The structure of 4-way DNA junctions: specific binding of bis-intercalators with rigid linkers.
During replication and recombination, two DNA duplexes lie side by side. We have developed reagents that might be used to probe structure during these critical processes; they contain two intercalating groups connected by a rigid linker that forces those groups to point in opposite directions. If their stereochemistry proves appropriate, such structure-specific agents should intercalate specifically into adjacent duplexes in the Y- and X-shaped structures (i.e. 3- and 4-way junctions, now known as 3H and 4H junctions) found at replication and recombination sites. We prepared DNA structures in which four duplexes were arranged in all possible combinations around 2- and 4-way junctions and then probed the accessibility to DNase I of all their phosphodiester bonds. In the absence of any bis-intercalators, 7-9 nucleotides (nt) in each of the strands in 4-way junctions were protected from attack; protected regions were significantly offset to the 3' side of the junction in continuous strands, but only slightly offset, if at all, in exchanging strands. All the intercalators decreased accessibility throughout the structure, but none did so at specific points in the two adjacent arms of 4-way junctions. However, one bis-intercalator--but not its sister with a shorter linker--strikingly increased access to a particular CpT bond that lay 9 nt away from the centre of some 4-way junctions without reducing access to neighbouring bonds. Binding was both sequence and structure specific, and depended on complementary stereochemistry between bis-intercalator and junction.


Development and validation of a spontaneous preterm delivery predictor in asymptomatic women.
Preterm delivery remains the leading cause of perinatal mortality. Risk factors and biomarkers have traditionally failed to identify the majority of preterm deliveries. To develop and validate a mass spectrometry-based serum test to predict spontaneous preterm delivery in asymptomatic pregnant women. A total of 5501 pregnant women were enrolled between 17(0/7) and 28(6/7) weeks gestational age in the prospective Proteomic Assessment of Preterm Risk study at 11 sites in the United States between 2011 and 2013. Maternal blood was collected at enrollment and outcomes collected following delivery. Maternal serum was processed by a proteomic workflow, and proteins were quantified by multiple reaction monitoring mass spectrometry. The discovery and verification process identified 2 serum proteins, insulin-like growth factor-binding protein 4 (IBP4) and sex hormone-binding globulin (SHBG), as predictors of spontaneous preterm delivery. We evaluated a predictor using the log ratio of the measures of IBP4 and SHBG (IBP4/SHBG) in a clinical validation study to classify spontaneous preterm delivery cases (<37(0/7) weeks gestational age) in a nested case-control cohort different from subjects used in discovery and verification. Strict blinding and independent statistical analyses were employed. The predictor had an area under the receiver operating characteristic curve value of 0.75 and sensitivity and specificity of 0.75 and 0.74, respectively. The IBP4/SHBG predictor at this sensitivity and specificity had an odds ratio of 5.04 for spontaneous preterm delivery. Accuracy of the IBP4/SHBG predictor increased using earlier case-vs-control gestational age cutoffs (eg, <35(0/7) vs ≥35(0/7) weeks gestational age). Importantly, higher-risk subjects defined by the IBP4/SHBG predictor score generally gave birth earlier than lower-risk subjects. A serum-based molecular predictor identifies asymptomatic pregnant women at risk of spontaneous preterm delivery, which may provide utility in identifying women at risk at an early stage of pregnancy to allow for clinical intervention. This early detection would guide enhanced levels of care and accelerate development of clinical strategies to prevent preterm delivery.


Representational power of restricted boltzmann machines and deep belief networks.
Deep belief networks (DBN) are generative neural network models with many layers of hidden explanatory factors, recently introduced by Hinton, Osindero, and Teh (2006) along with a greedy layer-wise unsupervised learning algorithm. The building block of a DBN is a probabilistic model called a restricted Boltzmann machine (RBM), used to represent one layer of the model. Restricted Boltzmann machines are interesting because inference is easy in them and because they have been successfully used as building blocks for training deeper models. We first prove that adding hidden units yields strictly improved modeling power, while a second theorem shows that RBMs are universal approximators of discrete distributions. We then study the question of whether DBNs with more layers are strictly more powerful in terms of representational power. This suggests a new and less greedy criterion for training RBMs within DBNs.


Electroosmotic transport of mannitol across human nail during constant current iontophoresis.
This work aimed to elucidate the role of electroosmosis during trans-nail iontophoresis. Passive and iontophoretic experiments were performed after short hydration (10-15 min) of human nail tips. The electroosmotic fluxes of mannitol were determined during anodal and cathodal iontophoresis and at different pH values. Passive controls were also carried out. Four sets of experiments were performed: (a) three anodal delivery experiments using different nails, at pH 4.0, 5.0 and 7.4, (b) one anodal delivery experiment that kept the same nails across two pH stages, (c) one experiment, comprising an anodal delivery stage (pH 4 and 7.4) followed by a cathodal delivery stage (pH 7.4 and 4), which kept the same nails across the different polarities and pH stages, and (d) a passive experiment keeping the same nails across different pH values (4 and 7.4). The fluxes of mannitol measured were very variable and little difference between passive and electroosmotic transport was observed. Cathodal and anodal fluxes were not always significantly different. Experiments which minimised internail variability suggested that the nails were negatively charged at physiological pH, and that this negative charge was lost at pH 4. These results suggest a modest and highly variable contribution of electroosmosis to the iontophoretic transungual flux.


Colorectal carcinoma with dome-like phenotype: an under-recognised subset of colorectal carcinoma?
The term dome carcinoma has been applied to a variant of colorectal carcinoma, thought to derive from M-cells of the gut-associated lymphoid tissue. Its distinguishing morphological features include a non-polypoid plaque-like lesion composed of closely apposed cystically dilated glands lined by a single layer of non-mucinous cells, intensely PAS-positive intraluminal material, and a close spatial relation to lymphoid stroma. A search in the literature for such cases and the authors' experience with carcinomas sharing morphological details with dome carcinoma are presented to direct focus on this unique phenotype of colorectal carcinoma and to expand on its morphology. Four such examples, all stage pT1, pN0 have been previously reported. Here two additional cases, with several features of dome carcinoma, stage pT1 and pT2, respectively, are added. An extensive intramucosal component, unassociated with adenomatous growth, a pink quality of the lesional cells, low grade budding, absence of cytoplasmic pseudofragments, and absence of necrosis characterised the present cases as well as intact MMR-proteins and loss of APC. As opposed to two of the previously reported cases, intraepithelial lymphocytes were unapparent in these cases and the lymphoid stroma was effaced along with tumour progression in one of the present cases. Hence, a range of appearances is encompassed by the dome carcinoma. The uncommon reporting of dome carcinoma may be due to lack of awareness of this particular subset of colorectal carcinoma. Indeed, one of the current cases was signed out as a conventional carcinoma, despite the comment in the pathology report of an unusual morphology. Dome carcinoma may be more under-recognised than rare. The reporting of variants of colorectal carcinoma, displaying histological features suggestive of dome carcinoma, is encouraged in order to obtain more exact knowledge on its putative clinical significance.


Local difference binary for ultrafast and distinctive feature description.
The efficiency and quality of a feature descriptor are critical to the user experience of many computer vision applications. However, the existing descriptors are either too computationally expensive to achieve real-time performance, or not sufficiently distinctive to identify correct matches from a large database with various transformations. In this paper, we propose a highly efficient and distinctive binary descriptor, called local difference binary (LDB). LDB directly computes a binary string for an image patch using simple intensity and gradient difference tests on pairwise grid cells within the patch. A multiple-gridding strategy and a salient bit-selection method are applied to capture the distinct patterns of the patch at different spatial granularities. Experimental results demonstrate that compared to the existing state-of-the-art binary descriptors, primarily designed for speed, LDB has similar construction efficiency, while achieving a greater accuracy and faster speed for mobile object recognition and tracking tasks.


The perirhinal cortex modulates V2 activity in response to the agreement between part familiarity and configuration familiarity.
Research has demonstrated that the perirhinal cortex (PRC) represents complex object-level feature configurations, and participates in familiarity versus novelty discrimination. Barense et al. [(in press) Cerebral Cortex, 22:11, doi:10.1093/cercor/bhr347] postulated that, in addition, the PRC modulates part familiarity responses in lower-level visual areas. We used fMRI to measure activation in the PRC and V2 in response to silhouettes presented peripherally while participants maintained central fixation and performed an object recognition task. There were three types of silhouettes: Familiar Configurations portrayed real-world objects; Part-Rearranged Novel Configurations created by spatially rearranging the parts of the familiar configurations; and Control Novel Configurations in which both the configuration and the ensemble of parts comprising it were novel. For right visual field (RVF) presentation, BOLD responses revealed a significant linear trend in bilateral BA 35 of the PRC (highest activation for Familiar Configurations, lowest for Part-Rearranged Novel Configurations, with Control Novel Configurations in between). For left visual field (LVF) presentation, a significant linear trend was found in a different area (bilateral BA 38, temporal pole) in the opposite direction (Part-Rearranged Novel Configurations highest, Familiar Configurations lowest). These data confirm that the PRC is sensitive to the agreement in familiarity between the configuration level and the part level. As predicted, V2 activation mimicked that of the PRC: for RVF presentation, activity in V2 was significantly higher in the left hemisphere for Familiar Configurations than for Part-Rearranged Novel Configurations, and for LVF presentation, the opposite effect was found in right hemisphere V2. We attribute these patterns in V2 to feedback from the PRC because receptive fields in V2 encompass parts but not configurations. These results reveal two new aspects of PRC function: (1) it is sensitive to the congruency between the familiarity of object configurations and the parts comprising those configurations and (2) it likely modulates familiarity responses in visual area V2.


Bone morphogenetic proteins regulate the developmental program of human hematopoietic stem cells.
The identification of molecules that regulate human hematopoietic stem cells has focused mainly on cytokines, of which very few are known to act directly on stem cells. Recent studies in lower organisms and the mouse have suggested that bone morphogenetic proteins (BMPs) may play a critical role in the specification of hematopoietic tissue from the mesodermal germ layer. Here we report that BMPs regulate the proliferation and differentiation of highly purified primitive human hematopoietic cells from adult and neonatal sources. Populations of rare CD34(+)CD38(-)Lin- stem cells were isolated from human hematopoietic tissue and were found to express the BMP type I receptors activin-like kinase (ALK)-3 and ALK-6, and their downstream transducers SMAD-1, -4, and -5. Treatment of isolated stem cell populations with soluble BMP-2, -4, and -7 induced dose-dependent changes in proliferation, clonogenicity, cell surface phenotype, and multilineage repopulation capacity after transplantation in nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice. Similar to transforming growth factor beta, treatment of purified cells with BMP-2 or -7 at high concentrations inhibited proliferation yet maintained the primitive CD34(+)CD38(-) phenotype and repopulation capacity. In contrast, low concentrations of BMP-4 induced proliferation and differentiation of CD34(+) CD38(-)Lin- cells, whereas at higher concentrations BMP-4 extended the length of time that repopulation capacity could be maintained in ex vivo culture, indicating a direct effect on stem cell survival. The discovery that BMPs are capable of regulating repopulating cells provides a new pathway for controlling human stem cell development and a powerful model system for studying the biological mechanism of BMP action using primary human cells.


PP1α, PP1β and Wip-1 regulate H4S47 phosphorylation and deposition of histone H3 variant H3.3.
Phosphorylation of histone H4 serine 47 (H4S47ph) is catalyzed by Pak2, a member of the p21-activated serine/threonine protein kinase (Pak) family and regulates the deposition of histone variant H3.3. However, the phosphatase(s) involved in the regulation of H4S47ph levels was unknown. Here, we show that three phosphatases (PP1α, PP1β and Wip1) regulate H4S47ph levels and H3.3 deposition. Depletion of each of the three phosphatases results in increased H4S47ph levels. Moreover, PP1α, PP1β and Wip1 bind H3-H4 in vitro and in vivo, whereas only PP1α and PP1β, but not Wip1, interact with Pak2 in vivo. These results suggest that PP1α, PP1β and Wip1 regulate the levels of H4S47ph through directly acting on H4S47ph, with PP1α and PP1β also likely regulating the activity of Pak2. Finally, depletion of PP1α, PP1β and Wip1 leads to increased H3.3 occupancy at candidate genes tested, elevated H3.3 deposition and enhanced association of H3.3 with its chaperones HIRA and Daxx. These results reveal a novel role of three phosphatases in chromatin dynamics in mammalian cells.


Genetic dissection of age-related changes of immune function in mice.
Understanding of the genetic basis of normal and abnormal development of the immune response is an enormous undertaking. The immune response, at the most minimal level, involves interactions of antigen presenting cells (APCs), T and B cells. Each of these cells produce cell surface and soluble factors (cytokines) that affect both autocrine and paracrine functions. A second level of complexity needs to consider the development of the macrophage/monocyte lineage as well as the production of the common lymphoid precursor which undergoes distinct maturation steps in the thymus and periphery to form mature T cells as well as in BM (BM) and lymphoid organs to form mature B cells. A third level of complexity involves the immune response to infectious agents including viruses and also the response to tumour antigens. In addition, there are imbalances that predispose to decreased responses (immunodeficiencies) or increased responses (autoimmunity). A fourth level of complexity involves attempts to understand the differences in the immune response that occurs at a very young age, in adults, and at a very old age. This review will focus on the use of C57BL/6 J X DBA/2 J (BXD) recombinant inbred (RI) strains of mice to map genetic loci associated with the production of lymphoid precursors in the BM, development of T cells in the thymus, and T-cell responses to stimulation in the peripheral lymphoid organs in adult and in aged mice. Strategies to improve the power and precision in which complex traits such as the age-related immune response can be mapped is limited with the current set of 35 strains of BXD mice. Strategies to increase these strains by generating recombinant intercross (RIX) strains of mice are being developed to enable this large set of lines to detect quantitative trait loci (QTLs) with a much higher consistency and statistical power. More importantly, the resolution with which these QTLs can be mapped would be greatly improved and, in many cases, adequate to carry out direct identification of candidate genes. It is likely that, given the complexity of the immune system development, the number of cells involved in an immune response, and especially the changes in the immune system with ageing, mapping hundreds of genes will be required to fully understand age-related changes in the immune response. This review outlines ongoing and future strategies that will enable the mapping and identification of these genes.


Dendritic discrimination of temporal input sequences in cortical neurons.
The detection and discrimination of temporal sequences is fundamental to brain function and underlies perception, cognition, and motor output. By applying patterned, two-photon glutamate uncaging, we found that single dendrites of cortical pyramidal neurons exhibit sensitivity to the sequence of synaptic activation. This sensitivity is encoded by both local dendritic calcium signals and somatic depolarization, leading to sequence-selective spike output. The mechanism involves dendritic impedance gradients and nonlinear synaptic N-methyl-D-aspartate receptor activation and is generalizable to dendrites in different neuronal types. This enables discrimination of patterns delivered to a single dendrite, as well as patterns distributed randomly across the dendritic tree. Pyramidal cell dendrites can thus act as processing compartments for the detection of synaptic sequences, thereby implementing a fundamental cortical computation.


Functional aspects of estrogen neuroprotection.
Evidence that estrogen protects neurons against toxic/ ischemic insults or degenerative/aging processes is evident in a variety of in vitro and in vivo systems. However, a critical remaining question is: Does the demonstrated morphologic and neurochemical protection by estrogen lead to a preservation of brain function or an enhanced ability to recover? To date, little basic research is available on this issue. Cognition is a critical function that might provide a sensitive way to examine this question. As a first step, we present results showing that two chronic environmental insults, psychoactive drugs and stress, produce gender-specific responses in cognitive abilities. Specifically, females appear less sensitive than males to cognitive impairments following chronic exposure to these factors. Results are presented in male and female rats utilizing cognitive tests that assess visual (object recognition) and spatial memory (object placement and radial arm maze) following chronic amphetamine, methamphetamine, or daily restraint stress. Following regimes of chronic stress or amphetamine, males were impaired on these tasks while females were either unaffected, less affected, or enhanced in performance. These observations suggest that differences in circulating gonadal hormone levels between the sexes may contribute to the differential sensitivity of the sexes and provide endogenous neuroprotection for females. Surprisingly, ovariectomized females were still not impaired following a stress regimen that impaired males (21 d of daily restraint). These data taken together with neurochemical data on estrogen neuroprotective effects indicate that it is possible that neuroprotection by estrogen may result from hormone action both during sexual differentiation (organizational effect) and in adulthood (activational effect). These considerations and possible unwanted/untoward effects of chronic estrogen use are discussed in relation to the use of selective estrogen receptor modulators for chronic treatment of both males and females. In conclusion, although compelling evidence for neuroprotection by estrogen has been presented in anatomic and neurochemical studies, it is clear that the functional/ behavioral aspects need further investigation.


Deoxynivalenol and nivalenol accumulation in wheat infected with Fusarium graminearum during grain development.
The manner in which deoxynivalenol (DON) and nivalenol (NIV) accumulation progresses in wheat grain infected with Fusarium graminearum and the influence of the time of infection on the accumulation of toxins were investigated. Four cultivars were tested in a greenhouse environment, where the plants were spray inoculated at three different stages with a mixture of DON and NIV chemotypes of F. graminearum. The results indicate that high levels of DON and NIV can be produced beyond 20 days after anthesis (DAA), even by early infection. The results of field experiments performed on seven cultivars, where inoculation was conducted using colonized maize kernel inoculum, were consistent with the greenhouse results. In addition, in the greenhouse experiments, late infection, at least as late as 20 DAA, caused grain contamination with these toxins even without clear disease symptoms on the spike. These results indicate the importance of the late stage in grain development in DON and NIV contamination, suggesting that control strategies that cover the late as well as the early stage of grain development should be established to effectively reduce the risk of these toxins' contaminating wheat.


Using nurses for preventive activities with computer assisted follow up: a randomised controlled trial.
To assess whether an organised programme of prevention including the use of a health promotion nurse noticeably improved recording and follow up of cardiovascular risk factors and cervical smears in a general practice that had access to computerised cell and recall. Randomised controlled trial. General practice in inner London. All 3206 men and women aged 30-64 registered with the practice. The intervention group had their risk factors ascertained and followed up by the health promotion nurse and the general practitioner, whereas those in the control group were managed by the general practitioner alone. Recording and follow up of blood pressure and cervical smears after three years. Recording of smoking, family history of ischaemic heart disease, and serum cholesterol concentrations were also examined. When the trial was stopped after two years the measurements of blood pressure in the preceding five years were 93% (1511/1620) v 73% (1160/1586) (95% confidence interval for difference 17.5 to 22.7%) for intervention and control groups respectively. For patients with hypertension the figures were 97% (104/107) v 69% (80/116) (18.2 to 38.2%). For women the proportion who had had a cervical smear in the preceding three years were 76% (606/799) v 49% (392/806) (22.5 to 31.9%). Recording of smoking, family history of ischaemic heart disease, and serum cholesterol concentrations was also higher in the intervention group compared with the control group. An organised programme, which includes a nurse with specific responsibility for adult prevention, is likely to make an important contribution to recording of risk factors and follow up of those patients with known risks.


Molecular cloning of Aplysia neuronal cDNAs that encode carboxypeptidases related to mammalian prohormone processing enzymes.
The bag cell neurons of Aplysia synthesize an egg-laying hormone (ELH) precursor that initially is cleaved into two fragments in the Golgi apparatus, and the fragments are differentially packaged in separate granule populations and further processed. Aplysia Afurin, Afurin2, prohormone convertase 1 (PC1), and PC2 are thought to be involved in the posttranslational processing of the ELH prohormone. In the present study, we have cloned Aplysia neuronal cDNAs that encode an enzyme most closely related to mammalian carboxypeptidase E (CPE), a peptide hormone processing enzyme that removes basic residues during prohormone processing. Northern blot analysis identified a single Aplysia CPE mRNA (approximately 5.2 kb) in central nervous system tissue. The C-terminal region of Aplysia CPE contains amphiphilic alpha-helices that may serve as a hydrophobic membrane anchor. A novel neuronal Aplysia enzyme was also identified by the polymerase chain reaction that was most closely related to the carboxypeptidase D (CPD)-related duck protein gp180 and the Drosophila silver gene carboxypeptidases. Aplysia CPE and the CPD-related enzyme are candidate processing enzymes that may play a role in the processing of the ELH prohormone and other Aplysia prohormones.


Influence of noninvasive peripheral arterial blood pressure measurements on assessment of dynamic cerebral autoregulation.
Assessment of dynamic cerebral autoregulation (CA) requires continuous recording of arterial blood pressure (ABP). In humans, noninvasive ABP recordings with the Finapres device have often been used for this purpose. We compared estimates of dynamic CA derived from Finapres with those from invasive recordings in the aorta. Measurements of finger noninvasive ABP (Finapres), intra-aortic ABP (Millar catheter), surface ECG, transcutaneous CO2, and bilateral cerebral blood flow velocity (CBFV) in the middle cerebral arteries were simultaneously and continuously recorded in 27 patients scheduled for percutaneous coronary interventions. Phase, gain, coherence, and CBFV step response from both the Finapres and intra-arterial catheter were estimated by transfer function analysis. A dynamic autoregulation index (ARI) was also calculated. For both hemispheres, the ARI index and the CBFV step response recovery at 4 s were significantly greater for the Finapres-derived estimates than for the values obtained from aortic pressure. The transfer function gain for frequencies <0.1 Hz was significantly smaller for the Finapres estimates. The phase frequency response was significantly greater for the Finapres estimates at frequencies >0.1 Hz, but not at lower frequencies. The Finapres gives higher values for the efficiency of dynamic CA compared with values derived from aortic pressure measurements, as indicated by biases in the ARI index, CBFV step response, gain, and phase. Despite the significance of these biases, their relatively small amplitude indicates a good level of agreement between indexes of CA derived from the Finapres compared with corresponding estimates obtained from invasive measurements of aortic ABP.


Oxidative stress alters specific membrane currents in isolated cardiac myocytes.
To evaluate the effects of oxidative stress on cardiac membrane currents, single cells from frog ventricle were exposed to tert-butyl hydroperoxide (t-BHP). Incubation of these cells with 2 mM t-BHP causes a rapid depletion of cellular glutathione, followed by a more gradual increase in the contents of malonaldialdehyde and conjugated dienes. Effects of this rapidly evolving oxidative stress were studied on sodium, calcium, and potassium currents of isolated ventricular cells. t-BHP caused a progressive decrease in the magnitude of sodium current obtained on depolarization from a holding potential of -85 mV, which was accompanied by a shift in the reversal potential toward more negative potentials. The voltage dependence of the steady-state parameters for activation and inactivation was shifted, such that in peroxide-exposed cells, there was a greater overlap of activation and inactivation parameters, which would be expected to result in an increased window current. In addition, in the presence of t-BHP, the time constant for activation was decreased at most depolarizing potentials, whereas the time constant for inactivation was increased. The resultant sodium current transients were, therefore, slower in the presence of the peroxide because of slower inactivation. Prolonged exposure of the cells to t-BHP led to a complete and selective inhibition of the Na+ current. However, even when all the Na+ current was inhibited, the K+ and Ca2+ currents remained essentially unaltered. Also, no large outward currents were observed at this stage, indicating that ATP concentration was not drastically decreased. The barrier properties of plasma membrane remained intact, as it was possible to form gigohm seals between the patch pipette and the plasma membrane of cells treated with 2-14 mM t-BHP for up to 30 minutes. These results account for the proarrhythmic effects of free radicals and oxidative stress on cardiac tissues.


Influence of the Gastrointestinal Environment on the Bioavailability of Ethinyl Estradiol Sorbed to Single-Walled Carbon Nanotubes.
Recent evidence suggests that, because of their sorptive nature, if single-walled carbon nanotubes (SWCNTs) make their way into aquatic environments, they may reduce the toxicity of other waterborne contaminants. However, few studies have examined whether contaminants remain adsorbed following ingestion by aquatic organisms. The objective of this study was to examine the bioavailability and bioactivity of ethinyl estradiol (EE2) sorbed onto SWCNTs in a fish gastrointestinal (GI) tract. Sorption experiments indicated that SWCNTs effectively adsorbed EE2, but the chemical was still able to bind and activate soluble estrogen receptors (ERs) in vitro. However, centrifugation to remove SWCNTs and adsorbed EE2 significantly reduced ER activity compared to that of EE2 alone. Additionally, the presence of SWCNTs did not reduce the extent of EE2-driven induction of vitellogenin 1 in vivo compared to the levels in organisms exposed to EE2 alone. These results suggest that while SWCNTs adsorb EE2 from aqueous solutions, under biological conditions EE2 can desorb and retain bioactivity. Additional results indicate that interactions with gastrointestinal proteins may decrease the level of adsorption of estrogen to SWCNTs by 5%. This study presents valuable data for elucidating how SWCNTs interact with chemicals that are already present in our aquatic environments, which is essential for determining their potential health risk.


Immunopathogenesis and proposed clinical score for identifying Kelch-like protein-11 encephalitis.
In this study, we report the clinical features of Kelch-like protein 11 antibody-associated paraneoplastic neurological syndrome, design and validate a clinical score to facilitate the identification of patients that should be tested for Kelch-like protein 11 antibodies, and examine in detail the nature of the immune response in both the brain and the tumour samples for a better characterization of the immunopathogenesis of this condition. The presence of Kelch-like protein 11 antibodies was retrospectively assessed in patients referred to the French Reference Center for paraneoplastic neurological syndrome and autoimmune encephalitis with (i) antibody-negative paraneoplastic neurological syndrome [limbic encephalitis (n = 105), cerebellar degeneration (n = 33)] and (ii) antibody-positive paraneoplastic neurological syndrome [Ma2-Ab encephalitis (n = 34), antibodies targeting N-methyl-D-aspartate receptor encephalitis with teratoma (n = 49)]. Additionally, since 1 January 2020, patients were prospectively screened for Kelch-like protein 11 antibodies as new usual clinical practice. Overall, Kelch-like protein 11 antibodies were detected in 11 patients [11/11, 100% were male; their median (range) age was 44 (35-79) years], 9 of them from the antibody-negative paraneoplastic neurological syndrome cohort, 1 from the antibody-positive (Ma2-Ab) cohort and 1 additional prospectively detected patient. All patients manifested a cerebellar syndrome, either isolated (4/11, 36%) or part of a multi-system neurological disorder (7/11, 64%). Additional core syndromes were limbic encephalitis (5/11, 45%) and myelitis (2/11, 18%). Severe weight loss (7/11, 64%) and hearing loss/tinnitus (5/11, 45%) were common. Rarer neurologic manifestations included hypersomnia and seizures (2/11, 18%). Two patients presented phenotypes resembling primary neurodegenerative disorders (progressive supranuclear palsy and flail arm syndrome, respectively). An associated cancer was found in 9/11 (82%) patients; it was most commonly (7/9, 78%) a spontaneously regressed ('burned-out') testicular germ cell tumour. A newly designed clinical score (MATCH score: male, ataxia, testicular cancer, hearing alterations) with a cut-off ≥4 successfully identified patients with Kelch-like protein 11 antibodies (sensitivity 78%, specificity 99%). Pathological findings (three testicular tumours, three lymph node metastases of testicular tumours, one brain biopsy) showed the presence of a T-cell inflammation with resulting anti-tumour immunity in the testis and one chronic, exhausted immune response-demonstrated by immune checkpoint expression-in the metastases and the brain. In conclusion, these findings suggest that Kelch-like protein 11 antibody paraneoplastic neurological syndrome is a homogeneous clinical syndrome and its detection can be facilitated using the MATCH score. The pathogenesis is probably T-cell mediated, but the stages of inflammation are different in the testis, metastases and the brain.


Relationship of Friend murine leukemia virus production to growth and hemoglobin synthesis in cultured erythroleukemia cells.
The factors that control oncornavirus formation were analyzed in Friend leukemia cells that undergo hematopoiesis when treated with dimethyl sulfoxide. Suspension cultures of Ostertag FSD-1 cell line were found to enter a G or resting state at the end of their proliferative phase and to simultaneously cease producing helper and dependent components of Friend virus. Whereas the decline in virus production is at least 100-fold, rates of cellular RNA and protein synthesis are only slightly lower in resting than in growing cells. Both resting and growing cells contain similarly large concentrations of the viral proteins P(30) and P(12). Dimethyl sulfoxide induces hemoglobin synthesis in growing cells, but its effects on virus production appear to be indirect results of its action to inhibit cell growth and thus to delay entry of cells into the G resting state. Furthermore, variant cell lines were obtained with differing abilities to synthesize virus or hemoglobin. Some lines no longer produce infectious virus, although they all harbor murine leukemia virus genes which are expressed to varying extents. The major internal protein of these oncornaviruses, P(30), is synthesized in large amounts by all of the cell lines. These results suggest that Friend virus production is not coinduced with erythroid differentiation, as had been proposed, but rather is controlled by a cellular growth cycle.


START lipid/sterol-binding domains are amplified in plants and are predominantly associated with homeodomain transcription factors.
In animals, steroid hormones regulate gene expression by binding to nuclear receptors. Plants lack genes for nuclear receptors, yet genetic evidence from Arabidopsis suggests developmental roles for lipids/sterols analogous to those in animals. In contrast to nuclear receptors, the lipid/sterol-binding StAR-related lipid transfer (START) protein domains are conserved, making them candidates for involvement in both animal and plant lipid/sterol signal transduction. We surveyed putative START domains from the genomes of Arabidopsis, rice, animals, protists and bacteria. START domains are more common in plants than in animals and in plants are primarily found within homeodomain (HD) transcription factors. The largest subfamily of HD-START proteins is characterized by an HD amino-terminal to a plant-specific leucine zipper with an internal loop, whereas in a smaller subfamily the HD precedes a classic leucine zipper. The START domains in plant HD-START proteins are not closely related to those of animals, implying collateral evolution to accommodate organism-specific lipids/sterols. Using crystal structures of mammalian START proteins, we show structural conservation of the mammalian phosphatidylcholine transfer protein (PCTP) START domain in plants, consistent with a common role in lipid transport and metabolism. We also describe putative START-domain proteins from bacteria and unicellular protists. The majority of START domains in plants belong to a novel class of putative lipid/sterol-binding transcription factors, the HD-START family, which is conserved across the plant kingdom. HD-START proteins are confined to plants, suggesting a mechanism by which lipid/sterol ligands can directly modulate transcription in plants.


Higher Rates of DZ Twinning in a Twenty-First Century Birth Cohort.
The Colorado Twin Registry is a population based registry initiated in 1984 with the involvement of the Colorado Department of Health, Division of Vital Statistics. Recruitment includes birth cohorts several years prior to 1984 and all subsequent years. As part of a recent evaluation of Colorado birth records for the years 2006 through 2008 we became aware of a shifting trend in the proportion of MZ and DZ twins in the Colorado population. Historically (Bulmer 1970 The biology of twinning in man, Clarendon, Oxford) we have expected a 1/3, 1/3, 1/3 ratio of MZ, same-sex DZ and opposite sex DZ twins in Caucasian populations. An excess of MZ pairs in most studies was assumed to be due to selection bias. Somewhat more recently, Hur et al.(1995 Behav Genet 25, 337-340) provided evidence that the DZ twinning rate was falling and that therefore selection bias was not the reason for higher MZ enrollment in most twin studies. They suggested that twin researchers might consider strategies to over-enroll DZ pairs to maximize statistical power. In contrast, we now find that of the 3217 twin births in Colorado from 2006 to 2008 with identified sex information the MZ rate is estimated at only 22%, and we have corroborating reports from other states of similar estimates. These were calculated applying Weinberg's rule which assumes an equal birth rate for same sex and opposite sex DZ pairs so that the proportion of MZ in a sample is the proportion of same sex (MM + FF) minus the proportion of opposite-sex (MF, FM). We explore factors, such as an increase in the proportion of non-Caucasian parents and an increase in average maternal age, which may contribute to this shift.


Patterning and process parameter effects in 3D suspension near-field electrospinning of nanoarrays.
The extracellular matrix (ECM) contains nanofibrous proteins and proteoglycans. Nanofabrication methods have received growing interest in recent years as a means of recapitulating these elements within the ECM. Near-field electrospinning (NFES) is a versatile fibre deposition method, capable of layer-by-layer nano-fabrication. The maximum layer height is generally limited in layer-by-layer NFES as a consequence of electrostatic effects of the polymer at the surface, due to residual charge and polymer dielectric properties. This restricts the total volume achievable by layer-by-layer techniques. Surpassing this restriction presents a complex challenge, leading to research innovations aimed at increasing patterning precision, and achieving a translation from 2D to 3D additive nanofabrication. Here we investigated a means of achieving this translation through the use of 3D electrode substrates. This was addressed by in-house developed technology in which selective laser melt manufactured standing pillar electrodes were combined with a direct suspension near-field electrospinning (SNFES) technique, which implements an automated platform to manoeuvre the pillar electrodes around the emitter in order to suspend fibres in the free space between the electrode support structures. In this study SNFES was used in multiple operation modes, investigating the effects of varying process parameters, as well as pattern variations on the suspended nanoarrays. Image analysis of the nanoarrays allowed for the assessment of fibre directionality, isotropy, and diameter; identifying optimal settings to generate fibres for tissue engineering applications.


Safety and tolerability of tenofovir vaginal gel in abstinent and sexually active HIV-infected and uninfected women.
To establish the highest practical dose and frequency (HPDF) of 0.3% or 1% tenofovir vaginal gel applied once or twice daily by sexually abstinent HIV-uninfected women, and to evaluate the safety, tolerability and systemic pharmacokinetics of the HPDF in abstinent and sexually active HIV-negative and HIV-infected women. Eighty-four women, enrolled in sequential cohorts, used the study product for 14 consecutive intermenstrual days. Safety laboratory assessments and pelvic examinations were carried out during five study visits, with colposcopy at enrollment and on day 14. Samples for pharmacokinetics were collected before and after the initial tenofovir gel use and at day 13. The 1% tenofovir gel used twice daily was as well tolerated as other regimens used by the 48 HIV-negative sexually abstinent women, establishing the HPDF. Although 92% of the women reported at least one adverse event, the majority were mild (87%) and involved the genitourinary tract (70%). One possibly product-related severe adverse event involving lower abdominal cramping was reported by a sexually abstinent woman who used 0.3% gel twice daily. Serum tenofovir levels were low but detectable in 14 of the 25 women. No new HIV RNA resistance mutations were detected after 2 weeks of tenofovir gel in the 24 HIV-infected participants. No significant systemic toxicity was detected. A 2-week course of 1% tenofovir vaginal gel used twice daily was well tolerated in sexually abstinent and sexually active HIV-negative and HIV-positive women. Systemic tenofovir absorption occurred. Expanded safety and effectiveness testing is warranted.


Feasibility and Preliminary Effectiveness of the Homework Intervention Strategy (eHIS) Program to Enhance Male Condom Use: Research Protocol.
Although condoms are effective in reducing the risk of sexually transmitted infections (STIs) and unintended pregnancy, they are still often not used consistently and correctly. Negative impact on sensation and pleasure, ruining the mood, causing problems with maintaining erection, and condom slippage or breakage are some of the reasons given by men explaining why they do not want to use condoms. Although many interventions promoting condom use exist, some of them delivered online are complex and time- and resource-intensive. The Homework Intervention Strategy (eHIS) program, adapted from the existing face-to-face Kinsey Institute Homework Intervention Strategy (KIHIS) program, aims to address these issues by encouraging men to focus on sensation and pleasure when trying different types of condoms and lubricants in a low-pressure situation (on their own, without a partner present). The objectives of this study are to assess the feasibility, acceptability, and users' engagement with the eHIS program, its preliminary effectiveness in increasing condom use frequency and consistency, as well as the feasibility of the program's evaluation approach, including choice of measures and participant recruitment and retaining strategies (primary outcomes). Secondary outcomes include condom use experience, condom use attitudes, condom use self-efficacy, condom use errors and problems, and condom fit-and-feel. All of these will be analyzed in the context of participants' demographics, sexual history, and previous condom use. The study has a pre-post-test, within-subjects design. Men aged 18 to 69 and living in the United Kingdom are recruited through posters, leaflets, social media, and emails. Study participants are asked to complete T1 (baseline) measures before entering the eHIS website. After completing the T1 measures, they can order a free condoms and lubricants kit and have access to the eHIS website for 4 weeks. During that time they are asked to practice using different types of condoms and lubricants on their own in a no-pressure situation. Following T1, participants are asked to complete the T2 and T3 measures at 4 and 10 weeks, respectively. Data collection for the study is completed. Data analysis is in progress and is expected to be completed by February 2018. This brief, home-based, self-guided program may lead to increased consistent and correct condom use. Online delivery can make the program an easily accessible and low-cost health promotion intervention, which has the potential to reach a wide and diverse audience. If results of the current study show the program's feasibility and preliminary effectiveness in changing condom use related outcomes, a larger scale randomized controlled trial (RCT) will be conducted. Research Registry: researchregistry2325; http://www.researchregistry.com/browse-the-registry.html# home/registrationdetails/58da6cad1d7ab0314337d076/ (Archived by WebCite at http://www.webcitation.org/6vXs6S9XW).


The impact of next-generation sequencing in immunogenetics: current status and future directions.
Next-generation sequencing (NGS) has now been established, and widely recognized, to be the preferred choice for human leukocyte antigen (HLA) typing. This transformation is based upon the many scientific, operational and economic benefits this technology affords. In this report, we review the major advantages, existing limitations and significant promise derived from adopting this technology in immunogenetics. Significant benefits have emerged from the usage of NGS in a relatively short period, whereby we realize that this technology not only helps addressing the technical and operational problems we have had with the legacy methods for HLA typing, but equally important, it also allows for creative applications in stem cell and organ transplantation, new ways to investigate associations of the major histocompatibility complex (MHC) with many diseases and enhance our understanding regarding the MHC and non-MHC genomic interactions. The emerging picture is one of significant benefits in the diagnostic sphere of immunogenetics and transplantation and one of interconnectivity, integrating the many biological pathways controlled and affected by this unique genomic region. NGS has revolutionized the science and practice of immunogenetics. In this article, we identify the still unresolved issues, the current benefits to transplantation and the potential for dissecting the complexity of the MHC, one of the most fascinating regions of the human genome. Using current trends, an attempt is made to predict future directions and outcomes.


Failure of rabbit neutrophils to secrete endogenous pyrogen when stimulated with staphylococci.
Cells obtained from acute peritoneal exudates in rabbits were separated into neutrophil and mononuclear populations by centrifugation on colloidal silica gradients. When these populations were separately incubated in tissue culture medium in the presence of opsonized Staphylococcus epidermidis, endogenous pyrogen was secreted only by the adherent cells of the mononuclear population. Pyrogen production by neutrophils could not have amounted to as much as 1% of the pyrogen produced by macrophages. When mononuclear cells were added back to purified neutrophils, no pyrogen was produced that could not be accounted for by the number of macrophages added. Rabbit blood cells were similarly fractionated on colloidal silica gradients. Again, endogenous pyrogen was made only by the adherent mononuclear population. The neutrophils isolated on these gradients appeared to be morphologically normal and were 85% viable as judged by dye exclusion. They showed normal random motility. Both blood and exudate neutrophils responded chemotactically to N-formyl Met-Leu-Phe, and blood neutrophils responded chemotactically to zymosan-activated serum. Both kinds of neutrophils phagocytosed zymosan particles and both killed opsonized S. epidermidis in a roller tube system. Both blood and exudate neutrophils showed normal superoxide production when stimulated with opsonized zymosan particles. This evidence suggests that macrophages are the only source of endogenous pyrogens, and that pyrogens secreted by cell populations that are rich in neutrophils are to be attributed to the monocytes or macrophages that they contain.


Detection and genotyping by real-time PCR/RFLP analyses of Giardia duodenalis from human faeces.
A nested PCR assay (TPILC-PCR) was developed to detect and distinguish between Giardia duodenalis assemblages A and B from human faeces by analysis of the triose phosphate isomerase gene (tpi). The assay comprised an initial multiplexed block-based amplification. This was followed by two separate real-time PCR assays specific for assemblages A and B using a LightCycler and SYBR Green I to identify PCR products by melting-point analysis. RFLP analysis was applied to distinguish G. duodenalis assemblage A groups I and II. The real-time nested PCR was evaluated using DNA extracted from purified giardial trophozoites, Cryptosporidium oocysts, whole faeces containing a range of potential pathogens (including G. duodenalis), faecal smears and bacterial suspensions. The assay was specific, sensitive, reproducible and rapid.


Low frequency of target organ damage in Taiwanese with white coat hypertension.
The clinical importance of white coat hypertension (WCH) remains to be clarified. This study investigated the target organ damage in Taiwanese with WCH. A total of 188 consecutive Taiwanese (88 men and 100 women), aged 26 to 75 years who had an abnormal office casual blood pressure (systolic blood pressure >/= 140 mm Hg or diastolic blood pressure >/= 90 mm Hg or both) and a normal ambulatory blood pressure (ABP) average (systolic ABP average < 140 mm Hg and diastolic ABP average < 90 mm Hg) at the outpatient clinic or from a mass survey were enrolled. Office casual blood pressure measurements were obtained by standard sphygmomanometric methods. Twenty-four-hour blood pressures were recorded by a commercial ambulatory pressure recorder (Del Mar Avionics, Model 1990 Pressurometer IV System). Hypertension-related target organ complications were assessed by electrocardiogram, chest X-ray, urinalysis and eye fundus examinations. Target organ damage was found in 6.4% of subjects with WCH. Roentgenographic left ventricular hypertrophy (LVH) was found in 1.1% of subjects and electrocardiographic LVH in 2.7%. Proteinuria was found in 1.6% of subjects and retinopathy in 1.1%. The frequencies of various target organ damage were not significantly associated with age, gender and the definition of normal ABP average as 135/85 mm Hg or 140/90 mm Hg. WCH represents a low-risk stratum for target organ damage in Taiwanese. These subjects should be identified and followed up regularly. The factors responsible for the low frequency of target organ damage in Taiwanese with WCH need further study.


The role of microbiota in tissue repair and regeneration.
A comprehensive understanding of the human body endogenous microbiota is essential for acquiring an insight into the involvement of microbiota in tissue healing and regeneration process in order to enable development of biomaterials with a better integration with human body environment. Biomaterials used for biomedical applications are normally germ-free, and the human body as the host of the biomaterials is not germ-free. The complexity and role of the body microbiota in tissue healing/regeneration have been underestimated historically. Traditionally, studies aiming at the development of novel biomaterials had focused on the effects of environment within the target tissue, neglecting the signals generated from the microbiota and their impact on tissue regeneration. The significance of the human body microbiota in relation to metabolism, immune system, and consequently tissue regeneration has been recently realised and is a growing research field. This review summarises recent findings on the role of microbiota and mechanisms involved in tissue healing and regeneration, in particular skin, liver, bone, and nervous system regrowth and regeneration highlighting the potential new roles of microbiota for development of a new generation of biomaterials.


Magnolol treatment attenuates dextran sulphate sodium-induced murine experimental colitis by regulating inflammation and mucosal damage.
Magnolol, the main and active ingredient of the Magnolia officinalis, has been widely used in traditional prescription to the human disorders. Magnolol has been proved to have several pharmacological properties including anti-bacterial, anti-oxidant and anti-inflammatory activities. However, the effects of magnolol on ulcerative colitis (UC) have not been reported. The aim of this study was to investigate the protective effects and mechanisms of magnolol on dextran sulphate sodium (DSS)-induced colitis in mice. The results showed that magnolol significantly alleviated DSS-induced body weight loss, disease activities index (DAI), colon length shortening and colonic pathological damage. In addition, magnolol restrained the expression of TNF-α, IL-1β and IL-12 via the regulation of nuclear factor-κB (NF-κB) and Peroxisome proliferator-activated receptor-γ (PPAR-γ) pathways. Magnolol also enhanced the expression of ZO-1 and occludin in DSS-induced mice colonic tissues. These results showed that magnolol played protective effects on DSS-induced colitis and may be an alternative therapeutic reagent for colitis treatment.


Why gases dissolve in liquids.
The thermodynamics and statistical mechanics of solubility are fairly well understood. It is still very difficult, however, to make quantitative predictions of solubility for real systems from first principles. The purposes of this article are to present the results of solubility experiments in some prototype solute-solvent systems, to show how far they may be understood from molecular first principles, and to discuss some of the things that are still missing. The main systems used as examples have the inert gas xenon as solute and some simple organic liquids as solvents.


Future basic science directions into mechanisms of neuropathic pain.
The aim of this article is to outline mechanisms underlying generation and maintenance of pain arising from trauma to peripheral nerve fibers and to present an overview of our recent studies of animal models of peripheral neuropathic pain and pain of temporomandibular disorders (TMD). The former model was induced by placing a polyethylene cuff around the sciatic nerve of the Sprague-Dawley rat and the TMD model was induced by injection of complete Freund's adjuvant into the rat's temporomandibular joint. In cuff-implanted rats, ongoing activity of dorsal horn neurons was greater than in controls, the cutaneous receptive field size of the neurons was greater, and both noxious and innocuous mechanical stimuli to the receptive field elicited an excitatory response during stimulation but also a marked afterdischarge that lasted up to 30 minutes; this afterdischarge was never observed in control rats in response to innocuous stimulation. The model of TMD was characterized by joint space narrowing, bone remodeling, infiltration of immune cells, loss in the range of jaw opening, and signs of nociception. Alterations in the neural substrate of nociception in animal models, and therefore also possibly in humans, appear to include changes in peripheral as well as central neurons. In the periphery, changes include alterations in the phenotype and central projections of large-diameter sensory nerve fibers. At the level of the trigeminal brainstem and spinal cord, there appear to be several types of change. One type is an increased efficacy of synaptic transmission onto second-order neurons. Another type of change is a reduction in inhibitory mechanisms, including a shift of gamma-amino butyric acid (GABAA) receptor activation to excitation. There is a need for further studies to focus on mechanisms for either the generation or the maintenance, or both, of neuropathic pain.


UPF2 is a critical regulator of liver development, function and regeneration.
Nonsense-mediated mRNA decay (NMD) is a post-transcriptional RNA surveillance process that facilitates the recognition and destruction of mRNAs bearing premature terminations codons (PTCs). Such PTC-containing (PTC+) mRNAs may arise from different processes, including erroneous processing and expression of pseudogenes, but also from more regulated events such as alternative splicing coupled NMD (AS-NMD). Thus, the NMD pathway serves both as a silencer of genomic noise and a regulator of gene expression. Given the early embryonic lethality in NMD deficient mice, uncovering the full regulatory potential of the NMD pathway in mammals will require the functional assessment of NMD in different tissues. Here we use mouse genetics to address the role of UPF2, a core NMD component, in the development, function and regeneration of the liver. We find that loss of NMD during fetal liver development is incompatible with postnatal life due to failure of terminal differentiation. Moreover, deletion of Upf2 in the adult liver results in hepatosteatosis and disruption of liver homeostasis. Finally, NMD was found to be absolutely required for liver regeneration. Collectively, our data demonstrate the critical role of the NMD pathway in liver development, function and regeneration and highlights the importance of NMD for mammalian biology.


Omega-3 Fatty Acids and their Role in Central Nervous System - A Review.
Polyunsaturated fatty acids (PUFAs) are crucial for our health and wellbeing; therefore, they have been widely investigated for their roles in maintaining human health and in disease treatment. Most Western diets include significant amount of saturated and omega-6 fatty acids and insufficient quantity of omega-3; however, the balance between omega-6 and omega-3 PUFA, in particular, is essential for the formation of pro- and anti-inflammatory lipids to promote health and prevent disease. As our daily diet affects our health, this paper draws attention to unique representatives of the omega-3 fatty acid group: alpha-linolenic acid and its derivatives. Recently, this has been shown to be effective in treating and preventing various diseases. It has been confirmed that omega-3 PUFAs may act as therapeutic agents as well and their significant role against inflammatory diseases, such as cardiovascular and neurodegenerative diseases, has been described. Some of nutritional factors have been described as a significant modifiers, which can influence brain elasticity and thus, effect on central nervous system functioning. Therefore, appropriate dietary management appears to be a non-invasive and effective approach to counteract neurological and cognitive disorders.


Nitrogen dynamics under Lolium perenne after a single application of three different sewage sludge types from the same treatment stream.
Three sludge types from the same treatment stream (undigested liquid, anaerobically digested liquid and dewatered, anaerobically digested cake) were used in a field based tub study. Amendments (4, 8, and 16 Mg dry solid (ds)ha(-1)) were incorporated into the upper 15 cm of a sandy loam soil prior to sowing with rye-grass (Lolium perenne L.). Nitrogen transformations in the soil were determined for the 80 d period following incorporation. Nitrogen uptake and crop yield were measured in the cut sward 35 and 70 d after sowing. The study showed that application of sewage sludge at rates as low as 4 Mgha(-1) can have a nutritional benefit to rye-grass over the two harvests. Differences in N transformation, and hence crop nutritional benefit, between sludge types were evident throughout the experiment. In particular, the dewatering process changed the mineral N characteristics of the anaerobically digested sludge, which, when not dewatered, outperformed the other sludges in terms of yield and mineralisation rate at both harvests. The dewatered sludge produced the lowest yield of rye-grass. The undigested liquid sludge had the lowest foliar N and soil NO(3)-N concentrations, possibly immobilised as the large oxidisable C component of this sludge was metabolised by the microbial biomass. Correlation data support the concept of preferential uptake of NH(4)-N over NO(3)-N in Lolium perenne. Results are discussed in the context of managing sludge type and application for a plant nutrient source and NO(3)-N release.


New drugs in cutaneous T-cell lymphomas.
Currently, there are no curative therapies for cutaneous T-cell lymphoma (CTCL), and consecutive treatments tend to be given until loss of response. There is an urgent need for new and improved therapies in CTCL to treat symptoms such as pruritus and painful skin lesions and prolong survival. This article reviews new drugs available for CTCL. CTCL encompasses a group of T-cell neoplasms presenting in the skin without systemic involvement. Mycosis fungoides being the most common type and Sézary syndrome the leukaemic form. Treatment is dependent on stage and responses to previous therapy. Treatments are broadly divided into skin-directed therapies which are first-line for early stage disease and systemic therapy reserved for refractory or advanced stage CTCL. This article reviews mode of action, responses and adverse effects of new drugs being considered for CTCL. Most drugs for CTCL have response rates between 30 and 40%, and response durations tend to be less than a year. As such new studies looking at drug combinations or as maintenance therapy in those with a response to previous therapy should be trialled and may offer improved quality of life and outcome in CTCL.


Primary cutaneous non-Hodgkin's lymphoma of Ann Arbor stage I: preferential cutaneous relapses but high cure rate with doxorubicin-based therapy.
Establish frequency, presenting features, response and relapse patterns, and outcome of primary cutaneous non-Hodgkin's lymphoma (PCNHL). Review of untreated patients, older than 16 years, presenting between 1971 and 1993 with cutaneous lymphoma, not mycosis fungoides, and Ann Arbor stage I. We identified 46 patients, 27 males, with median age of 57 years. Treatment was radiotherapy in 10 patients, doxorubicin-based therapy in 33 patients that was followed by radiotherapy in 25 patients, and other combination with radiotherapy in one patient. The complete response rate was 95%. After a median follow-up of 140 months (range, 61 to 284 months), 18 patients have relapsed, and 14 have died from lymphoma. The first failure was exclusively cutaneous in 50% of relapses. For the 44 treated patients, progression-free survival (PFS; actuarial +/- SE) was 61% +/- 7% and survival was 58% +/- 9% at 12 years. For the 18 patients with diffuse large B-cell lymphoma, after doxorubicin-based regimens, PFS was 71% +/- 12% (P = .0003) versus 0% after radiotherapy; survival was 77% +/- 12% versus 25% +/- 22% (P = 004), respectively. For the nine patients with follicular center-cell lymphoma treated with combined modality, the 12-year PFS was 89% +/- 11% and survival 70% +/- 18%. PCNHL is rare, and its first relapse is exclusively cutaneous in 50% of patients. Patients with diffuse large B-cell lymphoma are curable with doxorubicin-based regimens but not with radiotherapy. Prospective studies in PCNHL should define the cytogenetics, the basis for cutaneous tropism, the prognosis of histologic subtypes, and the role of radiotherapy.


Optical microscopic observation of fluorescence enhanced by grating-coupled surface plasmon resonance.
On the substrate carrying a sub-wavelength grating covered with a thin metal layer, a fluorescent dye-labeled cell was observed by fluorescence microscope. The fluorescence intensity was more than 20 times greater than that on an optically flat glass substrate. Such a great fluorescence enhancement from labeled cells bound to the grating substrate was due to the excitation by grating coupled surface plasmon resonance. The application of a grating substrate to two-dimensional detection and fluorescence microscopy appears to offer a promising method of taking highly sensitive fluorescence images.


The identification of intermediates in the reaction of pig heart lactate dehydrogenase with its substrates.
Pig heart lactate dehydrogenase was studied in the direction of pyruvate and NADH formation by recording rapid changes in extinction, proton concentration, nucleotide fluorescence and protein fluorescence. Experiments measuring extinction changes show that there is a very rapid formation of NADH within the first millisecond and that the amplitude of this phase (phase 1) increases threefold over the pH range 6-8. A second transient rate (phase 2) can also be distinguished (whose rate is pH-dependent), followed by a steady-state rate (phase 3) of NADH production. The sum of the amplitudes of the first two phases corresponds to 1mol of NADH produced/mol of active sites of lactate dehydrogenase. Experiments that measured the liberation of protons by using Phenol Red as an indicator show that no proton release occurs during the initial very rapid formation of NADH (phase 1), but protons are released during subsequent phases of NADH production. Fluorescence experiments help to characterize these phases, and show that the very rapid phase 1 corresponds to the establishment of an equilibrium between E(NAD) (Lactate) right harpoon over left harpoon H(+)E(NADH) (Pyruvate). This equilibrium can be altered by changing lactate concentration or pH, and the H(+)E(NADH) (Pyruvate) species formed has very low nucleotide fluorescence and quenched protein fluorescence. Phase 2 corresponds to the dissociation of pyruvate and a proton from the complex with a rate constant of 1150s(-1). The observed rate constant is slower than this and is proportional to the position of the preceding equilibrium. The E(NADH) formed has high nucleotide fluorescence and quenched protein fluorescence. The reaction, which is rate-limiting during steady-state turnover, must then follow this step and be involved with dissociation of NADH from the enzyme or some conformational change immediately preceding dissociation. Several inhibitory complexes have also been studied including E(NAD+) (Oxamate) and E(NADH) (Oxamate') and the abortive ternary complex E(NADH) (Lactate). The rate of NADH dissociation from the enzyme was measured and found to be the same whether measured by ligand displacement or by relaxation experiments. These results are discussed in relation to the overall mechanism of lactate dehydrogenase turnover and the independence of the four binding sites in the active tetramer.


Patterns of fusimotor innervation by gamma-efferents in cat peroneus tertius.
The pattern of gamma-efferent innervation of the muscle spindle was investigated in the peroneus tertius muscle of the cat. A number of spindle group Ia afferents were isolated and monitored during tetanic stimulation of isolated gamma-axons. The sample was dominated by efferents producing a static fusimotor effect on the afferent. An individual static axon normally projected to less than five but at times as many as seven muscle spindles. Each spindle normally received innervation from three to five static gamma-efferents but occasionally up to eight. The number of spindles innervated by a static gamma-axon was directly related to the efferent axonal conduction velocity. For each experiment, a probability distribution of the number of fusimotor effects was constructed from all available connections between the muscle spindles and static gamma-efferents considered in matrices of four afferents and four efferents. This distribution was then compared to a random binomial distribution. In each of the ten experiments, statistically significant differences (p less than 0.01) were noted between the experimental and random distributions. In order to interpret such deviations from the random distributions, similar analyses were performed on various combinations of afferents and efferents in simulated sets displaying grouping of effects. It was concluded that the observed differences between experimental and random distributions may be produced by a grouping of fusimotor innervation limited to a small set of spindles.


The potential of antisense oligonucleotide therapies for inherited childhood lung diseases.
Antisense oligonucleotides are an emerging therapeutic option to treat diseases with known genetic origin. In the age of personalised medicines, antisense oligonucleotides can sometimes be designed to target and bypass or overcome a patient's genetic mutation, in particular those lesions that compromise normal pre-mRNA processing. Antisense oligonucleotides can alter gene expression through a variety of mechanisms as determined by the chemistry and antisense oligomer design. Through targeting the pre-mRNA, antisense oligonucleotides can alter splicing and induce a specific spliceoform or disrupt the reading frame, target an RNA transcript for degradation through RNaseH activation, block ribosome initiation of protein translation or disrupt miRNA function. The recent accelerated approval of eteplirsen (renamed Exondys 51™) by the Food and Drug Administration, for the treatment of Duchenne muscular dystrophy, and nusinersen, for the treatment of spinal muscular atrophy, herald a new and exciting era in splice-switching antisense oligonucleotide applications to treat inherited diseases. This review considers the potential of antisense oligonucleotides to treat inherited lung diseases of childhood with a focus on cystic fibrosis and disorders of surfactant protein metabolism.


Two new methods of improving optical image quality.
Two simple methods are presented by which the coherence between a laser light source and an illuminated object can be destroyed in optical systems where this coherence is undesirable. Both methods employ rotating phase changing disks; the first introduces a random time varying phase relationship across the area illuminated in the object plane, whereas the second produces a rapid, regular phase variation across this area. Results are claimed to be comparable to those obtained using normal incoherent light.


Mobile Apps to Support Family Caregivers of People With Alzheimer Disease and Related Dementias in Managing Disruptive Behaviors: Qualitative Study With Users Embedded in a Scoping Review.
People with Alzheimer disease and related dementias often display disruptive behaviors (eg, aggression, wandering, and restlessness), which increase family caregivers' burden of care. However, there are few tools currently available to help these caregivers manage disruptive behaviors. Mobile apps could meet this need, but to date little is known about them. The aims of our study were to identify existing mobile apps designed to support family caregivers of people with Alzheimer disease and related dementias in managing disruptive behaviors; explore whether family caregivers view these mobile apps as relevant to meeting their needs and as useful in managing disruptive behaviors; and document the types of mobile apps that are of interest and appeal to most family caregivers (with regard to format, ergonomics, and clarity). A review of mobile apps initially conducted in February 2018 was updated in March 2019 with 2 platforms (App Store [Apple Inc.] and Google Play [Google]). The selected apps were first analyzed independently by 3 raters (2 students and 1 researcher) for each of the platforms. A focus group discussion was then held with 4 family caregivers to explore their perceptions of the apps according to their needs and interests. The content of the discussion was analyzed. Initially, 7 of 118 apps identified met the inclusion criteria. An eighth app, recommended by one of the knowledge users, was added later. Four family caregivers (women aged between 58 and 78 years) participated in the discussion. Participants expressed a preference for easy-to-understand apps that provide concrete intervention strategies. They reported being most inclined to use two apps, Dementia Advisor and DTA Behaviours. Few mobile apps on the market meet the needs of family caregivers in terms of content and usability. Our results could help to address this gap by identifying what family caregivers deem relevant in a mobile app to help them manage disruptive behaviors.


Unique alpha-spectrin mutant in a kindred with common hereditary elliptocytosis.
We report here a unique variant of alpha spectrin in a kindred with hereditary elliptocytosis. This novel red blood cell-membrane protein migrated to a position between the normal alpha- and beta-spectrin subunits in SDS polyacrylamide gel electrophoresis. It was identified as an alpha spectrin by its binding to anti-alpha spectrin antibodies, by the absence of a phosphorylation site, and by the normal 1:1 stoichiometry between total alpha- and beta-spectrin molecules. The quantity of the alpha-spectrin mutant, expressed as a percentage of the total alpha spectrin, varied from 9.9-45.2% among six affected individuals. Two-dimensional electrophoretic analysis of spectrin tryptic digests was qualitatively normal but showed a decreased quantity of a normal alpha IV fragment. The variable quantity of alpha-spectrin mutant among family members correlated directly with the increased percentage of spectrin dimers in cold low ionic strength spectrin extracts (r = 0.92) and inversely with red blood cell ghost mechanical stability (r = -0.98). The data suggest that this new alpha-spectrin mutant is responsible for decreased spectrin dimer-dimer association and for red cell instability in affected individuals.


The role of transglutaminase in the rat subtotal nephrectomy model of renal fibrosis.
Tissue transglutaminase is a calcium-dependent enzyme that catalyzes the cross-linking of polypeptide chains, including those of extracellular matrix (ECM) proteins, through the formation of epsilon-(gamma-glutamyl) lysine bonds. This crosslinking leads to the formation of protein polymers that are highly resistant to degradation. As a consequence, the enzyme has been implicated in the deposition of ECM protein in fibrotic diseases such as pulmonary fibrosis and atherosclerosis. In this study, we have investigated the involvement of tissue transglutaminase in the development of kidney fibrosis in adult male Wistar rats submitted to subtotal nephrectomy (SNx). Groups of six rats were killed on days 7, 30, 90, and 120 after SNx. As previously described, these rats developed progressive glomerulosclerosis and tubulo-interstitial fibrosis. The tissue level of epsilon-(gamma-glutamyl) lysine cross-link (as determined by exhaustive proteolytic digestion followed by cation exchange chromatography) increased from 3.47+/- 0.94 (mean+/-SEM) in controls to 13.24+/-1.43 nmol/g protein 90 d after SNx, P </= 0.01. Levels of epsilon-(gamma-glutamyl) lysine cross-link correlated well with the renal fibrosis score throughout the 120 observation days (r = 0.78, P </= 0.01). Tissue homogenates showed no significant change in overall transglutaminase activity (14C putrescine incorporation assay) unless adjusted for the loss of viable tubule cells, when an increase from 5.77+/-0.35 to 13.93+/-4.21 U/mg DNA in cytosolic tissue transglutaminase activity was seen. This increase was supported by Western blot analysis, showing a parallel increase in renal tissue transglutaminase content. Immunohistochemistry demonstrated that this large increase in epsilon-(gamma-glutamyl) lysine cross-link and tissue transglutaminase took place predominantly in the cytoplasm of tubular cells, while immunofluorescence also showed low levels of the epsilon-(gamma-glutamyl) lysine cross-link in the extracellular renal interstitial space. The number of cells showing increases in tissue transglutaminase and its cross-link product, epsilon-(gamma-glutamyl) lysine appeared greater than those showing signs of typical apoptosis as determined by in situ end-labeling. This observed association between tissue transglutaminase, epsilon-(gamma-glutamyl) lysine cross-link, and renal tubulointerstitial scarring in rats submitted to SNx suggests that tissue transglutaminase may play an important role in the development of experimental renal fibrosis and the associated loss of tubule integrity.


Confocal imaging of Pseudomonas syringae pv. phaseolicola colony development in bean reveals reduced multiplication of strains containing the genomic island PPHGI-1.
Pseudomonas syringae pv. phaseolicola is the seed borne causative agent of halo blight in the common bean Phaseolus vulgaris. Pseudomonas syringae pv. phaseolicola race 4 strain 1302A contains the avirulence gene hopAR1 (located on a 106-kb genomic island, PPHGI-1, and earlier named avrPphB), which matches resistance gene R3 in P. vulgaris cultivar Tendergreen (TG) and causes a rapid hypersensitive reaction (HR). Here, we have fluorescently labeled selected Pseudomonas syringae pv. phaseolicola 1302A and 1448A strains (with and without PPHGI-1) to enable confocal imaging of in-planta colony formation within the apoplast of resistant (TG) and susceptible (Canadian Wonder [CW]) P. vulgaris leaves. Temporal quantification of fluorescent Pseudomonas syringae pv. phaseolicola colony development correlated with in-planta bacterial multiplication (measured as CFU/ml) and is, therefore, an effective means of monitoring Pseudomonas syringae pv. phaseolicola endophytic colonization and survival in P. vulgaris. We present advances in the application of confocal microscopy for in-planta visualization of Pseudomonas syringae pv. phaseolicola colony development in the leaf mesophyll to show how the HR defense response greatly affects colony morphology and bacterial survival. Unexpectedly, the presence of PPHGI-1 was found to cause a reduction of colony development in susceptible P. vulgaris CW leaf tissue. We discuss the evolutionary consequences that the acquisition and retention of PPHGI-1 brings to Pseudomonas syringae pv. phaseolicola in planta.


Why do physicians vary so widely in their referral rates?
To determine which physician practice and psychological factors contribute to observed variation in primary care physicians' referral rates. Cross-sectional questionnaire-based survey and analysis of claims database. A large managed care organization in the Rochester, NY, metropolitan area. Internists and family physicians. Patient referral status (referred or not) was derived from the 1995 claims database of the managed care organization. The claims data were also used to generate a predicted risk of referral based on patient age, gender, and case mix. A physician survey completed by a sample of 182 of the physicians (66% of those eligible) included items on their practice and validated psychological scales on anxiety from uncertainty, risk aversiveness, fear of malpractice, satisfaction with practice, autonomous and controlled motivation for referrals and test ordering, and psycho-social beliefs. The relation between the risk of referral and the physician practice and psychological factors was examined using logistic regression. After adjustment for predicted risk of referral (case mix), patients were more likely to be referred if their physician was female, had more years in practice, was an internist, and used a narrower range of diagnoses (a higher Herfindahl index, also derived from the claims data). Of the psychological factors, only greater psychosocial orientation and malpractice fear was associated with greater likelihood of referral. When the physician practice factors were excluded from the analysis, risk aversion was positively associated with referral likelihood. Most of the explainable variation in referral likelihood was accounted for by patient and physician practice factors like case mix, physician gender, years in practice, specialty, and the Herfindahl index. Relatively little variation was explained by any of the examined physician psychological factors.


Identifying Persuasive Public Health Messages to Change Community Knowledge and Attitudes About Bulimia Nervosa.
Addressing stigma through social marketing campaigns has the potential to enhance currently low rates of treatment seeking and improve the well-being of individuals with the eating disorder bulimia nervosa. This study aimed to evaluate the persuasiveness of health messages designed to reduce stigma and improve mental health literacy about this disorder. A community sample of 1,936 adults (48.2% male, 51.8% female) from Victoria, Australia, provided (a) self-report information on knowledge and stigma about bulimia nervosa and (b) ratings of the persuasiveness of 9 brief health messages on dimensions of convincingness and likelihood of changing attitudes. Messages were rated moderately to very convincing and a little to moderately likely to change attitudes toward bulimia nervosa. The most persuasive messages were those that emphasized that bulimia nervosa is a serious mental illness and is not attributable to personal failings. Higher ratings of convincingness were associated with being female, with having more knowledge about bulimia nervosa, and with lower levels of stigma about bulimia nervosa. Higher ratings for likelihood of changing attitudes were associated with being female and with ratings of the convincingness of the corresponding message. This study provides direction for persuasive content to be included in social marketing campaigns to reduce stigma toward bulimia nervosa.


FGF signaling delineates the cardiac progenitor field in the simple chordate, Ciona intestinalis.
Comprehensive gene networks in Ciona intestinalis embryos provide a foundation for characterizing complex developmental processes, such as the initial phases of chordate heart development. The basic helix-loop-helix regulatory gene Ci-Mesp is required for activation of cardiac transcription factors. Evidence is presented that Ci-Ets1/2, a transcriptional effector of receptor tyrosine kinase (RTK) signaling, acts downstream from Mesp to establish the heart field. Asymmetric activation of Ets1/2, possibly through localized expression of FGF9, drives heart specification within this field. During gastrulation, Ets1/2 is expressed in a group of four cells descended from two Mesp-expressing founder cells (the B7.5 cells). After gastrulation, these cells divide asymmetrically; the smaller rostral daughters exhibit RTK activation (phosphorylation of ERK) and form the heart lineage while the larger caudal daughters form the anterior tail muscle lineage. Inhibition of RTK signaling prevents heart specification. Targeted inhibition of Ets1/2 activity or FGF receptor function also blocks heart specification. Conversely, application of FGF or targeted expression of constitutively active Ets1/2 (EtsVp16) cause both rostral and caudal B7.5 lineages to form heart cells. This expansion produces an unexpected phenotype: transformation of a single-compartment heart into a functional multicompartment organ. We discuss these results with regard to the development and evolution of the multichambered vertebrate heart.


Comparison of intensity-modulated radiotherapy and 3-dimensional conformal radiotherapy as adjuvant therapy for gastric cancer.
The current study was performed to compare the clinical outcomes and toxicity in patients treated with postoperative chemoradiotherapy for gastric cancer using intensity-modulated radiotherapy (IMRT) versus 3-dimensional conformal radiotherapy (3D CRT). Fifty-seven patients with gastric or gastroesophageal junction cancer were treated postoperatively: 26 with 3D CRT and 31 with IMRT. Concurrent chemotherapy was capecitabine (n=31), 5-fluorouracil (5-FU) (n=25), or none (n=1). The median radiation dose was 45 Gy. Dose volume histogram parameters for kidney and liver were compared between treatment groups. The 2-year overall survival rates for 3D CRT versus IMRT were 51% and 65%, respectively (P=.5). Four locoregional failures occurred each in the 3D CRT (15%) and the IMRT (13%) patients. Grade>or=2 acute gastrointestinal toxicity was found to be similar between the 3D CRT and IMRT patients (61.5% vs 61.2%, respectively) but more treatment breaks were needed (3 vs 0, respectively). The median serum creatinine from before radiotherapy to most recent creatinine was unchanged in the IMRT group (0.80 mg/dL) but increased in the 3D CRT group from 0.80 mg/dL to 1.0 mg/dL (P=.02). The median kidney mean dose was higher in the IMRT versus the 3D CRT group (13.9 Gy vs 11.1 Gy; P=.05). The median kidney V20 was lower for the IMRT versus the 3D CRT group (17.5% vs 22%; P=.17). The median liver mean dose for IMRT and 3D CRT was 13.6 Gy and 18.6 Gy, respectively (P=.19). The median liver V30 was 16.1% and 28%, respectively (P<.001). Adjuvant chemoradiotherapy was well tolerated. IMRT was found to provide sparing to the liver and possibly renal function.


Lacosamide as adjunctive therapy for partial-onset seizures: a randomized controlled trial.
To evaluate the efficacy and safety of lacosamide (400 and 600 mg/day) as adjunctive treatment in patients with uncontrolled partial-onset seizures taking one to three concomitant antiepileptic drugs (AEDs). This multicenter, double-blind, placebo-controlled trial randomized patients 1:2:1 to placebo, lacosamide 400 mg, or lacosamide 600 mg/day. After an 8-week baseline period, patients began treatment with placebo or lacosamide 100 mg/day, were force-titrated weekly (100 mg/day increments) to the target dose, and entered a 12-week maintenance period. A total of 405 patients were randomized and received trial medication. Most (82.1%) were taking two to three concomitant AEDs. Median percent reductions in seizure frequency per 28 days from baseline to maintenance (intention-to-treat, ITT) were 37.3% for lacosamide 400 mg/day (p = 0.008) and 37.8% for lacosamide 600 mg/day (p = 0.006) compared to 20.8% for placebo, with responder rates of 38.3% and 41.2%, respectively, compared to placebo (18.3%, p < 0.001; ITT). Patients randomized to lacosamide showed large reductions in secondarily generalized tonic-clonic seizures, with median percent reductions in seizure frequency of 59.4% for lacosamide 400 mg/day and 93.0% for lacosamide 600 mg/day compared to 14.3% for placebo, and responder rates of 56.0% and 70.2% compared to placebo (33.3%). Dose-related adverse events included dizziness, nausea, and vomiting. Adjunctive treatment with lacosamide 400 and 600 mg/day reduced seizure frequency for patients with uncontrolled partial-onset seizures. Lacosamide 400 mg/day provided a good balance of efficacy and tolerability; lacosamide 600 mg/day may provide additional benefit for some patients as suggested by secondary efficacy analyses, including response in patients with secondarily generalized tonic-clonic seizures.


Utility of Inter-subject Transfer Learning for Wearable-Sensor-Based Joint Torque Prediction Models.
Generalizability between individuals and groups is often a significant hurdle in model development for human subjects research. In the domain of wearable-sensor-controlled exoskeleton devices, the ability to generalize models across subjects or fine-tune more general models to individual subjects is key to enabling widespread adoption of these technologies. Transfer learning techniques applied to machine learning models afford the ability to apply and investigate the viability and utility such knowledge-transfer scenarios. This paper investigates the utility of single- and multi-subject based parameter transfer on LSTM models trained for "sensor-to-joint torque" prediction tasks, with regards to task performance and computational resources required for network training. We find that parameter transfer between both single- and multi-subject models provide useful knowledge transfer, with varying results across specific "source" and "target" subject pairings. This could be leveraged to lower model training time or computational cost in compute-constrained environments or, with further study to understand causal factors of the observed variance in performance across source and target pairings, to minimize data collection and model retraining requirements to select and personalize a generic model for personalized wearable-sensor-based joint torque prediction technologies.


Triple-negative breast cancer: molecular subtypes and new targets for therapy.
Triple-negative breast cancer (TNBC) is a molecularly diverse disease. This heterogeneity has limited the success of targeted therapy in unselected patients to date. Recent transcriptional analysis has divided TNBC into transcriptionally similar subtypes that may have different sensitivity to neoadjuvant chemotherapy and targeted therapy. At present, chemotherapy is the mainstay of treatment for early-stage and advanced TNBC; however, several actionable targets show promise in preclinical studies. Novel therapeutic strategies are currently being tested in phase II and phase III trials and will likely require patient stratification before therapy. Examples of these tailored approaches include poly(ADP-ribose) polymerase inhibitors for BRCA-mutated TNBC, antiandrogens for androgen receptor (AR)-positive TNBC, fibroblast growth factor receptor (FGFR) inhibitors for TNBC harboring FGFR amplifications, and gamma-secretase inhibitors for TNBC with mutations in the PEST domain of NOTCH proteins. Treatment of TNBC based on molecular subsets represents a potential algorithm for the future. Well-designed clinical trials with incorporation of integrated biomarkers are necessary to advance the development of molecularly targeted therapy for different subgroups of TNBC.


Tonic regulation of satiety by 5-HT receptors in the mouse: converging evidence from behavioural and c-fos immunoreactivity studies?
Activation of 5-HT(1B) receptors is thought to play an important role in the inhibitory influence of serotonin on feeding behaviour and body weight in mammals. Earlier studies have shown that 5-HT(1B)-knockout (KO) mice eat more and are heavier than wild-type (WT) controls and that the selective 5-HT(1B) receptor agonist CP-94,253 reduces food intake in food-deprived mice. Here we characterize the behavioural effects of both CP-94,253 and the selective 5-HT(1B) receptor antagonist SB224289 on feeding and other behaviours within the behavioural satiety sequence, and also report a c-fos mapping study using CP-94,253. CP-94,253 produced a dose-dependent suppression of food intake with a profile consistent with a selective effect on feeding behaviour. These effects were absent or reduced in 5-HT(1B)-KO mice and in WT mice pretreated with SB224289. SB224289 administered alone enhanced food intake consistent with impaired satiation; a similar effect was apparent in 5-HT(1B)-KO mice compared to WT. CP-94,253 induced c-fos in a range of structures previously implicated in the expression of feeding behaviour. These results suggest that the activation of 5-HT(1B) receptors is an important component of endogenous satiation mechanisms in the mouse.


Oral administration of royal jelly restores tear secretion capacity in rat blink-suppressed dry eye model by modulating lacrimal gland function.
Tears are secreted from the lacrimal gland (LG), a dysfunction in which induces dry eye, resulting in ocular discomfort and visual impairment. Honey bee products are used as a nutritional source in daily life and medicine; however, little is known about their effects on dry eye. The aim of the present study was to investigate the effects of honey bee products on tear secretion capacity in dry eye. We selected raw honey, propolis, royal jelly (RJ), pollen, or larva from commercially available honey bee products. Tear secretion capacity was evaluated following the oral administration of each honey bee product in a rat blink-suppressed dry eye model. Changes in tear secretion, LG ATP content, and LG mitochondrial levels were measured. RJ restored the tear secretion capacity and decrease in LG ATP content and mitochondrial levels to the largest extent. Royal jelly can be used as a preventative intervention for dry eye by managing tear secretion capacity in the LG.


Soluble B-cell activation marker of sCD27 and sCD30 and future risk of B-cell lymphomas: A nested case-control study and meta-analyses.
Prediagnostic serum/plasma concentrations of B-cell activation markers have been associated with future risk of B-cell lymphomas (BCL) in HIV-infected patients and in the general population. Current evidence for the general population is however limited and relies on relatively small numbers of observations, especially for specific histologies. We carried out a nested case-control study, including 218 BCL and 218 matched controls, within two prospective cohorts, to investigate the association between plasma levels of soluble (s)CD27 and sCD30 and future risk of BCL, and main histologic subtypes separately. To expand the evidence further, we performed meta-analyses of the published data on these associations from prospective studies among the general population. Our study revealed a significant relationship between sCD30 concentration and BCL risk (OR = 0.86, 1.53, 1.76, for the 2nd-4th quartiles respectively, p trend = 0.01). Similar increased risks were observed for diffuse large B-cell lymphoma and follicular lymphoma. Analyses of sCD27 blood concentrations did not show significant associations with BCL, (OR = 0.90, 1.26, 1.65 for the 2nd-4th quartiles, respectively, p trend = 0.17), but significant associations were observed for chronic lymphocytic leukaemia and for the group of "other BCL" subtypes. Our findings involving sCD30 were confirmed within our meta-analyses of five prospective cohorts, while results were more heterogeneous for sCD27 with the exception of CLL which was found consistently in all studies. Data to date suggest that chronic B-cell stimulation might be an important mechanism involved in B-cell lymphomagenesis both in HIV-infected and in the general population.


OncoSurge: a strategy for improving resectability with curative intent in metastatic colorectal cancer.
Most patients with colorectal liver metastases present to general surgeons and oncologists without a specialist interest in their management. Since treatment strategy is frequently dependent on the response to earlier treatments, our aim was to create a therapeutic decision model identifying appropriate procedure sequences. We used the RAND Corporation/University of California, Los Angeles Appropriateness Method (RAM) assessing strategies of resection, local ablation and chemotherapy. After a comprehensive literature review, an expert panel rated appropriateness of each treatment option for a total of 1,872 ratings decisions in 252 cases. A decision model was constructed, consensus measured and results validated using 48 virtual cases, and 34 real cases with known outcomes. Consensus was achieved with overall agreement rates of 93.4 to 99.1%. Absolute resection contraindications included unresectable extrahepatic disease, more than 70% liver involvement, liver failure, and being surgically unfit. Factors not influencing treatment strategy were age, primary tumor stage, timing of metastases detection, past blood transfusion, liver resection type, pre-resection carcinoembryonic antigen (CEA), and previous hepatectomy. Immediate resection was appropriate with adequate radiologically-defined resection margins and no portal adenopathy; other factors included presence of < or = 4 or > 4 metastases and unilobar or bilobar involvement. Resection was appropriate postchemotherapy, independent of tumor response in the case of < or = 4 metastases and unilobar liver involvement. Resection was appropriate only for > 4 metastases or bilobar liver involvement, after tumor shrinkage with chemotherapy. When possible, resection was preferred to local ablation. The results were incorporated into a decision matrix, creating a computer program (OncoSurge). This model identifies individual patient resectability, recommending optimal treatment strategies. It may also be used for medical education.