Nitrogen fixation does not balance fire-induced nitrogen losses in longleaf pine savannas.
Fire is a critical force in structuring ecosystems, but it also removes substantial amounts of nitrogen (N), which can limit plant growth. Biological N fixation (BNF) may alleviate fire-induced N deficiencies that inhibit ecosystem recovery, yet if and how BNF achieves this under frequent fire is unclear. This problem is further complicated in the context of modern human influences (such as land-use history and atmospheric N deposition), which may confound the relationship between fire and fixation. Here, we investigate whether BNF supplies the N necessary to replace fire-induced N losses in restored longleaf pine savannas, and, if so, what factors control fixation. We established 54 1-ha plots of longleaf pine capturing 227 yr of forest recovery and a broad gradient of fire return interval (1.5-20 yr) at two sites in the southeastern United States. We quantified N fixation from three functional groups (herbaceous legumes, soil crusts, and asymbiotic N fixing bacteria), N losses from individual fire events and ecosystem dynamics of N supply and demand. We found that BNF rates were low but sustained over stand age but were substantially below estimated rates of atmospheric N deposition. While fire temporarily stimulated BNF from herbaceous legumes, neither BNF nor atmospheric N deposition were sufficient to balance N losses from fire and soil N stocks declined over stand age. However, rates of N mineralization were surprisingly high and tree productivity was unrelated to N availability, questioning the importance of N limitation in these temperate savannas. While it is possible that progressive N losses signal a decline in ecosystem resiliency, N enrichment from multiple land-use transitions and anthropogenic N deposition may suppress rates of BNF or diminish its importance as a long-term N balancing source in these pyrogenic ecosystems. In this case, fire may be acting as relief mechanism, critical for returning the modern longleaf pine landscape to its historical oligotrophic condition.


Heat shock protein 27 knockdown using nucleotide‑based therapies enhances sensitivity to 5-FU chemotherapy in SW480 human colon cancer cells.
Heat shock protein 27 (Hsp27) is a chaperone protein of low molecular weight that is produced in response to various stresses and has a cytoprotective function. In the present study we found that there is a strong correlation between sensitivity to 5-fluorouracil (5-FU) and the expression of Hsp27 in colorectal cancer. Apatorsen is an antisense oligonucleotide that targets Hsp27 and has various antitumor effects in some types of cancer, such as bladder and prostate. Although several clinical studies are currently studying apatorsen in many malignancies, to date no promising results have been reported for colorectal cancer. In the present study, we examined the impact of Hsp27 downregulation (via apatorsen) on 5-FU sensitivity in colon cancer both in vitro and in vivo. In vitro, apatorsen significantly decreased the levels of Hsp27 in a dose-dependent manner in human colon cancer SW480 cells. A cell proliferation assay revealed that although apatorsen did not inhibit tumor growth, it resulted in greater 5-FU sensitivity in comparison with treatment with OGX-411 (control). In vivo, intraperitoneal injection of apatorsen decreased the levels of Hsp27 in subcutaneous tumors in a xenograft mouse model using SW480 cells and enhanced 5-FU sensitivity, compared to controls. Although further research is warranted, the present study confirmed that concurrent treatment with Hsp27 knockdown using apatorsen and 5-FU could be a promising therapy for colon cancer.


Robustness of synthetic oscillators in growing and dividing cells.
Synthetic biology sets out to implement new functions in cells, and to develop a deeper understanding of biological design principles. Elowitz and Leibler [Nature (London) 403, 335 (2000)NATUAS0028-083610.1038/35002125] showed that by rational design of the reaction network, and using existing biological components, they could create a network that exhibits periodic gene expression, dubbed the repressilator. More recently, Stricker et al. [Nature (London) 456, 516 (2008)NATUAS0028-083610.1038/nature07389] presented another synthetic oscillator, called the dual-feedback oscillator, which is more stable. Detailed studies have been carried out to determine how the stability of these oscillators is affected by the intrinsic noise of the interactions between the components and the stochastic expression of their genes. However, as all biological oscillators reside in growing and dividing cells, an important question is how these oscillators are perturbed by the cell cycle. In previous work we showed that the periodic doubling of the gene copy numbers due to DNA replication can couple not only natural, circadian oscillators to the cell cycle [Paijmans et al., Proc. Natl. Acad. Sci. (USA) 113, 4063 (2016)PNASA60027-842410.1073/pnas.1507291113], but also these synthetic oscillators. Here we expand this study. We find that the strength of the locking between oscillators depends not only on the positions of the genes on the chromosome, but also on the noise in the timing of gene replication: noise tends to weaken the coupling. Yet, even in the limit of high levels of noise in the replication times of the genes, both synthetic oscillators show clear signatures of locking to the cell cycle. This work enhances our understanding of the design of robust biological oscillators inside growing and diving cells.


Viral Load Dynamics and Clinical Disease Severity in Infants With Respiratory Syncytial Virus Infection.
The association between respiratory syncytial virus (RSV) loads and clinical outcomes in children remains to be defined. In most studies, viral loads (VL) were evaluated in hospitalized children and at a single time-point. We investigated the relationship between VLs and disease severity in both outpatients and inpatients with RSV infection. We enrolled previously healthy children with RSV infection. Disease severity was defined by level of care (outpatients vs ward vs pediatric intensive care unit [PICU]), and a clinical disease severity score (CDSS). Nasopharyngeal VLs by polymerase chain reaction and CDSS were measured at enrollment and daily in inpatients. VL decay according to disease severity was analyzed using linear mixed modeling. From February 2015 to March 2017, we enrolled 150 infants: 39 outpatients and 111 inpatients. VLs were higher in outpatients than in age-matched inpatients. Among inpatients, initial VLs were comparable in ward and PICU patients, and preceded the peak CDSS. However, after excluding infants treated with steroids, those hospitalized in the ward had higher VLs than infants requiring PICU care (P < .001). Dynamic analyses showed that VL decay was delayed in PICU patients, especially in those treated with steroids. Higher VLs at presentation and a faster and consistent VL decline were both associated with less severe RSV disease in children. Infants with less severe respiratory syncytial virus (RSV) disease had higher viral loads (VL) at presentation, and faster and consistent VL decline. Conversely, VL decay and overall viral exposure were prolonged and higher in infants severe RSV disease receiving steroids.


Omentum transposition surgery for patients with Alzheimer's disease: a case series.
To examine effect of omentum transposition surgery (OT) in Alzheimer's disease (AD). Within-subjects design, also known as repeated-measures design, was used. OT was performed on six biopsy-confirmed AD patients (three to the left and right hemispheres each). Follow-up was conducted over 16-50 months. Outcome measures included the sum of the sub-scores of the clinical dementia rating scale (CDRSS), dementia severity rating scale (DSRS), mini-mental status exam (MMSE) and neuropsychiatric inventory (NPI), all normalized to 0-1.0. Outcomes were compared to baseline values and to expected decline with and without cholinesterase inhibitors therapy (ChEI). Compared to baseline and to expected decline with ChEI, CDRSS scores were 22 and 39% less impaired at means of 14 and 25 months post-OT, and DSRS scores were 12 and 22% less impaired at means of 14 and 19 months post-OT (p<0.0001). Compared to baseline and expected course with and without ChEI, the MMSE scores of the left hemisphere OT patients were not significantly different for 11, 17 and 22 months respectively (p>0.49), while those of the right hemisphere OT patients more rapidly declined. The two patients with significant pre-operative behavioral problems markedly improved; NPI severity scores decreased by 23 (16%) and 78 (54%) points and were sustained for 22 and 42 months. OT yielded cognitive, functional or behavioral improvement for up to 3.5 years in these AD patients. Compared to randomized ChEI clinical trials, OT was 34 times more likely to produce clinically significant improvement. Basic research to identify the mechanisms underlying the therapeutic effect of omentum is warranted.


Intrathecal Antibody Production Against Epstein-Barr, Herpes Simplex, and Other Neurotropic Viruses in Autoimmune Encephalitis.
Neurotropic viruses are suspected to play a role in the pathogenesis of autoimmune diseases of the CNS such as the association between the Epstein-Barr virus (EBV) and multiple sclerosis (MS). A group of autoimmune encephalitis (AE) is linked to antibodies against neuronal cell surface proteins. Because CNS infection with the herpes simplex virus can trigger anti-NMDA receptor (NMDAR) encephalitis, a similar mechanism for EBV and other neurotropic viruses could be postulated. To investigate for previous viral infections of the CNS, intrathecally produced virus-specific antibody synthesis was determined in patients with AE. Antibody-specific indices (AIs) against EBV and measles, rubella, varicella zoster, herpes simplex virus, and cytomegalovirus were determined in 27 patients having AE (anti-NMDAR encephalitis, n = 21, and LGI1 encephalitis, n = 6) and in 2 control groups comprising of 30 patients with MS and 21 patients with noninflammatory CNS diseases (NIND), which were sex and age matched. An intrathecal synthesis of antibodies against EBV was found in 5/27 (19%) patients with AE and 2/30 (7%) of the patients with MS. All these patients had also at least 1 additional elevated virus-specific AI. In contrast, in none of the patients with NIND, an elevated virus-specific AI was detected. Intrathecally produced antibodies against EBV can be found in patients with AE and MS but only together with antibodies against different neurotropic viruses. Evidence of these antibodies is the result of a polyspecific immune response similar yet distinct from MS response rather than an elapsed infection of the CNS.


Idiopathic generalised epilepsies of adult onset: a reappraisal and literature review.
Idiopathic generalised epilepsies are characterised by widespread, symmetric, bilateral spike-and-wave discharges on EEG. Onset typically occurs in children and adolescents, but may also start in adulthood. These forms of adult onset constitute the focus of this review. A critical analysis of the medical literature was conducted through a narrative review search of PubMed and Medline databases. Cases of idiopathic generalised epilepsies with adult onset, in general, are not considered to be independent nosological entities. The "grand mal on awakening" seems to prevail among the idiopathic syndromes of adult onset. The EEG findings that question the diagnosis of late-onset idiopathic generalised epilepsies consist mainly of patterns interpreted as representing focal epileptiform activity. Normal brain MRI and typical EEG abnormalities are essential for diagnosis. For all cases with symptomatology of suspected adult-onset idiopathic generalised epilepsy, it is mandatory to exclude neurological conditions that may be associated with epileptic seizures which appear in this age group. A correct diagnosis of adult-onset idiopathic generalised epilepsy alleviates concern for a symptomatic origin, leading to appropriate antiepileptic treatment.


[Textual research for Tibetan medicine Qumazi].
Qumazi is a commonly used Tibetan medicine. With a long history, it can be found in the Four Medical Tantras written by gYu-thog rNying-ma Yon-tan mGon-po since the 8th century AD. Qumazi grows in mudflats and fields, including species growing in highlands, lowlands, mountains and farmlands. According to records in Crystal Beads Materia Medica, it features green sword-shaped leaves, thin stems with red veins, inserted panicles, white chicken-like flowers and copper needle row-like roots. However, there are many inconsistent morphological descriptions for Qumazi plants in many Chinese versions of Tibetan medicine books. In this article, after studying ancient and modern Tibetan medicine books, consulting experts and conducting surveys, the authors confirmed that Qumazi belongs to Rheum of Polygonaceae, including Rheum nobile Hook. f. et. Thoms, R. globulosum Gage, R. alexandrae Hook. f. et. Thoms, R. pumilum Maxim and R. delavayi Franch. In some regions, Qumazi is substituted by R. spiciforme Royle and R. przewalskyi Losinsk. After the Chinese version of Qinghai-Tibet Plateau Drug Illustrations was published in 1972, Qumazi has been miswritten as P. sibiricum Laxm in many Chinese versions of Tibetan medicine books, perhaps because P. sibiricum Laxm has many similar features with Qumazi as described in Crystal Beads Materia Medica and then is mistranslated from Tibetan to Chinese versions. According to records, Qumazi can reduce edema and is mainly applied to treat the minamata disease in clinic.


PHOTOPROTECTION OF SEA-ICE MICROALGAL COMMUNITIES FROM THE EAST ANTARCTIC PACK ICE(1).
All photosynthetic organisms endeavor to balance energy supply with demand. For sea-ice diatoms, as with all marine photoautotrophs, light is the most important factor for determining growth and carbon-fixation rates. Light varies from extremely low to often relatively high irradiances within the sea-ice environment, meaning that sea-ice algae require moderate physiological plasticity that is necessary for rapid light acclimation and photoprotection. This study investigated photoprotective mechanisms employed by bottom Antarctic sea-ice algae in response to relatively high irradiances to understand how they acclimate to the environmental conditions presented during early spring, as the light climate begins to intensify and snow and sea-ice thinning commences. The sea-ice microalgae displayed high photosynthetic plasticity to increased irradiance, with a rapid decline in photochemical efficiency that was completely reversible when placed under low light. Similarly, the photoprotective xanthophyll pigment diatoxanthin (Dt) was immediately activated but reversed during recovery under low light. The xanthophyll inhibitor dithiothreitol (DTT) and state transition inhibitor sodium fluoride (NaF) were used in under-ice in situ incubations and revealed that nonphotochemical quenching (NPQ) via xanthophyll-cycle activation was the preferred method for light acclimation and photoprotection by bottom sea-ice algae. This study showed that bottom sea-ice algae from the east Antarctic possess a high level of plasticity in their light-acclimation capabilities and identified the xanthophyll cycle as a critical mechanism in photoprotection and the preferred means by which sea-ice diatoms regulate energy flow to PSII.


A snapshot of a coral "holobiont": a transcriptome assembly of the scleractinian coral, porites, captures a wide variety of genes from both the host and symbiotic zooxanthellae.
Massive scleractinian corals of the genus Porites are important reef builders in the Indo-Pacific, and they are more resistant to thermal stress than other stony corals, such as the genus Acropora. Because coral health and survival largely depend on the interaction between a coral host and its symbionts, it is important to understand the molecular interactions of an entire "coral holobiont". We simultaneously sequenced transcriptomes of Porites australiensis and its symbionts using the Illumina Hiseq2000 platform. We obtained 14.3 Gbp of sequencing data and assembled it into 74,997 contigs (average: 1,263 bp, N50 size: 2,037 bp). We successfully distinguished contigs originating from the host (Porites) and the symbiont (Symbiodinium) by aligning nucleotide sequences with the decoded Acropora digitifera and Symbiodinium minutum genomes. In contrast to previous coral transcriptome studies, at least 35% of the sequences were found to have originated from the symbionts, indicating that it is possible to analyze both host and symbiont transcriptomes simultaneously. Conserved protein domain and KEGG analyses showed that the dataset contains broad gene repertoires of both Porites and Symbiodinium. Effective utilization of sequence reads revealed that the polymorphism rate in P. australiensis is 1.0% and identified the major symbiotic Symbiodinium as Type C15. Analyses of amino acid biosynthetic pathways suggested that this Porites holobiont is probably able to synthesize most of the common amino acids and that Symbiodinium is potentially able to provide essential amino acids to its host. We believe this to be the first molecular evidence of complementarity in amino acid metabolism between coral hosts and their symbionts. We successfully assembled genes originating from both the host coral and the symbiotic Symbiodinium to create a snapshot of the coral holobiont transcriptome. This dataset will facilitate a deeper understanding of molecular mechanisms of coral symbioses and stress responses.


Axon guidance genes identified in a large-scale RNAi screen using the RNAi-hypersensitive Caenorhabditis elegans strain nre-1(hd20) lin-15b(hd126).
The navigation of axons toward their targets is a highly dynamic and precisely regulated process during nervous system development. The molecular basis of this navigation process is only partly understood. In Caenorhabditis elegans, we isolated the RNAi-hypersensitive strain nre-1(hd20) lin-15b(hd126), which allows us to phenocopy axon guidance defects of known genes by feeding RNAi. We used this mutant strain to systematically screen 4,577 genes on chromosomes I and III for axon guidance phenotypes. We identified 93 genes whose down-regulation led to penetrant ventral cord fasciculation defects or motoneuron commissure outgrowth defects. These genes encode various classes of proteins, ranging from secreted or putative cell surface proteins to transcription factors controlling gene expression. A majority of the genes is evolutionary conserved and previously uncharacterized. In addition, we found axon guidance functions for known genes like pry-1, a component of the Wnt-signaling pathway, and ced-1, a receptor required for the engulfment of neurons undergoing apoptosis during development. Our screen provides insights into molecular pathways operating during the generation of neuronal circuits and provides a basis for a more detailed analysis of gene networks regulating axon navigation.


Working Memory Training is Associated with Long Term Attainments in Math and Reading.
Training working memory (WM) using computerized programs has been shown to improve functions directly linked to WM such as following instructions and attention. These functions influence academic performance, which leads to the question of whether WM training can transfer to improved academic performance. We followed the academic performance of two age-matched groups during 2 years. As part of the curriculum in grade 4 (age 9-10), all students in one classroom (n = 20) completed Cogmed Working Memory Training (CWMT) whereas children in the other classroom (n = 22) received education as usual. Performance on nationally standardized tests in math and reading was used as outcome measures at baseline and two years later. At baseline both classes were normal/high performing according to national standards. At grade 6, reading had improved to a significantly greater extent for the training group compared to the control group (medium effect size, Cohen's d = 0.66, p = 0.045). For math performance the same pattern was observed with a medium effect size (Cohen's d = 0.58) reaching statistical trend levels (p = 0.091). Moreover, the academic attainments were found to correlate with the degree of improvements during training (p < 0.053). This is the first study of long-term (>1 year) effects of WM training on academic performance. We found performance on both reading and math to be positively impacted after completion of CWMT. Since there were no baseline differences between the groups, the results may reflect an influence on learning capacity, with improved WM leading to a boost in students' capacity to learn. This study is also the first to investigate the effects of CWMT on academic performance in typical or high achieving students. The results suggest that WM training can help optimize the academic potential of high performers.


Linking of the American Academy of Orthopaedic Surgeons Distal Radius Fracture Clinical Practice Guidelines to the International Classification of Functioning, Disability, and Health; International Classification of Diseases; and ICF Core Sets for Hand Conditions.
Background: American Academy of Orthopaedic Surgeons (AAOS) distal radius fracture (DRF) clinical practice guidelines (CPG) are readily available to clinicians, patients, and policymakers. International Classification of Functioning, Disability, and Health (ICF) provides a framework for describing the impact of health conditions. The International Classification of Diseases-10th Revision (ICD-10) is a classification system to classify health conditions as specific disease or disorders. The aim of this study is to analyze and describe the scope and focus of the AAOS DRF CPG using the ICF and ICD-10 as a basis for content analysis, and to compare the content of the CPG with the ICF hand core sets as the reference standard. Methods: Established linking rules were used by 2 independent raters to analyze the 29 recommendations of the AAOS DRF CPG. ICD-10 codes were assigned in the same process. Summary linkage statistics were used to describe the results for ICF and the hand core sets. Results: Among the 29 recommendations of the AAOS DRF CPG, 5 meaningful concepts were linked to the ICF codes. Of these, 5 codes appeared on the comprehensive ICF core set and only 3 codes appeared in the brief ICF core set, and 7 conditions were covered in ICD-10 codes. Conclusions: The AAOS DRF CPG focuses on surgical interventions and has minimal linkage to the constructs of the ICD-10 and ICF. It does not address activity or participation (disability), and is not well linked to key concepts relevant to hand conditions.


Knowledge generation about care-giving in the UK: a critical review of research paradigms.
While discourse about care and caring is well developed in the UK, the nature of knowledge generation about care and the research paradigms that underpin it have been subjected to limited critical reflection and analysis. An overarching synthesis of evidence - intended to promote debate and facilitate new understandings - identifies two largely separate bodies of carer-related research. The first body of work - referred to as Gathering and Evaluating - provides evidence of the extent of care-giving, who provides care to whom and with what impact; it also focuses on evaluating policy and service efficacy. This type of research tends to dominate public perception about caring, influences the type and extent of policy and support for carers and attracts funding from policy and health-related sources. However, it also tends to be conceptually and theoretically narrow, has limited engagement with carers' perspectives and adopts an atomistic purview on the care-giving landscape. The second body of work - Conceptualising and Theorising - explores the conceptual and experiential nature of care and aims to extend thinking and theory about caring. It is concerned with promoting understanding of care as an integral part of human relationships, embedded in the life course, and a product of interdependence and reciprocity. This work conceptualises care as both an activity and a disposition and foregrounds the development of an 'ethic of care', thereby providing a perspective within which to recognise both the challenges care-giving may present and the significance of care as a normative activity. It tends to be funded from social science sources and, while strong in capturing carers' experiences, has limited policy and service-related purchase. Much could be gained for citizens, carers and families, and the generation of knowledge advanced, if the two bodies of research were integrated to a greater degree.


A loss-of-function variant of the antiviral molecule MAVS is associated with a subset of systemic lupus patients.
Dysregulation of the antiviral immune response may contribute to autoimmune diseases. Here, we hypothesized that altered expression or function of MAVS, a key molecule downstream of the viral sensors RIG-I and MDA-5, may impair antiviral cell signalling and thereby influence the risk for systemic lupus erythematosus (SLE), the prototype autoimmune disease. We used molecular techniques to screen non-synonymous single nucleotide polymorphisms (SNPs) in the MAVS gene for functional significance in human cell lines and identified one critical loss-of-function variant (C79F, rs11905552). This SNP substantially reduced expression of type I interferon (IFN) and other proinflammatory mediators and was found almost exclusively in the African-American population. Importantly, in African-American SLE patients, the C79F allele was associated with low type I IFN production and absence of anti-RNA-binding protein autoantibodies. These serologic associations were not related to a distinct, functionally neutral, MAVS SNP Q198K. Hence, this is the first demonstration that an uncommon genetic variant in the MAVS gene has a functional impact upon the anti-viral IFN pathway in vivo in humans and is associated with a novel sub-phenotype in SLE. This study demonstrates the utility of functional data in selecting rare variants for genetic association studies, allowing for fewer comparisons requiring statistical correction and for alternate lines of evidence implicating the particular variant in disease.


Yeast gene CMR1/YDL156W is consistently co-expressed with genes participating in DNA-metabolic processes in a variety of stringent clustering experiments.
The binarization of consensus partition matrices (Bi-CoPaM) method has, among its unique features, the ability to perform ensemble clustering over the same set of genes from multiple microarray datasets by using various clustering methods in order to generate tunable tight clusters. Therefore, we have used the Bi-CoPaM method to the most synchronized 500 cell-cycle-regulated yeast genes from different microarray datasets to produce four tight, specific and exclusive clusters of co-expressed genes. We found 19 genes formed the tightest of the four clusters and this included the gene CMR1/YDL156W, which was an uncharacterized gene at the time of our investigations. Two very recent proteomic and biochemical studies have independently revealed many facets of CMR1 protein, although the precise functions of the protein remain to be elucidated. Our computational results complement these biological results and add more evidence to their recent findings of CMR1 as potentially participating in many of the DNA-metabolism processes such as replication, repair and transcription. Interestingly, our results demonstrate the close co-expressions of CMR1 and the replication protein A (RPA), the cohesion complex and the DNA polymerases α, δ and ε, as well as suggest functional relationships between CMR1 and the respective proteins. In addition, the analysis provides further substantial evidence that the expression of the CMR1 gene could be regulated by the MBF complex. In summary, the application of a novel analytic technique in large biological datasets has provided supporting evidence for a gene of previously unknown function, further hypotheses to test, and a more general demonstration of the value of sophisticated methods to explore new large datasets now so readily generated in biological experiments.


Shoulder instability surgery in Norway: the first report from a multicenter register, with 1-year follow-up.
In January 2008, we established the Norwegian Register for Shoulder Instability Surgery. We report on the establishment, the baseline data, and the results at 1-year follow-up. Primary and revision shoulder stabilization is reported by the surgeon on a 1-page paper form containing the patient's history of shoulder injury, clinical findings, and perioperative findings. The WOSI questionnaire for self-assessment of shoulder function is completed at baseline and at follow-up after 1, 2, and 5 years. To evaluate the completeness of registration, we compared our data with those in the Norwegian Patient Registry (NPR). The NPR reported 39 hospitals performing shoulder stabilizations. 20 of these started to report to our register during 2009, and 464 procedures (404 primary, 59 revisions) were included up to December 31, 2009, which represented 54% of the procedures reported to NPR. Of the 404 primary procedures, 83% were operations due to anterior instability, 10% were operations due to posterior instability, and 7% were operations due to multidirectional instability. Arthroscopic soft tissue techniques were used in 88% of the patients treated for primary anterior instability and open coracoid transfer was used in 10% of such patients. At 1-year follow-up of 213 patients, we found a statistically significantly improved WOSI score in all types of instability. 10% of the patients treated with arthroscopic anterior labral repair and 16% treated with arthroscopic posterior labral repair reported recurrent instability. No statistically significant difference in functional improvement or rate of recurrence was found between these groups. The functional results are in accordance with those in previous studies. However, the incidence of recurrent instability 1 year after arthroscopic labral repair is higher than expected.


Confinement-driven radical change in a sequence of rotator phases: a study on n-octacosane.
Rotator-phase forming n-alkanes have been studied extensively in both their bulk state and in nanoconfinement. While some alkanes maintain their bulk-state rotator phases in nanoconfinement albeit with increased disorder, there are others exhibiting new rotator phases upon confinement. We present here a temperature dependent X-ray diffraction (XRD) and differential scanning calorimetric (DSC) study on n-octacosane (C28H58), which almost completely loses its bulk state RIV phase and undergoes complete disappearance of its RIII phase. In their place, when confined in cylindrical anodized alumina nanopores, a phase highly resembling the hexatic mesophase is formed at a higher temperature and the RI rotator phase at a lower temperature. The effects of finite size, interfacial interactions with the host matrix and alkyl chain flexibility are used to provide an explanation for such unexpected behaviour.


Familial benign chronic pemphigus (Hailey-Hailey disease). Treatment with carbon dioxide laser vaporization.
Familial benign chronic pemphigus (Hailey-Hailey disease) is characterized by recurrent blistering lesions, mainly in the neck and intertriginous areas. No controlled studies on laser treatment of this condition have been published. We used carbon dioxide laser vaporization to treat skin lesions in eight patients. In the six patients with symmetrical skin lesions, one lesion was chosen for CO2 laser vaporization and a corresponding lesion of similar location, size, and severity on the other side of the body was left untreated. Laser vaporization was performed in defocus in four to five layers. In five of six patients with symmetrical control lesions, laser-treated lesions showed substantial improvement in comparison with the untreated lesions. A similar improvement was seen in the treated lesions of the two patients without control lesions. During the mean follow-up of 20 months (range, 10 to 27 months), skin lesions recurred in the laser-treated areas in three patients, but not in the other five. Histopathologic studies performed on two patients indicated that the effect of the CO2 treatment might be due to fibrosis of the upper dermal tissues. The adnexal glands were unaffected. Carbon dioxide laser vaporization is an effective treatment for familial benign chronic pemphigus.


Human height is positively related to interpersonal dominance in dyadic interactions.
Across cultures, taller stature is linked to increased social status, but the potential reasons why this should be are unclear. One potential explanation is that taller individuals are more likely to win a dyadic confrontation with a competitor (i.e., they are more dominant), which leads to higher social rank. Although some previous studies have shown that perceptions of status or dominance are related to height, and are therefore consistent with such an explanation, there is surprisingly little research testing whether height actually has any influence on the behavioural outcomes in real-life social interactions. Here, we present three naturalistic observational studies demonstrating that height predicts interpersonal dominance during brief dyadic interactions. Study 1 investigated the likelihood of giving way in a narrow passage (N = 92); Study 2 investigated giving way in a busy shopping street, plus the likelihood of colliding with another individual (N = 1,108); and Study 3 investigated the likelihood of maintaining a linear path while walking, and potentially entering another individual's personal space (N = 1,056). We conclude that human height is positively related to interpersonal dominance, and may well contribute to the widely observed positive association between height and social status.


Surface-anchored framework for generating RhD-epitope stealth red blood cells.
Rhesus D (RhD) is one of the most important immunogenic antigens on red blood cells (RBCs). However, the supply of RhD-negative blood frequently faces critical shortages in clinical practice, and the positive-to-negative transition of the RhD antigen remains a great challenge. Here, we developed an alternative approach for sheltering the epitopes on RhD-positive RBCs using a surface-anchored framework, which is flexible but can achieve an optimal shield effect with minimal physicochemical influence on the cell. The chemical framework completely obstructed the RhD antigens on the cell surface, and the assessments of both blood transfusion in a mouse model and immunostimulation with human RhD-positive RBCs in a rabbit model confirmed the RhD-epitope stealth characteristics of the engineered RBCs. This work provides an efficient methodology for improving the cell surface for universal blood transfusion and generally indicates the potential of rationally designed cell surface engineering for transfusion and transplantation medicine.


Live attenuated measles vaccine as a potential multivalent pediatric vaccination vector.
Live attenuated RNA viruses make highly efficient vaccines. Among them is the live attenuated measles virus (MV) vaccine that has been given to a very large number of children and has been shown to be highly efficacious and safe. MV vaccine induces a life-long immunity after a single injection or two low-dose injections. It is easily produced on a large scale in most countries and can be distributed at low cost. Reversion to pathogenicity has never been observed with this vaccine. For all of these characteristics, developing of MV vaccine vector as a multivalent vaccine to immunize children against both measles and other infectious agents such as human immunodeficiency virus (HIV), flaviviruses, or malaria might be very promising for worldwide use. As MV vaccine is inexpensive to produce, the generation of recombinant vaccines may remain affordable and attractive for the developing word. In this article, we describe the development of MV vector and present some recent data showing the capacity of recombinant MV vaccine to express various proteins from HIV and West Nile virus. In addition, the ability of recombinant MV to induce specific immune responses against these different pathogens are presented and discussed.


Lack of association between prepulse inhibition and antisaccadic deficits in chronic schizophrenia: implications for identification of schizophrenia endophenotypes.
Individuals with schizophrenia, compared to healthy individuals, are known to exhibit deficient prepulse inhibition (PPI) of the startle response as well as reduced performance on the antisaccade task. There is evidence for genetic transmission of both PPI and antisaccadic abnormalities in schizophrenia. It has been suggested that PPI and antisaccade measures identify separate endophenotypes, on the basis of a lack of relationship between PPI and antisaccade deficits in patients with schizotypal personality disorder. However, given that patients with schizotypal personality disorder are unlikely to manifest all the abnormalities associated with schizophrenia, it is important to determine that there is no relationship present between these two abnormalities in people affected with schizophrenia. The main objective of this investigation therefore was to establish the lack of the association between PPI and antisaccade deficits in schizophrenia in two independent studies. Study 1 involved 39 patients with schizophrenia and 14 healthy controls and study 2 involved 35 patients with schizophrenia and 22 healthy controls. PPI (uninstructed paradigm) of the acoustically elicited startle (eye blink) was measured electromyographically. Antisaccadic eye movements (standard, non-overlap version) were measured using infrared oculography. Patients displayed reduced PPI and a lower percentage of correct antisaccades relative to healthy controls in both studies. As expected, no relationship occurred between PPI and the percentage of correct antisaccade responses in either group. It is concluded that PPI and antisaccade abnormalities in schizophrenia represent separate endophenotypes, reflecting the functions of different genetic aetiologies and different or only partially overlapping neural systems.


Molecular determinants of emerging excitability in rat embryonic motoneurons.
Molecular determinants of excitability were studied in pure cultures of rat embryonic motoneurons. Using RT-PCR, we have shown here that the spike-generating Na(+) current is supported by Nav1.2 and/or Nav1.3 alpha-subunits. Nav1.1 and Nav1.6 transcripts were also identified. We have demonstrated that alternatively spliced isoforms of Nav1.1 and Nav1.6, resulting in truncated proteins, were predominant during the first week in culture. However, Nav1.6 protein could be detected after 12 days in vitro. The Nav beta 2.1 transcript was not detected, whereas the Nav beta 1.1 transcript was present. Even in the absence of Nav beta 2.1, alpha-subunits were correctly inserted into the initial segment. RT-PCR (at semi-quantitative and single-cell levels) and immunocytochemistry showed that transient K(+) currents result from the expression of Kv4.2 and Kv4.3 subunits. This is the first identification of subunits responsible for a transient K(+) current in spinal motoneurons. The blockage of Kv4.2/Kv4.3 using a specific toxin modified the shape of the action potential demonstrating the involvement of these conductance channels in regulating spike repolarization and the discharge frequency. Among the other Kv alpha-subunits (Kv1.3, 1.4, 1.6, 2.1, 3.1 and 3.3), we showed that the Kv1.6 subunit was partly responsible for the sustained K(+) current. In conclusion, this study has established the first correlation between the molecular nature of voltage-dependent Na(+) and K(+) channels expressed in embryonic rat motoneurons in culture and their electrophysiological characteristics in the period when excitability appears.


A well-posed, embedded constraint representation of joint moments from kinesiological measurements.
Joint moment estimation using the traditional inverse dynamics analysis presents two challenging problems, which limit its reliability. First, the quality of the computed moments depends directly on unreliable estimates of the segment accelerations obtained numerically by differentiating noisy marker measurements. Second, the representation of joint moments from combined video and force plate measurements belongs to a class of ill-posed problems, which does not possess a unique solution. This paper presents a well-posed representation derived from an embedded constraint equation. The proposed method, referred to as the embedded constraint representation (ECR), provides unique moment estimates, which satisfy all measurement constraints and boundary conditions and require fewer acceleration components than the traditional inverse dynamics method. Specifically, for an n-segment open chain planar system, the ECR requires n-3 acceleration components as compared to 3(n-1) components required by the traditional (from ground up) inverse dynamics analysis. Based on a simulated experiment using a simple three-segment model, the precision of the ECR is evaluated at different noise levels and compared to the traditional inverse dynamics technique. At the lowest noise levels, the inverse dynamics method is up to 50 percent more accurate while at the highest noise levels the ECR method is up to 100 percent more accurate. The ECR results over the entire range of noise levels reveals an average improvement on the order 20 percent in estimating the moments distal to the force plate and no significant improvement in estimating moments proximal to the force plate. The new method is particularly advantageous in a combined video, force plate, and accelerometery sensing strategy.


Post-dive blood lactate concentrations in emperor penguins, Aptenodytes forsteri.
In order to determine an aerobic diving limit (ADL) in emperor penguins (Aptenodytes forsteri), post-dive blood lactate concentrations were measured in penguins foraging at an isolated sea ice hole. Resting lactate concentrations were 1.2-2.7 mmol l-1. Serial samples revealed that lactate level usually peaked within 5 min after dives and that 7-12 min was required for lactate concentrations to decrease from 5-8 mmol l-1 to less than 2.5 mmol l-1. Post-dive lactate level was not elevated above 3 mmol l-1 for dives shorter than 5 min. Two-phase regression analysis revealed a transaction at 5.6 min in the post-dive lactate level versus diving duration relationship. All dives longer than 7 min were associated with lactate concentrations greater than 5 mmol l-1. We conclude that the ADL in emperor penguins ranges between 5 and 7 min. These are the first determinations of post-dive lactate concentrations in any free-diving bird and are currently the only physiological assessment of an ADL in an avian species.


p53 targets simian virus 40 large T antigen for acetylation by CBP.
Simian virus 40 (SV40) large T antigen (T Ag) interacts with the tumor suppressor p53 and the transcriptional coactivators CBP and p300. Binding of these cellular proteins in a ternary complex has been implicated in T Ag-mediated transformation. It has been suggested that the ability of CBP/p300 to modulate p53 function underlies p53's regulation of cell proliferation and tumorigenesis. In this study, we provide further evidence that CBP activity may be mediated through its synergistic action with p53. We demonstrate that SV40 T Ag is acetylated in vivo in a p53-dependent manner and T Ag acetylation is largely mediated by CBP. The acetylation of T Ag is dependent on its interaction with p53 and on p53's interaction with CBP. We have mapped the site of acetylation on T Ag to the C-terminal lysine residue 697. This acetylation site is conserved between the T antigens of the human polyomaviruses JC and BK, which are also known to interact with p53. We show that both JC and BK T antigens are also acetylated at corresponding sites in vivo. While other proteins are known to be acetylated by CBP/p300, none are known to depend on p53 for acetylation. T Ag acetylation may provide a regulatory mechanism for T Ag binding to a cellular factor or play a role in another aspect of T Ag function.


Involvement of cytosolic phospholipase A2, and the subsequent release of arachidonic acid, in signalling by rac for the generation of intracellular reactive oxygen species in rat-2 fibroblasts.
Although there have been a number of recent studies on the role of Rac in the generation of reactive oxygen species (ROS), details of the signalling pathway remain unclear. In the present study we analysed the extent to which the activation of cytosolic phospholipase A(2) and the resultant release of arachidonic acid (AA) are involved in the Rac-mediated generation of ROS. Transfection of Rat-2 cells with RacV12, a constitutively active form of Rac1, induced elevated levels of ROS, as reflected by increased H(2)O(2)-sensitive fluorescence of 2', 7'-dichlorofluorescein. These effects could be blocked by inhibiting phospholipase A(2) or 5-lipoxygenase but not by inhibiting cyclo-oxygenase. The application of exogenous AA increased levels of ROS but the effect was dependent on the further metabolism of AA to leukotrienes C(4)/D(4)/E(4) by 5-lipoxygenase. Indeed, the exogenous application of a mixture of leukotrienes C(4)/D(4)/E(4) elicited transient elevations in the levels of ROS that were blocked by catalase. These findings indicate that phospholipase A(2) and subsequent AA metabolism by 5-lipoxygenase act as downstream mediators in a Rac signalling pathway leading to the generation of ROS.


A pharmacoeconomic analysis of rimexolone for the treatment of ophthalmic inflammatory conditions.
Topical steroids are the standard first-line therapy for treating ophthalmic inflammatory conditions. However, potent ophthalmic steroids can lead to an elevation of intraocular pressure (IOP), which can result in greater medical resource utilization and increased costs. We have developed a decision analysis model from a societal perspective to evaluate the costs and consequences of the treatment of ophthalmic inflammatory conditions with two potent topical steroids: prednisolone and rimexolone. Data for the model are based on information from clinical trials, national data-bases, published literature, and responses by ophthalmologists to a questionnaire on treatment patterns for elevated IOP. Three steroid-responsive conditions are examined separately with the model: uveitis; postoperative inflammation following cataract surgery; and other ophthalmic inflammatory conditions (blepharitis, episcleritis, postoperative refractive surgery, and corneal transplant). The model evaluates patients with acute conditions versus those with chronic conditions and those with mild to moderate elevation of IOP versus those with severe elevation of IOP. Although the unit cost of rimexolone is higher than that of prednisolone, use of rimexolone leads to cost savings because the incidence of elevated IOP is decreased. If rimexolone is used instead of prednisolone for the treatment of ophthalmic inflammatory conditions, the estimated cost saved (at 1995 AWP prices) is approximately $10 million across the entire US population. The savings across the health maintenance organization population on an annualized basis is approximately $3.9 million. Even if rimexolone were priced higher than current market charges (at 130% to 150% of the AWP of prednisolone), cost savings ranging from the $2.9 million to $720,000 would accrue with use of rimexolone compared with prednisolone. However if, rimexolone were priced at 160% of the AWP of prednisolone, its use would incur an additional cost of $300,000. The primary medical resource utilized in treating elevated IOP in ophthalmic inflammatory conditions is physician visits. Medications are responsible for only one-fifth to one-third of the total cost of treating elevated IOP. This analysis indicates that rimexolone is associated with decreased medical resource utilization and cost savings to the entire healthcare system.


Is normal or less than normal overall loudness preferred by first-time hearing aid users?
Most prescriptive methods for nonlinear, wide dynamic range compression (WDRC) hearing aids are based on the assumption that a hearing-impaired listener should perceive amplified sounds at the same overall loudness as would a normal-hearing listener without amplification. However, some previous research on linear amplification has indicated that subjects prefer less overall gain than prescribed by the most commonly used prescriptive method for linear hearing aids, NAL-R, a method that gives close to normal overall loudness for a mid-level input. The current study aims at comparing two prescriptive methods for WDRC hearing aids. The methods differ in the overall loudness they aim to give the hearing aid user. One method, called NormLoudn, is based on a generic method that prescribes gain so that the overall loudness is restored to normal. Another method, called LessLoudn, is based on a hearing aid specific prescription, and gives the hearing aid user less than normal overall loudness. Do first-time hearing aid users prefer the method that restores overall loudness to normal or the method that gives less than normal overall loudness? Twenty-one first-time hearing aid users with typical hearing losses for this group of clients participated in a crossover blinded field study where the two fitting methods were compared using a multi-programmable hearing aid, Danalogic 163D. Preference in the field was evaluated using interview, questionnaire, and diary. The field test was accompanied by laboratory tests, which included paired comparison judgments of preference and loudness and a speech recognition test. Loudness calculations were also used when interpreting the results, and a theoretical comparison with other prescriptive methods for WDRC hearing aids was made. After necessary adjustments, the measured gain for the two methods was similar in gain-frequency shape, but NormLoudn gave more overall gain than LessLoudn. Generally, NormLoudn fittings led to calculated overall loudness that was close to normal, whereas LessLoudn fittings, in median, led to 3-7 phon less than normal calculated overall loudness according to the loudness model used. During the interview performed after the field test, 19 out of the 21 subjects stated that they preferred LessLoudn. Also the questionnaire and the diary showed a clear preference for LessLoudn in all types of listening situations. Paired comparisons of preference in the laboratory supported the findings in the field. LessLoudn was preferred to NormLoudn in all tested situations, except for soft speech in very soft noise where there was no significant preference for either method. Speech recognition scores were similar for the two fittings. The difference in calculated loudness was clearly distinguishable to the subjects and seemed to govern their preferences. LessLoudn, which gave less than normal overall loudness according to the loudness model used, was preferred both in the field and in the laboratory tests. Speech recognition scores were similar for both methods. A comparison between the measured gain for NormLoudn and the gain prescribed by CAMEQ, NAL-NL1, and DSL[i/o], suggests that all three prescriptive procedures (DSL[i/o] in particular) would probably overestimate the required gain for subjects without hearing aid experience and with mild to moderate hearing loss. When providing these clients with hearing aids, it seems important to include a careful adjustment of the overall gain to avoid overamplification if the prescription used aims at restoring overall loudness to normal according to the loudness model used here.


Loss of C9orf72 Enhances Autophagic Activity via Deregulated mTOR and TFEB Signaling.
The most common cause of the neurodegenerative diseases amyotrophic lateral sclerosis and frontotemporal dementia is a hexanucleotide repeat expansion in C9orf72. Here we report a study of the C9orf72 protein by examining the consequences of loss of C9orf72 functions. Deletion of one or both alleles of the C9orf72 gene in mice causes age-dependent lethality phenotypes. We demonstrate that C9orf72 regulates nutrient sensing as the loss of C9orf72 decreases phosphorylation of the mTOR substrate S6K1. The transcription factor EB (TFEB), a master regulator of lysosomal and autophagy genes, which is negatively regulated by mTOR, is substantially up-regulated in C9orf72 loss-of-function animal and cellular models. Consistent with reduced mTOR activity and increased TFEB levels, loss of C9orf72 enhances autophagic flux, suggesting that C9orf72 is a negative regulator of autophagy. We identified a protein complex consisting of C9orf72 and SMCR8, both of which are homologous to DENN-like proteins. The depletion of C9orf72 or SMCR8 leads to significant down-regulation of each other's protein level. Loss of SMCR8 alters mTOR signaling and autophagy. These results demonstrate that the C9orf72-SMCR8 protein complex functions in the regulation of metabolism and provide evidence that loss of C9orf72 function may contribute to the pathogenesis of relevant diseases.


Improvement in time to treatment, but not time to diagnosis, in patients with mucopolysaccharidosis type I.
Early diagnosis and treatment initiation are important factors for successful treatment of mucopolysaccharidosis type I (MPS I). The purpose of this observational study was to assess whether age at diagnosis and time to first treatment for individuals with MPS I have improved over the last 15 years. Data from the MPS I Registry (NCT00144794) for individuals with attenuated or severe disease who initiated therapy with laronidase enzyme replacement therapy (ERT) and/or hematopoietic stem cell transplantation (HSCT) between 1 January 2003 and 31 December 2017 were included. Data were available for 740 individuals with attenuated (n=291) or severe (n=424) MPS I (unknown n=25). Median age at diagnosis for attenuated disease did not change over time and ranged between 4.5 and 6 years of age while the median duration from diagnosis to first ERT decreased from 5.6 years before/during 2004 to 2.4 months in 2014-2017. For severe MPS I treated with HSCT, median age at diagnosis was less than 1 year and median time to first treatment was less than 3 months throughout the 15-year observation period. Times to diagnosis and HSCT initiation for individuals with severe MPS I were consistent over time. For individuals with attenuated MPS I, the time to ERT initiation after diagnosis has improved substantially in the last 15 years, but median age at diagnosis has not improved. Efforts to improve early diagnosis in attenuated MPS I are needed to ensure that patients receive appropriate treatment at the optimal time.


Urinary leukotriene E4/exhaled nitric oxide ratio and montelukast response in childhood asthma.
A subset of children with asthma respond better to leukotriene receptor antagonists than to inhaled corticosteroids. Information is needed to identify children with these preferential responses. We sought to determine whether the ratio of urinary leukotriene E(4) (LTE(4)) to fractional exhaled nitric oxide (FE(NO)) delineates children with preferential responsiveness to montelukast compared with fluticasone propionate (FP) therapy. Data from 318 children with mild-to-moderate asthma enrolled in 2 National Heart, Lung, and Blood Institute Childhood Asthma Research and Education Network studies (Characterizing the Response to a Leukotriene Receptor Antagonist and an Inhaled Corticosteroid [CLIC] and the Pediatric Asthma Controller Trial [PACT]) were analyzed. The association between LTE(4)/FE(NO) ratios at baseline and improved lung function or asthma control days (ACDs) with montelukast and FP therapy was determined, and phenotypic characteristics related to high ratios were assessed. LTE(4)/FE(NO) ratios were associated with a greater response to montelukast than FP therapy for FEV(1) measurements (2.1% increase per doubling of ratio, P = .001) and for ACDs per week (0.3-ACD increase, P = .009) in the CLIC study. In PACT the ratio was associated with greater ACD responsiveness to MT than FP therapy (0.6 ACD increase, P=.03) [corrected]. In a combined study analysis, LTE(4): FE(NO) ratios were associated with greater response to MT than FP therapy for FEV(1) (1.8% increase, P =.0005) and ACDs (0.4 increase, P =.001)[corrected].Children with LTE(4)/FE(NO) ratios at or above the 75th percentile were likely (P < .05) to be younger and female and exhibit lower levels of atopic markers and methacholine reactivity. LTE(4)/FE(NO) ratios predict a better response to montelukast than FP therapy in children with mild-to-moderate asthma.


Methods for studying ER stress and UPR markers in human cells.
Many experimentally induced or disease-related cellular dysfunctions stress the endoplasmic reticulum, commonly resulting in an accumulation of unfolded proteins in the ER lumen which is sensed by three ER-resident transmembrane proteins, PERK, ATF6, and IRE1. Their activation by such ER stress affects the unfolded protein response, which consists of a shutoff of protein translation and at the same time the switching-on of specific transcription factors that control genes which function to reduce the burden of unfolded proteins to the ER. Here, we describe two sets of methods for monitoring the occurrence of ER stress and UPR signaling in human cells by analyzing markers of activation of all three ER stress sensor proteins. The first set of methods is based on the qualitative and quantitative analysis of UPR-induced transcripts by qPCR. The second set of methods consists of Western blot-based analysis of UPR-induced proteins or protein modifications. Their combined analysis allows assessment of activation of all three ER stress-activated signaling pathways that in combination are characteristic for the UPR.


Dietary intake of soluble fiber and risk of islet autoimmunity by 5 y of age: results from the TEDDY study.
Deficient soluble fiber intake has been suggested to dysregulate the immune response either directly or through alterations of the microbial composition in the gut. We hypothesized that a high intake of dietary soluble fiber in early childhood decreases the risk of type 1 diabetes (T1D)-associated islet autoimmunity. We analyzed 17,620 food records collected between age 9 and 48 mo from 3358 children from the United States and Germany prospectively followed in the TEDDY (The Environmental Determinants of Diabetes in the Young) study. HRs for the development of any/multiple islet autoantibodies (242 and 151 events, respectively) and T1D (71 events) by soluble fiber intake were calculated in Cox regression models and adjusted for potential confounders. There were no statistically significantly protective associations observed between a high intake of soluble fiber and islet autoimmunity or T1D. For example, the adjusted HRs (95% CIs) for high intake (highest compared with lowest quintile) at age 12 mo were 0.90 (0.55, 1.45) for any islet autoantibody, 1.20 (0.69, 2.11) for multiple islet autoantibodies, and 1.24 (0.57, 2.70) for T1D. In analyzing soluble fiber intake as a time-varying covariate, there were also no short-term associations between soluble fiber intake and islet autoimmunity development, with adjusted HRs of 0.85 (0.51, 1.42) for high intake and development of any islet autoantibody, for example. These results indicate that the intake level of dietary soluble fiber is not associated with islet autoimmunity or T1D in early life.


Near-total gastric bypass for morbid obesity.
Among 50 morbidly obese patients who underwent gastric bypass, the gastric pouch was made only large enough to permit an anastomosis with the jejunum. Eighteen months after operation, the mean weight loss was 55 kg, and the mean excess weight loss was 70%. One half of the patients had less than 22.7 kg of residual excess weight. The most frequent immediate postoperative complication involved the respiratory tract (ten patients). Staple line failure in three of ten patients who had pouch construction by a single application of staples and iron deficiency anemia in six patients were the most important late complications. Near-total gastric bypass in which the pouch is constructed with two applications of staples is an effective operation for weight control and should virtually eliminate the need for revision caused by staple line failure or for a pouch that is too large.


Individual variability in the core interthreshold zone as related to body physique, somatotype, and physical constitution.
For evaluating the effect of body physique, somatotype, and physical constitution on individual variability in the core interthreshold zone (CIZ), data from 22 healthy young Japanese male subjects were examined. The experiment was carried out in a climatic chamber in which air temperature was maintained at 20-24 degrees C. The subjects' body physique and the maximum work load were measured. Somatotype was predicted from the Heath-Carter Somatotype method. In addition, factors reflecting physical constitution, for example, susceptibility to heat and cold, and quality of sleep were obtained by questionnaire. The subjects wore a water-perfused suit which was perfused with water at a temperature of 25 degrees C and at a rate of 600 cc/min, and exercised on an ergometer at 50% of their maximum work rate for 10-15 min until their sweating rate increased. They then remained continuously seated without exercise until shivering increased. Rectal temperature (T(re)) and skin temperatures at four sites were monitored by thermistors, and sweating rate was measured at the forehead with a sweat rate monitor. Oxygen uptake was monitored with a gas analyzer. The results showed individual variability in the CIZ. According to the reciprocal cross-inhibition (RCI) theory, thermoafferent information from peripheral and core sensors is activated by T(re), mean skin temperature (T(sk)), and their changes. Since T(sk) was relatively unchanged, the data were selected to eliminate the influence of the core cooling rate on the sensor-to-effector pathway before RCI, and the relationship between the CIZ and the various factors was then analyzed. The results revealed that susceptibility to heat showed a good correlation with the CIZ, indicating that individual awareness of heat may change the CIZ due to thermoregulatory behavior.


Retinoic acid prevents experimental Cushing syndrome.
Cushing syndrome is caused by an excess of adrenocorticotropic hormone (ACTH) production by neuroendocrine tumors, which subsequently results in chronic glucocorticoid excess. We found that retinoic acid inhibits the transcriptional activity of AP-1 and the orphan receptors Nur77 and Nurr1 in ACTH-secreting tumor cells. Retinoic acid treatment resulted in reduced pro-opiomelanocortin transcription and ACTH production. ACTH inhibition was also observed in human pituitary ACTH-secreting tumor cells and a small-cell lung cancer cell line, but not in normal cells. This correlated with the expression of the orphan receptor COUP-TFI, which was found in normal corticotrophs but not in pituitary Cushing tumors. COUP-TFI expression in ACTH-secreting tumor cells blocked retinoic acid action. Retinoic acid also inhibited cell proliferation and, after prolonged treatment, increased caspase-3 activity and induced cell death in ACTH-secreting cells. In adrenal cortex cells, retinoic acid inhibited corticosterone production and cell proliferation. The antiproliferative action and the inhibition of ACTH and corticosterone produced by retinoic acid were confirmed in vivo in experimental ACTH-secreting tumors in nude mice. Thus, we conclude that the effects of retinoic acid combine in vivo to reverse the endocrine alterations and symptoms observed in experimental Cushing syndrome.


Cerebral-evoked potential responses following direct vagal and esophageal electrical stimulation in humans.
Cerebral evoked responses following direct electrical stimulation of the vagus and esophagus were compared in 8 epileptic subjects and with those recorded after esophageal stimulation in 12 healthy nonepileptic controls. Direct vagal stimulation was performed using a left cervical vagal pacemaker, which is used in the treatment of epilepsy. Esophageal stimulation was obtained with the use of an esophageal assembly incorporating two electrodes positioned 5 and 20 cm orad to the lower esophageal sphincter. Evoked potential responses were recorded with the use of 20 scalp electrodes. The evoked potential responses consisted of three distinct negative peaks and were similar with the use of either vagal or esophageal stimulation. The measured conduction velocity of the afferent response was 7.5 m/s in epileptic subjects and 10 m/s in healthy controls, suggesting that afferent conduction is through A delta-fibers rather than slower C afferent fibers. We conclude that the cortical-evoked potential responses following esophageal electrical stimulation are comparable to direct electrical stimulation of the vagus nerve and involve mostly A delta-fibers. This approach provides a method for the assessment of vagal afferent gastrointestinal sensory pathways in health and disease.


Coliform mastitis.
Gram-negative bacteria that commonly cause bovine mastitis are classified as environmental pathogens. The point sources of coliform bacteria that cause infections include bedding materials, soil, manure and other organic matter in the environment of cows. Rates of coliform mastitis increase during climatic periods that maximize populations in the environment. The portal of entry into the mammary gland for Gram-negative bacteria is the teat canal. Once in the gland, bacteria must utilize available substrates in the mammary secretion to replicate and evade host defenses. Rates of coliform mastitis are greater during the transitional phases of the non- lactating period than during lactation. The ability to infect the non-lactating gland is directly related to the ability of bacteria to acquire iron from the mammary secretion. The primary host defense against coliform mastitis during lactation is the elimination of bacteria by neutrophils migrating into the gland in response to inflammation. Damage to the host is mediated by the release of endotoxin. The severity and duration of clinical signs associated with coliform mastitis are reduced by the use of core-antigen bacterins.


Medicinal Chemistry Aware Database GDBMedChem.
The generated database GDB17 enumerates 166.4 billion possible molecules up to 17 atoms of C, N, O, S and halogens following simple chemical stability and synthetic feasibility rules, however medicinal chemistry criteria are not taken into account. Here we applied rules inspired by medicinal chemistry to exclude problematic functional groups and complex molecules from GDB17, and sampled the resulting subset uniformly across molecular size, stereochemistry and polarity to form GDBMedChem as a compact collection of 10 million small molecules. This collection has reduced complexity and better synthetic accessibility than the entire GDB17 but retains higher sp3 -carbon fraction and natural product likeness scores compared to known drugs. GDBMedChem molecules are more diverse and very different from known molecules in terms of substructures and represent an unprecedented source of diversity for drug design. GDBMedChem is available for 3D-visualization, similarity searching and for download at http://gdb.unibe.ch.


Computational fluid dynamic measures of wall shear stress are related to coronary lesion characteristics.
To assess the distribution of pressure and shear-related forces acting on atherosclerotic plaques and their association with lesion characteristics using coronary CT angiography (cCTA)-based computational fluid dynamics (CFD) model of epicardial coronary arteries. Patient-specific models of epicardial coronary arteries were reconstructed from cCTA in 80 patients (12 women, 63.8±9.0 years). The pressure and wall shear stress (WSS) in left anterior descending coronary arteries were assessed using CFD. High-risk plaques were defined as the presence of at least one of the following adverse plaque characteristics: low-density plaque, positive remodelling, napkin-ring sign and spotty calcification. At resting condition, 39.5% of stenotic segments (% diameter stenosis 52.3±14.4%) were exposed to high WSS (>40 dyne/cm(2)). When the stenotic lesion was subdivided into three segments, the distribution of WSS was different from that of pressure change and its magnitude was highest at minimal lumen area (p<0.001). High pressure gradient, proximal location, small lumen and short length were independent determinants of WSS (all p<0.05). The plaques exposed to the highest WSS tertile had a significantly greater proportion of high-risk plaques. The addition of WSS to % diameter stenosis significantly improved the measures of discrimination and reclassification of high-risk plaques (area under the curves from 0.540 to 0.718, p=0.031; net reclassification index 0.827, p<0.001). The cCTA-based CFD method can improve the identification of high-risk plaques and the risk stratification for coronary artery disease patients by providing non-invasive measurements of WSS affecting coronary plaques.


Prevention of atherosclerotic complications: controlled trial of ketanserin. Prevention of Atherosclerotic Complications with Ketanserin Trial Group.
To determine whether ketanserin, an antagonist at the serotonin receptor, prevents important vascular events such as death, myocardial infarction, major stroke, and amputation of a leg in patients with claudication. Double blind, randomised, placebo controlled trial after a single blind run in period of placebo treatment for one month. One hundred and forty seven outpatient clinics in 14 countries. Total of 3899 patients over 40 years old who had had documented intermittent claudication for at least two months and in whom the ratio of systolic blood pressure in the ankle to that in the arm was less than or equal to 0.85 in both arteries of at least one foot. After the one month placebo run in period patients were randomly allocated to take 20 mg ketanserin three times daily for the first month and 40 mg three times daily thereafter or to take the same number of placebo tablets. Five months after the onset of the trial, on the recommendation of the ethical and safety committee, four patients stopped taking ketanserin and two stopped taking placebo because they had a corrected QT interval greater than 500 ms. Four months later the committee recommended that all patients taking diuretics should stop receiving trial treatment (167 of those taking ketanserin and 144 of those taking placebo). The first primary event after randomisation. Primary events were definite myocardial infarction, major stroke, amputation above the ankle, excision of ischaemic viscera, and death due to other vascular causes. There were 136 study end points in the 1930 patients treated with ketanserin, who were followed up for 2063 patient years, and 132 study end points in the 1969 patients treated with placebo, who were followed up for 2129 patient years. A harmful interaction of ketanserin and potassium losing diuretics resulted in an increase in the number of deaths. After patients taking potassium losing diuretics or antiarrhythmic agents were excluded [corrected] a secondary analysis showed that there were 65 end points in 1514 patients taking ketanserin and 87 in 1557 patients taking placebo, a reduction of 23% in the number of study end points in those taking ketanserin. Ketanserin can prolong the corrected QT interval, and the combined use of ketanserin and potassium losing diuretics can be harmful. A secondary analysis suggested a protective effect of ketanserin against cardiovascular complications in patients with claudication.


Statistical methods for characterizing transfusion-related changes in regional oxygenation using near-infrared spectroscopy (NIRS) in preterm infants.
Near infrared spectroscopy (NIRS) is an imaging-based diagnostic tool that provides non-invasive and continuous evaluation of regional tissue oxygenation in real-time. In recent years, NIRS has shown promise as a useful monitoring technology to help detect relative tissue ischemia that could lead to significant morbidity and mortality in preterm infants. However, some issues inherent in NIRS technology use on neonates, such as wide fluctuation in signals, signal dropout and low limit of detection of the device, pose challenges that may obscure reliable interpretation of the NIRS measurements using current methods of analysis. In this paper, we propose new nonparametric statistical methods to analyze mesenteric rSO2 (regional oxygenation) produced by NIRS to evaluate oxygenation in intestinal tissues and investigate oxygenation response to red blood cell transfusion (RBC) in preterm infants. Specifically, we present a mean area under the curve (MAUC) measure and a slope measure to capture the mean rSO2 level and temporal trajectory of rSO2, respectively. We develop estimation methods for the measures based on multiple imputation and spline smoothing and further propose novel nonparametric testing procedures to detect RBC-related changes in mesenteric oxygenation in preterm infants. Through simulation studies, we show that the proposed methods demonstrate improved accuracy in characterizing the mean level and changing pattern of mesenteric rSO2 and also increased statistical power in detecting RBC-related changes, as compared with standard approaches. We apply our methods to a NIRS study in preterm infants receiving RBC transfusion from Emory University to evaluate the pre- and post-transfusion mesenteric oxygenation in preterm infants.


Low-dose RUTF protocol and improved service delivery lead to good programme outcomes in the treatment of uncomplicated SAM: a programme report from Myanmar.
The treatment of uncomplicated severe acute malnutrition (SAM) requires substantial amounts of ready-to-use therapeutic food (RUTF). In 2009, Action Contre la Faim anticipated a shortfall of RUTF for their nutrition programme in Myanmar. A low-dose RUTF protocol to treat children with uncomplicated SAM was adopted. In this protocol, RUTF was dosed according to beneficiary's body weight, until the child reached a Weight-for-Height z-score of ≥-3 and mid-upper arm circumference ≥110 mm. From this point, the child received a fixed quantity of RUTF per day, independent of body weight until discharge. Specific measures were implemented as part of this low-dose RUTF protocol in order to improve service quality and beneficiary support. We analysed individual records of 3083 children treated from July 2009 to January 2010. Up to 90.2% of children recovered, 2.0% defaulted and 0.9% were classified as non-responders. No deaths were recorded. Among children who recovered, median [IQR] length of stay and weight gain were 42 days [28; 56] and 4.0 g kg(-1) day(-1) [3.0; 5.7], respectively. Multivariable logistic regression showed that children older than 48 months had higher odds of non-response to treatment than younger children (adjusted odds ratio: 3.51, 95% CI: 1.67-7.42). Our results indicate that a low-dose RUTF protocol, combined with specific measures to ensure good service quality and beneficiary support, was successful in treating uncomplicated SAM in this setting. This programmatic experience should be validated by randomised studies aiming to test, quantify and attribute the effect of the protocol adaptation and programme improvements presented here.


Administration in vivo of recombinant interleukin 2 protects mice against septic death.
Administration in vivo of recombinant interleukin 2 (rIL-2) to mice induces a polyclonal IgM response. When co-administered with a specific antigen, rIL-2 can enhance concentrations of murine IgM antibodies specific for the antigen by fivefold within 7 d of initial treatment. IgM antibodies that are induced after injection of rIL-2 include antibodies specific for J5, a cell wall core lipopolysaccharide (LPS) antigen that is shared by the different members of the Enterobactericeae family. We report here that mice pretreated with rIL-2 or immunized with J5 antigen 7 d before bacterial challenge were protected from septic death that is caused by intraperitoneal challenges with Escherichia coli. Optimal protection was provided by a combined J5 antigen and rIL-2 treatment. Acquisition of the rIL-2 and J5 antigen-induced protection against lethal bacterial infection coincided temporally with maximal serum IgM titers that also contained IgM antibodies specific for the J5 antigen. In passive immunization experiments, the affinity-purified IgM fraction in sera of rIL-2-treated animals was identified as necessary and sufficient for protection. The IgM-depleted serum had no protective effect. The nonspecific augmentation of host-defense mechanisms without the induction of endotoxin manifestations makes rIL-2 a potential candidate to any alternative LPS-containing vaccines for the prevention of bacterial infections by gram-negative organisms since the core LPS antigen is shared among gram-negative bacteria.


Immunotherapy: incorporation in the evolving paradigm of renal cancer management and future prospects.
Significant progress has been made in the management of renal cell carcinoma (RCC) during the last few decades. In early stage, localized disease, surgical resection remains the modality of choice, with no therapeutic interventions as options for post-operative therapy other than simple observation and clinical surveillance. However, treatment options in the advanced or metastatic setting are increasing at a dizzying pace, initially with cytokine therapy, then with the increased availability of targeted therapy including novel small-molecule inhibitors of receptor tyrosine kinases and monoclonal antibodies targeting novel proteins, establishing them as the current standard of care. Even more recently, immunotherapy has seen tremendous development in the form of immune checkpoint inhibition and vaccines. Overall, these interventions have gradually changed the landscape of cancer management in general, and metastatic renal cell carcinoma (mRCC) in particular. This is exemplified by the recent United States Food and Drug Administration (USFDA) approval of nivolumab for patients with mRCC after failure of TKI therapy. In this review, we present a brief overview of the current management of mRCC, primarily the clear cell subtype (ccRCC), and discuss the major clinical trials and data on the immunotherapy in advanced or mRCC.


A political history of federal mental health and addiction insurance parity.
This article chronicles the political history of efforts by the U.S. Congress to enact a law requiring "parity" for mental health and addiction benefits and medical/surgical benefits in private health insurance. The goal of the Paul Wellstone and Pete Domenici Mental Health Parity and Addiction Equity (MHPAE) Act of 2008 is to eliminate differences in insurance coverage for behavioral health. Mental health and addiction treatment advocates have long viewed parity as a means of increasing fairness in the insurance market, whereas employers and insurers have opposed it because of concerns about its cost. The passage of this law is viewed as a legislative success by both consumer and provider advocates and the employer and insurance groups that fought against it for decades. Twenty-nine structured interviews were conducted with key informants in the federal parity debate, including members of Congress and their staff; lobbyists for consumer, provider, employer, and insurance groups; and other key contacts. Historical documentation, academic research on the effects of parity regulations, and public comment letters submitted to the U.S. Departments of Labor, Health and Human Services, and Treasury before the release of federal guidance also were examined. Three factors were instrumental to the passage of this law: the emergence of new evidence regarding the costs of parity, personal experience with mental illness and addiction, and the political strategies adopted by congressional champions in the Senate and House of Representatives. Challenges to implementing the federal parity policy warrant further consideration. This law raises new questions about the future direction of federal policymaking on behavioral health.


IMP3 expression in lesions of the biliary tract: a marker for high-grade dysplasia and an independent prognostic factor in bile duct carcinomas.
The oncofetal protein IMP3 (insulin-like growth factor II mRNA binding protein 3) is expressed during embryogenesis and carcinogenesis. Various tumor types have been analyzed for IMP3 expression, which was exclusively found in tumor cells and correlated with increased tumor aggressiveness and reduced overall survival. To our knowledge, IMP3 expression has not been investigated in bile duct carcinomas. Using large tissue sections from resection specimens of the extrahepatic biliary tract, we analyzed IMP3 in normal bile ducts (n = 36), bile ducts with acute inflammation and reactive epithelial changes (n = 26), low-grade dysplasia (n = 9), and high-grade dysplasia (n = 11). Furthermore, IMP3 expression was assessed in bile duct carcinoma (n = 115) using clinically well-characterized tissue microarrays. The findings were correlated with clinical-pathologic parameters including survival. High-grade dysplasia was strongly positive for IMP3 in all cases studied compared with no or weak expression in normal, inflamed, and low-grade dysplastic bile ducts. Of the bile duct carcinomas 58.3% (67/115) were strongly positive for IMP3, which was associated with a higher proliferation rate (P = .004) and p53 positivity (P = .022). Patients with strong IMP3 expression had significantly reduced overall survival (P = .037) similarly to the subgroup of pT3 carcinomas (P = .007). In multivariate analysis, IMP3 expression was an independent prognostic factor for overall survival (P = .040, RR = 1.809). This comprehensive study shows that IMP3 is an independent prognostic biomarker in bile duct carcinoma. In addition, it may be a marker for high-grade dysplasia in the extrahepatic biliary tract.


Relationship between insulin response to oral glucose load and creatinine clearance.
In order to investigate the relationship between insulin response to oral glucose load and renal function, a 100-gm. oral glucose tolerance test was performed in twenty-two patients with chronic glomerulonephritis, whose creatinine clearances ranged form 5 to 96 ml. per minute. Glucose areas during oral glucose load were little affected by the creatinine clearance in this study. Insulin area during oral glucose load increased in proportion to the decrease in creatinine clearance. The ratio of insulin area to glucose area correlated closely with creatinine clearance and a linear relationship was obtained (y = 1.46 - 0.01x, r = -0.82, p less than 0.001). There were also significant correlations with serum creatinine, blood urea nitrogen, and PSP (r = 0.6, 0.63, and -0.62, respectively). These results show that the impaired renal function has a significant influence on the plasma insulin levels, and it seems likely that such influence becomes manifest below approximately 60 ml. per minute of creatinine clearance.


Endoplasmic reticulum degradation-enhancing α-mannosidase-like protein 1 targets misfolded HLA-B27 dimers for endoplasmic reticulum-associated degradation.
HLA-B27 forms misfolded heavy chain dimers, which may predispose individuals to inflammatory arthritis by inducing endoplasmic reticulum (ER) stress and the unfolded protein response (UPR). This study was undertaken to define the role of the UPR-induced ER-associated degradation (ERAD) pathway in the disposal of HLA-B27 dimeric conformers. HeLa cell lines expressing only 2 copies of a carboxy-terminally Sv5-tagged HLA-B27 were generated. The ER stress-induced protein ER degradation-enhancing α-mannosidase-like protein 1 (EDEM1) was overexpressed by transfection, and dimer levels were monitored by immunoblotting. EDEM1, the UPR-associated transcription factor X-box binding protein 1 (XBP-1), the E3 ubiquitin ligase hydroxymethylglutaryl-coenzyme A reductase degradation 1 (HRD1), and the degradation-associated proteins derlin 1 and derlin 2 were inhibited using either short hairpin RNA or dominant-negative mutants. The UPR-associated ERAD of HLA-B27 was confirmed using ER stress-inducing pharamacologic agents in kinetic and pulse chase assays. We demonstrated that UPR-induced machinery can target HLA-B27 dimers and that dimer formation can be controlled by alterations to expression levels of components of the UPR-induced ERAD pathway. HLA-B27 dimers and misfolded major histocompatibility complex class I monomeric molecules bound to EDEM1 were detected, and overexpression of EDEM1 led to inhibition of HLA-B27 dimer formation. EDEM1 inhibition resulted in up-regulation of HLA-B27 dimers, while UPR-induced ERAD of dimers was prevented in the absence of EDEM1. HLA-B27 dimer formation was also enhanced in the absence of XBP-1, HRD1, and derlins 1 and 2. The present findings indicate that the UPR ERAD pathway can dispose of HLA-B27 dimers, thus presenting a potential novel therapeutic target for modulation of HLA-B27-associated inflammatory disease.


Modulation of face-sensitive event-related potentials by canonical and distorted human faces: the role of vertical symmetry and up-down featural arrangement.
This study examined the sensitivity of early face-sensitive event-related potential (ERP) components to the disruption of two structural properties embedded in faces, namely, "updown featural arrangement" and "vertical symmetry." Behavioral measures and ERPs were recorded as adults made an orientation judgment for canonical faces and distorted faces that had been manipulated for either or both of the mentioned properties. The P1, the N170, and the vertex positive potential (VPP) exhibited a similar gradient in sensitivity to the two investigated properties, in that they all showed a linear increase in amplitude or latency as the properties were selectively disrupted in the order of (1) up-down featural arrangement, (2) vertical symmetry, and (3) both up-down featural arrangement and vertical symmetry. Exceptions to this finding were seen for the amplitudes of the N170 and VPP, which were largest for the stimulus in which solely vertical symmetry was disrupted. Interestingly, the enhanced amplitudes of the N170 and VPP are consistent with a drop in behavioral performance on the orientation judgment for this stimulus.


CT in the Emergency Department: A Real-Time Study of Changes in Physician Decision Making.
To determine how physicians' diagnoses, diagnostic uncertainty, and management decisions are affected by the results of computed tomography (CT) in emergency department settings. This study was approved by the institutional review board and compliant with HIPAA. Data were collected between July 12, 2012, and January 13, 2014. The requirement to obtain patient consent was waived. In this prospective, four-center study, patients presenting to the emergency department who were referred for CT with abdominal pain, chest pain and/or dyspnea, or headache were identified. Physicians were surveyed before and after CT to determine the leading diagnosis, diagnostic confidence (on a scale of 0% to 100%), alternative "rule out" diagnosis, and management decisions. Primary measures were the proportion of patients for whom the leading diagnosis or admission decision changed and median changes in diagnostic confidence. Secondary measures addressed alternative diagnoses and return-to-care visits (eg, to emergency department) at 1-month follow-up. Regression analysis was used to identify associations between primary measures and site and participant characteristics. Both surveys were completed for 1280 patients by 245 physicians. The leading diagnosis changed in 235 of 460 patients with abdominal pain (51%), 163 of 387 with chest pain and/or dyspnea (42%), and 103 of 433 with headache (24%). Pre-CT diagnostic confidence was inversely associated with the likelihood of a diagnostic change (P < .0001). Median changes in confidence were substantial (increases of 25%, 20%, and 13%, respectively, for patients with abdominal pain, chest pain and/or dyspnea, and headache; P < .0001); median post-CT confidence was high (95% for all three groups). CT helped confirm or exclude at least 95% of alternative diagnoses. Admission decisions changed in 116 of 457 patients with abdominal pain (25%), 72 of 387 with chest pain and/or dyspnea (19%), and 81 of 426 with headache (19%). During follow-up, 70 of 450 patients with abdominal pain (15%), 53 of 387 with chest pain and/or dyspnea (14%), and 49 of 433 with headache (11%) returned for the same indication. In general, changes in leading diagnosis, diagnostic confidence, and admission decisions were not well explained with site or participant characteristics. Physicians' diagnoses and admission decisions changed frequently after CT, and diagnostic uncertainty was alleviated.


Serum CagA antibodies in asymptomatic subjects and patients with peptic ulcer: lack of correlation of IgG antibody in patients with peptic ulcer or asymptomatic Helicobacter pylori gastritis.
Several studies have suggested that Helicobacter pylori which express CagA may be more virulent than those that do not, but limited populations have been studied to date. The aim of this study was to confirm and extend the association of CagA positive H pylori strains in a different geographical area and to a large, well defined patient population. A validated ELISA for serum IgG to CagA was used to investigate the prevalence of CagA seropositivity in 100 patients with peptic ulcer compared with 77 with H pylori infection without ulcer disease in a North American population. The extent of antral and corpus inflammation and H pylori density in relation to CagA seropositivity in 40 subjects with H pylori infection were assessed semiquanitatively. All studies were carried out in a coded and blinded manner. The prevalence of serum IgG CagA antibodies was higher in H pylori infected patients with ulcer (59%) compared with healthy H pylori infected volunteers (44%), but the difference was not significant. In contrast, the titre of serum IgG anti-CagA antibodies was higher among the seropositive subjects without ulcer disease, but again the difference was not significant. Comparison of histological features between asymptomatic individuals with H pylori infection in relation to CagA IgG antibody status revealed no differences in infiltration with acute inflammatory cells, H pylori density, or gastritis index. There was no relation evident between the degree of polymorphonuclear cell infiltration and the serum IgG antibody titre to CagA. Mononuclear cell infiltration in the antrum, but not the corpus, was greater in those with CagA IgG compared with those without (median score 5 v 3). A right association between the presence or titre of serum IgG to CagA and peptic ulcer disease, greater H pylori density or infiltration of the mucosa with acute inflammatory cells could not confirmed in a North American population. Perhaps geographical differences in the prevalence of circulating H pylori strains are responsible for the discrepant results reported.


Coblation-assisted Lewis and MacKay operation (CobLAMO): new technique for tongue reduction in sleep apnoea surgery.
Obstructive sleep apnoea is a common condition that is unfortunately associated with a high rate of patient non-compliance regarding device use. Newer surgical interventions have focused on procedures at the palate level, using variants of palatoplasty and transpalatal advancement. However, the extent of tongue reduction surgery required remains controversial. The authors propose an in-between variant that combines midline glossectomy resection (with minimal mucosal sacrifice) and lateral coblation tongue channelling. Four patients underwent a coblation-assisted Lewis and MacKay operation, which is a new technique for tongue reduction. This involved a midline glossectomy combined with lateral coblation channelling of the tongue, alone or as part of major airway reconstruction. Demographic, polysomnographic and quality of life questionnaire data were collected prospectively and analysed. No significant complications were noted in the four patients. (Results of the post-surgical outcomes are presented in another paper.) The coblation-assisted Lewis and MacKay operation reduced the potential complications of aggressive tongue surgery. The contours of the tongue were maintained, but significant reduction was still achieved.


Investigating the role of filamin C in Belgian patients with frontotemporal dementia linked to GRN deficiency in FTLD-TDP brains.
TAR DNA-binding protein 43 (TDP-43) inclusions are pathological hallmarks of patients with frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). Loss of TDP-43 in zebrafish engenders a severe muscle and vascular phenotype with a concomitant elevation of filamin C (FLNC) levels, an observation confirmed in the frontal cortex of FTLD-TDP patients. Here, we aimed to further assess the contribution of FLNC to frontotemporal dementia (FTD) etiology. We conducted a mutational screening of FLNC in a cohort of 529 unrelated Belgian FTD and FTD-ALS patients, and a control cohort of 920 unrelated and age-matched individuals. Additionally we performed an in-depth characterization of FLNC expression levels in FTD patients and a murine FTD model.In total 68 missense variants were identified of which 19 (MAF < 1%) were patient-only. Gene burden analysis demonstrated a significant association between the presence of rare variants in FLNC and disease (P = 0.0349, RR = 1.46 [95% CI 1.03-2.07]). Furthermore, elevated FLNC expression levels, observed previously in FTLD-TDP patients, were mainly attributable to FTD patients with the progranulin (GRN) p.0(IVS1 + 5G > C) loss-of-function mutation. Increased FLNC levels were, to a lesser extent, also identified in a FLNC p.V831I variant carrier and in FTD patients with the p.R159H mutation in valosin-containing protein (VCP). The GRN-associated increase of FLNC was confirmed in the frontal cortex of aged Grn knockout mice starting at 16-18 months of age. Combined quantitative proteomic and bioinformatic analyses of the frontal cortex of FTD patients possessing elevated FLNC levels, identified multiple altered protein factors involved in accelerated aging, neurodegeneration and synaptogenesis.Our findings further support the involvement of aberrant FLNC expression levels in FTD pathogenesis. Identification of increased FLNC levels in aged Grn mice and impaired pathways related to aging and neurodegeneration, implies a potential role for FLNC in mediating or accelerating the aging process.


A Test of Perfectionistic Vulnerability Following Competitive Failure Among College Athletes.
Perfectionism purportedly bestows vulnerability to distress through an interaction with achievement and interpersonal stress. The authors test this by assessing athletes' perfectionism and subsequent self-conscious emotion following repeated competitive failure. A total of 60 college athletes undertook three 4-min competitive sprint trials on a cycle ergometer and were instructed that they had performed the worst of all competitors on each occasion. Measures of perfectionism (self-oriented and socially prescribed) were taken at baseline and measures of pride, guilt, and shame were taken at baseline and three times following each successive failure. Across the successive failures, self-oriented perfectionism predicted within-person trajectories of decreasing pride and increasing guilt. Socially prescribed perfectionism predicted within-person trajectories of increasing shame and guilt. Furthermore, a combination of high self-oriented and high socially prescribed perfectionism predicted the steepest within-person increases in shame and guilt. Findings support an achievement-specific vulnerability hypothesis whereby those higher in perfectionism experience pronounced distress following competitive failure.


Influence of L-citrulline and watermelon supplementation on vascular function and exercise performance.
L-Citrulline, either synthetic or in watermelon, may improve vascular function through increased L-arginine bioavailability and nitric oxide synthesis. This article analyses potential vascular benefits of L-citrulline and watermelon supplementation at rest and during exercise. There is clear evidence that acute L-citrulline ingestion increases plasma L-arginine, the substrate for endothelial nitric oxide synthesis. However, the subsequent acute improvement in nitric oxide production and mediated vasodilation is inconsistent, which likely explains the inability of acute L-citrulline or watermelon to improve exercise tolerance. Recent studies have shown that chronic L-citrulline supplementation increases nitric oxide synthesis, decreases blood pressure, and may increase peripheral blood flow. These changes are paralleled by improvements in skeletal muscle oxygenation and performance during endurance exercise. The antihypertensive effect of L-citrulline/watermelon supplementation is evident in adults with prehypertension or hypertension, but not in normotensives. However, L-citrulline supplementation may attenuate the blood pressure response to exercise in normotensive men. The beneficial vascular effects of L-citrulline/watermelon supplementation may stem from improvements in the L-arginine/nitric oxide pathway. Reductions in resting blood pressure with L-citrulline/watermelon supplementation may have major implications for individuals with prehypertension and hypertension. L-Citrulline supplementation, but not acute ingestion, have shown to improve exercise performance in young healthy adults.