Report of the Primary Outcomes for Gait Mechanics in Men of the ACL-SPORTS Trial: Secondary Prevention With and Without Perturbation Training Does Not Restore Gait Symmetry in Men 1 or 2 Years After ACL Reconstruction.
Movement asymmetries during walking are common after anterior cruciate ligament (ACL) injury and reconstruction and may influence the early development of posttraumatic osteoarthritis. Preoperative neuromuscular training (like perturbation training, which is neuromuscular training requiring selective muscle activation in response to surface perturbations) improves gait asymmetries and functional outcomes among people who are ACL-deficient, but the effect of postoperative perturbation training on gait mechanics after ACL reconstruction is unknown. Among men undergoing ACL reconstruction, we sought to compare strength, agility, and secondary prevention (SAP) treatment with SAP plus perturbation training (SAP+PERT) with respect to (1) gait mechanics; and (2) elimination of gait asymmetries 1 and 2 years after ACL reconstruction. Forty men were randomized into a SAP group or a SAP+PERT group after ACL reconstruction and before returning to preinjury activities. Participants were required to achieve ≥ 80% quadriceps muscle strength symmetry, minimal knee effusion, full ROM, no reports of pain, and completion of a running progression (all between 3 and 9 months postoperatively) before enrollment. Of 94 potentially eligible athletic male patients evaluated < 9 months after ACL reconstruction, 54 were excluded for prespecified reasons. Participants underwent motion analysis during overground walking at 1 and 2 years postoperatively. Variables of interest included (1) sagittal and frontal plane hip and knee angles and moments at peak knee flexion angle; (2) sagittal plane hip and knee angles and moments at peak knee extension angle; (3) sagittal plane hip and knee excursion during weight acceptance; and (4) sagittal plane hip and knee excursion during midstance. We also calculated the proportion of athletes in each group who walked with clinically meaningful interlimb asymmetry in sagittal plane hip and knee variables and compared these proportions using odds ratios. There was no differential loss to followup between groups. There were no differences between the SAP or SAP+PERT groups for the biomechanical gait variables. The involved limb's knee excursion during midstance for the SAP (mean ± SD: 1 year: 15° ± 5°; 2 years: 16° ± 5°) and SAP+PERT (1 year: 16° ± 5°; 2 years: 15° ± 4°) athletes was not different between groups at 1 year (mean difference: -1°; 95% confidence interval [CI], -5° to 2°; p = 0.49) or 2 years (mean difference: 1°; 95% CI, -2° to 4°; p = 0.54). There were no differences between SAP and SAP+PERT athletes regarding the elimination of gait asymmetries, and gait asymmetries persisted to a large degree in both groups 1 and 2 years postoperatively. At 1 year, 11 of 18 SAP and 11 of 20 SAP+PERT athletes walked with truncated knee excursions during weight acceptance (odds ratio: 0.8, p = 0.70) and midstance (SAP 12 of 18, SAP+PERT 12 of 20; odds ratio: 0.8, p = 0.67), whereas at 2 years postoperatively, truncated knee excursions during weight acceptance (SAP seven of 17, SAP+PERT eight of 19; odds ratio: 1.0, p = 0.96) and midstance (SAP five of 17, SAP+PERT 11 of 19; odds ratio: 3.3, p = 0.09) remained prevalent. We found that a comprehensive, progressive return-to-sport training program with or without perturbation was not effective at restoring interlimb symmetry among men 1 or 2 years after ACL reconstruction. Although gait asymmetries improved from 1 to 2 years postoperatively, meaningful asymmetries persisted in both groups. To restore gait symmetry after ACL reconstruction, additional interventions likely are necessary. Level II, therapeutic study.


Subunit organization in a soluble complex of tar, CheW, and CheA by electron microscopy.
The Salmonella and Escherichia coli aspartate receptor, Tar, is representative of a large class of membrane receptors that generate chemotaxis responses by regulating the activity of an associated histidine protein kinase, CheA. Tar is composed of an NH(2)-terminal periplasmic ligand-binding domain linked through a transmembrane sequence to a COOH-terminal coiled-coil signaling domain in the cytoplasm. The isolated cytoplasmic domain of Tar fused to a leucine zipper sequence forms a soluble complex with CheA and the Src homology 3-like kinase activator, CheW. Activity of the CheA kinase in the soluble complex is essentially the same as in fully active complexes with the intact receptor in the membrane. The soluble complex is composed of approximately 28 receptor cytoplasmic domain chains, 6 CheW chains, and 4 CheA chains. It has a molecular weight of 1,400,000 (Liu, I., Levit, M., Lurz, R., Surette, M.G., and Stock, J.B. (1997) EMBO J. 16, 7231-7240). Electron microscopy reveals an elongated barrel-like structure with a largely hollow center. Immunoelectron microscopy has provided a general picture of the subunit and domain organization of the complex. CheA and CheW appear to be in the middle of the complex with the leucine zippers of the receptor construct at the ends. These findings show that the receptor signaling complex forms higher ordered structures with defined geometric architectures. Coupled with atomic models of the subunits, our results provide insights into the functional architecture by which the receptor regulates CheA kinase activity during bacterial chemotaxis.


Mayo clinical Text Analysis and Knowledge Extraction System (cTAKES): architecture, component evaluation and applications.
We aim to build and evaluate an open-source natural language processing system for information extraction from electronic medical record clinical free-text. We describe and evaluate our system, the clinical Text Analysis and Knowledge Extraction System (cTAKES), released open-source at http://www.ohnlp.org. The cTAKES builds on existing open-source technologies-the Unstructured Information Management Architecture framework and OpenNLP natural language processing toolkit. Its components, specifically trained for the clinical domain, create rich linguistic and semantic annotations. Performance of individual components: sentence boundary detector accuracy=0.949; tokenizer accuracy=0.949; part-of-speech tagger accuracy=0.936; shallow parser F-score=0.924; named entity recognizer and system-level evaluation F-score=0.715 for exact and 0.824 for overlapping spans, and accuracy for concept mapping, negation, and status attributes for exact and overlapping spans of 0.957, 0.943, 0.859, and 0.580, 0.939, and 0.839, respectively. Overall performance is discussed against five applications. The cTAKES annotations are the foundation for methods and modules for higher-level semantic processing of clinical free-text.


Reproductive hormone analyses and effects of adjuvant zoledronic acid in early breast cancer - An AZURE (BIG 01/04) sub-study.
Adjuvant bisphosphonates have been shown to improve disease outcomes in early breast cancer in women who are postmenopausal at the start of treatment. We explored the influence of pretreatment serum levels of reproductive hormones in the hypothalamic-pituitary-gonadal (HPG) axis from a subset of patients included in the AZURE trial to investigate their impact on disease recurrence and whether reproductive hormone measurements are of value in selecting patients for treatment with adjuvant zoledronic acid.Patients and methods; The AZURE trial is an academic, multi-centre, international phase III trial that randomised patients to standard adjuvant therapy (chemotherapy and/or endocrine therapy)±intravenous zoledronic acid, 4 mg for 5 years. Serum from 865 patients taken at randomisation was stored at -80 °C prior to central batch analysis for inhibin A, oestradiol and follicle stimulating hormone (FSH). We assessed the clinical value of pretreatment hormone levels for predicting invasive disease free survival (IDFS), skeletal recurrence and distant recurrence and response to treatment with zoledronic acid. Oestradiol in the postmenopausal range (<50 pmol/l) was associated with a significantly shorter IDFS (HR 1.36 95%CI: 1.05-1.78 p=0.022), predominantly due to distant recurrence (HR 1.33 95%CI: 0.98-1.81 p=0.065), compared to oestradiol ≥50pmol/l. In contrast, FSH in the postmenopausal range (>26 IU/l) was associated with a longer time to bone as first recurrence (HR 0.66 95%CI: 0.41-1.04 p=0.072) compared to an FSH ≤26 IU/l. When all 3 hormone levels were within the assay specified postmenopausal range, a trend to improved IDFS was seen with addition of zoledronic acid in biochemically postmenopausal women only (postmenopausal HR=0.81; 95%CI: 0.54-1.22, non-postmenopausal HR=0.99; 95%CI: 0.69-1.39) with risk reductions that mirrored the results of the main AZURE study, although the interaction between menopausal status and treatment effect was not statistically significant (p=0.47). Oestradiol and FSH may influence the pattern of disease recurrence with postmenopausal levels possibly creating a less conducive environment for the formation of bone metastases, therefore disseminated tumour cells could seek alternative niches outside of bone. Biochemical evaluation of a panel of reproductive hormones may be helpful to assist selection of patients for adjuvant zoledronic acid when menopausal status is unknown.


The influence of media coverage of a celebrity suicide on subsequent suicide attempts.
To investigate the impact of media reporting of a celebrity suicide on subsequent suicide attempts. A Poisson time series autoregression analysis was conducted to examine whether there was a significant increase in suicide attempts during the 3-week period after the start of extensive media reporting of a celebrity suicide. The reporting began on May 2, 2005, and lasted about 17 days. To investigate the influence of media reporting on suicide attempts, a structured interview was conducted with 124 suicide attempters identified from 2 counties in Mid Taiwan who had exposure to the media reporting. After controlling for seasonal variation, calendar year, temperature, and humidity, there was a marked increase in the number of suicide attempts during the 3-week period after media reporting began (adjusted relative risk = 1.55, 95% CI = 1.26 to 1.91). Among 124 suicide attempters exposed to the media reports, 23.4% reported an influence from them. There was no relationship between the attempters' ages and the age of the celebrity or the method, but male attempters had a significantly higher risk for such influence. A considerably higher risk for such influence was found among subjects with a history of suicide attempt(s) in the previous year (odds ratio = 52.3, 95% CI = 5.96 to 459.1). The extensive media reporting of the suicide of a celebrity was followed by an increase in suicide attempts. The effect was particularly marked in individuals with a recent history of a suicide attempt. The results provide further support for the need for more restrained reporting of suicides as part of suicide prevention strategies and for special vigilance for contagious effects of such reporting on people who have carried out recent suicidal acts.


Symmetry-protected collisions between strongly interacting photons.
Realizing robust quantum phenomena in strongly interacting systems is one of the central challenges in modern physical science. Approaches ranging from topological protection to quantum error correction are currently being explored across many different experimental platforms, including electrons in condensed-matter systems, trapped atoms and photons. Although photon-photon interactions are typically negligible in conventional optical media, strong interactions between individual photons have recently been engineered in several systems. Here, using coherent coupling between light and Rydberg excitations in an ultracold atomic gas, we demonstrate a controlled and coherent exchange collision between two photons that is accompanied by a π/2 phase shift. The effect is robust in that the value of the phase shift is determined by the interaction symmetry rather than the precise experimental parameters, and in that it occurs under conditions where photon absorption is minimal. The measured phase shift of 0.48(3)π is in excellent agreement with a theoretical model. These observations open a route to realizing robust single-photon switches and all-optical quantum logic gates, and to exploring novel quantum many-body phenomena with strongly interacting photons.


Treatment of Lethal Caffeine Overdose with Haemodialysis: A Case Report and Review.
Caffeine, chemically 1,3,7-trimethylxanthine, is the most widely consumed central nervous system stimulant in the world with pleiotropic effects on the cardiovascular, pulmonary, and renal systems. The advent of over the counter (OTC) caffeine formulations has opened the window for potential toxicity, either by inadvertent or intentional overdosing. We present the case of a patient who attempted suicide by caffeine overdose treated with emergent haemodialysis and a review of the literature.


Water channel properties of major intrinsic protein of lens.
The functions of major intrinsic protein (MIP) of lens are still unresolved; however the sequence homology with channel-forming integral membrane protein (CHIP) and other Aquaporins suggests that MIP is a water channel. Immunolocalizations confirmed that Xenopus oocytes injected with bovine MIP cRNA express the protein and target it to the plasma membrane. Control oocytes or oocytes expressing MIP or CHIP exhibited small, equivalent membrane currents that could be reversibly increased by osmotic swelling. When compared with water-injected control oocytes, the coefficient of osmotic water permeability (Pf) of MIP oocytes was increased 4-5-fold with a low Arrhenius activation energy, while the Pf of CHIP oocytes increased > 30-fold. To identify structures responsible for these differences in Pf, recombinant MIP proteins were expressed. Analysis of MIP-CHIP chimeric proteins revealed that the 4-kDa cytoplasmic domain of MIP did not behave as a negative regulator. Individual residues in MIP were replaced by residues conserved among the Aquaporins, and introduction of a proline in the 5th transmembrane domain of MIP raised the Pf by 50%. Thus oocytes expressing MIP failed to exhibit ion channel activity and consistently exhibited water transport by a facilitated pathway that was qualitatively similar to the Aquaporins but of lesser magnitude. We conclude that MIP functions as an Aquaporin in lens, but the protein may also have other essential functions.


Methyltestosterone alters sex determination in the American alligator (Alligator mississippiensis).
Effects of xenobiotics can be organizational, permanently affecting anatomy during embryonic development, and/or activational, influencing transitory actions during adulthood. The organizational influence of endocrine-disrupting contaminants (EDC's) produces a wide variety of reproductive abnormalities among vertebrates that exhibit temperature-dependent sex determination (TSD). Typically, such influences result in subsequent activational malfunction, some of which are beneficial in aquaculture. For example, 17-αmethyltestosterone (MT), a synthetic androgen, is utilized in tilapia farming to bias sex ratio towards males because they are more profitable. A heavily male-biased hatchling sex ratio is reported from a crocodile population near one such tilapia operation in Guanacaste, Costa Rica. In this study we test the effects of MT on sexual differentiation in American alligators, which we used as a surrogate for all crocodilians. Experimentally, alligators were exposed to MT in ovo at standard ecotoxicological concentrations. Sexual differentiation was determined by examination of primary and secondary sex organs post hatching. We find that MT is capable of producing male embryos at temperatures known to produce females and demonstrate a dose-dependent gradient of masculinization. Embryonic exposure to MT results in hermaphroditic primary sex organs, delayed renal development and masculinization of the clitero-penis (CTP).


Barriers and Facilitators to Preparedness for Death: Experiences of Family Caregivers of Elders with Dementia.
Less is known about how caregivers prepare (or not) for the death of a family member with dementia. This study's purpose was to explore how caregivers handle these dementia deaths, including identification of barriers and facilitators to preparing caregivers for the death of an elder family member dying with dementia. This qualitative, descriptive study employed a purposive sampling strategy in which the principal investigator interviewed 36 caregivers of family members age 65 and older who died from a dementia-related diagnosis. Directed content analysis was used to analyze the data. Four primary themes were identified as barriers: (1) hindrances to information; (2) barriers to hospice; (3) ineffective attempts to comfort; and (4) the nature of death with dementia. Six themes were identified as facilitators: (1) religious/spiritual beliefs; (2) caregiver initiative; (3) prior experience; (4) bearing witness to decline; (5) professionals alerting caregiver (of what to expect of impending death); and (6) culture and legacy of family caregiving. The results support an increased role of social work in addressing caregivers' awareness of impending death and helping prepare them for the death of an elder with dementia.


First skull of Antillothrix bernensis, an extinct relict monkey from the Dominican Republic.
The nearly pristine remains of Antillothrix bernensis, a capuchin-sized (Cebus) extinct platyrrhine from the Dominican Republic, have been found submerged in an underwater cave. This represents the first specimen of an extinct Caribbean primate with diagnostic craniodental and skeletal parts in association, only the second example of a skull from the region, and one of the most complete specimens of a fossil platyrrhine cranium yet discovered. Cranially, it closely resembles living cebines but is more conservative. Dentally, it is less bunodont and more primitive than Cebus, with crowns resembling Saimiri (squirrel monkeys) and one of the oldest definitive cebines, the late Early Miocene Killikaike blakei from Argentina. The tricuspid second molar also resembles the enigmatic marmosets and tamarins, whose origins continue to present a major gap in knowledge of primate evolution. While the femur is oddly short and stout, the ulna, though more robust, compares well with Cebus. As a member of the cebid clade, Antillothrix demonstrates that insular Caribbean monkeys are not monophyletically related and may not be the product of a single colonizing event. Antillothrix bernensis is an intriguing mosaic whose primitive characters are consistent with an early origin, possibly antedating the assembly of the modern primate fauna in greater Amazonia during the La Venta horizon. While most Greater Antillean primate specimens are quite young geologically, this vanished radiation, known from Cuba (Paralouatta) and Jamaica (Xenothrix) as well as Hispaniola, appears to be composed of long-lived lineages like several other mainland clades.


Detection of viruses using discarded plants from wild mountain gorillas and golden monkeys.
Infectious diseases pose one of the most significant threats to the survival of great apes in the wild. The critically endangered mountain gorilla (Gorilla beringei beringei) is at high risk for contracting human pathogens because approximately 60% of the population is habituated to humans to support a thriving ecotourism program. Disease surveillance for human and non-human primate pathogens is important for population health and management of protected primate species. Here, we evaluate discarded plants from mountain gorillas and sympatric golden monkeys (Cercopithecus mitis kandti), as a novel biological sample to detect viruses that are shed orally. Discarded plant samples were tested for the presence of mammalian-specific genetic material and two ubiquitous DNA and RNA primate viruses, herpesviruses, and simian foamy virus. We collected discarded plant samples from 383 wild human-habituated mountain gorillas and from 18 habituated golden monkeys. Mammalian-specific genetic material was recovered from all plant species and portions of plant bitten or chewed by gorillas and golden monkeys. Gorilla herpesviral DNA was most consistently recovered from plants in which leafy portions were eaten by gorillas. Simian foamy virus nucleic acid was recovered from plants discarded by golden monkeys, indicating that it is also possible to detect RNA viruses from bitten or chewed plants. Our findings show that discarded plants are a useful non-invasive sampling method for detection of viruses that are shed orally in mountain gorillas, sympatric golden monkeys, and potentially other species. This method of collecting specimens from discarded plants is a new non-invasive sampling protocol that can be combined with collection of feces and urine to evaluate the most common routes of viral shedding in wild primates. Am. J. Primatol. 78:1222-1234, 2016. © 2016 Wiley Periodicals, Inc.


A key region of molecular specificity orchestrates unique ephrin-B1 utilization by Cedar virus.
The emergent zoonotic henipaviruses, Hendra, and Nipah are responsible for frequent and fatal disease outbreaks in domestic animals and humans. Specificity of henipavirus attachment glycoproteins (G) for highly species-conserved ephrin ligands underpins their broad host range and is associated with systemic and neurological disease pathologies. Here, we demonstrate that Cedar virus (CedV)-a related henipavirus that is ostensibly nonpathogenic-possesses an idiosyncratic entry receptor repertoire that includes the common henipaviral receptor, ephrin-B2, but, distinct from pathogenic henipaviruses, does not include ephrin-B3. Uniquely among known henipaviruses, CedV can use ephrin-B1 for cellular entry. Structural analyses of CedV-G reveal a key region of molecular specificity that directs ephrin-B1 utilization, while preserving a universal mode of ephrin-B2 recognition. The structural and functional insights presented uncover diversity within the known henipavirus receptor repertoire and suggest that only modest structural changes may be required to modulate receptor specificities within this group of lethal human pathogens.


Diffuse brain injury induces acute post-traumatic sleep.
Clinical observations report excessive sleepiness immediately following traumatic brain injury (TBI); however, there is a lack of experimental evidence to support or refute the benefit of sleep following a brain injury. The aim of this study is to investigate acute post-traumatic sleep. Sham, mild or moderate diffuse TBI was induced by midline fluid percussion injury (mFPI) in male C57BL/6J mice at 9:00 or 21:00 to evaluate injury-induced sleep behavior at sleep and wake onset, respectively. Sleep profiles were measured post-injury using a non-invasive, piezoelectric cage system. In separate cohorts of mice, inflammatory cytokines in the neocortex were quantified by immunoassay, and microglial activation was visualized by immunohistochemistry. Immediately after diffuse TBI, quantitative measures of sleep were characterized by a significant increase in sleep (>50%) for the first 6 hours post-injury, resulting from increases in sleep bout length, compared to sham. Acute post-traumatic sleep increased significantly independent of injury severity and time of injury (9:00 vs 21:00). The pro-inflammatory cytokine IL-1β increased in brain-injured mice compared to sham over the first 9 hours post-injury. Iba-1 positive microglia were evident in brain-injured cortex at 6 hours post-injury. Post-traumatic sleep occurs for up to 6 hours after diffuse brain injury in the mouse regardless of injury severity or time of day. The temporal profile of secondary injury cascades may be driving the significant increase in post-traumatic sleep and contribute to the natural course of recovery through cellular repair.


Dual activities of emodin--DNA protectivity vs mutagenicity.
Emodin is a bioactive anthraquinone that has diverse biological effects. It is also known as a biosynthetic precursor of hypericin. The purpose of this study was to assess mechanisms of potential genotoxic and antioxidant effects of emodin. We also investigated the potential genotoxic effect of photoactivated emodin. Potential genotoxicity was determined by the alkaline comet assay and the Ames test. The potential DNA protectivity of emodin was determined by the DNA-topology assay. On purpose to clarify molecular mechanism of its DNA protectivity against Fe(2+)-induced DNA breaks, three different assays were used (Reducing power-, DPPH- and Fe(2+)-chelating assay). Using the alkaline comet assay and the Ames test we confirmed the genotoxic effect of both non-photoactivated and photoactivated emodin in a dose-dependent manner. Genotoxicity of photoactivated emodin did not differ from that obtained with non-photoactivated one. The DNA-topology assay revealed a DNA-protective activity of emodin. In the reducing power and DPPH assays emodin exhibited weak antioxidant activities. We did not observe any chelating activity of emodin in the Fe(2+)-chelating assay. We found out that emodin exhibited dual activities. On one side it was genotoxic inducing primary DNA lessions (determined by the comet assay) as well as gene mutations (determined by the Ames test). On the other side it exhibited DNA-protective activity (determined by the DNA-topology assay). Molecular mechanism underlying this DNA protective effect can be attributed to its free radicals scavenging and reducing activities.


Human herpesvirus 8 K14 protein mimics CD200 in down-regulating macrophage activation through CD200 receptor.
Many viral proteins limit host immune defenses, and their genes often originate from their hosts. CD200 (OX2) is a broadly distributed cell surface glycoprotein that interacts with a receptor on myeloid cells (CD200R) that is implicated in locally preventing macrophage activation. Distant, but recognizable, homologues of CD200 have been identified in many herpesviruses and poxviruses. Here, we show that the product of the K14 open reading frame from human herpesvirus 8 (Kaposi's sarcoma-associated herpesvirus) interacts with human CD200R and is expressed at the surfaces of infected cells solely during the lytic cycle. Despite sharing only 40% primary sequence identity, K14 and CD200 interacted with CD200R with an almost identical and low affinity (K(D) = 0.5 microM), in contrast to other characterized viral homologue interactions. Cells expressing CD200 or K14 on the cell surface were able to inhibit secretion by activated macrophages of proinflammatory cytokines such as tumor necrosis factor alpha, an effect that could be specifically relieved by addition of monoclonal antibodies and soluble monomeric CD200 protein. We conclude that CD200 delivers local down-modulatory signals to myeloid cells through direct cell-cell contact and that the K14 viral homologue closely mimics this.


Amygdalin blocks the in vitro adhesion and invasion of renal cell carcinoma cells by an integrin-dependent mechanism.
Information about the natural compound amygdalin, which is employed as an antitumor agent, is sparse and thus its efficacy remains controversial. In this study, to determine whether amygdalin exerts antitumor effects on renal cell carcinoma (RCC) cells, its impact on RCC metastatic activity was investigated. The RCC cell lines, Caki-1, KTC-26 and A498, were exposed to amygdalin from apricot kernels, and adhesion to human vascular endothelium, immobilized collagen or fibronectin was investigated. The influence of amygdalin on chemotactic and invasive activity was also determined, as was the influence of amygdalin on surface and total cellular α and β integrin expression, which are involved in metastasis. We noted that amygdalin caused significant reductions in chemotactic activity, invasion and adhesion to endothelium, collagen and fibronectin. Using FACScan analysis, we noted that amygdalin also induced reductions, particularly in integrins α5 and α6, in all three cell lines. Functional blocking of α5 resulted in significantly diminished adhesion of KTC-26 and A498 to collagen and also in decreased chemotactic behavior in all three cell lines. Blocking α6 integrin significantly reduced chemotactic activity in all three cell lines. Thus, we suggest that exposing RCC cells to amygdalin inhibits metastatic spread and is associated with downregulation of α5 and α6 integrins. Therefore, we posit that amygdalin exerts antitumor activity in vitro, and this may be linked to integrin regulation.


Large-scale replication and heterogeneity in Parkinson disease genetic loci.
Eleven genetic loci have reached genome-wide significance in a recent meta-analysis of genome-wide association studies in Parkinson disease (PD) based on populations of Caucasian descent. The extent to which these genetic effects are consistent across different populations is unknown. Investigators from the Genetic Epidemiology of Parkinson's Disease Consortium were invited to participate in the study. A total of 11 SNPs were genotyped in 8,750 cases and 8,955 controls. Fixed as well as random effects models were used to provide the summary risk estimates for these variants. We evaluated between-study heterogeneity and heterogeneity between populations of different ancestry. In the overall analysis, single nucleotide polymorphisms (SNPs) in 9 loci showed significant associations with protective per-allele odds ratios of 0.78-0.87 (LAMP3, BST1, and MAPT) and susceptibility per-allele odds ratios of 1.14-1.43 (STK39, GAK, SNCA, LRRK2, SYT11, and HIP1R). For 5 of the 9 replicated SNPs there was nominally significant between-site heterogeneity in the effect sizes (I(2) estimates ranged from 39% to 48%). Subgroup analysis by ethnicity showed significantly stronger effects for the BST1 (rs11724635) in Asian vs Caucasian populations and similar effects for SNCA, LRRK2, LAMP3, HIP1R, and STK39 in Asian and Caucasian populations, while MAPT rs2942168 and SYT11 rs34372695 were monomorphic in the Asian population, highlighting the role of population-specific heterogeneity in PD. Our study allows insight to understand the distribution of newly identified genetic factors contributing to PD and shows that large-scale evaluation in diverse populations is important to understand the role of population-specific heterogeneity.


Attenuation of fructose-induced hypertension in rats by exercise training.
This study was initiated to see if the insulin resistance, hyperinsulinemia, and hypertension that follow feeding normotensive Sprague-Dawley rats a fructose-rich diet could be prevented by letting rats run spontaneously in exercise wheel cages. Blood pressure in sedentary rats increased from (mean +/- SEM) 125 +/- 2 to 148 +/- 3 mm Hg in response to 2 weeks of a high fructose diet, and this increment was significantly (p less than 0.001) attenuated in exercising rats (from 121 +/- 1 to 131 +/- 2 mm Hg). In addition, mean (+/- SEM) plasma insulin concentration was lower in fructose-fed rats allowed to run spontaneously (44 +/- 2 vs 62 +/- 5 microU/ml; p less than 0.01). Finally, resistance to insulin-stimulated glucose uptake was assessed by determining the steady state plasma glucose response to a continuous glucose and exogenous insulin infusion during a period in which endogenous insulin secretion was suppressed. The results of these studies indicated that the mean (+/- SEM) steady state plasma glucose concentration was significantly lower in the exercise-trained rats (127 +/- 5 vs 168 +/- 6 mg/dl; p less than 0.001), despite the fact that the steady state plasma insulin levels were also lower in rats allowed to run spontaneously (75 +/- 4 vs 90 +/- 5 microU/ml; p less than 0.05). Thus, the ability of exercise-trained rats to stimulate glucose disposal was enhanced as compared with that of sedentary rats fed the same fructose-rich diet. These data demonstrate that the insulin resistance, hyperinsulinemia, and hypertension produced in normotensive rats by feeding them a high fructose diet can be attenuated if rats are allowed to run spontaneously.(ABSTRACT TRUNCATED AT 250 WORDS)


A new dromaeosaurid (Dinosauria: Theropoda) with Asian affinities from the latest Cretaceous of North America.
Dromaeosaurids from the Maastrichtian of North America have a poor fossil record and are known largely from isolated teeth, which have typically been referred to taxa based on more complete material from earlier Campanian strata. An almost complete maxilla with well-preserved dentition and an associated dentary from the Hell Creek Formation of Montana are used to establish a new dromaeosaurid taxon in the latest Maastrichtian, immediately prior to the end-Cretaceous extinction event. Acheroraptor temertyorum gen. et sp. nov. is differentiated from other dromaeosaurids on the basis of a hypertrophied postantral wall that projects posteriorly into the antorbital fenestra, a maxillary fenestra positioned low in the antorbital fossa and directly posterior to the promaxillary fenestra, and distinctive dentition with marked apicobasal ridges. The new material allows a dromaeosaurid from the Maastrichtian of North America to be placed within a phylogenetic framework for the first time. Phylogenetic analysis suggests Acheroraptor is a velociraptorine that is more closely related to Asian dromaeosaurids, including Tsaagan and Velociraptor, than it is to Dromaeosaurus, Saurornitholestes, or any other taxon from North America. As part of the Lancian Tyrannosaurus-Triceratops fauna, A. temertyorum is the latest occurring dromaeosaurid. Its relationships and occurrence suggest a complex historical biogeographic scenario that involved multiple, bi-directional faunal interchanges between Asia and North America during the Late Cretaceous.


Seasonal changes of DNA fragmentation and quality of raw and cold-stored stallion spermatozoa.
In this study annual fluctuations of DNA fragmentation and quality of cold-stored equine sperm were evaluated. Ejaculates were collected weekly during one year from 15 stallions. Ejaculate volume, sperm concentration and total sperm count were determined and semen was then extended and cold-stored for 48 h. Sperm motility was evaluated by CASA before and after 24 as well as 48 h of cold storage. In addition, the percentages of sperm with intact plasma membrane and acrosome (PMAI %) and with low intracellular Ca2+ level were determined in cold-stored semen (24 h, 48 h). SCSA™ was performed to assess mean DFI, SD of DFI and % DFI in raw frozen-thawed as well as in extended sperm after 24 and 48 h of storage. The month of semen collection affected (P < 0.05) all parameters evaluated in raw semen and all criteria except progressive motility as well as rapid cells in semen stored for 24 and 48 h, respectively. Ejaculate volume was higher and sperm concentration lower in summer compared to winter and motility lower in July than in any other month of the year (P < 0.05). In semen processed in April and stored for 24 h the percentage of rapid cells was improved compared to January and after 48 h of storage progressive motility (%) was higher in January and October than in July (P < 0.05). After 24 h of cold storage PMAI % was higher in October than in January and after 48 h values were higher in September compared to January and February as well as from April to July (P < 0.05). Regarding sperm with low intracellular Ca+2 level (%) after storage for 24 and 48 h, higher values were measured in winter and in October compared to April, June and July (P < 0.01). Seasonal changes in DNA fragmentation were most evident with respect to mean DFI. In raw frozen-thawed semen mean DFI was lower from August to November than in June and July (P < 0.001). Values were lower during winter compared to spring and early summer (P < 0.05) and lower in December than from April to September (P < 0.001). After 24 h of cold storage mean DFI was lower in September and October when compared to January, February, May, July and November (P < 0.05) and after 48 h storage mean DFI was reduced in spring and autumn compared to February, June and July (P < 0.05). In conclusion, a seasonal effect was evident on semen characteristics of raw and cold-stored sperm. Semen quality was impaired in midsummer when low sperm motility and viability were combined with an elevated DNA fragmentation and Ca2+ level of sperm.


As mental health nursing roles expand, is education expanding mental health nurses? An emotionally intelligent view towards preparation for psychological therapies and relatedness.
Mental health nurses (MHN) in the UK currently occupy a challenging position. This positioning is one that offers a view of expanding roles and responsibilities in both mental health act legislation and the delivery of psychological therapies, while simultaneously generic pre-registration training is being considered. Clearly, the view from this position, although not without challenge and internal discipline dispute, can also offer growing professional prestige, influence and respect from other health disciplines, as well as the wider public. Conversely, if the training, education and strategic enactment for new MHN roles is formulated and delivered from predominantly non-MHN axiomatic and epistemological stances, MHN identity can be seriously and potentially permanently diminished. This paper offers the construct of emotional intelligence as a framework to respond to these future challenges through making individual MHN enablement a primacy. This enablement of MHNs through enhanced emotional intelligence competencies is argued as requiring priority over the standard approach of enhancing strategies alone.


ATPase-dependent control of the Mms21 SUMO ligase during DNA repair.
Modification of proteins by SUMO is essential for the maintenance of genome integrity. During DNA replication, the Mms21-branch of the SUMO pathway counteracts recombination intermediates at damaged replication forks, thus facilitating sister chromatid disjunction. The Mms21 SUMO ligase docks to the arm region of the Smc5 protein in the Smc5/6 complex; together, they cooperate during recombinational DNA repair. Yet how the activity of the SUMO ligase is controlled remains unknown. Here we show that the SUMO ligase and the chromosome disjunction functions of Mms21 depend on its docking to an intact and active Smc5/6 complex, indicating that the Smc5/6-Mms21 complex operates as a large SUMO ligase in vivo. In spite of the physical distance separating the E3 and the nucleotide-binding domains in Smc5/6, Mms21-dependent sumoylation requires binding of ATP to Smc5, a step that is part of the ligase mechanism that assists Ubc9 function. The communication is enabled by the presence of a conserved disruption in the coiled coil domain of Smc5, pointing to potential conformational changes for SUMO ligase activation. In accordance, scanning force microscopy of the Smc5-Mms21 heterodimer shows that the molecule is physically remodeled in an ATP-dependent manner. Our results demonstrate that the ATP-binding activity of the Smc5/6 complex is coordinated with its SUMO ligase, through the coiled coil domain of Smc5 and the physical remodeling of the molecule, to promote sumoylation and chromosome disjunction during DNA repair.


Teaching evidence-based decision-making.
Evidence-based decision-making is important in surgery, but the nature of the work makes it difficult. Teaching it requires an interactive approach with a clinical team willing to consider it seriously,and to derive practical solutions. Decision-making and its influences must be understood, so that surgeons have a realistic idea of the role of evidence. Cognitive factors are particularly important.Strategies developed in the context of this knowledge are more likely to be adopted and used. Experts must be involved in searching for evidence and members of the management team in the learning process, the former to provide expertise on searching,the latter to ensure that the reasons for proposed changes are understood and treated sympathetically by those with financial control.


Descemet stripping and endothelial keratoplasty in endothelial dysfunctions: three-month results in 75 eyes.
To analyze the results of Descemet stripping and endothelial keratoplasty (DSEK) in the first consecutive 75 cases. Prospective, non-randomized, non-comparative interventional case series. Seventy-five eyes of 75 patients with endothelial dysfunctions of different etiology, scheduled for DSEK, were included in this study. Healthy donor cornea with a cell count of> 2000 cells/sq mm was considered for transplantation in each case. Indications, operative problems and postoperative complications were noted. Best corrected visual acuity (BCVA), refractive and keratometric astigmatism, central corneal thickness (CCT) and endothelial cell density (ECD) were analyzed for each patient after a minimum follow-up of three months. Main indication was pseudophakic corneal edema and bullous keratopathy in 53 (70.7%) eyes. Seventeen (22.7%) cases had moderate to severe Fuchs' dystrophy with various grades of cataract; and DSEK was combined with manual small-incision cataract surgery (MSICS) with posterior chamber intraocular lens (PCIOL) in those cases. After three months, BCVA was 20/60 or better in 62 (82.7%) cases. Mean refractive and keratometric astigmatism were 1.10 +/- 0.55 diopter cylinder (DCyl) and 1.24 +/- 0.92 DCyl. The CCT and ECD were 670.8 +/- 0.32 microm and 1485.6 +/- 168.6/sq mm respectively. The mean endothelial cell loss after three months was 26.8 +/- 4.24% (range: 13.3-38.4%). Dislocation of donor lenticule occurred in six (8.0%) eyes. Graft failure occurred in one case. Descemet stripping and endothelial keratoplasty is a safe and effective procedure in patients with endothelial dysfunctions with encouraging surgical and visual outcomes. It can be safely combined with MSICS with PCIOL in patients with moderate to severe Fuchs' dystrophy with cataract.


The stimulatory role of human cytochrome b5 in the bioactivation activities of human CYP1A2, 2A6 and 2E1: a new cell expression system to study cytochrome P450 mediated biotransformation.
Cytochrome b(5) (b(5)) is increasingly recognized to be of importance for specific cytochrome P450 (CYP) activities. We developed human b(5)/CYP-competent mutagenicity tester bacteria to study the role of b(5) in the bioactivation activity of human CYP. These new tester bacteria were derived from the previously engineered human CYP-competent Escherichia coli K12 tester strain MTC, containing a bi-plasmid system for the co-expression of a specific CYP form (CYP1A2, 2A6 or 2E1) with human b(5), and human NADPH cytochrome P450 reductase (RED), resulting in the strain BTC-b(5)-1A2, BTC-b(5)-2A6 and BTC-b(5)-2E1, respectively. The relative content of b(5) with CYP and RED in these three BTC-b(5)-CYP strains demonstrated physiologically relevant co-expression levels and typical CYP-specific activities could be determined with their specific chemical probes. These strains were applied in mutagenicity assays along with their corresponding b(5)-void strains to determine the effect of b(5) on the CYP1A2-, CYP2A6- and CYP2E1-mediated bioactivation of several promutagens. For CYP1A2, of the 5 compounds tested [2-aminoanthracene (2AA), 1-aminopyrene, 6-aminochrysene, 2-amino-3-methylimidazo(4,5-f)quinoline and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)], only the mutagenicity of 2AA was slightly increased ( approximately 1.5-fold) in the presence of b(5). The CYP2E1- and CYP2A6-dependent mutagenicity of N-nitrosodiethylamine increased approximately 3- and 23-fold, respectively when the bacteria contained b(5). The CYP2A6-mediated mutagenicity of NNK increased approximately 9-fold when co-expressed with b(5). The stimulatory effect of b(5) on the bioactivation of N-nitrosodi-n-propylamine was most striking. The mutagenicity of this procarcinogen was completely dependent on the co-expression of b(5) with CYP2A6 or CYP2E1. This demonstrates the prominent role of b(5) in the bioactivation of this carcinogen.


Selenium in reproductive health.
Selenium is an essential trace element of importance to human biology and health. Increasing evidence suggests that this mineral plays an important role in normal growth and reproduction in animals and humans, and selenium supplementation is now recommended as part of public health policy in geographical areas with severe selenium deficiency in soil. This review addresses the biological functions of selenium followed by a detailed review of associations between selenium status and reproductive health. In many countries, selenium dietary intake falls below the recommended nutrient intakes and is inadequate to support maximal expression of the selenoenzymes. Numerous reports implicate selenium deficiency in several reproductive and obstetric complications including male and female infertility, miscarriage, preeclampsia, fetal growth restriction, preterm labor, gestational diabetes, and obstetric cholestasis. Currently, there is inadequate information from the available small intervention studies to inform public health strategies. Larger intervention trials are required to reinforce or refute a beneficial role of selenium supplementation in disorders of reproductive health.


OLT1177 (Dapansutrile), a Selective NLRP3 Inflammasome Inhibitor, Ameliorates Experimental Autoimmune Encephalomyelitis Pathogenesis.
IL-1β and IL-18 are pro-inflammatory cytokines that are linked to inflammation. Activation of the NOD-like receptor protein 3 (NLRP3) inflammasome is involved in the maturation and secretion of IL-1β and IL-18 and, thus, plays a key role in the pathogenesis of many inflammatory conditions, including multiple sclerosis (MS). OLT1177™ (Dapansutrile) is a newly developed drug that is safe in humans and inhibits specifically the NLRP3 inflammasome. In the present study, we investigated whether OLT1177 exerts therapeutic effects in experimental autoimmune encephalomyelitis (EAE), a mouse model of MS. We found that EAE mice fed an OLT1177-enriched diet prophylactically were significantly protected against functional deficits and demyelination in the spinal cord. We also demonstrated that prophylactic oral administration of OLT1177 led to marked reduction (~2- to 3-fold) in the protein levels of IL-1β and IL-18, as well as, IL-6 and TNFα, in the spinal cord of EAE mice. Moreover, prophylactic oral administration of OLT1177 significantly attenuated the infiltration of CD4 T cells and macrophages in the spinal cord. We also demonstrated that oral administration of OLT1177, starting at disease onset, resulted in significant amelioration of the clinical signs of EAE. Overall, these first data suggest that OLT1177 could have clinical benefit for the treatment of MS in humans.


Pressure-induced insulator-to-metal transitions for enhancing thermoelectric power factor in bismuth telluride-based alloys.
First-principles calculations revealing insulator-to-metal transitions in Bi2Te3 and Bi2Te2Se, at 9 GPa and 12.5 GPa, respectively, match with prior experiments. Our electronic band structure calculations and accompanying Boltzmann transport calculations of thermoelectric properties for Bi2-xSbxTe2-ySey alloys explain and predict large power factor changes induced by pressure. Complex band degeneracy changes preceding insulator-to-metal transitions significantly alter the density of states near the Fermi level, and foster the disentangling of the unfavorable coupling between Seebeck coefficient and electrical conductivity. Our findings on pressure-induced changes in thermoelectric power factor provide insights for designing V2VI3-based high-performance thermoelectric materials through strategies such as alloying, high-pressure processing, and strain engineering.


Observer agreement for small bowel ultrasound in Crohn's disease: results from the METRIC trial.
To prospectively evaluate interobserver agreement for small bowel ultrasound (SBUS) in newly diagnosed and relapsing Crohn's disease. A subset of patients recruited to a prospective trial comparing the diagnostic accuracy of MR enterography and SBUS underwent a second SBUS performed by one of a pool of six practitioners, who recorded the presence, activity and location of small bowel and colonic disease. Detailed segmental mural and extra-mural observations were also scored. Interobserver variability was expressed as percentage agreement with a construct reference standard, split by patient cohort, grouping disease as present or absent. Prevalence adjusted bias adjusted kappa (PABAK), and simple percentage agreement between practitioners, irrespective of the reference standard, were calculated. Thirty-eight patients (11 new diagnosis, 27 relapse) were recruited from two sites. Overall percentage agreement for small bowel disease presence against the consensus reference was 82% (52-95% (95%CI)), kappa coefficient (κ) 0.64, (substantial agreement) for new diagnosis and 81%, κ 0.63 (substantial agreement) for the relapsing cohort. Agreement for colonic disease presence was 64%, κ 0.27 (fair agreement) in new diagnosis and 78%,κ 0.56 (moderate agreement) in the relapsing cohort. Simple agreement between practitioners was 84% and 87% for small bowel and colonic disease presence respectively. Practitioners agreed on small bowel disease activity in 24/27 (89%) where both identified disease. Kappa agreement for detailed mural observations ranged from κ 0.00 to 1.00. There is substantial practitioner agreement for small bowel disease presence in newly diagnosed and relapsing CD patients, supporting wider dissemination of enteric US.


Oral lipoid proteinosis.
This literature review of oral lipoid proteinosis and a case report of an infant with this condition describe an uncommon condition inherited as an autosomal recessive trait, but one which is more likely to occur in this country than elsewhere. The article discusses other lesions which could be mistaken for oral lipoid proteinosis, and offers some pertinent aspects of its diagnosis and management.


Two new balancer chromosomes on mouse chromosome 4 to facilitate functional annotation of human chromosome 1p.
To facilitate genetic screens to identify and maintain recessive mutations that map to the short arm of human chromosome 1, we have utilized chromosome engineering to generate two mouse strains that carry large inversions on the distal region of mouse chromosome 4. The inversion intervals are 16 and 22 cM in size together they cover approximately half of chromosome 4. Since recombination between the wild-type and inversion chromosomes does not occur within these inversion intervals, mutant alleles of genes mapping to this region can be identified and maintained. Therefore, these inversion chromosomes work as balancer chromosomes. These inversions have the additional advantage that they are tagged with genes encoding the visible coat color markers tyrosinase and agouti, and therefore the dosage of the inversion chromosome (+/+, Inv/+, Inv/Inv) can be visually recognized. These inversion strains will be extremely useful for mutagenesis screens that focus on functional annotation of human chromosome 1p.


Virtual endoscopy using perspective volume-rendered three-dimensional sonographic data: technique and clinical applications.
We present a technique for obtaining three-dimensional external and virtual endoscopy views of organs using perspective volume-rendered gray-scale and Doppler sonographic data, and we explore potential clinical applications in the carotid artery, the female pelvis, and the bladder. Using the proposed methods, radiologists will find it possible to create virtual endoscopy and external perspective views using sonographic data. The technique works well for revealing the interior of fluid-filled structures and cavities. However, expected improvements in computer performance and integration with existing sonographic equipment will be necessary for the technique to become practical in the clinical environment.


3D hierarchical porous graphene aerogel with tunable meso-pores on graphene nanosheets for high-performance energy storage.
New and novel 3D hierarchical porous graphene aerogels (HPGA) with uniform and tunable meso-pores (e.g., 21 and 53 nm) on graphene nanosheets (GNS) were prepared by a hydrothermal self-assembly process and an in-situ carbothermal reaction. The size and distribution of the meso-pores on the individual GNS were uniform and could be tuned by controlling the sizes of the Co3O4 NPs used in the hydrothermal reaction. This unique architecture of HPGA prevents the stacking of GNS and promises more electrochemically active sites that enhance the electrochemical storage level significantly. HPGA, as a lithium-ion battery anode, exhibited superior electrochemical performance, including a high reversible specific capacity of 1100 mAh/g at a current density of 0.1 A/g, outstanding cycling stability and excellent rate performance. Even at a large current density of 20 A/g, the reversible capacity was retained at 300 mAh/g, which is larger than that of most porous carbon-based anodes reported, suggesting it to be a promising candidate for energy storage. The proposed 3D HPGA is expected to provide an important platform that can promote the development of 3D topological porous systems in a range of energy storage and generation fields.


Reconstruction of transcriptional regulatory networks by stability-based network component analysis.
Reliable inference of transcription regulatory networks is a challenging task in computational biology. Network component analysis (NCA) has become a powerful scheme to uncover regulatory networks behind complex biological processes. However, the performance of NCA is impaired by the high rate of false connections in binding information. In this paper, we integrate stability analysis with NCA to form a novel scheme, namely stability-based NCA (sNCA), for regulatory network identification. The method mainly addresses the inconsistency between gene expression data and binding motif information. Small perturbations are introduced to prior regulatory network, and the distance among multiple estimated transcript factor (TF) activities is computed to reflect the stability for each TF's binding network. For target gene identification, multivariate regression and t-statistic are used to calculate the significance for each TF-gene connection. Simulation studies are conducted and the experimental results show that sNCA can achieve an improved and robust performance in TF identification as compared to NCA. The approach for target gene identification is also demonstrated to be suitable for identifying true connections between TFs and their target genes. Furthermore, we have successfully applied sNCA to breast cancer data to uncover the role of TFs in regulating endocrine resistance in breast cancer.


Surface TLR2 and TLR4 expression on mature rat mast cells can be affected by some bacterial components and proinflammatory cytokines.
The aim of our study was to determine whether some bacterial components as well as some proinflammatory cytokines can affect surface mast cell levels. By the use of flow cytometry technique, we documented that freshly isolated mature rat peritoneal mast cells do express surface TLR2 and TLR4 protein, but not CD14 molecules, and respond to stimulation with TLR2 and TLR4 ligands by cysteinyl leukotriene generation. The level of TLR2 protein is modulated by PGN and CCL5 treatment, but not by LPS, LAM, TNF, or IL-6. Surface mast cell TLR4 expression is affected by LPS, LAM, IL-6, and CCL5. Considering that TLR-mediated activation conditions not only engaged these cells in antibacterial defense and development of inflammation but also might influence allergic processes, our observations that surface TLR2 and TLR4 expression can be regulated both bacterial components and proinflammatory cytokines seem to be very intriguing and importance.


Design of thiazole orange oligonucleotide probes for detection of DNA and RNA by fluorescence and duplex melting.
We have synthesised a range of thiazole orange (TO) functionalised oligonucleotides for nucleic acid detection in which TO is attached to the nucleobase or sugar of thymidine. The properties of duplexes between TO-probes and their DNA and RNA targets strongly depend on the length of the linker between TO and the oligonucleotide, the position of attachment of TO to the nucleotide (major or minor groove) and the mode of attachment of thiazole orange (via benzothiazole or quinoline moiety). This information can be used to design probes for detection of target nucleic acids by fluorescence or duplex melting. With cellular imaging in mind we show that 2'-OMe RNA probes with TO at the 5-position of uracil or the 2'-position of the ribose sugar are particularly effective, exhibiting up to 44-fold fluorescence enhancement against DNA and RNA, and high duplex stability. Excellent mismatch discrimination is achieved when the mispaired base is located adjacent to the TO-modified nucleotide rather than opposite to it. The simple design, ease of synthesis and favourable properties of these TO probes suggest applications in fluorescent imaging of DNA and RNA in a cellular context.


Hepatic stellate cell-mediated three-dimensional hepatocyte and endothelial cell triculture model.
Hepatic stellate cells (HSCs) form a functional unit with endothelia and hepatocytes in the liver to play a pivotal role in heterotypic cellular communication. To investigate this role of HSCs, it is of great benefit to establish a triculture model that forms the functional unit from proximal layers of hepatocytes, HSCs, and endothelial cells (ECs). Here, we established a three-dimensional triculture model, using a microporous membrane to create the functional unit. HSC behavior was controlled by the membrane pore size, which was critical for achieving proximal cell layers. With a specific pore size, the HSCs intercalated between layers of hepatocytes and ECs, due to the limitation on HSC behavior. When only cytoplasmic processes of quiescent HSCs were adjacent to ECs, while the HSC bodies remained on the side of the hepatocytes, the ECs changed morphologically and were capable of long-term survival. We confirmed that HSCs mediated the communication between hepatocytes and ECs in terms of EC morphogenesis. This triculture model allows us to investigate the roles of HSCs as both facilitators and integrators of cell-cell communication between hepatocytes and ECs, and is useful for investigating heterotypic cellular communication in vitro.


Comparison of sonography and magnetic resonance imaging for spring ligament abnormalities: preliminary study.
The purpose of this study was to determine whether sonography is as accurate as magnetic resonance (MR) imaging for depicting abnormalities of the spring ligament in patients with symptomatic posterior tibial tendon (PTT) dysfunction. Sixteen patients (18 ligaments) with symptomatic PTT dysfunction were prospectively evaluated with sonography and MR imaging. Magnetic resonance imaging showed spring ligament tears in 8 of 18 feet, including 6 incomplete tears and 2 complete tears. Sonography showed spring ligament tears in 7 of 18 feet, including 6 incomplete tears and 1 complete tear. The findings of sonography and MR imaging were concordant in 17 of 18 feet (94%). Six of the 8 spring ligament tears on MR imaging were associated with posterior tibial tendinosis or tears. Sonography is an effective imaging option in assessing spring ligament abnormalities in patients with symptomatic PTT dysfunction.


Contribution of peroxisomes to secondary metabolism and pathogenicity in the fungal plant pathogen Alternaria alternata.
The filamentous fungus Alternaria alternata includes seven pathogenic variants (pathotypes) which produce different host-selective toxins and cause diseases on different plants. The Japanese pear pathotype produces the host-selective AK-toxin, an epoxy-decatrienoic acid ester, and causes black spot of Japanese pear. Previously, we identified four genes, AKT1, AKT2, AKT3, and AKTR, involved in AK toxin biosynthesis. AKT1, AKT2, and AKT3 encode enzyme proteins with peroxisomal targeting signal type 1 (PTS1)-like tripeptides, SKI, SKL, and PKL, respectively, at the C-terminal ends. In this study, we verified the peroxisome localization of Akt1, Akt2, and Akt3 by using strains expressing N-terminal green fluorescent protein (GFP)-tagged versions of the proteins. To assess the role of peroxisome function in AK-toxin production, we isolated AaPEX6, which encodes a peroxin protein essential for peroxisome biogenesis, from the Japanese pear pathotype and made AaPEX6 disruption-containing transformants from a GFP-Akt1-expressing strain. The DeltaAaPEX6 mutant strains did not grow on fatty acid media because of a defect in fatty acid beta oxidation. The import of GFP-Akt1 into peroxisomes was impaired in the DeltaAaPEX6 mutant strains. These strains completely lost AK toxin production and pathogenicity on susceptible pear leaves. These data show that peroxisomes are essential for AK-toxin biosynthesis. The DeltaAaPEX6 mutant strains showed a marked reduction in the ability to cause lesions on leaves of a resistant pear cultivar with defense responses compromised by heat shock. This result suggests that peroxisome function is also required for plant invasion and tissue colonization in A. alternata. We also observed that mutation of AaPEX6 caused a marked reduction of conidiation.


Samples in applied psychology: over a decade of research in review.
This study examines sample characteristics of articles published in Journal of Applied Psychology (JAP) from 1995 to 2008. At the individual level, the overall median sample size over the period examined was approximately 173, which is generally adequate for detecting the average magnitude of effects of primary interest to researchers who publish in JAP. Samples using higher units of analyses (e.g., teams, departments/work units, and organizations) had lower median sample sizes (Mdn ≈ 65), yet were arguably robust given typical multilevel design choices of JAP authors despite the practical constraints of collecting data at higher units of analysis. A substantial proportion of studies used student samples (~40%); surprisingly, median sample sizes for student samples were smaller than working adult samples. Samples were more commonly occupationally homogeneous (~70%) than occupationally heterogeneous. U.S. and English-speaking participants made up the vast majority of samples, whereas Middle Eastern, African, and Latin American samples were largely unrepresented. On the basis of study results, recommendations are provided for authors, editors, and readers, which converge on 3 themes: (a) appropriateness and match between sample characteristics and research questions, (b) careful consideration of statistical power, and (c) the increased popularity of quantitative synthesis. Implications are discussed in terms of theory building, generalizability of research findings, and statistical power to detect effects.


Leaf-level photosynthetic capacity in lowland Amazonian and high-elevation Andean tropical moist forests of Peru.
We examined whether variations in photosynthetic capacity are linked to variations in the environment and/or associated leaf traits for tropical moist forests (TMFs) in the Andes/western Amazon regions of Peru. We compared photosynthetic capacity (maximal rate of carboxylation of Rubisco (Vcmax ), and the maximum rate of electron transport (Jmax )), leaf mass, nitrogen (N) and phosphorus (P) per unit leaf area (Ma , Na and Pa , respectively), and chlorophyll from 210 species at 18 field sites along a 3300-m elevation gradient. Western blots were used to quantify the abundance of the CO2 -fixing enzyme Rubisco. Area- and N-based rates of photosynthetic capacity at 25°C were higher in upland than lowland TMFs, underpinned by greater investment of N in photosynthesis in high-elevation trees. Soil [P] and leaf Pa were key explanatory factors for models of area-based Vcmax and Jmax but did not account for variations in photosynthetic N-use efficiency. At any given Na and Pa , the fraction of N allocated to photosynthesis was higher in upland than lowland species. For a small subset of lowland TMF trees examined, a substantial fraction of Rubisco was inactive. These results highlight the importance of soil- and leaf-P in defining the photosynthetic capacity of TMFs, with variations in N allocation and Rubisco activation state further influencing photosynthetic rates and N-use efficiency of these critically important forests.


Different binding sites of serum albumins in the protein corona of gold nanoparticles.
The interaction of bovine serum albumin (BSA) and human serum albumin (HSA), sharing a sequence similarity of 77.5%, with gold nanoparticles of a size of ∼30 nm was investigated by surface-enhanced Raman scattering (SERS). The spectra provide information on those residues of the proteins in proximity of the nanoparticles. The SERS signals indicate an electrostatic interaction of both proteins with the citrate ligands at the nanoparticle surface via lysine residues. HSA, different from BSA also binds directly to the gold surface by particularly flexible protein segments that were identified by comparison of the vibrational bands with the known amino acid sequence of the molecule. The data suggest that both the direct binding as well as interaction with the citrate ligands determine the interaction, yet to varying extent in the two very similar serum proteins. This has implications for their use in bio-functionalization, and for the application of gold nanostructures in bioanalytics and medicine.


Transparency in European Medicines Agency and US Food and Drug Administration Decision Making: Is It Possible to Identify the Rationale for Divergences in Approved Indication From Public Assessment Reports?
Although it cannot be expected that different medicines' regulatory agencies always reach the same review outcome, it is important that decision making is documented and communicated to ensure transparency. This study examines whether justification for divergences between the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) regarding approved indications could be identified from the agencies' public assessment reports (PARs). We focused on 9 products previously identified to have been submitted simultaneously to both agencies with the same indication but had a different indication approved; there were 15 differences in indications. Our analysis confirms that the rationale for observed divergent indication decisions was predominantly found in the benefit-risk section of the PAR (9 of 15 cases for the FDA and 10 of 15 for the EMA). If not found in the benefit-risk section, the rationale for these decisions was found in other PAR sections (eg, labeling or clinical efficacy section) or not at all. Our study found a small number of inconsistencies or gaps in how, where, and whether regulatory decision making on approved indications are documented by the FDA and the EMA. We believe it is important for regulators to standardize their approach and systematically and transparently document their rationale for the approved indication, using a structured benefit-risk assessment format within the PAR. This process is especially important for innovative products for which experience in evaluating similar products worldwide is limited, particularly as agencies are striving to build effective regulatory processes by leveraging assessments by trusted reference agencies through approaches such as reliance. Clear and systematic communication and documentation of the decisions in the PAR are central and should continue to evolve as a best practice; an enabling step toward this would be a harmonized PAR template for use by agencies globally.


The highs and lows of plant life: temperature and light interactions in development.
Plants must constantly respond to changes in the environment whilst maintaining developmental and growth processes if they are to survive into the next generation. A complex network of signals from temperature and light must correctly converge to achieve successful development, through vegetative to reproductive growth. Temperature can be thought of as an environmental factor that provides both 'inductive' and 'maintenance' signals in development. It can stimulate developmental processes such as seed dormancy release, germination and vernalization. However, when temperature is not regarded as inductive, an accommodating network of genes work in concert to ensure growth responses occur regardless of fluctuating microclimate conditions. Many of the temperature-regulated developmental pathways are intimately linked with light signaling. For example, light-temperature interactions are major determinants in the timing of reproductive development. Indeed, the ability to process and react to complex environmental cues is crucial for both normal and adaptive development in a changing environment. These responses are frequently mediated by manipulating the phytohormone network, which serves as a powerful, yet adaptable controller of development. This paper illustrates the influential role temperature perception plays throughout plant development and the close interaction between temperature, light and hormone signaling.


Low Yield of Positive Cerebrospinal Fluid (CSF) Culture and Bacterial PCR Tests In Paediatric Patients With A Normal CSF White Cell Count.
The aim was to review paediatric patients who had a positive cerebrospinal fluid culture or bacterial PCR test, yet had a normal CSF white cell count for age. Patients were included if they had a CSF sample sent for culture (between 2005 and 2015) or bacterial PCR (2010-2015), however neurosurgical and neurology patients were excluded. Of the 2,482 patients reviewed, there were 101 patients with laboratory-confirmed bacterial meningitis included, of which 27 were positive by culture and PCR, 26 by culture alone and 48 were positive by PCR only. Eighteen (18%) of these patients had CSF white cell counts within normal range. Only one case with a normal CSF white cell count, where the lumbar puncture was done after six days of antibiotics, was deemed to be clinically significant. Bacterial PCR should not be routinely requested in patients with a normal CSF white cell count, unless their blood culture is positive or unless clinically indicated based on the assessment of a senior paediatrician.


Enzymatically crosslinked dendritic polyglycerol nanogels for encapsulation of catalytically active proteins.
The enormous potential of nanogel scaffolds for protein encapsulation has been widely recognized. However, constructing stable polymeric nanoscale networks in a facile, mild, and controllable fashion still remains a technical challenge. Here, we present a novel nanogel formation strategy using horseradish peroxidase (HRP) catalyzed crosslinking on phenolic derivatized dendritic polyglycerol (dPG) in the presence of H2O2 in an inverse miniemulsion. This "enzymatic nanogelation" approach was efficient to produce stable 200 nm dPG nanogel particles, and was performed under physiological conditions, thus making it particularly beneficial for encapsulating biological proteins. Purification of the nanogels was easy to handle and practical because there was no need for a post-quenching step. Interestingly, the use of dPG resulted in higher HRP laden nanogels than for linear polyethylene glycol (PEG) analogs, which illustrates the benefits of dendritic backbones in nanogels for protein encapsulation. In addition, the mild immobilization contributed to the enhanced thermal stability and reusability of HRP. The nanogel preparation could be easily optimized to achieve the best HRP activity. Furthermore, a second enzyme, Candida antarctica lipase B (CalB), was successfully encapsulated and optimized for activity in dPG nanogels by the same enzymatic methodology, which shows the perspective applications of such techniques for encapsulation of diverse proteins.


A re-examination of the taxonomic status of Prostoma jenningsi-a Freshwater Nemertean.
Prostoma jenningsi was first recorded at the Clay 'Ole pond in Lancashire, UK, in 1969 and was distinguished histologically from other Prostoma by the presence of 11 proboscidial nerves (with all other Prostoma species thought to have 9-10). P. jenningsi was considered to be the only species endemic to Lancashire and listed in the British Red Data Book as 'Insufficiently Known' as well as a 'Species of Principal Importance' under the UK Natural Environment and Rural Communities Act (2006). A limited number of Prostoma spp were recovered from the Clay 'Ole in 2011 (the first confirmation of the presence of Prostoma spp. since 1999). In 2015, further sampling was undertaken and expanded to other ponds in Lancashire resulting in the discovery of Prostoma spp. at a further 3 locations. Thereafter, DNA sequencing of nuclear 18S ribosomal RNA and mitochondrial Cytochrome Oxidase I (COI) genes were undertaken and phylogenetic analyses performed to establish the taxonomic status of recovered specimens. All available Prostoma sequences (Prostoma eilhardi and Prostoma graecense) were downloaded from GenBank® and Barcode of Life Data System (BOLD) databases for comparison. All 18S sequences from samples in Lancashire were identical to each other and to all downloaded Prostoma sequences, allowing no further analyses. With COI, 50 individuals were collected from 4 locations across Lancashire and sequenced, comparing a total of 480 base pairs. Average uncorrected p-distances between UK and European samples were low, although some more geographically distant samples from California, USA, displayed higher uncorrected p-distance values. Results suggest that the Prostoma recovered from the Clay 'Ole (and all other sampled locations in Lancashire) are not distinct from P. eilhardi and P. graecense (as downloaded from GenBank® and BOLD) suggesting that there is a strong case for the species status of P. jenningsi to be revoked. Further regional and national sampling is required to obtain a clearer evaluation of the distribution of Prostoma and the levels of genetic diversity present in the UK. In addition, results from this study indicate that thorough taxonomical re-evaluation of species within the Prostoma genus is required.


Impact of improved classification on the association of human papillomavirus with cervical precancer.
Misclassification of exposure and surrogate endpoints of disease can obscure causal relations. Using data from the Atypical Squamous Cells of Undetermined Significance/Low-Grade Squamous Intraepithelial Lesion Triage Study (ALTS, 1997-2001), the authors explored the impact of exposure (human papillomavirus (HPV) detection) and endpoint (histologic cervical precancer) classification on their mutual association. Women referred into this study with an atypical squamous cells of undetermined significance Papanicolaou test with satisfactory results for all 4 HPV tests were included in this analysis (n = 3,215; 92.2%). HPV testing results were related to different definitions of cervical precancer, based on paired, worst 2-year histologic diagnoses, by calculating clinical sensitivity, specificity, and odds ratios. The authors found that HPV test sensitivity increased and specificity decreased with increasing certainty of cervical precancer, with HPV testing having the highest sensitivity (92%-98%) and lowest specificity (46%-54%) for consensus cervical intraepithelial neoplasia grade 3 (CIN 3). The overall accuracy of each HPV test, as measured by odds ratios, was greatest for consensus CIN-3 diagnoses, from 2- to 4-fold greater than for a less stringent precancer definition of any diagnosis of CIN 2 or more severe. In summary, there was convergence of greater certainty of carcinogenic HPV with greater certainty of a precancerous diagnosis, such that all 4 HPV tests almost always tested positive in women most likely to have cervical precancer. Finding increasingly strong associations when both test and diagnostic misclassification are reduced is a useful sign of "true association" in molecular epidemiology.


IMI - Industry Guidelines and Ethical Considerations for Myopia Control Report.
To discuss guidelines and ethical considerations associated with the development and prescription of treatments intended for myopia control (MC). Critical review of published papers and guidance documents was undertaken, with a view to carefully considering the ethical standards associated with the investigation, development, registration, marketing, prescription, and use of MC treatments. The roles and responsibilities of regulatory bodies, manufacturers, academics, eye care practitioners, and patients in the use of MC treatments are explored. Particular attention is given to the ethical considerations for deciding whether to implement a MC strategy and how to implement this within a clinical trial or practice setting. Finally, the responsibilities in marketing, support, and education required to transfer required knowledge and skills to eye care practitioners and academics are discussed. Undertaking MC treatment in minors creates an ethical challenge for a wide variety of stakeholders. Regulatory bodies, manufacturers, academics, and clinicians all share an ethical responsibility to ensure that the products used for MC are safe and efficacious and that patients understand the benefits and potential risks of such products. This International Myopia Institute report highlights these ethical challenges and provides stakeholders with recommendations and guidelines in the development, financial support, prescribing, and advertising of such treatments.


Genetic studies on the functional relevance of the protein prenyltransferases in skin keratinocytes.
The modification of proteins with farnesyl or geranylgeranyl lipids, a process called protein prenylation, facilitates interactions of proteins with membrane surfaces. Protein prenylation is carried out by a pair of cytosolic enzymes, protein farnesyltransferase (FTase) and protein geranylgeranyltransferase type I (GGTase-I). FTase and GGTase-I have attracted interest as therapeutic targets for both cancer and progeria, but very little information exists on the importance of these enzymes for homeostasis of normal tissues. One study actually suggested that FTase is entirely dispensable. To explore the importance of the protein prenyltransferases for normal tissues, we used conditional knockout alleles for Fntb and Pggt1b (which encode the beta-subunits of FTase and GGTase-I, respectively) and a keratin 14-Cre transgene to create mice lacking FTase or GGTase-I in skin keratinocytes. Keratinocyte-specific Fntb knockout mice were viable but developed severe alopecia. Although hair follicles appeared normal during development, they were morphologically abnormal after birth, and ultrastructural and immunohistochemical studies revealed many apoptotic cells. The interfollicular epidermis of Fntb-deficient mice appeared normal; however, keratinocytes from these mice could not proliferate in culture. As expected, non-farnesylated prelamin A and non-farnesylated DNAJA1 accumulated in Fntb-deficient keratinocytes. Keratinocyte-specific Pggt1b knockout mice survived development but died shortly after birth. Like Fntb-deficient keratinocytes, Pggt1b-deficient keratinocytes did not proliferate in culture. Thus, both FTase and GGTase-I are required for the homeostasis of skin keratinocytes.


Manual Therapy for Hip Osteoarthritis: A Systematic Review and Meta-analysis.
Hip osteoarthritis (HOA) is one of the major causes of disability in seniors and is costly to society. Manual therapy is one therapeutic approach to treating HOA. To assess the effect of manual therapy compared to the placebo or wait-list/no treatment or a minimal intervention control for HOA at post-treatment and short-, intermediate- and long-term follow-ups. A systematic review and meta-analysis of randomized controlled trials (RCTs). Hospital outpatient clinic in China. We searched PubMed, EMBASE, the Cochrane Library, CINAHL, ISI web of knowledge, and Chinese databases from the inception to October 2014 without language restrictions. References of systematic reviews and other related reviews, files in our department, and conference proceedings as grey literature were also screened by hand. RCTs compared manual therapy to the placebo, wait-list/no treatment or a minimal intervention control with an appropriate and precise description of randomization. Two reviewers independently conducted the search results identification, data extraction, and methodological quality assessment. We calculated the risk difference (RD) for dichotomous data and the mean difference (MD) or standardized mean difference (SMD) for continuous data in a fixed or random effect model. The primary outcomes were self-reported pain in the past week and physical function. The secondary outcomes were the quality of life, global perceived effect, patients' satisfaction, cost, and adverse events. Six studies involving 515 HOA patients were included. Five of the 6 studies ranked as high quality in the methodological assessment. Immediately post-treatment, there was low-quality evidence that manual therapy could not statistically significantly relieve pain (SMD: -0.07 [95%CI -0.38 to 0.24]); for physical function, a moderate quality of evidence showed that manual therapy could not improve the physical function significantly (SMD: 0.14 [95%CI -0.08 to 0.37]). We still found low-quality evidence that manual therapy did not benefit the patients in the global perceived effect (RD: 0.12 [95%CI -0.12 to 0.36]), and in terms of quality of life. In addition, the risks of patients in the manual therapy group was 0.13 times higher than that in the controls (RD: 0.13 [95%CI -0.05 to 0.31]) in the low-quality evidence studies. We could not find any evidence that manual therapy benefits the patients at short-, intermediate- or long-term follow-up. There were no studies reporting patients' satisfaction or cost. The limitations of this systematic review include the paucity of literature and inevitable heterogeneity between included studies. This review did not suggest there was enough evidence for manual therapy for the management of HOA. However, we are not confident in making such a conclusion due to the limitations listed above.


Intermetal oxygen atom transfer from an FeVO complex to a MnIII complex: an experimental and theoretical approach.
Oxygen atom transfer (OAT) reaction between an FeVO complex and a MnIII complex resulted in the eventual formation of their corresponding FeIII and MnVO complexes. The reaction proceeded via an initial fast OAT reaction between the FeVO and MnIII complexes, yielding a half equivalent of a MnVO complex and a μ-oxo bridged FeIV dimer. The dimer regenerated the FeVO species via equilibrium, which then reacted with the remaining MnIII complex to produce another half equivalent of the MnVO complex.


Linewidth reduction and wavelength tuning of an erbium-doped fiber laser by use of a single-mode-selected and side-mode-suppressed Fabry-Perot laser diode.
A single-mode and highly side-mode-suppressed 1.55-microm Fabry-Perot laser diode (FPLD) is achieved by feedback injection with an erbium-doped fiber laser (EDFL). For selection of the strongest longitudinal mode from the gain spectrum of the FPLD for lasing in the EDFL, the FPLD is operated at just below the threshold condition and is feedback injected by 0.02% of the EDFL output power. The lasing mode and center wavelength of the proposed single-mode FPLD source are decided by cross-correlated gain profiles of the EDFL and the FPLD; however, the effect of FPLD injection modes is found to be more pronounced. The optimized lasing linewidth (system limitation) and side-mode suppression ratio of 0.01 nm and > 49 dB are obtained, which are far better than those of a FPLD at free-running condition. The worst linewidths at 3- and 10-dB decay are observed to be at approximately 0.016 and 0.05 nm, respectively. Linear wavelength tuning of as much as 4.5 nm (from 1558.7 to 1563.2 nm) by adjustment of the temperature of the FPLD from 10 degrees C to 40 degrees C at just below threshold is reported. The wavelength-tuning slope is approximately 0.14 nm/degrees C under temperature accuracy of 0.1 degrees C.


Single oral dose pharmacokinetics of decursin and decursinol angelate in healthy adult men and women.
The ethanol extract of Angelica gigas Nakai (AGN) root has promising anti-cancer and other bioactivities in rodent models. It is currently believed that the pyranocoumarin isomers decursin (D) and decursinol angelate (DA) contribute to these activities. We and others have documented that D and DA were rapidly converted to decursinol (DOH) in rodents. However, our in vitro metabolism studies suggested that D and DA might be metabolized differently in humans. To test this hypothesis and address a key question for human translatability of animal model studies of D and DA or AGN extract, we conducted a single oral dose human pharmacokinetic study of D and DA delivered through an AGN-based dietary supplement Cogni.Q (purchased from Quality of Life Labs, Purchase, NY) in twenty healthy subjects, i.e., 10 men and 10 women, each consuming 119 mg D and 77 mg DA from 4 vegicaps. Analyses of plasma samples using UHPLC-MS/MS showed mean time to peak concentration (Tmax) of 2.1, 2.4 and 3.3 h and mean peak concentration (Cmax) of 5.3, 48.1 and 2,480 nmol/L for D, DA and DOH, respectively. The terminal elimination half-life (t1/2) for D and DA was similar (17.4 and 19.3 h) and each was much longer than that of DOH (7.4 h). The mean area under the curve (AUC0-48h) for D, DA and DOH was estimated as 37, 335 and 27,579 h∙nmol/L, respectively. Gender-wise, men absorbed the parent compounds faster and took shorter time to reach DOH peak concentration. The human data supported an extensive conversion of D and DA to DOH, even though they metabolized DA slightly slower than rodents. Therefore, the data generated in rodent models concerning anti-cancer efficacy, safety, tissue distribution and pharmacodynamic biomarkers will likely be relevant for human translation. ClinicalTrials.gov NCT02114957.


A system for real-time XMR guided cardiovascular intervention.
The hybrid magnetic resonance (MR)/X-ray suite (XMR) is a recently introduced imaging solution that provides new possibilities for guidance of cardiovascular catheterization procedures. We have previously described and validated a technique based on optical tracking to register MR and X-ray images obtained from the sliding table XMR configuration. The aim of our recent work was to extend our technique by providing an improved calibration stage, real-time guidance during cardiovascular catheterization procedures, and further off-line analysis for mapping cardiac electrical data to patient anatomy. Specially designed optical trackers and a dedicated calibration object have resulted in a single calibration step that can be efficiently checked and updated before each procedure. An X-ray distortion model has been implemented that allows for distortion correction for arbitrary c-arm orientations. During procedures, the guidance system provides a real-time combined MR/X-ray image display consisting of live X-ray images with registered recently acquired MR derived anatomy. It is also possible to reconstruct the location of catheters seen during X-ray imaging in the MR derived patient anatomy. We have applied our registration technique to 13 cardiovascular catheterization procedures. Our system has been used for the real-time guidance of ten radiofrequency ablations and one aortic stent implantation. We demonstrate the real-time guidance using two exemplar cases. In a further two cases we show how off-line analysis of registered image data, acquired during electrophysiology study procedures, has been used to map cardiac electrical measurements to patient anatomy for two different types of mapping catheters. The cardiologists that have used the guidance system suggest that real-time XMR guidance could have substantial value in difficult interventional and electrophysiological procedures, potentially reducing procedure time and delivered radiation dose. Also, the ability to map measured electrical data to patient specific anatomy provides improved visualization and a path to investigation of cardiac electromechanical models.


Extracorporeal Membrane Oxygenation in Nivolumab Associated Pneumonitis.
Newly approved immunotherapeutic agents, like CTLA-4 inhibitors and antibodies against PD-1, are a promising therapeutic option in cancer therapy. A 74-year-old man, with a history of advanced stage melanoma and treatment with ipilimumab, pembrolizumab and nivolumab, was admitted to the hospital due to respiratory failure with hypoxemia and dyspnoea. He rapidly developed severe acute respiratory distress syndrome (ARDS), which required treatment in the intensive care unit which included mechanical ventilation and extracorporeal membrane oxygenation (ECMO). Computed tomographic imaging (CT) showed signs of a pneumonitis, with an ARDS pattern related to the use of PD-1 antibodies. Treating the patient with high-dose immunosuppressive steroids led to an overall improvement. He was transferred to a rehabilitation hospital and subsequently to his home. This is a unique case report of a patient suffering a grade 4 adverse event under nivolumab who survived having been treated with ECMO. It highlights the possibility of associated adverse reactions as well as the use of ECMO in palliative care patients. ECMO can be of great success even in patients with malignancies, but careful decision making should be done on a case by case basis.


EULAR 'points to consider' for the conduction of workforce requirement studies in rheumatology.
Current methods used for forecasting workforce requirements in rheumatology are disparate, as are the parameters incorporated into workforce projection studies. The objective of these European League Against Rheumatism (EULAR points to consider (PTC) is to guide future workforce studies in adult rheumatology in order to produce valid and reliable manpower estimates. The EULAR Standardised Operating Procedures were followed. A multidisciplinary task force with experts including patients with rheumatic diseases from 11 EULAR countries and the USA was assembled. A systematic literature review (SLR) was conducted to retrieve workforce models in rheumatology and other medical fields. PTC were based on expert opinion informed by the SLR, followed by group discussions with consensus obtained through informal voting. The level of agreement with the PTC was voted anonymously. A total of 10 PTC were formulated. The task force recommends models integrating supply (=workforce available in rheumatology), demand (=health services requested by the population) and need (=health services that are considered appropriate to serve the population). In general, projections of workforce requirements should consider all factors relevant for current and future workload in rheumatology inside and outside of direct patient care. Forecasts of workforce supply should consider demography and attrition of rheumatologists, as well as the effects of new developments in healthcare. Predictions of future need/demand should take demographic, sociocultural and epidemiological development of the population into account. These EULAR-endorsed PTC will provide guidance on the methodology and the parameters to be applied in future national and international workforce requirement studies in rheumatology.


Population dynamics of spiking neurons: fast transients, asynchronous states, and locking.
An integral equation describing the time evolution of the population activity in a homogeneous pool of spiking neurons of the integrate-and-fire type is discussed. It is analytically shown that transients from a state of incoherent firing can be immediate. The stability of incoherent firing is analyzed in terms of the noise level and transmission delay, and a bifurcation diagram is derived. The response of a population of noisy integrate-and-fire neurons to an input current of small amplitude is calculated and characterized by a linear filter L. The stability of perfectly synchronized"locked"solutions is analyzed.


Constitutive IKK2 activation in intestinal epithelial cells induces intestinal tumors in mice.
Many cancers display increased NF-κB activity, and NF-κB inhibition is known to diminish tumor development in multiple mouse models, supporting an important role of NF-κB in carcinogenesis. NF-κB activation in premalignant or cancer cells is believed to promote tumor development mainly by protecting these cells from apoptosis. However, it remains unclear to what extent NF-κB activation exhibits additional protumorigenic functions in premalignant cells that could be sufficient to induce spontaneous tumor development. Here we show that expression of constitutively active IκB kinase 2 (IKK2ca) in mouse intestinal epithelial cells (IECs) induced spontaneous tumors in aged mice and also strongly enhanced chemical- and Apc mutation-mediated carcinogenesis. IECs expressing IKK2ca displayed altered Wnt signaling and increased proliferation and elevated expression of genes encoding intestinal stem cell-associated factors including Ascl2, Olfm4, DLK1, and Bmi-1, indicating that increased IKK2/NF-κB activation synergized with Wnt signaling to drive intestinal tumorigenesis. Moreover, IECs expressing IKK2ca produced cytokines and chemokines that induced the recruitment of myeloid cells and activated stromal fibroblasts to become myofibroblasts, thus creating a tumor-promoting microenvironment. Taken together, our results show that constitutively increased activation of IKK2/NF-κB signaling in the intestinal epithelium is sufficient to induce the full spectrum of cell-intrinsic and stromal alterations required for intestinal tumorigenesis.


Limb contractures in progressive neuromuscular disease and the role of stretching, orthotics, and surgery.
Contractures are exceedingly common impairments in selected progressive NMD conditions, particularly those with excessive fibrosis and fatty infiltration into muscle (i.e., dystrophic myopathies) and more severe NMD conditions, resulting in significant weakness and wheel-chair reliance, such as SMA. Less than antigravity strength produces an inability to achieve full active range of motion. Static positioning of limbs (generally in flexion) and lack of weight bearing results in fixed contractures. This article has reviewed the prevalence and distribution of contractures in specific NMD conditions. Aggressive rehabilitation strategies, including stretching, positioning, splinting, upright weight bearing, and orthopaedic surgical management may help minimize the degree of disability in NMD patients with contractures.


Stimulatory effect of estrogen on prolactin secretion from primate pituitary cells cultured on extracellular matrix and in serum-free medium.
To determine the direct effect of estrogen on primate PRL production, cultures of dispersed monkey pituitary cells were established in serum-free medium on an extracellular matrix secreted by bovine corneal endothelial cells. Medium PRL levels were monitored by RIA every fourth day after plating. PRL secretion was maintained for 24-28 days in cultures from female monkeys and for 16-20 days in cultures from male monkeys using a 1:1 mixture of Dulbecco's Modified Eagle's Medium H-16 (DME) and Ham's F-12 medium (F12) supplemented with insulin (I), transferrin (T), PTH, T4, fibroblastic growth factor, putrescine, ethanolamine, lipids (oleic, lecithin, and cholesterol), selenium (S), and cadmium (C). The mean percent changes in medium PRL of seven cultures of female pituitaries and two cultures of male pituitaries compared to the first sample (day 4) were: +26% (day 8), +17% (day 12), +11% (day 16), -4% (day 20), -13% (day 24), and -24% (day 28). The elimination of supplements except ITSC did not appear to affect PRL secretion in a culture of cells from ovariectomized female monkeys, but secretion in two cultures of male pituitary cells declined after day 12. Addition of 10(-8) M estrogen to three cultures of male pituitary cells in DME/F12 containing all supplements significantly elevated PRL over control levels and, in addition, prevented the decline observed in control wells of one culture for 28 days. In two cultures of male pituitary cells maintained in DME/F12 plus ITSC, estrogen significantly elevated medium PRL levels for the 28-day period, but did not totally prevent the decline observed in control wells after day 12. In two cultures of female pituitary cells maintained in DME/F12 plus all supplements and in three cultures of female pituitary cells maintained in DME/F12 plus ITSC, medium PRL levels were significantly higher when estrogen was present. However, estrogen addition had no effect on the pattern of PRL secretion in two cultures of female pituitary cells maintained in DME/F12 plus 10% charcoal-treated fetal calf serum. In five of seven cultures, the presence of estrogen for 28 days resulted in a significantly higher cellular content of PRL. These experiments suggest that estrogen can directly increase PRL production by primate mammotrophs and that this effect is best seen in serum-free medium. In summary, extracellular matrix and serum-free medium provide an adequate in vitro environment for studies of PRL processing by primate pituitary cells for periods up to 1 month. In this system, estrogen effectively elevated PRL secretion and cell content.