Polarization- and wavelength-independent SBS-based filters for high resolution optical spectrum measurement.
A polarization-independent narrow passband optical filter with a FWHM bandwidth of ~10 MHz based on stimulated Brillouin scattering (SBS) effect is proposed and experimentally demonstrated. By optimizing the parameters of a depolarizer consisting of a power-splitting Mach-Zehnder interferometer (MZI) structure, degree of polarization (DOP) of the pump source can be reduced to less than 5%. Consequently frequency response of the SBS-based filter remains almost unchanged when the state of polarization (SOP) of the input signal varies and the corresponding polarization-dependent gain (PDG) is less than 1 dB. And the experimental results also indicate that the proposed filter can realize the wavelength-independent operation over a range of ~30 nm. Furthermore, high resolution optical spectrum measurement utilizing this novel filter is investigated. For an input signal with a frequency interval of 30 MHz in arbitrary SOP, spectral details can be clearly observed and the power stability of the measured spectra can be improved from 3~5 dB to less than 0.5 dB, which benefitting from the polarization independent operation of the forementioned filter. Moreover, considering the resolution degradation of the measured spectra induced by the frequency shift in the depolarizer, a sweep speed of 5 nm/s for the pump source and a delayed fiber length of 2000 m in the MZI should be used to guarantee the desired high spectral resolution of ~10 MHz.


Development of GABAergic Inputs Is Not Altered in Early Maturation of Adult Born Dentate Granule Neurons in Fragile X Mice.
Fragile X syndrome (FXS) is the most common form of inherited mental retardation and the most common known cause of autism. Loss of fragile X mental retardation protein (FMRP) in mice (Fmr1 KO) leads to altered synaptic and circuit maturation in the hippocampus that is correlated with alterations in hippocampal-dependent behaviors. Previous studies have demonstrated that loss of FMRP increased the rate of proliferation of progenitor cells and altered their fate specification in adult Fmr1 KO mice. While these studies clearly demonstrate a role for FMRP in adult neurogenesis in the hippocampus, it is not known whether the functional synaptic maturation and integration of adult-born dentate granule cells (abDGCs) into hippocampal circuits is affected in Fmr1 KO mice. Here, we used retroviral labeling to birthdate abDGCs in Fmr1 KO mice which allowed us to perform targeted patch clamp recording to measure the development of synaptic inputs to these neurons at precise time points after differentiation. The frequency and amplitude of spontaneous GABAergic events increased over the first three weeks after differentiation; however, this normal development of GABAergic synapses was not altered in Fmr1 KO mice. Furthermore, the relatively depolarized GABA reversal potential (EGABA) in immature abDGCs was unaffected by loss of FMRP as was the development of dendritic arbor of the adult generated neurons. These studies systematically characterized the functional development of abDGCs during the first four weeks after differentiation and demonstrate that the maturation of GABAergic synaptic inputs to these neurons is not grossly affected by the loss of FMRP.


The Explanatory Effect of a Label: Its Influence on a Category Persists Even If We Forget the Label.
In this study we replicated the explanatory effect of a label which had been found by Giffin et al. (2017). In their experiments, they used vignettes describing an odd behavior of a person based on culturally specific disorders that were unfamiliar to respondents. It turned out that explanations which explain an odd behavior through a person's tendency to behave that way (circulus vitiosus) seemed more persuasive if the disorder was given a label that was used in the explanation. We replicated these results in Experiment 1, and in a follow-up Experiment 2 we examined the familiarity with category information and the evaluation of that category over time (the delay lasted one week). We realized that the label effect persists even when people make judgments based on their recollections about a category. Furthermore, according to a content analysis of the recollections, participants in the label condition remembered more information from the vignettes but tended to forget an artificial label; however, they used other words from the disorder domain instead (like "disease" or "kleptomania"). This allowed us to suggest a new interpretation of this effect: we suppose that in the Giffin et al. (2017) experiments the label did not bring any new features to a category itself, but pointed to a relevant domain instead, so the effect appeared from the activation of areas of knowledge in semantic memory and the application of relevant schema for learning a new phenomenon.


A Phase 1 study of GDC-0134, a dual leucine zipper kinase inhibitor, in ALS.
Dual leucine zipper kinase (DLK), which regulates the c-Jun N-terminal kinase pathway involved in axon degeneration and apoptosis following neuronal injury, is a potential therapeutic target in amyotrophic lateral sclerosis (ALS). This first-in-human study investigated safety, tolerability, and pharmacokinetics (PK) of oral GDC-0134, a small-molecule DLK inhibitor. Plasma neurofilament light chain (NFL) levels were explored in GDC-0134-treated ALS patients and DLK conditional knockout (cKO) mice. The study included placebo-controlled, single and multiple ascending-dose (SAD; MAD) stages, and an open-label safety expansion (OLE) with adaptive dosing for up to 48 weeks. Forty-nine patients were enrolled. GDC-0134 (up to 1200 mg daily) was well tolerated in the SAD and MAD stages, with no serious adverse events (SAEs). In the OLE, three study drug-related SAEs occurred: thrombocytopenia, dysesthesia (both Grade 3), and optic ischemic neuropathy (Grade 4); Grade ≤2 sensory neurological AEs led to dose reductions/discontinuations. GDC-0134 exposure was dose-proportional (median half-life = 84 h). Patients showed GDC-0134 exposure-dependent plasma NFL elevations; DLK cKO mice also exhibited plasma NFL compared to wild-type littermates. This trial characterized GDC-0134 safety and PK, but no adequately tolerated dose was identified. NFL elevations in GDC-0134-treated patients and DLK cKO mice raised questions about interpretation of biomarkers affected by both disease and on-target drug effects. The safety profile of GDC-0134 was considered unacceptable and led to discontinuation of further drug development for ALS. Further work is necessary to understand relationships between neuroprotective and potentially therapeutic effects of DLK knockout/inhibition and NFL changes in patients with ALS.


Development of numerical processing in children with typical and dyscalculic arithmetic skills-a longitudinal study.
Numerical processing has been demonstrated to be closely associated with arithmetic skills, however, our knowledge on the development of the relevant cognitive mechanisms is limited. The present longitudinal study investigated the developmental trajectories of numerical processing in 42 children with age-adequate arithmetic development and 41 children with dyscalculia over a 2-year period from beginning of Grade 2, when children were 7; 6 years old, to beginning of Grade 4. A battery of numerical processing tasks (dot enumeration, non-symbolic and symbolic comparison of one- and two-digit numbers, physical comparison, number line estimation) was given five times during the study (beginning and middle of each school year). Efficiency of numerical processing was a very good indicator of development in numerical processing while within-task effects remained largely constant and showed low long-term stability before middle of Grade 3. Children with dyscalculia showed less efficient numerical processing reflected in specifically prolonged response times. Importantly, they showed consistently larger slopes for dot enumeration in the subitizing range, an untypically large compatibility effect when processing two-digit numbers, and they were consistently less accurate in placing numbers on a number line. Thus, we were able to identify parameters that can be used in future research to characterize numerical processing in typical and dyscalculic development. These parameters can also be helpful for identification of children who struggle in their numerical development.


Regulation of Ca2+-dependent cyclic AMP accumulation and Ca2+ metabolism in intact pituitary tumor cells by modulators of prolactin production.
The responsiveness of anterior pituitary tumor (GH3) cells to promoters of prolactin secretion and/or synthesis and cyclic AMP accumulation was studied as a function of cellular Ca2+ content. GH3 cells exposed to media containing 1 mM ethylene glycol bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid were reduced 7-fold in Ca2+ content without loss of viability. Preparations of Ca2+-depleted cells were largely unchanged in cyclic AMP content when challenged by thyrotropin-releasing hormone (TRH), whereas cells which were subsequently restored at optimal Ca2+ (0.5 mM) responded to the hormone with 2- to 3-fold increases in cyclic AMP content. The decreased responsiveness of Ca2+-depleted cells to TRH was not influenced by phosphodiesterase inhibitors, incubation time, or hormone concentration. TRH-dependent cyclic AMP accumulation was markedly potentiated by forskolin in Ca2+-restored, but not in Ca2+-depleted, cell preparations. Forskolin extended the time period during which cyclic AMP accumulated in response to TRH without altering the TRH concentration dependency of the cells. Varying increases in GH3 cyclic AMP content occurred in response to other hormones or agents which enhance prolactin secretion and/or synthesis. In Ca2+-restored cells, cyclic AMP content was increased 2-fold by prostaglandin E1 (PGE1) and epidermal growth factor (EGF), 10- to 15-fold by vasoactive intestinal polypeptide (VIP) and 6-fold by phorbol myristate acetate (PMA); the capacity of Ca2+-depleted cells, however, to accumulate cyclic AMP in response to PGE1, EGF, and VIP was greatly reduced. Accumulation of cyclic AMP following short-term incubations with cholera toxin similarly was dependent on Ca2+. Exposure of GH3 cells preloaded with 45Ca to TRH, PGE1, EGF, PMA, or VIP resulted in losses of cell-associated 45Ca. Pretreatment with these agents resulted in a decreased capacity of the cells to accumulate 45Ca from the extracellular medium. The results of this study support the hypothesis that various putative humoral regulators of prolactin secretion and/or synthesis act on GH3 cells to alter intracellular Ca2+ metabolism which in turn results in an increased cyclic AMP content through stimulation of adenylate cyclase activity.


Age-related changes in pulmonary muscarinic receptor binding properties.
The goal of this study was to elucidate mechanisms responsible for age-related reductions in responsiveness to cholinergic muscarinic stimulation in guinea pigs, by examining the binding properties of muscarinic receptors and their coupling to guanine nucleotide regulatory proteins as a function of animal age. In addition, the binding constants of three selective muscarinic receptor antagonists pirenzepine, [11-((2-[(diethylamino)methyl]-1-piperidinyl)-acetyl)-5, 11-dihydro-6H-pyrido(2,3)(1,4)benzodiazepine-6-on], and 4-diphenylacetoxy-N-methylpiperidine methobromide were examined. We found that there were no changes in either the receptor density or the affinity of the muscarinic receptor with age. There was a significant reduction in the affinity constant for the high-affinity agonist binding site in the old tissues (7.63 +/- 0.08) compared with the young tissues (8.31 +/- 0.10). Guanine nucleotides lowered agonist affinity for the receptor in young lungs, however, they had no effect on agonist binding in old tissues. Antagonist competition binding curves in young tissues revealed that 73% of the receptors are of the M2 type, with 27% being of the M3 subtype. In contrast, antagonist competition binding curves in the old tissues revealed that 37% of the receptors were of the M2 subtype, 30% were M3, and 33% were of the M1 subtype. Our studies provide evidence that the loss of sensitivity to cholinergic muscarinic stimulation in the senescent lung may be due to changes in both muscarinic receptor subtypes and receptor coupling to G proteins.


O-GlcNAcylation of myosin phosphatase targeting subunit 1 (MYPT1) dictates timely disjunction of centrosomes.
The role of O-linked N-acetylglucosamine (O-GlcNAc) modification in the cell cycle has been enigmatic. Previously, both O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA) disruptions have been shown to derail the mitotic centrosome numbers, suggesting that mitotic O-GlcNAc oscillation needs to be in concert with mitotic progression to account for centrosome integrity. Here, using both chemical approaches and biological assays with HeLa cells, we attempted to address the underlying molecular mechanism and observed that incubation of the cells with the OGA inhibitor Thiamet-G strikingly elevates centrosomal distances, suggestive of premature centrosome disjunction. These aberrations could be overcome by inhibiting Polo-like kinase 1 (PLK1), a mitotic master kinase. PLK1 inactivation is modulated by the myosin phosphatase targeting subunit 1 (MYPT1)-protein phosphatase 1cβ (PP1cβ) complex. Interestingly, MYPT1 has been shown to be abundantly O-GlcNAcylated, and the modified residues have been detected in a recent O-GlcNAc-profiling screen utilizing chemoenzymatic labeling and bioorthogonal conjugation. We demonstrate here that MYPT1 is O-GlcNAcylated at Thr-577, Ser-585, Ser-589, and Ser-601, which antagonizes CDK1-dependent phosphorylation at Ser-473 and attenuates the association between MYPT1 and PLK1, thereby promoting PLK1 activity. We conclude that under high O-GlcNAc levels, PLK1 is untimely activated, conducive to inopportune centrosome separation and disruption of the cell cycle. We propose that too much O-GlcNAc is equally deleterious as too little O-GlcNAc, and a fine balance between the OGT/OGA duo is indispensable for successful mitotic divisions.


Exocytotic "constipation" is a mechanism of tubulin/lysosomal interaction in colchicine myopathy.
Colchicine, a known microtubule disrupting agent, produces a human myopathy, characterized by accumulation of lysosomes. We have created a reliable animal model of colchicine myopathy that replicates the subacute myopathy seen in humans, reproducing the chronic proximal weakness and vacuolar changes in nonnecrotic myofibers. If a microtubule network plays a role in lysosomal function in muscle, disturbance of it could alter degradation of intrinsic membrane receptors, presumably at some intracellular processing site or at exocytosis. Thus, we examined, as a possible cellular pathogenesis of colchicine myopathy, how the muscle cytoskeleton affects the degradation of membrane proteins, which are processed through the endosomal/lysosomal pathway. We used the acetylcholine receptor as a model membrane component in cultured myotubes allowed to preincubate with colchicine. We tested at which step colchicine interferes with receptor trafficking by accounting for internalization, delivery to lysosomes, hydrolysis, or exocytotic release of debris. We report that colchicine significantly decreases the exocytosis of AChRs but does not affect receptor internalization, lysosomal hydrolysis, or the number of surface membrane receptors. Further, our immunofluorescence observations revealed a morphologic tubulin network in rat skeletal muscle that is more densely distributed in white (mitochondria-poor) muscle fibers than in red (mitochondria-rich) fibers but is present in both. Ultrastructurally, immunogold labeling localized tubulin in the intermyofibrillar region in a long and linear fashion, unassociated with myofibers or mitochondria. Taken together, our findings suggest the following: (1) Microtubules likely play a functional role in the pathway of lysosomal degradation in normal adult skeletal muscle; (2) The observed decrease in overall apparent degradation of membrane receptors by colchicine must be due primarily to inhibition of exocytosis. These data indicate that lysosomal "constipation" underlies colchicine myopathy. (3) An animal model faithful to the human disorder will allow further pathogenetic studies.


Laboratory screening of coating libraries for algal adhesion.
Coatings libraries achieved through a combinatorial chemistry approach, which may generate tens to hundreds of formulations, can be deposited in an array of 12 patches, each approximately 9 cm(2), on 10 x 20 cm primed aluminum panels. However, existing methods to quantify algal biomass on coatings are unsuitable for this type of array format. This paper describes an algorithm modelled on a probability distribution that quantifies the area of surface covered by a green alga from digital images. The method allows coatings with potential fouling-release properties to be down-selected for further evaluation. The use of the algorithm is illustrated by a set of eight siloxane-polyurethane coatings made using organofunctional poly(dimethylsiloxane) (PDMS) and poly(epsilon-caprolactone)-PDMS-poly(epsilon-caprolactone) (PCL-PDMS-PCL) triblock copolymers along with four PDMS standards which were deposited on one panel. Six replicate panels were seeded with Ulva zoospores which grew into sporelings (small plants) that completely covered the surface. The ease of removal of the Ulva sporeling biofilms was determined by automated water jetting at six different impact pressures. The coverage of the biofilm on the twelve individual formulations after jet washing was quantified from the green colour of digital images. The data are discussed in relation to the composition of the coatings.


Predicting outcome in ex-premature infants supported with extracorporeal membrane oxygenation for acute hypoxic respiratory failure.
To identify predictors of outcome in ex-premature infants supported with extracorporeal membrane oxygenation (ECMO) for acute hypoxic respiratory failure. Retrospective review of ex-premature infants with acquired acute hypoxic respiratory failure requiring ECMO support in the United Kingdom from 1992 to 2001. Review of follow up questionnaires completed by general practitioners and local paediatricians. Sixty four ex-premature infants (5-10 each year) received ECMO support, despite increased use of advanced conventional treatments over the decade. The most common infective agent was respiratory syncytial virus (85% of cases). Median birth gestation was 29 weeks and median corrected age at the time of ECMO support was 42 weeks. Median ECMO support duration was relatively long, at 229 hours. Survival to hospital discharge and to 6 months was 80%, remaining similar throughout the period of review. At follow up, 60% had long term neurodisability and 79% had chronic pulmonary problems. Of pre-ECMO factors, baseline oxygen dependence, younger age, and inpatient status were associated with non-survival (p < or = 0.05). Of ECMO related factors, patient complications were independently associated with adverse neurodevelopmental outcome and death (p < 0.01). Survival rates for ex-premature infants after ECMO support are favourable, but patients suffer a high burden of morbidity during intensive care and over the long term. At the time of ECMO referral, baseline oxygen dependence is the most important predictor of death, but no combination of the factors considered was associated with a mortality that would preclude ECMO support.


A noncoding RNA is a potential marker of cell fate during mammary gland development.
PINC is a large, alternatively spliced, developmentally regulated, noncoding RNA expressed in the regressed terminal ductal lobular unit-like structures of the parous mammary gland. Previous studies have shown that this population of cells possesses not only progenitor-like qualities (the ability to proliferate and repopulate a mammary gland) and the ability to survive developmentally programmed cell death but also the inhibition of carcinogen-induced proliferation. Here we report that PINC expression is temporally and spatially regulated in response to developmental stimuli in vivo and that PINC RNA is localized to distinct foci in either the nucleus or the cytoplasm in a cell-cycle-specific manner. Loss-of-function experiments suggest that PINC performs dual roles in cell survival and regulation of cell-cycle progression, suggesting that PINC may contribute to the developmentally mediated changes previously observed in the terminal ductal lobular unit-like structures of the parous gland. This is one of the first reports describing the functional properties of a large, developmentally regulated, mammalian, noncoding RNA.


Human immunodeficiency virus (HIV) and JC virus in acquired immune deficiency syndrome (AIDS) patients with progressive multifocal leukoencephalopathy.
Of the 93 acquired immune deficiency syndrome (AIDS) patients autopsied between 1983 and 1986, 27 had evidence of viral encephalitis of which 3 had progressive multifocal leukoencephalopathy (PML), confirmed by electron microscopy. Using in situ hybridization with biotinylated JC virus probes, paraffin sections from the brains of these 27 patients were examined. JC virus was found only in those patients with histologically proven PML, while no evidence of JC virus was detected in the brains of the other 24 AIDS patients despite the presence of white matter pathology. Brain biopsies of the PML patients demonstrated human immunodeficiency virus (HIV)-infected macrophages infiltrating regions of demyelination. When the patients died (2 to 6 months after diagnosis of PML), many more macrophages contained HIV antigens and some had fused to form multinucleated giant cells. These findings suggest that in AIDS patients, papovaviruses not only cause damage by directly infecting oligodendroglia but causes additional damage by eliciting the ingress of macrophages latently infected with HIV. As was seen with other infections (e.g., cytomegalovirus) of the CNS this might be a general mechanism of HIV entry into the brain.


Transcriptomic Changes Highly Similar to Alzheimer's Disease Are Observed in a Subpopulation of Individuals During Normal Brain Aging.
Aging is a major risk factor for late-onset Alzheimer's disease (LOAD). How aging contributes to the development of LOAD remains elusive. In this study, we examined multiple large-scale transcriptomic datasets from both normal aging and LOAD brains to understand the molecular interconnection between aging and LOAD. We found that shared gene expression changes between aging and LOAD are mostly seen in the hippocampal and several cortical regions. In the hippocampus, the expression of phosphoprotein, alternative splicing and cytoskeleton genes are commonly changed in both aging and AD, while synapse, ion transport, and synaptic vesicle genes are commonly down-regulated. Aging-specific changes are associated with acetylation and methylation, while LOAD-specific changes are more related to glycoprotein (both up- and down-regulations), inflammatory response (up-regulation), myelin sheath and lipoprotein (down-regulation). We also found that normal aging brain transcriptomes from relatively young donors (45-70 years old) clustered into several subgroups and some subgroups showed gene expression changes highly similar to those seen in LOAD brains. Using brain transcriptomic datasets from another cohort of older individuals (>70 years), we found that samples from cognitively normal older individuals clustered with the "healthy aging" subgroup while AD samples mainly clustered with the "AD similar" subgroups. This may imply that individuals in the healthy aging subgroup will likely remain cognitively normal when they become older and vice versa. In summary, our results suggest that on the transcriptome level, aging and LOAD have strong interconnections in some brain regions in a subpopulation of cognitively normal aging individuals. This supports the theory that the initiation of LOAD occurs decades earlier than the manifestation of clinical phenotype and it may be essential to closely study the "normal brain aging" to identify the very early molecular events that may lead to LOAD development.


The Use of Cannabidiol in Metabolic Syndrome-An Opportunity to Improve the Patient's Health or Much Ado about Nothing?
Cannabis-derived therapies are gaining popularity in the medical world. More and more perfect forms of cannabinoids are sought, which could be used in the treatment of many common diseases, including metabolic syndrome, whose occurrence is also increasing. The purpose of this review was to investigate the usefulness of cannabinoids, mainly cannabidiol (CBD), in individuals with obesity, impaired glucose and lipid metabolism, high blood pressure, and non-alcoholic fatty liver disease (NAFLD). We summarised the most recent research on the broad topic of cannabis-derived influence on metabolic syndrome components. Since there is a lot of work on the effects of Δ9-THC (Δ9-tetrahydrocannabinol) on metabolism and far less on cannabidiol, we felt it needed to be sorted out and summarised in this review. The research results on the use of cannabidiol in obesity are contraindicatory. When it comes to glucose homeostasis, it appears that CBD maintains it, sensitises adipose tissue to insulin, and reduces fasting glucose levels, so it seems to be a potential target in this kind of metabolic disorder, but some research results are inconclusive. CBD shows some promising results in the treatment of various lipid disorders. Some studies have proven its positive effect by decreasing LDL and increasing HDL as well. Despite their probable efficacy, CBD and its derivatives will likely remain an adjunctive treatment rather than a mainstay of therapy. Studies have also shown that CBD in patients with hypertension has positive effects, even though the hypotensive properties of cannabidiol are small. However, CBD can be used to prevent blood pressure surges, stabilise them, and have a protective effect on blood vessels. Results from preclinical studies have shown that the effect of cannabidiol on NAFLD may be potentially beneficial in the treatment of the metabolic syndrome and its components. Nevertheless, there is limited data on CBD and NAFLD in human studies. Because of the numerous confounding factors, the conclusions are unclear, and more research in this field is required.


Age-related reduction in daytime sleep propensity and nocturnal slow wave sleep.
To investigate whether age-related and experimental reductions in SWS and sleep continuity are associated with increased daytime sleep propensity. Assessment of daytime sleep propensity under baseline conditions and following experimental disruption of SWS. Healthy young (20-30 y, n = 44), middle-aged (40-55 y, n = 35) and older (66-83 y, n = 31) men and women, completed a 2-way parallel group study. After an 8-h baseline sleep episode, subjects were randomized to 2 nights with selective SWS disruption by acoustic stimuli, or without disruption, followed by 1 recovery night. Objective and subjective sleep propensity were assessed using the Multiple Sleep Latency Test (MSLT) and the Karolinska Sleepiness Scale (KSS). During baseline sleep, SWS decreased (P < 0.001) and the number of awakenings increased (P < 0.001) across the 3 age groups. During the baseline day, MSLT values increased across the three age groups (P < 0.0001) with mean values of 8.7 min (SD: 4.5), 11.7 (5.1) and 14.2 (4.1) in the young, middle-aged, and older adults, respectively. KSS values were 3.7 (1.0), 3.2 (0.9), and 3.4 (0.6) (age-group: P = 0.031). Two nights of SWS disruption led to a reduction in MSLT and increase in KSS in all 3 age groups (SWS disruption vs. control: P < 0.05 in all cases). Healthy aging is associated with a reduction in daytime sleep propensity, sleep continuity, and SWS. In contrast, experimental disruption of SWS leads to an increase in daytime sleep propensity. The age-related decline in SWS and reduction in daytime sleep propensity may reflect a lessening in homeostatic sleep requirement. Healthy older adults without sleep disorders can expect to be less sleepy during the daytime than young adults.


[Ascending and descending efferent pathways of the midbrain reticular formation of the cat (radioautographic study)].
By means of the anterograde axoplasmic transport technique for a mixture of labelled aminoacids (3H-leucine and 3H-proline), ascending and descending systems of the reticular formation fibers in the cat mesencephalon have been studied. Projections from the mesencephalon reticular formation (MRF) ascend to the subthalamus, lateral, dorsal and periventricular hypothalamus, to the periventricular nuclei of the midline and to the intralaminar nuclei of the thalamus. The descending pathways project to the grey substance surrounding the aqueduct of cerebrum, locus coeruleus, parabrachial region and reticular formation of the pons and medulla oblongata. The projections to the reticular nucleus of the thalamus, ventral nucleus of the external geniculate body and superior colliculi arise from the dorsal half of the MRF, and projections to the striatum, lateral reticular nucleus of the medulla oblongata--from its ventral half. Most of the structures are reciprocally connected with the MRF.


Nitric oxide-mediated tumoricidal activity of murine microglial cells.
Experimental metastases in the brain of mice are infiltrated by microglia, and parabiosis experiments of green fluorescent protein (GFP(+)) and GFP(-) mice revealed that these microglia are derived from circulating monocytes (GFP(+), F4/80(+), and CD68(+)). These findings raised the question as to whether microglia (specialized macrophages) possess tumoricidal activity. C8-B4 murine microglia cells were incubated in vitro in medium (control) or in medium containing both lipopolysaccharide and interferon-γ. Control microglia were not tumoricidal against a number of murine and human tumor cells, whereas lipopolysaccharide/interferon-γ-activated microglia lysed murine and human tumor cells by release of nitric oxide. Parallel experiments with murine peritoneal macrophages produced identical results. Neither activated microglia nor activated macrophages lysed nontumorigenic murine or human cells. Collectively, these data demonstrate that brain metastasis-associated microglia are derived from circulating mononuclear cells and exhibit selective and specific tumoricidal activity.


JIGSAW: Joint Inhomogeneity estimation via Global Segment Assembly for Water-fat separation.
Water-fat separation in magnetic resonance imaging (MRI) is of great clinical importance, and the key to uniform water-fat separation lies in field map estimation. This work deals with three-point field map estimation, in which water and fat are modelled as two single-peak spectral lines, and field inhomogeneities shift the spectrum by an unknown amount. Due to the simplified spectrum modelling, there exists inherent ambiguity in forming field maps from multiple locally feasible field map values at each pixel. To resolve such ambiguity, spatial smoothness of field maps has been incorporated as a constraint of an optimization problem. However, there are two issues: the optimization problem is computationally intractable and even when it is solved exactly, it does not always separate water and fat images. Hence, robust field map estimation remains challenging in many clinically important imaging scenarios. This paper proposes a novel field map estimation technique called JIGSAW. It extends a loopy belief propagation (BP) algorithm to obtain an approximate solution to the optimization problem. The solution produces locally smooth segments and avoids error propagation associated with greedy methods. The locally smooth segments are then assembled into a globally consistent field map by exploiting the periodicity of the feasible field map values. In vivo results demonstrate that JIGSAW outperforms existing techniques and produces correct water-fat separation in challenging imaging scenarios.


Life course health and socioeconomic profiles of Americans aging with disability.
While cross-sectional data have been invaluable for describing national trends in disability over time, we know comparatively little, at a population level, about the long term experiences of persons living with a disability over the adult life course. In this paper we use nationally representative data from the U.S. Panel Study of Income Dynamics to describe the life course health and socioeconomic profiles of Americans who are aging with a work-limiting disability. Data come from a cohort of adults age 20-34 in 1979, who were followed annually for 30 years to 2009 (to age 50-64). Disability is defined according to repeated measures of work limitations in prime working years. Using growth curve models we describe the life course profile of these Americans aging with work-limiting disability with respect to health, educational attainment, family formation, economic fortunes, and occupational history, and compare them to those who have not experienced repeated work-limiting disability in adulthood. Persons with persistent work-limiting disability prior to age 50 experienced lower rates of employment and lower household incomes over adulthood in comparison to those aging without a work-limiting disability. Additionally, in the mid-life period, adults with work-limiting disabilities were more likely to practice poor health behaviors (reflected by smoking, obesity, and sedentary activity) and to experience restrictions in functional independence than those without a work-limiting disability. Our findings suggest that there are critical risk factors that make adults aging with work-limiting disability more vulnerable with respect to their health and independence as they age, suggesting avenues for intervention that may equalize the health and independence of Americans aging with and aging into disability in the years ahead.


Erythromycin resistance in italian isolates of Streptococcus pyogenes and correlations with pulsed-field gel electrophoresis analysis.
Erythromycin resistance among Streptococcus pyogenes strains has been reported in Italy at high rates during the last few years. A total of 152 erythromycin-resistant isolates of this species from southern Italian regions were characterized for the macrolide-resistance phenotype and screened by PCR for the corresponding genetic determinant. A close correlation was found between these phenotypic/genotypic data concerning macrolide resistance and results of Sma I macrorestriction fragment patterns (PFGE) analysis. In fact, the vast majority of the isolates assigned to individual PFGE classes mostly belonged to a single phenotype of macrolide resistance. All untypeable isolates belonged to the M phenotype. Twenty-two distinct PFGE types were recognized, of which 11 were recorded in only one isolate (one-strain type); about 50% of typeable isolates fell into five type clusters and 70% in seven. The increased erythromycin resistance among Italian isolates of S. pyogenes does not appear to be due to the spread of a single clone, but results indicate that the majority of group A streptococci examined are probably spread from a limited number of clones.


Surface modification of electrospun fibre meshes by oxygen plasma for bone regeneration.
Plasma treatment is a method to modify the physicochemical properties of biomaterials, which consequently may affect interactions with cells. Based on the rationale that physical cues on the surface of culture substrates and implants, such as surface roughness, have proven to alter cell behaviour, we used electrospinning to fabricate fibrous three-dimensional scaffolds made of a poly (ethylene oxide terephthalate)/poly (butylene terephthalate) copolymer to mimic the physical microenvironment of extracellular matrix and applied radio-frequency oxygen plasma treatment to create nanoscale roughness. Scanning electron microscopy (SEM) analysis revealed a fibre diameter of 5.49 ± 0.96 µm for as-spun meshes. Atomic force microscopy (AFM) measurements determined an exponential increase of surface roughness with plasma treatment time. An increase in hydrophilicity after plasma treatment was observed, which was associated with higher oxygen content in plasma treated scaffolds compared to untreated ones. A more pronounced adsorption of bovine serum albumin occurred on scaffolds treated with plasma for 15 and 30 min compared to untreated fibres. Clinically relevant human mesenchymal stromal cells (hMSCs) were cultured on untreated, 15 and 30 min treated scaffolds. SEM analysis confirmed cell attachment and a pronounced spindle-like morphology on all scaffolds. No significant differences were observed between different scaffolds regarding the amount of DNA, metabolic activity and alkaline phosphatase (ALP) activity after 7 days of culture. The amount of ALP positive cells increased between 7 and 21 days of culture on both untreated and 30 min treated meshes. In addition, ALP staining of cells on plasma treated meshes appeared more pronounced than on untreated meshes after 21 days of culture. Quantitative polymerase chain reaction showed significant upregulation of bone sialoprotein and osteonectin expression on oxygen plasma treated fibres compared to untreated fibres in basic culture medium after 7 days of culture, while no differences were observed in the expression of other osteogenic markers. At 21 days, no osteocalcin protein could be detected by ELISA at any of the substrates. In conclusion, this study shows that oxygen plasma treatment can successfully be applied to modify the nanoscale surface properties of polymeric electrospun fibre meshes, which in turn may positively affect osteogenic differentiation of hMSCs.


Novel genotypes of H9N2 influenza A viruses isolated from poultry in Pakistan containing NS genes similar to highly pathogenic H7N3 and H5N1 viruses.
The impact of avian influenza caused by H9N2 viruses in Pakistan is now significantly more severe than in previous years. Since all gene segments contribute towards the virulence of avian influenza virus, it was imperative to investigate the molecular features and genetic relationships of H9N2 viruses prevalent in this region. Analysis of the gene sequences of all eight RNA segments from 12 viruses isolated between 2005 and 2008 was undertaken. The hemagglutinin (HA) sequences of all isolates were closely related to H9N2 viruses isolated from Iran between 2004 and 2007 and contained leucine instead of glutamine at position 226 in the receptor binding pocket, a recognised marker for the recognition of sialic acids linked alpha2-6 to galactose. The neuraminidase (NA) of two isolates contained a unique five residue deletion in the stalk (from residues 80 to 84), a possible indication of greater adaptation of these viruses to the chicken host. The HA, NA, nucleoprotein (NP), and matrix (M) genes showed close identity with H9N2 viruses isolated during 1999 in Pakistan and clustered in the A/Quail/Hong Kong/G1/97 virus lineage. In contrast, the polymerase genes clustered with H9N2 viruses from India, Iran and Dubai. The NS gene segment showed greater genetic diversity and shared a high level of similarity with NS genes from either H5 or H7 subtypes rather than with established H9N2 Eurasian lineages. These results indicate that during recent years the H9N2 viruses have undergone extensive genetic reassortment which has led to the generation of H9N2 viruses of novel genotypes in the Indian sub-continent. The novel genotypes of H9N2 viruses may play a role in the increased problems observed by H9N2 to poultry and reinforce the continued need to monitor H9N2 infections for their zoonotic potential.


Conflicting evidence about long-distance animal navigation.
Because of conflicting evidence about several fundamental issues, long-distance animal navigation has yet to be satisfactorily explained. Among the unsolved problems are the nature of genetic spatial control of migration and the relationships between celestial and magnetic compass mechanisms and between different map-related cues in orientation and homing, respectively. In addition, navigation is expected to differ between animal groups depending on sensory capabilities and ecological conditions. Evaluations based on modern long-term tracking techniques of the geometry of migration routes and individual migration history, combined with behavioral experiments and exploration of the sensory and genetic mechanisms, will be crucial for understanding the spatial principles that guide animals on their global journeys.


Evaluation of Outcomes of Peritoneal Dialysis Patients in the Post-COVID-19 Period: A National Multicenter Case-Control Study from Turkey.
There are not enough data on the post-CO-VID-19 period for peritoneal dialysis (PD) patients affected from COVID-19. We aimed to compare the clinical and laboratory data of PD patients after COVID-19 with a control PD group. This study, supported by the Turkish Society of Nephrology, is a national, multicenter retrospective case-control study involving adult PD patients with confirmed COVID-19, using data collected from April 21, 2021, to June 11, 2021. A control PD group was also formed from each PD unit, from patients with similar characteristics but without COVID-19. Patients in the active period of COVID-19 were not included. Data at the end of the first month and within the first 90 days, as well as other outcomes, including mortality, were investigated. A total of 223 patients (COVID-19 group: 113, control group: 110) from 27 centers were included. The duration of PD in both groups was similar (median [IQR]: 3.0 [1.88-6.0] years and 3.0 [2.0-5.6]), but the patient age in the COVID-19 group was lower than that in the control group (50 [IQR: 40-57] years and 56 [IQR: 46-64] years, p < 0.001). PD characteristics and baseline laboratory data were similar in both groups, except serum albumin and hemoglobin levels on day 28, which were significantly lower in the COVID-19 group. In the COVID-19 group, respiratory symptoms, rehospitalization, lower respiratory tract infection, change in PD modality, UF failure, and hypervolemia were significantly higher on the 28th day. There was no significant difference in laboratory parameters at day 90. Only 1 (0.9%) patient in the COVID-19 group died within 90 days. There was no death in the control group. Respiratory symptoms, malnutrition, and hypervolemia were significantly higher at day 90 in the COVID-19 group. Mortality in the first 90 days after COVID-19 in PD patients with COVID-19 was not different from the control PD group. However, some patients continued to experience significant problems, especially respiratory system symptoms, malnutrition, and hypervolemia.


Combined effects of prone positioning and airway pressure release ventilation on gas exchange in patients with acute lung injury.
Prone positioning has been shown to improve oxygenation in 60-70% of patients with acute lung injury (ALI) or acute respiratory distress syndrome (ARDS). Another way to improve matching of ventilation to perfusion is the use of partial ventilatory support. Preserving spontaneous breathing during mechanical ventilation has been shown to improve oxygenation in comparison with controlled mechanical ventilation. However, no randomized studies are available exploring the effects of preserved spontaneous breathing on gas exchange in combination with prone positioning. Our aim was to determine whether the response of oxygenation to the prone position differs between pressure-controlled synchronized intermittent mandatory ventilation with pressure support (SIMV-PC/PS) and airway pressure release ventilation with unsupported spontaneous breathing (APRV). We undertook a prospective randomized intervention study in a medical-surgical adult intensive care unit of a university hospital. Of 45, 33 ALI patients (acute lung injury) within 72 h after initiation of mechanical ventilation, and in whom the prone position was applied according to a predefined strategy, were included in the study. After initial stabilization the patients were randomized to receive either SIMV-PC/PS or APRV with predefined general ventilatory goals (PEEP, tidal volume, inspiratory pressure and PaCO2-level). The protocol for prone positioning was the same for both treatment arms. Prone positioning was triggered by finding a PaO2/FiO2-ratio below 200 mmHg evaluated twice per day. The duration of each prone episode was 6 h. The first two episodes of prone positioning were analyzed. Gas exchange was measured before and at the end of prone positioning. Of the 45 patients enrolled, 33 were turned prone once and 28 twice. No significant differences were detected in baseline characteristics. Changes in oxygenation were analyzed in response to the first and second prone episodes 5 h and 24 h after randomization and initiation of SIMV-PC/PS or APRV respectively. Before the first prone episode the PaO2/FiO2-ratio was significantly better (P = 0.02) in the APRV-group (median; interquartile range) (162; 108-192 mmHg) than in the SIMV-PC/PS-group (123; 78-154 mmHg). The response in oxygenation to the first prone episode was similar in both groups: PaO2/FiO2-ratio increased 39.5; 17.75-77.5 mmHg in the SIMV-PC/PS-group and 75.0; 9.0-125.0 mmHg in the APRV-group (P = 0.49). Before the second prone episode, the PaO2/FiO2-ratio was comparable (SIMV-PC/PS 130.5; 61.0-161.0 mmHg vs. APRV 134; 98.3-175.0 mmHg). Improvement in oxygenation was significantly (P = 0.02) greater in the APRV group (82; 37.0-141.0 mmHg) than in the SIMV-PC/PS group (50; 24.0-68.8 mmHg) during the second prone episode. General ventilatory and hemodynamic variables and use of sedatives were similar in both groups during the study. APRV during prone positioning is feasible in the treatment of ALI patients. APRV after 24 h appears to enhance improvement in oxygenation in response to prone positioning.


Burden of cerebral small vessel disease and changes of diastolic blood pressure affect clinical outcome after acute ischemic stroke.
Elevated and low blood pressure (BP) may lead to poor functional outcome after ischemic stroke, which is conflicting. Hence, there must be another factor-such as cerebral small vessel disease (cSVD) -interacting with BP and thus, affecting outcome. Here, we investigate the relationship between BP and cSVD regarding outcome after stroke. Data of 423/503 stroke patients were prospectively analyzed. Diastolic (DBP) and systolic BP (SBP) were collected on hospital admission (BPad) and over the first 72 h (BP72h). cSVD-burden was determined on MR-scans. Good functional outcome was defined as a modified Rankin Scale score ≤ 2 at hospital discharge and 12 months thereafter. cSVD was a predictor of poor outcome (OR 2.8; p < 0.001). SBPad, DBPad and SBP72h were not significantly associated with outcome at any time. A significant relationship was found between DBP72h, (p < 0.01), cSVD (p = 0.013) and outcome at discharge. At 12 months, we found a relationship between outcome and DBP72h (p = 0.018) and a statistical tendency regarding cSVD (p = 0.08). Changes in DBP72h were significantly related with outcome. There was a U-shaped relationship between DBP72h and outcome at discharge. Our results suggest an individualized stroke care by either lowering or elevating DBP depending on cSVD-burden in order to influence functional outcome.


Chemical heterogeneity of structural proteins of cancers with a common low electron spin resonance signal.
Electron spin resonance measurements are presented for the separated structural and soluble components of a variety of both normal and cancerous tissues. The signal at g = 2 from the structural part of the normal tissues was at least an order of magnitude stronger than the corresponding signal from the structural part of the cancers. In contrast, no significant difference in radical concentration was found between the soluble fractions of normal and cancerous tissues. Despite their common low signal at g = 2, the structural cancer fractions displayed a remarkable chemical heterogeneity. An important finding was that even cancers of the same histology reacted differently from one another when treated with a variety of chemical probes.


Outcomes of patients with acute coronary syndrome and previous coronary artery bypass grafting (from the Pravastatin or Atorvastatin Evaluation and Infection Therapy [PROVE IT-TIMI 22] and the Aggrastat to Zocor [A to Z] trials).
We examined the effects of intensive statin therapy in patients with acute coronary syndromes (ACSs) and previous coronary artery bypass graft surgery (CABG) participating in the Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis In Myocardial Infarction 22 (PROVE-IT TIMI 22) and the Aggrastat to Zocor (A to Z) trials. Of the 8,655 patients enrolled in PROVE IT-TIMI 22 or A to Z, 640 (7.4%) had undergone CABG before enrollment. After a median follow-up of 2 years, compared with patients without previous CABG, those with previous CABG had a higher risk of cardiovascular death (6.2% vs 2.8%), myocardial infarction (14.2% vs 6.6%), and readmission for ACS (7.9% vs 4.4%, p <0.001 for all comparisons) but a lower rate of repeat coronary revascularization (22.7% vs 26.9%, p = 0.01). Compared with moderate statin therapy, intensive statin therapy appeared to decrease the composite of cardiovascular death, myocardial infarction, stoke, and readmission for an ACS (A to Z primary end point) to a similar extent in patients with (26.1% vs 21.6%, hazard ratio 0.84, p = 0.27) and without (13.9% vs 12.0%, hazard ratio 0.86, p = 0.016) previous CABG, although the decrease was not statistically significant in the previous CABG group, likely due to the small number of patients with previous CABG. In conclusion, compared with patients with ACS without previous CABG, those with previous CABG have a higher risk for adverse cardiac events and may derive similar benefit from intensive statin therapy.


Dynamic Effects of Two-Time Delays on a Model for Tumor Growth.
In order to understand the dynamic mechanisms of tumor growth and make a contribution to develop anti-cancer treatment strategies, a mathematical model for tumor growth with two-time delays is proposed in this article. First, the relationships among host cells, tumor cells and effector cells, and the biological meaning of two-time delays are explained. Moreover, the system stability is discussed by analyzing the characteristic equation of the model. In addition, the existence and properties of oscillatory dynamic are also researched by using normative theory and central manifold method. Finally, the numerical simulations are performed to further illustrate and support the theoretical results. Both two-time delays in the model can affect the dynamics of tumor growth. Meanwhile, the system can experience a Hopf bifurcation when the delay crosses a series of critical values. Further, a clear formula is deduced to determine the Hopf bifurcation and the direction of stability of the periodic solution. Finally, these results are verified by using numerical simulation. The results demonstrated that the time from identifying tumor cells to making the appropriate response for the immune system and the time needed for competition between host cells and tumor cells for natural resources and living space is significant for tumor growth. These findings in this paper may help us better understand the behaviors of tumors and develop better anti-cancer treatment strategies.


Fisheries-induced neutral and adaptive evolution in exploited fish populations and consequences for their adaptive potential.
Fishing may induce neutral and adaptive evolution affecting life-history traits, and molecular evidence has shown that neutral genetic diversity has declined in some exploited populations. Here, we theoretically study the interplay between neutral and adaptive evolution caused by fishing. An individual-based eco-genetic model is devised that includes neutral and functional loci in a realistic ecological setting. In line with theoretical expectations, we find that fishing induces evolution towards slow growth, early maturation at small size and higher reproductive investment. We show, first, that the choice of genetic model (based on either quantitative genetics or gametic inheritance) influences the evolutionary recovery of traits after fishing ceases. Second, we analyse the influence of three factors possibly involved in the lack of evolutionary recovery: the strength of selection, the effect of genetic drift and the loss of adaptive potential. We find that evolutionary recovery is hampered by an association of weak selection differentials with reduced additive genetic variances. Third, the contribution of fisheries-induced selection to the erosion of functional genetic diversity clearly dominates that of genetic drift only for the traits related to maturation. Together, our results highlight the importance of taking into account population genetic variability in predictions of eco-evolutionary dynamics.


Omovertebral bone associated with Sprengel deformity and Klippel-Feil syndrome leading to cervical myelopathy.
The unusual association of an omovertebral bone with Sprengel deformity and Klippel-Feil syndrome is a complex bone anomaly of unknown incidence and etiology. However, several cases of this rare disease pattern have been reported in the literature. In this paper, the authors present the case of a 34-year-old woman with a 5-month history of progressive gait ataxia and intermittent urinary incontinence, which was found to be caused by aberrant bone growth into the spinal canal from an omovertebral bone that extended from the left scapula pressing into the C-6 vertebral arch and subsequently causing cervical myelopathy. The patient underwent isolated resection of the omovertebral bone and decompression of the spinal canal, and her functional and neurological outcome was favorable.


KRAS mutation in lung metastases from colorectal cancer: prognostic implications.
KRAS mutant colorectal cancer (CRC) patients develop lung and brain metastases more frequently than KRAS wild-type (WT) counterpart. We retrospectively investigated the prognostic role of KRAS, BRAF, and PIK3CA (exon 20) mutations and loss of phosphatase and tensin homolog (PTEN) in surgically resected lung metastases. Lung specimens from 75 metastatic CRC (mCRC) patients treated with one or more metastasectomies with curative intent were analyzed. Sixty-four percent of patients had KRAS WT lung metastases. PTEN loss-of-function was found in 75%. BRAF and PIK3CA exon 20 mutations were not found. Seven patients subsequently developed brain metastases and 43% of them had KRAS mutation. In univariate analysis, median overall survival (OS) for KRAS WT patients was longer, compared to KRAS mutant patients (median 60.9 vs. 36.6 months, P = 0.035). In addition, both progression-free survival (PFS) and lung disease-free survival (LDFS) between lung surgery and relapse were not associated with KRAS and PTEN status. In multivariate analysis, the risk of death was significantly increased by KRAS mutational status (OS Hazard ratio (HR) 2.17, 95% IC 1.19-3.96, P = 0.012) and lack of adjuvant chemotherapy (OS HR 0.10, 95% IC 0.01-0.74, P = 0.024). The proportion of KRAS mutations in lung metastases was similar to the expected proportion in primary tumors. Patients harboring KRAS mutation had a poorer survival rate compared to WT group both in univariate and multivariate analysis. Moreover, administration of adjuvant chemotherapy after lung metastasectomy (LM) significantly improved both PFS and OS. KRAS mutation is a negative prognostic factor in mCRC patients undergoing LM. Further larger and prospective studies are necessary to confirm these findings.


Computed tomography angiography spot sign predicts intraprocedural aneurysm rupture in subarachnoid hemorrhage.
To analyze whether the computed tomography angiography (CTA) spot sign predicts the intraprocedural rupture rate and outcome in patients with aneurysmal subarachnoid hemorrhage (aSAH). From a prospective nationwide multicenter registry database, 1023 patients with aneurysmal subarachnoid hemorrhage (aSAH) were analyzed retrospectively. Descriptive statistics and logistic regression analysis were used to compare spot sign-positive and -negative patients with aneurysmal intracerebral hemorrhage (aICH) for baseline characteristics, aneurysmal and ICH imaging characteristics, treatment and admission status as well as outcome at discharge and 1-year follow-up (1YFU) using the modified Rankin Scale (mRS). A total of 218 out of 1023 aSAH patients (21%) presented with aICH including 23/218 (11%) patients with spot sign. Baseline characteristics were comparable between spot sign-positive and -negative patients. There was a higher clip-to-coil ratio in patients with than without aICH (both spot sign positive and negative). Median aICH volume was significantly higher in the spot sign-positive group (50 ml, 13-223 ml) than in the spot sign-negative group (18 ml, 1-416; p < 0.0001). Patients with a spot sign-positive aICH thus were three times as likely as those with spot sign-negative aICH to show an intraoperative aneurysm rupture [odds ratio (OR) 3.04, 95% confidence interval (CI) 1.04-8.92, p = 0.046]. Spot sign-positive aICH patients showed a significantly worse mRS at discharge (p = 0.039) than patients with spot sign-negative aICH (median mRS 5 vs. 4). Logistic regression analysis showed that the spot sign was an aICH volume-dependent predictor for outcome. Both spot sign-positive and -negative aICH patients showed comparable rates of hospital death, death at 1YFU and mRS at 1YFU. In this multicenter data analysis, patients with spot sign-positive aICH showed higher aICH volumes and a higher rate of intraprocedural aneurysm rupture, but comparable long-term outcome to spot sign-negative aICH patients.


Spatially variable risk factors for malaria in a geographically heterogeneous landscape, western Kenya: an explorative study.
Large reductions in malaria transmission and mortality have been achieved over the last decade, and this has mainly been attributed to the scale-up of long-lasting insecticidal bed nets and indoor residual spraying with insecticides. Despite these gains considerable residual, spatially heterogeneous, transmission remains. To reduce transmission in these foci, researchers need to consider the local demographical, environmental and social context, and design an appropriate set of interventions. Exploring spatially variable risk factors for malaria can give insight into which human and environmental characteristics play important roles in sustaining malaria transmission. On Rusinga Island, western Kenya, malaria infection was tested by rapid diagnostic tests during two cross-sectional surveys conducted 3 months apart in 3632 individuals from 790 households. For all households demographic data were collected by means of questionnaires. Environmental variables were derived using Quickbird satellite images. Analyses were performed on 81 project clusters constructed by a traveling salesman algorithm, each containing 50-51 households. A standard linear regression model was fitted containing multiple variables to determine how much of the spatial variation in malaria prevalence could be explained by the demographic and environmental data. Subsequently, a geographically-weighted regression (GWR) was performed assuming non-stationarity of risk factors. Special attention was taken to investigate the effect of residual spatial autocorrelation and local multicollinearity. Combining the data from both surveys, overall malaria prevalence was 24%. Scan statistics revealed two clusters which had significantly elevated numbers of malaria cases compared to the background prevalence across the rest of the study area. A multivariable linear model including environmental and household factors revealed that higher socioeconomic status, outdoor occupation and population density were associated with increased malaria risk. The local GWR model improved the model fit considerably and the relationship of malaria with risk factors was found to vary spatially over the island; in different areas of the island socio-economic status, outdoor occupation and population density were found to be positively or negatively associated with malaria prevalence. Identification of risk factors for malaria that vary geographically can provide insight into the local epidemiology of malaria. Examining spatially variable relationships can be a helpful tool in exploring which set of targeted interventions could locally be implemented. Supplementary malaria control may be directed at areas, which are identified as at risk. For instance, areas with many people that work outdoors at night may need more focus in terms of vector control. Trialregister.nl NTR3496-SolarMal, registered on 20 June 2012.


Identification of a novel transcriptional activity of mammalian Id proteins.
The Id proteins are a family of related mammalian helix-loop-helix (HLH) proteins which can interact with other HLH proteins but lack a basic region and are thus not thought to bind to DNA. Instead, they are hypothesized to act as dominant negative regulators of DNA-binding basic HLH (bHLH) proteins, by forming inactive heterodimers with these proteins. All four Id family proteins possess related HLH dimerization domains and can interact with similar bHLH proteins, although with differing affinities. The functions of the largely unrelated N- and C-terminal regions of the proteins are unknown. In this study, we have identified a novel transcriptional activity of the mammalian Id proteins. We show that when fused to the heterologous GAL4 DNA-binding domain, all four of the mammalian Id proteins can activate GAL4-dependent transcription. The HLH domain is necessary for the transactivation activity observed, suggesting that interaction with a cellular HLH protein is required. Co-transfection with exogenous Class A bHLH proteins (E-proteins) greatly potentiates the transactivation, which is abolished upon co-transfection with Class B bHLH proteins. These results are consistent with the idea that the Id proteins have a transcriptional activity when present in a DNA-binding complex.


Retrospective analysis of the outcome of patients with idiopathic inflammatory myopathy: a long-term follow-up study.
Several factors have been implicated in the prognosis of idiopathic inflammatory myopathies, including age, gender, delay in diagnosis, neoplasia, creatine kinase levels and some autoantibodies. We have reviewed the main factors contributing to mortality in patients with idiopathic inflammatory myopathy (IIM) diagnosed between 1976 and 2007 who were followed for at least 5 years in the Rheumatology Unit at University College Hospital in London. An observational retrospective study was carried out on patients with IIM diagnosed between 1976 and 2007. All the patients fullfilled at least three out of four of the Bohan and Peter criteria. The subjects were divided into the following groups: adult-onset polymyositis (APM); adult-onset dermatomyositis (ADM); juvenile dermatomyositis (JDM); Overlap syndromes with another autoimmune rheumatic disease. 90 patients were identified. The female to male ratio was 2.5:1 and the mean age at diagnosis was 38.5 years (SD 15.03). 47.8% of the patients had APM, 30% adult-onset ADM, 15.6% Overlap and 6.7% JDM. Among the extramuscular features, 18.9% had pulmonary involvement. In 70% the highest CK was >5 times the upper normal. Prednisolone was prescribed in 98.9%. 11.1% received rituximab. 34.4% had monophasic, 31.1% relapsing and remitting and 34.4% continuous progressive course of the disease. The median follow-up was 11.5 years (IQR 12.00). 14.4% of the patients died, 30.8% due to infection, 30.8% from a cardiovascular event and 23.1% due to neoplasia. The 1, 5 and 10-year survival was 100%, 97.8% and 91%, respectively. Male gender (Hazards Ratio (HR) 3.222; p=0.037), pulmonary involvement (HR 5.247; p=0.009), chronic progressive course (HR 3.711; p=0.030) and use of rituximab (HR 3.562; p=0.036) were the only risk factors to be statistically significantly associated (p<0.05) with death. We conclude that long-term survival in these patients is generally quite good with an estimated 10-year survival >90% in our cohort, which is even higher than previously reported.


The impact of non-compliance with the therapeutic regimen on the development of stroke among hypertensive men and women in Gaza, Palestine.
Hypertension and stroke are 2 major public health problems worldwide. Several biological and non-biological risk factors for stroke have been identified in the past. Little is known regarding risk factors for stroke among the Arabic population in Gaza. To identify potential risk factors we investigated compliance with the therapeutic regimen and life style factors which may increase the risk for stroke. To research this study question, a pair matched case control study was conducted in Gaza Strip (Shefa Hospital, Nasser Hospital, Khan Younis Hospital, and related primary health care clinics) in 2001 (from January through to December) among 112 patients, who had been hospitalized for acute stroke and history of hypertension, and 224 controls with history of hypertension from primary health care clinics. Conditional logistic regression models show significant associations between stroke and medication not taking as prescribed (odds ratio (OR)=6.07; 95% confidence interval (CI)=1.53, 24.07), using excessive salt at meals (OR=4.51; 95% CI=2.05, 9.90), eating diet high in fat (OR=4.67; 95% CI=2.09, 10.40), and high levels of stress (OR=2.77; 95% CI=1.43, 5.38). No significant association between smoking and the development of stroke (OR=2.12; 95 CI 0.82, 5.51) was found. Regular physical exercise was a protective factor (OR=0.26; 95% CI=0.12, 0.57). Our results on risk factors for stroke confirm several other studies. In future programs on health promotion among hypertensive men and women in Gaza these modifiable risk factors could be addressed by health education strategies.


Targeted disruption of the Wnt2 gene results in placentation defects.
Wnt genes have been implicated in a range of developmental processes in the mouse including the patterning of the central nervous system and limbs. Reported here for the first time is the expression of Wnt2 in the early heart field of 7.5-8.5 dpc (days post-coitum) mouse embryos, making Wnt2 a potentially useful gene marker for the early stages of heart development. Expression was also detected in the allantois from 8.0 dpc and at later stages in the placenta and umbilicus. Mice deficient in Wnt2, generated by gene targeting, displayed runting and approximately 50% died perinatally. Histological analysis revealed alterations in the size and structure of placentas from these mice from 14.5 dpc. The placental defects were associated primarily with the labyrinthine zone and included oedema and tissue disruption and accumulation of maternal blood in large pools. There was also an apparent decrease in the number of foetal capillaries and an increase in the amount of fibrinoid material in the Wnt2 mutant placentas. These results suggest that Wnt2 is required for the proper vascularisation of the mouse placenta and the placental defects in Wnt2-deficient mice result in a reduction in birthweight and perinatal lethality.


Improving access to health care among the poor--the neighborhood health center experience.
Utilization, cost, and productivity patterns at neighborhood health centers (NHCs) are examined on the basis of data from 82 centers. Minority groups and residents of the South and rural areas are found to have achieved levels of care and benefits closer to equality with other groups at NHCs than has been their health care experience generally. Continuity and comprehensiveness of care and the use of paramedical personnel are shown to be important contributory factors to utilization of NHCs. The impact of alternative cost-saving devices at NHCs is considered. It appears unlikely that professional productivity can be markedly improved. Increasing third-party payments is the most likely means of reducing dependence on operating grants without deleterious effects on utilization. The problem NHCs have had in maintaining stable professional staffs is shown to be a problem which needs further attention if the program is to expand.


The role of antisense oligonucleotide therapy against apolipoprotein-CIII in hypertriglyceridemia.
Increased triglyceride levels (higher than ∼1000 mg/dL) are associated with an increased risk for pancreatitis. Apolipoprotein-CIII (apo-CIII) plays a key role in the metabolism of triglycerides and triglyceride-rich lipoproteins. While loss of function mutations in the gene encoding apo-CIII (APOC3) are associated with low triglyceride levels and a decreased risk for cardiovascular disease (CVD), overexpression of APOC3 is associated with hypertriglyceridemia. Although many drugs such as fibrates, statins and omega-3 fatty acids modestly decrease triglyceride levels (and apo-CIII concentrations), there are many patients who still have severe hypertriglyceridemia and are at risk for pancreatitis and potentially CVD. The antisense oligonucleotide (ASO) against APOC3 mRNA volanesorsen (previously called ISIS 304801, ISIS-ApoCIIIRx and IONIS-ApoCIIIRx) robustly decreases both, apo-CIII production and triglyceride concentrations and is being currently evaluated in phase 3 trials. In this narrative review we present the currently available clinical evidence on the efficacy and safety of volanesorsen for the treatment of hypertriglyceridemia.


[Pharmacological reminder of the emotional condition facilitates the amnestic memory trace retrieval].
Passive avoidance reflex was shown to be differently reproduced in rats. The reproduction was more stable in rats with a higher level of learning. Amnestic effects induced seizures were shown to depend on relationships between the intensity of learning and the intensity of seizures. Unconditioned stimuli acting as a reminder decreased the amnestic effects of seizures. Learning process significantly reduced the seizure severity. A dissociated convulsive state was reproduced with the aid of a pharmacological reminder of anxiety formed in the course of learning. Haloperidol produced anxiety and suppressed amnestic effects of seizures, facilitated conditioning in rats with a low level of learning.


The first nationwide surveillance of bacterial respiratory pathogens conducted by the Japanese Society of Chemotherapy. Part 1: a general view of antibacterial susceptibility.
The Japanese Society of Chemotherapy (JSC) conducted the first nationwide surveillance of bacterial respiratory pathogens during the period from January to August 2006. With the cooperation of 32 medical institutions throughout Japan, a total of 924 strains belonging to seven clinically relevant bacterial species were collected from adult patients with well-diagnosed respiratory tract infections (RTIs). Antimicrobial susceptibility testing of the 887 evaluable strains (205 Staphylococcus aureus, 200 Streptococcus pneumoniae, 9 Streptococcus pyogenes, 165 Haemophilus influenzae, 91 Moraxella catarrhalis, 74 Klebsiella pneumoniae, and 143 Pseudomonas aeruginosa) to 42 antibacterial agents was conducted at the Central Laboratory of the Research Center for Anti-infective Drugs of the Kitasato Institute, according to recommendations issued by the Clinical and Laboratory Standards Institute (CLSI). The antibacterial agents employed were 25 beta-lactams, three aminoglycosides, four macrolides (including one azalide and one ketolide), one lincosamide, one tetracycline, two glycopeptides, five fluoroquinolones, and one oxazolidinone. The incidence of methicillin-resistant S. aureus (MRSA) was 63.4%, and the incidences of penicillin-intermediately resistant S. pneumoniae (PISP) and penicillin-resistant S. pneumoniae (PRSP) were 35.0% and 4.0%, respectively. Among H. influenzae, 21.2% of the strains were found to be beta-lactamase-nonproducing ampicillin (ABPC)-intermediately resistant (BLNAI), 29.1% to be beta-lactamase-nonproducing ABPC-resistant (BLNAR), and 4.8% to be beta-lactamaseproducing ABPC-resistant (BLPAR) strains. The incidence of extended-spectrum beta-lactamase-producing K. pneumoniae was 2.7% (2 of 74 strains). Three (2.1%) of the 143 P. aeruginosa strains were found to be metallo-beta-lactamaseproducing, including 1 (0.7%) multidrug-resistant strain. Through the nationwide surveillance, we obtained fundamental antimicrobial susceptibility data of clinically relevant bacterial pathogens in adult RTI to various antibacterial agents. These data will be a useful reference for future periodic surveillance studies, as well as for investigations to control antimicrobial-resistant pathogens.


Restricted 12p amplification and RAS mutation in human germ cell tumors of the adult testis.
Human testicular germ-cell tumors of young adults (TGCTs), both seminomas and nonseminomas, are characterized by 12p overrepresentation, mostly as isochromosomes, of which the biological and clinical significance is still unclear. A limited number of TGCTs has been identified with an additional high-level amplification of a restricted region of 12p including the K-RAS proto-oncogene. Here we show that the incidence of these restricted 12p amplifications is approximately 8% in primary TGCTs. Within a single cell formation of i(12p) and restricted 12p amplification is mutually exclusive. The borders of the amplicons cluster in short regions, and the amplicon was never found in the adjacent carcinoma in situ cells. Seminomas with the restricted 12p amplification virtually lacked apoptosis and the tumor cells showed prolonged in vitro survival like seminoma cells with a mutated RAS gene. However, no differences in proliferation index between these different groups of seminomas were found. Although patients with a seminoma containing a homogeneous restricted 12p amplification presented at a significantly younger age than those lacking it, the presence of a restricted 12p amplification/RAS mutation did not predict the stage of the disease at clinical presentation and the treatment response of primary seminomas. In 55 primary and metastatic tumors from 44 different patients who failed cisplatinum-based chemotherapy, the restricted 12p amplification and RAS mutations had the same incidence as in the consecutive series of responding patients. These data support the model that gain of 12p in TGCTs is related to invasive growth. It allows tumor cells, in particular those showing characteristics of early germ cells (ie, the seminoma cells), to survive outside their specific microenvironment. Overexpression of certain genes on 12p probably inhibits apoptosis in these tumor cells. However, the copy numbers of the restricted amplification of 12p and K-RAS mutations do not predict response to therapy and survival of the patients.


The quality assurance program of organ donation in Tuscany.
Constant monitoring is paramount in order to detect the criticalities and improve the results of the deceased donation process. Concomitant with the institution of a regional transplantation service authority--Organizzazione Toscana Trapianti--in 2003, Tuscany adopted a program of quality assurance of the deceased donation process by compulsory reporting of all encephalic deaths from local intensive care units to the regional transplant office in Florence. The indicators we adopted were the efficiency of deceased donor (DD) identification, expressed as the ratio of encephalic deaths (ED) to total deaths with encephalic lesions (EL) (ie, ED/EL); the efficiency of DD reporting, expressed as the ratio of reported potential DD (RPDD) to total ED (ie, RPDD/ED); the efficacy of the DD process, as the ratio between actual DD (ADD) to total ED (ie, ADD/ED); the conversion rate; the percent of opposition to donation; and the incidence of DD maintenance failures. Data were collected prospectively, stratified by regional hospital consortia (Aziende Sanitarie Locali) and compared with international benchmarks. In the period 2003-2006 the mean efficiency of DD identification was 48.3%+/-4.4% (range 42.6%-53.2%); the mean efficiency of DD reporting was 95.2%+/-2.5% (range 92.5%-98.5%); the mean efficacy of the deceased donation process was 51.8%+/-2.4% (range 48.6%-54.4%); the mean conversion rate was 59.6%+/-2.2% (range 57.6%-62.7%); the mean opposition rate was 31.9%+/-1.1% (range 30.6%-33.2%); and the incidence of DD maintenance failure was 5%+/-2.9% (range 2.2%-8.7%). The breakdown analysis revealed wide interhospital variability in terms of efficiency of DD identification (from a low of 25% to a high of 80%); efficacy of the donation process (from a low of 22% to a high of 79%); and conversion rate (from a low of 29% to a high of 79%). Our results highlight that the donation process gets started in about 50% of eligible cases. Further strategies are favored to address this critical area.


Radiosensitization of epidermal growth factor receptor/HER2-positive pancreatic cancer is mediated by inhibition of Akt independent of ras mutational status.
Epidermal growth factor receptor (EGFR) family members (e.g., EGFR, HER2, HER3, and HER4) are commonly overexpressed in pancreatic cancer. We investigated the effects of inhibition of EGFR/HER2 signaling on pancreatic cancer to elucidate the role(s) of EGFR/HER2 in radiosensitization and to provide evidence in support of further clinical investigations. Expression of EGFR family members in pancreatic cancer lines was assessed by quantitative reverse transcription-PCR. Cell growth inhibition was determined by MTS assay. The effects of inhibition of EGFR family receptors and downstream signaling pathways on in vitro radiosensitivity were evaluated using clonogenic assays. Growth delay was used to evaluate the effects of nelfinavir on in vivo tumor radiosensitivity. Lapatinib inhibited cell growth in four pancreatic cancer cell lines, but radiosensitized only wild-type K-ras-expressing T3M4 cells. Akt activation was blocked in a wild-type K-ras cell line, whereas constitutive phosphorylation of Akt and extracellular signal-regulated kinase (ERK) was seen in lines expressing mutant K-ras. Overexpression of constitutively active K-ras (G12V) abrogated lapatinib-mediated inhibition of both Akt phosphorylation and radiosensitization. Inhibition of MAP/ERK kinase/ERK signaling with U0126 had no effect on radiosensitization, whereas inhibition of activated Akt with LY294002 (enhancement ratio, 1.2-1.8) or nelfinavir (enhancement ratio, 1.2-1.4) radiosensitized cells regardless of K-ras mutation status. Oral nelfinavir administration to mice bearing mutant K-ras-containing Capan-2 xenografts resulted in a greater than additive increase in radiation-mediated tumor growth delay (synergy assessment ratio of 1.5). Inhibition of EGFR/HER2 enhances radiosensitivity in wild-type K-ras pancreatic cancer. Nelfinavir, and other phosphoinositide 3-kinase/Akt inhibitors, are effective pancreatic radiosensitizers regardless of K-ras mutation status.


Identification of blottin: a novel gastric trefoil factor family-2 binding protein.
The trefoil factor family (TFF) peptides are important in gastro-intestinal mucosal protection and repair. Their mechanism of action remains unclear and receptors are sought. We aimed to identify and characterise proteins binding to TFF2. A fusion protein of mouse TFF2 with alkaline phosphatase was generated and used to probe 2-D protein blots of mouse stomach. The resulting spots were analysed by MS. The protein identified was characterised by bioinformatics, rapid amplification of cDNA ends, in situ hybridisation (ISH) and immunohistochemistry (IHC). Functional assays were performed in gastrointestinal cell lines. A single major murine protein was identified and named blottin. It was previously unknown as a translated product. Blottin is also present in rat and human; the latter gene is also known as GDDR. The predicted full-length proteins are 184 amino acids long (20 kDa), reducing to 164 amino acids (18 kDa) after signal peptide cleavage. ISH of gastrointestinal tissues shows abundant blottin mRNA in gastric surface and foveolar epithelium. IHC shows cytoplasmic staining for blottin protein, and by immunoelectron microscopy in mucus granules and Golgi stacks. Previous work showed that blottin is down-regulated in gastric cancers. Blottin contains a BRICHOS domain, and has 56% similarity with gastrokine-1. Cultured HT-29 cells express blottin and show increased DNA synthesis with antiblottin antibody; however, this effect is reversed by the immunising peptide. We have identified and characterised a TFF2-binding protein produced by gastric epithelium. Blottin may play a role in gastrointestinal mucosal protection and modulate gut epithelial cell proliferation.


Desmin-lacZ transgene expression and regeneration within skeletal muscle transplants.
The purpose of this study was to investigate the initiation and time course of the regeneration process in fragments of skeletal muscle transplants as a function of muscle tissue age at implantation. The appearance of desmin occurs at the very beginning of myogenesis. The transgenic desmin nls lacZ mice used in the study bear a transgene in which the 1 kb DNA 5' regulatory sequence of the desmin gene is linked to a reporter gene coding for Escherichia coli beta-galactosidase. The desmin lacZ transgene labels muscle cells in which the desmin synthesis programme has commenced. We implanted pectoralis muscle fragments from fetal transgenic embryos and mature and old transgenic mice into mature non-transgenic mice. Early events of myogenesis occurring during regeneration started sooner in transplants from 4-month-old (day 3 post-implantation) muscle than in those from 24-month-old (day 5-6 post-implantation) muscle, and they lasted longer in those from young (day 17 post-implantation) than in those from old (day 14 post-implantation) muscle fragments. In adult muscle, transgene activation proceeded from the periphery toward the centre of the transplant. In transplants from fetal 18-day-old pectoralis, myotubes with transgene activity were observed from day 1 to day 19. Desmin immunoreactivity, which appeared about one day after transgene activation, was followed by myosin expression. In adult transplants, the continuity of laminin labelling was disrupted around degenerative fibres, illustrating alteration of the extracellular matrix. Our data suggest that satellite cells from old muscle tissue have lower proliferative capacity and/or less access to trophic substances released by the host (damaged fibres, vascularization) than those from fetal or young adult muscle.


Primary and secondary safety endpoints from IMPACT II. Integrilin to Minimize Platelet Aggregation and Coronary Thrombosis.
Glycoprotein (GP) IIb-IIIa receptor inhibitors have recently emerged as potentially valuable new agents for the prevention of the acute ischemic complications of coronary angioplasty. The potent antiplatelet activity of these agents may not only reduce the rate of ischemic events but also increase bleeding risk. A rapidly reversible peptide inhibitor of the GP IIb-IIIa receptor, eptifibatide (INTEGRILIN), has been recently evaluated in the pivotal Integrilin to Minimize Platelet Aggregation and Coronary Thrombosis (IMPACT II) phase III trial, which demonstrated a favorable adverse effects profile for this agent. Patients undergoing elective, urgent, or emergency percutaneous coronary intervention who were treated with eptifibatide were not at increased risk for major hemorrhage, thrombocytopenia, or the need for transfusions of red blood cells or platelets, compared with a placebo-treated group. The incidence of minor bleeding events in patients treated with eptifibatide was slightly increased. Additionally, administration of eptifibatide did not lead to the development of anti-eptifibatide antibodies. The lack of increased risk of major bleeding and other adverse effects, combined with encouraging efficacy results, indicates that treatment with eptifibatide may safely provide clinical benefit to all patients scheduled to undergo coronary angioplasty.


[Studies on the life cycle of Paragonimus heterotremus].
In order to clarify the biological features of the lung fluke, Paragonimus heterotremus, it is necessary to replicate its complete life cycle in the laboratory. Tricula wumingensis infected with the miracidiae of P. heterotremus were regularly dissected after infection for larvae observation. The cercariae of P. heterotremus from positive snails were used for experimental infection of the crab, Samanniathelphusa nanningensis. The crabs were then examined for the metacercariae at regular intervals. The infection of mammals (cats and rats) was performed with the metacercariae obtained from experimentally infected crabs. The miracidia were hatched by incubating the eggs in water (room temperature 20 degrees C to 31 degrees C) for 16 days to 21 days. The epidermal cells of the miracidia were arranged in 4 transverse rows, 6 in the first row, 7 in the second, 3 in the third, and a single terminal cell at the posterior end of the body. The cells of the first row have indentation in their bases. Mature sporocysts, first generation rediae and second generation rediae(containing dissociative cercariae), were found on the 26th day, 41st day and 58th day after infection of the snails respectively(room temperature 21 degrees C-30 degrees C). The sporocyst had a birth pore at its anterior tip. The length ratio of the gut to the body was 1:3 in the first and 1:6 in the second generation rediae. The mature second generation rediae contains 5-21 mature cercariae which emerge from its pharynx. The cercaria has general characteristics of Paragonimus. Its flame cell pattern was formulated as 2[(2 + 2 + 2) + (2 + 2 + 2)] = 24. After the infection of crabs with cercariae, the mature metacercariae were found in the crabs on the 60th day. The crabs could be successfully infected by either: giving mature cercariae orally to them or raising them in water with positive snails. After the metacercariae obtained from experimental crabs were given to cats and rats, P. heterotremus adult worms were recovered from the worm-cyst in their lungs. The morphology of various larval stages and adult worms were described. The life cycle of P. heterotremus was completed for the first time in the laboratory. The whole life cycle from egg to adult worm has been described in the present study.


The role of intravascular ultrasound and quantitative angiography in the functional assessment of intermediate coronary lesions: correlation with fractional flow reserve.
The correlation between fractional flow reserve (FFR) and intravascular ultrasound (IVUS) metrics including minimal lumen area (MLA), plaque burden and morphology remain a matter of debate. Between June 2008 and May 2013, 132 intermediate stenoses in 109 patients were assessed by FFR, IVUS and quantitative angiography. Receiver-operating characteristic (ROC) curve analyses were used to identify MLA/lesion length/plaque burden cut-off values predictive of FFR <0.80. FFR <0.80 was observed in 39 lesions. In the entire cohort, MLA value <2.70mm(2) had 79.5% sensitivity, 76.3% specificity, 0.822 area under curve (AUC), 58.5% positive predictive value, 89.9% negative predictive value and 77.3% accuracy in predicting a positive FFR. In lesions with reference diameter vessel (RVD) ≥3.0mm, the MLA cut-off value was 2.84mm(2) (sensitivity 72.2%, specificity 83.0%, AUC 0.842) whereas in lesions with RVD <3.0mm, 2.59mm(2) (sensitivity 90.5%, specificity 69.6%, AUC 0.823). A moderate correlation was observed between MLA and FFR (r=0.429, p<0.001). The cut-off lesion length predictive of FFR <0.80 was 11.0mm with a weak correlation between the two (r=-0.348, p<0.001). Plaque morphology did not significantly affect FFR (p=0.485). On multivariable analysis, MLA (OR: 0.15; 95% CI: 0.05-0.40; p<0.001) and plaque burden (OR: 1.11; 95% CI: 1.04-1.20; p<0.003) were independent predictors of FFR <0.80. A modest, yet significant correlation was observed between MLA and FFR. The high negative predictive value of large MLAs (using afore-mentioned cut-off values) may provide some degree of confidence that the lesion in question is not functionally significant.


Effect of blue and violet light on polymerization shrinkage vectors of a CQ/TPO-containing composite.
To evaluate the effect of light-curing wavelengths on composite filler particle displacement, and thus to visualize localized polymerization shrinkage in a resin-based composite (RBC) containing camphorquinone (CQ) and Lucirin TPO (TPO). Three light-curing units (LCUs) were used to light-cure a RBC containing CQ and TPO: a violet-only, a blue-only, and a dual-wavelength, conventional (Polywave®, emitting violet and blue wavelengths simultaneously). Zirconia fillers were added to the RBC to act as filler particle displacement tracers. LCUs were characterized for total emitted power (mW) and spectral irradiant output (mW/cm2/nm). 2-mm high, 7-mm diameter silanized glass cylindrical specimens were filled in a single increment with the RBC, and micro-computed tomography (μ-CT) scans were obtained before and after light-curing, according to each LCU (n=6). Filler particle movement identified polymerization shrinkage vectors, traced using software, at five depths (from 0 up to 2mm): top, top-middle, middle, middle-bottom and bottom. Considering different RBC depths within the same LCU, use of violet-only and conventional LCUs showed filler particle movement decreased with increased depth. Blue-only LCU showed homogeneous filler particle movement along the depths. Considering the effect of different LCUs within the same depth, filler particle movement within LCUs was not statistically different until the middle of the samples (P>.05). However, at the middle-bottom and bottom depths (1.5 and 2mm, respectively), blue-only LCU compared to violet-only LCU showed higher magnitude of displacement vector values (P<.05). Use of the conventional LCU showed filler displacement magnitudes that were not significantly different than blue-only and violet-only LCUs at any depth (P>.05). With respect to the direction of particle movement vectors, use of violet-only LCU showed a greater displacement when close to the incident violet LED; blue-only LCU showed equally distributed particle displacement values within entire depth among the samples; and the conventional LCU showed greater filler displacement closer to the blue LED locations. Filler particle displacement in a RBC as a result of light-curing is related to localized application of light wavelength and total emitted power of the light emitted on the top surface of the RBC. When the violet LED is present (violet-only and conventional LCUs), filler particle displacement magnitude decreased with increased depth, while results using the blue-only LED show a more consistent pattern of displacement. Clinically, these results correlate to production of different characteristics of curing within a RBC restoration mass, depending on localized wavelengths applied to the irradiated surface.


Intrapersonal and interpersonal concomitants of facial blushing during everyday social encounters.
Facial blushing may usually be undesirable but may have an ameliorative function for some individuals under some circumstances. Researchers have studied the blush in laboratory settings, but not in daily life. In the present research, conducted with young adults, we employed for the first time an event-contingent recording method for assessing facial blushing during every-day social encounters. Blushing was associated with feeling embarrassed, ashamed, and exposed. These findings, though based on correlational analyses, are consistent with the idea that blushing is often unpleasant and can be maladaptive, and may contribute to the common belief that blushing is an undesirable response. Frequent blushers generally reported lower levels of dominant behavior, higher levels of submissive behavior, and perceived their social interaction partners as more powerful and less affiliative. This was independent of whether they blushed or not, suggesting that altered social behaviors and perceptions are associated with blushing-associated traits rather than with the blushing state. The experience of the blush varied as a function of the frequency with which a person blushed. Blushing was associated with higher levels of shame in frequent blushers than in infrequent blushers. In infrequent blushers, blushing was associated with higher levels of pleasant affect, suggesting that for infrequent blushers the blush may occur in positive social encounters.


High curative resection rate with weekly cisplatin, 5-fluorouracil, epidoxorubicin, 6S-leucovorin, glutathione, and filgastrim in patients with locally advanced, unresectable gastric cancer: a report from the Italian Group for the Study of Digestive Tract Cancer (GISCAD).
The aim of the present study was to evaluate the role of a weekly preoperative chemotherapy in locally advanced, unresectable gastric cancer. In all, 82 patients with an Eastern Oncology Cooperative Group PS <or=2 and normal cardiac function were enrolled onto the study. Surgical unresectability was confirmed in 52 patients (63%) at laparotomy, and in 30 (27%) cases by CT scan of the abdomen and endoscopic ultrasonography. Chemotherapy treatment was: cisplatin 40 mg x m(-2); 5-fluorouracil 500 mg x m(-2); epidoxorubicin 35 mg x m(-2); 6S-leucovorin 250 mg x m(-2) and glutathione 1.5 g x m(-2) (PELF). One cycle consisted of 8 weekly treatments. Response to chemotherapy was observed in 40 of 82 patients (49%): six (7%) complete and 34 (41%) partial responses, and in four (5%) cases a complete pathological response was confirmed. Of the 40 responding patients, 37 (45%) had potentially curative surgery. Grade 3/4 leucopenia and thrombocytopenia occurred in three and two patients. At a median follow-up of 48 months, 25 of the 37 resected patients (68%) were alive and 24 (65%) were disease free. The median and 4-year survival for the whole group was 17 months and 31%, respectively. The median survival was 12 months for inoperable patients and it was not reached in resected patients.


Development of Isoselenocyanate Compounds' Syntheses and Biological Applications.
As the number of cases and cancer-related deaths are projected to rise in upcoming years, it is urgent to find ways to prevent or treat cancer. As such, food-derived products have gained attention as potential chemopreventive agents due to their availability, safety, and low cost. Isothiocyanates, the breakdown products of sulfur-containing glucosinolates in cruciferous vegetables, have shown substantial anticarcinogenic and chemopreventive activities for different human cancers. Furthermore, organoselenium compounds are known to exhibit chemopreventive and chemotherapeutic activity; moreover, these compounds are more effective anticancer agents than their sulfur isosteres. Hence, isothiocyanates have been modified to yield isoselenocyanates, which are more cytotoxic toward cancer cells when compared to their corresponding sulfur analogues. Herein, the synthesis and development of isoselenocyanates as novel treatments for cancer and other diseases are reviewed, highlighting the diverse chemistry and computational studies of this class of compounds as well as their pertinent biological applications.


Dialysis-related amyloid arthropathy: MR findings in four patients.
Dialysis-related amyloidosis is a recently recognized complication of long-term hemodialysis. It is caused by the deposition of a unique form of amyloid derived from circulating beta 2-microglobulin. This study describes the MR imaging characteristics in five articular sites of four symptomatic patients with biopsy-proved (three patients) or clinically and radiographically suspected (one patient) dialysis-related amyloidosis. Three wrists, one knee, and one cervical spine were examined. The extent of osseous and soft-tissue involvement at each joint site was well shown by MR imaging. Lesions that were apparently intraosseous on conventional radiographs were shown to be caused by well-defined erosions that extended to the articular surface. The MR signal characteristics of the amyloid deposition were intermediate between those of fibrocartilage and muscle on all sequences, distinguishing the deposition from cellular lesions or those containing large amounts of water, such as inflammatory masses, acute or chronic synovitis, and brown tumors of hyperparathyroidism. The intraarticular masses were associated with a moderate joint effusion in the large joint imaged, and small effusions were present in the wrist. Use of a fat-suppression sequence enhanced visualization of amyloid deposits within the wrist of one patient but provided no additional information in the knee of a second patient. Our experience suggests that MR imaging is well suited to showing the extent and distribution of articular disease in dialysis-related amyloidosis.