Exploring the effect of aquatic exercise on behaviour and psychological well-being in people with moderate to severe dementia: a pilot study of the Watermemories Swimming Club.
To explore the effects of a dementia-specific, aquatic exercise intervention on behavioural and psychological symptoms in people with dementia (BPSD). Residents from two aged care facilities in Queensland, Australia, received a 12-week intervention consisting of aquatic exercises for strength, agility, flexibility, balance and relaxation. The Psychological Well-Being in Cognitively Impaired Persons Scale (PW-BCIP) and the Revised Memory and Behaviour Problems Checklist (RMBPC) were completed by registered nurses at baseline, week 6, week 9 and post intervention. Ten women and one man (median age = 88.4 years, interquartile range = 12.3) participated. Statistically significant declines in the RMBPC and PW-BCIP were observed over the study period. Preliminary evidence suggests that a dementia-specific, aquatic exercise intervention reduces BPSD and improves psychological well-being in people with moderate to severe dementia. With further testing, this innovative intervention may prove effective in addressing some of the most challenging aspects of dementia care.


Investigation of optical currents in coherent and partially coherent vector fields.
We present the computer simulation results of the spatial distribution of the Poynting vector and illustrate motion of micro and nanoparticles in spatially inhomogeneously polarized fields. The influence of phase relations and the degree of mutual coherence of superimposing waves in the arrangements of two-wave and four-wave superposition on the characteristics of the microparticle's motion has been analyzed. The prospects of studying temporal coherence using the proposed approach are made. For the first time, the possibility of diagnostics of optical currents in liquids caused by polarization characteristics of an optical field alone, using nanoscale metallic particles has been shown experimentally.


Genetic diversity of the Eurasian Otter (Lutra lutra) population in Israel.
The Israeli population of Eurasian otter (Lutra lutra) marks the Palearctic southern boundary of the species' distribution in the Levant. During the 20th century, the otter population in Israel experienced a dramatic decline due to anthropogenic habitat alterations. Currently, the otter population in Israel is estimated at about 100 individuals and defined as "Critically Endangered". The aim of this research was to characterize the Israeli otter population in order to determine its genetic diversity and fragmentation state for conservation purposes. Monitoring spraint sites during 2000-2011 along active and historic otter distribution regions indicate both stable and unstable otter subpopulations, mainly along the Jordan River. Four otter subpopulations, representing 57 individuals, were characterized by 12 microsatellites, previously used to characterize the European otter populations. The genetic results indicated three subpopulations correlating with three geographical regions: the Hula Valley, Sea of Galilee, and the Harod Valley. A moderate genetic diversity (F (st) = 0.087-0.123) was found among the subpopulations, suggesting sporadic interactions between individuals from distinct geographical locations along the Jordan Rift Valley. The Israeli otter population was found to be very small, demographically remote and genetically distinct, harboring unique alleles absent from the studied European populations. Therefore, immediate conservation actions are recommended to prevent the deterioration of the isolated, unique, and critically endangered otter population in Israel.


Design and engineering colloidal magnetic particles for nanoscale thermometry.
Thermometry based on magnetic nanoparticles (MNPs) is an emerging technology that allows for remote temperature measurements throughout a volume that are impossible to achieve using conventional probe-based or optical methods. This metrology is based on the temperature-dependent nature of these particles' magnetization; however, commercially available MNPs generally display insufficient magneto-thermosensitivity for practical use in applications near room temperature. Here we present engineered MNPs based on cobalt-doped ferrites developed for 200 K - 400 K thermometry applications. The synthesis relies on easily scalable solution chemistry routes, and is tunable to afford MNPs of controlled size and composition. These improved nanothermometers form the basis of our effort to develop a practical means for spatially resolved, 3D, high-sensitivity measurements of temperature based on AC magnetometry.


Trial designs for personalizing cancer care: a systematic review and classification.
There is an increasing interest in the evaluation of prognostic and predictive biomarkers for personalizing cancer care. The literature on the trial designs for evaluation of these markers is diverse and there is no consensus in the classification or nomenclature. We set this study to review the literature systematically, to identify the proposed trial designs, and to develop a classification scheme. We searched MEDLINE, EMBASE, Cochrane Methodology Register, and MathSciNet up to January 2013 for articles describing these trial designs. In each eligible article, we identified the trial designs presented and extracted the term used for labeling the design, components of patient flow (marker status of eligible participants, intervention, and comparator), study questions, and analysis plan. Our search strategy resulted in 88 eligible articles, wherein 315 labels had been used by authors in presenting trial designs; 134 of these were unique. By analyzing patient flow components, we could classify the 134 unique design labels into four basic patient flow categories, which we labeled with the most frequently used term: single-arm, enrichment, randomize-all, and biomarker-strategy designs. A fifth category consists of combinations of the other four patient flow categories. Our review showed that a considerable number of labels has been proposed for trial designs evaluating prognostic and predictive biomarkers which, based on patient flow elements, can be classified into five basic categories. The classification system proposed here could help clinicians and researchers in designing and interpreting trials evaluating predictive biomarkers, and could reduce confusion in labeling and reporting.


Chasing the FOXO3: Insights into Its New Mitochondrial Lair in Colorectal Cancer Landscape.
Colorectal cancer (CRC) poses a formidable challenge in terms of molecular heterogeneity, as it involves a variety of cancer-related pathways and molecular changes unique to an individual's tumor. On the other hand, recent advances in DNA sequencing technologies provide an unprecedented capacity to comprehensively identify the genetic alterations resulting in tumorigenesis, raising the hope that new therapeutic approaches based on molecularly targeted drugs may prevent the occurrence of chemoresistance. Regulation of the transcription factor FOXO3a in response to extracellular cues plays a fundamental role in cellular homeostasis, being part of the molecular machinery that drives cells towards survival or death. Indeed, FOXO3a is controlled by a range of external stimuli, which not only influence its transcriptional activity, but also affect its subcellular localization. These regulation mechanisms are mediated by cancer-related signaling pathways that eventually drive changes in FOXO3a post-translational modifications (e.g., phosphorylation). Recent results showed that FOXO3a is imported into the mitochondria in tumor cells and tissues subjected to metabolic stress and cancer therapeutics, where it induces expression of the mitochondrial genome to support mitochondrial metabolism and cell survival. The current review discusses the potential clinical relevance of multidrug therapies that drive cancer cell fate by regulating critical pathways converging on FOXO3a.


Peripheral anterior synechiae formation after trabeculoplasty.
Argon laser trabeculoplasty (ALT) was performed on 60 eyes with primary open angle glaucoma and 59 eyes with capsular (pseudoexfoliation) glaucoma. Laser applications of four different power levels (500, 600, 700, and 800 mW) were directed either at the anterior trabecular meshwork or at the posterior trabecular meshwork. Gonioscopic examination to reveal peripheral anterior synechiae (PAS) formation was performed before and six months after ALT. Peripheral anterior synechiae were found in 26 (22%) of the eyes. With 500-mW laser power and anterior trabecular meshwork burns, no PAS developed. With 800-mW posterior trabecular meshwork burns, PAS developed in 12 (40%) of the eyes. No correlation between PAS formation and sex, age, glaucoma type, preoperative antiglaucoma medication, pigmentation of the chamber angle, and visible burn effect was found. Intraocular pressure decrease after ALT was significantly smaller in eyes with PAS.


Connecting mutations of the RNA polymerase II C-terminal domain to complex phenotypic changes using combined gene expression and network analyses.
The C-terminal domain (CTD) of the largest subunit in DNA-dependent RNA polymerase II (RNAP II) is essential for mRNA synthesis and processing, through coordination of an astounding array of protein-protein interactions. Not surprisingly, CTD mutations can have complex, pleiotropic impacts on phenotype. For example, insertions of five alanine residues between CTD diheptads in yeast, which alter the CTD's overall tandem structure and physically separate core functional units, dramatically reduce growth rate and result in abnormally large cells that accumulate increased DNA content over time. Patterns by which specific CTD-protein interactions are disrupted by changes in CTD structure, as well as how downstream metabolic pathways are impacted, are difficult to target for direct experimental analyses. In an effort to connect an altered CTD to complex but quantifiable phenotypic changes, we applied network analyses of genes that are differentially expressed in our five alanine CTD mutant, combined with established genetic interactions from the Saccharomyces cerevisiae Genome Database (SGD). We were able to identify candidate genetic pathways, and several key genes, that could explain how this change in CTD structure leads to the specific phenotypic changes observed. These hypothetical networks identify links between CTD-associated proteins and mitotic function, control of cell cycle checkpoint mechanisms, and expression of cell wall and membrane components. Such results can help to direct future genetic and biochemical investigations that tie together the complex impacts of the CTD on global cellular metabolism.


Global metabolic profiling to model biological processes of aging in twins.
Aging is intimately linked to system-wide metabolic changes that can be captured in blood. Understanding biological processes of aging in humans could help maintain a healthy aging trajectory and promote longevity. We performed untargeted plasma metabolomics quantifying 770 metabolites on a cross-sectional cohort of 268 healthy individuals including 125 twin pairs covering human lifespan (from 6 months to 82 years). Unsupervised clustering of metabolic profiles revealed 6 main aging trajectories throughout life that were associated with key metabolic pathways such as progestin steroids, xanthine metabolism, and long-chain fatty acids. A random forest (RF) model was successful to predict age in adult subjects (≥16 years) using 52 metabolites (R2 = .97). Another RF model selected 54 metabolites to classify pediatric and adult participants (out-of-bag error = 8.58%). These RF models in combination with correlation network analysis were used to explore biological processes of healthy aging. The models highlighted established metabolites, like steroids, amino acids, and free fatty acids as well as novel metabolites and pathways. Finally, we show that metabolic profiles of twins become more dissimilar with age which provides insights into nongenetic age-related variability in metabolic profiles in response to environmental exposure.


Impact of tinnitus on quality of life, loudness and pitch match, and high-frequency audiometry.
Our objective was to compare quality of life, high-frequency audiometry, and loudness-pitch match in individuals with tinnitus with and without hearing loss. We divided 52 individuals into two groups: one with hearing impairment (HI; n = 24) and the other with no hearing loss (NL; n = 28). All participants underwent loudness-pitch match and high-frequency audiometry and responded to the Tinnitus Handicap Inventory (THI) and World Health Organization Quality of Life (WHOQOL) questionnaires. On high-frequency audiometry, older individuals required 77.15% more intensity than did young individuals. On the THI questionnaire, individuals in the NL group exhibited mild handicap, whereas those in the HI group exhibited moderate handicap. On the WHOQOL questionnaires, the HI group demonstrated greater impairment on the physical and psychological domains than did the NL group. Individuals with HI experienced greater discomfort with tinnitus. On high-frequency audiometry, individuals with tinnitus and HI exhibited higher thresholds, with complete hearing loss at some frequencies. The WHOQOL and THI questionnaires revealed that individuals with HI experienced a poorer quality of life than did those with normal hearing.


Systematic review: exercise-induced gastrointestinal syndrome-implications for health and intestinal disease.
"Exercise-induced gastrointestinal syndrome" refers to disturbances of gastrointestinal integrity and function that are common features of strenuous exercise. To systematically review the literature to establish the impact of acute exercise on markers of gastrointestinal integrity and function in healthy populations and those with chronic gastrointestinal conditions. Search literature using five databases (PubMed, EBSCO, Web of Science, SPORTSdiscus, and Ovid Medline) to review publications that focused on the impact of acute exercise on markers of gastrointestinal injury, permeability, endotoxaemia, motility and malabsorption in healthy populations and populations with gastrointestinal diseases/disorders. As exercise intensity and duration increases, there is considerable evidence for increases in indices of intestinal injury, permeability and endotoxaemia, together with impairment of gastric emptying, slowing of small intestinal transit and malabsorption. The addition of heat stress and running mode appears to exacerbate these markers of gastrointestinal disturbance. Exercise stress of ≥2 hours at 60% VO2max appears to be the threshold whereby significant gastrointestinal perturbations manifest, irrespective of fitness status. Gastrointestinal symptoms, referable to upper- and lower-gastrointestinal tract, are common and a limiting factor in prolonged strenuous exercise. While there is evidence for health benefits of moderate exercise in patients with inflammatory bowel disease or functional gastrointestinal disorders, the safety of more strenuous exercise has not been established. Strenuous exercise has a major reversible impact on gastrointestinal integrity and function of healthy populations. The safety and health implications of prolonged strenuous exercise in patients with chronic gastrointestinal diseases/disorders, while hypothetically worrying, has not been elucidated and requires further investigation.


Aberrant p63 and WT-1 expression in myoepithelial cells of pregnancy-associated breast cancer: implications for tumor aggressiveness and invasiveness.
Our recent studies revealed that focal alterations in breast myoepithelial cell layers significantly impact the biological presentation of associated epithelial cells. As pregnancy-associated breast cancer (PABC) has a significantly more aggressive clinical course and mortality rate than other forms of breast malignancies, our current study compared tumor suppressor expression in myoepithelial cells of PABC and non-PABC, to determine whether myoepithelial cells of PABC may have aberrant expression of tumor suppressors. Tissue sections from 20 cases of PABC and 20 cases of stage, grade, and age matched non-PABC were subjected to immunohistochemistry, and the expression of tumor suppressor maspin, p63, and Wilms' tumor 1 (WT-1) in calponin positive myoepithelial cells were statistically compared. The expression profiles of maspin, p63, and WT-1 in myoepithelial cells of all ducts encountered were similar between PABC and non-PABC. PABC, however, displayed several unique alterations in terminal duct and lobular units (TDLU), acini, and associated tumor tissues that were not seen in those of non-PABC, which included the absence of p63 and WT-1 expression in a vast majority of the myoepithelial cells, cytoplasmic localization of p63 in the entire epithelial cell population of some lobules, and substantially increasing WT-1 expression in vascular structures of the invasive cancer component. All or nearly all epithelial cells with aberrant p63 and WT-1 expression lacked the expression of estrogen receptor and progesterone receptor, whereas they had a substantially higher proliferation index than their counterparts with p63 and WT-1 expression. Hyperplastic cells with cytoplasmic p63 expression often adjacent to, and share a similar immunohistochemical and cytological profile with, invasive cancer cells. To our best knowledge, our main finings have not been previously reported. Our findings suggest that the functional status of myoepithelial cells may be significantly associated with tumor aggressiveness and invasiveness.


Life in standby: hemodialysis patients' experiences of waiting for kidney transplantation.
Our aim was to explore the experiences of hemodialysis patients who are waiting for a kidney transplant. Currently, more than 100,000 persons are waiting for kidney transplantation in the United States. In Sweden, the number is exceeding 600. The waiting period for a deceased donor can be one to three years or even longer in Sweden. This can be challenging, since the patients' situation, with chronic treatment and illness, is burdensome and requires advanced self-care. This study included a purposeful sample of eight patients (33-53 years old) who had been undergoing hemodialysis treatment for at least six months and were waiting for kidney transplantation. The patients were interviewed, and descriptive content analysis was performed. Four categories emerged: (1) 'The waiting process,' what thoughts and expectations occur and what to do and how to be prepared for the transplant. (2) 'Awareness that time is running out,' patients felt tied up by treatment and by needing to be available for transplantation, and they had concerns about health. (3) 'Need for communication,' patients described needing support from others and continuous information from the staff. (4) 'Having relief and hope for the future,' patients described how to preserve the hope of being able to participate fully in life once again. This study reveals the need for extra attention paid to patients waiting for kidney transplantation. Patients' experiences during the waiting period indicate that pretransplant patients have an increased need to be prepared for the transition and for life post-transplantation. Dialysis patients on waiting lists must be prepared for the upcoming life change. This includes preserving hope during the waiting period and being mentally prepared for transplantation and a dialysis-free life. A pretransplant education program to prevent medical and psychosocial issues is highly recommended.


A Murine Model of Robotic Training to Evaluate Skeletal Muscle Recovery after Injury.
In vivo studies have suggested that motor exercise can improve muscle regeneration after injury. Nevertheless, preclinical investigations still lack reliable tools to monitor motor performance over time and to deliver optimal training protocols to maximize force recovery. Here, we evaluated the utility of a murine robotic platform (i) to detect early impairment and longitudinal recovery after acute skeletal muscle injury and (ii) to administer varying intensity training protocols to enhance forelimb motor performance. A custom-designed robotic platform was used to train mice to perform a forelimb retraction task. After an acute injury to bilateral biceps brachii muscles, animals performed a daily training protocol in the platform at high (HL) or low (LL) loading levels over the course of 3 wk. Control animals were not trained (NT). Motor performance was assessed by quantifying force, time, submovement count, and number of movement attempts to accomplish the task. Myofiber number and cross-sectional area at the injury site were quantified histologically. Two days after injury, significant differences in the time, submovement count, number of movement attempts, and exerted force were observed in all mice, as compared with baseline values. Interestingly, the recovery time of muscle force production differed significantly between intervention groups, with HL group showing a significantly accelerated recovery. Three weeks after injury, all groups showed motor performance comparable with baseline values. Accordingly, there were no differences in the number of myofibers or average cross-sectional area among groups after 3 wk. Our findings demonstrate the utility of our custom-designed robotic device for the quantitative assessment of skeletal muscle function in preclinical murine studies. Moreover, we demonstrate that this device may be used to apply varying levels of resistance longitudinally as a means manipulate physiological muscle responses.


Synthesis and characterization of oligodeoxyribonucleotides modified with 2'-amino-α-L-LNA adenine monomers: high-affinity targeting of single-stranded DNA.
The development of conformationally restricted nucleotide building blocks continues to attract considerable interest because of their successful use within antisense, antigene, and other gene-targeting strategies. Locked nucleic acid (LNA) and its diastereomer α-L-LNA are two interesting examples thereof. Oligonucleotides modified with these units display greatly increased affinity toward nucleic acid targets, improved binding specificity, and enhanced enzymatic stability relative to unmodified strands. Here we present the synthesis and biophysical characterization of oligodeoxyribonucleotides (ONs) modified with 2'-amino-α-L-LNA adenine monomers W-Z. The synthesis of the target phosphoramidites 1-4 is initiated from pentafuranose 5, which upon Vorbrüggen glycosylation, O2'-deacylation, O2'-activation and C2'-azide introduction yields nucleoside 8. A one-pot tandem Staudinger/intramolecular nucleophilic substitution converts 8 into 2'-amino-α-L-LNA adenine intermediate 9, which after a series of nontrivial protecting-group manipulations affords key intermediate 15. Subsequent chemoselective N2'-functionalization and O3'-phosphitylation give targets 1-4 in ~1-3% overall yield over 11 steps from 5. ONs modified with pyrene-functionalized 2'-amino-α-L-LNA adenine monomers X-Z display greatly increased affinity toward DNA targets (ΔTm/modification up to +14 °C). Results from absorption and fluorescence spectroscopy suggest that the duplex stabilization is a result of pyrene intercalation. These characteristics render N2'-pyrene-functionalized 2'-amino-α-L-LNAs of considerable interest for DNA-targeting applications.


Progressive and nonprogressive rheumatoid arthritis over a 10-year period in Japan.
We followed 207 patients with rheumatoid arthritis who were registered at our hospital over a 10-year period from between 1989 and 1990. The number of patients who were still treated at our hospital in 2001 was 87. Sixty patients had died, 39 had changed hospitals, 11 had interrupted treatment, and 10 had not had further followup. The patients at our hospital in 2001 were divided into 2 groups: progressive and nonprogressive disease. We compared clinical and laboratory data obtained for the 2 groups from the initial examination against data obtained from the final examination. The progressive group had a greater number of operations, used a greater variety of disease modifying antirheumatic drugs, and received higher dosages of steroids than the nonprogressive group. In the progressive group the levels of C-reactive protein, erythrocyte sedimentation rate, and IgG were significantly higher, while the levels of hemoglobin were lower at final laboratory examination. However, the initial laboratory examination revealed no significant differences between these groups that could be used to predict the likely progression of disease.


Relation of abdominal fat depots to systemic markers of inflammation in type 2 diabetes.
Both visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) have been linked to systemic inflammation in nondiabetic cohorts. We examined the relationships between VAT and SAT and systemic inflammatory markers in a large well-characterized cohort of subjects with type 2 diabetes. Three hundred eighty-two subjects with type 2 diabetes in the CHICAGO (Carotid Intima-Media Thickness in Atherosclerosis Using Pioglitazone) study cohort underwent abdominal computed tomography to determine SAT and VAT distribution. Fasting blood was obtained for measurement of inflammatory markers. The relationships between inflammatory markers and BMI, SAT, and VAT were examined using regression models adjusted for age, sex, diabetes treatment, duration of diabetes, smoking, statin use, and A1C. VAT was positively related to CRP, monocyte chemoattractant protein (MCP), intracellular adhesion molecule (ICAM)-1, and plasminogen activator inhibitor type 1 (PAI-1) antigen before adjustment for BMI. After adjustment for BMI, the relationship to CRP was lost but positive associations with MCP (P < 0.01), PAI-1 (P < 0.0001), ICAM-1 (P < 0.01), and vascular cell adhesion molecule (P = 0.01) were evident. BMI was positively related to CRP (P < 0.0001) and IL-6 (P < 0.01) even after adjustment for VAT and SAT. SAT was not related to any inflammatory marker after adjustment for BMI. In this large group of subjects with type 2 diabetes, BMI was most strongly associated with CRP and IL-6 levels. SAT was not associated with markers of systemic inflammation. The size of the VAT depot provided information additional to that provided by BMI regarding inflammatory markers that are strongly related to vascular wall remodeling and coagulation. Our findings suggest that adipose tissue distribution remains an important determinant of systemic inflammation in type 2 diabetes.


Cerebral perfusion imaging with technetium-99m HMPAO following cerebral trauma. Initial experience.
Thirteen patients with cerebral trauma were studied for cerebral perfusion by the use of Tc-99m HMPAO scanning. CT imaging was performed on nine patients. Because of their clinical condition, four patients were scanned only in the planar mode to help establish the diagnosis of brain death. Other indications for study included gunshot wound and blunt or sharp object trauma with or without skull fracture. In all cases, HMPAO scans showed defects with a quality equivalent to or greater than that demonstrated by CT. Our initial results suggest that HMPAO may predict the degree of permanent damage and which patients may develop post-traumatic headache. A diagnosis of brain death can be established without the withdrawal of medical therapy.


Body image distortions in bulimia nervosa: investigating body size overestimation and body size satisfaction by fMRI.
Body image distortion is a key symptom of eating disorders. In behavioral research two components of body image have been defined: attitudes towards the body and body size estimation. Only few fMRI-studies investigated the neural correlates of body image in bulimia; those are constrained by the lack of a direct distinction between these different body image components. The present study investigates the neural correlates of two aspects of the body image using fMRI: satisfaction rating and size estimation of distorted own body photographs in bulimia nervosa patients (15) and controls (16). Patients were less satisfied with their current body shape than controls and preferred to be thinner. The amount of insula activity reflects the pattern of the satisfaction rating for patients and controls. Patients also overestimated their own body size. For control subjects, an activated cluster in lateral occipital cortex was sensitive for body size distortions, whereas bulimic patients did not demonstrate such a modulation. Furthermore, bulimic subjects did not recruit the middle frontal gyrus (MFG) in contrast to controls during the body size estimation task, maybe indicating a reduced spatial manipulation capacity. Therefore, this activation pattern of lateral occipital cortex and MFG might be responsible for body size overestimation in bulimia. The present results show that bulimic patients exhibit two distinct deficits in body image representations similar to anorectic patients and that specifically associated neuronal correlates can be identified. Concludingly, our study support psychotherapeutic strategies specifically targeting these two aspects of body image distortions.


Optical near-field data analysis through time-frequency distributions: application to the characterization and separation of the image spectral content by reassignment.
The near-field optical images have been traditionally analyzed by Fourier analysis and, recently, by wavelet analysis. Those data are nonstationary, which means that their spectral content varies with time, owing to the scanning-probe recording process; therefore time-frequency representations are, potentially, powerful tools for local characteristics extraction or shape separation, since they distribute the energy of the analyzed signal over the time and frequency variables and faithfully depict the signal local behavior. In this study we show that Cohen's class time-frequency distributions and their modified version by the reassignment method are appropriate tools for the analysis of near-field optical data. We demonstrate this by using these tools first on simulated data and second on experimental near-field optical images. Within this context we observe that time-frequency analysis allows one to easily characterize local frequencies, which involves a possible separation of relevant optical signal from artifacts.


Comparative investigation of dynamic loading of prepared and intact human premolars.
The aim of this study was to obtain some data on the dynamic strength of premolar teeth. Experiments were performed on three groups of human premolars: intact teeth, teeth prepared for partial veneer crowns with flat occlusal surfaces, and teeth prepared for partial veneer crowns with rounded occlusal surfaces. The loading procedure was performed in a modified Amslers high-frequency pulsator. The greatest dynamic strength was exhibited by the intact specimens. The highest continual (unlimited number of loading cycles) dynamic stress withstood by all three groups of premolars was about 300 N. A statistically significant negative correlation was found between Fmax and the number of cycles in all three tested groups.


LRP-1-mediated endocytosis regulates extracellular activity of ADAMTS-5 in articular cartilage.
Aggrecan is a major matrix component of articular cartilage, and its degradation is a crucial event in the development of osteoarthritis (OA). Adamalysin-like metalloproteinase with thrombospondin motifs 5 (ADAMTS-5) is a major aggrecan-degrading enzyme in cartilage, but there is no clear correlation between ADAMTS-5 mRNA levels and OA progression. Here, we report that post-translational endocytosis of ADAMTS-5 by chondrocytes regulates its extracellular activity. We found 2- to 3-fold reduced aggrecanase activity when ADAMTS-5 was incubated with live porcine cartilage, resulting from its rapid endocytic clearance. Studies using receptor-associated protein (RAP), a ligand-binding antagonist for the low-density lipoprotein receptor-related proteins (LRPs), and siRNA-mediated gene silencing revealed that the receptor responsible for ADAMTS-5 clearance is LRP-1. Domain-deletion mutagenesis of ADAMTS-5 identified that the noncatalytic first thrombospondin and spacer domains mediate its endocytosis. The addition of RAP to porcine cartilage explants in culture increased the basal level of aggrecan degradation, as well as ADAMTS-5-induced aggrecan degradation. Notably, LRP-1-mediated endocytosis of ADAMTS-5 is impaired in chondrocytes of OA cartilage, with ∼90% reduction in protein levels of LRP-1 without changes in its mRNA levels. Thus, LRP-1 dictates physiological and pathological catabolism of aggrecan in cartilage as a key modulator of the extracellular activity of ADAMTS-5.


Optical trapping and manipulation of plasmonic nanoparticles: fundamentals, applications, and perspectives.
This feature article discusses the optical trapping and manipulation of plasmonic nanoparticles, an area of current interest with potential applications in nanofabrication, sensing, analytics, biology and medicine. We give an overview over the basic theoretical concepts relating to optical forces, plasmon resonances and plasmonic heating. We discuss fundamental studies of plasmonic particles in optical traps and the temperature profiles around them. We place a particular emphasis on our own work employing optically trapped plasmonic nanoparticles towards nanofabrication, manipulation of biomimetic objects and sensing.


Structure pre-requisites for isoflavones as effective antibacterial agents.
Recent reports reveal that there is increasing incidence of infections of multidrug-resistant bacteria, including methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE). Flavonoids and related compounds have been shown to possess potent antimicrobial activities. Most of the flavonoids are considered as constitutive antimicrobial substances recently termed as "Phytoanticipins," especially those belonging to prenylated flavonoids and isoflavones. The current review highlights the structure prerequisites for isoflavones as antibacterial agents. Structure-activity relationship (SAR) conclusions have been drawn by comparing the reported minimum inhibitory concentration values for the various isoflavones against S. aureus and MRSA. There exists a significant co-relationship between the presence of certain functional groups (prenyl group, phenolic hydroxyl) at particular positions and antibacterial activity of the compounds. These trends have been postulated with a view of assisting better drug designing of future next-generation antiinfectives, particularly against the bothersome multidrug-resistant microbes. The SAR of these isoflavones has also proved to be a basis to explore the mechanism of antibacterial action. Thus, the study would prove extremely useful to synthesize antibacterial isoflavones in future, which would eventually be beneficial for optimizing the lead molecule for the antibacterial action.


Optical three-port circulators made with ring resonators.
We propose a circulator consisting of a ring resonator coupled to three waveguides with Bragg reflectors at one end of each waveguide. A magneto-optically active material placed inside the ring resonator causes the two counter-propagating modes to split in resonance frequency, which can be exploited for perfect circulation by properly adjusting the coupling between the three waveguides and the ring. Such a device features a transmission spectrum that is similar to three-port photonic crystal circulators but is much simpler to build as it only contains elements that have already been experimentally realized.


A double blind randomized placebo controlled pilot study of single-dose preoperative modafinil for functional recovery after general anesthesia in patients with obstructive sleep apnea.
We theorized that modafinil, an atypical psychomotor stimulant, utilized to improve daytime somnolence in patients with obstructive sleep apnea, would improve functional recovery after general anesthesia by improving time to extubation, post-anesthesia care unit (PACU) length of stay and subjective recovery after general anesthesia. A double blind, randomized, placebo-controlled pilot study was performed. 102 patients with the diagnosis of obstructive sleep apnea (OSA) were randomized to receive either 200 mg of modafinil or placebo before general anesthesia. The trial was terminated for futility. The primary outcome was PACU length of stay between groups. Secondary functional metrics of improved post-anesthesia recovery were compared between groups. No difference between groups was found on the primary outcome of PACU length of stay (PACULOS). Emergence from general anesthesia was not significantly different when assessed by the time period between termination of volatile anesthetic and extubation. Similarly, no difference between groups was found in intraoperative bispectral index (BIS) values, postoperative pain scores or narcotic consumption (morphine equivalent units). In the post-anesthesia care unit, respiratory rate was increased and mean arterial pressure was lower in the modafinil group. Our results suggest that the use of single-dose preoperative modafinil may not improve functional recovery after general anesthesia in patients with the diagnosis of OSA. Further research is needed before use of atypical psychomotor stimulants in this surgical population.


Intralocus sexual conflict over immune defense, gender load, and sex-specific signaling in a natural lizard population.
In species with separate sexes, antagonistic selection on males and females (intralocus sexual conflict) can result in a gender load that can be resolved through the evolution of sexual dimorphism. We present data on intralocus sexual conflict over immune defense in a natural population of free-ranging lizards (Uta stansburiana) and discuss the resolution of this conflict. Intralocus sexual conflict arises from correlational selection between immune defense and orange throat coloration in these lizards. Males with orange throats and high antibody responses had enhanced survival, but the same trait combination reduced female fitness. This sexual antagonism persisted across the life cycle and was concordant between the juvenile and adult life stages. The opposing selective pressure on males and females is ameliorated by a negative intersexual genetic correlation (r(m,f)=-0.86) for immune defense. Throat coloration was also genetically correlated with immune defense, but the sign of this genetic correlation differed between the sexes. This resulted in sex-specific signaling of immunological condition. We also found evidence for a sex-specific maternal effect on sons with potential to additionally reduce the gender load. These results have implications for signaling evolution, genetic integration between adaptive traits, sex allocation, and mutual mate choice for indirect fitness benefits.


Exposure to Cigarette Smoke Enhances the Stemness of Alveolar Type 2 Cells.
Chronic exposure to cigarette smoke (CS) causes chronic inflammation, oxidative stress, and apoptosis of epithelial cells, which results in destruction of the lung matrix. However, the mechanism by which the lung fails to repair the CS-induced damage, thereby succumbing to emphysema, remains unclear. Alveolar type 2 (AT2) cells comprise the stem cells of the alveolar compartments and are responsible for repairing and maintaining lung tissues. In this study, we examined the effect of chronic CS on AT2 stem cells. Adult mice expressing GFP in their AT2 cells were exposed to CS for > 3 months. Histological assessment showed that CS not only induced emphysematous changes but also increased the number of AT2 cells compared with that of air-exposed lungs. Assessment of sorted GFP+/AT2 cells via the stem cell three-dimensional organoid/colony-forming assay revealed that the number and size of the colonies formed by the CS-exposed AT2 stem cells were significantly higher than those of air-exposed control AT2 cells. Although CS-exposed lungs had more apoptotic cells, examination of the surviving AT2 stem cells in two-dimensional in vitro culture revealed that they developed a higher ability to resist apoptosis. Microarray analysis of CS-exposed AT2 stem cells revealed the upregulation of genes related to circadian rhythm and inflammatory pathways. In conclusion, we provide evidence that AT2 stem cells respond to chronic CS exposure by activating their stem cell function, thereby proliferating and differentiating faster and becoming more resistant to apoptosis. Disturbances in expression levels of several circadian rhythm-related genes might be involved in these changes.


Continuum-Based Geometry/Analysis Approach for Flexible and Soft Robotic Systems.
Control and stability of flexible and soft robotic systems (FSRS), which have complex geometry and experience desirable and undesirable deformations, are of major concern, particularly when lightweight soft materials are used. Nonetheless, there is no unified continuum-based geometry/analysis approach that can be used for the efficient FSRS virtual prototyping and design. The goal of this article is to propose a new FSRS geometric modeling and analysis methodology by addressing fundamental virtual prototyping challenges that include: (1) integration of the robot geometry and analysis; (2) implementation of general and unconventional material models and actuation forces; (3) use of new concepts for modeling FSRS joints; and (4) development of efficient and robust algorithms for the FSRS virtual prototyping. To address these challenges, the finite element (FE) absolute nodal coordinate formulation (ANCF) and multibody system computational algorithms are used. ANCF FEs allow for modeling arbitrarily large and coupled displacements, correctly capture complex geometries, allow for implementing general and nonconventional material models, provide accurate definitions of conventional and nonconventional actuation forces, lead to a constant inertia matrix that defines optimally sparse matrix structure of the dynamic equations, and allow for exploiting new geometry concepts to define linear and more general joint constraints instead of the less general and nonlinear joint constraints currently used for robot systems. Using the general structure of the FSRS nonlinear dynamic equations of motion, a nonmodal continuum-based approach can be developed and used to correctly capture the FSRS complex geometry and large deformations.


A randomized controlled trial on a multicomponent intervention for overweight school-aged children - Copenhagen, Denmark.
Obesity amongst children is a growing problem worldwide. In contrast to adults, little is known on the effects of controlled weight loss on components of the metabolic syndrome in children. The primary aim of the study was to evaluate the effects of a 20-week exercise and diet guidance intervention on body mass index (BMI) in a group of overweight children. Our hypothesis was an observed reduction in BMI and secondarily in body fat content, insulin insensitivity, and other components of the metabolic syndrome in the intervention group. School children from Copenhagen were randomly allocated to an intervention group (n = 19) or a control group (n = 19). Anthropometric assessment, whole body dual-energy X-ray absorptiometry scan, two hours oral glucose tolerance test, steps measured by pedometer, and fitness tests were measured at baseline and at 20 weeks. Thirty-seven children (30 girls) participated at baseline, aged 8.7 ± 0.9 years with a BMI of 21.8 ± 3.7 kg/m2 (mean ± SD), and 36 children completed the study. The intervention group decreased their BMI (the intervention effect is the difference in change between the groups adjusted for the respective baseline values (DELTA) = -2.0 kg/m2, 95% CI: -2.5; -1.5, P <0.001), total body mass (DELTA = -4.0 kg, 95% CI: -4.9; -3.0, P <0.001), and fat mass (DELTA = -3.3 kg, 95% CI: -4.2; -2.7, P <0.001) compared to the control group after the intervention. The intervention group displayed decreased waist, hip and waist-to-height ratio (WHtR) (all three variables; P <0.001), area under curve for plasma insulin (P <0.05), and increased mean and minimum steps/day (P <0.05 and P <0.01, respectively). The multicomponent intervention had significant favorable effects on BMI, weight, WHtR, mean and minimum steps/day, and fat mass. In addition, similar beneficial metabolic effects were found in the children as shown in adults, e.g. increase in peripheral insulin sensitivity. Clinicaltrials.gov Identifier number NCT01660789.


Monoclonal antibodies for treating cancer.
To assess the current status of in-vivo use of monoclonal antibodies for treating cancer. Publications appearing between 1980 and 1988 were identified by computer searches using MEDLINE and CANCERLIT, by reviewing the table of contents of recently published journals, and by searching bibliographies of identified books and articles. More than 700 articles, including peer-reviewed articles and book chapters, were identified and selected for analysis. The literature was reviewed and 235 articles were selected as relevant and representative of the current issues and future applications for in-vivo monoclonal antibodies for cancer therapy and of the toxicity and efficacy which has been associated with clinical trials. RESULTS OF DATA SYNTHESES: Approaches include using antibody alone (interacting with complement or effector cells or binding directly with certain cell receptors) and immunoconjugates (antibody coupled to radioisotopes, drugs, toxins, or other biologicals). Most experience has been with murine antibodies. Trials of antibody alone and radiolabeled antibodies have confirmed the feasibility of this approach and the in-vivo trafficking of antibodies to tumor cells. However, tumor cell heterogeneity, lack of cytotoxicity, and the development of human antimouse antibodies have limited clinical efficacy. Although the immunoconjugates are very promising, heterogeneity and the antimouse immune response have hampered this approach as has the additional challenge of chemically or genetically coupling antibody to cytotoxic agents. As a therapeutic modality, monoclonal antibodies are still promising but their general use will be delayed for several years. New approaches using human antibodies and reducing the human antiglobulin response should facilitate treatment.


Anti-Fatigue Effects of Small Molecule Oligopeptides Isolated from Panax ginseng C. A. Meyer in Mice.
Panax ginseng C. A. Meyer (ginseng) is an edible and medicinal Chinese herb, which is often used in Asian countries for physical fitness. Ginseng is reported to have a wide range of biological activity and pharmaceutical properties. There were more studies on ginsenosides and polysaccharides, but fewer studies on ginseng oligopeptides (GOP), which are small molecule oligopeptides isolated from ginseng. The present study was designed to evaluate the anti-fatigue effects of GOP in mice and explore the possible underlying mechanism. Mice were randomly divided into four experimental sets for the detection of different indicators. Each set of mice were then divided into four groups. The control group was administered distilled water, and three GOP intervention groups were administered 125, 250, and 500 mg/kg of body weight, respectively, of GOP by gavage each day. After 30 days of GOP treatment, it was observed that GOP could significantly increase the forced swimming time, enhance lactate dehydrogenase (LDH) activity and hepatic glycogen levels, and retard the accumulation of serum urea nitrogen (SUN) and blood lactic acid (BLA) in mice. GOP also markedly ameliorated fatigue-induced alterations of inoxidative stress biomarkers and antioxidant enzymes. Notably, GOP increased the mRNA expression of mitochondrial biogenesis factors and mitochondrial DNA content in skeletal muscles of mice. These results suggest that GOP possess anti-fatigue effects, which may be attributed to the inhibition of oxidative stress and the improvement of mitochondrial function in skeletal muscles. GOP could be a novel natural agent for relieving exercise fatigue.


Sgk-1 is a positive regulator of constitutive albumin uptake in renal proximal tubule cells.
Receptor-mediated endocytosis of albumin by the renal proximal tubule requires a number of proteins including megalin/cubilin, sodium/hydrogen exchanger isoform 3 (NHE3) and ClC-5, as well as the PSD-95/Dlg/Zo-1 (PDZ) scaffold sodium/hydrogen exchanger regulatory factor 2 (NHERF2). Despite members from the AGC kinase family, v-Akt Murine Thymoma Viral Oncogene (Akt or Protein Kinase B) and Serum/Glucocorticoid regulated Kinase 1 (Sgk-1) regulating a number of essential proteins in the albumin handling pathway, their role in uptake is largely unknown. Opossum kidney (OK) cells were exposed to Texas-Red albumin, in the presence of silencing constructs against Sgk-1, Akt and NHERF2, in addition to the NHE3 inhibitor 5-(N-ethyl-N-isopropyl)-amiloride (EIPA) and NHE3 activator dexamethasone. Target protein was also measured by Western blot analysis in OK cells following exposure to dexamethasone and albumin. Silencing Sgk-1 or overexpression of a dominant negative mutant (DN-Sgk-1) led to a significant reduction of albumin endocytosis compared to control. Conversely, over-expression of wildtype (WT) or constitutively active (CA) Sgk-1 significantly increased uptake. Previous reports have shown Sgk-1 can activate NHE3 through an interaction mediated by NHERF2. We found that silencing both Sgk-1 and NHERF2 demonstrated no additive effect on uptake, suggesting signaling via similar endpoints. Treatment with dexamethasone increased Sgk-1 protein levels and increased albumin endocytosis in OK cells. Interestingly, silencing Akt also lead to a reduction in albumin endocytosis, however in cells silenced for both Sgk-1 and Akt, the additive change in albumin uptake demonstrated that these proteins may act via separate pathways. We have characterized a Sgk-dependent pathway that regulates albumin uptake in the proximal tubule which also includes NHE3 and NHERF2. These data provide further insights into this essential tubular process.


Highly efficacious nontoxic preclinical treatment for advanced metastatic breast cancer using combination oral UFT-cyclophosphamide metronomic chemotherapy.
Metronomic antiangiogenic chemotherapy, the prolonged administration of relatively low drug doses, at close regular intervals with no significant breaks, has been mainly studied at the preclinical level using single chemotherapeutic drugs, frequently in combination with a targeted antiangiogenic drug, and almost always evaluated on primary localized tumors. We tested a "doublet" combination metronomic chemotherapy treatment using two oral drugs, UFT, a 5-fluorouracil (5-FU) prodrug administered by gavage, and cyclophosphamide, for efficacy and toxicity in a new mouse model of advanced, terminal, metastatic human breast cancer. The optimal biological dose of each drug was first determined by effects on levels of circulating endothelial progenitor cells as a surrogate marker for angiogenesis, which was assessed to be 15 mg/kg for UFT and 20 mg/kg for cyclophosphamide. A combination treatment was then evaluated in mice with advanced metastatic disease using a serially selected metastatic variant of the MDA-MB-231 breast cancer-cell line, 231/LM2-4. UFT or cyclophosphamide treatment showed only very modest survival advantages whereas a combination of the two resulted in a remarkable prolongation of survival, with no evidence of overt toxicity despite 140 days of continuous therapy, such that a significant proportion of mice survived for over a year. In contrast, this striking therapeutic effect of the combination treatment was not observed when tested on primary orthotopic tumors. We conclude that combination oral low-dose daily metronomic chemotherapy, using cyclophosphamide and UFT, is superior to monotherapy and seems to be a safe and highly effective experimental antimetastatic therapy, in this case, for advanced metastatic breast cancer.


Invertebrate Iridoviruses: A Glance over the Last Decade.
Members of the family Iridoviridae (iridovirids) are large dsDNA viruses that infect both invertebrate and vertebrate ectotherms and whose symptoms range in severity from minor reductions in host fitness to systemic disease and large-scale mortality. Several characteristics have been useful for classifying iridoviruses; however, novel strains are continuously being discovered and, in many cases, reliable classification has been challenging. Further impeding classification, invertebrate iridoviruses (IIVs) can occasionally infect vertebrates; thus, host range is often not a useful criterion for classification. In this review, we discuss the current classification of iridovirids, focusing on genomic and structural features that distinguish vertebrate and invertebrate iridovirids and viral factors linked to host interactions in IIV6 (Invertebrate iridescent virus 6). In addition, we show for the first time how complete genome sequences of viral isolates can be leveraged to improve classification of new iridovirid isolates and resolve ambiguous relations. Improved classification of the iridoviruses may facilitate the identification of genus-specific virulence factors linked with diverse host phenotypes and host interactions.


Memory in mice analyzed with antibiotics. Antibiotics are useful to study stages of memory and to indicate molecular events which sustain memory.
It is apparent that antibiotics are useful in differentiating different stages in the formation of memory. Puromycin gave the first indication that very early memory can be established and survive, for a short period at least, in spite of inhibition of protein synthesis (12). Injection of actinomycin D indicates that RNA synthesis is not essential during this early stage (13). The duration of this early period seems to vary with the inhibiting agent; with puromycin memory was notably degraded in less than an hour, but with actinomycin D or with acetoxycycloheximide it persisted for several hours or more. The fixation or consolidation of memory involves whatever processes give permanence to memory. These processes are disrupted when electroconvulsive shock is administered shortly after a learning experience, presumably because of the interference with organized patterns of neuronal electrical activity. Memory acquired in the presence of antibiotics appears to proceed to a stage beyond that based purely on electrical activity because the memory persists beyond the period usually reported as sensitive to electroconvulsive shock. Further work should show whether this stage is truly insensitive to electroconvulsive shock. Memory acquired in the presence of puromycin does not seem to achieve any durable consolidation. In contrast, memory acquired in the presence of or immediately before injection of acetoxycycloheximide does appear to initiate the later stages of consolidation, as permanent memory. reappears some days after the initial stages have become ineffective in controlling performance. Finally, puromycin has provided evidence of the enlarged area of the neocortex which participates as memory matures. Puromycin also indicates the time required for this maturation process. Since antibiotics have also been useful in studying learning and memory in goldfish (14), this approach seems to have general applicability in defining various stages in the process of memory formation. The initial purpose of these investigations was to determine the molecular basis of the "memory trace" This goal still remains distant, although there are some indications that protein synthesizing systems are involved. This objective, though of enormous interest, is to be regarded as only a necessary first step. Whether new proteins or some other molecules cause the changes in synapses thought to underlie memory, this knowledge of itself will contribute only a beginning to our understanding of the events which account for the functioning of the brain. A determination of the composition of computer components would provide very little information towards unraveling their function. As the experiments proceeded, however, information of a more general nature was being obtained. The identification of different stages of consolidation show how injections of antibiotics can supplement electroconvulsive shock as a way of disrupting the establishment of memory and how it can supplement ablation in destroying memory already laid down in a permanent mode. Applied to larger animals the localization of various regions sensitive or insensitive to the action of the drugs should become more definitive. We hope that such experiments will contribute increasingly to the general problem of brain function.


Amyloid fibrils composed of hexameric peptides attenuate neuroinflammation.
The amyloid-forming proteins tau, αB crystallin, and amyloid P protein are all found in lesions of multiple sclerosis (MS). Our previous work established that amyloidogenic peptides from the small heat shock protein αB crystallin (HspB5) and from amyloid β fibrils, characteristic of Alzheimer's disease, were therapeutic in experimental autoimmune encephalomyelitis (EAE), reflecting aspects of the pathology of MS. To understand the molecular basis for the therapeutic effect, we showed a set of amyloidogenic peptides composed of six amino acids, including those from tau, amyloid β A4, major prion protein (PrP), HspB5, amylin, serum amyloid P, and insulin B chain, to be anti-inflammatory and capable of reducing serological levels of interleukin-6 and attenuating paralysis in EAE. The chaperone function of the fibrils correlates with the therapeutic outcome. Fibrils composed of tau 623-628 precipitated 49 plasma proteins, including apolipoprotein B-100, clusterin, transthyretin, and complement C3, supporting the hypothesis that the fibrils are active biological agents. Amyloid fibrils thus may provide benefit in MS and other neuroinflammatory disorders.


Death and football: an analysis of men's talk about emotions.
This study is concerned with men's talk about emotions and with how emotion discourses function in the construction and negotiation of masculine ways of doing emotions and of consonant masculine subject positions. A sample group of 16 men, who were recruited from two social contexts in England, participated in focus groups on 'men and emotions'. Group discussions were transcribed and analysed using discourse analysis. Participants drew upon a range of discursive resources in constructing masculine emotional behaviour and negotiating masculine subject positions. They constructed men as emotional beings, but only within specific, rule-governed contexts, and cited death, a football match and a nightclub scenario as prototypical contexts for the permissible/understandable expression of grief, joy and anger, respectively. However, in the nightclub scenario, the men distanced themselves from the expression of anger as violence, whilst maintaining a masculine subject position. These discursive practices are discussed in terms of the possibilities for effecting change in men's emotional lives.


Targeting the arginine phosphatase YwlE with a catalytic redox-based inhibitor.
Protein phosphatases are critical regulators of cellular signaling in both eukaryotes and prokaryotes. The majority of protein phosphatases dephosphorylate phosphoserine/phosphothreonine or phosphotyrosine residues. Recently, however, YwlE, a member of the low-molecular weight protein tyrosine phosphatase (LMW-PTP) family, was shown to efficiently target phosphoarginine. YwlE shares several sequence motifs with this family including the C(X)4 CR(S/T) motif that is crucial for catalysis and redox regulation of the enzyme. Herein we confirm that Cys9 and Cys14 play important roles in YwlE catalysis and regulation. On the basis of these observations, we designed and synthesized a YwlE inhibitor, denoted cyc-SeCN-amidine, that irreversibly inhibits YwlE (kinact/KI = 310 M(-1) min(-1)) by inducing disulfide bond formation between the two active site cysteine residues. Interestingly, inactivation appears to be catalytic, since the compound is neither destroyed nor altered after enzyme inhibition. Although the exact mechanism of disulfide induction remains elusive, we propose several potential mechanisms accounting for the cyc-SeCN-amidine mediated inhibition of YwlE. These findings could stimulate the design of similar selenium-based compounds targeting other redox-sensitive enzymes.


RhoA signaling in cardiomyocytes protects against stress-induced heart failure but facilitates cardiac fibrosis.
The Ras-related guanosine triphosphatase RhoA mediates pathological cardiac hypertrophy, but also promotes cell survival and is cardioprotective after ischemia/reperfusion injury. To understand how RhoA mediates these opposing roles in the myocardium, we generated mice with a cardiomyocyte-specific deletion of RhoA. Under normal conditions, the hearts from these mice showed functional, structural, and growth parameters similar to control mice. Additionally, the hearts of the cardiomyocyte-specific, RhoA-deficient mice subjected to transverse aortic constriction (TAC)-a procedure that induces pressure overload and, if prolonged, heart failure-exhibited a similar amount of hypertrophy as those of the wild-type mice subjected to TAC. Thus, neither normal cardiac homeostasis nor the initiation of compensatory hypertrophy required RhoA in cardiomyocytes. However, in response to chronic TAC, hearts from mice with cardiomyocyte-specific deletion of RhoA showed greater dilation, with thinner ventricular walls and larger chamber dimensions, and more impaired contractile function than those from control mice subjected to chronic TAC. These effects were associated with aberrant calcium signaling, as well as decreased activity of extracellular signal-regulated kinases 1 and 2 (ERK1/2) and AKT. In addition, hearts from mice with cardiomyocyte-specific RhoA deficiency also showed less fibrosis in response to chronic TAC, with decreased transcriptional activation of genes involved in fibrosis, including myocardin response transcription factor (MRTF) and serum response factor (SRF), suggesting that the fibrotic response to stress in the heart depends on cardiomyocyte-specific RhoA signaling. Our data indicated that RhoA regulates multiple pathways in cardiomyocytes, mediating both cardioprotective (hypertrophy without dilation) and cardio-deleterious effects (fibrosis).


[Predicting drop-out during the systems training for emotional predictability and problem solving (STEPPS)].
Drop-out is a complex problem in mental health care and in STEPPS. Research has revealed a variety of predicting factors and has produced contradictory results. To investigate whether the information available at the start of STEPPS can pinpoint predictors of drop-out. The ROM data for 150 patients were used to test the link between the following factors: age, gender, education, employment, substance abuse, anxiety, hostility, interpersonal relations, responsibility and social concordance with drop-out. The method used for testing was logistic regression analysis. Factors that contributed significantly to the prediction of drop-out were gender and employment status. These factors made up 16% of the explained variation (R2 Nagelkerkes) in drop-out. Gender was the strongest predictive factor. Concerning the other factors, no differences were found between groups (drop-out and non-dropouts). In its present form STEPPS does not suit a large number of the male participants. Drop-out during STEPPS is hard to predict on the basis of ROM-questionnaires. Future research should focus on preconditions and marginal conditions that influence patients to complete their training.


Must Consent Be Informed? Patient rights, state authority, and the moral basis of the physician's duties of disclosure.
Legal standards of disclosure in a variety of jurisdictions require physicians to inform patients about the likely consequences of treatment, as a condition for obtaining the patient's consent. Such a duty to inform is special insofar as extensive disclosure of risks and potential benefits is not usually a condition for obtaining consent in non-medical transactions.What could morally justify the physician's special legal duty to inform? I argue that existing justifications have tried but failed to ground such special duties directly in basic and general rights, such as autonomy rights. As an alternative to such direct justifications, I develop an indirect justification of physicians' special duties from an argument in Kant's political philosophy. Kant argues that pre-legal rights to freedom are the source of a duty to form a state. The state has the authority to conclusively determine what counts as "consent" in various kinds of transactions. The Kantian account can subsequently indirectly justify at least one legal standard imposing a duty to inform, the reasonable person standard, but rules out one interpretation of a competitor, the subjective standard.


Nature and origins of mathematics difficulties in very preterm children: a different etiology than developmental dyscalculia.
Children born very preterm (<32 wk) are at high risk for mathematics learning difficulties that are out of proportion to other academic and cognitive deficits. However, the etiology of mathematics difficulties in very preterm children is unknown. We sought to identify the nature and origins of preterm children's mathematics difficulties. One hundred and fifteen very preterm children aged 8-10 y were assessed in school with a control group of 77 term-born classmates. Achievement in mathematics, working memory, visuospatial processing, inhibition, and processing speed were assessed using standardized tests. Numerical representations and specific mathematics skills were assessed using experimental tests. Very preterm children had significantly poorer mathematics achievement, working memory, and visuospatial skills than term-born controls. Although preterm children had poorer performance in specific mathematics skills, there was no evidence of imprecise numerical representations. Difficulties in mathematics were associated with deficits in visuospatial processing and working memory. Mathematics difficulties in very preterm children are associated with deficits in working memory and visuospatial processing not numerical representations. Thus, very preterm children's mathematics difficulties are different in nature from those of children with developmental dyscalculia. Interventions targeting general cognitive problems, rather than numerical representations, may improve very preterm children's mathematics achievement.


SugarDrawer: A Web-Based Database Search Tool with Editing Glycan Structures.
In life science fields, database integration is progressing and contributing to collaboration between different research fields, including the glycosciences. The integration of glycan databases has greatly progressed collaboration worldwide with the development of the international glycan structure repository, GlyTouCan. This trend has increased the need for a tool by which researchers in various fields can easily search glycan structures from integrated databases. We have developed a web-based glycan structure search tool, SugarDrawer, which supports the depiction of glycans including ambiguity, such as glycan fragments which contain underdetermined linkages, and a database search for glycans drawn on the canvas. This tool provides an easy editing feature for various glycan structures in just a few steps using template structures and pop-up windows which allow users to select specific information for each structure element. This tool has a unique feature for selecting possible attachment sites, which is defined in the Symbol Nomenclature for Glycans (SNFG). In addition, this tool can input and output glycans in WURCS and GlycoCT formats, which are the most commonly-used text formats for glycan structures.


Insulin replacement therapy in diabetic rats using an osmotic pump normalizes expression of enzymes key to hepatic carbohydrate metabolism.
Intensively treating type I diabetics with continuous subcutaneous insulin infusions or multiple daily insulin injections to normalize mean blood glucose concentrations significantly reduces the onset of secondary diabetic complications when compared to conventionally treated diabetics. Our studies focused on characterizing hepatic enzyme expression in intensively and conventionally treated diabetic rats. Alloxan-induced diabetic rats were conventionally treated with insulin injected twice daily or intensively treated with similar daily dosages of insulin administered via a surgically implanted osmotic pump. Our results demonstrate a significant difference in hepatic enzyme expression when these treatment regimes are compared. In conventionally treated diabetic rats, phosphoenolpyruvate carboxykinase (PEPCK) protein and mRNA levels remained slightly elevated when compared to normal animals, glycogen phosphorylase (GP) protein levels were still slightly decreased, and glycogen synthase (GS) protein and mRNA levels remained at the elevated levels observed in untreated diabetics. In contrast, the protein and mRNA levels of all three enzymes were normalized in the insulin pump-treated animals. These results suggest that intensive insulin therapy improves glycemia directly by normalizing hepatic gene expression while conventional insulin therapy normalizes plasma glucose concentrations indirectly.


Tunable hygromorphism: structural implications of low molecular weight gels and electrospun nanofibers in bilayer composites.
This investigation highlights the potential for electrospun nanofiber mats and self-assembled nanofiber networks to be interfaced synergistically to induce hygromorphic behaviour. Control poly(vinyl alcohol) (PVA) electrospun active layers and 1,3:2,4-di-p-methylbenyliedene sorbitol (MDBS) self-assembled passive layers encapsulated in an ethylene oxide-epichlorohydrin (EO-EPI) copolymer matrix were fabricated to examine the influence of composition on the properties guiding hygromorphism, such as water transport, layer thickness, and layer modulus. Experimentally determined material constants were utilized in conjunction with mathematical modeling to determine ideal layer properties. It was revealed that the active layer with the highest PVA content exhibited the fastest water transport, and the passive layer with the highest MDBS content displayed the slowest water transport. However, the hygromorphic bilayer fabricated utilizing the lowest PVA content and the highest MDBS fraction was predicted to induce the highest change in curvature due to the lower modulus and thickness of the PVA nanofiber active layer. Decreasing the MDBS content reduced the passive layer modulus while increasing water transport, which theoretically reduced the overall bilayer curvature. The hygromorphic bilayer composites fabricated using these ideal control layers exhibited folding bias and response variations dependent upon active layer composition and imposed folding directions. By utilizing the favorable force balances between the active layer with the lower PVA content and the passive layer with the highest MDBS amount in conjunction with folding bias in a non-preferential direction, it was possible to achieve hygromorphic unfolding and refolding with hydration. Through modelling and individual layer examination, a unique platform built on two independent fiber networks has been designed to achieve biomimetic hygromorphism in synthetic bilayer composites.


Differential distribution of mannose-6-phosphate receptors and furin in immature secretory granules.
In neuroendocrine cells sorting of proteins from immature secretory granules (ISGs) occurs during maturation and is achieved by clathrin-coated vesicles containing the adaptor protein (AP)-1. We have investigated the role of the mannose-6-phosphate receptors (M6PRs) in the recruitment of AP-1 to ISGs. M6PRs were detected in ISGs isolated from PC12 cells by subcellular fractionation, and by immuno-EM labelling on cryosections. In light of our previous results, where greater than 80% of the ISGs were found to contain furin, we examined the relationship between furin and M6PR on ISGs. By immunoisolation techniques we find that 50% at most of the ISGs contain the cation-independent (CI)-M6PR. Using sequential immunoisolation we could demonstrate that there are two populations of ISGs: those that have both M6PR and furin, and those which contain only furin. Furthermore, using immobilized GST-fusion proteins containing the cytoplasmic domain of the CI-M6PR we have shown binding of AP-1 requires casein kinase II phosphorylation of the CI-M6PR fusion protein, and in particular phosphorylation of Ser(2474). Addition of these phosphorylated GST-CI-M6PR fusion proteins to a cell-free assay reconstituting AP-1 binding to ISGs inhibits AP-1 recruitment to ISGs.


Comprehensive Proteomic Profiling of Wheat Gluten Using a Combination of Data-Independent and Data-Dependent Acquisition.
Wheat is the most important food crop in the world, the unique physiochemical properties of wheat gluten enabling a diverse range of food products to be manufactured. However, genetic and environmental factors affect the technological properties of gluten in unpredictable ways. Although newer proteomic methods have the potential to offer much greater levels of information, it is the older gel-based methods that remain most commonly used to identify compositional differences responsible for the variation in gluten functionality, in part due to the nature of their primary sequences. A combination of platforms were investigated for comprehensive gluten profiling: a QTOF with a data independent schema, which incorporated ion mobility (DIA-IM-MS) and a data dependent acquisition (DDA) workflow using a linear ion trap quadrupole (LTQ) instrument. In conjunction with a manually curated gluten sequence database a total of 2736 gluten peptides were identified with only 157 peptides identified by both platforms. These data showed 127 and 63 gluten protein accessions to be inferred with a minimum of one and three unique peptides respectively. Of the 63 rigorously identified proteins, 26 were gliadin species (4 ω-, 14 α-, and 8 γ-gliadins) and 37 glutenins (including 29 LMW glutenin and 8 HMW glutenins). Of the HMW glutenins, three were 1Dx type and five were 1Bx type illustrating the challenge of unambiguous identification of highly polymorphic proteins without cultivar specific gene sequences. The capacity of the platforms to sequence longer peptides was crucial to achieving the number of identifications, the combination of QTOF-LTQ technology being more important than extraction method to obtain a comprehensive profile. Widespread glutamine deamidation, a post-translational modification, was observed adding complexity to an already highly polymorphic mixture of proteins, with numerous insertions, deletions and substitutions. The data shown is the most comprehensive and detailed proteomic profile of gluten to date.


Real-time imaging of endothelial cell-cell junctions during neutrophil transmigration under physiological flow.
During inflammation, leukocytes leave the circulation and cross the endothelium to fight invading pathogens in underlying tissues. This process is known as leukocyte transendothelial migration. Two routes for leukocytes to cross the endothelial monolayer have been described: the paracellular route, i.e., through the cell-cell junctions and the transcellular route, i.e., through the endothelial cell body. However, it has been technically difficult to discriminate between the para- and transcellular route. We developed a simple in vitro assay to study the distribution of endogenous VE-cadherin and PECAM-1 during neutrophil transendothelial migration under physiological flow conditions. Prior to neutrophil perfusion, endothelial cells were briefly treated with fluorescently-labeled antibodies against VE-cadherin and PECAM-1. These antibodies did not interfere with the function of both proteins, as was determined by electrical cell-substrate impedance sensing and FRAP measurements. Using this assay, we were able to follow the distribution of endogenous VE-cadherin and PECAM-1 during transendothelial migration under flow conditions and discriminate between the para- and transcellular migration routes of the leukocytes across the endothelium.


Determination of lorazepam in plasma from children by high-performance liquid chromatography with UV detection.
A simple, sensitive, selective, and reproducible reversed-phase high-performance liquid chromatographic (HPLC) method with UV detection was developed for the determination of lorazepam (LZP) in human plasma, using oxazepam (OZP) as internal standard. LZP and OZP were extracted from alkalinized (pH 9.5) spiked and clinical plasma samples using a single step liquid-liquid extraction with a mixture of n-hexane-dichloromethane (70:30%; v/v). Chromatographic separation was performed on a reversed-phase Synergi Max RP analytical column (150 mmx4.6 mm i.d.; 4 microm particle size), using an aqueous mobile phase (10 mM KH2PO4 buffer (pH 2.4)-acetonitrile; 65:35%, v/v) delivered at a flow-rate of 2.5 ml/min. Retention times for OZP and LZP were 10.2 and 11.9 min, respectively. Calibration curves were linear from 10 to 300 ng with correlation coefficients (r2) better than 0.99. The limits of detection (LOD) and quantification (LOQ) were 2.5 and 10 ng/ml, respectively, using 0.5 ml samples. The mean relative recoveries at 20 and 300 ng/ml were 84.1+/-5.5% (n=6) and 72.4+/-5.9% (n=7), respectively; for OZP at 200 ng the value was 68.2+/-6.8% (n=14). The intra-assay relative standard deviations (R.S.D.) at 20, 150 and 270 ng/ml of LZP were 7.8%, 9.8% (n=7 in all cases) and 6.6% (n=8), respectively. The inter-assay R.S.D. at the above concentrations were 15.9%, 7.7% and 8.4% (n=7 in all cases), respectively. Intra- and inter-assay accuracy data were within the acceptance interval of +/-20% of the nominal values. There was no interference from other commonly co-administered anticonvulsant, antimicrobial, antipyretic, and antimalarial drugs. The method has been successfully applied to a pharmacokinetic study of LZP in children with severe malaria and convulsions following administration of a single intravenous dose (0.1 mg/kg body weight) of LZP.


The effects of Tribulus terrestris on body composition and exercise performance in resistance-trained males.
The purpose of this study was to determine the effects of the herbal preparation Tribulus terrestris (tribulus) on body composition and exercise performance in resistance-trained males. Fifteen subjects were randomly assigned to a placebo or tribulus (3.21 mg per kg body weight daily) group. Body weight, body composition, maximal strength, dietary intake, and mood states were determined before and after an 8-week exercise (periodized resistance training) and supplementation period. There were no changes in body weight, percentage fat, total body water, dietary intake, or mood states in either group. Muscle endurance (determined by the maximal number of repetitions at 100-200% of body weight) increased for the bench and leg press exercises in the placebo group (p <.05; bench press +/-28.4%, leg press +/-28.6%), while the tribulus group experienced an increase in leg press strength only (bench press +/-3.1%, not significant; leg press +/-28.6%, p <.05). Supplementation with tribulus does not enhance body composition or exercise performance in resistance-trained males.


A general framework for predicting the transcriptomic consequences of non-coding variation and small molecules.
Genome wide association studies (GWASs) for complex traits have implicated thousands of genetic loci. Most GWAS-nominated variants lie in noncoding regions, complicating the systematic translation of these findings into functional understanding. Here, we leverage convolutional neural networks to assist in this challenge. Our computational framework, peaBrain, models the transcriptional machinery of a tissue as a two-stage process: first, predicting the mean tissue specific abundance of all genes and second, incorporating the transcriptomic consequences of genotype variation to predict individual abundance on a subject-by-subject basis. We demonstrate that peaBrain accounts for the majority (>50%) of variance observed in mean transcript abundance across most tissues and outperforms regularized linear models in predicting the consequences of individual genotype variation. We highlight the validity of the peaBrain model by calculating non-coding impact scores that correlate with nucleotide evolutionary constraint that are also predictive of disease-associated variation and allele-specific transcription factor binding. We further show how these tissue-specific peaBrain scores can be leveraged to pinpoint functional tissues underlying complex traits, outperforming methods that depend on colocalization of eQTL and GWAS signals. We subsequently: (a) derive continuous dense embeddings of genes for downstream applications; (b) highlight the utility of the model in predicting transcriptomic impact of small molecules and shRNA (on par with in vitro experimental replication of external test sets); (c) explore how peaBrain can be used to model difficult-to-study processes (such as neural induction); and (d) identify putatively functional eQTLs that are missed by high-throughput experimental approaches.


Coding of color and form in the geniculostriate visual pathway (invited review).
We review how neurons in the principal pathway connecting the retina to the visual cortex represent information about the chromatic and spatial characteristics of the retinal image. Our examination focuses particularly on individual neurons: what are their visual properties, how might these properties arise, what do these properties tell us about visual signal transformations, and how might these properties be expressed in perception? Our discussion is inclined toward studies on old-world monkeys and where possible emphasizes quantitative work that has led to or illuminates models of visual signal processing.


Affective psychotherapy in post-traumatic reactions guided by affective neuroscience: memory reconsolidation and play.
This paper reviews the affective neuroscience dealing with the effects of traumatic events. We give an overview of the normal fear reactions, the pathological fear reaction, and the character of emotional episodic memories. We find that both emotions and emotional memories are a tripartite unit of sensory information, autonomic reaction, and motor impulse (the PRM complex). We propose that emotions and movements are part and parcel of the same complex. This is our main finding from the review of affective neuroscience, and from here we focus on psychotherapy with post-trauma reactions. The finding of the process of memory reconsolidation opens up a new treatment approach: affective psychotherapy focused on reconsolidation. The meaning of reconsolidation is that an emotional memory, when retrieved and being active, will rest in a labile form, amenable to change, for a brief period of time, until it reconsolidates in the memory. This leads us to the conclusion that emotions, affects, must be evoked during the treatment session and that positive emotion must come first, because safety must be part of the new memories. In the proposed protocol of affective psychotherapy based on reconsolidation the emotional episodic memory is relived in a safe and positive setting, focused in turn on the sensory experience, the autonomic reaction, and the motor impulse. Then it is followed by a fantasy of a different positive version of the same event. All in all treatment should provide a series of new memories without fear related to the original event. With the focus on the motor program, and the actions, there is a natural link to art therapy and to the mode of play, which can rehearse and fantasize new positive actions.


Development and psychometric evaluation of the Treatment Adherence Questionnaire for Patients with Hypertension.
This article is a report of the development and psychometric testing of the Treatment Adherence Questionnaire for Patients with Hypertension. Hypertension is the most prevalent health problem among adult patients affecting approximately 200 million people in China and about 1 billion persons worldwide. Adherence to medication and lifestyle for hypertensive patients result in blood pressure control and reduce adverse outcomes. At present, few specific adherence instruments are available to completely evaluate medication and lifestyle for hypertensive patients. A multi-phase psychometric questionnaire development method was used to develop the instrument. The item pool was generated using literature review and focus group. Content validity was evaluated by expert panel. Then, the field testing was conducted by a convenience sampling of 278 hypertensive patients from December 2009 to May 2010 in Guangdong Province of China. Exploratory and confirmatory factor analyses were used to test construct validity. Finally, internal consistency and test-retest reliability were assessed. The new measure consisted of six dimensions with 28 items, explaining 62·54% of the total variance in the data. Confirmative factor analysis supported a good overall fit of the six-factor model. Cronbach's α of the overall questionnaire was 0·86 and 0·82 for test-retest reliability. The questionnaire was a brief and psychometrically sound instrument to evaluate hypertensive patients' treatment adherence and to be applied in the research and clinical fields.


Multiplexed detection of RNA using MERFISH and branched DNA amplification.
Multiplexed error-robust fluorescence in situ hybridization (MERFISH) allows simultaneous imaging of numerous RNA species in their native cellular environment and hence spatially resolved single-cell transcriptomic measurements. However, the relatively modest brightness of signals from single RNA molecules can become limiting in a number of applications, such as increasing the imaging throughput, imaging shorter RNAs, and imaging samples with high degrees of background, such as some tissue samples. Here, we report a branched DNA (bDNA) amplification approach for MERFISH measurements. This approach produces a drastic signal increase in RNA FISH samples without increasing the fluorescent spot size for individual RNAs or increasing the variation in brightness from spot to spot, properties that are important for MERFISH imaging. Using this amplification approach in combination with MERFISH, we demonstrated RNA imaging and profiling with a near 100% detection efficiency. We further demonstrated that signal amplification improves MERFISH performance when fewer FISH probes are used for each RNA species, which should allow shorter RNAs to be imaged. We anticipate that the combination of bDNA amplification with MERFISH should facilitate many other applications and extend the range of biological questions that can be addressed by this technique in both cell culture and tissues.


Azoospermia: is sample centrifugation indicated? A national survey of practice and the Oxford experience.
Some men with azoospermia on general laboratory testing have low quantities of sperm in the ejaculate that can only be identified through sample centrifugation and careful examination of the pellet droplets (extended sperm preparation [ESP]). Such sperm can be used for IVF-ICSI as an alternative to either surgical sperm retrieval (SSR) or donor sperm. The aims of the present study were to: 1) assess UK IVF clinic practice with regard to ESP in men with azoospermia; and 2) to analyze the outcome of ESP and SSR in azoospermic men attending the Oxford Fertility Unit. National survey of all 70 IVF units plus chart review. Assisted conception unit. One hundred twenty-two azoospermic men referred to the Oxford Fertility Unit. Proportions of UK IVF clinics performing ESP for azoospermia. Proportions of azoospermic men in Oxford with sperm identified at ESP and, if necessary, SSR. Relationship between serum FSH and outcome. In part 1 of the study, 55 (79%) of the 70 UK IVF clinics returned completed questionnaires. Fifty clinics (91%) routinely performed ESP for men with azoospermia on general laboratory testing, four clinics (7%) proceeded straight to SSR without prior ESP, and one clinic varied in their approach. When clinics were asked whether they used serum FSH levels when considering whether to proceed to SSR 28 (51%) did, 9 (16%) did not, and 18 (33%) varied in their approach. The value placed on testicular volume similarly varied. Part 2 of the study included 122 men referred to the Oxford Fertility Unit with azoospermia on general laboratory testing. Eighty-seven men underwent ESP. Motile sperm was found, cryopreserved, and later used during IVF-ICSI treatment in 19 men (22%). Eighty-one men underwent SSR (after either a negative ESP or declining ESP). Viable sperm was found in 66 men undergoing SSR (81%). There was a statistically significant relationship between serum FSH and the chance of retrieving sperm with SSR (P=0.002) but not with ESP. The majority (91%) of IVF clinics in the UK routinely perform ESP in men with azoospermia on general testing. Only half routinely used serum FSH levels as predictors of SSR outcome. The value of ESP is confirmed by our findings in Oxford. Twenty-two percent of men with azoospermia on general laboratory testing had sufficient sperm found at ESP to proceed to IVF-ICSI without resorting to the use of either SSR or donor sperm. Serum FSH levels were not related to the chance of finding sperm during ESP but were related to the outcome of SSR. Our results suggest that ESP should be considered for all men with azoospermia and no apparent obstruction.


Optimized delivery system achieves enhanced endomyocardial stem cell retention.
Regenerative cell-based therapies are associated with limited myocardial retention of delivered stem cells. The objective of this study is to develop an endocardial delivery system for enhanced cell retention. Stem cell retention was simulated in silico using 1- and 3-dimensional models of tissue distortion and compliance associated with delivery. Needle designs, predicted to be optimal, were accordingly engineered using nitinol, a nickel and titanium alloy displaying shape memory and superelasticity. Biocompatibility was tested with human mesenchymal stem cells. Experimental validation was performed with species-matched cells directly delivered into Langendorff-perfused porcine hearts or administered percutaneously into the endocardium of infarcted pigs. Cell retention was quantified by flow cytometry and real-time quantitative polymerase chain reaction methodology. Models, computing optimal distribution of distortion calibrated to favor tissue compliance, predicted that a 75°-curved needle featuring small-to-large graded side holes would ensure the highest cell retention profile. In isolated hearts, the nitinol curved needle catheter (C-Cath) design ensured 3-fold superior stem cell retention compared with a standard needle. In the setting of chronic infarction, percutaneous delivery of stem cells with C-Cath yielded a 37.7±7.1% versus 10.0±2.8% retention achieved with a traditional needle without effect on biocompatibility or safety. Modeling-guided development of a nitinol-based curved needle delivery system with incremental side holes achieved enhanced myocardial stem cell retention.


Pulmonary disease in polymyositis/dermatomyositis: a clinicopathological analysis of 65 autopsy cases.
The clinical and autopsy records of 65 patients with either polymyositis (24) or dermatomyositis (41) and pulmonary disease were reviewed. Pulmonary symptoms were recorded in 43 of the cases and included dyspnoea in 31, cough in 23, and chest pain in six. Interstitial lung disease was noted at autopsy in 27 patients; almost half of these had arthritis. Bronchopneumonia was found in 35 patients, 31 of these had received prednisone. Dysphagia was present in a similar proportion of patients with and without pneumonia. Pulmonary vasculitis was seen in five patients; pulmonary symptoms, arthritis, and raised erythrocyte sedimentation rate were present in four of these cases and all five had associated interstitial lung disease. Other pulmonary manifestations included pulmonary oedema, primary pulmonary malignancy, diffuse alveolar damage, fibrinous pleuritis, pulmonary emboli, and diaphragmatic atrophy. The mean survival after disease onset was 29 months but was much less for those with interstitial lung disease and pulmonary vasculitis.


Brain networks in Huntington disease.
Recent studies have focused on understanding the neural mechanisms underlying the emergence of clinical signs and symptoms in early stage Huntington disease (HD). Although cell-based assays have focused on cell autonomous effects of mutant huntingtin, animal HD models have revealed alterations in the function of neuronal networks, particularly those linking the cerebral cortex and striatum. These findings are complemented by metabolic imaging studies of disease progression in premanifest subjects. Quantifying metabolic progression at the systems level may identify network biomarkers to aid in the objective assessment of new disease-modifying therapies and identify new regions that merit mechanistic study in HD models.


Cognitive function at 3 years of age after fetal exposure to antiepileptic drugs.
Fetal exposure of animals to antiepileptic drugs at doses lower than those required to produce congenital malformations can produce cognitive and behavioral abnormalities, but cognitive effects of fetal exposure of humans to antiepileptic drugs are uncertain. Between 1999 and 2004, we enrolled pregnant women with epilepsy who were taking a single antiepileptic agent (carbamazepine, lamotrigine, phenytoin, or valproate) in a prospective, observational, multicenter study in the United States and the United Kingdom. The primary analysis is a comparison of neurodevelopmental outcomes at the age of 6 years after exposure to different antiepileptic drugs in utero. This report focuses on a planned interim analysis of cognitive outcomes in 309 children at 3 years of age. At 3 years of age, children who had been exposed to valproate in utero had significantly lower IQ scores than those who had been exposed to other antiepileptic drugs. After adjustment for maternal IQ, maternal age, antiepileptic-drug dose, gestational age at birth, and maternal preconception use of folate, the mean IQ was 101 for children exposed to lamotrigine, 99 for those exposed to phenytoin, 98 for those exposed to carbamazepine, and 92 for those exposed to valproate. On average, children exposed to valproate had an IQ score 9 points lower than the score of those exposed to lamotrigine (95% confidence interval [CI], 3.1 to 14.6; P=0.009), 7 points lower than the score of those exposed to phenytoin (95% CI, 0.2 to 14.0; P=0.04), and 6 points lower than the score of those exposed to carbamazepine (95% CI, 0.6 to 12.0; P=0.04). The association between valproate use and IQ was dose dependent. Children's IQs were significantly related to maternal IQs among children exposed to carbamazepine, lamotrigine, or phenytoin but not among those exposed to valproate. In utero exposure to valproate, as compared with other commonly used antiepileptic drugs, is associated with an increased risk of impaired cognitive function at 3 years of age. This finding supports a recommendation that valproate not be used as a first-choice drug in women of childbearing potential.


Flight activity and age cause wing damage in house flies.
Wing damage attenuates aerial performance in many flying animals such as birds, bats and insects. Insect wings are especially light in order to reduce inertial power requirements for flight at elevated wing flapping frequencies. There is a continuing debate on the factors causing wing damage in insects, including collisions with objects, mechanical stress during flight activity, and aging. This experimental study addressed the reasons for and significance of wing damage for flight in the house fly Musca domestica. We determined natural wing area loss under two housing conditions and recorded flight activity and flight ability throughout the animals' lifetime. Our data show that in animals with eventually pronounced damage, wing damage occurs on average after 6 h of flight, is sex specific and depends on housing conditions. Statistical tests show that physiological age and flight activity have similar significance as predictors for wing damage. Tests on freely flying flies showed that minimum wing area for active flight is approximately 10-34% below the initial area and requires a left-right wing area asymmetry of less than approximately 25%. Our findings broadly confirm predictions from simple aerodynamic theory based on mean wing velocity and area, and are also consistent with previous wing damage measurements in other insect species.


Artificial ears for a biomimetic sonarhead: from multiple reflectors to surfaces.
This work presents an evolutionary approach to pinna design. Narrowband echolocating bats move the pinna to alter the directional sensitivity of their perceptual systems. Adding pinnae to RoBat--a biomimetic sonarhead mounted on a mobile robot--is the goal of this work. After a description of the earlier work on artificial pinnae consisting of multiple reflectors around the transducer, an acoustic model, inspired by a physical model of sound diffraction and reflections in the human concha, is described and revisited as the model to use for evolving complex shapes. A genetic algorithm evolved the shape of the pinnae with respect to desired features of the directivity pattern of the receiver transducers. Some interesting paraboloid shapes for specific echolocating behaviors were evolved, improving performance with respect to the bare transducer's performance.