Retinoic acid inhibits the proliferative response induced by CD40 activation and interleukin-4 in mantle cell lymphoma.
Mantle cell lymphoma (MCL) is an aggressive B-cell non-Hodgkin's lymphoma with poor response to therapy and unfavorable prognosis. Here, we show that retinoic acid (RA) isomers significantly inhibit the proliferation of both primary MCL cultures (n = 7) and established cell lines (Granta 519 and SP-53) as shown by [(3)H]thymidine uptake and carboxyfluorescein diacetate succinimidyl ester labeling coupled with cyclin D1 staining. RA induces cell accumulation in G(0)-G(1) together with a marked up-regulation of p27(Kip1) by inhibiting ubiquitination and proteasome-dependent degradation of the protein. The p21(Cip1) inhibitor was also up-regulated by RA in Granta 519 cells, whereas the expression of cyclin D1 is unaffected. Most of RA-induced p27(Kip1) was bound to cyclin D1/cyclin-dependent kinase 4 complexes, probably contributing to the decreased cyclin-dependent kinase 4 kinase activity and pRb hypophosphorylation observed in RA-treated cells. Experiments with receptor-selective ligands indicate that RA receptor alpha cooperates with retinoid X receptors in mediating RA-dependent MCL cell growth inhibition. Notably, RA isomers, and particularly 9-cis-RA, also inhibited the growth-promoting effect induced in primary MCL cells by CD40 activation alone or in combination with interleukin-4. Immunohistochemical analysis showed that significant numbers of CD40L-expressing lymphoid cells are present in lymph node biopsies of MCL patients. These results therefore further strengthen the possibility that triggering of CD40 by infiltrating CD40L+ cells may continuously promote the growth of MCL cells in vivo. On these grounds, our findings that RA inhibits basal MCL proliferation as well as MCL growth-promoting effects exerted by microenvironmental factors make these compounds highly attractive in terms of potential clinical efficacy in this setting.


Age, sex, and the changing disability burden of compensated work-related musculoskeletal disorders in Canada and Australia.
The objectives of this study were (1) to identify age and sex trends in the disability burden of compensated work-related musculoskeletal disorders (MSDs) in Canada and Australia; and (2) to demonstrate a means of comparing workers' compensation data internationally. All non-fatal, work-related MSD claims with at least one day of compensated time-loss were extracted for workers aged 15-80 during a 10-year period (2004-2013) using workers' compensation data from five Canadian and eight Australian jurisdictions. Disability burden was calculated for both countries by sex, age group, and injury classification, using cumulative compensated time-loss payments of up to two years post-injury. A total of 1.2 million MSD claims were compensated for time-loss in the Canadian and Australian jurisdictions during 2004-2013. This resulted in time-loss equivalent to 239,345 years in the Canadian jurisdictions and 321,488 years in the Australian jurisdictions. The number of time-loss years declined overall among male and female workers, but greater declines were observed for males and younger workers. The proportion of the disability burden grew among older workers (aged 55+), particularly males in the Canadian jurisdictions (Annual Percent Change [APC]: 7.2, 95% CI 6.7 to 7.7%) and females in the Australian jurisdictions (APC: 7.5, 95% CI 6.2 to 8.9%). The compensated disability burden of work-related MSDs is shifting towards older workers and particularly older females in Australia and older males in Canada. Employers and workers' compensation boards should consider the specific needs of older workers to reduce injuries and time off work. Comparative research made possible through research-stakeholder partnerships offers a unique opportunity to use existing administrative data to identify long-term trends in disability burden. Future research can apply similar approaches for estimating long-term trends in occupational health.


Low molecular weight heparin in atrial fibrillation management: facts, fiction, future.
Atrial fibrillation (AF) is the most common sustained arrhythmia and various AF disease management strategies can be utilized. A prospective, randomized pilot study of two AF disease management strategies was conducted at a single university hospital in patients newly diagnosed with AF. The impact of low molecular weight heparin (LMWH) on AF management strategies is discussed with respect to the current guidelines for AF management, existing data on LMWH for AF, and recent investigations pertaining to AF. 18 patients were enrolled. The accelerated emergency department based strategy utilizing LMWH resulted in a significant reduction in length of stay (2.1 +/- 2.3 versus <1 day) and a trend toward lower costs (1,706 +/- 1,512 dollars versus 879 +/- 394 dollars; p = 0.15) when compared to the more traditional strategy of hospital admission. Measured clinical outcomes were similar for both treatment strategies. The investigation showed that an outpatient, emergency department based disease management strategy for new, uncomplicated AF could result in clinically acceptable, cost-effective innovations in AF treatment strategies. LMWH is an example of an agent allowing innovations in disease management strategies.


Remineralization Potential of Three Different Dentifrices using Raman Spectroscopy and Confocal Laser Scanning Microscope.
Aim: The aim of this study was to compare the remineralization potential of three different dentifrices using Raman spectroscopy and confocal laser scanning microscopy (CLSM). Materials and methods: Totally, 30 extracted intact impacted third molar teeth were selected and the crown of each tooth in a group was separated from the root and longitudinally sectioned into four parts with each section under a subgroup, of which one section was an untreated section, the second and the third sections were demineralized in a demineralizing solution, and the third section was remineralized after demineralization. The teeth in the three groups were demineralized for 4 days and then treated with 0.21% sodium fluoride dentifrice with trical-cium phosphate, casein phosphopeptide-amorphous calcium phosphate (CPP-ACP), and NovaMin for 14 days, following which the teeth surfaces were studied using Raman spec-troscopy and CLSM to assess the remineralization potential of the three dentifrices. The data were recorded and analyzed statistically. Results: Raman spectroscopic analysis revealed better remin-eralization with CPP-ACP, which was statistically significant from the groups treated with the NovaMin dentifrice and the fluoride-containing dentifrice.Confocal laser scanning microscopic examination also revealed significant differences between the three groups with the NovaMin-containing dentifrice demonstrating a greater remineralization of the surface when compared with the CPP-ACP dentifrice. The teeth samples treated with fluoride-containing dentifrice demonstrated the least reminer-alization among the three groups. Conclusion: It can be concluded that the demineralized samples of teeth treated with CPP-ACP showed the highest concentration of phosphate ions when analyzed using Raman spectroscopy, and the microscopic examination using confocal laser revealed a better surface remineralization of the demin-eralized samples when treated with the NovaMin technology. Clinical significance: There is a great need to find ways to enhance the remineralization process and transfer such knowledge into clinical therapy to alter caries balance for the better, especially in individuals with a high cariogenic bacterial challenge. Keywords: Casein phosphopeptide-amorphous calcium phosphate, Fluoride, NovaMin, Remineralization, Tricalcium phosphate.


Nucleotide sequence and comparative analysis of the frd operon encoding the fumarate reductase of Proteus vulgaris. Extensive sequence divergence of the membrane anchors and absence of an frd-linked ampC cephalosporinase gene.
The fumarate reductase of Escherichia coli is a bioenergetically important membrane-bound flavoenzyme consisting of four subunits. A and B comprise a membrane-extrinsic catalytic domain whereas C and D are hydrophobic polypeptides which link the catalytic centres to the electron-transport chain. The nucleotide sequence of the frd operon encoding the fumarate reductase of the distantly related bacterium, Proteus vulgaris has been determined and used to predict the primary structures of the respective subunits. Extensive amino acid sequence identity (greater than 80%) was found between the fumarate reductase A and B subunits of P. vulgaris and E. coli. In contrast, the primary structures of the P. vulgaris and E. coli C and D proteins are much less closely related (about 60% homology) although the overall hydrophobicity of their three membrane-spanning segments has been conserved. In most enteric bacteria, the frd operon is followed by genes, ampR and/or ampC, required for the genetic regulation and biosynthesis of a cephalosporinase. The corresponding region of the P. vulgaris genome is occupied by an operon (orf A'BCD) containing at least four genes which are clearly unrelated to the ampC system. Intriguingly the primary structures of the OrfA and OrfD proteins suggest that, like fumarate reductase, they may be components of a membrane-bound enzyme complex involved in energy metabolism.


Influence of variations in CCL3L1 and CCR5 on tuberculosis in a northwestern Colombian population.
We investigated the association of polymorphisms in CCR5, the major human immunodeficiency virus (HIV)-1 coreceptor, and copy number of its potent ligand CCL3L1 with tuberculosis in 298 individuals from Colombia. The CCR5-HHD haplotype, a known genetic determinant of increased susceptibility to HIV-AIDS, and a high copy number of CCL3L1, a known genetic determinant of enhanced CCL3/CCL3L1 chemokine expression, each associated with presence of tuberculosis. Furthermore, CCR5-HHD was associated with higher CCR5 gene and surface expression. These results substantiate the strong link between the pro-inflammatory effects of CCR5 and its ligands with active tuberculosis and suggest that chemokine-chemokine receptor genetic determinants may influence tuberculosis in addition to HIV/AIDS.


Revisions of monoblock metal-on-metal THAs have high early complication rates.
A relatively high percentage of monoblock metal-on-metal total hip arthroplasties (THAs) undergo early revision. Revision of these THAs poses challenges unique to this implant type. The early complications after these revisions remain unreported as do the clinical and demographic factors associated with these complications. We describe (1) the frequency of early complications after revision of monoblock metal-on-metal THA; and (2) the clinical and demographic factors associated with complications. A review of our institution's total joint registry identified 107 patients who underwent 114 revisions of monoblock metal-on-metal THAs. Mean patient age at revision was 60 years (range, 17-84 years), and 65% of the patients were women. Mean followup after revision was 14 months (range, 0-122 months). Revision diagnoses included metallosis (51%), aseptic loosening (27%), infection (7%), pain (6%), malposition (4%), instability (3%), iliopsoas impingement (2%), and periprosthetic fracture (1%). Major complications (instability, infection, aseptic loosening, and wound complications) were documented and included in the analysis. Minor postoperative complications such as urinary tract infection were excluded. Twenty-three of 114 procedures (20%) involved at least one early complication after revision of monoblock metal-on-metal THA with 18 (16%) undergoing at least one additional subsequent surgery. The most common complications included aseptic loosening (6%), deep infection (6%), dislocation (4%), and acetabular fracture (3%). Patients who sustained a complication after revision surgery were older on average than those who did not (66 years versus 58 years, p=0.003). There were no differences in complication rate with respect to sex, time to revision, or revision diagnosis. Complications and reoperations occur frequently after revision for failed monoblock metal-on-metal THA (20% and 16%, respectively), and older patients appear to be at greater risk for complications after these revisions. Aseptic loosening, deep infection, and instability are all of great concern after revision and surgeons should be aware of these potential complications when undertaking revision of these THAs. Level IV, therapeutic study. See Instructions for Authors for a complete description of levels of evidence.


New glass sponges (Porifera: Hexactinellida) from deep waters of the central Aleutian Islands, Alaska.
Hexactinellida from deep-water communities of the central Aleutian Islands, Alaska, are described. They were mostly collected by the remotely operated vehicle 'Jason II' from 494–2311 m depths during a 2004 RV 'Roger Revelle' expedition, but one shallow-water species collected with a shrimp trawl from 155 m in the same area is included. The excellent condition of the ROV-collected specimens enabled valuable redescription of some species previously known only from badly damaged specimens. New taxa include one new genus and eight new species in five families. Farreidae consist of two new species, Farrea aleutiana and F. aspondyla. Euretidae consists of only Pinulasma fistulosum n. gen., n. sp. Tretodictyidae include only Tretodictyum amchitkensis n. sp. Euplectellidae consists of only the widespread species Regadrella okinoseana Ijima, reported here over 3,700 km from its closest previously known occurrence. The most diverse family, Rossellidae, consists of Aulosaccus ijimai (Schulze), Aulosaccus schulzei Ijima, Bathydorus sp. (young stage not determinable to species), Caulophacus (Caulophacus) adakensis n. sp., Acanthascus koltuni n. sp., Staurocalyptus psilosus n. sp., Staurocalyptus tylotus n. sp. and Rhabdocalyptus mirabilis Schulze. We present argument for reinstatement of the abolished rossellid subfamily Acanthascinae and return of the subgenera Staurocalyptus Ijima and Rhabdocalyptus Schulze to their previous generic status. These fauna provides important complexity to the hard substrate communities that likely serve as nursery areas for the young stages of commercially important fish and crab species, refuge from predation for both young and adult stages, and also as a focal source of prey for juvenile and adult stages of those same species.


Concordant effects of aromatase inhibitors on gene expression in ER+ Rat and human mammary cancers and modulation of the proteins coded by these genes.
Aromatase inhibitors are effective in therapy/prevention of estrogen receptor-positive (ER⁺) breast cancers. Rats bearing methylnitrosourea (MNU)-induced ER⁺ mammary cancers were treated with the aromatase inhibitor vorozole (1.25 mg/kg BW/day) for five days. RNA expression showed 162 downregulated and 180 upregulated (P < 0.05 and fold change >1.5) genes. Genes modulated by vorozole were compared with published data from four clinical neoadjuvant trials using aromatase inhibitors (anastrozole or letrozole). More than 30 genes and multiple pathways exhibited synchronous changes in animal and human datasets. Cell-cycle genes related to chromosome condensation in prometaphase [anaphase-prometaphase complex (APC) pathway, including Aurora-A kinase, BUBR1B, TOP2, cyclin A, cyclin B CDC2, and TPX-2)] were downregulated in animal and human studies reflecting the strong antiproliferative effects of aromatase inhibitors. Comparisons of rat arrays with a cell culture study where estrogen was removed from MCF-7 cells showed decreased expression of E2F1-modulated genes as a major altered pathway. Alterations of the cell cycle and E2F-related genes were confirmed in a large independent set of human samples (81 pairs baseline and two weeks anastrozole treatment). Decreases in proliferation-related genes were confirmed at the protein level for cyclin A2, BuRB1, cdc2, Pttg, and TPX-2. Interestingly, the proteins downregulated in tumors were similarly downregulated in vorozole-treated normal rat mammary epithelium. Finally, decreased expression of known estrogen-responsive genes (including TFF, 1,3, progesterone receptor, etc.) were decreased in the animal model. These studies demonstrate that gene expression changes (pathways and individual genes) are similar in humans and the rat model.


LSD-induced increases in social adaptation to opinions similar to one's own are associated with stimulation of serotonin receptors.
Adapting one's attitudes and behaviors to group norms is essential for successful social interaction and, thus, participation in society. Yet, despite its importance for societal and individual functioning, the underlying neuropharmacology is poorly understood. We therefore investigated its neurochemical and neural correlates in a pharmacological functional magnetic resonance imaging study. Lysergic acid diethylamide (LSD) has been shown to alter social processing and therefore provides the unique opportunity to investigate the role of the 5-HT2A receptor in social influence processing. Twenty-four healthy human volunteers received either (1) placebo + placebo, (2) placebo + LSD (100 µg), or (3) the 5-HT2A receptor antagonist ketanserin (40 mg) + LSD (100 µg) at three different occasions in a double-blind, randomized, counterbalanced, cross-over design. LSD increases social adaptation but only if the opinions of others are similar to the individual's own. These increases were associated with increased activity in the medial prefrontal cortex while participants received social feedback. Furthermore, pretreatment with the 5-HT2A antagonist ketanserin fully blocked LSD-induced changes during feedback processing, indicating a key role of the 5-HT2A system in social feedback processing. Our results highlight the crucial role of the 5-HT-system in social influence and, thus, provide important insight into the neuropharmacological basis of social cognition and behavior.


Phenotypes of Drosophila brain neurons in primary culture reveal a role for fascin in neurite shape and trajectory.
Subtle cellular phenotypes in the CNS may evade detection by routine histopathology. Here, we demonstrate the value of primary culture for revealing genetically determined neuronal phenotypes at high resolution. Gamma neurons of Drosophila melanogaster mushroom bodies (MBs) are remodeled during metamorphosis under the control of the steroid hormone 20-hydroxyecdysone (20E). In vitro, wild-type gamma neurons retain characteristic morphogenetic features, notably a single axon-like dominant primary process and an arbor of short dendrite-like processes, as determined with microtubule-polarity markers. We found three distinct genetically determined phenotypes of cultured neurons from grossly normal brains, suggesting that subtle in vivo attributes are unmasked and amplified in vitro. First, the neurite outgrowth response to 20E is sexually dimorphic, being much greater in female than in male gamma neurons. Second, the gamma neuron-specific "naked runt" phenotype results from transgenic insertion of an MB-specific promoter. Third, the recessive, pan-neuronal "filagree" phenotype maps to singed, which encodes the actin-bundling protein fascin. Fascin deficiency does not impair the 20E response, but neurites fail to maintain their normal, nearly straight trajectory, instead forming curls and hooks. This is accompanied by abnormally distributed filamentous actin. This is the first demonstration of fascin function in neuronal morphogenesis. Our findings, along with the regulation of human Fascin1 (OMIM 602689) by CREB (cAMP response element-binding protein) binding protein, suggest FSCN1 as a candidate gene for developmental brain disorders. We developed an automated method of computing neurite curvature and classifying neurons based on curvature phenotype. This will facilitate detection of genetic and pharmacological modifiers of neuronal defects resulting from fascin deficiency.


Caspase-dependent Proteolysis of Human Ribonucleotide Reductase Small Subunits R2 and p53R2 during Apoptosis.
Ribonucleotide reductase (RnR) is a key enzyme synthesizing deoxyribonucleotides for DNA replication and repair. In mammals, the R1 catalytic subunit forms an active complex with either one of the two small subunits R2 and p53R2. Expression of R2 is S phase-specific and required for DNA replication. The p53R2 protein is expressed throughout the cell cycle and in quiescent cells where it provides dNTPs for mitochondrial DNA synthesis. Participation of R2 and p53R2 in DNA repair has also been suggested. In this study, we investigated the fate of the RnR subunits during apoptosis. The p53R2 protein was cleaved in a caspase-dependent manner in K-562 cells treated with inhibitors of the Bcr-Abl oncogenic kinase and in HeLa 229 cells incubated with TNF-α and cycloheximide. The cleavage site was mapped between Asp(342) and Asn(343). Caspase attack released a C-terminal p53R2 peptide of nine residues containing the conserved heptapeptide essential for R1 binding. As a consequence, the cleaved p53R2 protein was inactive. In vitro, purified caspase-3 and -8 could release the C-terminal tail of p53R2. Knocking down these caspases, but not caspase-2, -7, and -10, also inhibited p53R2 cleavage in cells committed to die via the extrinsic death receptor pathway. The R2 subunit was subjected to caspase- and proteasome-dependent proteolysis, which was prevented by siRNA targeting caspase-8. Knocking down caspase-3 was ineffective. Protein R1 was not subjected to degradation. Adding deoxyribonucleosides to restore dNTP pools transiently protected cells from apoptosis. These data identify RnR activity as a prosurvival function inactivated by proteolysis during apoptosis.


Mapping the protein binding site of the (pro)renin receptor using in silico 3D structural analysis.
We have previously reported that monoclonal antibodies against the (pro)renin receptor [(P)RR] can reduce the Wnt/β-catenin-dependent development of pancreatic ductal adenocarcinoma (PDAC), the most common pancreatic cancer. Antibodies against two (P)RR regions (residues 47-60 and 200-213) located in the extracellular domain (ECD) reduced the proliferation of human PDAC cells in vitro. Although these regions probably participate in the activation of Wnt/β-catenin signaling, their functional significance remains unclear. Moreover, the (P)RR ECD is predicted to possess an intrinsically disordered region (IDR), which allows multiple protein interactions because of its conformational flexibility. In this study, we investigated the significance of the two regions and the IDR by in silico 3D structural analysis using the AlphaFold2 program and evolutionary sequence conservation profile. The model showed that ECD adopted a folded domain (residues 17-269) and had an IDR (residues 270-296). The two regions mapped onto the structural model formed a continuous surface patch comprising evolutionarily conserved hydrophobic residues. The homodimeric structure predicted by AlphaFold2 showed that full-length (P)RR comprising the ECD, single-span transmembrane, and cytoplasmic domains formed a twofold symmetric dimer via the ECD, which explains the experimentally proven homodimerization. The dimer model possessed two hand-shaped grooves with residues 47-60 and 200-213 in their palms and the IDR as their fingers. Based on these findings, we propose that the IDR-containing hydrophobic grooves act as a binding site for (P)RR and perform multiple functions, including Wnt signaling activation. Antibodies against the (pro)renin receptor residues 47-60 and 200-213 can inhibit pancreatic ductal adenocarcinoma (PDAC) cell proliferation by suppressing Wnt signaling. This study provides 3D structural insights into receptor binding and one-to-many interactions, which underpin the functional versatility of this receptor.


Incomplete fracture of the talus secondary to maladaptive stress remodeling in a horse.
A 6-year-old Quarter Horse gelding used for barrel racing was evaluated for acute onset of non-weight-bearing lameness of the left hind limb following strenuous exercise. Nuclear scintigraphic imaging revealed focal increased radiopharmaceutical uptake centrally within the left talus. Subsequent standard radiographic and ultrasonographic examinations of the tarsus failed to identify the cause of the increased radiopharmaceutical uptake; however, the lameness was definitively localized to the tarsocrural joint by intra-articular anesthesia. Subsequent MRI sequences of the left tarsus revealed an incomplete fracture of the talus that extended distally from the trochlear groove and evidence of maladaptive stress remodeling of the trochlear groove of the talus and distal intermediate ridge of the tibia. The horse was treated conservatively, with management consisting of stall confinement, physical rehabilitation, therapeutic laser therapy, and intra-articular autologous conditioned serum administration. The lameness resolved, and the horse was competing at its previous level within 15 months after lameness onset. Although rare, incomplete fracture of the talus should be considered as a differential diagnosis for horses that develop acute hind limb lameness following strenuous exercise, especially when that exercise involves abrupt changes in direction while the horse is traveling at maximal speed. Acquisition of additional oblique projections during radiographic evaluation of the tarsus might be useful for identification of such fractures, but definitive diagnosis may require advanced diagnostic imaging modalities such as CT and MRI. Horses with incomplete fractures of the talus can be successfully treated with conservative management.


Autonomic nervous system and immune system interactions.
The present review assesses the current state of literature defining integrative autonomic-immune physiological processing, focusing on studies that have employed electrophysiological, pharmacological, molecular biological, and central nervous system experimental approaches. Central autonomic neural networks are informed of peripheral immune status via numerous communicating pathways, including neural and non-neural. Cytokines and other immune factors affect the level of activity and responsivity of discharges in sympathetic and parasympathetic nerves innervating diverse targets. Multiple levels of the neuraxis contribute to cytokine-induced changes in efferent parasympathetic and sympathetic nerve outflows, leading to modulation of peripheral immune responses. The functionality of local sympathoimmune interactions depends on the microenvironment created by diverse signaling mechanisms involving integration between sympathetic nervous system neurotransmitters and neuromodulators; specific adrenergic receptors; and the presence or absence of immune cells, cytokines, and bacteria. Functional mechanisms contributing to the cholinergic anti-inflammatory pathway likely involve novel cholinergic-adrenergic interactions at peripheral sites, including autonomic ganglion and lymphoid targets. Immune cells express adrenergic and nicotinic receptors. Neurotransmitters released by sympathetic and parasympathetic nerve endings bind to their respective receptors located on the surface of immune cells and initiate immune-modulatory responses. Both sympathetic and parasympathetic arms of the autonomic nervous system are instrumental in orchestrating neuroimmune processes, although additional studies are required to understand dynamic and complex adrenergic-cholinergic interactions. Further understanding of regulatory mechanisms linking the sympathetic nervous, parasympathetic nervous, and immune systems is critical for understanding relationships between chronic disease development and immune-associated changes in autonomic nervous system function.


Current treatments and trials in malignant pleural mesothelioma.
This article aims to review the evidence from recent clinical trials in mesothelioma, and to provide an overview of relevant clinical trials that are currently in progress. Ovid MEDLINE, 1946 to present. Clinical trials of therapeutic interventions were considered for inclusion, regardless of phase. Of 258 papers identified in the literature search, 88 were potentially eligible based on abstract screening. Following evaluation of full-text articles, 35 were selected for inclusion in the review. Since the original trial that demonstrated the efficacy of pemetrexed and cisplatin in mesothelioma, multiple trials have been conducted that have further informed management options. Anti-angiogenesis agents such as bevacizumab and nintedanib appear promising as adjuncts to first-line chemotherapy. Meanwhile, immunotherapy, anti-mesothelin agents and molecular targeted therapies are potential areas for development, with ongoing trials promising to deliver interesting results over the next few years. Current evidence does not support surgical intervention; however, investigations are ongoing as to the role of extended pleurectomy/decortication, and surgery in the context of trapped lung. Finally radiotherapy is effective as a palliative measure for pain control, but is not indicated prophylactically to prevent the development of procedure tract metastases. A large amount of high-quality mesothelioma research has been conducted in the past decade. As a result, several new therapies are likely to become available in clinical practice in the near future. With multiple trials ongoing, the horizon for patients with mesothelioma looks brighter than ever before.


Modeling the Dynamics of Protein-Protein Interfaces, How and Why?
Protein-protein assemblies act as a key component in numerous cellular processes. Their accurate modeling at the atomic level remains a challenge for structural biology. To address this challenge, several docking and a handful of deep learning methodologies focus on modeling protein-protein interfaces. Although the outcome of these methods has been assessed using static reference structures, more and more data point to the fact that the interaction stability and specificity is encoded in the dynamics of these interfaces. Therefore, this dynamics information must be taken into account when modeling and assessing protein interactions at the atomistic scale. Expanding on this, our review initially focuses on the recent computational strategies aiming at investigating protein-protein interfaces in a dynamic fashion using enhanced sampling, multi-scale modeling, and experimental data integration. Then, we discuss how interface dynamics report on the function of protein assemblies in globular complexes, in fuzzy complexes containing intrinsically disordered proteins, as well as in active complexes, where chemical reactions take place across the protein-protein interface.


Receptor editing: an approach by autoreactive B cells to escape tolerance.
To determine the fate of anti-DNA antibody-bearing B cells in normal mice, we generated transgenic mice bearing the heavy (H) and light (L) chain genes of a well-characterized anti-double-stranded DNA antibody. This antibody was originally isolated from a diseased MRL/lpr mouse and has characteristics common to spontaneously arising anti-DNA antibodies. Results show that the H/L transgene (tg) immunoglobulin receptor is not expressed by animals bearing both tgs, although single tg animals (H or L) express their transgenes. Young H/L tg animals express few B cells, whereas adult H/L tg animals maintain almost normal B cell numbers. Analysis of the immunoglobulin receptors used by adult B cells shows that all contain the tg H chain in association with endogenous L chains. These B cells transcribe the L tg as well as the rearranged endogenous L chain gene, and loss of endogenous L chain gene transcription results in resurrection of the 3H9 H/L tg product. Examination of the endogenous L chains used by these cells shows that they represent a highly restricted subset of V genes. Taken together, these data suggest that autoreactive transgenic B cells can rearrange endogenous L chain genes to alter surface receptors. Those L chains that compete successfully with the L tg for H chain binding, and that create a nonautoreactive receptor, allow the B cell to escape deletion. We suggest that this receptor editing is a mechanism used by immature autoreactive B cells to escape tolerance.


Probiotics function mechanistically as delivery vehicles for neuroactive compounds: Microbial endocrinology in the design and use of probiotics.
I hypothesize here that the ability of probiotics to synthesize neuroactive compounds provides a unifying microbial endocrinology-based mechanism to explain the hitherto incompletely understood action of commensal microbiota that affect the host's gastrointestinal and psychological health. Once ingested, probiotics enter an interactive environment encompassing microbiological, immunological, and neurophysiological components. By utilizing a trans-disciplinary framework known as microbial endocrinology, mechanisms that would otherwise not be considered become apparent since any candidate would need to be shared among all three components. The range of neurochemicals produced by probiotics includes neurochemicals for which receptor-based targets on immune and neuronal elements (intestinal and extra-intestinal) have been well characterized. Production of neurochemicals by probiotics therefore allows for their consideration as delivery vehicles for neuroactive compounds. This unifying microbial endocrinology-based hypothesis, which may facilitate the selection and design of probiotics for clinical use, also highlights the largely unrecognized role of neuroscience in understanding how microbes may influence health.


Endovascular treatment of jugular bulb diverticula causing debilitating pulsatile tinnitus.
We describe the case of a patient who presented with debilitating pulsatile tinnitus in association with two jugular bulb diverticula. The diverticula were treated with stenting of the jugular bulb and coil embolization of the diverticula over two procedures. This resulted in successful resolution of symptoms and at 10 months follow-up the patient is asymptomatic. The technique is discussed with regard to similar published cases and surrogate measures of safety taken from the literature pertaining to idiopathic intracranial hypertension.


Soluble CD146 is generated by ectodomain shedding of membrane CD146 in a calcium-induced, matrix metalloprotease-dependent process.
CD146 is a cell adhesion molecule localized at the endothelial junction and is involved in the control of cell-cell cohesion. In this study, we showed that calcium influx in human microvascular lung endothelial cells results in the loss of surface CD146 and the release of soluble CD146. This calcium-induced CD146 shedding could be prevented with inhibitors of matrix metalloproteases indicating a central role of matrix metalloproteases in this process. We also investigated if CD146 shedding influences vascular permeability. Endothelial cell monolayers cultured on filter membranes showed an increased permeability for albumin when stimulated with ionomycin. This calcium-induced increase in permeability was inhibited when CD146 shedding was prevented by a matrix metalloprotease inhibitor. Our data indicate that surface CD146 plays a central role in the regulation of vascular permeability and demonstrate that CD146 and matrix metalloproteases are potential targets to modify endothelial barrier function.


Kupffer cells and macrophages are not required for hepatic hepcidin activation during iron overload.
Hepcidin, the iron hormone, is produced by the liver in response to iron and inflammation. Its synthesis during inflammation is triggered by cytokines, but the details of iron activation are obscure. We tested the role of Kupffer cells and macrophages by studying iron-loaded or inflamed mice with selective inactivation of Kupffer cells or the in vitro effect of conditioned human macrophages on hepcidin expression. Hepcidin messenger RNA (mRNA) expression was studied by Northern blot and reverse transcriptase polymerase chain reaction analysis in mice that were treated with 40 mg/kg gadolinium (III) chloride (GdCl(3)) as a Kupffer cell inactivating agent and subjected to inflammatory challenges with either lipopolysaccharide (LPS) and turpentine or iron overload by iron-dextran administration. Similar analyses were performed in human hepatoma cells (HepG2) cultured with medium from LPS- or iron-conditioned macrophages from blood donors or patients with HFE-linked hereditary hemochromatosis (HH). In vivo, LPS and particularly turpentine stimulated hepcidin mRNA expression, and this effect was prevented by the inactivation of Kupffer cells. Also, iron overload markedly upregulated hepatic hepcidin mRNA, but this activity persisted in spite of Kupffer cell blockade. In vitro, the medium of LPS-treated normal or hemocromatotic macrophages turned on hepcidin expression. On the contrary, medium of iron-manipulated macrophages, regardless of their HFE status, did not affect hepcidin mRNA steady-state levels. In conclusion, Kupffer cells are required for the activation of hepcidin synthesis during inflammation, and HH inflamed macrophages are capable of mounting a normal response, eventually leading to hepcidin stimulation. However, both Kupffer cells and human macrophages are dispensable for the regulatory activity exerted by iron on hepatic hepcidin.


Effects of two amino acid substitutions in the capsid proteins on the interaction of two cell-adapted PanAsia-1 strains of foot-and-mouth disease virus serotype O with heparan sulfate receptor.
Some cell-adapted strains of foot-and-mouth disease virus (FMDV) can utilize heparan sulfate (HS) as a receptor to facilitate viral infection in cultured cells. A number of independent sites on the capsid that might be involved in FMDV-HS interaction have been studied. However, the previously reported residues do not adequately explain HS-dependent infection of two cell-adapted PanAsia-1 strains (O/Tibet/CHA/6/99tc and O/Fujian/CHA/9/99tc) of FMDV serotype O. To identify the molecular determinant(s) for the interaction of O/Tibet/CHA/6/99tc and O/Fujian/CHA/9/99tc with HS receptor, several chimeric viruses and site-directed mutants were generated by using an infectious cDNA of a non-HS-utilizing rescued virus (Cathay topotype) as the genomic backbone. Phenotypic properties of these viruses were determined by plaque assays and virus adsorption and penetration assays in cultured cells. Only two of the rescued viruses encoding VP0 of O/Tibet/CHA/6/99tc or VP1 of O/Fujian/CHA/9/99tc formed plaques on wild-type Chinese hamster ovary (WT-CHO; HS+) cells, but not on HS-negative pgsD-677 cells. The formation of plaques by these two chimeric viruses on WT-CHO cells could be abolished by the introduction of single amino acid mutations Gln-2080 → Leu in VP2 of O/Tibet/CHA/6/99tc and Lys-1083 → Glu in VP1 of O/Fujian/CHA/9/99tc, respectively. Nonetheless, the introduced mutation Leu-2080 → Gln in VP2 of O/Fujian/CHA/9/99tc for the construction of expectant recombinant plasmid led to non-infectious progeny virus in baby hamster kidney 21 (BHK-21) cells, and the site-directed mutant encoding Glu-1083 → Lys in VP1 of O/Tibet/CHA/6/99tc did not acquire the ability to produce plaques on WT-CHO cells. Significant differences in the inhibition of the infectivity of four HS-utilizing viruses by heparin and RGD-containing peptide were observed in BHK-21 cells. Interestingly, the chimeric virus encoding VP0 of O/Fujian/CHA/9/99tc, and the site-directed mutant encoding Gln-2080 → Leu in VP2 of O/Tibet/CHA/6/99tc could bind to HS, but there was no expression of the 3A protein of these two viruses in WT-CHO cells. The results suggest that the cooperation of certain specific amino acid residues in the capsid proteins of these two cell-adapted PanAsia-1 strains is essential for viral infectivity, the heparin affinity and the capability on FMDV-HS interaction.


Duration and clinical features of cardiac arrest predict early severe cerebral edema.
Severe brain edema appears early after cardiopulmonary resuscitation (CPR) in a subset of patients and portends a poor prognosis. We tested whether clinical features of patients or resuscitation during out-of-hospital cardiac arrest (OHCA) are associated with early, severe cerebral edema. We reviewed pre-hospital and hospital records for comatose patients surviving to hospital admission after OHCA who had computed tomography (CT) of brain at the time of hospital admission available for inspection. We measured the gray-white ratio (GWR) of X-ray attenuation between the caudate nucleus and posterior limb of the internal capsule, defining severe cerebral edema as GWR < 1.20. We calculated associations between severe cerebral edema and patient or resuscitation variables. Between 2010 and 2019, 1340 subjects were admitted of whom 296 (22%) showed severe cerebral edema on initial CT. Subjects with severe edema had lower survival (5/296, 2% vs. 377/1044, 36%). Severe edema was independently associated with total CPR duration, total dose of epinephrine, younger age, non-shockable arrest rhythms, fewer total number of rescue shocks, rearrest after initial return of pulses, and non-cardiac arrest etiology. Prevalence of severe cerebral edema increased from 2% among subjects with 0-10 min of CPR to 31% among subjects with >40 min of CPR. CPR duration along with easily measurable clinical and resuscitation characteristics predict early severe cerebral edema after OHCA. Future interventional trials should consider targeting or preventing cerebral edema after prolonged hypoxic-ischemic brain injury especially in patients with high risk clinical features.


Ventricular sensory endings mediate reflex bradycardia during coronary arteriography in humans.
It has been suggested that the response to the intracoronary injection of radiographic contrast is reflex in origin and results from stimulation of ventricular sensory endings. Cardiac transplantation results in denervation of the ventricles, and thus, may interrupt the afferent limb of this reflex. In contrast, the recipient sinus node and atrial remnant remain innervated, leaving the efferent cardiac limb of this reflex intact. We hypothesized that if contrast-induced reflex bradycardia and hypotension occurred from stimulation of ventricular chemosensitive endings, then this response would be abolished after cardiac transplantation. To test this hypothesis, we determined the changes in recipient (innervated) and donor (denervated) sinus-node rates (SNR) and mean arterial pressure during selective right (RCA) and left coronary artery (LCA) injection during arteriography in cardiac transplant patients and in patients with intact cardiac innervation. An increase in the recipient SNR was observed in cardiac transplant patients during left and right coronary injections (LCA, 6.6 +/- 1.7 beats/min; RCA, 2.4 +/- 1.4 beats/min) compared with a decrease in the control subjects (LCA, -15.3 +/- 2.3 beats/min; RCA, -6.9 +/- 1.9 beats/min; p less than 0.05 vs. control). This occurred despite significant and comparable decreases in mean arterial pressure in cardiac transplant patients (LCA, -12.7 +/- 2.3 mm Hg; RCA, -11.4 +/- 2.2 mm Hg) and control subjects (LCA, -18.7 +/- 1.7 mm Hg; RCA, -10.7 +/- 1.6 mm Hg). The donor SNR slowed for LCA injection (-5.4 +/- 2.1 beats/min, p less than 0.05) and RCA injection (-3.0 +/- 1.7 beats/min), which, for the LCA, was less than the slowing of control subjects (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)


Risk of Colorectal Cancer After Ovarian Stimulation for In Vitro Fertilization.
Apart from lifestyle factors, sex hormones also seem to have a role in the etiology of colorectal cancer. This raises interest in the possible effects of fertility drugs, especially because the use of ovarian stimulation for in vitro fertilization (IVF) has strongly increased over the past decades. In 1996, a nationwide cohort study was set up to examine cancer risk in a population that included 19,158 women who received ovarian stimulation for IVF (IVF group) and 5950 women who underwent subfertility treatments other than IVF (non-IVF group). Cancer incidence was ascertained through linkage with the Netherlands Cancer Registry. Colorectal cancer risk in the IVF group was compared with those in the general population and in the non-IVF group. After a median follow-up of 21 years, 109 colorectal cancers were observed. Compared with the general population, risk of colorectal cancer was not increased in the IVF group (standardized incidence ratio, 1.00; 95% confidence interval [CI], 0.80-1.23), and was significantly decreased in the non-IVF group (standardized incidence ratio, 0.58; 95% CI, 0.36-0.88). Women in the IVF group had a significant increase in risk compared with women in the non-IVF group (multivariable-adjusted hazard ratio, 1.80; 95% CI, 1.10-2.94). No trend emerged with more IVF cycles or more ampules of gonadotropins administered. Colorectal cancer risk did not increase with longer follow-up periods. Although women who receive ovarian stimulation for IVF do not have an increased risk for colorectal cancer compared with the general population, findings from our nationwide cohort study indicate that their risk is increased compared with women who received subfertility treatments other than IVF. Further research is warranted to examine whether ovarian stimulation for IVF contributes to development of colorectal cancer.


Fluorosis-like effects of acidosis, but not NH+4, on rat incisor enamel.
Previous studies have shown that chronic acidosis induced by NH4Cl is associated with disturbances in enamel mineralization that resemble severe fluorosis and increased fluoride concentrations in both soft and hard tissues. It has not been shown whether these effects are due to acidosis per se or exposure to high levels of NH+4. This 42-day study with rats fed a low-fluoride diet was done to identify the etiological factor. Two control groups received deionized water or water containing NaCl. Two groups received NH+4-containing compounds that did not produce acidosis (NH4HCO3 or HN4 acetate). Two other groups were rendered acidotic by exposure to NH4Cl in the drinking water (metabolic acidosis) or to an atmosphere containing 10% CO2 (respiratory acidosis). The femur epiphysial fluoride concentrations were elevated in the NH4Cl and NH4 acetate groups, and the magnesium concentrations were elevated in the groups exposed to NH+4 compounds and in the 10% CO2 group. Microradiographic analysis revealed severe disturbances in the mineralization pattern of incisor enamel in both acidotic groups, but normal enamel in the other groups. Enamel fluoride and magnesium concentrations were highest in the acidotic groups. The enamel fluoride concentrations were low (8-14 ppm) and not regarded as the cause of the defective mineralization. It was concluded that the effects on structure and composition of enamel were due to acidosis and not to exposure to high levels of NH+4.


Targeting angiogenesis in metastatic breast cancer.
Angiogenesis has become an important target in the treatment of several solid tumors, including breast cancer. As monotherapy, antiangiogenic agents have demonstrated limited activity in metastatic breast cancer (MBC); therefore, they have generally been developed for use in combination with chemotherapies. Thus far, the experience with antiangiogenic agents for MBC has been mixed. The results from one study assessing addition of the monoclonal antibody bevacizumab to paclitaxel led to approval of bevacizumab for MBC. However, the modest improvement of progression-free survival rates in subsequent MBC studies has led to reappraisal of bevacizumab. Phase III studies have not produced evidence supporting use of the multikinase inhibitor sunitinib alone or in combination with MBC chemotherapy. Experience with sorafenib in a phase IIb program indicates potential when used in select combinations, particularly with capecitabine; however, phase III confirmatory data are needed. Although antiangiogenic therapies combined with chemotherapy have increased progression-free survival rates for patients with MBC, increases in overall survival times have not been observed. Some studies have tried to combine antiangiogenic agents such as bevacizumab and sunitinib or sorafenib, but that approach has been limited because of toxicity concerns. Sequential use of antiangiogenic agents with differing mechanisms of action may be an effective approach. Despite setbacks, angiogenesis will likely remain an important target of treatment for selected patients with MBC.


Non-collinear CPOPA seeded by an Yb(3+)-doped self-starting passive mode-locked fiber laser.
Using a home-made seed at 1053 nm from a Yb(3+)-doped passively mode-locked fiber laser of 1.5 nJ/pulse, 362 ps pulse duration with a repetition rate of 3.842 MHz, a compact, low cost, stable and excellent beam quality non-collinear chirped pulse optical parametric amplifier omitting the bulky pulse stretcher has been demonstrated. A gain higher than 4.0 x 10(6), single pulse energy exceeding 6 mJ with fluctuations less than 2% rms, 14 nm amplified signal spectrum and recompressed pulse duration of 525 fs are achieved. This provides a novel and simple amplification scheme.


Healthcare providers' knowledge and attitudes about rapid tissue donation (RTD): phase one of establishing a rapid tissue donation programme in thoracic oncology.
In preparation for the development of a rapid tissue donation (RTD) programme, we surveyed healthcare providers (HCPs) in our institution about knowledge and attitudes related to RTD with lung cancer patients. A 31-item web based survey was developed collecting data on demographics, knowledge and attitudes about RTD. The survey contained three items measuring participants' knowledge about RTD, five items assessing attitudes towards RTD recruitment and six items assessing HCPs' level of agreement with factors influencing decisions to discuss RTD. Response options were presented on a 5-point Likert scale. Ninety-one HCPs participated in the study. 66% indicated they had never heard of RTD prior to the survey, 78% rated knowledge of RTD as none or limited and 95.6% reported not having ethical or religious concerns about discussing RTD with patients. The majority were either not comfortable (17.8%) or not sure if they felt comfortable discussing RTD with cancer patients (42.2%). 56.1% indicated their knowledge of RTD would play an integral role in their decision to discuss RTD with patients. 71.4% reported concerns with RTD discussion and the emotional state of the patient. Physicians and nurses play an important role in initiating conversations about recruitment and donation to research that can ultimately influence uptake. Increasing HCP knowledge about RTD is a necessary step towards building an RTD programme. Our study provides important information about characteristics associated with low levels of knowledge and practice related to RTD where additional education and training may be warranted.


Visual attention to faces in children with autism spectrum disorder: are there sex differences?
The male bias in autism spectrum disorder (ASD) diagnoses is well documented. As a result, less is known about the female ASD phenotype. Recent research suggests that conclusions drawn from predominantly male samples may not accurately capture female behavior. In this study, we explore potential sex differences in attention to social stimuli, which is generally reported to be diminished in ASD. Population-based sex differences in attention to faces have been reported, such that typically developing (TD) females attend more to social stimuli (including faces) from infancy through adulthood than TD males. It is yet unknown whether population-based sex differences in the face domain are preserved in ASD. A dynamic, naturalistic infrared eye-tracking paradigm measured attention to social stimuli (faces) in 74 school-aged males and females with ASD (male N = 23; female N = 19) and without ASD (male N = 16; female N = 16). Two kinds of video stimuli were presented that varied in social content: rich social scenes (dyadic play between two children) and lean social scenes (parallel play by two children). Results revealed a significant 3-way interaction between sex, diagnosis, and condition after controlling for chronological and mental age. ASD females attended more to faces than ASD males in the socially lean condition. This effect was not found in the typically developing (TD) group. ASD males attended less to faces regardless of social context; however, ASD females only attended significantly less to faces compared to TD females in the socially rich condition. TD males and ASD females did not differ in their attention to faces in either condition. This study has implications for how the field understands core social deficits in children with ASD, which should ideally be benchmarked against same-sex peers (male and female). Social attention in ASD females fell on a continuum-greater than their ASD male peers, but not as great as TD females. Overall, their social attention mirrored that of TD males. Improved understanding of the female social phenotype in ASD will enhance early screening and diagnostic efforts and will guide the development of sex-sensitive experimental paradigms and social interventions.


A key role for gp130 expressed on peripheral sensory nerves in pathological pain.
Interleukin-6 (IL-6) is a key mediator of inflammation. Inhibitors of IL-6 or of its signal transducing receptor gp130 constitute a novel class of anti-inflammatory drugs, which raise great hopes for improved treatments of painful inflammatory diseases such as rheumatoid arthritis. IL-6 and gp130 may enhance pain not only indirectly through their proinflammatory actions but also through a direct action on nociceptors (i.e., on neurons activated by painful stimuli). We found indeed that the IL-6/gp130 ligand-receptor complex induced heat hypersensitivity both in vitro and in vivo. This process was mediated by activation of PKC-delta via Gab1/2/PI(3)K and subsequent regulation of TRPV1, a member of the transient receptor potential (TRP) family of ion channels. To assess the relevance of this direct pain promoting effect of IL-6, we generated conditional knock-out mice, which lack gp130 specifically in nociceptors, and tested them in models of inflammatory and tumor-induced pain. These mice showed significantly reduced levels of inflammatory and tumor-induced pain but no changes in immune reactions or tumor growth. Our results uncover the significance of gp130 expressed in peripheral pain sensing neurons in the pathophysiology of major clinical pain disorders and suggest their use as novel pain relieving agents in inflammatory and tumor pain.


Discriminating nutritional quality of foods using the 5-Color nutrition label in the French food market: consistency with nutritional recommendations.
Our objectives were to assess the performance of the 5-Colour nutrition label (5-CNL) front-of-pack nutrition label based on the Food Standards Agency nutrient profiling system to discriminate nutritional quality of foods currently on the market in France and its consistency with French nutritional recommendations. Nutritional composition of 7777 foods available on the French market collected from the web-based collaborative project Open Food Facts were retrieved. Distribution of products across the 5-CNL categories according to food groups, as arranged in supermarket shelves was assessed. Distribution of similar products from different brands in the 5-CNL categories was also assessed. Discriminating performance was considered as the number of color categories present in each food group. In the case of discrepancies between the category allocation and French nutritional recommendations, adaptations of the original score were proposed. Overall, the distribution of foodstuffs in the 5-CNL categories was consistent with French recommendations: 95.4% of 'Fruits and vegetables', 72.5% of 'Cereals and potatoes' were classified as 'Green' or 'Yellow' whereas 86.0% of 'Sugary snacks' were classified as 'Pink' or 'Red'. Adaptations to the original FSA score computation model were necessary for beverages, added fats and cheese in order to be consistent with French official nutritional recommendations. The 5-CNL label displays a high performance in discriminating nutritional quality of foods across food groups, within a food group and for similar products from different brands. Adaptations from the original model were necessary to maintain consistency with French recommendations and high performance of the system.


Low-Volume Lymph Node Metastases in Endometrial Carcinoma.
The aim of this study was to determine the histopathologic characteristics of patients with endometrial carcinoma with low-volume metastases (micrometastases and isolated tumor cells) compared with macrometastases. We performed a retrospective review of patients with endometrial carcinoma. Among 350 robotic-assisted hysterectomies for endometrial cancer, 187 (53%) underwent attempted sentinel lymph node (SLN) biopsy. At least 1 SLN was detected in 185, a 99% overall detection rate; 108 (58%) also had non-SLNs removed. Among 91 patients with SLNs and non-SLNs from the ipsilateral hemipelvis, both were negative in 74 (81%) and positive in 7 (8%), and 10 (11%) had a positive SLN with negative non-SLNs. Among 17 patients with SLNs and non-SLNs from the contralateral hemipelvis, both were negative in 12 (71%), both were positive in 3 (18%), and 2 patients (12%) had negative SLNs with contralateral positive non-SLNs. Among 79 patients with only a SLN dissection, 4 (5%) were positive; among 69 patients with only a non-SLN dissection, 14 (20%) had positive lymph nodes. Among 24 patients with metastatic SLNs, 9 (38%) had isolated tumor cells, 3 (13%) had micrometastases, and 12 (50%) had macrometastases. Among the 40 total patients with metastatic lymph nodes, low-volume metastases represented the largest metastatic deposit in one third of patients, all of which had SLN dissection. All 12 with low-volume metastases had endometrioid histology compared with less than half (46%) of those with macrometastases (P < 0.01). Grade 1 carcinoma was present in 7 (58%) of the patients with low-volume metastases compared with 4 (14%) of those with macrometastases (P < 0.01) Furthermore, significantly more patients with low-volume metastases versus macrometastases had less than 50% myometrial invasion (67% vs 4%, P < 0.001). Low-volume disease was present in one third of patients with nodal metastases, the largest metastatic deposit only in patients who had SLN dissection; these patients were significantly more likely to have grade 1 endometrioid carcinoma with less than 50% myometrial invasion, traditional "low-risk" features.


Exertional heat illness incidence and on-site medical team preparedness in warm weather.
To investigate the influence of estimated wet bulb globe temperature (WBGT) and the International Institute of Race Medicine (IIRM) activity modification guidelines on the incidence of exertional heat stroke (EHS) and heat exhaustion (HEx) and the ability of an on-site medical team to treat those afflicted. Medical records of EHS and HEx patients over a 17-year period from the New Balance Falmouth Road Race were examined. Climatologic data from nearby weather stations were obtained to calculate WBGT with the Australian Bureau of Meteorology (WBGTA) and Liljegren (WBGTL) models. Incidence rate (IR) of EHS, HEx, and combined total of EHS and HEx (COM) were calculated, and linear regression analyses were performed to assess the relationship between IR and WBGTA or WBGTL. One-way ANOVA was performed to compare differences in EHS, HEx, and COM incidence to four alert levels in the IIRM guidelines. Incidence of EHS, HEx, and COM was 2.12, 0.98, and 3.10 cases per 1000 finishers. WBGTA explained 48, 4, and 46% of the variance in EHS, HEx, and COM IR; WBGTL explained 63, 13, and 69% of the variance in EHS, HEx, and COM IR. Main effect of WBGTA and WBGTL on the alert levels were observed in EHS and COM IR (p < 0.05). The cumulative number of EHS patients treated did not exceed the number of cold water immersion tubs available to treat them. EHS IR increased as WBGT and IIRM alert level increased, indicating the need for appropriate risk mitigation strategies and on-site medical treatment.


Ocular findings in Quarter Horses with hereditary equine regional dermal asthenia.
To compare ocular structures of Quarter Horses homozygous for hereditary equine regional dermal asthenia (HERDA) with those of Quarter Horses not affected by HERDA (control horses) and to determine the frequency of new corneal ulcers for horses with and without HERDA during a 4-year period. Cohort study of ocular structures and retrospective case series of horses with and without HERDA. The cohort portion of the study involved 10 Quarter Horses with HERDA and 10 Quarter Horses without HERDA; the retrospective case series involved 28 horses with HERDA and 291 horses without HERDA. Ophthalmic examinations, Schirmer tear tests, tonometry, corneal pachymetry, histologic examinations, and scanning electron microscopy (SEM) were performed in cohorts of Quarter Horses with and without HERDA. Records were reviewed to determine the incidence of corneal ulcers in horses with and without HERDA during a 4-year period. Corneal thickness of horses with HERDA was significantly less than that of control horses, but tear production of horses with HERDA was significantly greater than that of control horses. Results of SEM revealed zones of disorganized, haphazardly arranged collagen fibrils in corneas of horses with HERDA that were not evident in corneas of control horses. The incidence of corneal ulcers was significantly greater for horses with HERDA than for horses without HERDA during the 4-year period. Alterations in corneal thickness, arrangement of collagen fibers, and incidence of corneal ulcers indicated that abnormalities in horses with HERDA were not limited to the skin.


Apps for asthma self-management: a systematic assessment of content and tools.
Apps have been enthusiastically adopted by the general public. They are increasingly recognized by policy-makers as a potential medium for supporting self-management of long-term conditions. We assessed the degree to which current smartphone and tablet apps for people with asthma offer content and tools of appropriate quality to support asthma self-management. We adapted systematic review methodology to the assessment of apps. We identified English-language asthma apps for all ages through a systematic search of official app stores. We systematically assessed app content using criteria derived from international guidelines and systematic review of strategies for asthma self-management. We covered three domains: comprehensiveness of asthma information, consistency of advice with evidence and compliance with health information best practice principles. We identified 103 apps for asthma in English, of which 56 were sources of information about the condition and 47 provided tools for the management of asthma. No apps offered both types of functionality. Only three information apps approached our definition of comprehensiveness of information about asthma. No apps provided advice on lay management of acute asthma that included details of appropriate reliever medication use. In 32 of 72 instances, apps made unequivocal recommendations about strategies for asthma control or prophylaxis that were unsupported by current evidence. Although 90% of apps stated a clear purpose, compliance with other best practice principles for health information was variable. Contact details were located for 55%, funding source for 18% and confidentiality policy for 17%. No apps for people with asthma combined reliable, comprehensive information about the condition with supportive tools for self-management. Healthcare professionals considering recommending apps to patients as part of asthma self-management should exercise caution, recognizing that some apps like calculators may be unsafe; that no current app will meet the need of every patient; and that ways of working must be adapted if apps are to be introduced, supported and sustained in routine care. Policy-makers need to consider the potential role for assurance mechanisms in relation to apps. There remains much to be done if apps are to find broad use in clinical practice; clinicians cannot recommend tools that are inaccurate, unsafe or lack an evidence base.


Two different regimes in alcohol-induced coil-helix transition: effects of 2,2,2-trifluoroethanol on proteins being either independent of or enhanced by solvent structural fluctuations.
Inhomogeneous distribution of constituent molecules in a mixed solvent has been known to give remarkable effects on the solute, e.g., conformational changes of biomolecules in an alcohol-water mixture. We investigated the general effects of 2,2,2-trifluoroethanol (TFE) on proteins/peptides in a mixture of water and TFE using melittin as a model protein. Fluctuations and Kirkwood-Buff integrals (KBIs) in the TFE-H2O mixture, quantitative descriptions of inhomogeneity, were determined by small-angle X-ray scattering investigation and compared with those in the aqueous solutions of other alcohols. The concentration fluctuation for the mixtures ranks as methanol < ethanol ≪ TFE < tert-butanol < 1-propanol, indicating that the inhomogeneity of molecular distribution in the TFE-H2O mixture is unexpectedly comparable to those in the series of mono-ols. On the basis of the concentration dependence of KBIs between the TFE molecules, it was found that a strong attraction between the TFE molecules is not necessarily important to induce helix conformation, which is inconsistent with the previously proposed mechanism. To address this issue, by combining the KBIs and the helix contents reported by the experimental spectroscopic studies, we quantitatively evaluated the change in the preferential binding parameter of TFE to melittin attributed to the coil-helix transition. As a result, we found two different regimes on TFE-induced helix formation. In the dilute concentration region of TFE below ∼2 M, where the TFE molecules are not aggregated among themselves, the excess preferential binding of TFE to the helix occurs due to the direct interaction between them, namely independent of the solvent fluctuation. In the higher concentration region above ∼2 M, in addition to the former effect, the excess preferential binding is significantly enhanced by the solvent fluctuation. This scheme should be held as general cosolvent effects of TFE on proteins/peptides.


Interactions of persistent sodium and calcium-activated nonspecific cationic currents yield dynamically distinct bursting regimes in a model of respiratory neurons.
The preBötzinger complex (preBötC) is a heterogeneous neuronal network within the mammalian brainstem that has been experimentally found to generate robust, synchronous bursts that drive the inspiratory phase of the respiratory rhythm. The persistent sodium (NaP) current is observed in every preBötC neuron, and significant modeling effort has characterized its contribution to square-wave bursting in the preBötC. Recent experimental work demonstrated that neurons within the preBötC are endowed with a calcium-activated nonspecific cationic (CAN) current that is activated by a signaling cascade initiated by glutamate. In a preBötC model, the CAN current was shown to promote robust bursts that experience depolarization block (DB bursts). We consider a self-coupled model neuron, which we represent as a single compartment based on our experimental finding of electrotonic compactness, under variation of g (NaP), the conductance of the NaP current, and g (CAN), the conductance of the CAN current. Varying these two conductances yields a spectrum of activity patterns, including quiescence, tonic activity, square-wave bursting, DB bursting, and a novel mixture of square-wave and DB bursts, which match well with activity that we observe in experimental preparations. We elucidate the mechanisms underlying these dynamics, as well as the transitions between these regimes and the occurrence of bistability, by applying the mathematical tools of bifurcation analysis and slow-fast decomposition. Based on the prevalence of NaP and CAN currents, we expect that the generalizable framework for modeling their interactions that we present may be relevant to the rhythmicity of other brain areas beyond the preBötC as well.


Sinefungin, a natural nucleoside analogue of S-adenosylmethionine, inhibits Streptococcus pneumoniae biofilm growth.
Pneumococcal colonization and disease is often associated with biofilm formation, in which the bacteria exhibit elevated resistance both to antibiotics and to host defense systems, often resulting in infections that are persistent and difficult to treat. We evaluated the effect of sinefungin, a nucleoside analogue of S-adenosylmethionine, on pneumococcal in vitro biofilm formation and in vivo colonization. Sinefungin is bacteriostatic to pneumococci and significantly decreased biofilm growth and inhibited proliferation and structure of actively growing biofilms but did not alter growth or the matrix structure of established biofilms. Sinefungin significantly reduced pneumococcal colonization in rat middle ear. The quorum sensing molecule (autoinducer-2) production was significantly reduced by 92% in sinefungin treated samples. The luxS, pfs, and speE genes were downregulated in biofilms grown in the presence of sinefungin. This study shows that sinefungin inhibits pneumococcal biofilm growth in vitro and colonization in vivo, decreases AI-2 production, and downregulates luxS, pfs, and speE gene expressions. Therefore, the S-adenosylmethionine (SAM) inhibitors could be used as lead compounds for the development of novel antibiofilm agents against pneumococci.


Ubiquitination and regulation of AURKA identifies a hypoxia-independent E3 ligase activity of VHL.
The hypoxia-regulated tumor-suppressor von Hippel-Lindau (VHL) is an E3 ligase that recognizes its substrates as part of an oxygen-dependent prolyl hydroxylase (PHD) reaction, with hypoxia-inducible factor α (HIFα) being its most notable substrate. Here we report that VHL has an equally important function distinct from its hypoxia-regulated activity. We find that Aurora kinase A (AURKA) is a novel, hypoxia-independent target for VHL ubiquitination. In contrast to its hypoxia-regulated activity, VHL mono-, rather than poly-ubiquitinates AURKA, in a PHD-independent reaction targeting AURKA for degradation in quiescent cells, where degradation of AURKA is required to maintain the primary cilium. Tumor-associated variants of VHL differentiate between these two functions, as a pathogenic VHL mutant that retains intrinsic ability to ubiquitinate HIFα is unable to ubiquitinate AURKA. Together, these data identify VHL as an E3 ligase with important cellular functions under both normoxic and hypoxic conditions.


Effects of Interventions Addressing School Environments or Educational Assets on Adolescent Sexual Health: Systematic Review and Meta-analysis.
School-based interventions that aim to modify sexual health knowledge, attitudes and behaviors have mixed and often unsustained effects on adolescent sexual health outcomes. However, observational evidence suggests that broader school-related factors, such as school climate and academic attainment, can influence outcomes. Nine databases were searched in July 2017 for randomized and quasi-experimental evaluations of interventions addressing school-level environment or student-level educational assets, to examine whether such interventions can promote young people's sexual health. Searches were limited to studies published since 1990 but were not restricted by language. Studies were assessed for risk of bias and synthesized narratively and meta-analytically. Searches yielded 11 evaluations, published from 1999 to 2016, of interventions related to school-level environment or student-level educational assets. Because of inconsistent reporting, the risk of bias was not clear for most studies, and meta-analysis was possible for only one outcome. The meta-analysis of three randomized trials provided some evidence that school-environment interventions may delay sexual debut (pooled odds ratio, 0.5). Narrative synthesis of the remaining outcomes found mixed results, but suggests that interventions addressing school-level environment may delay sexual debut and that those addressing student-level educational assets may reduce risk of pregnancy and STDs. Additional and more rigorous evidence is needed to assess the probability that interventions addressing school-related factors are effective and to provide better understanding of the mechanisms by which they may work to improve adolescent sexual health.


Prevention of perioperative hypothermia with forced-air warming systems and upper-body blankets.
Forced-air warming is known as an effective procedure in prevention and treatment of perioperative hypothermia. Hypothermia is associated with disturbances of coagulation, raises postoperative oxygen consumption by shivering, increases cardiac morbidity, leads to a higher incidence of wound infection, and prolongs hospital stay. Additionally, preoperative local warming reduces the incidence of wound infection after clean surgery. In an animal experiment it has been demonstrated that even during large abdominal operations the major source of heat loss was the skin. Although evaporation accounted for the largest heat loss from the abdominal cavity, it was a minor source due to the smaller heat losing area. As a consequence, reduction of heat loss from the skin is the most promising approach to avoid hypothermia. During abdominal surgery and lower-limb surgery, the use of upper blankets is favourable. The use of upper-body blankets implies a reduction of heat loss in a relevant area and, furthermore, a heat gain. The covered area is approximately 0.35 m2, or approximately 15%-20% of body surface. The heat balance in this area can be changed by 46.1W to 55.0W by forced-air warming systems with upper body blankets. Depending on the surgical procedure and resulting fluid demand, forced-air warming with upper-body blankets-in combination with insulation and fluid warming-is an effective method to prevent perioperative hypothermia.


HCV substitutions and IL28B polymorphisms on outcome of peg-interferon plus ribavirin combination therapy.
A number of recent studies have shown that human polymorphisms near the IL28B type III interferon (IFNλ) gene influence the response to peg-interferon plus ribavirin combination therapy for infection with chronic hepatitis C virus (HCV). Viral polymorphisms, including substitutions within the HCV core and NS5A proteins, have also been shown to influence treatment outcome, but it is not known whether these factors act independently of the IL28B polymorphism or if they reflect the same or a different underlying mechanism. Multiple logistic regression was used to determine whether host and viral polymorphisms independently predict sustained virological response (SVR). Two single nucleotide polymorphisms were genotyped in the IL28B locus (rs12979860 and rs8099917) from 817 patients with chronic HCV infection, and substitutions at amino acids 70 and 91 of the HCV core protein and within the NS5A interferon sensitivity-determining region (ISDR) were analysed. It was found that independent predictors of an SVR included IL28B rs12979860 CC genotype (OR=4.98; p=4.00E-08), core amino acid 70 substitutions (OR=0.53; p=0.016), age and baseline viral load. For non-virological response, the IL28B rs12979860 CT/TT genotype (OR=0.23; p=1.96E-8) and age were independent predictors. IL28B rs12979860 genotype (p=1.4E-8), core amino acid 70 substitutions (p=0.0013), ISDR substitutions (p=0.0019), baseline viral load, γ-glutamyltranspeptidase, alanine aminotransferase and platelet count were independent predictors for change in viral load by week 4 of treatment. IL28B polymorphisms and HCV core amino acid 70 substitutions contribute independently to an SVR to peg-interferon plus ribavirin combination therapy.


Transformation of standardized clinical models based on OWL technologies: from CEM to OpenEHR archetypes.
The semantic interoperability of electronic healthcare records (EHRs) systems is a major challenge in the medical informatics area. International initiatives pursue the use of semantically interoperable clinical models, and ontologies have frequently been used in semantic interoperability efforts. The objective of this paper is to propose a generic, ontology-based, flexible approach for supporting the automatic transformation of clinical models, which is illustrated for the transformation of Clinical Element Models (CEMs) into openEHR archetypes. Our transformation method exploits the fact that the information models of the most relevant EHR specifications are available in the Web Ontology Language (OWL). The transformation approach is based on defining mappings between those ontological structures. We propose a way in which CEM entities can be transformed into openEHR by using transformation templates and OWL as common representation formalism. The transformation architecture exploits the reasoning and inferencing capabilities of OWL technologies. We have devised a generic, flexible approach for the transformation of clinical models, implemented for the unidirectional transformation from CEM to openEHR, a series of reusable transformation templates, a proof-of-concept implementation, and a set of openEHR archetypes that validate the methodological approach. We have been able to transform CEM into archetypes in an automatic, flexible, reusable transformation approach that could be extended to other clinical model specifications. We exploit the potential of OWL technologies for supporting the transformation process. We believe that our approach could be useful for international efforts in the area of semantic interoperability of EHR systems.


Serological prevalence of leptospiral infection in wild rats at the National Service Training Centres in Kelantan and Terengganu.
One hundred and sixty eight rats were trapped from the National Service Training Centres (NSTC) in Kelantan and Terengganu from October 2008 to May 2009. Microscopic agglutination test (MAT) was performed to detect the presence of agglutinating antibodies to Leptospira among the rats caught. All the MAT positive rats were identified as Rattus tiomanicus. In Kelantan, 17.3 % (14/81) of the rats had leptospiral antibodies to serovars Icterohaemorrhagiae (12.3%), Canicola (2.5%), Ballum (1.2%), and Pyrogenes (1.2%). In Terengganu, 18.4% (16/87) of the rats had antibodies to serovars Icterohaemorrhagiae (15%), Canicola (1.1%), Pyrogenes (1.1%) and Hebdomadis (1.1%). This study indicated that Leptospira serovars were prevalent in the rat population in the study areas and could be a source of infection to humans. Therefore, control of the rat population in all NSTC is critical to prevent outbreaks of leptospirosis amongst the NSTC trainees.


Quality of life domains affected in children with developmental coordination disorder: a systematic review.
The quality of life (QOL) of children with developmental coordination disorder (DCD) is largely unknown, but evidence suggests that multiple QOL domains are affected by the disorder. While DCD is primarily considered a motor disorder, multiple studies have reported psychological and social concerns in children with this condition. Our primary aim was to present the current state of the evidence regarding the physical, psychological, and social QOL domains that can be affected in children with DCD. Systematic review of articles from seven databases through November 2010 (MEDLINE, EMBASE, CINAHL, PsycINFO, ERIC, CDSR, DARE) was conducted. Search terms included developmental coordination disorder, dyspraxia, quality of life, life satisfaction, well-being, activities of daily living, and participation. Two independent reviewers screened titles, abstracts, and full-text articles. Studies meeting the following criteria were selected: (1) sample comprised solely of individuals with coordination difficulties consistent with DCD; (2) outcome measures related to physical, psychological, or socials domains of QOL; and (3) articles published in English. Data were extracted by one author and verified by a second. Outcomes were categorized according to physical, psychological and social domains of QOL and study quality was rated by case definitions of DCD based on diagnostic criteria as per the Diagnostic and Statistical Manual - 4th edition. Forty-one articles were included. Most studies reported significantly poorer results in physical, psychological and social functioning in children with DCD compared with peers. Despite the impact of DCD on multiple domains, only one study used a QOL measure as an outcome. Although DCD impacts several QOL domains, the QOL of children with this disorder remains largely unknown. The next critical step is for clinicians and researchers to use QOL measures to gather information on how DCD may affect the QOL of children with this disorder.


Enhanced cortical excitability in grapheme-color synesthesia and its modulation.
Synesthesia is an unusual condition characterized by the over-binding of two or more features and the concomitant automatic and conscious experience of atypical, ancillary images or perceptions. Previous research suggests that synesthetes display enhanced modality-specific perceptual processing, but it remains unclear whether enhanced processing contributes to conscious awareness of color photisms. In three experiments, we investigated whether grapheme-color synesthesia is characterized by enhanced cortical excitability in primary visual cortex and the role played by this hyperexcitability in the expression of synesthesia. Using transcranial magnetic stimulation, we show that synesthetes display 3-fold lower phosphene thresholds than controls during stimulation of the primary visual cortex. We next used transcranial direct current stimulation to discriminate between two competing hypotheses of the role of hyperexcitability in the expression of synesthesia. We demonstrate that synesthesia can be selectively augmented with cathodal stimulation and attenuated with anodal stimulation of primary visual cortex. A control task revealed that the effect of the brain stimulation was specific to the experience of synesthesia. These results indicate that hyperexcitability acts as a source of noise in visual cortex that influences the availability of the neuronal signals underlying conscious awareness of synesthetic photisms.


Tools & techniques--statistics: propensity score techniques.
Propensity score (PS) techniques are useful if the number of potential confounding pretreatment variables is large and the number of analysed outcome events is rather small so that conventional multivariable adjustment is hardly feasible. Only pretreatment characteristics should be chosen to derive PS, and only when they are probably associated with outcome. A careful visual inspection of PS will help to identify areas of no or minimal overlap, which suggests residual confounding, and trimming of the data according to the distribution of PS will help to minimise residual confounding. Standardised differences in pretreatment characteristics provide a useful check of the success of the PS technique employed. As with conventional multivariable adjustment, PS techniques cannot account for confounding variables that are not or are only imperfectly measured, and no PS technique is a substitute for an adequately designed randomised trial.


Early start: an integrated model of substance abuse intervention for pregnant women.
Untreated perinatal substance abuse is associated with serious adverse maternal and neonatal outcomes. Historically, many barriers have prevented pregnant women from seeking treatment. Early Start (ES) breaks new ground by sidestepping these barriers with a fully integrated service delivery model.ES is the largest HMO-based prenatal substance-abuse program in the United States targeting all pregnant women seen at Kaiser Permanente Northern California (KPNC) prenatal clinics, currently screening more than 39,000 women each year. The program is based on the premise that substance abuse is a treatable disease and addresses it in a nonjudgmental, accepting manner. A substance-abuse counselor is located in each obstetrics clinic providing accessible one-to-one counseling to pregnant women screened at risk for alcohol, tobacco, or drug use as part of the routine prenatal care package offered to all patients.A 2006 ES study, sponsored by the Kaiser Foundation Research Institute, evaluated program effectiveness in terms of its impact on neonatal and maternal outcomes. Preliminary results that included 49,986 KPNC patients indicate that compared with pregnant women whose results on screening for substance use were positive but who were untreated, ES-treated women had significantly lower rates on a number of outcome measures.The originality and transferability of ES has led to both local and national recognition. Universal screening of all pregnant women with access to an integrated model of substance-abuse treatment should be the standard of care for every prenatal patient because of the significant benefits for mothers and their babies.


Effortful swallowing training coupled with electrical stimulation leads to an increase in hyoid elevation during swallowing.
We tested the effects of surface electrical stimulation on hyoid elevation during swallowing in healthy volunteers. Sixteen people were recruited and randomly divided into two groups. Electrical stimulation was applied to the skin above the infrahyoid muscle in the experimental group. The stimulation current was adjusted until muscle contraction occurred and the hyoid bone became depressed. Participants were asked to swallow forcefully so as to elevate the hyolaryngeal complex when the stimulation began. The same experiment was performed in the control group except the intensity of stimulation was adjusted to just above the sensory threshold. The two groups received ten 20-min treatments over 2 weeks. We recorded the myoelectrical activity of the submental muscles and the amount of hyoid bone movement at three time points (pretreatment, immediately post-treatment, and 2 weeks after treatment). In the experimental group, the amount of y-axis hyoid bone excursion was increased immediately post-treatment, but this effect faded within 2 weeks following the treatment. Myoelectrical activity was not affected by either treatment regimen. We concluded that effortful swallowing coupled with electrical stimulation increases the degree of hyoid elevation in healthy volunteers. It needs to be evaluated for its long-term effectiveness in increasing the elevation of hyolaryngeal complex.


Frequency and Distribution of Refractive Error in Adult Life: Methodology and Findings of the UK Biobank Study.
To report the methodology and findings of a large scale investigation of burden and distribution of refractive error, from a contemporary and ethnically diverse study of health and disease in adults, in the UK. U K Biobank, a unique contemporary resource for the study of health and disease, recruited more than half a million people aged 40-69 years. A subsample of 107,452 subjects undertook an enhanced ophthalmic examination which provided autorefraction data (a measure of refractive error). Refractive error status was categorised using the mean spherical equivalent refraction measure. Information on socio-demographic factors (age, gender, ethnicity, educational qualifications and accommodation tenure) was reported at the time of recruitment by questionnaire and face-to-face interview. Fifty four percent of participants aged 40-69 years had refractive error. Specifically 27% had myopia (4% high myopia), which was more common amongst younger people, those of higher socio-economic status, higher educational attainment, or of White or Chinese ethnicity. The frequency of hypermetropia increased with age (7% at 40-44 years increasing to 46% at 65-69 years), was higher in women and its severity was associated with ethnicity (moderate or high hypermetropia at least 30% less likely in non-White ethnic groups compared to White). Refractive error is a significant public health issue for the UK and this study provides contemporary data on adults for planning services, health economic modelling and monitoring of secular trends. Further investigation of risk factors is necessary to inform strategies for prevention. There is scope to do this through the planned longitudinal extension of the UK Biobank study.


Characterization of intracytoplasmic prokaryote infections in Dreissena sp. (Bivalvia: Dreissenidae).
This study characterizes intracytoplasmic infections with prokaryote microorganisms in Dreissena sp. (near Dreissena polymorpha) from northeastern Greece and represents the first report of such infections in freshwater bivalves. Light microscope observations of stained tissues revealed basophilic, cytoplasmic inclusion bodies in 87.5% (28/32) of the mussels sectioned. Inclusions in epithelial cells and connective tissues were noted, respectively, in 34.4 and 71.9% of the sample, with 5 mussels (15.6%) having both tissue types infected. Epithelial cell infections were observed in histological sections only in digestive gland tubules and ducts; within tubules, inclusions were present more often in secretory than digestive cells. Connective tissue infections, however, were systemic; among the 32 mussels sectioned, inclusions were found in the gills (65.6%), foot (12.5%), mantle (9.4%), labial palps (6.3%), digestive gland (6.3%), stomach (6.3%), and gonads (3.1%). Cytoplasmic inclusions (maximum dimension, 138 microm) were prominent enough in the gills to be visible in 17.0% of the 247 mussels dissected. Ultrastructurally, prokaryote cells in gill connective tissues were clearly characteristic of Chlamydiales-like organisms, with each intracytoplasmic inclusion containing a loosely packed mixture of elementary, reticulate, intermediate bodies, and blebs. Prokaryote colonies in digestive gland epithelial cells exclusively contained 1 of 4 morphological cell types and were considered Rickettsiales-like. Hexagonal, virus-like particles were present in the cytoplasm of the largest of these Rickettsiales-like prokaryotes. Although host stress was evident from localized cell necrosis and dense hemocyte infiltration, overall infection was fairly benign, with no major, adverse impact on body condition evident among sectioned or dissected mussels. A possible negative effect was partial constriction of gill water tubes, but at the infection intensity observed (typical range 1 to 7 inclusion bodies per section), significant interference with respiration and other metabolic functions of the gills was highly unlikely.


Discussing measurement-based care with patients: An analysis of clinician-patient dyads.
Abstract Measurement-based care (MBC) refers to the use of three integrated strategies to improve effectiveness of behavioral health care: routine outcomes monitoring using symptom measures; regularly sharing these data with patients; and using these data to inform treatment decisions. This study examined how clinicians discuss MBC data with patients, including identifying what aspects of these discussions contribute to clinician-patient agreement on the value of MBC, and how clinicians use MBC data to inform treatment decisions. Twenty-six clinician-patient dyads participated in semi-structured interviews and provided a treatment session recording in which MBC data were discussed. Qualitative data analyses revealed four subtypes of dyads: clinician and patient both valued MBC; clinician valued MBC, patient passively participated in MBC; clinician valued MBC, patient had mixed perceptions of MBC; clinician and patient reported moderate or low value for MBC. In dyads for whom both the clinician and patient valued MBC, the clinician provided clear and repeated rationale for MBC, discussed data with patients at every administration, and connected observed scores to patient skills or strategies. Emerging best practices for discussing MBC include providing a strong rationale, discussing results frequently, actively engaging patients in discussions, and using graphs to visualize progress.


Organic solvents and MS susceptibility: Interaction with MS risk HLA genes.
We hypothesize that different sources of lung irritation may contribute to elicit an immune reaction in the lungs and subsequently lead to multiple sclerosis (MS) in people with a genetic susceptibility to the disease. We aimed to investigate the influence of exposure to organic solvents on MS risk, and a potential interaction between organic solvents and MS risk human leukocyte antigen (HLA) genes. Using a Swedish population-based case-control study (2,042 incident cases of MS and 2,947 controls), participants with different genotypes, smoking habits, and exposures to organic solvents were compared regarding occurrence of MS, by calculating odds ratios with 95% confidence intervals using logistic regression. A potential interaction between exposure to organic solvents and MS risk HLA genes was evaluated by calculating the attributable proportion due to interaction. Overall, exposure to organic solvents increased the risk of MS (odds ratio 1.5, 95% confidence interval 1.2-1.8, p = 0.0004). Among both ever and never smokers, an interaction between organic solvents, carriage of HLA-DRB1*15, and absence of HLA-A*02 was observed with regard to MS risk, similar to the previously reported gene-environment interaction involving the same MS risk HLA genes and smoke exposure. The mechanism linking both smoking and exposure to organic solvents to MS risk may involve lung inflammation with a proinflammatory profile. Their interaction with MS risk HLA genes argues for an action of these environmental factors on adaptive immunity, perhaps through activation of autoaggressive cells resident in the lungs subsequently attacking the CNS.


Cyclic arginine-glycine-aspartate attenuates acute lung injury in mice after intestinal ischemia/reperfusion.
Intestinal ischemia is a critical problem resulting in multiple organ failure and high mortality of 60 to 80%. Acute lung injury (ALI) is a common complication after intestinal ischemia/reperfusion (I/R) injuries and contributes to the high mortality rate. Moreover, activated neutrophil infiltration into the lungs is known to play a significant role in the progression of ALI. Integrin-mediated interaction is involved in neutrophil transmigration. Synthetic peptides containing an arginine-glycine-aspartate sequence compete with adhesive proteins and inhibit integrin-mediated interaction and signaling. Thus, we hypothesized that the administration of a cyclic arginine-glycine-aspartate peptide (cRGD) inhibited neutrophil infiltration and provided protection against ALI induced by intestinal I/R. Ischemia in adult male C57BL/6 mice was induced by fastening the superior mesenteric artery with 4-0 suture. Forty-five minutes later, the vascular suture was released to allow reperfusion. cRGD (5 mg/kg body weight) or normal saline (vehicle) was administered by intraperitoneal injection 1 hour prior to ischemia. Blood, gut, and lung tissues were collected 4 hours after reperfusion for various measurements. Intestinal I/R caused severe widespread injury to the gut and lungs. Treatment with cRGD improved the integrity of microscopic structures in the gut and lungs, as judged by histological examination. Intestinal I/R induced the expression of β₁, β₂ and β₃ integrins, intercellular adhesion molecule-1, and fibronectin. cRGD significantly inhibited myeloperoxidase activity in the gut and lungs, as well as neutrophils and macrophages infiltrating the lungs. cRGD reduced the levels of TNF-α and IL-6 in serum, in addition to IL-6 and macrophage inflammatory protein-2 in the gut and lungs. Furthermore, the number of TUNEL-staining cells and levels of cleaved caspase-3 in the lungs were significantly lowered in the cRGD-treated mice in comparison with the vehicle mice. Treatment with cRGD effectively protected ALI and gut injury, lowered neutrophil infiltration, suppressed inflammation, and inhibited lung apoptosis after intestinal I/R. Thus, there is potential for developing cRGD as a treatment for patients suffering from ALI caused by intestinal I/R.


High-order nodal discontinuous Galerkin methods for the Maxwell eigenvalue problem.
The Maxwell eigenvalue problem is known to pose difficulties for standard numerical methods, predominantly due to its large null space. As an alternative to the widespread use of Galerkin finite-element methods based on curl-conforming elements, we propose to use high-order nodal elements in a discontinuous element scheme. We consider both two- and three-dimensional problems and show the former to be without problems in a wide range of cases. Numerical experiments suggest the validity of this for general problems. For the three-dimensional eigenproblem, we encounter difficulties with a naive formulation of the scheme and propose minor modifications, intimately related to the discontinuous nature of the formulation, to overcome these concerns. We conclude by connecting the findings to time domain solution of Maxwell's equations. The discussion, analysis, and numerous computational experiments suggest that using discontinuous element schemes for solving Maxwell's equation in the frequency- or time-domain present a high-order accurate, efficient and robust alternative to classical Galerkin finite-element methods.