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The adsorption capacity of uncalcined and calcined layered double hydroxide (LDH) for fluoride removal was studied in this work. The LDH was synthesized by a co-precipitation method and calcined at various temperatures. The equilibrium data for fluoride adsorption on the LDHs were obtained in a batch adsorber, and the Freundlich isotherm model showed a better fit to the data. The LDH was chemically stable over the pH range of 5–12, but readily dissolved when the pH was below 5. The fluoride adsorption capacity of LDH decreased by raising the pH due to electrostatic interactions, and presented a maximum at 25 °C. The adsorption capacity of LDH was influenced by the calcination temperature and was enhanced by increasing the calcination temperature. The calcination destroyed the crystalline structure of the LDH, which was recovered when the calcined LDH was rehydrated in aqueous solution. The calcined LDH had a very high adsorption capacity towards fluoride.

The paper analyses extremum-seeking control technique for maximum power point tracking circuits in PV systems. Specifically, the paper describes and analyses the sinusoidal extremum-seeking control considering stability issues by means a Lyapunov function. Based on this technique, a new architecture of MPPT for PV generation is proposed. In order to assess the proposed solution, the paper provides some experimental measurements in a 100 W prototype which corroborate the effectiveness of the approach.

The adsorption capacity of sepiolite towards the removal of heavy metal ions from aqueous solution was studied in this work, with adsorption equilibrium data being obtained with a bath adsorber. The sepiolite sample was chemically stable over the pH range 2–12, but dissolved in acidic solutions with pH values less than 2. The Langmuir isotherm gave a better fit of the experimental adsorption equilibrium data, since the average absolute percentage deviation of the Langmuir isotherm was lower than that of the Freundlich isotherm. The adsorption capacity of sepiolite towards metal ions decreased in the following order: Cr(III) > Cd(II) > Cu(II) > Zn(II) > Ni(II) > Ag(I). Increasing the temperature from 15 °C to 35 °C led to an increase in the adsorption capacity. The capacity of sepiolite towards the adsorption of Cd(II) ions was diminished considerably on reducing the solution pH from 7 to 3. The effect of the solution pH was attributed to electrostatic interaction between the negatively charged sepiolite surface and the positively charged Cd(II) ions in the aqueous solution. The surface charge of sepiolite became less negative when Cd(II) ions were adsorbed onto the sepiolite surface. This result indicates that electrostatic interaction between the sepiolite surface and the Cd(II) ions in the aqueous solution played a very important role in determining the adsorption capacity of sepiolite. The adsorption of Cd(II) ions onto sepiolite at pH 7 was reversible when desorption was undertaken at pH 3, but not when desorption was undertaken at pH 7.

The adsorption rate of 1-naphthalenesulphonic (NS), 1,5-naphthalenedisulphonic (NDS) and 1,3,6-naphthalenetrisulphonic (NTS) acids onto activated carbon (AC) was studied in this work. In addition, the effect of oxidizing the AC with ozone on the rate of adsorption was investigated. The adsorption equilibrium data as well as the concentration decay data for the naphthalenesulphonic acids (NSAs) were obtained in a batch adsorber. The Freundlich, Langmuir and Prausnitz–Radke isotherms were fitted to the experimental adsorption equilibrium data when it was found that the Prausnitz–Radke isotherm gave the best fit. The experimental concentration decay data were interpreted via a diffusional model which considered the adsorption rate at a surface site, external mass transport and intraparticle diffusion. The results revealed that intraparticle diffusion was the controlling mechanism in the diffusional model and that this model predicted the experimental data satisfactorily. The effective diffusion coefficients of the NSAs could be estimated using the tortuosity factor equation together with tortuosity factors for the ACs ranging from 3.7 to 5.5.

The effects of solvent, particle size and temperature on the adsorption isotherm for phenol on to activated carbon were investigated in this work. The first two effects were studied by determining the adsorption isotherm at 298 K in both aqueous and cyclohexane solutions, and using particle diameters of 0.338, 0.635, 0.940 and 1.494 mm. The last effect was analyzed by measuring the adsorption isotherm at temperatures of 283 K, 298 K and 313 K in both solvents, and using a particle diameter of 0.940 mm. It was found that in the aqueous solution the amount of phenol adsorbed is greater than that in the cyclohexane solution, which was attributed to the fact that phenol has a higher affinity for cyclohexane than for water. Furthermore, the results revealed that in aqueous solution the amount of phenol adsorbed increased when the particle size decreased and was slightly reduced by an increase in the temperature; however, in cyclohexane solution, the amount of phenol adsorbed was independent of particle size and considerably reduced by increasing temperature.

Brown seaweeds are keystone species of coastal ecosystems, often forming extensive underwater forests, and are under considerable threat from climate change. In this study, analysis of multiple genomes has provided insights across the entire evolutionary history of this lineage, from initial emergence, through later diversification of the brown algal orders, down to microevolutionary events at the genus level. Emergence of the brown algal lineage was associated with a marked gain of new orthologous gene families, enhanced protein domain rearrangement, increased horizontal gene transfer events, and the acquisition of novel signaling molecules and key metabolic pathways, the latter notably related to biosynthesis of the alginate-based extracellular matrix, and halogen and phlorotannin biosynthesis. We show that brown algal genome diversification is tightly linked to phenotypic divergence, including changes in life cycle strategy and zoid flagellar structure. The study also showed that integration of large viral genomes has had a significant impact on brown algal genome content throughout the emergence of the lineage., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: To assess the safety and effectiveness of peripheral vasoactive drugs initiated during pre-hospital care and retrieval missions, in Queensland, Australia., Methods: Three years of retrospective data was gathered from two sources. Medical notes were reviewed using a search for any patient having 'inotrope' recorded on an electronic medical record. Each case was reviewed to include only peripheral infusions of adrenaline or noradrenaline. Clinical Governance records were searched for adverse events related to vasoactive drugs, alerted for review to ensure complete capture., Results: A total of 418 patients received peripheral infusions of adrenaline and noradrenaline over the 3-year period. No major complications were recorded either immediately or at Clinical Governance review. Minor complications were recorded in 4.7% of the cases, of which 3.5% occurred with peripheral vasoactives during the presence of the retrieval team. The frequency of use of peripheral vasoactives increased over the study period., Conclusions: In this retrospective data set there were no major complications of peripheral vasoactive drugs. Minor complications were similar to in-hospital use and related to vascular access and drug delivery., (© 2024 Australasian College for Emergency Medicine.)

We sought to better understand how intestinal microbiota confer protection against Clostridioides difficile ( C. difficile ) infection (CDI). We utilized gnotobiotic altered Schaedler flora (ASF) mice, which lack the abnormalities of germfree (GF) mice as well as the complexity and heterogeneity of antibiotic-treated mice. Like GF mice, ASF mice were highly prone to rapid lethal CDI, without antibiotics, while very low infectious doses resulted in chronic CDI. Administering such chronic CDI mice an undefined preparation of Clostridia lowered C. difficile levels by several logs. Importantly, such resolution of CDI was associated with colonization of Lachnospiraceae. Fractionation of the Clostridia population to enrich for Lachnospiraceae led to the appreciation that its CDI-impeding property strongly associated with a specific Lachnospiraceae strain, namely uncultured bacteria and archaea (UBA) 3401. UBA3401 was recalcitrant to being propagated as a pure culture but could be maintained in ASF mice, wherein it comprised up to about 50% of the intestinal microbiota, which was sufficient to generate a high-quality genomic sequence of this bacterium. Sequence analysis and ex vivo study of UBA3401 indicated that it had the ability to secrete substance(s) that directly impeded C. difficile growth. Moreover, in vivo administration of UBA3401/ASF feces provided strong protection to C. difficile challenge. Thus, UBA3401 may contribute to and/or provide a means to study microbiota-mediated CDI resistance.

Background and Objectives: Standard pediatric growth curves cannot be used to impute missing height or weight measurements in individual children. The Michaelis-Menten equation, used for characterizing substrate-enzyme saturation curves, has been shown to model growth in many organisms including nonhuman vertebrates. We investigated this equation could be used to interpolate missing growth data in children in the first three years of life., Methods: We developed a modified Michaelis-Menten equation and compared expected to actual growth, first in a local birth cohort (N=97) then in a large, outpatient, pediatric sample (N=14,695)., Results: The modified Michaelis-Menten equation showed excellent fit for both infant weight (median RMSE: boys: 0.22kg [IQR:0.19; 90%<0.43]; girls: 0.20kg [IQR:0.17; 90%<0.39]) and height (median RMSE: boys: 0.93cm [IQR:0.53; 90%<1.0]; girls: 0.91cm [IQR:0.50;90%<1.0]). Growth data were modeled accurately with as few as four values from routine well-baby visits in year 1 and seven values in years 1-3; birth weight or length was essential for best fit., Conclusions: A modified Michaelis-Menten equation accurately describes growth in healthy babies aged 0-36 months, allowing interpolation of missing weight and height values in individual longitudinal measurement series. The growth pattern in healthy babies in resource-rich environments mirrors an enzymatic saturation curve., Competing Interests: Conflict of interest disclosures: The authors have no conflicts of interest relevant to this article to disclose.

Background & Aims: Fiber-rich foods promote health, but mechanisms by which they do so remain poorly defined. Screening fiber types, in mice, revealed psyllium had unique ability to ameliorate 2 chronic inflammatory states, namely, metabolic syndrome and colitis. We sought to determine the mechanism of action of the latter., Methods: Mice were fed grain-based chow, which is naturally rich in fiber or compositionally defined diets enriched with semi-purified fibers. Mice were studied basally and in models of chemical-induced and T-cell transfer colitis., Results: Relative to all diets tested, mice consuming psyllium-enriched compositionally defined diets were markedly protected against both dextran sulfate sodium- and T-cell transfer-induced colitis, as revealed by clinical-type, histopathologic, morphologic, and immunologic parameters. Such protection associated with stark basal changes in the gut microbiome but was independent of fermentation and, moreover, maintained in mice harboring a minimal microbiota (ie, Altered Schaedler Flora). Transcriptomic analysis revealed psyllium induced expression of genes mediating bile acids (BA) secretion, suggesting that psyllium's known ability to bind BA might contribute to its ability to prevent colitis. As expected, psyllium resulted in elevated level of fecal BA, reflecting their removal from enterohepatic circulation but, in stark contrast to the BA sequestrant cholestyramine, increased serum BA levels. Moreover, the use of BA mimetics that activate the farnesoid X receptor (FXR), as well as the use of FXR-knockout mice, suggested that activation of FXR plays a central role in psyllium's protection against colitis., Conclusions: Psyllium protects against colitis via altering BA metabolism resulting in activation of FXR, which suppresses pro-inflammatory signaling., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

The gut microbiota plays an integral role in human health and its dysbiosis is associated with many chronic diseases. There are still large gaps in understanding the host and environmental factors that directly regulate the gut microbiota, and few effective strategies exist to modulate the microbiota in therapeutic applications. Recent reports suggest that certain microRNAs (miRNAs) released by mammalian cells can regulate bacterial gene expression to influence the microbiome composition and propose extracellular vesicles as one natural mechanism for miRNA transport in the gut. These new findings interface with a burgeoning body of data showing that miRNAs are present in a stable form in extracellular environments and can mediate cell-to-cell communication in mammals. Here, we review the literature on RNA-mediated modulation of the microbiome to bring cross-disciplinary perspective to this new type of interaction and its potential implications in biology and medicine., Competing Interests: None declared., (© The Author(s) 2021. Published by Oxford University Press on behalf of FEMS.)

Introduction: Statutory duty of candour was introduced in November 2014 for NHS bodies in England. Contained within the regulation were definitions regarding the threshold for what constitutes a notifiable patient safety incident. However, it can be difficult to determine when the process should be implemented. The aim of this survey was to evaluate the interpretation of these definitions by British neurosurgeons., Materials and Methods: All full (consultant) members of the Society of British Neurological Surgeons were electronically invited to participate in an online survey. Surgeons were presented with 15 cases and asked to decide in the case of each one whether they would trigger the process of duty of candour. Cases were stratified according to their likelihood and severity., Results: In all, 106/357 (29.7%) members participated in the survey. Responses varied widely, with almost no members triggering the process of duty of candour in cases where adverse events were common (greater than 10% likelihood) and required only outpatient follow-up (7/106; 6.6%), and almost all members doing so in cases where adverse events were rare (less than 0.1% likelihood) and resulted in death (102/106; 96.2%). However, there was clear equipoise in triggering the process of duty of candour in cases where adverse events were uncommon (0.1-10% likelihood) and resulted in moderate harm (38/106; 35.8%), severe harm (57/106; 53.8%) or death (49/106; 46.2%)., Conclusion: There is considerable nationwide variation in the interpretation of definitions regarding the threshold for duty of candour. To this end, we propose a framework for the improved application of duty of candour in clinical practice.

Strain in InGaN/GaN multiple-quantum well (MQW) light emitters was relaxed via nanopatterning using colloidal lithography and top-down plasma etching. Colloidal lithography was performed using Langmuir-Blodgett dip-coating of samples with silica particles (d = 170, 310, 690, 960 nm) and a Cl 2 /N 2 inductively coupled plasma etch to produce nanorod structures. The InGaN/GaN MQW nanorods were characterized using X-ray diffraction (XRD) reciprocal space mapping to quantify the degree of relaxation. A peak relaxation of 32% was achieved for the smallest diameter features tested (120 nm after etching). Power-dependent photoluminescence at 13 K showed blue-shifted quantum well emission upon relaxation, which is attributed to reduction of the inherent piezoelectric field in the III-nitrides. Poisson-Schrödinger simulations of single well structures also predicted increasing spectral blueshift with strain relaxation, in agreement with experiments.

Optoelectronic effects of sidewall passivation on micro-sized light-emitting diodes (µLEDs) using atomic-layer deposition (ALD) were investigated. Moreover, significant enhancements of the optical and electrical effects by using ALD were compared with conventional sidewall passivation method, namely plasma-enhanced chemical vapor deposition (PECVD). ALD yielded uniform light emission and the lowest amount of leakage current for all µLED sizes. The importance of sidewall passivation was also demonstrated by comparing leakage current and external quantum efficiency (EQE). The peak EQEs of 20 × 20 µm 2 µLEDs with ALD sidewall passivation and without sidewall passivation were 33% and 24%, respectively. The results from ALD sidewall passivation revealed that the size-dependent influences on peak EQE can be minimized by proper sidewall treatment.

Introduction: The SICOT Conference Committee continually tries to improve the quality of presentations at their annual international meetings. However to the author's best knowledge, no previous study has been undertaken to determine abstract quality. This study aimed to determine the five-year publication rate of presentations made at the 2009 SICOT Annual International Conference (AIC), recognise predictors of full-text publication, identify inconsistencies between presentations and publications, and determine presentation-publication delay., Methods: We retrieved all 329 oral presentation abstracts from the 2009 SICOT Conference, recorded fundamental study details and conducted a comprehensive, electronic search of Medline and PubMed to determine publication status. For subsequent publications, we examined for inconsistencies between presentation abstracts and full-text publications, whether there were retrospectively identifiable publication predictors and calculated presentation-publication delay., Results: The five-year publication rate for all presentations was 31.3%, for oral presentations. The average presentation-publication delay was 23.4 months. Observational studies were the most commonly published studies. Publications most commonly resulted from studies related to hip and knee subspecialties., Conclusion: Our study shows that almost one third of all abstracts presented at SICOT led to a full-text publication. This is a positive outcome particularly when made in comparison to similar studies of other reputable international conferences such as European Federation of Orthopaedics and Traumatology (EFORT) and American Academy of Orthopaedic Surgeons (AAOS). This study re-enforces SICOT's reputation as a world leading international conference with a strict peer-review process yielding high-quality presentations., (© The Authors, published by EDP Sciences, 2017.)

Conventional catheter-based systems used for ambulatory esophageal pH monitoring have been reported to affect patient behavior. As physical activity has been associated with gastroesophageal reflux disease (GERD), there is a risk that abnormal behavior will degrade the value of this diagnostic investigation and consequent management strategies. The aim of this study was to quantify the effect of conventional pH monitoring on behavior and to investigate the temporal association between activity and reflux. A total of 20 patients listed for 24 hours pH monitoring underwent activity monitoring using a lightweight ear-worn accelerometer (e-AR sensor, Imperial College London) 2 days prior to, and during their investigation. PH was measured and recorded using a conventional nasogastric catheter and waist-worn receiver. Daily activity levels, including subject-specific activity intensity quartiles, were calculated and compared. Physical activity was added to the standard pH output to supplement interpretation. Average patient activity levels decreased by 26.5% during pH monitoring (range -4.5 to 51.0%, P = 0.036). High-intensity activity decreased by 24.4% (range -4.0 to 75.6%, P = 0.036), and restful activity increased on average by 34% although this failed to reach statistical significance (-24.0 to 289.2%, P = 0.161). Some patients exhibited consistent associations between bouts of activity and acidic episodes. The results of this study support the previously reported reduction in activity during ambulatory esophageal pH monitoring, with the added reliability of objective data. In the absence of more pervasive pH monitoring systems (e.g. wireless), quantifying activity changes in the setting of activity-induced reflux might guide the physicians' interpretation of patient DeMeester scores resulting in more appropriate management of GERD., (© 2015 International Society for Diseases of the Esophagus.)

Plants and animals each have evolved specialized organs dedicated to nutrient acquisition, and these harbor specific bacterial communities that extend the host's metabolic repertoire. Similar forces driving microbial community establishment in the gut and plant roots include diet/soil-type, host genotype, and immune system as well as microbe-microbe interactions. Here we show that there is no overlap of abundant bacterial taxa between the microbiotas of the mammalian gut and plant roots, whereas taxa overlap does exist between fish gut and plant root communities. A comparison of root and gut microbiota composition in multiple host species belonging to the same evolutionary lineage reveals host phylogenetic signals in both eukaryotic kingdoms. The reasons underlying striking differences in microbiota composition in independently evolved, yet functionally related, organs in plants and animals remain unclear but might include differences in start inoculum and niche-specific factors such as oxygen levels, temperature, pH, and organic carbon availability., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Aim: To investigate whether dysplastic Barrett's Oesophagus can be safely and effectively treated endoscopically in low volume centres after structured training., Methods: After attending a structured training program in Amsterdam on the endoscopic treatment of dysplastic Barrett's Oesophagus, treatment of these patients was initiated at St Marys Hospital. This is a retrospective case series conducted at a United Kingdom teaching Hospital, of patients referred for endoscopic treatment of Barrett's oesophagus with high grade dysplasia or early cancer, who were diagnosed between January 2008 and February 2012. Data was collected on treatment provided (radiofrequency ablation and endoscopic resection), and success of treatment both at the end of treatment and at follow up. Rates of immediate and long term complications were assessed., Results: Thirty-two patients were referred to St Marys with high grade dysplasia or intramucosal cancer within a segment of Barrett's Oesophagus. Twenty-seven met the study inclusion criteria, 16 of these had a visible nodule at initial endoscopy. Treatment was given over a median of 5 mo, and patients received a median of 3 treatment sessions over this time. At the end of treatment dysplasia was successfully eradicated in 96% and intestinal metaplasia in 88%, on per protocol analysis. Patients were followed up for a median of 18 mo. At which time complete eradication of dysplasia was maintained in 86%. Complications were rare: 2 patients suffered from post-procedural bleeding, 4 cases were complicated by oesophageal stenosis. Recurrence of cancer was seen in 1 case., Conclusion: With structured training good outcomes can be achieved in low volume centres treating dysplastic Barrett's Oesophagus.

Under conventional conditions, mice deficient in core 1-derived O-glycans (TM-IEC C1galt1(-/-)), which have a defective mucus layer, experienced spontaneous inflammation of the colon. Analysis of fecal bacterial populations by pyrosequencing of 16S rRNA gene showed that disease in conventional TM-IEC C1galt1(-/-) was associated with shifts in the microbiota manifested by increases in Lactobacillus and Clostridium species, and decreases in unclassified Ruminococcaceae and Lachnospiraceae. Under germ-free (GF) conditions, TM-IEC C1galt1(-/-) presented decreased goblet cells, but did not develop inflammation. Monoassociation of GF TM-IEC C1galt1(-/-) revealed that bacterial species differ significantly in their ability to induce inflammatory changes. Bacteroides thetaiotaomicron caused inflammation, while Lactobacillus johnsonii (enriched during colitis) did not. These observations demonstrate that not all microbiota shifts that correlate with disease contribute to pathogenesis.

Recent advances in our understanding of the community structure and function of the human microbiome have implications for the potential role of probiotics and prebiotics in promoting human health. A group of experts recently met to review the latest advances in microbiota/microbiome research and discuss the implications for development of probiotics and prebiotics, primarily as they relate to effects mediated via the intestine. The goals of the meeting were to share recent advances in research on the microbiota, microbiome, probiotics, and prebiotics, and to discuss these findings in the contexts of regulatory barriers, evolving healthcare environments, and potential effects on a variety of health topics, including the development of obesity and diabetes; the long-term consequences of exposure to antibiotics early in life to the gastrointestinal (GI) microbiota; lactose intolerance; and the relationship between the GI microbiota and the central nervous system, with implications for depression, cognition, satiety, and mental health for people living in developed and developing countries. This report provides an overview of these discussions., (© 2013 The Authors. Annals of the New York Academy of Sciences published by Wiley Periodicals, Inc. on behalf of New York Academy of Sciences.)

The mammalian intestine is home to ~100 trillion bacteria that perform important metabolic functions for their hosts. The proximity of vast numbers of bacteria to host intestinal tissues raises the question of how symbiotic host-bacterial relationships are maintained without eliciting potentially harmful immune responses. Here, we show that RegIIIγ, a secreted antibacterial lectin, is essential for maintaining a ~50-micrometer zone that physically separates the microbiota from the small intestinal epithelial surface. Loss of host-bacterial segregation in RegIIIγ(-/-) mice was coupled to increased bacterial colonization of the intestinal epithelial surface and enhanced activation of intestinal adaptive immune responses by the microbiota. Together, our findings reveal that RegIIIγ is a fundamental immune mechanism that promotes host-bacterial mutualism by regulating the spatial relationships between microbiota and host.

To what extent do host genetics control the composition of the gut microbiome? Studies comparing the gut microbiota in human twins and across inbred mouse lines have yielded inconsistent answers to this question. However, candidate gene approaches, in which one gene is deleted or added to a model host organism, show that a single host gene can have a tremendous effect on the diversity and population structure of the gut microbiota. Now, quantitative genetics is emerging as a highly promising approach that can be used to better understand the overall architecture of host genetic influence on the microbiota, and to discover additional host genes controlling microbial diversity in the gut. In this Review, we describe how host genetics and the environment shape the microbiota, and how these three factors may interact in the context of chronic disease.

The human gastrointestinal tract is divided into sections, allowing digestion and nutrient absorption in the proximal region to be separate from the vast microbial populations in the large intestine, thereby reducing conflict between host and microbes. In the distinct habitats of the gut, environmental filtering and competitive exclusion between microbes are the driving factors shaping microbial diversity, and stochastic factors during colonization history and in situ evolution are likely to introduce intersubject variability. Adaptive strategies of microbes with different niches are genomically encoded: Specialists have smaller genomes than generalists, and microbes with environmental reservoirs have large accessory genomes. A shift toward a Neolithic diet increased loads of simple carbohydrates and selected for their increased breakdown and absorption in the small intestine. Humans who outcompeted microbes for the new substrates obtained more energy from their diets and prospered, an evolutionary process reflected in modern population genetics. The three-way interactions between human genetics, diet, and the microbiota fundamentally shaped modern populations and continue to affect health globally.

This report details the outcome the first meeting of the Earth Microbiome Project to discuss sample selection and acquisition. The meeting, held at the Argonne National Laboratory on Wednesday October 6(th) 2010, focused on discussion of how to prioritize environmental samples for sequencing and metagenomic analysis as part of the global effort of the EMP to systematically determine the functional and phylogenetic diversity of microbial communities across the world.

Momentary reductions in the electrical activity of working muscles (EMG gaps) contribute to the explanation for the relationship between psychosocial stress and musculoskeletal problems in computer work. EMG activity and gaps in the left and right trapezii were monitored in 23 participants under low and high mental workload (LMW and HMW) demands during computer data entry. Increases in EMG activity and decreases in EMG-gap frequencies in both left and right trapezius muscles were greater during HMW than LMW. In addition, heart period and end-tidal CO2 were lower during HMW, whereas self-reported mood states were higher during HMW. The correspondence between lower end-tidal CO2 and lower EMG-gap frequencies suggests that hyperventilation (overbreathing) may mediate trapezius muscle activation. The reduction of EMG gaps suggests that the salutary benefits of momentary rest from musculoskeletal work are diminished during mental stress.

Polyarthralgia is a common problem with a wide range of differential diagnoses. Clinical assessment is the most important factor in making a diagnosis. History and examination should help to differentiate mechanical from inflammatory disorders, and investigations play a small role. Early intervention, regardless of aetiology, is the key to successful management. Treatment is likely to be a combination of lifestyle modification, physical therapy and medication, and this combined approach is most likely to negate the disability and chronic ill-health traditionally seen in patients with polyarthralgia.

The BH3-only protein, Bim, exists as three splice variants (Bim(S), Bim(L), and Bim(EL)) of differing pro-apoptotic potency. Bim(EL), the least effective killer, is degraded by the proteasome in response to phosphorylation by extracellular signal-regulated kinases 1 and 2 (ERK1/2). ERK1/2-dependent phosphorylation correlates with the presence of a domain unique to the Bim(EL) splice variant that includes the major ERK1/2 phosphorylation site Ser(65). However, efficient phosphorylation by ERK1/2, c-Jun N-terminal kinase, or p38 requires the presence in the substrate of a discrete kinase-docking domain as well as the phosphoacceptor site. Here we show that the region unique to Bim(EL) (amino acids 41-97) harbors two potential DEF-type ERK1/2 kinase-docking domains, DEF1 and DEF2. Peptide competition assays revealed that the DEF2 peptide could act autonomously to bind active ERK1/2, whereas the DEF1 peptide did not. Truncation analysis identified a minimal region, residues 80-97, containing the DEF2 motif as sufficient for ERK1/2 binding. Mutation of key residues in the DEF2 motif abolished the interaction of ERK1/2 and Bim(EL) and also abolished ERK1/2-dependent phosphorylation of Bim(EL) in vivo, thereby stabilizing the protein and enhancing cytotoxicity. Our results identify a new physiologically relevant functional motif in Bim(EL) that may account for the distinct biological properties of this splice variant.

This article discusses the hyperventilation theory (HVT) of panic attacks (PAs) proposed by R. Ley in the context of criticisms raised by W. T. Roth, F. H. Wilhelm, and D. Pettit. Their interpretation of HVT is flawed by misunderstanding, misinterpretation, and oversimplification of the complex psychophysiological principles on which current HVT is based. Consequently, the "propositions" they derive are inappropriate. Further, Roth et al. disregarded/overlooked: (a) differences among types of PAs, (b) abundant empirical evidence that PA patients are distinguished by presence or absence of prominent respiratory symptoms (e.g., overbreathing), and (c) Ley's (1992b) classification of PAs based on 10 psychophysiological distinctions. The review by Roth et al. falls short of standards required to falsify HVT. Current HVT of PAs is tenable and testable.

Data from permeability profiling using the parallel artificial membrane permeability assay (PAMPA) and cell monolayer (Caco-2 and MDR1-MDCKII) methods were compared for two published compound sets and one in-house set. A majority of compounds in each set correlated (R(2) = 0.76-0.92), indicating the predominance of passive diffusion in the permeation of these compounds. Compounds that did not correlate grouped into two subsets. One subset had higher PAMPA permeability than cell monolayer permeability and consisted of compounds that are subject to secretory mechanisms: efflux or reduced passive diffusion of bases under Caco-2 when run under a pH gradient. The other subset had higher cell monolayer permeability than PAMPA permeability and consisted of compounds that are subject to absorptive mechanisms: paracellular, active transport, or increased passive diffusion of acids under Caco-2 when run under a pH gradient. Given the characteristics of the two methods, these studies suggest how PAMPA and Caco-2 can be synergistically applied for efficient and rapid investigation of permeation mechanisms in drug discovery. During early discovery, all compounds can be rapidly screened using PAMPA at low pH and neutral pH to assess passive diffusion permeability to indicate potential for gastrointestinal and cell assay permeation. During intermediate discovery, selected compounds can be additionally assayed by apical-to-basolateral Caco-2, which, in combination with PAMPA data, indicates susceptibility to additional permeation mechanisms (secretory and absorptive). During mid-to-late discovery, selected candidates can be examined in detail via multiple directional Caco-2 experiments and with transporter inhibitors for complete characterization of permeation mechanisms., (Copyright 2004 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 93:1440-1453, 2004)

Bim, a "BH3-only" protein, is expressed de novo following withdrawal of serum survival factors and promotes cell death. We have shown previously that activation of the ERK1/2 pathway promotes phosphorylation of Bim(EL), targeting it for degradation via the proteasome. However, the nature of the kinase responsible for Bim(EL) phosphorylation remained unclear. We now show that Bim(EL) is phosphorylated on at least three sites in response to activation of the ERK1/2 pathway. By using the peptidylprolyl isomerase, Pin1, as a probe for proline-directed phosphorylation, we show that ERK1/2-dependent phosphorylation of Bim(EL) occurs at (S/T)P motifs. ERK1/2 phosphorylates Bim(EL), but not Bim(S) or Bim(L), in vitro, and mutation of Ser(65) to alanine blocks the phosphorylation of Bim(EL) by ERK1/2 in vitro and in vivo and prevents the degradation of the protein following activation of the ERK1/2 pathway. We also find that ERK1/2, but not JNK, can physically associate with GST-Bim(EL), but not GST-Bim(L) or GST-Bim(S), in vitro. ERK1/2 also binds to full-length Bim(EL) in vivo, and we have localized a potential ERK1/2 "docking domain" lying within a 27-amino acid stretch of the Bim(EL) protein. Our findings provide new insights into the post-translational regulation of Bim(EL) and the role of the ERK1/2 pathway in cell survival signaling.

Previous studies in our laboratory have shown that a single exposure to 100% carbon dioxide (CO2) can serve as an effective unconditioned stimulus (US) in a Pavlovian aversive-context conditioning paradigm in rats. Although the US exposure parameters employed in the initial studies were sufficient for producing a context-specific enhancement of behavioral freezing and analgesia, it had yet to be determined whether variations of these CO2 conditioning procedures would produce other conditioning effects. Thus, the purpose of the following experiment was to investigate the intensity of the US on the conditioned response (CR). The findings confirm that variations in CO2 concentrations produce changes in the CR that are consistent with principles of Pavlovian conditioning. The findings lend additional support to the tenability of a dyspneic suffocation fear theory of panic disorder, a theory that postulates that at least one type of panic attack could be a consequence of Pavlovian conditioning.

To investigate the role of thrombin in regulating apoptosis, we have used CCl39 cells, a fibroblast cell line in which thrombin-induced cell proliferation has been extensively studied. Withdrawal of serum from CCl39 cells resulted in a rapid apoptotic response that was completely prevented by the inclusion of thrombin. The protective effect of thrombin was reversed by pertussis toxin, suggesting that cell-survival signalling pathways are activated via a G(i) or G(o) heterotrimeric GTPase. Serum-withdrawal-induced death required de novo gene expression and was preceded by the rapid de novo expression of the pro-apoptotic 'BH3-only' protein Bim (Bcl-2-interacting mediator of cell death). Thrombin strongly inhibited the up-regulation of both Bim protein and Bim mRNA. The ability of thrombin to repress Bim expression, and to protect cells from apoptosis, was reversed by U0126, a MEK1/2 [MAPK (mitogen-activated protein kinase) or ERK (extracellular-signal-regulated kinase) 1/2] inhibitor, or LY294002, a phosphoinositide 3'-kinase (PI3K) inhibitor, suggesting that both the Raf-->MEK-->ERK1/2 and PI3K pathways co-operate to repress Bim and promote cell survival. A PAR1p (protease-activated receptor 1 agonist peptide) was also able to protect cells from serum-withdrawal-induced apoptosis, suggesting that thrombin acts via PAR1 to prevent apoptosis.

Both the ERK and phosphatidylinositol 3'-kinase (PI3K) signaling pathways can protect cells from apoptosis following withdrawal of survival factors. We have previously shown that the ERK1/2 pathway acts independently of PI3K to block expression of the BH3-only protein, BimEL, and prevent serum withdrawal-induced cell death, although the precise mechanism by which ERK reduced BimEL levels was unclear. By comparing Bim mRNA and Bim protein, expression we now show that the rapid expression of BimEL following serum withdrawal cannot be accounted for simply by increases in mRNA following inhibition of PI3K. In cells maintained in serum BimEL is a phosphoprotein. We show that activation of the ERK1/2 pathway is both necessary and sufficient to promote BimEL phosphorylation and that this leads to a substantial increase in turnover of the BimEL protein. ERK1/2-dependent degradation of BimEL proceeds via the proteasome pathway because it is blocked by proteasome inhibitors and is defective at the restrictive temperature in cells with a temperature-sensitive mutation in the E1 component of the ubiquitin-conjugating system. Finally, co-transfection of BimEL and FLAG-ubiquitin causes the accumulation of polyubiquitinated forms of Bim, and this requires the ERK1/2 pathway. Our findings provide new insights into the regulation of Bim and the role of the ERK pathway in cell survival.

CC139 fibroblasts are one of several model systems in which the Raf --> MEK --> ERK1/2 pathway can inhibit apoptosis independently of the PI3K pathway; however, the precise mechanism for this protective effect is not known. Serum withdrawal from CC139 fibroblasts resulted in the rapid onset of apoptosis, which was prevented by actinomycin D or cycloheximide. Serum withdrawal promoted the rapid, de novo accumulation of Bim(EL), a proapoptotic 'BH3-only' member of the Bcl-2 protein family. Bim(EL) expression was an early event, occurring several hours prior to caspase activation. In contrast to studies in neurons, activation of the JNK --> c-Jun pathway was neither necessary nor sufficient to induce Bim(EL) expression. Selective inhibition of either the ERK pathway (with U0126) or the PI3K pathway (with LY294002) caused an increase in the expression of Bim(EL). Furthermore, selective activation of the ERK1/2 pathway by deltaRaf-1:ER* substantially reduced Bim(EL) expression, abolished conformational changes in Bax and blocked the appearance of apoptotic cells. The ability of deltaRaf-1:ER* to repress Bim(EL) expression required the ERK pathway but was independent of the PI3K --> PDK --> PKB pathway. Thus, serum withdrawal-induced expression of Bim(EL) occurs independently of the JNK --> c-Jun pathway and can be repressed by the ERK pathway independently of the PI3K pathway. This may contribute to Raf- and Ras-induced cell survival at low serum concentrations.

Background: There is evidence of a link between job stress and upper extremity work-related musculoskeletal disorders. However, the biobehavioral mechanisms by which psychosocial stress factors contribute to the development of musculoskeletal disorders are uncertain., Methods: Based on established principles of breathing and job stress and the relevant empirical literatures, a hyperventilation theory of job stress and work-related musculoskeletal disorders was developed., Results: Hyperventilation (overbreathing) refers to a drop in arterial CO2 caused by ventilation that exceeds metabolic demands for O2. Excessive loss of CO2 (increase in rate of flow of CO2 from cells to longs) that results from hyperventilation produces a rise in blood pH (i.e., respiratory alkalosis). This disruption in the acid-base equilibrium triggers a chain of systemic physiological reactions that have adverse implications for musculoskeletal health, including increased muscle tension, muscle spasm, amplified response to catecholamines, and muscle ischemia and hypoxia. Hyperventilation is often characterized by a shift from a diaphragmatic to a thoracic breathing pattern, which imposes biomechanical stress on the neck/shoulder region due to the ancillary recruitment of sternocelidomastoid, scalene, and trapezius muscles in support of thoraci breathing., Conclusions: A hyperventilation theory provides an innovative framework for understanding how job stress contributes to pathophysiological processes that increase the risk of work-related musculoskeletal disorders. With respect to the control of these disorders, a hyperventilation theory has important implications for establishing effective work organization interventions and individual stress-management methods. In this regard, breathing is a biobehavioral metric for assessing whether psychosocial aspects of work organization are in balance with a worker's needs and resources. A hyperventilation theory also provides a unique rationale for coping with job stress and musculoskeletal discomfort through breathing training, light physical exercise, and rest breaks.

This article presents the results of a survey that investigated breathing-related symptoms of panic attacks together with the frequency of other symptoms reported by active panickers. All the participants of this study experienced naturally occurring panic attacks and sought treatment guidance by visiting a Web site devoted to the treatment of panic. The results of a symptom questionnaire showed that 195 respondents (95.1%) reported breathing changes during panic attacks, and remarkable dyspnea was reported by more than two thirds (68%) of respondents. These findings are consistent with earlier studies but are contrary to conclusions that only a small number of panickers report shortness of breath as a symptom. This study concludes that outside of the laboratory, a large majority of people who suffer from panic attacks experience symptoms of dyspnea.

This article was written as an introduction to a special issue of Behavior Modification dedicated to studies in the field of respiratory psychophysiology. Although the invited articles that constitute this special issue cover a fairly broad range of topics, priority was given to articles that focus on the role of respiration in panic disorder. Attention is directed to the fundamental role of breathing in applied psychophysiology and to the encouragement of research in the modification of breathing behavior. The connection between respiratory psychophysiology and behavior modification is explained by reference to (a) a recent article on Pavlovian and operant control of breathing behavior and (b) four published volumes of selected articles dedicated exclusively to the field of respiratory psychophysiology. The present special issue of Behavior Modification marks the fifth volume.