A systematic review of repetitive functional task practice with modelling of resource use, costs and effectiveness.
To determine whether repetitive functional task practice (RFTP) after stroke improves limb-specific or global function or activities of daily living and whether treatment effects are dependent on the amount of practice, or the type or timing of the intervention. Also to provide estimates of the cost-effectiveness of RFTP. The main electronic databases were searched from inception to week 4, September 2006. Searches were also carried out on non-English-language databases and for unpublished trials up to May 2006. Standard quantitative methods were used to conduct the systematic review. The measures of efficacy of RFTP from the data synthesis were used to inform an economic model. The model used a pre-existing data set and tested the potential impact of RFTP on cost. An incremental cost per quality-adjusted life-year (QALY) gained for RFTP was estimated from the model. Sensitivity analyses around the assumptions made for the model were used to test the robustness of the estimates. Thirty-one trials with 34 intervention-control pairs and 1078 participants were included. Overall, it was found that some forms of RFTP resulted in improvement in global function, and in both arm and lower limb function. Overall standardised mean difference in data suitable for pooling was 0.38 [95% confidence interval (CI) 0.09 to 0.68] for global motor function, 0.24 (95% CI 0.06 to 0.42) for arm function and 0.28 (95% CI 0.05 to 0.51) for functional ambulation. Results suggest that training may be sufficient to have an impact on activities of daily living. Retention effects of training persist for up to 6 months, but whether they persist beyond this is unclear. There was little or no evidence that treatment effects overall were modified by time since stroke or dosage of task practice, but results for upper limb function were modified by type of intervention. The economic modelling suggested that RFTP was cost-effective. Given a threshold for cost-effectiveness of 20,000 pounds per QALY gained, RFTP is cost-effective so long as the net cost per patient is less than 1963 pounds. This result showed some sensitivity to the assumptions made for the model. The cost-effectiveness of RFTP tends to stem from the relatively modest cost associated with this intervention. The evidence suggests that some form of RFTP can be effective in improving lower limb function at any time after stroke, but that the duration of intervention effect is unclear. There is as yet insufficient good-quality evidence to make any firm recommendations for upper limb interventions. If task-specific training is used, adverse effects should be monitored. While the effectiveness of RFTP is relatively modest, this sort of intervention appears to be cost-effective. Owing to the large number of ongoing trials, this review should be updated within 2 years and any future review should include a comparison against alternative treatments. Further research should evaluate RFTP upper limb interventions and in particular constraint-induced movement therapy, address practical ways of delivering RFTP interventions, be directed towards the evaluation of suitable methods to maintain functional gain, and be powered to detect whether RFTP interventions are cost-effective.


A crossover in the mechanical response of nanocrystalline ceramics.
Multimillion-atom molecular dynamics simulation of indentation of nanocrystalline silicon carbide reveals unusual deformation mechanisms in brittle nanophase materials, resulting from the coexistence of brittle grains and soft amorphous grain boundary phases. Simulations predict a crossover from intergranular continuous deformation to intragrain discrete deformation at a critical indentation depth. The crossover arises from the interplay between cooperative grain sliding, grain rotations, and intergranular dislocation formation similar to stick-slip behavior. The crossover is also manifested in switching from deformation dominated by indentation-induced crystallization to deformation dominated by disordering, leading to amorphization. This interplay between deformation mechanisms is critical for the design of ceramics with superior mechanical properties.


[Simultaneous determination of residues of organochlorine and pyrethroid pesticides in tea by microwave assisted extraction solid phase microextraction-gas chromatography].
The issue of residues including organochlorine and pyrethroid pesticides in tea has made a great attention of researchers and customers in the world. Although some analytical methods have well been established to detect these pesticides, the sample preparations are generally laborious, time-consuming, and some of the procedures caused environmental pollution. Solid phase microextraction (SPME) is a novel sample preparation technique since it is of simplicity, high efficiency and solvent free. SPME was firstly developed to address the need to facilitate environment monitoring. In recent years, great efforts have been made in the analysis of pesticide residues in agricultural products by SPME. In this research, a microwave assisted extraction solid phase microextraction-gas chromatography (MAE-SPME-GC) was applied for the simultaneous determination of organochlorine and pyrethroid pesticides, such as benzene hexa chlorides (alpha-BHC, beta-BHC, gamma-BHC and delta-BHC), 1-(2-chlorophenyl)-1-(4-chlorophenyl)-2, 2, 2-trichloroethane (o, p'-DDT), 2, 2-bis (4-chlorophenyl)-1, 1-dichloroethylene (DDE), 2, 2-bis (4-chlorophenyl)-1, 1-dichloroethane (DDD), 2-(2-chlorophenyl)-2-(4-chlorophenyl)-1, 1, 1-trichloroethane (p, p'-DDT), cypermethrin and fenvalerate. All the tested pesticides were baseline separated under the experimental conditions, except for DDD and o, p'-DDT. The concentration of each pesticide was calibrated by external standard method. The linearities were found to be in the correlation coefficient range of 0.970 5 to 0.998 4 for the tested pesticides between the mass concentrations and peak areas, except for fenvalerate. The recoveries, relative standard deviations and detection limits for the 10 pesticides were 64% - 121%, 10.4% -22.9%, and 1 - 50 ng/L, respectively. The proposed method was successfully applied to the determination of organochlorine pesticide residues in three kinds of teas from the local market. The experimental results demonstrated that MAE-SPME-GC was a fast, sensitive and green technique for the analysis of trace quantity of pesticides in solid substrate foods.


Feasibility and Acceptability of Screening for Adverse Childhood Experiences in Prenatal Care.
Adverse childhood experiences (ACEs) are common among pregnant women and contribute to increased risk for negative perinatal outcomes, yet few clinicians screen prenatal patients for ACEs. The purpose of this study was to evaluate the feasibility and acceptability of screening for ACEs in standard prenatal care. We evaluated a 4-month pilot (March 2016-June 2016) to screen pregnant women (at ∼14-23 weeks of gestation) for ACEs and resiliency in two Kaiser Permanente Northern California medical centers (N = 480). We examined the acceptability of the screening to patients through telephone surveys (N = 210) and to clinicians through surveys and focus groups (N = 26). Most eligible patients (78%) were screened. Patients who received the screening were significantly more likely to be non-Hispanic White, Asian, or of "Other" or "Unknown" race/ethnicity than African American or Hispanic race/ethnicity (p = 0.02). Among those screened, 88% completed the questionnaires; 54% reported 0 ACEs, 28% reported 1-2 ACEs, and 18% reported ≥3 ACEs. Most patients were somewhat or very comfortable completing the questionnaires (91%) and discussing ACEs with their clinician (93%), and strongly or somewhat strongly agreed that clinicians should ask their prenatal patients about ACEs (85%). Clinicians reported significant pre- to postpilot increases in comfort discussing ACEs, providing education, and offering resources (ps < 0.01). Clinicians' willingness to screen for ACEs was contingent on adequate training, streamlined workflows, inclusion of resilience screening, and availability of mental health, parenting, and social work resources. ACEs screening as part of standard prenatal care is feasible and generally acceptable to patients. Women's health clinicians are willing to screen patients for ACEs when appropriately trained and adequate behavioral health referral resources are available.


A Survey of Collaborative UAV-WSN Systems for Efficient Monitoring.
Integrated systems based on wireless sensor networks (WSNs) and unmanned aerial vehicles (UAVs) with electric propulsion are emerging as state-of-the-art solutions for large scale monitoring. Main advances stemming both from complex system architectures as well as powerful embedded computing and communication platforms, advanced sensing and networking protocols have been leveraged to prove the viability of this concept. The design of suitable algorithms for data processing, communication and control across previously disparate domains has thus currently become an intensive area of interdisciplinary research. The paper was focused on the collaborative aspects of UAV-WSN systems and the reference papers were analyzed from this point of view, on each functional module. The paper offers a timely review of recent advances in this area of critical interest with focus on a comparative perspective across multiple recent theoretical and applied contributions. A systematic approach is carried out in order to structure a unitary from conceptual design towards key implementation aspects. Focus areas are identified and discussed such as distributed data processing algorithms, hierarchical multi-protocol networking aspects and high level WSN-constrained UAV-control. Application references are highlighted in various domains such as environmental, agriculture, emergency situations and homeland security. Finally, a research agenda is outlined to advance the field towards tangible economic and social impact.


Anti-apolipoprotein A-1 auto-antibodies as active modulators of atherothrombosis.
Humoral autoimmune-mediated inflammation plays a role in atherogenesis, and potentially in arterial thrombosis. Anti-apolipoprotein A-1 (apoA-1) IgG have been reported to represent emergent mediators of atherogenesis through Toll-like receptors (TLR) 2, 4 and CD14 signalling. We investigated the role of anti-apoA-1 IgG on tissue factor (TF) expression and activation, a key coagulation regulator underlying atherothrombosis. Atherothrombosis features were determined by immunohistochemical TF staining of human carotid biopsies derived from patients with severe carotid stenosis undergoing elective surgery (n=176), and on aortic roots of different genetic backgrounds mice (ApoE-/-; TLR2-/-ApoE-/- and TLR4-/-ApoE-/-) exposed to passive immunisation with anti-apoA-1 IgG. Human serum levels of anti-apoA-1 IgG were measured by ELISA. In vitro, on human-monocyte-derived-macrophages (HMDM) the anti-apoA-1 IgG increased TF expression and activity were analysed by FACS and chromogenic assays in presence of different pharmacological inhibitors. Human serum anti-apoA-1 IgG levels significantly correlated to intraplaque TF expression in carotid biopsies (r=0.31, p<0.001), which was predictive of clinically symptomatic lesions. On HMDM, anti-apoA-1 IgG induced a TLR2, 4 and CD14-dependent increase in TF expression and activity, involving NF-kappaB and a c-Jun N-terminal kinase-dependent AP-1 transcription factors. In ApoE-/- mice, anti-apoA-1 IgG passive immunisation significantly enhanced intraplaque TF expression when compared to control IgG. This effect was lost in both TLR2-/-ApoE-/- and TLR4-/-ApoE-/- mice. These results demonstrate that anti-apoA-1 IgG are associated with TF expression in human atherosclerotic plaques, induce TF expression in vitro and in vivo through TLR2 and 4 signalling, supporting a possible causal relationship between anti-apoA-1 IgG and atherothrombosis.


Reversing chromatin accessibility differences that distinguish homologous mitotic metaphase chromosomes.
Chromatin-modifying reagents that alter histone associating proteins, DNA conformation or its sequence are well established strategies for studying chromatin structure in interphase (G1, S, G2). Little is known about how these compounds act during metaphase. We assessed the effects of these reagents at genomic loci that show reproducible, non-random differences in accessibility to chromatin that distinguish homologous targets by single copy DNA probe fluorescence in situ hybridization (scFISH). By super-resolution 3-D structured illumination microscopy (3D-SIM) and other criteria, the differences correspond to 'differential accessibility' (DA) to these chromosomal regions. At these chromosomal loci, DA of the same homologous chromosome is stable and epigenetic hallmarks of less accessible interphase chromatin are present. To understand the basis for DA, we investigate the impact of epigenetic modifiers on these allelic differences in chromatin accessibility between metaphase homologs in lymphoblastoid cell lines. Allelic differences in metaphase chromosome accessibility represent a stable chromatin mark on mitotic metaphase chromosomes. Inhibition of the topoisomerase IIα-DNA cleavage complex reversed DA. Inter-homolog probe fluorescence intensity ratios between chromosomes treated with ICRF-193 were significantly lower than untreated controls. 3D-SIM demonstrated that differences in hybridized probe volume and depth between allelic targets were equalized by this treatment. By contrast, DA was impervious to chromosome decondensation treatments targeting histone modifying enzymes, cytosine methylation, as well as in cells with regulatory defects in chromatid cohesion. These data altogether suggest that DA is a reflection of allelic differences in metaphase chromosome compaction, dictated by the localized catenation state of the chromosome, rather than by other epigenetic marks. Inhibition of the topoisomerase IIα-DNA cleavage complex mitigated DA by decreasing DNA superhelicity and axial metaphase chromosome condensation. This has potential implications for the mechanism of preservation of cellular phenotypes that enables the same chromatin structure to be correctly reestablished in progeny cells of the same tissue or individual.


Insect baculoviruses strongly potentiate adaptive immune responses by inducing type I IFN.
Baculoviruses (BVs) are dsDNA viruses that are pathogenic for insects. They have been used worldwide as selective bioinsecticides and for producing recombinant proteins in insect cells. Surprisingly, despite their widespread use in research and industry and their dissemination in the environment, the potential effects of these insect viruses on the immune responses of mammals remain totally unknown. We show in this study that BVs have strong adjuvant properties in mice, promoting potent humoral and CD8(+) T cell adaptive responses against coadministered Ag. BVs also induce the in vivo maturation of dendritic cells and the production of inflammatory cytokines. We demonstrate that BVs play a major role in the strong immunogenicity of virus-like particles produced in the BV-insect cell expression system. The presence of even small numbers of BVs among the recombinant proteins produced in the BV expression system may therefore strengthen the immunological properties of these proteins. This adjuvant behavior of BVs is mediated primarily by IFN-alphabeta, although mechanisms independent of type I IFN signaling are also involved. This study demonstrates that nonpathogenic insect viruses may have a strong effect on the mammalian immune system.


Phototherapy for treating pressure ulcers.
A pressure ulcer is defined as "an area of localized injury to the skin and/or underlying tissue, usually over a bony prominence, as a result of pressure, or pressure in combination with shear". The use of phototherapy - that is, light (or laser) used as an adjuvant, non-surgical intervention, with the aim of having a therapeutic effect on healing - has increased recently. To determine the effects of phototherapy on the healing of pressure ulcers. In January 2014, we searched the Cochrane Wounds Group Specialised Register; The Cochrane Central Register of Controlled Trials (CENTRAL); Ovid MEDLINE; Ovid EMBASE; Ovid MEDLINE (In-Process & Other Non-Indexed Citations); and EBSCO CINAHL. We did not restrict the search by language or publication date. Randomised controlled trials (RCTs) comparing the effects of phototherapy (in addition to standard treatment) with sham phototherapy (in addition to standard treatment), another type of phototherapy (in addition to standard treatment) or standard or conventional treatment alone. Two review authors assessed studies for relevance and design according to the selection criteria, extracted data and evaluated study quality. The authors made attempts to obtain missing data by contacting study authors. Disagreement was resolved by consensus and discussion with a third review author. We identified seven RCTs involving 403 participants. All the trials were at unclear risk of bias. Trials compared the use of phototherapy with standard care only (six trials) or sham phototherapy (one trial). Only one of the trials included a third arm in which another type of phototherapy was applied. Overall, there was insufficient evidence to determine the relative effects of phototherapy for healing pressure ulcers. Time to complete healing was reported in three studies. Two studies showed the ultraviolet (UV) treated group had a shorter mean time to complete healing than the control group (mean difference -2.13 weeks (95% CI -3.53 to -0.72, P value 0.003)). One study reported that the laser group had a longer mean time to complete healing than the control group (mean difference 5.77 weeks; 95% CI -0.25 to 11.79). However, this result should be interpreted with caution, as these were small studies and the findings may have been due to chance. Three studies reported proportions of ulcers healed with a variety of results. One study reported a different outcome measure, and the other two studies had different treatment durations. These variations did not allow us to pool the studies and draw any conclusions as to whether phototherapy is effective or not. Adverse effects were reported in only two studies that compared phototherapy with control; the risk ratio for adverse events was imprecise. One study reported risk ratio (RR) 0.72 (95%CI 0.18 to 2.80). However, another study reported RR 0.89 (95% CI: 0.71 to 1.12) based on the number of events in each group, rather than the number of people with events. Among five studies reporting the rate of change in ulcer area, three studies found no statistically significant difference between the two groups. Pooling was not undertaken because of differences in outcome measures reported. The results were based on data from trials with unclear risk of bias for which generation of the randomisation sequence, concealment allocation and blinding of outcome assessors were unclear. No studies reported on quality of life, length of hospital stay, pain or cost. We are very uncertain as to the effects of phototherapy in treating pressure ulcers. The quality of evidence is very low due to the unclear risk of bias and small number of trials available for analysis. The possibility of benefit or harm of this treatment cannot be ruled out. Further research is recommended.


Microcircuitry of agranular frontal cortex: testing the generality of the canonical cortical microcircuit.
We investigated whether a frontal area that lacks granular layer IV, supplementary eye field, exhibits features of laminar circuitry similar to those observed in primary sensory areas. We report, for the first time, visually evoked local field potentials (LFPs) and spiking activity recorded simultaneously across all layers of agranular frontal cortex using linear electrode arrays. We calculated current source density from the LFPs and compared the laminar organization of evolving sinks to those reported in sensory areas. Simultaneous, transient synaptic current sinks appeared first in layers III and V followed by more prolonged current sinks in layers I/II and VI. We also found no variation of single- or multi-unit visual response latency across layers, and putative pyramidal neurons and interneurons displayed similar response latencies. Many units exhibited pronounced discharge suppression that was strongest in superficial relative to deep layers. Maximum discharge suppression also occurred later in superficial than in deep layers. These results are discussed in the context of the canonical cortical microcircuit model originally formulated to describe early sensory cortex. The data indicate that agranular cortex resembles sensory areas in certain respects, but the cortical microcircuit is modified in nontrivial ways.


Monolayers of a model anesthetic-binding membrane protein: formation, characterization, and halothane-binding affinity.
hbAP0 is a model membrane protein designed to possess an anesthetic-binding cavity in its hydrophilic domain and a cation channel in its hydrophobic domain. Grazing incidence x-ray diffraction shows that hbAP0 forms four-helix bundles that are vectorially oriented within Langmuir monolayers at the air-water interface. Single monolayers of hbAP0 on alkylated solid substrates would provide an optimal system for detailed structural and dynamical studies of anesthetic-peptide interaction via x-ray and neutron scattering and polarized spectroscopic techniques. Langmuir-Blodgett and Langmuir-Schaeffer deposition and self-assembly techniques were used to form single monolayer films of the vectorially oriented peptide hbAP0 via both chemisorption and physisorption onto suitably alkylated solid substrates. The films were characterized by ultraviolet absorption, ellipsometry, circular dichroism, and polarized Fourier transform infrared spectroscopy. The alpha-helical secondary structure of the peptide was retained in the films. Under certain conditions, the average orientation of the helical axis was inclined relative to the plane of the substrate, approaching perpendicular in some cases. The halothane-binding affinity of the vectorially oriented hbAP0 peptide in the single monolayers, with the volatile anesthetic introduced into the moist vapor environment of the monolayer, was found to be similar to that for the detergent-solubilized peptide.


Biomimetics of photonic nanostructures.
Biomimetics is the extraction of good design from nature. One approach to optical biomimetics focuses on the use of conventional engineering methods to make direct analogues of the reflectors and anti-reflectors found in nature. However, recent collaborations between biologists, physicists, engineers, chemists and materials scientists have ventured beyond experiments that merely mimic what happens in nature, leading to a thriving new area of research involving biomimetics through cell culture. In this new approach, the nanoengineering efficiency of living cells is harnessed and natural organisms such as diatoms and viruses are used to make nanostructures that could have commercial applications.


POZ/BTB and AT-Hook-Containing Zinc Finger Protein 1 (PATZ1) Suppresses Progression of Ovarian Cancer and Serves as an Independent Prognosis Factor.
BACKGROUND The POZ/BTB and AT-hook-containing Zinc finger protein 1 (PATZ1) is a ubiquitously expressed transcription factor belonging to the POZ domain Krüppel-like zinc finger (POK) family. It is involved in the pathogenesis of a growing list of human diseases, including cancer. The effect of PATZ1 on serous ovarian carcinoma (SOC) remains unclear. This study initially explored the clinical significance of PATZ1 in patients with SOC, the relationship between its expression and the prognosis of SOC patients, and its role in tumor proliferation and invasion. MATERIAL AND METHODS Immunohistochemistry and quantitative real-time polymerase chain reaction (qPCR) were performed to characterize the expression of PATZ1 in SOC tissues. The relationship between PATZ1 expression and the clinicopathological features of patients with SOC was analyzed by chi-square test. Kaplan-Meier method and Cox regression analyses were utilized to evaluate the prognosis of SOC. PATZ1-constructed transfection-mediated overexpression was conducted. The CCK-8 assay was performed to examine the proliferation, while Transwell assay was used to detect the invasive capability. RESULTS The results of IHC and qPCR analyses showed that the expression of PATZ1 in cancerous tissue was significantly lower than that in non-cancerous tissues. Meanwhile, PATZ1 expression was significantly associated with tumor differentiation and LN metastasis. Survival analysis showed that PATZ1 expression was one of the independent prognosis factors for overall survival of SOC patients. In addition, overexpression of PATZ1 inhibited the proliferation and invasion of OVCAR3 cells by in vitro experiments. CONCLUSIONS Our data suggest that PATZ1 is a novel prognostic marker in SOC.


Evidence for the overexpression of the VH4-34 (VH4.21) Ig gene segment in the normal adult human peripheral blood B cell repertoire.
The VH4-34 (VH4.21) gene has been repeatedly found to encode monoclonal anti-i/l cold agglutinins and is occasionally used by other autoantibodies with anti-DNA and rheumatoid factor specificity. To understand the basis for the frequent expression of the VH4-34 gene in autoimmunity, we prepared linker-based, amplified C mu and C gamma V gene (cDNA) libraries from the peripheral blood of two healthy adults (PBL-3 and PBL-4). The frequency of VH4 family gene-containing clones was determined with VH family-specific oligonucleotide probes, and by random sequencing we examined the frequency of VH4-34 gene expression among the VH4+ C mu clones. Collectively, these studies suggested that VH4-34 gene expression accounted for 7.8 and 10.3% of all IgM clones in the cDNA libraries of PBL-3 and PBL-4, respectively. In VH4 family-specific libraries prepared from genomic rearranged Ig DNA, the VH4-34 gene was also overrepresented relative to other VH4 family genes. In both the mu-cDNA as well as the rearranged Ig DNA libraries, the VH4-34-expressing clones were 95 to 100% homologous to the germline sequence and contained different CDR3 sequences. By contrast, the VH4-34-expressing C gamma clones showed somatic diversification from germline; in addition, the C gamma clones often had the same CDR3 sequences, suggesting that these clones were derived from either activated B cells or expanded, clonally related B cells. Multiparameter flow cytometric analysis of peripheral blood lymphocytes indicated that 3.2 to 6.2% of mu+CD20+ cells express the VH4-34-related Id 9G4. These current findings are relevant to the interpretation of restricted Ig gene usage reported in monoclonal cold agglutinin disease and other autoimmune disorders.


Gut microbiota metabolism of dietary fiber influences allergic airway disease and hematopoiesis.
Metabolites from intestinal microbiota are key determinants of host-microbe mutualism and, consequently, the health or disease of the intestinal tract. However, whether such host-microbe crosstalk influences inflammation in peripheral tissues, such as the lung, is poorly understood. We found that dietary fermentable fiber content changed the composition of the gut and lung microbiota, in particular by altering the ratio of Firmicutes to Bacteroidetes. The gut microbiota metabolized the fiber, consequently increasing the concentration of circulating short-chain fatty acids (SCFAs). Mice fed a high-fiber diet had increased circulating levels of SCFAs and were protected against allergic inflammation in the lung, whereas a low-fiber diet decreased levels of SCFAs and increased allergic airway disease. Treatment of mice with the SCFA propionate led to alterations in bone marrow hematopoiesis that were characterized by enhanced generation of macrophage and dendritic cell (DC) precursors and subsequent seeding of the lungs by DCs with high phagocytic capacity but an impaired ability to promote T helper type 2 (TH2) cell effector function. The effects of propionate on allergic inflammation were dependent on G protein-coupled receptor 41 (GPR41, also called free fatty acid receptor 3 or FFAR3), but not GPR43 (also called free fatty acid receptor 2 or FFAR2). Our results show that dietary fermentable fiber and SCFAs can shape the immunological environment in the lung and influence the severity of allergic inflammation.


Enhanced depth imaging optical coherence tomography of precursor cell leukemic choroidopathy before and after chemotherapy.
Serous retinal detachment (SRD) can be the initial manifestation of leukemia. Herein, we explore the retinal and choroidal features on enhanced depth imaging optical coherence tomography (EDI-OCT) of SRD in a patient with undiagnosed leukemia. A 23-year-old male developed blurred visual acuity of 20/200 in the right eye oculus dexter (OD) and 20/200 in the left eye oculus sinister (OS). Funduscopically, he manifested serous macular detachment in both eyes oculi uterque (OU) without hemorrhagic retinal abnormalities. EDI-OCT disclosed macular detachment OU and homogeneous, marked choroidal opacification with thickening to 724 μm OD and estimated >600 μm OS and with loss of choroidal detail OU. Peripheral blood smears revealed severe thrombocytopenia and normal leukocyte count. Peripheral cytochemisty, immunophenotyping, and bone marrow aspirate confirmed the presence of atypical lymphoblasts, fulfilling criteria for precursor cell leukemia. Following systemic chemotherapy, the visual acuity improved to 20/25 OD and 20/20 OS. On EDI-OCT, the choroidal thickening resolved to 431 um OD and 443 um OS, leaving a normal choroidal appearance. Massive choroidal infiltration with leukemic cells could be the cause of serous macular detachment found in patients with newly diagnosed leukemia.


The INeS study: prevention of multiple pregnancies: a randomised controlled trial comparing IUI COH versus IVF e SET versus MNC IVF in couples with unexplained or mild male subfertility.
Multiple pregnancies are high risk pregnancies with higher chances of maternal and neonatal mortality and morbidity. In the past decades the number of multiple pregnancies has increased. This trend is partly due to the fact that women start family planning at an increased age, but also due to the increased use of ART.Couples with unexplained or mild male subfertility generally receive intrauterine insemination IUI with controlled hormonal stimulation (IUI COH). The cumulative pregnancy rate is 40%, with a 10% multiple pregnancy rate.This study aims to reveal whether alternative treatments such as IVF elective Single Embryo Transfer (IVF e SET) or Modified Natural Cycle IVF (MNC IVF) can reduce the number of multiple pregnancy rates, but uphold similar pregnancy rates as IUI COH in couples with mild male or unexplained subfertility. Secondly, the aim is to perform a cost effective analyses and assess treatment preference of these couples. We plan a multicentre randomised controlled clinical trial in the Netherlands comparing six cycles of intra-uterine insemination with controlled ovarian hyperstimulation or six cycles of Modified Natural Cycle (MNC) IVF or three cycles with IVF-elective Single Embryo Transfer (eSET) plus cryo-cycles within a time frame of 12 months.Couples with unexplained subfertility or mild male subfertility and a poor prognosis for treatment independent pregnancy will be included. Women with anovulatory cycles, severe endometriosis, double sided tubal pathology or serious endocrine illness will be excluded.Our primary outcome is the birth of a healthy singleton. Secondary outcomes are multiple pregnancy, treatment costs, and patient experiences in each treatment arm. The analysis will be performed according tot the intention to treat principle. We will test for non-inferiority of the three arms with respect to live birth. As we accept a 12.5% loss in pregnancy rate in one of the two IVF arms to prevent multiple pregnancies, we need 200 couples per arm (600 couples in total). Determining the safest and most cost-effective treatment will ensure optimal chances of pregnancy for subfertile couples with substantially diminished perinatal and maternal complications. Should patients find the most cost-effective treatment acceptable or even preferable, this could imply the need for a world wide shift in the primary treatment. Current Controlled Trials ISRCTN 52843371.


Anti-Vascular Endothelial Growth Factor and the Evolving Management Paradigm for Retinopathy of Prematurity.
Diagnosis and management of pediatric retinal conditions such as retinopathy of prematurity (ROP) have been evolving significantly with the availability of new technology and treatments. New imaging systems, telemedicine, tele-education, and anti‒vascular endothelial growth factor (VEGF) intravitreal pharmacotherapy are all changing the way we diagnose and deliver care to children with pediatric retinal disease. Fluorescein angiography and optical coherence tomography have the potential to improve our diagnosis and management of disease, and with improvements in retinal imaging, telemedicine is becoming more feasible. Telemedicine, tele-education, and computer-based image analysis may overcome many of the challenges we face in providing adequate care and access for children with pediatric retinal disease. Treatment options have also expanded with the use of anti-VEGF therapy. Although the use of intravitreal anti-VEGF for ROP has been documented in the literature for more than a decade, many questions still remain about its safety in the pediatric patient population. Several ongoing prospective studies are exploring the utility of anti-VEGF agents for ROP, with attention to the optimal dose of drug, systemic safety, and our understanding of recurrence of disease. This review aims to provide an update on current diagnostic and therapeutic modalities, focusing predominantly on the role of anti-VEGF therapy, for the management of ROP and other pediatric retinal vascular diseases.


A genetic assessment of polyandry and breeding-site fidelity in lemon sharks.
We here employ 11 microsatellite markers and recently developed litter reconstruction methods to infer mating system parameters (i.e. polyandry and breeding-site fidelity) at a lemon shark nursery site in Marquesas Key, Florida. Four hundred and eight juvenile or subadult sharks were genotyped over eight complete breeding seasons. Using this information, we were able to infer family structure, as well as fully or partially reconstruct genotypes of 46 mothers and 163 fathers. Multiple litter reconstruction methods were used, and novel simulations helped define apparent bias and precision of at least some mating system parameters. For Marquesas Key, we find that adult female lemon sharks display high levels of polyandry (81% of all litters sampled) and stronger fidelity to the nursery site than do males. Indeed, few male sharks sired offspring from more than one litter during the course of the study. These findings were quite similar to previous results from another lemon shark nursery site (Bimini, Bahamas), suggesting conserved mating system parameters despite significant variation in early life-history traits (i.e. body size and growth) among sites. The finding of at least some site fidelity in females also supports the need for careful conservation of each nursery.


Receptor-mediated signaling at plasmodesmata.
Plasmodesmata (PD) generate continuity between plant cells via the cytoplasm, endoplasmic reticulum (ER) and plasma membrane (PM), allowing movement of different classes of molecules between cells. Proteomic data indicates that the PD PM hosts many receptors and receptor kinases, as well as lipid raft and tetraspanin enriched microdomain associated proteins, suggesting the hypothesis that the PD PM is specialized with respect to both composition and function. PD-located receptor proteins and receptor kinases are responsible for perception of microbe associated molecular patterns at PD and initiate signaling that mediates changes to PD flux. In addition, developmentally relevant receptor kinases have different interactions dependent upon whether located at the PD PM or the cellular PM. The implications of these findings are that receptor-mediated signaling in PD membranes differs from that in the cellular PM and, in light the identification of PD-located proteins associated with membrane microdomains and the role of membrane microdomains in analogous signaling processes in animals, suggests that the PD PM contains specialized signaling platforms.


Loss of p53 in craf-induced transgenic lung adenoma leads to tumor acceleration and phenotypic switch.
One of the most frequent malignancies in humans is lung adenocarcinoma.To develop novel diagnostic and therapeutic approaches for the management of this disease, animal models are required. We have used transgenic mice with lung-targeted expression of the CRaf kinase to evaluate genes altered frequently in human lung adenocarcinoma for their effect on tumor progression. Here we report that loss of p53 dramatically accelerates tumor development and induces a phenotypic switch in the target cell from cuboid to a nonciliated columnar morphology. Coexpression of lung epithelial cell markers surfactant protein C and Clara cell antigen suggests that tumor cell dedifferentiation could be involved in this process. The effect of p53 is specific, because loss of one of its target genes, p21(CIP1/WAF1), did not have this effect on cell phenotype although tumor latency was also reduced significantly. Neither loss of p53 nor p21 stimulated acquisition of the metastasis program beyond the stage of bronchiolar extension. This mouse model for pulmonary adenoma and adenocarcinoma should be very helpful for a better understanding of pathogenesis and treatment of this most deadly human cancer.


The tobacco carcinogen NNK drives accumulation of DNMT1 at the GR promoter thereby reducing GR expression in untransformed lung fibroblasts.
Small cell lung cancer (SCLC) is a highly aggressive, predominantly cigarette smoke-induced tumour with poor prognosis. The glucocorticoid receptor (GR), a SCLC tumour suppressor gene, is typically reduced in SCLC. We now show that SCLC cells express high levels of DNA methyltransferase 1 (DNMT1) which accumulates at the GR promoter. DNMT1 expression is further increased by exposure to the tobacco carcinogen NNK. In the untransformed human lung fibroblast cell line, MRC-5, short term NNK treatment decreases GRα mRNA and protein expression due to accumulation of DNMT1 at the GR promoter. Long term NNK treatment results in persistently augmented DNMT1 levels with lowered GR levels. Long term exposure to NNK slows cell proliferation and induces DNA damage, while the GR antagonist RU486 stimulates proliferation and protects against DNA damage. Although both NNK and RU486 treatment increases methylation at the GR promoter, neither are sufficient to prevent senescence in this context. NNK exposure results in accumulation of DNMT1 at the GR promoter in untransformed lung cells mimicking SCLC cells, directly linking tobacco smoke exposure to silencing of the GR, an important step in SCLC carcinogenesis.


Investigating physical cognition in rooks, Corvus frugilegus.
Although animals (particularly tool-users) are capable of solving physical tasks in the laboratory , the degree to which they understand them in terms of their underlying physical forces is a matter of contention. Here, using a new paradigm, the two-trap tube task, we report the performance of non-tool-using rooks. In contrast to the low success rates of previous studies using trap-tube problems , seven out of eight rooks solved the initial task, and did so rapidly. Instead of the usual, conceptually flawed control, we used a series of novel transfer tasks to test for understanding. All seven transferred their solution across a change in stimuli. However, six out of seven were unable to transfer to two further tasks, which did not share any one visual constant. One female was able to solve these further transfer tasks. Her result is suggestive evidence that rooks are capable of sophisticated physical cognition, if not through an understanding of unobservable forces , perhaps through rule abstraction. Our results highlight the need to investigate cognitive mechanisms other than causal understanding in studying animal physical cognition.


Treatment of benign prostatic hyperplasia at Mater Hospital, Nairobi.
To evaluate the use of medical therapy in the management of patients with mild, moderate and severe symptoms of benign prostatic hyperplasia. Prospective study. Private urology clinic in Mater Hospital, Nairobi between 1995 and 2005. Six hundred and eighty patients with benign prostatic hypertrophy aged 50-80 years. Two hundred and eighty (43.8%) patients benefited from the drug treatment alone and were released from the clinic follow up after five years. Two hundred and seventy (42.2%) cases could not complete the five years follow up on drugs alone due to symptoms recurrence or severity or unavailability of drugs. They were removed from the drugs alone treatment and put on other interventions. Ninety (15.9%) cases were operated on based on their decision and insistence or severity of their symptoms or no drugs response. This observational study confirms that medical treatment is beneficial in the management of benign prostatic hyperplasia (BPH) and is cheap and gives better first line option of treatment choice to many patients. It also gives hopes to the surgical risk patients. The quality of life (QOL) of patients and their family disturbance is also improved.


Lobular neoplasia in breast core needle biopsy specimens is associated with a low risk of ductal carcinoma in situ or invasive carcinoma on subsequent excision.
To address the significance of lobular neoplasia (LN) in breast core needle biopsy specimens, we prospectively obtained LN cases and correlated results of subsequent tissue sampling. LN was diagnosed by core needle biopsy in 467 women; in 101 (21.6%), invasive carcinoma (IC) or ductal carcinoma in situ (DCIS) was diagnosed concurrently. Two patients (0.4%) had previous diagnoses of IC or DCIS, and 17 (3.6%) had a concurrent diagnosis of contralateral IC or DCIS. Of 366 patients without a concurrent diagnosis of IC or DCIS, subsequent tissue diagnoses were available for 156 cases (42.6%). Of 60 cases of LN and atypical ductal hyperplasia on the biopsy, 5 had IC and 10 had DCIS on the excision (total, 25%). Of 4 women with LN and a mucocele-like lesion on the biopsy, none had IC or DCIS on excision. Of 92 with LN alone on the biopsy, 7 had IC (6) or DCIS (1) on excision. Two cases were in sites away from the biopsy site, 3 in subsequent excisions of the biopsy site, and 2 after previous excision of the biopsy site without finding IC or DCIS. Although LN is associated with a high overall rate of IC and DCIS (30%), excision of the biopsy site for women with LN alone on core needle biopsy has a very low rate of IC and DCIS in our center. Women in whom biopsy sites are excised are still at risk for subsequent DCIS and IC.


Therapeutic benefit of eletriptan compared to sumatriptan for the acute relief of migraine pain--results of a model-based meta-analysis that accounts for encapsulation.
A novel model-based meta-analysis was used to quantify the dose-response relationship of sumatriptan and eletriptan for the proportion of patients that achieve migraine pain relief up to 4 h after treatment. The proportion of patients that became pain free was also evaluated. This analysis includes some unique features, allowing comparison of sumatriptan and eletriptan doses that have not been directly compared in a head to head study and also permitting comparison between the two drugs at multiple time points up to 4 h after treatment. Because the analysis allows comparison of response to blinded sumatriptan with that to marketed sumatriptan and contains timepoints as early as 0.5 h, it is especially suited to detection of possible effects of encapsulation on sumatriptan's therapeutic effectiveness and thus was employed to assess this also. Data from 19 randomized placebo controlled clinical trials were jointly analysed using a random-effects logistic regression model. The results of this analysis show a significant clinical benefit of eletriptan 40 mg compared to sumatriptan 100 mg at any point in time up to 4 h after treatment. The benefit of eletriptan 40 mg is greatest around 1.5-2 h after treatment with an absolute difference at 2 h of 9.1% (7.4-11.5%) more patients achieving pain relief and 7.3% (5.8-8.6%) more patient achieving pain free when compared to sumatriptan 100 mg. An absolute benefit of more than 5% of patients is maintained from 45 min up to 4 h after treatment for pain relief and from 1.5 h up to 4 h for pain free. Eletriptan 20 mg was superior to sumatriptan 50 mg and similar to sumatriptan 100 mg for pain relief while it was similar to sumatriptan 50 mg for pain free. The benefit of eletriptan 20 mg when compared to sumatriptan 50 mg is greatest around 1.5-2 h after treatment with an absolute difference at 2 h of 5.0% (2.9-8.1%) more patients achieving pain relief. An absolute benefit of more than 3% of patients was maintained from 1 h up to 3 h after treatment. No significant difference was found between eletriptan 20 mg and sumatriptan 50 mg for the fraction of patients that became pain free. No significant effect of encapsulation of sumatriptan was found on the time course of response up to 4 h after treatment when compared to commercial sumatriptan.


Bone marrow stromal cells of young and adult rats respond similarly to platelet-released supernatant and bone morphogenetic protein-6 in vitro.
Age-related changes in periodontal bone regeneration, osseointegration of dental implants, and graft consolidation are increasingly considered in treatment planning. This study was intended to show whether aging is associated with a diminished responsiveness of osteoprogenitor cells to growth and differentiation factors. We compared the capacity of bone marrow stromal cells harvested from young and adult rats to proliferate, migrate, and differentiate into the osteogenic lineage following exposure to platelet-released supernatant (PRS) or bone morphogenetic protein-6 (BMP-6). Bone marrow stromal cells were isolated from 12 young rats aged 6 weeks and 12 adult rats aged 9 months. Proliferation was assessed by 3[H]thymidine incorporation, migration was evaluated with the Boyden chamber assay, and osteogenic differentiation was deduced from alkaline phosphatase activity. Irrespective of the donor age, bone marrow stromal cells showed increased mitogenic activity and chemotactic motility when exposed to PRS. Adult bone marrow stromal cells had higher alkaline phosphatase activities at baseline and upon incubation with BMP-6 than cells obtained from young animals. There was no difference between the two groups in the slope of the alkaline phosphatase activity curve following stimulation with BMP-6. The data demonstrate that, irrespective of their age, bone marrow stromal cells respond similarly to PRS and BMP-6 under in vitro conditions. These findings suggest that osteoprogenitor cells within the bone marrow of adult rats retain their juvenile potential to respond to growth and differentiation factors, which are released naturally or are applied therapeutically at sites of bone regeneration.


An integrative approach to the facile functional classification of dorsal root ganglion neuronal subclasses.
Somatosensory neurons have historically been classified by a variety of approaches, including structural, anatomical, and genetic markers; electrophysiological properties; pharmacological sensitivities; and more recently, transcriptional profile differentiation. These methodologies, used separately, have yielded inconsistent classification schemes. Here, we describe phenotypic differences in response to pharmacological agents as measured by changes in cytosolic calcium concentration for the rapid classification of neurons in vitro; further analysis with genetic markers, whole-cell recordings, and single-cell transcriptomics validated these findings in a functional context. Using this general approach, which we refer to as tripartite constellation analysis (TCA), we focused on large-diameter dorsal-root ganglion (L-DRG) neurons with myelinated axons. Divergent responses to the K-channel antagonist, κM-conopeptide RIIIJ (RIIIJ), reliably identified six discrete functional cell classes. In two neuronal subclasses (L1 and L2), block with RIIIJ led to an increase in [Ca] i Simultaneous electrophysiology and calcium imaging showed that the RIIIJ-elicited increase in [Ca] i corresponded to different patterns of action potentials (APs), a train of APs in L1 neurons, and sporadic firing in L2 neurons. Genetically labeled mice established that L1 neurons are proprioceptors. The single-cell transcriptomes of L1 and L2 neurons showed that L2 neurons are Aδ-low-threshold mechanoreceptors. RIIIJ effects were replicated by application of the Kv1.1 selective antagonist, Dendrotoxin-K, in several L-DRG subclasses (L1, L2, L3, and L5), suggesting the presence of functional Kv1.1/Kv1.2 heteromeric channels. Using this approach on other neuronal subclasses should ultimately accelerate the comprehensive classification and characterization of individual somatosensory neuronal subclasses within a mixed population.


Natural selection and parallel speciation in sympatric sticklebacks.
Natural selection plays a fundamental role in most theories of speciation, but empirical evidence from the wild has been lacking. Here the post-Pleistocene radiation of threespine sticklebacks was used to infer natural selection in the origin of species. Populations of sticklebacks that evolved under different ecological conditions show strong reproductive isolation, whereas populations that evolved independently under similar ecological conditions lack isolation. Speciation has proceeded in this adaptive radiation in a repeatable fashion, ultimately as a consequence of adaptation to alternative environments.


Career choices for cardiology: cohort studies of UK medical graduates.
Cardiology is one of the most popular of the hospital medical specialties in the UK. It is also a highly competitive specialty in respect of the availability of higher specialty training posts. Our aims are to describe doctors' early intentions about seeking careers in cardiology, to report on when decisions about seeking a career in cardiology are made, to compare differences between men and women doctors in the choice of cardiology, and to compare early career choices with later specialty destinations. Questionnaire surveys were sent to all UK medical graduates in selected qualification years from 1974-2009, at 1, 3, 5, 7 and 10 years after graduation. One year after graduation, the percentage of doctors specifying cardiology as their first choice of long-term career rose from the mid-1990s from 2.4% (1993 cohort) to 4.2% (2005 cohort) but then fell back to 2.7% (2009 cohort). Men were more likely to give cardiology as their first choice than women (eg 4.1% of men and 1.9% of women in the 2009 cohort). The percentage of doctors who gave cardiology as their first choice of career declined between years one and five after qualification: the fall was more marked for women. 34% of respondents who specified cardiology as their sole first choice of career one year post-graduation were later working in cardiology. 24% of doctors practising as cardiologists several years after qualification had given cardiology as their sole first choice in year one. The doctors' 'domestic circumstances' were a relatively unimportant influence on specialty choice for aspiring cardiologists, while 'enthusiasm/commitment', 'financial prospects', 'experiences of the job so far' and 'a particular teacher/department' were important. Cardiology grew as a first preference one year after graduation to 2005 but is now falling. It consistently attracts a higher percentage of men than women doctors. The correspondence between early choice and later destination was not particularly strong for cardiology, and was less strong than that for several other specialties.


Developmental haemostasis. Impact for clinical haemostasis laboratories.
Developmental haemostasis is a concept, now universally accepted, introduced by Andrew et al. in the late 1980's. However, coagulation analysers and reagents have changed significantly over the past 15 years. Coagulation testing is known to be sensitive to changes in individual reagents and analysers. We hypothesised that the reference ranges developed by Andrew et al. may not be appropriate for use in a modern coagulation laboratory. Our study was designed to determine whether a current day coagulation testing system (STA Compact analyser and Diagnostica Stago reagent system) was sensitive to age-related changes in coagulation assays. This is the first large scale study since Andrew et al. to determine the age associated numerical changes in coagulation proteins. Our results confirm the concepts of developmental haemostasis elucidated by Andrew et al. However, our results clearly demonstrate that the absolute values of reference ranges for coagulation assays in neonates and children vary with analyser and reagent systems. The results confirm the need for coagulation laboratories to develop age-related reference ranges specific to their own testing systems. Without this, accurate diagnosis and management of neonates and children with suspected bleeding or clotting disorders is not possible. Finally we present age related reference ranges for D-dimers, TFPI, and endogenous thrombin potential, previously not described.


Characteristics of females who sexually offend: a comparison of solo and co-offenders.
Although recent typologies of female sexual offenders have recognized the importance of having a co-offender, the clinical characteristics of solo and co-female sexual offenders remain poorly understood. The aim of this study was to compare solo (n = 20) and co- (n = 20) female sexual offenders on a variety of clinical characteristics. It was found that although solo and co-offenders reported similar developmental experiences and psychological dispositions, differences were found in environmental niche, offense preceding, and positive factors. Specifically, solo offenders demonstrated a greater presence of personal vulnerabilities including mental health and substance abuse difficulties. Co-offenders reported a greater presence of environmentally based factors, including a current partner who was a known sex offender and involvement with antisocial peers. It is suggested that these results have implications for understanding assessment and intervention needs for these groups of sexual offenders.


Pulmonary metastases from soft tissue sarcoma: analysis of patterns of diseases and postmetastasis survival.
To report the patterns of disease and postmetastasis survival for patients with pulmonary metastases from soft tissue sarcoma in a large group of patients treated at a single institution. Clinical factors that influence postmetastasis survival are analyzed. For patients with soft tissue sarcoma, the lungs are the most common site of metastatic disease. Although pulmonary metastases most commonly arise from primary tumors in the extremities, they may arise from almost any primary site or histology. To date, resection of disease has been the only effective therapy for metastatic sarcoma. From July 1982 to February 1997, 3149 adult patients with soft tissue sarcoma were admitted and treated at Memorial Sloan-Kettering Cancer Center. During this interval, 719 patients either developed or presented with lung metastases. Patients were treated with resection of metastatic disease whenever possible. Disease-specific survival was the endpoint of the study. Time to death was modeled using the method of Kaplan and Meier. The association of factors to time-to-event endpoints was analyzed using the log-rank test for univariate analysis and the Cox proportional hazards model for multivariate analysis. The overall median survival from diagnosis of pulmonary metastasis for all patients was 15 months. The 3-year actuarial survival rate was 25%. The ability to resect all metastatic disease completely was the most important prognostic factor for survival. Patients treated with complete resection had a median survival of 33 months and a 3-year actuarial survival rate of 46%. For patients treated with nonoperative therapy, the median survival was 11 months. A disease-free interval of more than 12 months before the development of metastases was also a favorable prognostic factor. Unfavorable factors included the histologic variants of liposarcoma and malignant peripheral nerve tumors and patient age older than 50 years at the time of treatment of metastasis. Resection of metastatic disease is the single most important factor that determines outcome in these patients. Long-term survival is possible in selected patients, particularly when recurrent pulmonary disease is resected. Surgical excision should remain the treatment of choice for metastases of soft tissue sarcoma to the lung.


Thymoquinone inhibits biofilm formation and has selective antibacterial activity due to ROS generation.
The present study was aimed to investigate the antibacterial potential and antibiofilm activity of thymoquinone and its mechanism of action. Antibacterial activity of thymoquinone was studied using minimum inhibitory concentration, minimum bactericidal concentration, time-kill assay, and post-antibiotic effect. Thymoquinone exhibited antibacterial activity against both Gram-negative and Gram-positive bacteria. In this study, the minimum inhibitory concentration was found to be in the range of 1.56 to 100 μg/ml. Scanning electron microscopy imaging revealed changes in cell morphology with dents, cell lysis, and reduction in cell size. Live/dead imaging using acridine orange and ethidium bromide confirmed the bactericidal activity as treated bacteria showed selective uptake of ethidium bromide over acridine orange. Cell viability was also studied using HaCaT (human keratinocytes) cell line by MTT assay, and IC90 value was found to be 50 μg/ml. This IC90 value was higher than that of MICbacteria (except for MIC of E. coli), demonstrating that its selectivity is higher towards bacteria than normal human cells. Thymoquinone also showed promising antibiofilm activity against Gram-negative (E. coli and P. aeruginosa) and Gram-positive bacteria (B. subtilis and S. aureus), which was studied by crystal violet assay, CFU method, and SEM. For understanding the mechanism of action of thymoquinone, DiSC3, NPN, and ROS assay was performed. DiSC3 and NPN assay has not shown any membrane damage whereas bacterial cells treated with thymoquinone at MIC showed increased dichlorofluorescin fluorescence, suggesting that the probable mechanism of action of thymoquinone against bacterial cells is due to the production of reactive oxygen species.


Contraction of glycerinated muscle fibers as a function of the ATP concentration.
We have measured the force-velocity curves of glycerinated rabbit psoas fibers over a range of ATP concentration from 2.5 microM to 5 mM. As the ATP concentration is increased, the isometric tension increases to a maximum around 50 microM, then decreases to a plateau at 70% of the maximum by 1 mM ATP. At low ATP concentrations the maximum velocity of contraction is low and increases with increasing ATP, reaching a plateau at approximately 2 lengths per second by 1 mM ATP. Our studies suggest that the binding of ATP dissociates the myosin head from actin in the contracting muscle, a reaction similar to that seen in solution. We have constructed models of the actin-myosin-nucleotide interactions based on a kinetic scheme derived from solution studies. The fit of these models to the data shows that the rates of some reactions in the fiber must be considerably different from the rates of the analogous reactions in solution. The data is best fit by models in which head attachment occurs rapidly at the beginning of a power stroke, head detachment occurs rapidly at the end of the power stroke, and the force produced by a myosin head in a power stroke is independent of velocity.


DARNED: a DAtabase of RNa EDiting in humans.
RNA editing is a phenomenon, which is responsible for the alteration of particular nucleotides in RNA sequences relative to their genomic templates. Recently, a large number of RNA editing instances in humans have been identified using bioinformatic screens and high-throughput experimental investigations utilizing next-generation sequencing technologies. However, the available data on RNA editing are not uniform and difficult to access. Here, we describe a new database DARNED (DAtabase of RNa EDiting) that provides centralized access to available published data related to RNA editing. RNA editing locations are mapped on the reference human genome. The current release of the database contains information on approximately 42 000 human genome coordinates corresponding to RNA locations that undergo RNA editing, mostly involving adenosine-to-inosine (A-to-I) substitutions. The data can be queried using a range of genomic coordinates, their corresponding functional localization in RNA molecules [Exons, Introns, CoDing Sequence (CDS) and UnTranslated Regions (UTRs)] and information regarding tissue/organ/cell sources where RNA editing has been observed. It is also possible to obtain RNA editing information for a specific gene or an RNA molecule using corresponding accession numbers. Search results provide information on the number of expressed sequence tags (ESTs) supporting edited and genomic bases, functional localization of RNA editing and existence of known single nucleotide polymorphisms (SNPs). Editing data can be explored in UCSC and Ensembl genome browsers, in conjunction with additional data provided by these popular genome browsers. DARNED has been designed for researchers seeking information on RNA editing and for the developers of novel algorithms for its prediction. DARNED is accessible at http://darned.ucc.ie


Craniometric ratios of microcephaly and LB1, Homo floresiensis, using MRI and endocasts.
The designation of Homo floresiensis as a new species derived from an ancient population is controversial, because the type specimen, LB1, might represent a pathological microcephalic modern Homo sapiens. Accordingly, two specific craniometric ratios (relative frontal breadth and cerebellar protrusion) were ascertained in 21 microcephalic infants and children by using MRI. Data on 118 age-equivalent control (normocephalic) subjects were collected for comparative purposes. In addition, the same craniometric ratios were determined on the endocasts of 10 microcephalic individuals, 79 normal controls (anatomically modern humans), and 17 Homo erectus specimens. These ratios were then compared with those of two LB1 endocasts. The findings showed that the calculated cerebral/cerebellar ratios of the LB1 endocast [Falk D, et al. (2007) Proc Natl Acad Sci USA 104:2513-2518] fall outside the range of living normocephalic individuals. The ratios derived from two LB1 endocasts also fall largely outside the range of modern normal human and H. erectus endocasts and within the range of microcephalic endocasts. The findings support but do not prove the contention that LB1 represents a pathological microcephalic Homo sapiens rather than a new species, (i.e., H. floresiensis).


Redox-dependent increases in glutathione reductase and exercise preconditioning: role of NADPH oxidase and mitochondria.
We have previously shown that exercise leads to sustainable cardioprotection through a mechanism involving improved glutathione replenishment. This study was conducted to determine if redox-dependent modifications in glutathione reductase (GR) were involved in exercise cardioprotection. Furthermore, we sought to determine if reactive oxygen species generated by NADPH oxidase and/or mitochondria during exercise were triggering events for GR modulations. Rats were exercised for 10 consecutive days, after which isolated hearts were exposed to ischaemia/reperfusion (25 min/120 min). Exercise protected against infarction and arrhythmia, and preserved coronary flow. The GR inhibitor BCNU abolished the beneficial effects. GR activity was increased following exercise in a redox-dependent manner, with no change in GR protein levels. Because fluorescent labelling of GR protein thiols showed lower amounts of reduced thiols after exercise, we sought to determine the source of intracellular reactive oxygen species that may be activating GR. Subsets of animals were exercised immediately after treatment with either NADPH-oxidase inhibitors apocynin or Vas2870, or with mitoTEMPO or Bendavia, which reduce mitochondrial reactive oxygen species levels. The cardioprotective effects of exercise were abolished if animals exercised in the presence of NADPH oxidase inhibitors, in clear contrast to the mitochondrial reagents. These changes correlated with thiol-dependent modifications of GR. Adaptive cardioprotective signalling is triggered by reactive oxygen species from NADPH oxidase, and leads to improved glutathione replenishment through redox-dependent modifications in GR.


Characterization of silver-polymer core-shell nanoparticles using electron microscopy.
Silver-polymer core-shell nanoparticles show interesting optical properties, making them widely applicable in the field of plasmonics. The uniformity, thickness and homogeneity of the polymer shell will affect the properties of the system which makes a thorough structural characterization of these core-shell silver-polymer nanoparticles of great importance. However, visualizing the shell and the particle simultaneously is far from straightforward due to the sensitivity of the polymer shell towards the electron beam. In this study, we use different 2D and 3D electron microscopy techniques to investigate different structural aspects of the polymer coating.


Comparison of genetic variability and parentage in different ploidy classes of the Japanese oyster Crassostrea gigas.
Chemical treatments with cytochalasin B were used to induce triploidy in the progeny of a mass fertilization of 3 male and 7 female Crassostrea gigas parents. Triploids were produced either by retention of the first (meiosis I (MI) triploids) or the second (meiosis II (MII) triploids) polar bodies. These animals, together with their diploid siblings, were divided for two experiments. One set was used to compare physiological performance, and the other set deployed to compare growth in two different natural environments. For both experiments, genetic variability in different ploidy classes was estimated using three microsatellite loci and eight allozyme loci. The microsatellite loci were highly polymorphic, allowing independent confirmation of ploidy status and the unambiguous identification of parentage for each oyster. Significant differences in parentage were found between ploidy classes, despite the fact they originated from the same mass fertilization. This indicates that the assumptions of a common genetic background among random samples of animals taken from the same mass fertilization may not be generally valid. Knowledge of parentage also allowed the more accurate scoring of allozyme loci. As expected, triploids were found to be significantly more polymorphic than diploids. However, MI triploids were not significantly more polymorphic than MII triploids. MII triploid genotypes were used to estimate recombination rates between loci and their centromeres. These rates varied between 0.29 and 0.71, indicating only moderate chiasma interference.


A distinct and replicable variant of the squamous cell carcinoma gene inositol polyphosphate-5-phosphatase modifies the susceptibility of arsenic-associated skin lesions in Bangladesh.
Single-nucleotide polymorphisms (SNPs) in inflammation, one-carbon metabolism, and skin cancer genes might influence susceptibility to arsenic-induced skin lesions. A case-control study was conducted in Pabna, Bangladesh (2001-2003), and the drinking-water arsenic concentration was measured for each participant. A panel of 25 candidate SNPs was analyzed in 540 cases and 400 controls. Logistic regression was used to estimate the association between each SNP and the potential for gene-environment interactions in the skin lesion risk, with adjustments for relevant covariates. Replication testing was conducted in an independent Bangladesh population with 488 cases and 2,794 controls. In the discovery population, genetic variants in the one-carbon metabolism genes phosphatidylethanolamine N-methyltransferase (rs2278952, P for interaction = .004; rs897453, P for interaction = .05) and dihydrofolate reductase (rs1650697, P for interaction = .02), the inflammation gene interleukin 10 (rs3024496, P for interaction =.04), and the skin cancer genes inositol polyphosphate-5-phosphatase (INPP5A; rs1133400, P for interaction = .03) and xeroderma pigmentosum complementation group C (rs2228000, P for interaction = .01) significantly modified the association between arsenic and skin lesions after adjustments for multiple comparisons. The significant gene-environment interaction between a SNP in the INPP5A gene (rs1133400) and water arsenic with respect to the skin lesion risk was successfully replicated in an independent population (P for interaction = .03). Minor allele carriers of the skin cancer gene INPP5A modified the odds of arsenic-induced skin lesions in both main and replicative populations. Genetic variation in INPP5A appears to have a role in susceptibility to arsenic toxicity.


The synthetic amphipathic peptidomimetic LTX109 is a potent fungicide that disturbs plasma membrane integrity in a sphingolipid dependent manner.
The peptidomimetic LTX109 (arginine-tertbutyl tryptophan-arginine-phenylethan) was previously shown to have antibacterial properties. Here, we investigated the activity of this novel antimicrobial peptidomimetic on the yeast Saccharomyces cerevisiae. We found that LTX109 was an efficient fungicide that killed all viable cells in an exponentially growing population as well as a large proportion of cells in biofilm formed on an abiotic surface. LTX109 had similar killing kinetics to the membrane-permeabilizing fungicide amphotericin B, which led us to investigate the ability of LTX109 to disrupt plasma membrane integrity. S. cerevisiae cells exposed to a high concentration of LTX109 showed rapid release of potassium and amino acids, suggesting that LTX109 acted by destabilizing the plasma membrane. This was supported by the finding that cells were permeable to the fluorescent nucleic acid stain SYTOX Green after a few minutes of LTX109 treatment. We screened a haploid S. cerevisiae gene deletion library for mutants resistant to LTX109 to uncover potential molecular targets. Eight genes conferred LTX109 resistance when deleted and six were involved in the sphingolipid biosynthetic pathway (SUR1, SUR2, SKN1, IPT1, FEN1 and ORM2). The involvement of all of these genes in the biosynthetic pathway for the fungal-specific lipids mannosylinositol phosphorylceramide (MIPC) and mannosyl di-(inositol phosphoryl) ceramide (M(IP)2C) suggested that these lipids were essential for LTX109 sensitivity. Our observations are consistent with a model in which LTX109 kills S. cerevisiae by nonspecific destabilization of the plasma membrane through direct or indirect interaction with the sphingolipids.


Alcohol alters luteinizing hormone secretion in immature female rhesus monkeys by a hypothalamic action.
We determined whether the effect of alcohol (ALC) to suppress LH secretion in immature female monkeys is due to a hypothalamic or pituitary site of action. Beginning at 20 months of age, four monkeys received a single intragastric dose of ALC (2.4 g/kg), and four monkeys received an equal volume of a saline/sucrose solution daily until they were 36 months old. For the hypothalamic response test, two basal samples (3.5 ml) were collected at 15-min intervals via the saphenous vein, and then N-methyl-D-L-aspartic acid (NMA; 20 mg/kg) was given iv and four more blood samples collected. Three weeks later, this protocol was repeated except LH-releasing hormone (LHRH) (5 microg/kg) was used to test pituitary responsiveness. NMA or LHRH was administered 3 h after the ALC. After the pituitary challenge, each monkey was ovariectomized and 6 wk later, implanted with an indwelling subclavian vein catheter. Blood samples were drawn every 10 min for 8 h to assess effects of ALC on post-ovariectomy LH levels and the profile of LH pulsatile secretion. The hypothalamic challenge showed NMA stimulated LH release in control monkeys, an action that was blocked by ALC. The pituitary challenge revealed that LHRH stimulated LH release equally well in control and ALC-treated monkeys. A post-ovariectomy rise in LH was observed in both groups, but levels were 45% lower in ALC-treated monkeys. This reduction was attributed to an ALC-induced suppression of both baseline and amplitude of pulses. Results demonstrate that the ALC-induced suppression of LH in immature female rhesus monkeys is due to an inhibitory action of the drug at the hypothalamic level.


Distributed coordination of simulated robots based on self-organization.
Distributed coordination of groups of individuals accomplishing a common task without leaders, with little communication, and on the basis of self-organizing principles, is an important research issue within the study of collective behavior of animals, humans, and robots. The article shows how distributed coordination allows a group of evolved, physically linked simulated robots (inspired by a robot under construction) to display a variety of highly coordinated basic behaviors such as collective motion, collective obstacle avoidance, and collective approach to light, and to integrate them in a coherent fashion. In this way the group is capable of searching and approaching a lighted target in an environment scattered with obstacles, furrows, and holes, where robots acting individually fail. The article shows how the emerged coordination of the group relies upon robust self-organizing principles (e.g., positive feedback) based on a novel sensor that allows the single robots to perceive the group's "average" motion direction. The article also presents a robust solution to a difficult coordination problem, which might also be encountered by some organisms, caused by the fact that the robots have to be capable of moving in any direction while being physically connected. Finally, the article shows how the evolved distributed coordination mechanisms scale very well with respect to the number of robots, the way in which robots are assembled, the structure of the environment, and several other aspects.


Genomic characterization of novel Neisseria species.
Of the ten human-restricted Neisseria species two, Neisseria meningitidis, and Neisseria gonorrhoeae, cause invasive disease: the other eight are carried asymptomatically in the pharynx, possibly modulating meningococcal and gonococcal infections. Consequently, characterizing their diversity is important for understanding the microbiome in health and disease. Whole genome sequences from 181 Neisseria isolates were examined, including those of three well-defined species (N. meningitidis; N. gonorrhoeae; and Neisseria polysaccharea) and genomes of isolates unassigned to any species (Nspp). Sequence analysis of ribosomal genes, and a set of core (cgMLST) genes were used to infer phylogenetic relationships. Average Nucleotide Identity (ANI) and phenotypic data were used to define species clusters, and morphological and metabolic differences among them. Phylogenetic analyses identified two polyphyletic clusters (N. polysaccharea and Nspp.), while, cgMLST data grouped Nspp isolates into nine clusters and identified at least three N. polysaccharea clusters. ANI results classified Nspp into seven putative species, and also indicated at least three putative N. polysaccharea species. Electron microscopy identified morphological differences among these species. This genomic approach provided a consistent methodology for species characterization using distinct phylogenetic clusters. Seven putative novel Neisseria species were identified, confirming the importance of genomic studies in the characterization of the genus Neisseria.


Venlafaxine versus fluvoxamine in the treatment of delusional depression: a pilot double-blind controlled study.
Previous studies have reported the efficacy of selective serotonin reuptake inhibitors as monotherapy in the treatment of delusional depression. The clinical efficacy of venlafaxine, a serotonin-norepinephrine reuptake blocker, has been demonstrated in the treatment of patients with moderate-to-severe depression, but, to date, no evidence is available about its use in depressed patients with psychotic features. Under double-blind conditions, 28 hospitalized patients who met DSM-IV criteria for major depression, severe with psychotic features, were randomly assigned to receive fluvoxamine or venlafaxine, 300 mg/day, for 6 weeks. Severity was evaluated using the Hamilton Rating Scale for Depression (HAM-D) and the Dimensions of Delusional Experience Rating Scale (DDERS) administered at baseline and every week thereafter. Side effects were also recorded. Clinical response was defined as a reduction of the scores in the 21-item HAM-D to 8 or below and in the DDERS to 0. At study completion, the response rates were 78.6% (N = 11) and 58.3% (N = 7) for fluvoxamine and venlafaxine, respectively. No significant difference was found between drugs (Fisher exact test, p = .40). Analysis of covariance on HAM-D scores did not reveal a significantly different decrease of depressive symptomatology between the 2 treatment groups (p = .14). Treatment response appeared to be unrelated to the demographic and clinical characteristics recorded. The overall safety profile of both fluvoxamine and venlafaxine was favorable. The results of this pilot double-blind trial show that fluvoxamine is useful in the treatment of delusional depression and suggest that venlafaxine may also be an effective compound in the treatment of this disorder. The latter finding, although promising, warrants further replication in a larger sample of patients.


Diagnostic accuracy of second-generation dual-source computed tomography coronary angiography with iterative reconstructions: a real-world experience.
The authors evaluated the diagnostic accuracy of second-generation dual-source (DSCT) computed tomography coronary angiography (CTCA) with iterative reconstructions for detecting obstructive coronary artery disease (CAD). Between June 2010 and February 2011, we enrolled 160 patients (85 men; mean age 61.2±11.6 years) with suspected CAD. All patients underwent CTCA and conventional coronary angiography (CCA). For the CTCA scan (Definition Flash, Siemens), we use prospective tube current modulation and 70-100 ml of iodinated contrast material (Iomeprol 400 mgI/ ml, Bracco). Data sets were reconstructed with iterative reconstruction algorithm (IRIS, Siemens). CTCA and CCA reports were used to evaluate accuracy using the threshold for significant stenosis at ≥50% and ≥70%, respectively. No patient was excluded from the analysis. Heart rate was 64.3±11.9 bpm and radiation dose was 7.2±2.1 mSv. Disease prevalence was 30% (48/160). Sensitivity, specificity and positive and negative predictive values of CTCA in detecting significant stenosis were 90.1%, 93.3%, 53.2% and 99.1% (per segment), 97.5%, 91.2%, 61.4% and 99.6% (per vessel) and 100%, 83%, 71.6% and 100% (per patient), respectively. Positive and negative likelihood ratios at the per-patient level were 5.89 and 0.0, respectively. CTCA with second-generation DSCT in the real clinical world shows a diagnostic performance comparable with previously reported validation studies. The excellent negative predictive value and likelihood ratio make CTCA a first-line noninvasive method for diagnosing obstructive CAD.


The relationship of Asperger's syndrome to autism: a preliminary EEG coherence study.
It has long been debated whether Asperger's Syndrome (ASP) should be considered part of the Autism Spectrum Disorders (ASD) or whether it constitutes a unique entity. The Diagnostic and Statistical Manual, fourth edition (DSM-IV) differentiated ASP from high functioning autism. However, the new DSM-5 umbrellas ASP within ASD, thus eliminating the ASP diagnosis. To date, no clear biomarkers have reliably distinguished ASP and ASD populations. This study uses EEG coherence, a measure of brain connectivity, to explore possible neurophysiological differences between ASP and ASD. Voluminous coherence data derived from all possible electrode pairs and frequencies were previously reduced by principal components analysis (PCA) to produce a smaller number of unbiased, data-driven coherence factors. In a previous study, these factors significantly and reliably differentiated neurotypical controls from ASD subjects by discriminant function analysis (DFA). These previous DFA rules are now applied to an ASP population to determine if ASP subjects classify as control or ASD subjects. Additionally, a new set of coherence based DFA rules are used to determine whether ASP and ASD subjects can be differentiated from each other. Using prior EEG coherence based DFA rules that successfully classified subjects as either controls or ASD, 96.2% of ASP subjects are classified as ASD. However, when ASP subjects are directly compared to ASD subjects using new DFA rules, 92.3% ASP subjects are identified as separate from the ASD population. By contrast, five randomly selected subsamples of ASD subjects fail to reach significance when compared to the remaining ASD populations. When represented by the discriminant variable, both the ASD and ASD populations are normally distributed. Within a control-ASD dichotomy, an ASP population falls closer to ASD than controls. However, when compared directly with ASD, an ASP population is distinctly separate. The ASP population appears to constitute a neurophysiologically identifiable, normally distributed entity within the higher functioning tail of the ASD population distribution. These results must be replicated with a larger sample given their potentially immense clinical, emotional and financial implications for affected individuals, their families and their caregivers.


Clinical inquiries. How should we follow athletes after a concussion?
Athletes sustaining a concussion should be held from contact activities a minimum of 7 days; they must be asymptomatic and their coordination and neuropsychological tests should have returned to their pre-injury baseline (strength of recommendation [SOR]: B, based on multiple prospective cohort studies). High-risk athletes (eg, those with a history of previous concussion, high-school age or younger, or female) may need to avoid contact even after all these criteria are met (SOR: C, expert opinion).


Effects of L-Carnitine supplement on plasma coagulation and anticoagulation factors in hemodialysis patients.
Hypercoagulability is an important risk factor for thrombosis and its complications in hemodialysis patients. This study was designed to investigate the effects of l-carnitine supplement on plasma coagulation and anticoagulation factors in hemodialysis patients. Thirty-six hemodialysis patients were randomly assigned to either a carnitine or a placebo group. Patients in the carnitine group received 1000 mg/day oral l-carnitine for 12 weeks, whereas patients in the placebo group received a corresponding placebo. At baseline and the end of week 12, 5 mL blood was collected after a 12- to 14-hour fast and plasma fibrinogen concentration, activity of plasma protein C, coagulation factors V, VII, IX, and serum concentrations of tissue plasminogen activator (tPA), plasminogen activator inhibitor type-1 (PAI-1), free carnitine, and C-reactive protein (CRP) were measured. In the carnitine group, mean serum free carnitine concentration increased significantly to 150% of baseline (p < 0.001), whereas plasma fibrinogen and serum CRP had 98 mg/dL (p < 0.01) and 41% (p < 0.01) significant decreases, respectively, at the end of week 12 compared with baseline. The reductions were significant compared with the placebo group (p < 0.05). No significant differences were observed between the two groups with regard to mean changes of the activity of plasma protein C, coagulation factors V, VII, IX, and serum PAI-1 to tPA ratio. l-Carnitine supplement reduces serum CRP, a marker of systemic inflammation, and plasma fibrinogen, an inflammation-related coagulation factor, in hemodialysis patients. Therefore, l-carnitine may play an effective role in preventing cardiovascular diseases in these patients.


Predicting the effects of COVID-19 related interventions in urban settings by combining activity-based modelling, agent-based simulation, and mobile phone data.
Epidemiological simulations as a method are used to better understand and predict the spreading of infectious diseases, for example of COVID-19. This paper presents an approach that combines a well-established approach from transportation modelling that uses person-centric data-driven human mobility modelling with a mechanistic infection model and a person-centric disease progression model. The model includes the consequences of different room sizes, air exchange rates, disease import, changed activity participation rates over time (coming from mobility data), masks, indoors vs. outdoors leisure activities, and of contact tracing. It is validated against the infection dynamics in Berlin (Germany). The model can be used to understand the contributions of different activity types to the infection dynamics over time. It predicts the effects of contact reductions, school closures/vacations, masks, or the effect of moving leisure activities from outdoors to indoors in fall, and is thus able to quantitatively predict the consequences of interventions. It is shown that these effects are best given as additive changes of the reproduction number R. The model also explains why contact reductions have decreasing marginal returns, i.e. the first 50% of contact reductions have considerably more effect than the second 50%. Our work shows that is is possible to build detailed epidemiological simulations from microscopic mobility models relatively quickly. They can be used to investigate mechanical aspects of the dynamics, such as the transmission from political decisions via human behavior to infections, consequences of different lockdown measures, or consequences of wearing masks in certain situations. The results can be used to inform political decisions.


Characterization and Functional Analysis of Extracellular Vesicles and Muscle-Abundant miRNAs (miR-1, miR-133a, and miR-206) in C2C12 Myocytes and mdx Mice.
Duchenne muscular dystrophy (DMD) is a progressive neuromuscular disorder. Here, we show that the CD63 antigen, which is located on the surface of extracellular vesicles (EVs), is associated with increased levels of muscle-abundant miRNAs, namely myomiRs miR-1, miR-133a, and miR-206, in the sera of DMD patients and mdx mice. Furthermore, the release of EVs from the murine myoblast C2C12 cell line was found to be modulated by intracellular ceramide levels in a Ca2+-dependent manner. Next, to investigate the effects of EVs on cell survival, C2C12 myoblasts and myotubes were cultured with EVs from the sera of mdx mice or C2C12 cells overexpressing myomiRs in presence of cellular stresses. Both the exposure of C2C12 myoblasts and myotubes to EVs from the serum of mdx mice, and the overexpression of miR-133a in C2C12 cells in presence of cellular stress resulted in a significant decrease in cell death. Finally, to assess whether miRNAs regulate skeletal muscle regeneration in vivo, we intraperitoneally injected GW4869 (an inhibitor of exosome secretion) into mdx mice for 5 and 10 days. Levels of miRNAs and creatine kinase in the serum of GW4869-treated mdx mice were significantly downregulated compared with those of controls. The tibialis anterior muscles of the GW4869-treated mdx mice showed a robust decrease in Evans blue dye uptake. Collectively, these results indicate that EVs and myomiRs might protect the skeletal muscle of mdx mice from degeneration.


A randomized controlled trial of expressive writing in breast cancer survivors with lymphedema.
Breast cancer survivors who develop lymphedema report poorer quality of life (QoL) than those without lymphedema. Expressive writing is a potential intervention to address QoL. Adult women (N = 107) with breast cancer and chronic Stage II lymphedema were randomised to writing about thoughts and feelings specific to lymphedema and its treatment (intervention) or about daily activities (control) for four, 20-min sessions. Outcome measures were several indicators of QoL assessed at baseline, one, three, and six months post-intervention (total scores and subscales of Upper Limb Lymphedema 27 and Functional Assessment of Cancer Therapy-Breast). Hypothesised moderators of change in QoL were dispositional optimism, avoidant behaviours, and time since lymphedema diagnosis. There was no statistically significant intent-to-treat main effects of expressive writing on QoL. Statistically significant moderating effects on change in different indicators of QoL were observed for all three moderators. Expressive writing was more effective for improving QoL in women who were higher on optimism, lower on avoidance and had less time since a lymphedema diagnosis. These results provide further evidence that there are subsets of individuals for whom expressive writing is more effective. Future research may investigate targeting expressive writing based on identified moderators.


Chewing gums has stimulatory effects on bowel function in patients undergoing cesarean section: a randomized controlled trial.
The aim of study was to investigate the effect of postoperative gum chewing on the recovery of bowel function after cesarean section. Total 100 women delivered by lower uterine segment section cesarean under local anesthesia (spinal). Eligible patients were randomly allocated into two groups: a gum-chewing group (n=50) or a control group (n= 50). The gum-chewing group participants who received one stick of sugarless gum for one hours, three times daily immediately after recovery from anesthesia and the control group had the usual postoperative care until being discharged. All women were followed up regularly until discharge from hospital, and recorded the times to the first bowel sounds of normal intestinal sounds, the time to the first passage of flatus, the time to the first feeling of hunger, and the time to the first defecation. The operative data, postoperative tolerance of gum chewing, and postoperative complications were documented. There was no statistically significant difference between the two groups in terms of demographic characteristics such as age, body mass index, parity, duration of surgery, number of miscarriages and curettages, time to the first feeding, the amount of serum intake, and type of cesarean section. The mean average postoperative interval of the first bowel sounds (21.9 versus 26.1 hours, p= 0.016), the first feeling of hunger (11.8 versus 14.5 hours, p= 0.050), the first passage of flatus (24.8 versus 30.0 hours, P=0.002), the first defecation (30.6 versus 38.4 hours, P= 0.0001) was significantly shorter compared to the control group.


Rare functional variants in the CRP and G6PC genes modify the relationship between obesity and serum C-reactive protein in white British population.
C-reactive protein (CRP) is a sensitive biomarker of inflammation with moderate heritability. The role of rare functional genetic variants in relation to serum CRP is understudied. We aimed to examine gene mutation burden of protein-altering (PA) and loss-of-function (LOF) variants in association with serum CRP, and to further explore the clinical relevance. We included 161,430 unrelated participants of European ancestry from the UK Biobank. Of the rare (minor allele frequency <0.1%) and functional variants, 1,776,249 PA and 266,226 LOF variants were identified. Gene-based burden tests, linear regressions, and logistic regressions were performed to identify the candidate mutations at the gene and variant levels, to estimate the potential interaction effect between the identified PA mutation and obesity, and to evaluate the relative risk of 16 CRP-associated diseases. At the gene level, PA mutation burdens of the CRP (β = -0.685, p = 2.87e-28) and G6PC genes (β = 0.203, p = 1.50e-06) were associated with reduced and increased serum CRP concentration, respectively. At the variant level, seven PA alleles in the CRP gene decreased serum CRP, of which the per-allele effects were approximately three to seven times greater than that of a common variant in the same locus. The effects of obesity and central obesity on serum CRP concentration were smaller among the PA mutation carriers in the CRP (pinteraction = 0.008) and G6PC gene (pinteraction = 0.034) compared to the corresponding non-carriers. PA mutation burdens in the CRP and G6PC genes are strongly associated with decreased serum CRP concentrations. As serum CRP and obesity are important predictors of cardiovascular risks in clinics, our observations suggest taking rare genetic factors into consideration might improve the delivery of precision medicine.


[Hyperthymic and depressive temperaments study in controls, as a function of their familial loading for mood disorders].
Since the two last decades, many authors have broadened the scope of mood disorders to include a larger bipolar spectrum which encompasses the sub-affective conditions, including temperaments. According to this view, the latter conditions represent milder or alternative expressions of the classic bipolar episodes. In successive elaborations, Akiskal et al. hypothesized a complex multicausal approach to bipolar disorder, and studied temperamental dysregulations, which could serve as risk factors for major episodes. Until recently, there have been several studies of patients populations, little is known in control populations. The aim of this report is to compare the rates of three affective temperaments (hyperthymic: TH; depressive: TD; irritable: TI) in non-ill subjects with different risk for mood disorders. (The cyclothymic temperament is studied as part of another report). We recruited 185 individuals from: a) staff hospital; b) sibling of patients suffering from bipolar disorder, type I. Twenty subjects were excluded: 7 suffered from personal affective trouble; 12 exhibited cyclothymic traits; and one had familial schizophrenia. In the 165 remaining subjects, the temperamental characteristics were assessed by mean of the Akiskal and Mallya's criteria (1987, semi-structured interviews for affective temperaments, TH, TD, TI). Then, the population of controls was divided in 3 groups as a function of the familial loading for affective disorder and bipolar disorders: the first subgroup (AFN) was free of any antecedent ("super-normal controls", n=99); the second subgroup (AFP) had familial antecedents at the first or second degree (normal controls but at risk for affective disorder, n=33); the third subgroup (FBP) was composed of the siblings of bipolar I patients (subjects at high risk, n=33). Statistical procedures included standard and non-parametric methods: means standard deviation, Fisher's test, Mann-Whitney' and Kuskall-Wallis' tests, Spearman's correlation coefficient. As described by Placidi and collaborators (12), we also used the Z-score (temperamental score strictly higher than the second positive standard deviation: m + 2 sd). The general demographic characteristics show a higher frequency of women (p=0.02) but a similar mean age (p=0.296, NS) among the groups. The mean scores of the TH and TD are strongly and negatively correlated (Rho coefficient=- 0.397, p=0.01), exhibiting the internal coherence of the responses. The comparison of the temperamental characteristics among the 3 groups exhibits significant differences for the TH and TI (p=0.003). The mean scores are respectively: for the TH, 9.16 4.18 in AFN, 8.33 4.11 in AFP, and 12.16 5.28 in FBP; and for the TI, 8.94 2.25 in AFN, 9.39 2.63 in AFP, and 10.84 2.76 in FBP. Conversely, the TD scores do not significantly differ: 6.01 3.27 in AFN, 6.76 4.34 in AFP, and 7.94 5.28 in FBP. Beyond these first pass results, we also considered the distribution of the subjects as function of the Z-score and the different groups. We found that hyperthymic traits were almost exclusively among the FBP: 15.1% vs 3.0% in the other groups. For the TD, expressed in mean scores, the groups at risk for affective disorders (AFP and FBP) clearly display a percentage of subjects with a more substantial Z-score than the frequencies observed in the AFN: respectively 12.1%, 18.1% and 4.0% for the TD. Concerning traits of all three temperaments, as function of the demographic variables and the Z-score, they are generally predominant in males; however, the TH is more frequent in males only in the AFP and FBP groups (respectively: 8.3% vs none; 21.4% vs 10.5%). The TD is more prevalent among females in AFP and FBP (respectively: 8.3% vs 14.3%; 21.1% vs 14.8%). Our results clearly show temperamental dysregulations in the subjects at risk for affective disorders: (1) the levels of all three affective temperaments under study are significantly higher in subjects at risk for affective disorder, as compared to individuals free of a family antecedent; (2) the depressive temperament is prevalent in both AFP and FBP, whereas the hyperthymic is specific for FBP. As for Akiskal's model on the multicausal origin of the mood disorders, our data supports temperamental dysregulation as an important familial genetic factor in the vulnerability to manic depressive episodes. We further posit that such temperaments--more specifically, the hyperthymic--could serve as proximal phenotypes for full-blown bipolar disorder.