studies, cohort studies, case series, and case reports. Risk of bias was assessed with the Agency for Healthcare Research and Quality design-specific recommended criteria. Results: Thirty-four studies were eligible for inclusion. All studies reported improvement in the insomnia symptoms of at least a portion of their participants. Of the 34 studies, 19 studies used CBD predominant therapy and 21 studies used nearly equal ratios of CBD to Δ9-tetrahydrocannabinol (THC). Of the studies that performed hypothesis testing, 4 of 7 studies with a CBD predominant arm and 12 of 16 studies with a nearly equal ratio of CBD to THC arm reported significant improvement in insomnia outcomes. However, only 2 of the 34 studies focused on patients with insomnia, of which 1 study was a case report. Additionally, several studies used nonvalidated subjective measures, and most studies failed to include objective measures for symptom assessment. Conclusions: The results of our systematic review suggest that CBD alone or with equal quantities of THC may be beneficial in alleviating the symptoms of insomnia. Nevertheless, future research assessing CBDs effectiveness in population of patients specifically with insomnia utilizing validated subjective and objective measures is necessary before definitive inferences can be made.


Partial validation of a TaqMan real-time quantitative PCR for the detection of ranaviruses.
Ranaviruses are globally emerging pathogens negatively impacting wild and cultured fish, amphibians, and reptiles. Although conventional and diagnostic real-time PCR (qPCR) assays have been developed to detect ranaviruses, these assays often have not been tested against the known diversity of ranaviruses. Here we report the development and partial validation of a TaqMan real-time qPCR assay. The primers and TaqMan probe targeted a conserved region of the major capsid protein (MCP) gene. A series of experiments using a 10-fold dilution series of Frog virus 3 (FV3) MCP plasmid DNA revealed linearity over a range of 7 orders of magnitude (107-101), a mean correlation coefficient (R2) of >0.99, and a mean efficiency of 96%. The coefficient of variation of intra- and inter-assay variability ranged from <0.1-3.5% and from 1.1-2.3%, respectively. The analytical sensitivity was determined to be 10 plasmid copies of FV3 DNA. The qPCR assay detected a panel of 33 different ranaviral isolates originating from fish, amphibian, and reptile hosts from all continents excluding Africa and Antarctica, thereby representing the global diversity of ranaviruses. The assay did not amplify highly divergent ranaviruses, members of other iridovirus genera, or members of the alloherpesvirus genus Cyprinivirus. DNA from fish tissue homogenates previously determined to be positive or negative for the ranavirus Epizootic hematopoietic necrosis virus by virus isolation demonstrated a diagnostic sensitivity of 95% and a diagnostic specificity of 100%. The reported qPCR assay provides an improved expedient diagnostic tool and can be used to elucidate important aspects of ranaviral pathogenesis and epidemiology in clinically and sublinically affected fish, amphibians, and reptiles.


Essential role of lymph nodes in contact hypersensitivity revealed in lymphotoxin-alpha-deficient mice.
Lymph nodes (LNs) are important sentinal organs, populated by circulating lymphocytes and antigen-bearing cells exiting the tissue beds. Although cellular and humoral immune responses are induced in LNs by antigenic challenge, it is not known if LNs are essential for acquired immunity. We examined immune responses in mice that lack LNs due to genetic deletion of lymphotoxin ligands or in utero blockade of membrane lymphotoxin. We report that LNs are absolutely required for generating contact hypersensitivity, a T cell-dependent cellular immune response induced by epicutaneous hapten. We show that the homing of epidermal Langerhans cells in response to hapten application is specifically directed to LNs, providing a cellular basis for this unique LN function. In contrast, the spleen cannot mediate contact hypersensitivity because antigen-bearing epidermal Langerhans cells do not access splenic white pulp. Finally, we formally demonstrate that LNs provide a unique environment essential for generating this acquired immune response by reversing the LN defect in lymphotoxin-alpha(-/)- mice, thereby restoring the capacity for contact hypersensitivity.


Reconciling cooperation, biodiversity and stability in complex ecological communities.
Empirical evidences show that ecosystems with high biodiversity can persist in time even in the presence of few types of resources and are more stable than low biodiverse communities. This evidence is contrasted by the conventional mathematical modeling, which predicts that the presence of many species and/or cooperative interactions are detrimental for ecological stability and persistence. Here we propose a modelling framework for population dynamics, which also include indirect cooperative interactions mediated by other species (e.g. habitat modification). We show that in the large system size limit, any number of species can coexist and stability increases as the number of species grows, if mediated cooperation is present, even in presence of exploitative or harmful interactions (e.g. antibiotics). Our theoretical approach thus shows that appropriate models of mediated cooperation naturally lead to a solution of the long-standing question about complexity-stability paradox and on how highly biodiverse communities can coexist.


[125I]iodo-epidermal growth factor binding and mitotic responsiveness of porcine granulosa cells are modulated by differentiation and follicle-stimulating hormone.
Epidermal growth factor (EGF) stimulates granulosa cell (GC) proliferation of certain species and modulates FSH-induced GC differentiation. The present study was undertaken to characterize the binding properties of the EGF receptor in porcine GCs to determine if the EGF responsiveness of mitotically active porcine GCs was related to their differentiated state and was regulated by reproductive hormones in vitro. Characterization of the EGF receptor-binding properties of porcine GCs revealed that saturation binding was achieved with 10 ng/ml [125I]iodo-EGF after 1 h at 37 C. In all states of differentiation, porcine GCs expressed few (less than 20,000/cell), specific, high affinity EGF receptors with apparent Kd values of 5.5 +/- 0.7 X 10(-10) M (mean +/- SEM; n = 6). Freshly harvested GCs obtained from small follicles were considered slightly differentiated (SDs) and bound, on the average, 2.6-fold more [125I]iodo-EGF than highly differentiated cells (HDs) obtained from large follicles which had further differentiated in vivo. The difference in binding was due to a decrease in receptor number and not to a change in receptor affinity. This relationship observed in freshly harvested cells was maintained in culture for a limited period. At 48 h of culture, the [125I]iodo-EGF-binding capacity of SDs was higher than that of HDs and was inversely related to the state of differentiation, as measured by [125I]iodo-LH/hCG-binding capacity. After 96 h, however, the EGF-binding capacity of HDs increased 3.7-fold from the level of binding at 48 h, while the LH/hCG-binding capacity decreased 10-fold. Conversely, the EGF-binding capacity of SDs decreased 28%, while the LH/hCG-binding capacity remained low. These experiments indicated that the state of GC differentiation was inversely correlated with EGF receptor number and that this relationship was not maintained in culture beyond 48 h. FSH treatment within the first 48 h of culture decreased the EGF-binding capacity of SDs 35% relative to the control value, but estradiol and dihydrotestosterone had no effect. FSH also regulated the mitotic responsiveness to EGF. EGF treatment of cultured SDs stimulated an 84% increase in cell number and a 178% increase in [3H]thymidine incorporation. These effects were suppressed by a high concentration of FSH. Thus, the ability of porcine GCs to bind EGF was changed with differentiation in vivo, while both EGF-binding capacity and mitotic responsiveness were regulated by exposure to FSH in vitro.


PPAR-γ is a major driver of the accumulation and phenotype of adipose tissue Treg cells.
Obesity and type-2 diabetes have increased markedly over the past few decades, in parallel. One of the major links between these two disorders is chronic, low-grade inflammation. Prolonged nutrient excess promotes the accumulation and activation of leukocytes in visceral adipose tissue (VAT) and ultimately other tissues, leading to metabolic abnormalities such as insulin resistance, type-2 diabetes and fatty-liver disease. Although invasion of VAT by pro-inflammatory macrophages is considered to be a key event driving adipose-tissue inflammation and insulin resistance, little is known about the roles of other immune system cell types in these processes. A unique population of VAT-resident regulatory T (Treg) cells was recently implicated in control of the inflammatory state of adipose tissue and, thereby, insulin sensitivity. Here we identify peroxisome proliferator-activated receptor (PPAR)-γ, the 'master regulator' of adipocyte differentiation, as a crucial molecular orchestrator of VAT Treg cell accumulation, phenotype and function. Unexpectedly, PPAR-γ expression by VAT Treg cells was necessary for complete restoration of insulin sensitivity in obese mice by the thiazolidinedione drug pioglitazone. These findings suggest a previously unknown cellular mechanism for this important class of thiazolidinedione drugs, and provide proof-of-principle that discrete populations of Treg cells with unique functions can be precisely targeted to therapeutic ends.


Endogenous reverse transcription of human immunodeficiency virus type 1 in physiological microenviroments: an important stage for viral infection of nondividing cells.
Endogenous reverse transcription (ERT) of retroviruses has long been considered a somewhat artificial process which only mimics reverse transcription occurring in target cells, as detergents or amphipathic peptides have classically been used to make the envelopes of retroviruses in these reaction systems permeable. Recently, several studies suggested that ERT of human immunodeficiency virus type 1 (HIV-1) might occur without detergent treatment. However, this phenomenon could be due to damage of the retroviral envelope during the process of virion purification or freezing and thawing. In this report, intravirion HIV-1 ERT, without detergent-induced permeabilization, is demonstrated to occur in the natural microenvironments of HIV-1 virions and is not caused by artificial processes. Therefore, this stage of the viral life cycle was termed natural ERT (NERT). The efficiency of NERT in HIV-1 virions was markedly augmented by several physiological substances in the extracellular milieu, such as polyamines and deoxyribonucleoside triphosphates. In addition, HIV-1 virions in seminal plasma samples harbored dramatically higher levels of full-length or nearly full-length reverse transcripts than virions isolated from peripheral blood plasma samples of HIV-1-seropositive men. When HIV-1 virions were incubated with seminal plasma samples, infectivity in initially nondividing cells was also significantly enhanced. Thus, we suggest that HIV-1 virions are actively altered by the extracellular microenvironment and that NERT may play an important role in viral infection of nondividing cells.


Phase I and pharmacokinetic study of taxotere (RP 56976) administered as a 24-hour infusion.
N-Debenzoyl-N-tert-butoxycarbonyl-10-deacytyl taxol (Taxotere, RP 56976) is a semisynthetic analogue of taxol, prepared from a noncytotoxic precursor extracted from the needles of the European yew tree (Taxus baccata L.). It has a broad spectrum of antitumor activity against a variety of transplantable tumors in mice. In vitro cytotoxicity assays suggest that it is 2-5-fold more potent than taxol. In this phase I study Taxotere was administered by 24 h i.v. infusion at 3-week intervals. Thirty patients with solid tumors refractory to conventional therapy were treated; 70 courses of Taxotere were administered at doses ranging from 10 to 90 mg/m2. Grade 4 neutropenia and grade 3 mucositis were dose limiting but reversible at 90 mg/m2. The pattern and grade of toxicity at this dose were similar in 3 heavily pretreated patients compared with 7 patients who had received a maximum of one previous chemotherapy regimen. Alopecia occurred at 55 mg/m2 and above. Other mild toxicities included phlebitis, diarrhea, emesis, and sensory peripheral neuropathy, but these were neither dose-limiting nor clearly dose-related. One patient treated at 70 mg/m2 had an anaphylactoid reaction following the second dose of Taxotere. No cardiovascular toxicity was observed. No partial or complete responses were documented. Plasma concentrations of Taxotere were determined by high-performance liquid chromatography, and end-of-fusion levels at the maximum tolerated dose exceeded drug concentrations which are cytotoxic in vitro. The maximum tolerated dose for Taxotere administered as a 24-h infusion is 90 mg/m2.


P2Y2 receptor up-regulation induced by guanosine or UTP in rat brain cultured astrocytes.
Among P2 metabotropic ATP receptors, P2Y2 subtype seems to be peculiar as its upregulation triggers important biological events in different cells types. In non-stimulated cells including astrocytes, P2Y2 receptors are usually expressed at levels lower than P2Y1 sites, however the promoter region of the P2Y2 receptors has not yet been studied and little is known about the mechanisms underlying the regulation of the expression of this ATP receptor. We showed that not only UTP and ATP are the most potent and naturally occurring agonist for P2Y2 sites, but also guanosine induced an up-regulation of astrocyte P2Y2 receptor mRNA evaluated by Northern blot analysis. We also focused our attention on this nucleoside since in our previous studies it was reported to be released by cultured astrocytes and to exert different neuroprotective effects. UTP and guanosine-evoked P2Y2 receptor up-regulation in rat brain cultured astrocytes was linked to an increased P2Y2-mediated intracellular calcium response, thus suggesting an increased P2Y2 activity. Actinomycin D, a RNA polymerase inhibitor, abrogated both UTP and guanosine-mediated P2Y2 up-regulation, thus indicating that de novo transcription was required. The effect of UTP and guanosine was also evaluated in astrocytes pretreated with different inhibitors of signal transduction pathways including ERK, PKC and PKA reported to be involved in the regulation of other cell surface receptor mRNAs. The results show that ERK1-2/MAPK pathway play a key role in the P2Y2 receptor up-regulation mediated by either UTP or guanosine. Moreover, our data suggest that PKA is also involved in guanosine-induced transcriptional activation of P2Y2 mRNA and that increased intracellular calcium levels and PKC activation may also mediate P2Y2 receptor up-regulation triggered by UTP. The extracellular release of ATP under physiological and pathological conditions has been widely studied. On the contrary, little is known about the release of pyrimidines and in particular of UTP. Here we show that astrocytes are able to release UTP, either at rest or during and following hypoxia/hypoglycemia obtained by submitting the cells to glucose-oxygen deprivation (OGD). Interestingly, also P2Y2 receptor mRNA increased by about two-fold the control values when the cultures were submitted to OGD. It has been recently reported that P2Y2 receptors can play a protective role in astrocytes, thus either guanosine administration or increased extracellular concentrations of guanosine and UTP reached locally following CNS injury may increase P2Y2-mediated biological events aimed at promoting a protective astrocyte response.


Physical exercise as prophylaxis against involutional vertebral bone loss: a controlled trial.
1. The skeletal effects of physical training were studied in a controlled trial involving 31 healthy women (aged 50-73 years) with previous Colles' fracture of the forearm. The bone mineral content of the lumbar spine and both distal forearms was measured by dual-photon (153Gd) absorptiometry. 2. The participants were allocated to either a physical exercise group or a control group. The former group followed a standardized exercise programme, exercising for 1 h twice weekly during 8 months. 3. Twenty-seven women completed the study. Lumbar spine bone mineral content of the exercise group increased by 3.5%, whereas that of the control group decreased by 2.7%. The rate of bone loss in the control group equalled that of age-matched normal women. 4. The changes in forearm bone mineral content appeared to be independent of the exercise. The bone mineral content of the previously fractured forearm remained nearly unchanged. The bone mineral content of the uninjured forearm decreased on average by 3.5%. 5. The data suggest that physical exercise can inhibit or reverse the involutional bone loss from the lumbar vertebrae in normal women. Physical exercise may prevent spinal osteoporosis.


Smart nanoporous metal-organic frameworks by embedding photochromic molecules - state of the art and future perspectives.
Smart, molecularly structured materials with remote-controllable properties and functionalities attract particular attention and may enable advanced applications. In this respect, the embedment of stimuli-responsive molecules, such as azobenzenes, spiropyrans or diarylethenes, in metal-organic frameworks (MOFs) is a very fascinating approach, resulting in easily accessible photoswitchable, nanoporous hybrid materials. It is an attractive alternative to the incorporation of the smart moieties in the MOF scaffold, which usually demands complex synthetic efforts. Here, the opportunities, properties and perspectives of the embedment of photochromic molecules in MOF pores are reviewed. In addition to presenting a straightforward route to prepare smart materials with, e.g., photoswitchable adsorption properties that can be used for remote-controllable membrane separation, the photoswitch@MOF compounds also represent unique model systems to investigate the dye as well as the MOF properties and their interactions with each other. For instance, the MOF pores possess a polarity similar to a solvent, so that the optical properties of the resulting materials may be influenced by a careful choice of the respective host material.


Effects of curcumin on sodium currents of dorsal root ganglion neurons in type 2 diabetic neuropathic pain rats.
Along with the development of economy and society, type 2 diabetic mellitus (T2DM) has become one of the most common diseases at the global level. As one of the complications of T2DM, diabetic neuropathic pain (DNP) stubbornly and chronically affects the health and life of human beings. In the pain field, dorsal root ganglion (DRG) is generally considered as the first stage of the sensory pathway where the hyperexcitability of injured neurons is associated with different kinds of peripheral neuropathic pains. The abnormal electrophysiology is mainly due to the changed properties of voltage-gated sodium channels (VGSCs) and the increased sodium currents (I(Na)). Curcumin is an active ingredient extracted from turmeric and has been demonstrated to ameliorate T2DM and its various complications including DNP effectively. The present study demonstrates that the I(Na) of small-sized DRG neurons are significantly increased with the abnormal electrophysiological characteristics of VGSCs in type 2 diabetic neuropathic pain rats. And these abnormalities can be ameliorated efficaciously by a period of treatment with curcumin.


Clinical Significances of Preoperative Classification of Intrahepatic Cholangiocarcinoma: Different Characteristics of Perihilar vs. Peripheral ICC.
The aim of this study was to evaluate the clinical significance of preoperative classification of intrahepatic cholangiocarcinoma (ICC) into perihilar and peripheral types using dynamic computed tomography (CT). A retrospective cohort study was performed to analyze the differences in clinical characteristics between perihilar and peripheral ICC samples from patients between 1990-2014. A total of 87 patients were divided into three ICC subtypes; perihilar (n=34), peripheral (n=44), and unclassifiable ICC (n=9). The positive rates of pathological lymphatic infiltration (ly) (p=0.02) and perineural invasion (pn) (p<0.0001) were significantly higher in perihilar ICC. There was no significant difference in the disease-free survival rate (p=0.2268); however, the overall survival rate of perihilar ICC was significantly worse (p=0.0031). The rate of systemic recurrence (>3 nodules) was significantly higher in perihilar ICC (p=0.0135). In perihilar ICC, the local tumor invasions such as ly and pn were more frequent. Therefore, it is important in such cases to attempt to achieve a sufficient tumor margin. Systemic recurrences were more frequent in perihilar ICC, so perioperative chemotherapy should be conducted as well.


Dietary calcium intake and rates of bone loss in women.
We measured bone mineral density (BMD) at the midradius and lumbar spine in 106 normal women, ages 23-84 yr (61 were postmenopausal). Three to nine measurements (median, four) were made over 2.6 to 6.6 yr (mean, 4.1 yr). The correlation between calcium intake (range, 260-2,035 mg/d) and rate of change in BMD was not significant at the midradius (r = 0.06) or lumbar spine (r = 0.08), even after adjusting for age, menopausal status, and serum estrogen levels by multiple regression analysis. Women in the lower (mean, 501 mg/d) and in the upper (mean, 1,397 mg/d) quartiles of dietary intake had similar rates of change in BMD (%/yr [mean +/- SE], at midradius, -0.78 +/- 0.24 and -0.91 +/- 0.17 for lower and upper quartiles, respectively; at lumbar spine, -1.06 +/- 0.24 and 0.98 +/- 0.24). These data do not support the hypothesis that insufficient dietary calcium is a major cause of bone loss in women.


Landscape risk factors for Lyme disease in the eastern broadleaf forest province of the Hudson River valley and the effect of explanatory data classification resolution.
This study assessed how landcover classification affects associations between landscape characteristics and Lyme disease rate. Landscape variables were derived from the National Land Cover Database (NLCD), including native classes (e.g., deciduous forest, developed low intensity) and aggregate classes (e.g., forest, developed). Percent of each landcover type, median income, and centroid coordinates were calculated by census tract. Regression results from individual and aggregate variable models were compared with the dispersion parameter-based R(2) (Rα(2)) and AIC. The maximum Rα(2) was 0.82 and 0.83 for the best aggregate and individual model, respectively. The AICs for the best models differed by less than 0.5%. The aggregate model variables included forest, developed, agriculture, agriculture-squared, y-coordinate, y-coordinate-squared, income and income-squared. The individual model variables included deciduous forest, deciduous forest-squared, developed low intensity, pasture, y-coordinate, y-coordinate-squared, income, and income-squared. Results indicate that regional landscape models for Lyme disease rate are robust to NLCD landcover classification resolution.


Persistent and selective deficiency of CD4+ T cell immunity to cytomegalovirus in immunocompetent young children.
Healthy young children who acquire CMV have prolonged viral shedding into the urine and saliva, but whether this is attributable to limitations in viral-specific immune responses has not been explored. In this study, we found that otherwise immunocompetent young children after recent primary CMV infection accumulated markedly fewer CMV-specific CD4(+) T cells that produced IFN-gamma than did adults. These differences in CD4(+) T cell function persisted for more than 1 year after viral acquisition, and did not apply to CMV-specific IFN-gamma production by CD8(+) T cells. The IFN-gamma-producing CD4(+) T cells of children or adults that were reactive with CMV Ags were mainly the CCR7(low) cell subset of memory (CD45R0(high)CD45RA(low)) cells. The decreased IFN-gamma response to CMV in children was selective, because their CCR7(low) memory CD4(+) T cells and those of adults produced similar levels of this cytokine after stimulation with staphylococcal enterotoxin B superantigen. CD4(+) T cells from children also had reduced CMV-specific IL-2 and CD154 (CD40 ligand) expression, suggesting an early blockade in the differentiation of viral-specific CD4(+) T cells. Following CMV acquisition, children, but not adults, persistently shed virus in urine, and this was observable for at least 29 mo postinfection. Thus, CD4(+) T cell-mediated immunity to CMV in humans is generated in an age-dependent manner, and may have a substantial role in controlling renal viral replication and urinary shedding.


Closed vs open surgical exposure of palatally displaced canines: surgery time, postoperative complications, and patients' perceptions: a multicentre, randomized, controlled trial.
Closed and open surgical techniques are two different main approaches to surgical exposure of palatally displaced canines (PDCs). Because there is insufficient evidence to support one technique over the other, there is a need for randomized controlled trials. To compare surgery time, complications and patients' perceptions between closed and open surgical techniques in PDCs. The trial was a multicentre, randomized, controlled trial with two parallel groups randomly allocated in a 1:1 ratio. Study participants were 119 consecutive patients from 3 orthodontic centres, with PDCs planned for surgical exposure, randomly allocated according to a computer-generated randomization list, using concealed allocation. Full-thickness mucoperiosteal flap was raised, and bone covering the canine was removed in both interventions. In closed exposure, an attachment with a chain was bonded to the canine and the flap was sutured back with the chain penetrating the mucosa. In open exposure, a window of tissue around the tooth was removed and glass ionomer cement placed on the canine crown, to prevent gingival overgrowth during spontaneous eruption. Patient perceptions were assessed with two questionnaires, for the evening on the day of operation and 7 days post-surgery. It was not possible to blind either patients or care providers to the interventions. The outcome assessors were blinded and were unaware of patients' intervention group. Seventy-five girls and 44 boys, mean age 13.4 years (SD 1.46) participated in the study and got either of the interventions (closed exposure, n = 60; open exposure, n = 59). Surgery time did not differ significantly between the interventions. Complications though were more severe in bilateral cases and the patients experienced more pain and impairment in the open group. There were no statistically significant differences regarding surgery time between the groups. Postoperative complications were similar between the groups in unilateral PDCs, but more common in the open group in bilateral cases. More patients in the open group experienced pain and impairment compared to the closed group. Trial registration: ClinicalTrials.gov, ID: NCT02186548 and Researchweb.org, ID: 127201.


Glutamate NMDA receptors within the amygdala participate in the modulatory effect of glucocorticoids on extinction of conditioned fear in rats.
Recent results show that brain glucocorticoids are involved in the dysregulation of fear memory extinction in post-traumatic stress disorder patients. The present study was aimed to elucidate the possible mechanism of glucocorticoids on the conditioned fear extinction. To achieve these goals, male SD rats, fear-potentiated startle paradigm, and Western blot were used. We found that (1) systemic administration of the synthetic glucocorticoid agonist dexamethasone (DEX) facilitated extinction of conditioned fear in a dose-dependent manner (0.05, 0.1, 0.5, or 1.0 mg/kg, i.p.); (2) systemic administration of the glutamate NMDA receptor antagonist (+/-)-HA966 (6.0 mg/kg, i.p.) and intra-amygdala infusion of the NMDA receptor antagonists MK801 (0.5 ng/side, bilaterally) or D,L-2-amino-5-phosphonovaleric acid (AP5, 2.0 ng/side, bilaterally) blocked the DEX facilitation effect; (3) the corticosteroid synthesis inhibitor metyrapone (25 mg/kg. s.c.) blocked extinction and this was prevented by co-administration of NMDA receptor agonist D-cycloserine (DCS, 5.0 mg/kg, i.p.); (4) co-administration of DEX and DCS in subthreshold doses provided a synergistic facilitation effect on extinction (0.2 and 5 mg/kg, respectively). Control experiments indicated that co-administration of DEX and DCS did not alter the expression of conditioned fear and the effect was not due to lasting damage to the amygdala. These results suggest that glutamate NMDA receptors within the amygdala participate in the modulatory effect of glucocorticoids on extinction.


Expression of porcine endometrial prostaglandin synthase during the estrous cycle and early pregnancy, and following endocrine disruption of pregnancy.
Porcine trophoblast attachment to the uterine surface is associated with increased conceptus and endometrial production of prostaglandins. Conceptus secretion of estrogen on Day 12 of gestation is important for establishment of pregnancy; however, early (Days 9 and 10) exposure to exogenous estrogens results in embryonic mortality. Present studies established the temporal and spatial pattern of endometrial PTGS1 (prostaglandin-endoperoxide synthase 1) and PTGS2 expression during the estrous cycle and early pregnancy and determined the effect of early estrogen treatment on endometrial PTGS expression in pregnant gilts. Endometrial PTGS1 mRNA expression increased 2- to 3-fold after Day 10 of the estrous cycle and pregnancy, whereas PTGS2 mRNA expression increased 76-fold between Days 5 and 15 of the estrous cycle and pregnancy. Increased expression of the PTGS2 transcript was detected in the lumenal epithelium after Day 10 in both cyclic and pregnant gilts. There was a 10- and 20-fold increase in endometrial PTGS2 protein expression between Days 5 and 18 of the estrous cycle and pregnancy respectively. Administration of estrogen on Days 9 and 10 of gestation increased endometrial PTGS2 mRNA and protein on Day 10, but decreased PTGS2 mRNA and protein in lumenal epithelium (LE) on Day 12 of gestation compared to vehicle-treated gilts. The present study demonstrates that an increase in uterine epithelial PTGS2 expression occurs after Day 10 of the estrous cycle and early pregnancy in the pig. The conceptus-independent increase in the uterine LE indicates that a novel pathway exists for endometrial induction PTGS2 expression before conceptus elongation and attachment to the uterine surface. Epithelial expression of PTGS2 may serve as one of the signals for placental attachment and embryo survival in the pig. Early administration of estrogen on Days 9 and 10 of pregnancy alters endometrial PTGS2 mRNA and protein expression, which may, at least in part, represent a mechanism by which endocrine disruption of pregnancy causes total embryonic loss during implantation in the pig.


Behavioral and biochemical characterization of benzodiazepine receptor partial agonists in pigeons.
The ability of benzodiazepine receptor partial agonists to exhibit full efficacy in preclinical anxiolytic tests, in conjunction with initial clinical results, has suggested the possibility of a reduced clinical side-effect profile compared to benzodiazepine receptor full agonists like diazepam. Because punished behavior of pigeons has been useful in detecting effects of novel anxiolytic drugs, effects of imidazobenzodiazepine and beta-carboline benzodiazepine receptor partial agonists and some related compounds were evaluated in this species. The abilities of these compounds to substitute for the discriminative stimulus effects of the full agonists midazolam also was determined. Intrinsic efficacy was assessed by the degree to which gamma-aminobutyric acid increased ligand potency to displace [(3)H]Ro15-1788 (flumazinil) from membranes of pigeon cerebrum, and ranged from full agonist-like efficacy (Ro 19-5470; 7-(3-cyclopropyl-1,2,4-oxodiazol-5-yl)-5,6-dihydro-5-methyl-4H- imidazo[1,5a]-thieno[3,2-f]diazin-4-one) to minimal gamma-aminobutyric acid potentiations close to that of the antagonist flumazenil (abecarnil and Ro 41-7812; 7-chloro-4,5-dihydro-3-(3-hydroxy-1-propynyl)-5-methyl-6H-imidazo[1,5-a] -[1,4 ]benzodiazepine-6-one). Punished responding was increased markedly by midazolam and by all partial agonists, except Ro 41-7812 and Ro 42-8773 (7-chloro-3-[3-(cyclopropylmethoxy)-1-propynyl]-4,5-dihyro-5 -methyl-6H-imidaz o[1,5-a][1,4]benzodiazepine-6-one), at doses that did not affect nonpunished responding. In contrast to the full substitution generally observed in mammals, all of the partial agonists produced incomplete substitution (40-70%) in the midazolam drug discrimination procedure in pigeons. A positive relationship was observed between the degree of substitution and intrinsic efficacy. The benzodiazepine antagonists, flumazenil and ZK 93,426 (ethyl-5-isopropoxy-4-methoxymethyl-beta-carboline-3-carboxylate), neither increased punished responding nor substituted for midazolam. The results of the present study suggest that benzodiazepine receptor partial agonists and related compounds may provide full anxiolytic activity at doses that do not fully reproduce the subjective effect profile of full agonists.


Role of cyclic AMP response element-binding protein in insulin-like growth factor-i receptor up-regulation by sex steroids in prostate cancer cells.
Insulin-like growth factor-I receptor (IGF-IR) overexpression may play a role in prostate cancer progression. We found previously that, in prostate cancer cells, IGF-IR is up-regulated by both androgens and estrogens via a nongenotropic pathway. We now show that, in prostate cancer cells, stimulation with either androgens or estrogens up-regulates IGF-IR by inducing cyclic AMP response element-binding protein (CREB) activation. Both sex steroids phosphorylated CREB at Ser(133) in a dose-dependent manner in androgen receptor (AR)-positive LNCaP cells, whereas only estrogens phosphorylated CREB in AR-negative PC3 cells. CREB phosphorylation involved c-Src-dependent extracellular signal-regulated kinase 1/2 activation, but not protein kinase A, protein kinase C, or calmodulin-dependent kinase II, and occurred also in cells transfected with AR or estrogen receptor mutants that do not localize into the nucleus. CREB silencing abrogated IGF-IR up-regulation and promoter activation. We also showed that CREB binds to IGF-IR promoter region and identified the relevant CREB-binding site at the 5'-untranslated region fragment of IGF-IR promoter. In conclusion, we describe a novel mechanism of IGF-IR up-regulation and promoter activity by CREB activation, induced by sex steroids, through a nongenotropic signaling.


Clinical Equipoise for Trials of Novel Biologic Therapies, Therapeutic Success Rates, and Predictors of Success: A Meta-Analysis.
The demand for more rapid access to novel biologic therapies than randomized controlled trials can deliver is a topic of ongoing study and debate. We aimed to inform this debate by estimating therapeutic success from phase III trials comparing novel biologic therapies with standard of care and identifying predictors of success. This was a meta-analysis of phase III trials evaluating novel biologic therapies in advanced breast, colorectal, lung, and prostate cancers. Therapeutic success was defined as statistically significant results for the primary end point favoring novel biologic therapies. Of 119 included phase III trials (76,726 patients), therapeutic success was 41%, with a statistically significant relative reduction in disease progression and death for novel biologic therapies over standard of care of 20% and 8%. Therapeutic success did not improve over time (pre-2010, 33%; 2010 to 2014, 44%; P = .2). Predictors of success were a biomarker-selected population (odds ratio, 4.74; 95% CI, 2.05 to 10.95) and progression-free survival end point compared with overall survival (odds ratio, 5.22; 95% CI, 2.41 to 11.39). Phase III trials with a biomarker-selected population showed a larger 28% progression-free survival benefit than phase III trials overall (hazard ratio, 0.72; 95% CI, 0.70 to 0.75) but similar 8% overall survival benefit (hazard ratio, 0.92; 95% CI, 0.90 to 0.94). Therapeutic success of phase III trials with and without a preceding phase II trial were 43% and 30%, respectively. Therapeutic success of novel biologic therapies in phase III trials, including therapies with a matching predictive biomarker, was modest and has not significantly improved over time. Equipoise remains and supports the ongoing ethical and scientific requirement for phase III randomized controlled trials to estimate treatment efficacy and assess the value of potential biomarkers.


Acute ITP due to insect bite: report of 2 cases.
Immune thrombocytopenic purpura (ITP) of childhood is a common hematologic disorder. Immune thrombocytopenic purpura is characterized by increased destruction of antibody-coated platelets in the reticuloendothelial system. In the majority of children with acute ITP, thrombocytopenia occurs within 1 to 3 weeks after an infectious disease. Immune thrombocytopenic purpura may also occur after rubella, rubeola, chickenpox, or live virus vaccination. Here we report 2 cases with acute ITP that were developed after honeybee and insect bite.


PER3, a gene required for peroxisome biogenesis in Pichia pastoris, encodes a peroxisomal membrane protein involved in protein import.
PER genes are essential for the biogenesis of peroxisomes in the yeast Pichia pastoris. Here we describe the cloning of PER3 and functional characterization of its product Per3p. The PER3 sequence predicts that Per3p is a 713-amino acid (81-kDa) hydrophobic protein with at least three potential membrane-spanning domains. We show that Per3p is a membrane protein of the peroxisome. Methanol- or oleate-induced cells of per3-1, a mutant strain generated by chemical mutagenesis, lack normal peroxisomes but contain numerous abnormal vesicular structures. The vesicles contain thiolase, a PTS2 protein, but only a small portion of several other peroxisomal enzymes, including heterologously expressed luciferase, a PTS1 protein. These results suggest that the vesicles in per3-1 cells are peroxisomal remnants similar to those observed in cells of patients with the peroxisomal disorder Zellweger syndrome, and that the mutant is deficient in PTS1 but not PTS2 import. In a strain in which most of PER3 was deleted, peroxisomes as well as peroxisomal remnants appeared to be completely absent, and both PTS1- and PTS2-containing enzymes were located in the cytosol. We propose that Per3p is an essential component of the machinery required for import of all peroxisomal matrix proteins and is composed of independent domains involved in the import of specific PTS groups.


Serum magnesium and not vitamin D is associated with better QoL in COPD: A cross-sectional study.
Deficiency of serum levels of vitamin D3 (se vitD), magnesium (se Mg) and calcium (se Ca) may be associated with increased exacerbation risk in chronic obstructive pulmonary disease (COPD). However, associations with other aspects of COPD, e.g. lung function and quality of life (QoL), have been studied less extensively. To investigate se vitD, se Mg and se Ca in COPD and their associations with both forced expiratory volume in 1st second (FEV1) and QoL. FEV1 and se vitD (assessed by 25-(OH)-D3), se Mg and se Ca were measured during summertime. Generic and health related QoL were characterized. This cross-sectional study included 143 participants with COPD. Women had a significantly higher se vitD than men (P = 0.0028), and 27% of participants were se vitD deficient. FEV1 was not correlated with se vitD, se Mg or se Ca in COPD. Mg deficiency group reported significantly impaired mobility, usual activities, pain/discomfort and COPD-related QoL. Se vitD and se Ca were not associated with QoL. Serum levels of vitD, Mg and Ca were not related to FEV1. Most participants in this study were vitD-, Mg- and Ca sufficient. Women had higher se vitD than men. Se Mg, but not se vitD and se Ca, was associated with QoL in COPD. Prospective randomized studies are needed to substantiate these finding. Clinical trials ID at www.clinicaltrials.gov: NCT01564953.


How mHealth will spur consumer-led healthcare.
Consumer attitudes about their healthcare are beginning to shift. They are taking more responsibility for their health and seeking to collaborate with their doctors. In some cases consumers will engage in self-diagnosis. Mobile health apps and devices, in combination with cloud computing, will play a major role to empower consumers. Consumer expectations for healthcare are rising by the day. mHealth has provided empowerment to patients through the power of the PSC, which I describe as personal supercomputers. The number of devices and apps are exploding onto the healthcare scene. Although some providers are not comfortable with consumer technology for self-diagnosis, the new technologies will lead to a new model for collaboration between patient and physician.


Nurses' perceptions of individualized care: an international comparison.
This paper is a report of a study of internationally-based differences in nurses' perceptions of individualized care in orthopaedic surgical in-patient wards. Individualized care is valued in healthcare policy, practice and ethical statements as an indicator of care quality. However, nurses' assessments of individualized care are limited and comparative cross-cultural studies on individualized nursing care are lacking. A descriptive comparative survey was used to sample orthopaedic surgical nurses (n = 1163) working in 91 inpatient wards in 34 acute hospitals in Finland, Cyprus, Greece, Portugal, Sweden, Turkey and the United States of America. Data were collected between March and November 2009 using the Individualized Care Scale-Nurse and analysed using descriptive and inferential statistics. Nurses in different countries perceived that they supported patients' individuality generally and provided individualized care during nursing activities. Although the highest scores were in support of patients' individuality in the clinical situation both through nursing provision and nurses' perceptions of individuality, there were between-country differences within these scores. Generally, the Greek and American nurses gave the highest scores and the Turkish, Cypriot and Portuguese nurses the lowest. Between-country differences found may be attributed to differing roles of nurses, care processes, healthcare systems and/or the ways nursing care is defined and organized. As this was the first time the Individualized Care Scale-Nurse was used in an international context, the results are formative and indicate the need to continue studies in this area.


Second lymphoid malignant neoplasms occurring in patients treated for Hodgkin's disease.
Patients who have been treated for Hodgkin's disease are at increased risk for second malignant neoplasms, particularly acute nonlymphoblastic leukemia and non-Hodgkin's lymphoid malignant neoplasms (NHLMs). We diagnosed five cases of NHLM in 242 patients initially treated for Hodgkin's disease between 1973 and 1980, giving a minimum incidence for this occurrence of 2.1%. The initial therapy for Hodgkin's disease, irradiation in three patients and chemotherapy in two patients, resulted in a complete remission in each case. The NHLM appeared 12, 13, 26, 30, and 54 months after the diagnosis of Hodgkin's disease. The cell type of NHLM and immunologic phenotype were as follows: large cell, immunoblastic T; large cell, immunoblastic null; large cell, cleaved and noncleaved B; large cell, cleaved and noncleaved (not studied); and lymphoblastic T. A review of 24 other cases of NHLMs, occurring in patients treated for Hodgkin's disease, reported in the literature, confirm the morphologic and immunologic heterogeneity. The poor response to therapy in our patients and those previously described demonstrate the seriousness of this phenomenon.


Acalculous cholecystitis after aortic reconstruction.
Acute acalculous cholecystitis is rare in patients undergoing aortic surgery; but, this condition is associated with a high mortality rate. With their comorbid medical problems, patients undergoing aortic reconstruction may have a higher mortality associated with acute acalculous cholecystitis. By retrospectively reviewing patient charts, we studied the prevalence, demographics, details of antecedant aortic procedures, hospital course, and outcome of patients with acute acalculous cholecystitis after aortic surgery. In the past 10 years, 7 of the 996 patients who underwent aortic reconstruction at our institution developed postoperative acute acalculous cholecystitis. These patients were all nondiabetic men with a mean age of 66 +/- 4 years (range, 50 to 76 years). Previous aortic operations included four infrarenal aneurysmorrhaphies (three elective, one urgent for a ruptured aneurysm), two aortofemoral bypasses for occlusive disease, and a removal of an infected aortic prosthesis. Six patients had prolonged intraoperative hypotension and increased blood transfusion requirements. All patients had postoperative multiorgan dysfunction. The patients developed fever, leukocytosis, elevated liver function test levels, and other signs and symptoms of acute acalculous cholecystitis a mean of 32 days (range, 9 to 90 days) after operation. Preoperative diagnosis was made in five patients based on clinical examination, laboratory test results, and adjunctive noninvasive test results. Two patients required laparotomy to make the diagnosis of acute acalculous cholecystitis. Five patients underwent cholecystectomy, and two had placement of cholecystostomy tubes. Gangrene or perforation was evident in most. Overall mortality was 71 percent. Acute acalculous cholecystitis is the most common postoperative biliary complication after aortic surgery. The diagnosis should be entertained in patients with signs of abdominal sepsis after aortic surgery, especially those with a complicated postoperative course. Even if acute acalculous cholecystitis is diagnosed before exploration, mortality remains high.


Evaluation of Apparent Diffusion Coefficient Values in Spinal Tuberculosis by MRI.
Spinal tuberculosis presents a radiological challenge in many cases when it presents with atypical pattern of involvement and has to be distinguished from various differentials, which include metastases. In such cases Diffusion Weighted Imaging (DWI) with Apparent Diffusion Co-efficient (ADC) value may play a role in reaching towards a conclusion, thereby preventing unnecessary biopsy in such patients. Measurement of mean ADC values in tubercular vertebrae and associated collection. The study was comprised of 55 patients and was conducted on 3.0 TESLA Siemens machine Magnetom Verio. Patients either known to have tuberculosis or those with classic tuberculous findings were included in the study. All these patients were followed up for post-treatment confirmation and ADC value. All the patients underwent routine MRI along with DW-MRI sequence, ADC values and FNAC/ Biopsy if required. The ADC values were calculated from the involved vertebral bodies and surrounding soft tissue and also from normal vertebrae preferably from one above and below the affected vertebrae to establish ADC of normal vertebrae, which was helpful in treatment response in patients with antitubercular therapy. At least six ADC value was taken from affected vertebrae and soft tissue. The mean ADC value of tubercular vertebrae was found out to be 1.47 ± 0.25 x 10(-3) mm(2)/sec, of adjacent soft tissue collection (abscess) was 1.94 ± 0.30 x 10(-3) mm(2)/sec and normal vertebrae was 0.48 ± 0.16 x 10(-3) mm(2)/sec. ADC value of post treated vertebrae decreased and complete resolution showed ADC near normal vertebrae. Normal range of the ADC values in spinal tuberculosis and associated paravertebral collection may be helpful in the differentiation of spinal tuberculosis from lesions with spinal involvement which are not proven to be tuberculosis and who did not have the classical appearance of either tuberculosis or metastasis. But there exists a zone of overlap of ADC values in metastatic and tubercular vertebrae, which can lead to false negative results. Therefore, in overlap cases there should be correlation with clinical history, other related investigations or biopsy.


Oxidative Epigallocatechin Gallate Coating on Polymeric Substrates for Bone Tissue Regeneration.
Plant derived flavonoids have not been well explored in tissue engineering applications due to difficulties in efficient formulations with biomaterials for controlled presentation. Here, the authors report that surface coating of epigallocatechin gallate (EGCG) on polymeric substrates including poly (L-lactic acid) (PLLA) nanofibers can be performed via oxidative polymerization of EGCG in the presence of cations, enabling regulation of biological functions of multiple cell types implicated in bone regeneration. EGCG coating on the PLLA nanofiber promotes osteogenic differentiation of adipose-derived stem cells (ADSCs) and is potent to suppress adipogenesis of ADSCs while significantly reduces osteoclastic maturation of murine macrophages. Moreover, EGCG coating serves as a protective layer for ADSCs against oxidative stress caused by hydrogen peroxide. Finally, the in vivo implantation of EGCG-coated nanofibers into a mouse calvarial defect model significantly promotes the bone regeneration (61.52 ± 28.10%) as compared to defect (17.48 ± 11.07%). Collectively, the results suggest that EGCG coating is a simple bioinspired surface modification of polymeric biomaterials and importantly can thus serve as a promising interface for tuning activities of multiple cell types associated with bone fracture healing.


Clinical Advances of Hypoxia-Activated Prodrugs in Combination With Radiation Therapy.
With the increasing incidence of cancer worldwide, the need for specific, effective therapies is ever more urgent. One example of targeted cancer therapeutics is hypoxia-activated prodrugs (HAPs), also known as bioreductive prodrugs. These prodrugs are inactive in cells with normal oxygen levels but in hypoxic cells (with low oxygen levels) undergo chemical reduction to the active compound. Hypoxia is a common feature of solid tumors and is associated with a more aggressive phenotype and resistance to all modes of therapy. Therefore, the combination of radiation therapy and bioreductive drugs presents an attractive opportunity for synergistic effects, because the HAP targets the radiation-resistant hypoxic cells. Hypoxia-activated prodrugs have typically been precursors of DNA-damaging agents, but a new generation of molecularly targeted HAPs is emerging. By targeting proteins associated with tumorigenesis and survival, these compounds may result in greater selectivity over healthy tissue. We review the clinical progress of HAPs as adjuncts to radiation therapy and conclude that the use of HAPs alongside radiation is vastly underexplored at the clinical level.


Significance of steatosis in pancreatic transplantation.
The on-going success of whole organ pancreatic transplantation is dependent on overcoming the imbalance between demand and supply of optimal organs as well as tackling the vast comorbidity associated with the procedure. Pancreas steatosis is a common contributing factor to the problem and with obesity pandemics affecting the global population; the size and type of organs received from donors will only make steatosis more of an issue. The aim of this review is to highlight what is known about steatosis in the context of pancreas transplantation identifying potential methods to help its evaluation. Narrative review of literature from inception to June 2017, using OVID interface searching EMBASE and MEDLINE databases as well recent transplant conference data. All studies related to pancreas steatosis examined for clinical relevance with no exclusion criteria. Key ideas extracted and referenced. Pancreatic steatosis is not innocuous and is precariously regarded by transplant surgeons, however its associations with obesity, metabolic syndrome and long list of associated complications clearly show it needs more careful consideration. Radiologic and surgical advances now allow assessment of the fat content of organs, which could be used to quantify organs allowing better optimisation, but there is still much work to be done to refine the optimal method to achieve this.


Are Over-the-Counter Alpha Blockers in the Best Interest of Men with Lower Urinary Tract Symptoms?
Lower urinary tract symptoms have a multifactorial etiology, are common in men and increase with age. In view of the unprecedented growth of the aging population worldwide and in the United States, an increase in the number of men with lower urinary tract symptoms is expected in the near future. In contrast, a decline in the number of practicing urologists is projected. Many men do not discuss their lower urinary tract symptoms with health care practitioners or seek treatment. Thus, they remain undiagnosed, untreated or both. For such men, self-treatment with over-the-counter alpha blockers with proven efficacy and safety is an unsubstantiated option. However, use of over-the-counter alpha blockers for the treatment of lower urinary tract symptoms is controversial owing to the multifactorial nature of these symptoms and concerns associated with over-the-counter use of alpha blockers. This review summarizes a debate held at the 2015 Annual Meeting of the American Urological Association (May 15-19, 2015, New Orleans, Louisiana) on whether over-the-counter alpha blockers are in the best interest of patients. Concerns about over-the-counter use of alpha blockers for the treatment of lower urinary tract symptoms, including inappropriate self-diagnosis and/or self-treatment by patients; potential for missing an important disease; and failure to adhere with guidelines on the assessment of lower urinary tract symptoms are reviewed, as are corresponding rebuttals supporting use of over-the-counter alpha blockers for the treatment of lower urinary tract symptoms. Over-the-counter alpha blockers are not yet available. Ongoing studies will determine whether appropriate safety and usage criteria can be achieved.


Targeted DNA methylation profiling reveals epigenetic signatures in peanut allergy.
DNA methylation (DNAm) has been shown to play a role in mediating food allergy; however, the mechanism by which it does so is poorly understood. In this study, we used targeted next-generation bisulfite sequencing to evaluate DNAm levels in 125 targeted highly informative genomic regions containing 602 CpG sites on 70 immune-related genes to understand whether DNAm can differentiate peanut allergy (PA) versus nonallergy (NA). We found PA-associated DNAm signatures associated with 12 genes (7 potentially novel to food allergy, 3 associated with Th1/Th2, and 2 associated with innate immunity), as well as DNAm signature combinations with superior diagnostic potential compared with serum peanut-specific IgE for PA versus NA. Furthermore, we found that, following peanut protein stimulation, peripheral blood mononuclear cell (PBMCs) from PA participants showed increased production of cognate cytokines compared with NA participants. The varying responses between PA and NA participants may be associated with the interaction between the modification of DNAm and the interference of environment. Using Euclidean distance analysis, we found that the distances of methylation profile comprising 12 DNAm signatures between PA and NA pairs in monozygotic (MZ) twins were smaller than those in randomly paired genetically unrelated individuals, suggesting that PA-related DNAm signatures may be associated with genetic factors.


A 2-stage genome-wide association study to identify single nucleotide polymorphisms associated with development of urinary symptoms after radiotherapy for prostate cancer.
We identified single nucleotide polymorphisms associated with change in the AUA Symptom Score after radiotherapy for prostate cancer. A total of 723 patients treated with brachytherapy with or without external beam radiation therapy were assessed at baseline and annually after radiotherapy using the AUA Symptom Score. A 2-stage genome-wide association study was performed with the primary end point of change in AUA Symptom Score from baseline at each of 4 followup periods. Single nucleotide polymorphism associations were assessed using multivariable linear regression adjusting for pre-radiotherapy AUA Symptom Score severity category and clinical variables. Fisher's trend method was used to calculate combined p values from the discovery and replication cohorts. A region on chromosome 9p21.2 containing 8 single nucleotide polymorphisms showed the strongest association with change in AUA Symptom Score (combined p values 8.8×10(-6) to 6.5×10(-7) at 2 to 3 years after radiotherapy). These single nucleotide polymorphisms form a haplotype block that encompasses the inflammation signaling gene IFNK. These single nucleotide polymorphisms were independently associated with change in AUA Symptom Score after adjusting for clinical predictors including smoking history, hypertension, α-blocker use and pre-radiotherapy AUA Symptom Score. An additional 24 single nucleotide polymorphisms showed moderate significance for association with change in AUA Symptom Score. Several of these single nucleotide polymorphisms were more strongly associated with change in specific AUA Symptom Score items, including rs13035033 in the MYO3B gene, which was associated with straining (beta coefficient 0.9, 95% CI 0.6-1.2, p = 5.0×10(-9)). If validated, these single nucleotide polymorphisms could provide insight into the biology underlying urinary symptoms following radiotherapy and could lead to development of an assay to identify patients at risk for experiencing these effects.


Community structure of corals and reef fishes at multiple scales.
Distributions of numerical abundance and resource use among species are fundamental aspects of community structure. Here we characterize these patterns for tropical reef fishes and corals across a 10,000-kilometer biodiversity gradient. Numerical abundance and resource-use distributions have similar shapes, but they emerge at markedly different scales. These results are consistent with a controversial null hypothesis regarding community structure, according to which abundance distributions arise from the interplay of multiple stochastic environmental and demographic factors. Our findings underscore the importance of robust conservation strategies that are appropriately scaled to the broad suite of environmental processes that help sustain biodiversity.


[Autoimmune-alloimmune neonatal neutropenia. Serum reactive IgG and neutrophil-specific phenotype detected by flow cytometry].
Auto or alloantibodies reactive with neutrophils define immune neutropenia. Alloimmune neonatal neutropenia is caused by maternal sensitization to paternal neutrophil antigens, resulting in IgG antibodies that are transferred to the fetus through the placenta. We present the studies in 4 children from 3 families with neutropenia of unknown origin (two of them were brothers). They were evaluated by flow cytometry in parallel with leukoagglutination. Reference values were established for serum reactive IgG in healthy volunteers for three dilutions (1/2, 1/5 and 1/20), both for the autologous reaction (serum and cells of the same individual) and for the heterologous reaction (serum and cells of different individuals). Results were expressed by an index defined by the quotient of the mean fluorescence intensity of the patient's serum divided by that of the reference serum. Serum reactive/agglutinant factors and circulating immune complexes were evaluated in patients and parents serum. Neutrophil specific phenotypes were determined for HNA-1a, HNA-1b and HNA-2a. Reactive IgG/agglutinant factors were found in 4 children. Two maternal sera were reactive against paternal and/or children neutrophils. Circulating immune complexes were detected in 2/4 children sera and were negative in 3/3 maternal sera. Maternal/children incompatibility was detected in the four cases. The three mothers had the same phenotype: homozygous NA1/NA1, NB1+.


From causal loop diagrams to future scenarios: Using the cross-impact balance method to augment understanding of urban health in Latin America.
Urban health is shaped by a system of factors spanning multiple levels and scales, and through a complex set of interactions. Building on causal loop diagrams developed via several group model building workshops, we apply the cross-impact balance (CIB) method to understand the strength and nature of the relationships between factors in the food and transportation system, and to identify possible future urban health scenarios (i.e., permutations of factor states that impact health in cities). We recruited 16 food and transportation system experts spanning private, academic, non-government, and policy sectors from six Latin American countries to complete an interviewer-assisted questionnaire. The questionnaire, which was pilot tested on six researchers, used a combination of questions and visual prompts to elicit participants' perceptions about the bivariate relationships between 11 factors in the food and transportation system. Each participant answered questions related to a unique set of relationships within their domain of expertise. Using CIB analysis, we identified 21 plausible future scenarios for the system. In the baseline model, 'healthy' scenarios (with low chronic disease, high physical activity, and low consumption of highly processed foods) were characterized by high public transportation subsidies, low car use, high street safety, and high free time, illustrating the links between transportation, free time and dietary behaviors. In analyses of interventions, low car use, high public transport subsidies and high free time were associated with the highest proportion of factors in a healthful state and with high proportions of 'healthy' scenarios. High political will for social change also emerged as critically important in promoting healthy systems and urban health outcomes. The CIB method can play a novel role in augmenting understandings of complex urban systems by enabling insights into future scenarios that can be used alongside other approaches to guide urban health policy planning and action.


Phytochrome A and phytochrome B mediate the hypocotyl-specific downregulation of TUB1 by light in arabidopsis.
Arabidopsis contains six alpha-tubulin and nine beta-tubulin genes that are expressed in a tissue-specific and developmentally regulated manner. We analyzed the effects of light on tubulin mRNA abundance in Arabidopsis seedlings using RNA gel blot hybridizations and gene-specific probes. Transcript levels of all 15 tubulin genes were decreased by continuous white light, although to different degrees. Detailed analysis was performed with the beta-tubulin TUB1 gene. The transcript level of TUB1 was high in etiolated seedlings and decreased to approximately 20% of the dark mRNA level after 2 to 6 hr of white light treatment. We showed that this downregulation requires high-irradiance light treatment and that multiple photoreceptors are involved. In particular, using phytochrome mutants and narrow wave band light, we demonstrated that both the phytochrome A (phyA)-mediated far-red light high-irradiance response and the phytochrome B (phyB)-mediated red light high-irradiance response are involved in the downregulation of TUB1 expression by white light. Histochemical analysis of transgenic plants expressing a TUB1-beta-glucuronidase chimeric transgene indicated that the downregulation observed only in hypocotyls and not in roots is controlled transcriptionally.


Flexible interlocked porous frameworks allow quantitative photoisomerization in a crystalline solid.
Photochromic molecules have shown much promise as molecular components of stimuli-responsive materials, but despite recent achievements in various photoresponsive materials, quantitative conversion in photochemical reactions in solids is hampered by the lack of intrinsic structural flexibility available to release stress and strain upon photochemical events. This issue remains one of the challenges in developing solid-state photoresponsive materials. Here, we report a strategy to realize photoresponsive crystalline materials showing quantitative reversible photochemical reactions upon ultraviolet and visible light irradiation by introducing structural flexibility into crystalline porous frameworks with a twofold interpenetration composed of a diarylethene-based ligand. The structural flexibility of the porous framework enables highly efficient photochemical electrocyclization in a single-crystal-to-single-crystal manner. CO2 sorption on the porous crystal at 195 K is reversibly modulated by light irradiation, and coincident X-ray powder diffraction/sorption measurements clearly demonstrate the flexible nature of the twofold interpenetrated frameworks.Organizing photochromic molecules into 3D networks is a key strategy to access photoresponsive materials, but framework rigidity typically limits conversion efficiency. Here, the authors exploit a flexible metal-organic framework to achieve quantitative and reversible photoisomerization in a porous crystalline solid.


Metabolic adaptation of intracellular bacteria and fungi to macrophages.
The mature phagosome of macrophages is a hostile environment for the vast majority of phagocytosed microbes. In addition to active destruction of the engulfed microbes by antimicrobial compounds, restriction of essential nutrients in the phagosomal compartment contributes to microbial growth inhibition and killing. However, some pathogenic microorganisms have not only developed various strategies to efficiently withstand or counteract antimicrobial activities, but also to acquire nutrients within macrophages for intracellular replication. Successful intracellular pathogens are able to utilize host-derived amino acids, carbohydrates and lipids as well as trace metals and vitamins during intracellular growth. This requires sophisticated strategies such as phagosome modification or escape, efficient nutrient transporters and metabolic adaptation. In this review, we discuss the metabolic adaptation of facultative intracellular bacteria and fungi to the intracellular lifestyle inside macrophages.


Role of hepatic arterial embolisation in the carcinoid syndrome.
Eighteen patients with severe symptoms of the carcinoid syndrome were assessed for hepatic embolisation. Four were too ill, and one had mild symptoms; thus 13 received a periembolisation regimen of cyproheptadine, fenclonine, aprotinin, methylprednisolone, tobramycin, flucloxacillin, and metronidazole. Embolisation was not performed in one patient with an occluded portal vein and was unsatisfactory in two others, in one because she was moribund and in the other because the hepatic artery had been ligated. Dramatic improvement in symptoms occurred in the nine patients in whom embolisation was successfully carried out, with abolition of flushing, severe abdominal pain, and wheeze and reduction in diarrhoea from 10.5 (SD 7.6) to 1.6 (0.9) stools/day. Urinary excretion of 5-hydroxyindole acetic acid fell from 1048 (716) to 289 (184) mumol/24 h (200 (137) to 55 (35) mg/24 h). Complications included one death from septicaemia, a hepatic abscess requiring surgical drainage, abdominal pain in three patients, pleural effusion in two, and transient encephalopathy in one. Relief of symptoms lasted for one to 24 months, and second embolisation in two patients produced further remissions of four to six months. Five patients died, one to 40 months after embolisation, in four cases because of metastases or heart failure. Hepatic embolisation is the treatment of choice for symptoms of the carcinoid syndrome resistant to medical treatment.


Differences in the enzymatic hydrolysis of glucosinolates increase the defense metabolite diversity in 19 Arabidopsis thaliana accessions.
Plants of the order Brassicales produce glucosinolates (GS), a group of secondary metabolites that are part of an elaborate defense system. But it is not the GS itself rather its enzymatic hydrolysis products that cause the bioactive effects protecting the plants against pests and pathogens. Thus the enzymatic hydrolysis and a variety of additional influential factors determine the structural outcome of the GS degradation process. To evaluate the possible diversity of defense metabolites a range of 19 Arabidopsis thaliana accessions were selected showing divergence in their geographical origin, in their phenotype, and in their GS profile. These particular accessions accumulate several alkenyl GS, hydroxyalkyl GS, methylthioalkyl GS, and methylsulfinylalkyl GS in their rosette leaves whereas the indole GS contents are relatively invariant, as analyzed by UHPLC-DAD. After tissue disruption the enzymatic formation of GS hydrolysis products was examined and breakdown products were identified and quantified by GC-MS. Great differences in the amount and structure of volatile enzymatic degradation products could be observed in the different accessions, with strong variation in formation of epithionitriles, nitriles, and isothiocyanates. The occurrence of specific GS hydrolysis products was put in relation to relative gene expression profiles of myrosinases and specifier proteins as measured by RT-qPCR, and in relation to relative protein abundance of epithiospecifier protein. Dependent on the different GS profiles and reliant on degradation protein abundance and composition the ecotypes strongly varied in their ability to form isothiocyanates, nitriles and epithionitriles, thus increasing the plants' equipment of defense metabolites.


The role of oxygen and water on molybdenum nanoclusters for electro catalytic ammonia production.
The presence of water often gives rise to oxygen adsorption on catalyst surfaces through decomposition of water and the adsorbed oxygen or hydroxide species often occupy important surfaces sites, resulting in a decrease or a total hindrance of other chemical reactions taking place at that site. In this study, we present theoretical investigations of the influence of oxygen adsorption and reduction on pure and nitrogen covered molybdenum nanocluster electro catalysts for electrochemical reduction of N2 to NH3 with the purpose of understanding oxygen and water poisoning of the catalyst. Density functional theory calculations are used in combination with the computational hydrogen electrode approach to calculate the free energy profile for electrochemical protonation of O and N2 species on cuboctahedral Mo13 nanoclusters. The calculations show that the molybdenum nanocluster will preferentially bind oxygen over nitrogen and hydrogen at neutral bias, but under electrochemical reaction conditions needed for nitrogen reduction, oxygen adsorption is severely weakened and the adsorption energy is comparable to hydrogen and nitrogen adsorption. The potentials required to reduce oxygen off the surface are -0.72 V or lower for all oxygen coverages studied, and it is thus possible to (re)activate (partially) oxidized nanoclusters for electrochemical ammonia production, e.g., using a dry proton conductor or an aqueous electrolyte. At lower oxygen coverages, nitrogen molecules can adsorb to the surface and electrochemical ammonia production via the associative mechanism is possible at potentials as low as -0.45 V to -0.7 V.


Hierarchical Encoding of Social Cues in Primate Inferior Temporal Cortex.
Faces convey information about identity and emotional state, both of which are important for our social interactions. Models of face processing propose that changeable versus invariant aspects of a face, specifically facial expression/gaze direction versus facial identity, are coded by distinct neural pathways and yet neurophysiological data supporting this separation are incomplete. We recorded activity from neurons along the inferior bank of the superior temporal sulcus (STS), while monkeys viewed images of conspecific faces and non-face control stimuli. Eight monkey identities were used, each presented with 3 different facial expressions (neutral, fear grin, and threat). All facial expressions were displayed with both a direct and averted gaze. In the posterior STS, we found that about one-quarter of face-responsive neurons are sensitive to social cues, the majority of which being sensitive to only one of these cues. In contrast, in anterior STS, not only did the proportion of neurons sensitive to social cues increase, but so too did the proportion of neurons sensitive to conjunctions of identity with either gaze direction or expression. These data support a convergence of signals related to faces as one moves anteriorly along the inferior bank of the STS, which forms a fundamental part of the face-processing network.


Properties of the surface envelope glycoprotein associated with virulence of simian-human immunodeficiency virus SHIV(SF33A) molecular clones.
In vivo adaptation of simian-human immunodeficiency virus (SHIV) clone SHIV(SF33) resulted in the emergence of pathogenic isolate SHIV(SF33A), which caused a rapid and severe CD4(+) T-cell depletion when inoculated into rhesus macaques. Two molecular clones generated by inserting the env V1-to-V5 region amplified from SHIV(SF33A)-infected animals into the parental SHIV(SF33) genome retained a pathogenic phenotype. The gp120 envelope glycoproteins of pathogenic clones SHIV(SF33A2) and SHIV(SF33A5) conferred a threefold increase in viral entry and fusogenicity compared to the parental glycoprotein. Changes in gp120 were also responsible for a higher replication capacity and cytopathicity in primary CD4(+) T-cell cultures. Last, gp120 carried the determinants of SHIV(SF33A) neutralization resistance. Thus, changes in SHIV(SF33A) gp120 produced a set of properties that could account for the pathogenic phenotype observed in vivo. Measurement of antibody binding to SHIV(SF33A) viral particles revealed an increased exposure of the CD4-induced epitope recognized by the 17b monoclonal antibody in a region that was shown to contribute to coreceptor binding. Exposure of this epitope occurred in the absence of CD4 binding, suggesting that the envelope glycoprotein of pathogenic SHIV(SF33A) clones folded in a conformation that was primed for interaction with CXCR4 or for the subsequent step of fusion.


Evaluation of Social Media Use by Emergency Medicine Residents and Faculty.
Clinicians and residency programs are increasing their use of social media (SM) websites for educational and promotional uses, yet little is known about the use of these sites by residents and faculty. The objective of the study is to assess patterns of SM use for personal and professional purposes among emergency medicine (EM) residents and faculty. In this multi-site study, an 18-question survey was sent by e-mail to the residents and faculty in 14 EM programs and to the Council of Emergency Medicine Residency Directors (CORD) listserv via the online tool SurveyMonkey™. We compiled descriptive statistics, including assessment with the chi-square test or Fisher's exact test. StatsDirect software (v 2.8.0, StatsDirect, Cheshire, UK) was used for all analyses. We received 1,314 responses: 63% of respondents were male, 40% were <30 years of age, 39% were between the ages 31 and 40, and 21% were older than 40. The study group consisted of 772 residents and 542 faculty members (15% were program directors, 21% were assistant or associate PDs, 45% were core faculty, and 19% held other faculty positions. Forty-four percent of respondents completed residency more than 10 years ago. Residents used SM markedly more than faculty for social interactions with family and friends (83% vs 65% [p<0.0001]), entertainment (61% vs 47% [p<0.0001]), and videos (42% vs 23% [p=0.0006]). Residents used Facebook™ and YouTube™ more often than faculty (86% vs 67% [p<0.001]; 53% vs 46% [p=0.01]), whereas residents used Twitter™ (19% vs 26% [p=0.005]) and LinkedIn™ (15% vs 32% [p<0.0001]) less than faculty. Overall, residents used SM sites more than faculty, notably in daily use (30% vs 24% [p<0.001]). For professional use, residents were most interested in its use for open positions/hiring (30% vs 18% [p<0.0001]) and videos (33% vs 26% [p=0.005]) and less interested than faculty with award postings (22% vs 33% [p<0.0001]) or publications (30% vs 38% [p=0.0007]). EM residents and faculty have different patterns and interests in the personal and professional uses of social media. Awareness of these utilization patterns could benefit future educational endeavors.


Diagnosis and treatment of human seminal plasma hypersensitivity.
Human seminal plasma hypersensitivity is a rare disorder that is often misdiagnosed. While this disorder is well described in the allergy and immunology literature, few cases exist in the gynecologic literature. A young woman presented to our allergy clinic with recurrent vaginal burning, swelling, and itching occurring approximately 10 minutes postcoitally. Semen allergy was suspected. Using her partner's semen, intradermal testing produced 1.6-cm wheal and 6.0-cm flare. The patient underwent intravaginal desensitization, and she and her partner were instructed to have intercourse every 48 hours to maintain desensitization. At 5-month follow-up, they were practicing coitus interruptus with success. Human seminal plasma hypersensitivity may mimic chronic vaginitis. The intravaginal graded challenge, a form of immunotherapy used by allergists, remains a mainstay in treatment, but is only effective if maintained correctly.


Recapitulation of erythropoiesis in congenital dyserythropoietic anaemia type I (CDA-I) identifies defects in differentiation and nucleolar abnormalities.
The investigation of inherited disorders of erythropoiesis has elucidated many of the principles underlying the production of normal red blood cells and how this is perturbed in human disease. Congenital Dyserythropoietic Anaemia type 1 (CDA-I) is a rare form of anaemia caused by mutations in two genes of unknown function: CDAN1 and CDIN1 (previously called C15orf41), whilst in some cases, the underlying genetic abnormality is completely unknown. Consequently, the pathways affected in CDA-I remain to be discovered. To enable detailed analysis of this rare disorder we have validated a culture system which recapitulates all of the cardinal haematological features of CDA-I, including the formation of the pathognomonic 'spongy' heterochromatin seen by electron microscopy. Using a variety of cell and molecular biological approaches we discovered that erythroid cells in this condition show a delay during terminal erythroid differentiation, associated with increased proliferation and widespread changes in chromatin accessibility. We also show that the proteins encoded by CDAN1 and CDIN1 are enriched in nucleoli which are structurally and functionally abnormal in CDA-I. Together these findings provide important pointers to the pathways affected in CDA-I which for the first time can now be pursued in the tractable culture system utilised here.


Metal artifact reduction MRI for total ankle replacement sagittal balance evaluation.
Restoration of anatomical relationship between talus and tibia is crucial for longevity of total ankle replacement (TAR). Weight-bearing (WB) radiographs are the standard for evaluating the sagittal balance alignment, but are prone to rotational misalignment and altered measurements. Metal artifact reduction sequence (MARS) MRI allows visualization of periprosthetic landmarks and alignment of the image plane to the true sagittal axis of the implant. The purpose of this study was to compare TAR sagittal balance measurements on MARS MRI and WB radiographs. Twenty-three subjects with TAR [10 men/13 women, age 60 (41-73) years; 13 (3-24) months post-op] underwent MARS MRI and standard lateral WB radiographs. Standardized MARS MR images were aligned to the sagittal talar component axis. Three observers performed sagittal balance alignment measurements twice in an independent, random and blinded fashion. Lateral Talar Station (LTS), tibial axis-to-talus (T-T) ratio and normalized tibial axis-to-lateral-process (T-L) distance were measured. Concordance correlation coefficients (CCC) and intraclass correlation coefficients (ICC) were used for statistical analysis. In addition, mixed effects linear models were employed to assess overall concordance of the two image types. The intraobserver agreement was excellent for radiographic (CCC=0.96) and MRI (CCC=0.90-0.97) measurements. Interobserver agreements were good-to-excellent with overall slightly higher agreements for MRI (ICC=0.78-0.94) than radiography (ICC=0.78-0.90) measurements. The T-T ratios of radiographs and MRI showed a high degree of concordance, whereas LTS was significantly lower on MRI when compared with radiographs, and T-L distance showed notable disagreement between the two imaging types. Sagittal balance measurements performed on standardized weight-bearing radiographs and standardized MARS MRI demonstrate substantial correlation and similarity. Given its high intra and interobserver agreement, MARS MRI may be helpful for the evaluation of TAR sagittal balance. Level II - Prospective Comparative Study.


Analysis of positive control STR experiments reveals that results obtained for FGA, D3S1358, and D13S317 condition the success rate of the analysis of routine reference samples.
About 120,000 reference samples are analyzed each year in the Forensic Laboratory of Lyon. A total of 1640 positive control experiments used to validate and optimize the analytical method in the routine process were submitted to a multivariate exploratory data analysis approach with the aim of better understanding the underlying sources of variability. The peak heights of the 16 genetic markers targeted by the AmpFℓSTR(®) Identifiler(®) STR kit were used as variables of interest. Six different 3130xl genetic analyzers located in the same controlled environment were involved. Two major sources of variability were found: (i) the DNA load of the sample modulates all peak heights in a similar way so that the 16 markers are highly correlated, (ii) the genetic analyzer used with a locus-specific response for peak height and a better sensitivity for the most recently acquired. Three markers (FGA, D3S1358, and D13S317) were found to be of special interest to predict the success rate observed in the routine process.


Simultaneous femtosecond X-ray spectroscopy and diffraction of photosystem II at room temperature.
Intense femtosecond x-ray pulses produced at the Linac Coherent Light Source (LCLS) were used for simultaneous x-ray diffraction (XRD) and x-ray emission spectroscopy (XES) of microcrystals of photosystem II (PS II) at room temperature. This method probes the overall protein structure and the electronic structure of the Mn4CaO5 cluster in the oxygen-evolving complex of PS II. XRD data are presented from both the dark state (S1) and the first illuminated state (S2) of PS II. Our simultaneous XRD-XES study shows that the PS II crystals are intact during our measurements at the LCLS, not only with respect to the structure of PS II, but also with regard to the electronic structure of the highly radiation-sensitive Mn4CaO5 cluster, opening new directions for future dynamics studies.