The IkappaB kinase complex and NF-kappaB act as master regulators of lipopolysaccharide-induced gene expression and control subordinate activation of AP-1.
Toll-like receptors (TLRs) recognize conserved products of microbial pathogens to initiate the innate immune response. TLR4 signaling is triggered upon binding of lipopolysaccharides (LPS) from gram-negative bacteria. Using comparative gene expression profiling, we demonstrate a master regulatory role of IkappaB kinase (IKK)/NF-kappaB signaling for immediate-early gene induction after LPS engagement in precursor B cells. IKK/NF-kappaB signaling controls a large panel of gene products associated with signaling and transcriptional activation and repression. Intriguingly, the induction of AP-1 activity by LPS in precursor B cells and primary dendritic cells fully depends on the IKK/NF-kappaB pathway, which promotes expression of several AP-1 family members, including JunB, JunD, and B-ATF. In pre-B cells, AP-1 augments induction of a subset of primary NF-kappaB targets, as shown for chemokine receptor 7 (CCR7) and immunoglobulin kappa light chain. Thus, our data illustrate that NF-kappaB orchestrates immediate-early effects of LPS signaling and controls secondary AP-1 activation to mount an appropriate biological response.


A nuclear gene, erd1, encoding a chloroplast-targeted Clp protease regulatory subunit homolog is not only induced by water stress but also developmentally up-regulated during senescence in Arabidopsis thaliana.
A cDNA, ERD1, isolated from one-hour-dehydrated plants of Arabidopsis thaliana L. encodes a putative protein that is similar to the regulatory ATPase subunit (ClpA) of the Clp protease and contains a putative chloroplast-targeting transit-peptide at the N-terminus. A chimeric gene with the putative plastid-targeting sequence of the erd1 gene fused to the synthetic green-fluorescent protein (sGFP) gene was constructed and introduced into Arabidopsis protoplasts. The N-terminal region of the ERD1 protein directed the sGFP protein into the plastids of the protoplasts, and functioned as a transit peptide. Northern blot analysis indicated that expression of the erd1 gene was induced not only by water stress, such as dehydration and high salinity, but also by natural senescence and dark-induced etiolation. The erd1 gene was not strongly induced by exogenous abscisic acid. A chimeric gene with the 0.9 kb promoter region of the erd1 gene fused to the beta-glucuronidase (GUS) reporter gene was constructed, and tobacco plants transformed with the construct. The GUS reporter gene driven by the erd1 promoter was induced by dehydration and high salt stress at significant levels in the transgenic plants. The GUS gene was strongly expressed in older leaves without dehydration, and was induced by dark-induced etiolation. Furthermore, GUS activity was reduced by cytokinin treatment during dark-induced etiolation. These results indicate that expression of the erd1 gene is developmentally up-regulated by senescence as well as by water stress.


[Validity of self-reported metabolic syndrome components in a cohort study].
To assess the accuracy of self-reported data needed to constitute the metabolic syndrome in the University of Navarra Follow-Up [Seguimiento Universidad de Navarra (SUN)] cohort. The SUN project is a multi-purpose prospective cohort, formed by more than 20,000 university graduates, followed-up using surface mail questionnaires every 2 years. In a sample of 287 cohort participants, self-reported data on the criteria needed to define the metabolic syndrome (waist circumference, blood pressure, triglycerides, high-density lipoprotein-cholesterol and glucose) were compared with the same biometric data obtained by blood tests or measured by trained medical staff. Intra-class correlation coefficients with 95% confidence intervals (95% CI), relative mean error and agreement limits according to the method proposed by Bland and Altman were calculated for each variable studied. High intraclass correlations were found for the values of waist circumference (r=0.86, 95% CI: 0.80-0.90) and triglycerides (r=0.71, 95%CI: 0.61-0.79). Moderate intraclass correlations were found (between 0.46 and 0.63) for the other factors. Relative mean errors were always<2.5%, and >91% of values were within the limits of agreement for all variables. The results suggest that self-declared data on the criteria of metabolic syndrome obtained in the SUN cohort, though with some caution, are sufficiently accurate to be used in epidemiological studies.


Dual neutral variables and knot solitons in triplet superconductors.
We derive a dual presentation of a free energy functional for spin-triplet superconductors in terms of gauge-invariant variables. The resulting equivalent model in ferromagnetic phase has a form of a version of the Faddeev model. This allows one, in particular, to conclude that spin-triplet superconductors allow formation of stable finite-length closed vortices (knotted solitons).


Qualitative Assessment of Barriers and Facilitators of Access to HIV Testing Among Men Who Have Sex with Men in China.
Diagnosis of HIV is the entry point into the continuum of HIV care; a well-recognized necessary condition for the ultimate prevention of onward transmission. In China, HIV testing rates among men who have sex with men (MSM) are low compared to other high risk subgroups, yet experiences with HIV testing among MSM in China are not well understood. To address this gap and prepare for intervention development to promote HIV testing and rapid linkage to treatment, six focus groups (FGs) were conducted with MSM in Beijing (40 HIV-positive MSM participated in one of four FGs and 20 HIV-negative or status unknown MSM participated in one of two FGs). Major themes reported as challenges to HIV testing included stigma and discrimination related to HIV and homosexuality, limited HIV knowledge, inconvenient clinic times, not knowing where to get a free test, fear of positive diagnosis or nosocomial infection, perceived low service quality, and concerns/doubts about HIV services. Key facilitators included compensation, peer support, professionalism, comfortable testing locations, rapid testing, referral and support after diagnosis, heightened sense of risk through engagement in high-risk behaviors, sense of responsibility to protect self, family and partner support, and publicity via social media. Themes and recommendations were generally consistent across HIV-positive and negative/status unknown groups, although examples of enacted stigma were more prevalent in the HIV-positive groups. Findings from our study provide policy suggestions for how to bolster current HIV prevention intervention efforts to enhance 'test-and-treat' strategies for Chinese MSM.


Diathermy smoke shown to be hazardous, so why are we not protecting ourselves?
Diathermy smoke has been studied for over three decades and data has been collected to establish its composition. Although its full structure has not been established, the compounds confirmed pose a health hazard to all exposed. Recommendations suggest that theatre staff need to protect themselves using smoke evacuating systems and masks. This review looks at the compliance of theatre staff within these guidelines and the reasons behind noncompliance.


Trap Design and Construction for High-Power Multinuclear Magnetic Resonance Experiments.
Performing multinuclear experiments requires one or more radiofrequency (RF) coils operating at both the proton and second-nucleus frequencies; however, inductive coupling between coils must be mitigated to retain proton sensitivity and coil tuning stability. The inclusion of trap circuits simplifies placement of multinuclear RF coils while maintaining inter-element isolation. Of the commonly investigated non-proton nuclei, perhaps the most technically demanding is carbon-13, particularly when applying a proton decoupling scheme to improve the resulting spectra. This work presents experimental data for trap circuits withstanding high-power broadband proton decoupling of carbon-13 at 7 T. The advantages and challenges of building trap circuits with various inductor and capacitor components are discussed. Multiple trap designs are evaluated on the bench and utilized on an RF coil at 7 T to detect broadband proton-decoupled carbon-13 spectra from a lipid phantom. A particular trap design, built from a coaxial stub inductor and high-voltage ceramic chip capacitors, is highlighted owing to both its performance and adaptability for planar array coil elements with diverse spatial orientations.


Identifying risk factors for surgical site complications after laparoscopic ventral hernia repair: evaluation of the Ventral Hernia Working Group grading system.
In 2010, the Ventral Hernia Working Group (VHWG) published a grading system to assess the risk of surgical site complications in patients undergoing ventral hernia repair. This study evaluated the predictive value of the VHWG classification for the surgical outcomes of laparoscopic ventral hernia repair (LVHR) and identified independent factors associated with surgical site infection (SSI) and surgical site occurrence (SSO). A retrospective review was performed of all patients who underwent LVHR over a 10-year period at two institutions. The U.S. Centers for Disease Control and Prevention definition of SSI and the VHWG definition of SSO were used. Univariable analysis was performed using the Student t-test, analysis of variance, chi-square test, or Fisher exact test, as appropriate. Multivariable analysis was used to identify independent factors associated with SSI and SSO. Differences in American Society of Anesthesiologists class, body mass index, diabetes mellitus, chronic obstructive pulmonary disease, tobacco use, hernia type, prior abdominal surgery, prior ventral hernia repair, hernia size, and total infections were identified by grade. There was no difference in SSI or SSO by grade. Multivariable analysis revealed institution and number of prior abdominal operations to be associated with SSI. Institution, prostate disease, and prior ventral hernia repair were associated with SSO. The VHWG classification was unable to predict SSI and SSO and may not be applicable in LVHR. This study identified independent factors associated with SSI and SSO in LVHR. Although further study is warranted to validate these results, the factors presented may be a useful tool to stratify patient risk of SSI and SSO with LVHR.


A multidimensional nonlinear edge-preserving filter for magnetic resonance image restoration.
The paper presents a multidimensional nonlinear edge-preserving filter for restoration and enhancement of magnetic resonance images (MRI). The filter uses both interframe (parametric or temporal) and intraframe (spatial) information to filter the additive noise from an MRI scene sequence. It combines the approximate maximum likelihood (equivalently, least squares) estimate of the interframe pixels, using MRI signal models, with a trimmed spatial smoothing algorithm, using a Euclidean distance discriminator to preserve partial volume and edge information. (Partial volume information is generated from voxels containing a mixture of different tissues.) Since the filter's structure is parallel, its implementation on a parallel processing computer is straightforward. Details of the filter implementation for a sequence of four multiple spin-echo images is explained, and the effects of filter parameters (neighborhood size and threshold value) on the computation time and performance of the filter is discussed. The filter is applied to MRI simulation and brain studies, serving as a preprocessing procedure for the eigenimage filter. (The eigenimage filter generates a composite image in which a feature of interest is segmented from the surrounding interfering features.) It outperforms conventional pre and post-processing filters, including spatial smoothing, low-pass filtering with a Gaussian kernel, median filtering, and combined vector median with average filtering.


Triggering TLR7 in mice induces immune activation and lymphoid system disruption, resembling HIV-mediated pathology.
Chronic immune activation is a major cause for progressive immunodeficiency in human immunodeficiency virus type-1 (HIV) infection. The underlying trigger, however, remains largely unknown. HIV single-stranded RNA is a potent immune activator by triggering Toll-like receptor (TLR) 7/8. Thus, we hypothesized that sustained TLR7 triggering induces chronic immune activation and thereby contributes to progressive immunodeficiency. We used the synthetic compound R848 or a mixture of uridine-rich HIV single-stranded (ss) RNA oligonucleotides--both are potent TLR7/8 agonists--to explore the effects of sustained TLR7 triggering on the murine lymphoid system. Sustained TLR7 triggering induced an immunopathology reminiscent of progressive lymphoid destruction in HIV disease; we observed lymphopenia, elevated proinflammatory cytokines, splenomegaly, contracted lymphoid subsets, and lymphoid microarchitecture alteration with reduced marginal zone B-lymphocytes. Upon exposure to inactivated vesiculo-stomatitis virus, antibody production was abolished, although splenic lymphocytes were activated and total IgG was elevated. Our data imply that HIV itself may directly contribute to immune activation and dysfunction by stimulating TLR7. Thus, manipulation of TLR7 signaling may be a potential strategy to reduce chronic hyper-immune activation and, thereby, disease progression in HIV infection.


Linking clinical registry data with administrative data using indirect identifiers: implementation and validation in the congenital heart surgery population.
The use of clinical registries and administrative data sets in pediatric cardiovascular research has become increasingly common. However, this approach is limited by relatively few existing datasets, each of which contain limited data, and do not communicate with one another. We describe the implementation and validation of methodology using indirect patient identifiers to link The Society of Thoracic Surgeons Congenital Heart Surgery (STS-CHS) Database to The Pediatric Health Information Systems (PHIS) Database (a pediatric administrative database). Centers submitting data to STS-CHS and PHIS during 2004 to 2008 were included (n=30). Both data sets were limited to patients 0 to 18 years old undergoing cardiac surgery. An exact match was defined as an exact match on each of the following: date of birth, date of admission, date of discharge, sex, and center. Likely matches were defined as an exact match for all variables except ±1 day for one of the date variables. Of 45,830 STS-CHS records, 87.4% matched to PHIS using the exact match criteria and 90.3% using the exact or likely match criteria. Validation in a subset of patients revealed that 100% of exact and likely matches were true matches. This analysis demonstrates that indirect identifiers can be used to create high-quality link between a clinical registry and administrative data set in the congenital heart surgery population. This methodology, which can also be applied to other data sets, allows researchers to capitalize on the strengths of both types of data and expands the pool of data available to answer important clinical questions.


Marsupials and monotremes possess a novel family of MHC class I genes that is lost from the eutherian lineage.
Major histocompatibility complex (MHC) class I genes are found in the genomes of all jawed vertebrates. The evolution of this gene family is closely tied to the evolution of the vertebrate genome. Family members are frequently found in four paralogous regions, which were formed in two rounds of genome duplication in the early vertebrates, but in some species class Is have been subject to additional duplication or translocation, creating additional clusters. The gene family is traditionally grouped into two subtypes: classical MHC class I genes that are usually MHC-linked, highly polymorphic, expressed in a broad range of tissues and present endogenously-derived peptides to cytotoxic T-cells; and non-classical MHC class I genes generally have lower polymorphism, may have tissue-specific expression and have evolved to perform immune-related or non-immune functions. As immune genes can evolve rapidly and are subject to different selection pressure, we hypothesised that there may be divergent, as yet unannotated or uncharacterised class I genes. Application of a novel method of sensitive genome searching of available vertebrate genome sequences revealed a new, extensive sub-family of divergent MHC class I genes, denoted as UT, which has not previously been characterized. These class I genes are found in both American and Australian marsupials, and in monotremes, at an evolutionary chromosomal breakpoint, but are not present in non-mammalian genomes and have been lost from the eutherian lineage. We show that UT family members are expressed in the thymus of the gray short-tailed opossum and in other immune tissues of several Australian marsupials. Structural homology modelling shows that the proteins encoded by this family are predicted to have an open, though short, antigen-binding groove. We have identified a novel sub-family of putatively non-classical MHC class I genes that are specific to marsupials and monotremes. This family was present in the ancestral mammal and is found in extant marsupials and monotremes, but has been lost from the eutherian lineage. The function of this family is as yet unknown, however, their predicted structure may be consistent with presentation of antigens to T-cells.


The optimal depth for femoral cement insertion in total hip replacement. An anatomical and clinical study into cementing technique in the proximal femur.
In retrograde cementing, blood often rises proximally on the surface of injected cement. This blood contamination weakens the cement-bone interface. The major source of bleeding into the proximal femoral medullary canal is the severed nutrient artery. The aims of this study were to define the clinically relevant anatomy of the nutrient artery supplying the proximal femur and establish the optimum depth of cement insertion to minimise blood contamination. Sixty cadaveric femora were radiographed with a wire placed in the nutrient foramen to assess the distance from the tip of the greater trochanter to its entry into the proximal femoral medullary canal. The nutrient artery entered the medullary canal at an average of 13.9 cm from the tip of the greater trochanter and never more proximal than 10.3cm. In 30 patients undergoing primary total hip replacement, cement was inserted retrogradely at 7.5cm, 10 cm or 15 cm from the tip of the greater trochanter and blood contamination recorded. There was blood in significantly fewer cases when cement was inserted at 10cm. Cement insertion 10cm distal to the tip of the greater trochanter appears to occlude the bleeding nutrient artery and should give a stronger proximal cement-bone interface. (Hip International 2002; 2: 135-8).


Few-Layer Graphene Island Seeding for Dendrite-Free Li Metal Electrodes.
Li metal batteries such as Li-air and Li-S systems have increasingly attracted the attention of researchers because of their high energy densities, which are enhanced by the use of Li metal negative electrodes. However, poor cycle efficiency and safety concerns, which are mainly related to dendritic Li growth during cycling, need to be addressed. Here we propose a solution to the Li dendrite problems. We distributed chemically prepared nitrogen-doped few-layer graphene (N-FLG) sheets on Cu substrates to create island structures. The island-type FLG on the Cu electrode was prepared via spin-coating using slurries that included a polymer binder. When the electrode was used for Li deposition, Li ions were first inserted into the graphene layers. Then, Li metal nucleation occurred at the N-FLG sheets owing to their high electrical conductivity; meanwhile, an insulating polymer layer on the Cu prevented the growth of metallic Li there. Lastly, Li metal grew from the edges of N-FLG sheets in both the lateral and vertical direction, and Li metal deposits filled the gaps between the N-FLG islands as well as covering the remainder of the electrode surface. Thus, stable cycling with flat voltage profiles was demonstrated over 100 cycles at a current density of 2 mA cm-2. The materials and electrochemical characterization results highlight the effectiveness of this method, which paves the way for the development of robust, dendrite-free Li metal electrodes.


Vitamin D and Lung Function Decline in Adults With Asthma: The HUNT Study.
We investigated whether low 25-hydroxyvitamin D (25(OH)D) levels were associated with more lung function decline in adults with asthma and whether this association was modified by smoking status or inhaled corticosteroid (ICS) use. We analyzed data on 395 adults with asthma from the Nord-Trøndelag Health Study (1995-2008), Norway. Plasma 25(OH)D and lung function were measured at baseline, and lung function measurements were repeated at follow-up, approximately 11 years later. Linear regression was used to estimate lung function decline. Participants with low 25(OH)D (<50 nmol/L) had more decline in lung function measurements for forced expiratory volume in 1 second (FEV1) (388 mL), forced vital capacity (298 mL), and the FEV1/forced vital capacity ratio (3.7%) over the follow-up, compared with those with high 25(OH)D (≥50 nmol/L) who declined 314 mL, 246 mL, and 3.0%, respectively (P = 0.08, 0.30, and 0.23, respectively). The associations were stronger in never smokers and non-ICS users. In never smokers, low 25(OH)D levels were associated with more decline in FEV1 (445 vs. 222 mL) (P = 0.01). In non-ICS users, low 25(OH)D levels were associated with more decline in FEV1 (467 vs. 320 mL) (P = 0.02). Low serum 25(OH)D levels were weakly associated with more lung function decline in adults with asthma, and stronger associations were observed in never smokers and non-ICS users.


IKKγ-Mimetic Peptides Block the Resistance to Apoptosis Associated with Kaposi's Sarcoma-Associated Herpesvirus Infection.
Primary effusion lymphoma (PEL) is a lymphogenic disorder associated with Kaposi's sarcoma-associated herpesvirus (KSHV) infection. Key to the survival and proliferation of PEL is the canonical NF-κB pathway, which becomes constitutively activated following overexpression of the viral oncoprotein KSHV vFLIP (ks-vFLIP). This arises from its capacity to form a complex with the modulatory subunit of the IκB kinase (IKK) kinase, IKKγ (or NEMO), resulting in the overproduction of proteins that promote cellular survival and prevent apoptosis, both of which are important drivers of tumorigenesis. Using a combination of cell-based and biophysical assays together with structural techniques, we showed that the observed resistance to cell death is largely independent of autophagy or major death receptor signaling pathways and demonstrated that direct targeting of the ks-vFLIP-IKKγ interaction both in cells and in vitro can be achieved using IKKγ-mimetic peptides. Our results further reveal that these peptides not only induce cell killing but also potently sensitize PEL to the proapoptotic agents tumor necrosis factor alpha and etoposide and are the first to confirm ks-vFLIP as a tractable target for the treatment of PEL and related disorders.IMPORTANCE KSHV vFLIP (ks-vFLIP) has been shown to have a crucial role in cellular transformation, in which it is vital for the survival and proliferation of primary effusion lymphoma (PEL), an aggressive malignancy associated with infection that is resistant to the majority of chemotherapeutic drugs. It operates via subversion of the canonical NF-κB pathway, which requires a physical interaction between ks-vFLIP and the IKK kinase modulatory subunit IKKγ. While this interaction has been directly linked to protection against apoptosis, it is unclear whether the suppression of other cell death pathways implicated in ks-vFLIP pathogenesis is an additional contributor. We demonstrate that the interaction between ks-vFLIP and IKKγ is pivotal in conferring resistance to apoptosis. Additionally, we show that the ks-vFLIP-IKKγ complex can be disrupted using peptides leading to direct killing and the sensitization of PEL cells to proapoptotic agents. Our studies thus provide a framework for future therapeutic interventions.


Metal-to-Ligand Charge-Transfer-based Visual Detection of Alkaline Phosphatase Activity.
The ability to directly detect alkaline phosphatase (ALP) activity in undiluted serum samples is of great importance for clinical diagnosis. In this work, we report the use of the distinctive metal-to-ligand charge-transfer (MLCT) absorption properties of the Cu(BCA)2+ (BCA = bicinchoninic acid) reporter for the visual detection of ALP activity. In the presence of ALP, the substrate ascorbic acid 2-phosphate (AAP) can be enzymatically hydrolyzed to release ascorbic acid (AA), which in turn reduces Cu2+ to Cu+. Subsequently, the complexation of Cu+ with the BCA ligand generates the chromogenic Cu(BCA)2+ reporter, accompanied by a color change of colorless-to-purple of the solution with a sharp absorption band at 562 nm. The underlying MLCT-based mechanism has been demonstrated on the basis of density functional theory (DFT) calculations. Needless of any sequential multistep operations and elaborately designed colorimetric probe, the proposed MLCT-based method allows for a fast and sensitive visual detection of ALP activity within a broad linear range of 20 - 200 mU mL-1 (R2 = 0.999), with a detection limit of 1.25 mU mL-1. The results also indicate that it is highly selective and has great potential for the screening of ALP inhibitors in drug discovery. More importantly, it shows a good analytical performance for the direct detection of the endogenous ALP levels of undiluted human serum samples. Owing to the prominent simplicity and practicability, it is reasonable to conclude that the proposed MLCT-based method has a high application prospect in clinical diagnosis.


The pyrrolizidine alkaloid senecionine induces CYP-dependent destruction of sinusoidal endothelial cells and cholestasis in mice.
Pyrrolizidine alkaloids (PAs) are widely occurring phytotoxins which can induce severe liver damage in humans and other mammalian species by mechanisms that are not fully understood. Therefore, we investigated the development of PA hepatotoxicity in vivo, using an acutely toxic dose of the PA senecionine in mice, in combination with intravital two-photon microscopy, histology, clinical chemistry, and in vitro experiments with primary mouse hepatocytes and liver sinusoidal endothelial cells (LSECs). We observed pericentral LSEC necrosis together with elevated sinusoidal marker proteins in the serum of senecionine-treated mice and increased sinusoidal platelet aggregation in the damaged tissue regions. In vitro experiments showed no cytotoxicity to freshly isolated LSECs up to 500 µM senecionine. However, metabolic activation of senecionine by preincubation with primary mouse hepatocytes increased the cytotoxicity to cultivated LSECs with an EC50 of approximately 22 µM. The cytochrome P450 (CYP)-dependency of senecionine bioactivation was confirmed in CYP reductase-deficient mice where no PA-induced hepatotoxicity was observed. Therefore, toxic metabolites of senecionine are generated by hepatic CYPs, and may be partially released from hepatocytes leading to destruction of LSECs in the pericentral region of the liver lobules. Analysis of hepatic bile salt transport by intravital two-photon imaging revealed a delayed uptake of a fluorescent bile salt analogue from the hepatic sinusoids into hepatocytes and delayed elimination. This was accompanied by transcriptional deregulation of hepatic bile salt transporters like Abcb11 or Abcc1. In conclusion, senecionine destroys LSECs although the toxic metabolite is formed in a CYP-dependent manner in the adjacent pericentral hepatocytes.


Mead ethanolamide, a novel eicosanoid, is an agonist for the central (CB1) and peripheral (CB2) cannabinoid receptors.
The recently discovered endogenous agonist for the cannabinoid receptor, anandamide (arachidonylethanolamide), can be formed enzymatically by the condensation of arachidonic acid with ethanolamine. 5Z,8Z,11Z-Eicosatrienoic acid (mead acid) has been found to substitute for arachidonic acid in the sn-2 position of phospholipids and accumulate during periods of dietary fatty acid deprivation in rats. In the present study, the chemically synthesized ethanolamide of mead acid was evaluated as a potential agonist at the two known subtypes of cannabinoid receptor: CB1 (central) and CB2 (peripheral). This compound was equipotent to anandamide in competing with [3H]CP55,940 binding to plasma membranes prepared from L cells expressing the human CB1 receptor and from ATt-20 cells expressing the human CB2 receptor. Mead ethanolamide was also equipotent to anandamide in inhibiting forskolin-stimulated cAMP accumulation in cells expressing the CB1 receptor. It inhibited N-type calcium currents with a lower potency than anandamide. Mead and arachidonic acid were equally efficacious as substrates for the enzymatic synthesis of their respective ethanolamides in rat and adult human hippocampal P2 membranes. Palmitic acid was not an effective substrate for the enzymatic synthesis of palmitoyl ethanolamide. Mead ethanolamide exhibits several characteristics of a novel agonist to CB1 and CB2 receptors and may represent another candidate endogenous ligand for the CB1 receptor. Due to the anticonvulsant properties of GABA and the positional similarity of L-serine to ethanolamine in membrane phospholipids, these compounds were synthetically coupled to arachidonic acid, and their resulting arachidonamides were tested as potential cannabinoid agonists. The arachidonamides of GABA and L-serine were inactive in both binding and functional assays at the CB1 receptor.


Prenatal restraint stress and long-term affective consequences.
Chronic or repeated stress during critical periods of human fetal brain development has been associated with various learning, behavioral and/or mood disorders in later life. In this investigation, pregnant Fischer 344 rats was individually restrained three times a day for 45 min during the last week of gestation in transparent plastic cylinders while at the same time being exposed to bright light. Control pregnant females were left undisturbed in their home cages. Anxiety and depressive-like behavior was measured in the offspring at an age of 6 months using the open field test, the home cage emergence test and the forced swim test. Prenatally stressed rats spent more time in the corners and less time along the walls of an open field, while no difference in total distance moved was observed. In addition, prenatally stressed rats took more time to leave their home cage in the home cage emergence test. On the other hand, no differences in immobility were observed in the forced swim test. Moreover, prenatally stressed rats showed lower stress-induced plasma corticosterone levels compared with control rats. Prenatal stress (PS) had no effect on the number of 5-bromo-2-deoxyuridine-positive cells - used as a measure for cell proliferation - in the dentate gyrus of these rats. These data further support the idea that PS may perturb normal anxiety-related development. However, the present data also suggest that an adaptive or protective effect of PS should not be ignored. Genetic factors are likely to play a role in this respect.


Lifespan alterations of basal dendritic trees of pyramidal neurons in the human prefrontal cortex: a layer-specific pattern.
The postnatal development and lifespan alterations in basal dendrites of large layer IIIC and layer V pyramidal neurons were quantitatively studied. Both classes of neurons were characterized by rapid dendritic growth during the first postnatal months. At birth, layer V pyramidal neurons had larger and more complex dendritic trees than those of layer IIIC; however, at 1 postnatal month both classes of neurons displayed a similar extent of dendritic outgrowth. In addition, after a more than year-long "dormant" period of only fine dendritic rearrangement, layer IIIC pyramidal neurons displayed a second period of dendritic growth, starting at the end of the second year and continuing in the third year. During that period, the dendritic tree of layer IIIC pyramidal neurons became more extensive than that of layer V pyramidal neurons. Thus, layer IIIC pyramidal neurons appear to show a biphasic pattern of postnatal dendritic development. Furthermore, the childhood period was characterized by transient increase in size of pyramidal cell somata, which was more pronounced for neurons in layer IIIC. These structural changes occurred during both the period of rapid cognitive development in preschool children and the period of protracted cognitive maturation during the childhood, puberty, and adolescence.


Similar biotherapeutic products: overview and reflections.
Biotherapeutic products (BPs) have revolutionized medicine, changing the way we treat several pathologies such as autoimmune diseases and cancer, among others. Herein, we present an overview of similar BPs (SBPs), also called biosimilars, including the manufacturing process and regulatory aspects involved. The objective of developing an SBP is to manufacture a molecule that is highly similar to a reference BP by conducting a comparability exercise (CE) that can demonstrate similar safety and efficacy. This CE consists of quality, as well as nonclinical and clinical evaluation. A case-by-case analysis approach guided by scientific and objective standards must be the foundation for the SBP approval process. The establishment of a balance between a comprehensive CE for SBPs and their reference BPs, and the design of costeffective strategies to provide better access to BPs, should be the key goal for national regulatory authorities.


[Relation between characteristics of the small mammal population and occurrence of Leptospira antibodies].
Five rodent species (Apodemus flavicollis, A. agrarius, A. microps, Clethrionomys glareolus and Microtus arvalis) were examined serologically for presence of antibodies to leptospira. Small mammals were caught in several areas of eastern Slovakia, an important part of host material coming from East Slovakian Lowland (45.7%), south part of Kosice basin (26.5%) and Slovak carst (10.1%). Serological examinations were used by Kmety and Bakoss (1978), the sexual condition of rodents were ascertained after Pelikán (1965). Altogether, 2,113 individuals of rodent species were examined during five years (1991-1995), antibodies to leptospires were demonstrated in 5.02% of examined hosts. In examined hosts antibodies to six serovars of leptospira (Leptospira grippothyphosa, L. sejroe, L. bataviae, L. bratislava, L. pomona and L. sorex-jalna) were found. The most frequently observed antibodies were those of the serovar L. grippothyphosa (65.1%) and L. sejroe (25.5%). Slightly higher percentage of positive hosts in mature group rodents (5.4%) comparing with immature rodents (4.6%) were statistically insignificant. Similarly, no differences were found between percentage of positive rodent females (5.3%) and group of males (4.7%). No statistical differences were found in positivities to leptospira antibodies among sexual and age groups of individual rodent species, too. Proportion of serological positivities to L. grippothyphosa and L. sejroe in compared sex and age rodent groups were very similar. In evaluated rodent species trend of increases of serological positive values from spring to autumn was observed, but it was statistically confirmed only in A. agrarius.


Rhino-orbital mucormycosis: Our experiences with clinical features and management in a tertiary care center.
Objective: To determine the prevalence, risk factors, and elaborate our experiences with diagnosis and treatment of patients with mucormycosis, enabling a better understanding of the disease and its management. Methods: This is a case series of patients with Covid-19 associated with Rhino-orbital-cerebral mucormycosis, managed in our tertiary care center from April 2021 to June 2021. Results: Six cases of Covid-19 associated with Rhino-orbital-cerebral mucormycosis have been analyzed in the study. The mean age of patients was 40.67 years with a male preponderance (83.3%). The most common complaint was headache (100%), while a minority (33%) came with ocular complaints. All the patients either had a previous history of diabetes mellitus or developed increased blood sugar levels following Covid infection, and were kept on insulin to control their blood sugar levels. 4 patients (66.67%) had a history of corticosteroid use during Covid-19 hospitalization. Treatment included intravenous liposomal Amphotericin B (100%), functional endoscopic sinus surgery (66.67%), maxillectomy (33.33%) and transcutaneous retrobulbar liposomal Amphotericin B (33.33%). Amphotericin B induced nephrotoxicity, which was seen in 1 patient (16.67%). Mortality occurred in only one patient (16.67%), 25 days following successful surgery. Conclusion: Diabetes Mellitus is the most important predisposing factor for the development of Covid-19 associated Rhino-orbital-cerebral mucormycosis. Early presentation, prompt diagnosis and timely initiation of treatment with liposomal Amphotericin B and surgical debridement along with strict blood sugar control can lead to a favorable outcome. However, regular follow-up and monitoring of serum electrolytes and kidney profile must be ensured for such patients.


[Disorders in lipid composition and properties of plasma membrane in epithelial cells of the placental villous chorion in chlamydial infection].
Lipid composition of plasma membranes of placental epithelial cells of villous chorion of healthy women and those with chlamydiosis has been studied. Lipid composition of plasma membranes of ill women differs from that of healthy women by reduction of total phospholipids quantity, by the increase of the level of free cholesterol and free fatty acids. A disturbance in the ratio between certain lipid fractions and increasing quantity of lysophospholipids is observed. Two-fold oppression of plasma membranes Na+, K+ -ATPase activity of placental epithelial cells of villous chorion in ill women has been detected but Mg2+, Ca2+ -ATPase activity has not changed. Thus chlamydial infection causes significant disorders in lipid composition and functioning of epithelial cells membranes of chorion.


Micro/Nanostructure Engineering of Epitaxial Piezoelectric α-Quartz Thin Films on Silicon.
The monolithic integration of sub-micron quartz structures on silicon substrates is a key issue for the future development of piezoelectric devices as prospective sensors with applications based on the operation in the high-frequency range. However, to date, it has not been possible to make existing quartz manufacturing methods compatible with integration on silicon and structuration by top-down lithographic techniques. Here, we report an unprecedented large-scale fabrication of ordered arrays of piezoelectric epitaxial quartz nanostructures on silicon substrates by the combination of soft-chemistry and three lithographic techniques: (i) laser interference lithography, (ii) soft nanoimprint lithography on Sr-doped SiO2 sol-gel thin films, and (iii) self-assembled SrCO3 nanoparticle reactive nanomasks. Epitaxial α-quartz nanopillars with different diameters (from 1 μm down to 50 nm) and heights (up to 2 μm) were obtained. This work demonstrates the complementarity of soft-chemistry and top-down lithographic techniques for the patterning of epitaxial quartz thin films on silicon while preserving its epitaxial crystallinity and piezoelectric properties. These results open up the opportunity to develop a cost-effective on-chip integration of nanostructured piezoelectric α-quartz MEMS with enhanced sensing properties of relevance in different fields of application.


Episodic selection and the maintenance of competence and natural transformation in Bacillus subtilis.
We present a new hypothesis for the selective pressures responsible for maintaining natural competence and transformation. Our hypothesis is based in part on the observation that in Bacillus subtilis, where transformation is widespread, competence is associated with periods of nongrowth in otherwise growing populations. As postulated for the phenomenon of persistence, the short-term fitness cost associated with the production of transiently nongrowing bacteria can be compensated for and the capacity to produce these competent cells can be favored due to episodes where the population encounters conditions that kill dividing bacteria. With the aid of a mathematical model, we demonstrate that under realistic conditions this "episodic selection" for transiently nongrowing (persisting) bacteria can maintain competence for the uptake and expression of exogenous DNA transformation. We also show that these conditions for maintaining competence are dramatically augmented even by rare episodes where selection favors transformants. Using experimental populations of B. subtilis and antibiotic-mediated episodic selection, we test and provide support for the validity of the assumptions behind this model and the predictions generated from our analysis of its properties. We discuss the potential generality of episodic selection for the maintenance of competence in other naturally transforming species of bacteria and critically evaluate other hypotheses for the maintenance (and evolution) of competence and their relationship to this hypothesis.


Influence of preshipment management on the adrenal response of beef calves to ACTH before and after transit.
The influence of preshipment management, transit (965 km) and postshipment management upon the ability of the adrenal gland to respond to exogenous adrenocorticotropic hormone (ACTH) was evaluated in 60 beef calves (47 bulls and 13 steers). Adrenal response to ACTH treatment was quantified before shipment (PRE), about 24 h (POST) and 3 wk after transit (3 WK). Calves were assembled for 4 or 10 d before shipment and fed either a hay or a high energy diet (HE). The area under the plotted curve for the plasma corticoid concentration response to ACTH was used as an adrenal response test (ART). The feeding of hay during the first 4 d of assembly resulted in a greater (P less than .05) PRE ART value than feeding of the HE diet, but after 10 d of assembly, the ART was similar for animals on the two diets. The ART at 24 h after transit was similar to that before shipment. The HE group had a greater (P less than .05) ART than the hay group 3 wk after arrival, however, values were dependent upon postshipment management. Placement of calves on winter wheat pasture soon after arrival resulted in greater ART (P less than .05) values after the 3 wk recovery period than for calves that grazed native range for 10 or 20 d before grazing winter wheat pasture. These data indicate that the ability of the adrenal gland to respond to ACTH is increased at preshipment if the assembly period is 4 d compared to 10 d and the adrenal response at 3 wk after arrival is greater if a HE diet is fed during assembly instead of hay.


A highly flexible and compact magnetoresistive analytic device.
A grand vision of realization of smart and compact multifunctional microfluidic devices for wearable health monitoring, environment sensing and point-of-care tests emerged with the fast development of flexible electronics. As a vital component towards this vision, magnetic functionality in flexible fluidics is still missing although demanded by the broad utility of magnetic nanoparticles in medicine and biology. Here, we demonstrate the first flexible microfluidic analytic device with integrated high-performance giant magnetoresistive (GMR) sensors. This device can be bent to a radius of 2 mm while still retaining its full performance. Various dimensions of magnetic emulsion droplets can be probed with high precision using a limit of detection of 0.5 pl, providing broad applicability in high-throughput droplet screening, flow cytometry and drug development. The flexible feature of this analytic device holds great promise in the realization of wearable, implantable multifunctional platforms for biomedical, pharmaceutical and chemical applications.


Early treatment response in non-small cell lung cancer patients using diffusion-weighted imaging and functional diffusion maps--a feasibility study.
The aim of this study was to prospectively evaluate the feasibility of monitoring treatment response to chemotherapy in patients with non-small cell lung carcinoma using functional diffusion maps (fDMs). This study was approved by the Cantonal Research Ethics Committee and informed written consent was obtained from all patients. Nine patients (mean age = 66 years; range = 53-76 years, 5 females, 4 males) with overall 13 lesions were included. Imaging was performed within two weeks before initiation of chemotherapy and at one, two, and six weeks after initiation of chemotherapy. Imaging included a respiratory-triggered diffusion-weighted sequence including three b-factors (100, 600, and 800 s/mm2). Treatment response was defined by change in tumor diameter on computed tomography (CT) after two cycles of chemotherapy. Changes in the apparent diffusion coefficient (ADC) on a per-lesion basis and the percentages of voxel with significantly increased or decreased ADCs on fDMs were analyzed using repeated measures analysis of variance (ANOVA). Changes in tumor size were used as covariate to examine the ability of ADCs and fDM parameters to predict treatment response. Repeated measures ANOVA revealed that the percentage of voxels with increased ADCs on fDMs (p = 0.002) as well as the mean ADC increase (p = 0.011) were significantly higher in good responders with a large reduction in tumor size on CT. Our results indicate that the percentage of voxels with significantly increased ADCs on fDMs seems to be a promising biomarker for early prediction of treatment response in patients with non-small cell lung carcinoma. Contrary to averaged values, this approach allows the spatial heterogeneity of treatment response to be resolved.


Hepatic portal vein gas: clinical features and outcomes.
Hepatic portal vein gas (HPVG) is found as branching gas extending to near the periphery of the liver. Increased utilization of CT may identify HPVG in more patients. In the past HPVG was associated with acute abdomen and high mortality. Our recent experience suggested a less morbid outcome with this entity. We wanted to identify clinical features associated with HPVG that could help us with planning care. We reviewed seven patients with CT-detected HPVG presenting over 4 months. We analyzed their histories, examinations, and laboratory data. Five of seven patients had laparotomies. Of these five one had a therapeutic resection of an ischemic bowel. All other laparotomies were nontherapeutic. Two of seven patients had no surgical intervention. One of the two refused surgery and subsequently died. The other was treated medically and recovered. Physical examination and laboratory findings were not reliable indicators of intra-abdominal catastrophe. Furthermore CT scans are inaccurate for predicting the etiology of HPVG. Close observation may be appropriate in stable patients with HPVG without other specific findings.


Potentiation of responses to adrenergic nerve stimulation in isolated rat atria during chronic tricyclic antidepressant administration.
Several weeks of tricyclic antidepressant administration are required to effectively reverse depression. To determine whether there are adaptive changes in andrenergic nerve function which correspond to the clinical onset of antidepressant action, the endogenous norepinephrine content, [3H]norepinephrine uptake and retention, responses to exogenous norepinephrine and the release of norepinephrine during field stimulation were studied using left atrial strips isolated from rats treated with either acutely or chronically with tricyclic antidepressants. Desipramine, nortriptyline, chlorimipramine and iprindole were administered to rats, 10 mg/kg i.p., twice daily. After 14 days of drug administration, the responses to field stimulation were potentiated markedly by all four tricyclics. In contrast, 1 day of tricyclic treatment had only slight potentiating effects. When phenoxybenzamine, 10(-7) M, was added to the organ bath in order to block the inhibitory presynaptic alpha receptor, the responses of control atria and atria from rats treated for 1 day with desipramine were potentiated but those of atria treated for 21 days with desipramine were not potentiated. The development of presynaptic alpha receptor subsensitivity during chronic tricyclic administration would explain these findings. Other possible explanations were also investigated. The uptake and retention of [3H]norepinephrine was markedly inhibited to a similar degree of either 1 or 14 days of desipramine or nortriptyline administration. One day of chlorimipramine treatment decreased the amount of [3H]norepinephrine taken up and retained by left atrial strips, and after 14 days of treatment decreased the amount further. In contrast, neither 1 nor 14 days of iprindole administration had any effect on the uptake and retention of [3H]norepinephrine. These data indicate that the potentiation of the responses to field stimulation cannot be explained by the inhibition of norepinephrine uptake. The inotropic response to exogenous norepinephrine was not altered by any duration of administration of any of the four tricyclics studied. Furthermore, the endogenous norepinephrine content of atria did not change after as many as 21 days of desipramine administration. The present results indicate that the potentiation of the effects of adrenergic nerve transmission during chronic tricyclic administration is the result of an increase in norepinephrine release which occurs due to the development of presynaptic alpha receptor subsensitivity. The time course of development of presynaptic receptor subsensitivity corresponds well with the onset of clinical activity of these drugs.


Surgery of the mind, mood, and conscious state: an idea in evolution.
Since the beginning of recorded history, humans have sought a physical means of altering disordered behavior and consciousness. This quest has spawned numerous innovations in neurosurgery and the neurosciences, from the earliest prehistoric attempts at trepanation to the electrocortical and anatomic localization of cerebral function that emerged in the 19th century. At the start of the 20th century, the overwhelming social impact of psychiatric illness intersected with the novel but imperfect understanding of frontal lobe function, establishing a decades-long venture into the modern origin of psychosurgery, the prefrontal lobotomy. The subsequent social and ethical ramifications of the widespread overuse of transorbital lobotomies drove psychosurgery to near extinction. However, as the pharmacologic treatment of psychiatric illness was established, numerous concomitant technical and neuroscientific innovations permitted the incremental development of a new paradigm of treating the disordered mind. In this article, we retrospectively examine these early origins of psychosurgery and then look to the recent past, present, and future for emerging trends in surgery of the psyche. Recent decades have seen a revolution in minimalism, noninvasive imaging, and functional manipulation of the human cerebrum that have created new opportunities and treatment modalities for disorders of the human mind and mood. Early contemporary efforts were directed at focal lesioning of abnormal pathways, but deep-brain stimulation now aims to reversibly alter and modulate those neurologic activities responsible for not only psychiatric disorders, but also to modulate and even to augment consciousness, memory, and other elements of cerebral function. As new tools become available, the social and medical impact of psychosurgery promises to revolutionize not only neurosurgery, but also humans' capability for positively impacting life and society.


The outcomes of patients with ESRD and ANCA-associated vasculitis in Australia and New Zealand.
This study aimed to evaluate dialysis and transplant outcomes of patients with ESRD secondary to ANCA-associated vasculitis (AAV). All ESRD patients who commenced renal replacement therapy in Australia and New Zealand between 1996 and 2010 were included. Outcomes were assessed by Kaplan-Meier, multivariable Cox regression, and competing-risks regression survival analyses. Of 36,884 ESRD patients, 228 had microscopic polyangiitis (MPA) and 221 had granulomatosis with polyangiitis (GPA). Using competing-risks regression, compared with other causes of ESRD, MPA patients (hazard ratio [HR], 0.89; 95% confidence interval [95% CI], 0.73-1.08; P=0.24) and GPA patients (HR, 0.94; 95% CI, 0.74-1.19; P=0.62) experienced comparable survival on dialysis. Forty-six MPA patients (21%) and 47 GPA (20%) patients received 98 renal allografts. Respective 10-year first graft survival rates in MPA, GPA, and non-AAV patients were 50%, 62%, 70%, whereas patient survival rates were 68%, 85% and 83%, respectively. Compared with non-AAV patients, MPA transplant recipients had higher risks of graft failure (HR, 1.87; 95% CI, 1.07-3.25; P=0.03) and death (HR, 1.94; 95% CI, 1.02-3.69; P=0.04), whereas GPA transplant recipients experienced comparable renal allograft survival (HR, 0.91; 95% CI, 0.43-1.93; P=0.81) and patient survival (HR, 0.58; 95% CI, 0.23-2.27; P=0.58). AAV recurrence was observed in two renal allografts (2%). Compared with ESRD patients without AAV, those with GPA have comparable renal replacement therapy outcomes, whereas MPA patients have comparable dialysis survival but poorer renal transplant allograft and patient survival rates.


Immunological predictors of HIV-related survival.
While the prognostic role of CD4 lymphocyte count is well established, little is known about how other immunological factors are associated with HIV-related survivorship. CD8 lymphocyte count is reported to inhibit growth of HIV in vitro and to deter the development of cytomeglovirus infections. Scarce information exists, however, on its association with HIV-related survivorship. The objective of the present study therefore was to assess whether survival estimation could be improved by including CD8 lymphocyte count as a prognostic factor. The study sample consisted of 904 adult HIV-infected patients who were treated between 1992 and 1997 at a large southwestern academic medical centre in the US. Survival analysis using proportional hazards modelling showed that baseline CD4 lymphocyte was highly and positively predictive of HIV-related survival. By contrast, baseline CD8 count was not predictive of survival in the study cohort. While the interaction between CD4 and CD8 was not statistically significant in the present study sample, decomposition of this effect indicates that these factors may operate synergistically to predict survival. In conclusion, these findings suggest that clinicians may improve their prognostic accuracy by relying on both CD4 and CD8 lymphocyte counts rather than relying exclusively on CD4 counts.


Body mass index and circulating oestrone sulphate in women treated with adjuvant letrozole.
Obesity is an independent adverse prognostic factor in early breast cancer patients, but it is still controversial whether obesity may affect adjuvant endocrine therapy efficacy. The aim of our study (ancillary to the two clinical trials Gruppo Italiano Mammella (GIM)4 and GIM5) was to investigate whether the circulating oestrogen levels during treatment with the aromatase inhibitor letrozole are related to body mass index (BMI) in postmenopausal women with breast cancer. Plasma concentration of oestrone sulphate (ES) was evaluated by radioimmunoassay in 370 patients. Plasma samples were obtained after at least 6 weeks of letrozole therapy (steady-state time). Patients were divided into four groups according to BMI. Differences among the geometric means (by ANOVA and ANCOVA) and correlation (by Spearman's rho) between the ES levels and BMI were assessed. Picomolar geometric mean values (95% confidence interval, n=patients) of circulating ES during letrozole were 58.6 (51.0-67.2, n=150) when BMI was <25.0 kg m(-2); 65.6 (57.8-74.6, n=154) when 25.0-29.9 kg m(-2); 59.3 (47.1-74.6, n=50) when 30.0-34.9 kg m(-2); and 43.3 (23.0-81.7, n=16) when ≥35.0 kg m(-2). No statistically significant difference in terms of ES levels among groups and no correlation with BMI were observed. Body mass index does not seem to affect circulating oestrogen levels in letrozole-treated patients.


Leukoencephalopathy due to variants in GFPT1-associated congenital myasthenic syndrome.
To determine the molecular etiology of disease in 4 individuals from 2 unrelated families who presented with proximal muscle weakness and features suggestive of mitochondrial disease. Clinical information and neuroimaging were reviewed. Genome sequencing was performed on affected individuals and biological parents. All affected individuals presented with muscle weakness and difficulty walking. In one family, both children had neonatal respiratory distress while the other family had 2 children with episodic deteriorations. In each family, muscle biopsy demonstrated ragged red fibers. MRI was suggestive of a mitochondrial leukoencephalopathy, with extensive deep cerebral white matter T2 hyperintense signal and selective involvement of the middle blade of the corpus callosum. Through genome sequencing, homozygous GFPT1 missense variants were identified in the affected individuals of each family. The variants detected (p.Arg14Leu and p.Thr151Lys) are absent from population databases and predicted to be damaging by in silico prediction tools. Following the genetic diagnosis, nerve conduction studies were performed and demonstrated a decremental response to repetitive nerve stimulation, confirming the diagnosis of myasthenia. Treatment with pyridostigmine was started in one family with favorable response. GFPT1 encodes a widely expressed protein that controls the flux of glucose into the hexosamine-biosynthesis pathway that produces precursors for glycosylation of proteins. GFPT1 variants and defects in other enzymes of this pathway have previously been associated with congenital myasthenia. These findings identify leukoencephalopathy as a previously unrecognized phenotype in GFPT1-related disease and suggest that mitochondrial dysfunction could contribute to this disorder.


Theoretical considerations concerning the effect of relativistic velocities on the rate of biological processes.
Theoretical considerations were advanced on the reaction rate of biological systems in a rocket accelerated at fractional levels of the velocity of light. The values of mass increase in reacting molecules and length contraction of space under these relativistic velocities attained by the hypothetical rocket were inserted in equations of the absolute reaction rate theory. The equations employed were for the frequency of collisions, and for the internal kinetic energy of molecular reactions. Results of both sets of equations indicated that reduction of reaction rates were correlated to the mass increase. This would imply a general slowing of all chemical, biochemical and biological processes taking place. A human would suffer a related decrease in metabolic rate. Contrary to what is generally accepted, the biological aging of the space traveler under velocities bearable by humans, namely under 0.50c, would follow a pace very similar to that of an observer remaining in the resting frame of reference. With increased increments of the velocity, the space traveler would display a more intense lowering of the metabolic rate, with signs and symptoms comparable to body core hypothermia. Metabolic rates at insufficient levels to maintain the vital functions would be attained at 0.70c and higher, leading swiftly to coma and death. The presence of an endocrine dysfunction such as hypothyroidism or obesity in the space traveler would aggravate the signs and symptoms. Space travel at efficient velocities would be unbearable for a warm-blooded animal.


Phase-only circular harmonic matched filtering.
The idea of a phase-only matched filter [J. L. Horner and P. D. Gianino, Appl. Opt. 23, 812-816 (1984)] is incorporated in the scheme of circular harmonic component matched filtering [Y. N. Hsu and H. H. Arsenault, Appl. Opt. 21, 4016-4019 (1982)]. Computer simulation showed that the phase-only circular harmonic matched filter possesses the rotational invariant property for 2-D recognition. Furthermore, it does a better job in recognizing closely placed targets compared with traditional circular harmonic filters. The simulation also demonstrated that a pure phase circular harmonic filter is less liable to give rise to false alarms in recognition because the sidelobe produced by it is much less pronounced and much less extensive than that produced by a traditional circular harmonic filter.


Pro and Cons of Transurethral Self-Catheterization in Boys: A Long-Term Teaching Experience in a Pediatric Rehabilitation Centre.
To describe the acceptance and efficacy of clean intermittent catheterization (CIC) in the management of lower urinary tract (LUT) dysfunction regardless of the age of the children and their degree of urethral sensation. We retrospectively evaluated boys managed with CIC at a pediatric teaching hospital between 1992 and 2014. Age, urethral sensation, acceptance, efficacy in terms of continence and preserving upper urinary tract and genitourinary complications were reviewed in the medical records. Sixty boys managed with CIC for LUT dysfunction due to neurological or urological disorders were identified. The median age at CIC initiation was 8.2 years (range, 1.4-18). With regard to age, CIC was well tolerated in younger boys and without genital sensation. Failure in the CIC protocol occurred within the first six months (n = 9). More boys with genital sensation were socially continent with CIC (91% versus 83%, P = .05). Vesicoureteral reflux was resolved in 69% of boys (P = .03), and hydronephrosis in 54% (P = .07). CIC was effective in terms of continence and renal protection. The procedure was feasible even in boys with preserved urethral sensation. Therapeutic education by a dedicated urotherapy nurse is the key factor in ensuring long-term CIC compliance and acceptability.


Individual differences in disgust sensitivity modulate neural responses to aversive/disgusting stimuli.
Little is known about how individual differences in trait disgust sensitivity modulate the neural responses to disgusting stimuli in the brain. Thirty-seven adult healthy volunteers completed the Disgust Scale (DS) and viewed alternating blocks of disgusting and neutral pictures from the International Affective Picture System while undergoing fMRI scanning. DS scores correlated positively with activations in brain regions previously associated with disgust (anterior insula, ventrolateral prefrontal cortex-temporal pole, putamen-globus pallidus, dorsal anterior cingulate, and visual cortex) and negatively with brain regions involved in the regulation of emotions (dorsolateral and rostral prefrontal cortices). The results were not confounded by biological sex, anxiety or depression scores, which were statistically controlled for. Disgust sensitivity, a behavioral trait that is normally distributed in the general population, predicts the magnitude of the individual's neural responses to a broad range of disgusting stimuli. The results have implications for disgust-related psychiatric disorders.


Effect of genetic obesity in mice on the induction of diabetes by encephalomyocarditis virus.
The "M" variant of the encephalomyocarditis (EMC) virus causes a diabetes-like disease in some, but not all, strains of mice. The genetic basis for either resistance or susceptibility to the diabetogenic effect of the virus is not known. After infection with EMC, C57BL/6 mice seldom develop hyperglycemia and the insular lesions are subtle. To explore the possible effects of metabolic influences on the viral susceptibility of the islets, we studied C57BL/6 mice that were carriers of the ob gene. After virus inoculation, obese homozygous C57BL/6-ob/ob mice consistently developed hyperglycemia during the acute stages of infection, whereas nonobese littermates did not. Infection induced more severe lesions in the pancreatic islets of obese mice than in islets of the lean littermates. These studies suggest that the functional activity of the beta-cells influences the severity of the viral injury to the beta-cell, and the consequent occurrence of diabetes.


Coronary collaterals in obese patients: impact of metabolic syndrome.
Obesity is a growing pandemic. Among obese patients with significant coronary artery stenosis, development of coronary collaterals was investigated. Consecutive 104 obese patients with stable angina pectoris were enrolled. Coronary collaterals were assessed according to the Cohen and Rentrop grading system and classified into 2 as those with poor collaterals (grade 0-1, Group 1) and those with good collaterals (grade 2-3, Group 2). Group 1 had higher body mass index, shorter duration of angina pectoris than Group 2. Poor collaterals were present in 82.3% and 59.5% of patients with and without (P = .019) metabolic syndrome, respectively. Metabolic syndrome score (sum of each component) was found to be negatively correlated with Rentrop score (r = -691; P < .001). After controlling for symptom duration and body mass index, metabolic syndrome kept independent association with poor collaterals among obese patients (P = .043, B = 1.8). Metabolic syndrome appears to influence the development of coronary collaterals among obese patients with stable coronary artery disease.


Topological critical slowing down: Variations on a toy model.
Numerical simulations of lattice quantum field theories whose continuum counterparts possess classical solutions with nontrivial topology face a severe critical slowing down as the continuum limit is approached. Standard Monte Carlo algorithms develop a loss of ergodicity, with the system remaining frozen in configurations with fixed topology. We analyze the problem in a simple toy model, consisting of the path integral formulation of a quantum mechanical particle constrained to move on a circumference. More specifically, we implement for this toy model various techniques which have been proposed to solve or alleviate the problem for more complex systems, like non-Abelian gauge theories, and compare them both in the regime of low temperature and in that of very high temperature. Among the various techniques, we propose an alternative algorithm which completely solves the freezing problem, but unfortunately is specifically tailored for this particular model and not easily exportable to more complex systems.


Preoperative high-intensity training in frail old patients undergoing pulmonary resection for NSCLC.
Thoracic surgery remains the better therapeutic option for non-small cell lung cancer patients that are diagnosed in early stage disease. Preoperative lung function assessment includes respiratory function tests (RFT) and cardio-pulmonary exercise testing (CPET). Vo2 peak, FEV1 and DLCO as well as recognition of performance status, presence of co-morbidities, frailty indexes, and age predict the potential impact of surgical resection on patient health status and survival risk. In this study we have retrospectively assessed the benefit of a high-intensity preoperative pulmonary rehabilitation program (PRP) in 14 patients with underlying lung function impairment prior to surgery. Amongst these, three patients candidate to surgical resection exhibited severe functional impairment associated with high score of frailty according CHS and SOF index, resulting in a substantial mortality risk. Our observations indicate that PRP appear to reduce the mortality and morbidity risk in frail patients with concurrent lung function impairment undergoing thoracic surgery. PRP produced improvement of VO2 peak degree and pulmonary function resulting in reduced postoperative complications in high-risk patients from our cases. Our results indicate that a preoperative training program may improve postoperative clinical outcomes in fraillung cancer patients with impaired lung function prior to surgical resection.


The use of interdisciplinary seminars for the development of caring dispositions in nursing and social work students.
This paper is a report of a study to evaluate the influence of interdisciplinary seminars for undergraduate nursing and social work students on development of their understanding of the meaning of caring. There is growing international interest in interprofessional education, which is believed to have the potential to improve patient care. If interprofessional education and subsequent collaboration are truly to be patient-centred, it is important to identify a value base which creates a healthcare professional identity that facilitates collaboration. Caring, as a humanistic value, is found in both nursing and social work professionals. A mixed method approach, primarily qualitative but with a quantitative component, was chosen for evaluation of the interprofessional seminars. The data were collected between 2007-2008 by videotape recordings of the sessions, follow-up telephone interviews and a questionnaire. There was cultivation in the nursing students of a deeper understanding of caring based on openness and a non-judgmental approach, learned from their social work counterparts. Reciprocally, social work students learned about the nursing students' daily activities as they observed the natural process of trust and communication in the context of caring. Enhanced understanding of caring in practice is not possible via learning through a uni-professional approach. Students' reflections and dialogue enable their development of relation-centred caring, particularly in the realm of biomedical and technical environments.


[Diagnosis and Treatment of Physical Frailty].
Physical frailty is a physiological syndrome of older people. It is characterized by a reduced reserve, a reduced stressor resistance, and vulnerability to negative health outcomes. The assessment of physical frailty is increasingly applied to identify high risk patients prior to medical or surgical interventions. The present article describes Fried's frailty phenotype, which is the most frequently applied diagnostic instrument of physical frailty, together with evidence based treatment options.


Practical Application of Coronary Physiologic Assessment: Asia-Pacific Expert Consensus Document: Part 1.
Coronary physiologic assessment is performed to measure coronary pressure, flow, and resistance or their surrogates to enable the selection of appropriate management strategy and its optimization for patients with coronary artery disease. The value of physiologic assessment is supported by a large body of evidence that has led to major recommendations in clinical practice guidelines. This expert consensus document aims to convey practical and balanced recommendations and future perspectives for coronary physiologic assessment for physicians and patients in the Asia-Pacific region based on updated information in the field that including both wire- and image-based physiologic assessment. This is Part 1 of the whole consensus document, which describes the general concept of coronary physiology, as well as practical information on the clinical application of physiologic indices and novel image-based physiologic assessment.


Revision of the Li13Si4 structure.
Besides Li17Si4, Li16.42Si4, and Li15Si4, another lithium-rich representative in the Li-Si system is the phase Li13Si4 (trideca-lithium tetra-silicide), the structure of which has been determined previously [Frank et al. (1975 ▶). Z. Naturforsch. Teil B, 30, 10-13]. A careful analysis of X-ray diffraction patterns of Li13Si4 revealed discrepancies between experimentally observed and calculated Bragg positions. Therefore, we redetermined the structure of Li13Si4 on the basis of single-crystal X-ray diffraction data. Compared to the previous structure report, decisive differences are (i) the introduction of a split position for one Li site [occupancy ratio 0.838 (7):0.162 (7)], (ii) the anisotropic refinement of atomic displacement parameters for all atoms, and (iii) a high accuracy of atom positions and unit-cell parameters. The asymmetric unit of Li13Si4 contains two Si and seven Li atoms. Except for one Li atom situated on a site with symmetry 2/m, all other atoms are on mirror planes. The structure consists of isolated Si atoms as well as Si-Si dumbbells surrounded by Li atoms. Each Si atom is either 12- or 13-coordinated. The isolated Si atoms are situated in the ab plane at z = 0 and are strictly separated from the Si-Si dumbbells at z = 0.5.


Measures of anxiety, amygdala volumes, and hippocampal scopolamine phMRI response in elderly female rhesus macaques.
In nonhuman primates, anxiety levels are typically assessed by observing social hierarchies or behavior in an intruder task. As measures of anxiety might influence performance on a particular cognitive task, it is important to analyze these measures in the same room as used for the cognitive task. As we use a playroom for the spatial maze test, we classified elderly female rhesus macaques (Macaca mulatta) monkeys, as bold or reserved monkeys based on the time spent in specific areas of this room. Based on their exploratory behavior in the playroom, bold monkeys were defined as animals that spent 20% more time in the unprotected areas of the room than in the protected areas, whereas reserved monkeys spent a comparable amount of time in both areas. MRI analyses showed that reserved monkeys had a smaller amygdala compared to bold monkeys but there were no group differences in hippocampal volumes. In addition, the amount of time spent in the corners of the room was negatively correlated with the right amygdala as well as the total amygdala size. Finally, reserved monkeys showed a lower phMRI response to the muscarinic receptor antagonist scopolamine compared to the bold monkeys. Thus, in elderly female nonhuman primates measures of anxiety are associated with structural amygdala differences and hippocampal muscarinic receptor function. This article is part of a Special Issue entitled 'Anxiety and Depression'.


Treprostinil for pulmonary hypertension.
Treprostinil is a stable, long-acting prostacyclin analogue which can be administered as a continuous subcutaneous infusion using a portable miniature delivery system. Subcutaneous treprostinil has been shown in a large multicenter randomized controlled trial to improve exercise capacity, clinical state, functional class, pulmonary hemodynamics, and quality of life in patients with pulmonary arterial hypertension, an uncommon disease of poor prognosis. Side effects include facial flush, headache, jaw pain, abdominal cramping, and diarrhea, all typical of prostacyclin, and manageable by symptom-directed dose adjustments, and infusion site pain which may make further treatment impossible in 7%-10% of the patients. Long-term survival in pulmonary arterial hypertension patients treated with subcutaneous treprostinil is similar to that reported with intravenous epoprostenol. There are uncontrolled data suggesting efficacy of subcutaneous treprostinil in chronic thromboembolic pulmonary hypertension. Treprostinil can also be administered intravenously, although increased doses, up to 2-3 times those given subcutaneously, appear to be needed to obtain the same efficacy. Preliminary results of a randomized controlled trial of inhaled treprostinil on top of bosentan and sildenafil therapies have shown significance on the primary endpoint, which was exercise capacity as assessed by the distance walked in 6 minutes. Trials of oral formulations of treprostinil have been initiated.


Effects of castor bean extract and ricin A-chain on ovulation and implantation in rabbits.
The anti-implantation and antiovulation effects of castor bean extract (CBE) and ricin A-chain (RAC) were evaluated in rabbits. Both CBE and RAC, administered intraperitoneally on days 5-9 of pregnancy, exhibited a pronounced decrease in maternal body weight gain and in death of all fetuses. A significant (p < 0.01) decrease of implantation sites resulted after rabbits were treated with RAC on the first 6 consecutive days of pregnancy. When female rabbits were treated with RAC for 10 consecutive days followed by human chorionic gonadotropin (hCG) (50 IU/kg intravenously), there was a 30% reduction in the number of corpora lutae. These data clearly indicate that CBE and RAC possess potent effects on implantation and ovulation in rabbits. The protein contents of castor bean extract, separated by polyacrylamide gel electrophoresis, revealed the presence of several protein bands, ricin toxin being a major constituent of the extract.


Single-well "push-pull" partitioning tracer test for NAPL detection in the subsurface.
Previous environmental applications of partitioning tracer tests to detect and quantify nonaqueous phase liquid (NAPL) contamination in the subsurface have been limited to well-to-well tests. However, theory and numerical modeling suggests that single-well injection-extraction ("push-pull") partitioning tracer tests can also potentially detect and quantify NAPL contamination. In this type of test, retardation factors for injected partitioning tracers are estimated from the increase in apparent dispersion observed in extraction-phase breakthrough curves in the presence of NAPL. A series of laboratory push-pull tests was conducted in physical aquifer models (PAMs) packed with natural aquifer sediment prepared with and without the presence of trichloroethene (TCE) NAPL. Field tests were conducted in an aquifer contaminated with petroleum hydrocarbon NAPL. Injected test solutions contained a suite of partitioning and conservative (nonpartitioning) alcohol tracers. Laboratory push-pull partitioning tracer tests were able to detect and quantify sorption of partitioning tracers to aquifer sediment (in the absence of NAPL) and to detect NAPL when it was present. NAPL saturations computed from estimated retardation factors bracketed those computed from known volumes of emplaced NAPL in the sediment pack. However, numerical modeling with assumed homogeneous NAPL distribution and linear equilibrium partitioning of tracers between aqueous and NAPL phases was unable to reproduce all features of observed breakthrough curves. Excavation of the sediment pack after all tests indicated that a portion of the emplaced NAPL had sunk to the bottom of the PAM invalidating the modeling assumption of homogeneous NAPL distribution. Moreover, the apparent dispersion in extraction-phase breakthrough curves decreased when the injection-extraction pumping rate was decreased, suggesting that mass transfer limitations existed during laboratory tests. Field push-pull partitioning tracer tests were able to detect NAPL in a portion of the aquifer known to contain NAPL; computed NAPL saturations were comparble to those obtained from sediment coring and the results of a partitioning interwell tracer test conducted in the same location. This study clearly demonstrates that the single-well partitioning tracer test can detect NAPL under both laboratory and field conditions. However, additional research is needed to verify the ability of the test to quantify NAPL saturations.


PPARalpha governs glycerol metabolism.
Glycerol, a product of adipose tissue lipolysis, is an important substrate for hepatic glucose synthesis. However, little is known about the regulation of hepatic glycerol metabolism. Here we show that several genes involved in the hepatic metabolism of glycerol, i.e., cytosolic and mitochondrial glycerol 3-phosphate dehydrogenase (GPDH), glycerol kinase, and glycerol transporters aquaporin 3 and 9, are upregulated by fasting in wild-type mice but not in mice lacking PPARalpha. Furthermore, expression of these genes was induced by the PPARalpha agonist Wy14643 in wild-type but not PPARalpha-null mice. In adipocytes, which express high levels of PPARgamma, expression of cytosolic GPDH was enhanced by PPARgamma and beta/delta agonists, while expression was decreased in PPARgamma(+/-) and PPARbeta/delta(-/-) mice. Transactivation, gel shift, and chromatin immunoprecipitation experiments demonstrated that cytosolic GPDH is a direct PPAR target gene. In line with a stimulating role of PPARalpha in hepatic glycerol utilization, administration of synthetic PPARalpha agonists in mice and humans decreased plasma glycerol. Finally, hepatic glucose production was decreased in PPARalpha-null mice simultaneously fasted and exposed to Wy14643, suggesting that the stimulatory effect of PPARalpha on gluconeogenic gene expression was translated at the functional level. Overall, these data indicate that PPARalpha directly governs glycerol metabolism in liver, whereas PPARgamma regulates glycerol metabolism in adipose tissue.


Preventive drug therapy and contralateral breast cancer: summary of the evidence of clinical trials and observational studies.
Background: Breast cancer patients have a lifelong 2-4-fold increased risk of developing a second primary tumor in the contralateral breast compared with the risk for a first primary breast cancer in the general female population. Prevention of contralateral breast cancer (CBC) has received increased attention during recent decades. Here, we summarize and discuss the available literature on drug preventive therapy and CBC.Results: The endocrine-targetting drugs, tamoxifen and aromatase inhibitors are used as standard adjuvant treatment for estrogen receptor (ER)-positive breast cancer. Both are associated with relative risk reductions of CBC of up to 50%, but incur serious side effects. Several prescription drugs originally developed for other purposes, including bisphosphonates, statins, non-steroidal anti-inflammatory drugs, metformin, anti-hypertensives and retinoids, have shown anti-cancer activity in preclinical models. However, results of observational studies on CBC are sparse and inconsistent, with only statins demonstrating promise as preventive agents and a potential treatment option for ER-negative breast cancer patients.Conclusion: Future studies are needed to assess the effect of statins in risk reduction and to identify other drugs with chemopreventive potential against CBC. Eventually, efforts must be directed towards identifying those breast cancer patients likely to benefit most from specific preventive therapies.


Fine mapping of the psoriasis susceptibility gene PSORS1: a reassessment of risk associated with a putative risk haplotype lacking HLA-Cw6.
Human leukocyte antigen (HLA)-Cw6 has long been associated with psoriasis, and PSORS1 (psoriasis susceptibility 1), a major gene for psoriasis susceptibility, has been mapped to its vicinity. A previous analysis identified multiple risk haplotypes carrying HLA-Cw6 and one haplotype (cluster 17, HLA-Cw8-B65) that appeared to carry risk for psoriasis but did not carry HLA-Cw6. This haplotype was very similar to other risk haplotypes for at least 60 kb telomeric to HLA-C, suggesting identity by descent with the remaining risk chromosomes. The association, however, between psoriasis and this haplotype as assessed by the transmission/disequilibrium test (TDT) was of borderline significance (p-value 0.048). In order to better assess the risk associated with cluster 17, a multicenter collaboration typed additional subjects for a single marker (M6S161) for which one allele (249 bp) was found only on cluster 17. The new sample included 1275 pedigrees as well as 300 cases and 913 controls. Transmission of this allele to affected individuals was examined using the TDT and the pedigree disequilibrium test (PDT), and case-control samples were analyzed by a trend test across genotype categories. By all methods, the newly acquired genotypes failed to confirm the association originally reported, despite adequate power. In contrast, the 248 bp allele, which is found on all HLA-Cw6-positive risk haplotypes as well as several non-risk haplotypes, shows significant excess transmission for all cohorts. Taken together, these results indicate that cluster 17 does not carry a psoriasis-susceptibility allele, and expand the PSORS1 risk interval to approximately 300 kb.


Preliminary results of the 'Surgilig' synthetic ligament in the management of chronic acromioclavicular joint disruption.
Chronic instability of the acromiocavicular joint is relatively common and normally occurs following a fall onto the point of the shoulder. Reconstruction of the joint [Weaver-Dunn procedure] using the coracoacromial ligament is often required in service personnel, and a number of methods to augment this repair have been used. Many of these operative methods require a second operation to remove the metalwork, and in addition can be associated with a failure rate of up to 30%. The 'Surgilig' was originally designed for use in the revision of failed Weaver-Dunn procedures. However this study evaluates its use in the primary operation, reinforcing the autologous graft, in an attempt to reduce the failurerate. We prospectively followed up the Modified Weaver Dunn procedures using Surgilig. The post-operative x-rays were reviewed at six weeks, three months and then six months to assess the radiological success of the procedure. Our patients were discharged at six months. We have performed this procedure in 11 patients. One of the 11 patients was excluded from the study as the Surgilig graft was used in addition to a hook plate. The remaining ten patients have all reached the six-month post-operative time with no incidence of radiological failure of the graft. After six months they were discharged from clinic follow-up asthe coracoacromial graft had sufficient strength to no longer rely on the augment for mechanical stability of the joint. All 10 patients had a good clinical and radiological result. One patient even had inadvertent stress/ weight-bearing x-rays taken at six weeks, with no discernable detrimental effect to outcome. Although a small study, these initial results for primary fixation of acromioclavicular joint disruption with Surgilig are extremely encouraging. The results suggest that Surgilig should continue to be used in its current role. As patient numbers increase, a follow-up study to evaluate these preliminary findings should be conducted.


A Transcriptome Array-Based Approach to Link SGLT-2 and Intrarenal Complement C5 Synthesis in Diabetic Nephropathy.
Diabetic nephropathy is a common microvascular complication of diabetes mellitus. It is characterized by progressive chronic kidney disease (CKD) with decline of kidney function by hyperfiltration. On a mechanistic level, activation of the complement system has been implicated in the pathogenesis of diabetic nephropathy. Therefore, here we pursued a transcriptome array-based approach to link intrarenal SGLT-2 and the synthesis of distinct complement components in diabetic nephropathy. Publicly available datasets for SLC5A2 (encoding SGLT-2) and complement system components were extracted specifically from microdissected tubulointerstitial (healthy controls: n = 31, diabetic nephropathy: n = 17) and glomerular compartments (healthy controls: n = 21, diabetic nephropathy: n = 12). First, we compared tubulointerstitial and glomerular log2SLC5A2 mRNA expression levels and confirmed a predominant synthesis within the tubulointerstitial compartment. Among various complement components and receptors, the only significant finding was a positive association between SLC5A2 and the tubulointerstitial synthesis of the complement component C5 in diabetic nephropathy (p = 0.0109). Finally, intrarenal expression of SLC5A2 was associated predominantly with pathways involved in metabolic processes. Interestingly, intrarenal complement C5 synthesis was also associated with enrichment of metabolic signaling pathways, overlapping with SLC5A2 for "metabolism" and "biological oxidations". These observations could be of relevance in the pathogenesis of diabetic nephropathy and implicate a mechanistic link between SGLT-2 and intrarenal complement synthesis.


Personality predictors of dementia diagnosis and neuropathological burden: An individual participant data meta-analysis.
The extent to which the Big Five personality traits and subjective well-being (SWB) are discriminatory predictors of clinical manifestation of dementia versus dementia-related neuropathology is unclear. Using data from eight independent studies (Ntotal = 44,531; Ndementia = 1703; baseline Mage = 49 to 81 years, 26 to 61% female; Mfollow-up range = 3.53 to 21.00 years), Bayesian multilevel models tested whether personality traits and SWB differentially predicted neuropsychological and neuropathological characteristics of dementia. Synthesized and individual study results indicate that high neuroticism and negative affect and low conscientiousness, extraversion, and positive affect were associated with increased risk of long-term dementia diagnosis. There were no consistent associations with neuropathology. This multistudy project provides robust, conceptually replicated and extended evidence that psychosocial factors are strong predictors of dementia diagnosis but not consistently associated with neuropathology at autopsy. N(+), C(-), E(-), PA(-), and NA(+) were associated with incident diagnosis. Results were consistent despite self-report versus clinical diagnosis of dementia. Psychological factors were not associated with neuropathology at autopsy. Individuals with higher conscientiousness and no diagnosis had less neuropathology. High C individuals may withstand neuropathology for longer before death.


Cellular organization and molecular differentiation model of breast cancer-associated fibroblasts.
The role of cancer-associated fibroblasts (CAFs) during tumour progression is obscured by the inherently complex, heterotypic nature of fibroblast cells and behaviours in various subtypes of malignancies. Therefore, we sought to identify distinct fibroblast subpopulations at the single-cell level. Using single-cell quantitative PCR as a powerful tool to study heterogeneity and rare cell events, in a high-throughput manner a panel of gene targets are run simultaneously on transcripts isolated from single cells obtained by fluorescence-activated cell sort. Assessment of cells with stem-like characteristics was attained by anchorage-independent, anoikis-resistant culture. Single-cell analysis of fibroblasts and their tumour-activated counterparts demonstrated molecularly distinct cell types defined by differential expression of characteristic mesenchymal and fibroblast activation markers. Identified subpopulations presented overlapping gene expression patterns indicating transitional molecular states during fibroblast differentiation. Using single-cell resolution data we generated a molecular differentiation model which enabled the classification of patient-derived fibroblasts, validating our modelling approach. Remarkably, a subset of fibroblasts displayed expression of pluripotency markers, which was enriched for in non-adherent conditions. Yet the ability to form single-cell derived spheres was generally reduced in CAFs and upon fibroblast activation through TGFβ1 ligand and cancer cell-secreted factors. Hence, our data imply the existence of putative stem/progenitor cells as a physiological feature of undifferentiated fibroblasts. Within this comprehensive study we have identified distinct and intersecting molecular profiles defining fibroblast activation states and propose that underlying cellular heterogeneity, fibroblasts are hierarchically organized. Understanding the molecular make-up of cellular organization and differentiation routes will facilitate the discovery of more specific markers for stromal subtypes and targets for anti-stromal therapies.


Lymphoepithelioma-like carcinoma of the ovary: a case report and review of the literature.
Lymphoepithelioma-like carcinoma is an undifferentiated carcinoma morphologically characterized by sheets of pleomorphic epithelioid cells with an intense lymphoid infiltrate. A 51-year-old woman presenting with low abdominal pain was found to have a right ovarian mass and enlarged pelvic, left para-aortic, and left supraclavicular lymph nodes. Based on a clinical diagnosis of right ovarian carcinoma with lymph node metastases, she received 9 cycles of chemotherapy, resulting in a reduction of her ovarian tumor, disappearance of the enlarged pelvic and para-aortic lymph nodes, and normalization of serum CA 125 level. The residual mass was removed surgically. The histology of the multinodular tumor resembled that of lymphoepithelioma of the nasopharynx and was observed in the right ovary. However, there was no viable tumor in either supraclavicular or para-aortic lymph nodes. Seven months after surgery, the patient has no evidence of disease. Lymphoepithelioma-like carcinoma appears to be rare in the female genital tract.


Recurrent abnormalities can be used for risk group stratification in pediatric AMKL: a retrospective intergroup study.
Genetic abnormalities and early treatment response are the main prognostic factors in acute myeloid leukemia (AML). Acute megakaryoblastic leukemia (AMKL) is a rare subtype of AML. Deep sequencing has identified CBFA2T3/GLIS2 and NUP98/KDM5A as recurrent aberrations, occurring in similar frequencies as RBM15/MKL1 and KMT2A-rearrangements. We studied whether these cytogenetic aberrations can be used for risk group stratification. To assess frequencies and outcome parameters of recurrent cytogenetic aberrations in AMKL, samples and clinical data of patients treated by the Associazione Italiana Ematologia Oncologia Pediatrica, Berlin-Frankfurt-Munster Study Group, Children's Oncology Group, Dutch Childhood Oncology Group, and the Saint Louis Hôpital were collected, enabling us to screen 153 newly diagnosed pediatric AMKL cases for the aforementioned aberrations and to study their clinical characteristics and outcome. CBFA2T3/GLIS2 was identified in 16% of the cases; RBM15/MKL1, in 12%; NUP98/KDM5A and KMT2A rearrangements, in 9% each; and monosomy 7, in 6%. These aberrations were mutually exclusive. RBM15/MKL1-rearranged patients were significantly younger. No significant differences in sex and white blood cell count were found. NUP98/KDM5A, CBFA2T3/GLIS2, KMT2A-rearranged lesions and monosomy 7 (NCK-7) independently predicted a poor outcome, compared with RBM15/MKL1-rearranged patients and those with AMKL not carrying these molecular lesions. NCK-7-patients (n = 61) showed a 4-year probability of overall survival of 35 ± 6% vs 70 ± 5% in the RBM15/MKL1-other groups (n = 92, P < .0001) and 4-year probability of event-free survival of 33 ± 6% vs 62 ± 5% (P = .0013), the 4-year cumulative incidence of relapse being 42 ± 7% and 19 ± 4% (P = .003), respectively. We conclude that these genetic aberrations may be used for risk group stratification of pediatric AMKL and for treatment tailoring.


Identification of atherosclerotic plaque components with intravascular ultrasound elastography in vivo: a Yucatan pig study.
Intravascular ultrasound elastography assesses the local strain of the atherosclerotic vessel wall. In the present study, the potential to identify different plaque components in vivo was investigated. Atherosclerotic external iliac and femoral arteries (n=24) of 6 Yucatan pigs were investigated. Before termination, elastographic data were acquired with a 20-MHz Visions catheter. Two frames acquired at end-diastole with a pressure differential of approximately 4 mm Hg were acquired to obtain the elastograms. Before dissection, x-ray was used to identify the arterial segments that had been investigated by ultrasound. Specimens were stained for collagen, fat, and macrophages. Plaques were classified as absent, early fibrous lesion, early fatty lesion, or advanced fibrous plaque. The average strains in the plaque-free arterial wall (0.21%) and the early (0.24%) and advanced fibrous plaques (0.22%) were similar. Higher average strain values were observed in fatty lesions (0.46%) compared with fibrous plaques (P=0.007). After correction for confounding by lipid content, no additional differences in average strain were found between plaques with and without macrophages (P=0.966). Receiver operating characteristic analysis revealed a sensitivity and a specificity of 100% and 80%, respectively, to identify fatty plaques. The presence of a high-strain spot (strain >1%) has 92% sensitivity and 92% specificity to identify macrophages. To the best of our knowledge, this is the first time that intravascular ultrasound elastography has been validated in vivo. Fatty plaques have an increased mean strain value. High-strain spots are associated with the presence of macrophages.