Inflammatory dilated cardiomyopathy in Abcg5-deficient mice.
Dilated cardiomyopathy (DCM) in A/J mice homozygous for the spontaneous thrombocytopenia and cardiomyopathy (trac) mutation results from a single base pair change in the Abcg5 gene. A similar mutation in humans causes sitosterolemia with high plant sterol levels, hypercholesterolemia, and early onset atherosclerosis. Analyses of CD3+ and Mac-3+ cells and stainable collagen in hearts showed inflammation and myocyte degeneration in A/J-trac/trac mice beginning postweaning and progressed to marked dilative and fibrosing cardiomyopathy by 140 days. Transmission electron microscopy (TEM) demonstrated myocyte vacuoles consistent with swollen endoplasmic reticulum (ER). Myocytes with cytoplasmic glycogen and irregular actinomyosin filament bundles formed mature intercalated disks with normal myocytes suggesting myocyte repair. A/J-trac/trac mice fed lifelong phytosterol-free diets did not develop cardiomyopathy. BALB/cByJ-trac/trac mice had lesser inflammatory infiltrates and later onset DCM. BALB/cByJ-trac/trac mice changed from normal to phytosterol-free diets had lesser T cell infiltrates but persistent monocyte infiltrates and equivalent fibrosis to mice on normal diets. B- and T-cell-deficient BALB/cBy-Rag1(null) trac/trac mice fed normal diets did not develop inflammatory infiltrates or DCM. We conclude that the trac/trac mouse has many features of inflammatory DCM and that the reversibility of myocardial T cell infiltration provides a novel model for investigating the progression of myocardial fibrosis.


Significance of Microbiota in Obesity and Metabolic Diseases and the Modulatory Potential by Medicinal Plant and Food Ingredients.
Metabolic syndrome is a cluster of three or more metabolic disorders including insulin resistance, obesity, and hyperlipidemia. Obesity has become the epidemic of the twenty-first century with more than 1.6 billion overweight adults. Due to the strong connection between obesity and type 2 diabetes, obesity has received wide attention with subsequent coining of the term "diabesity." Recent studies have identified unique contributions of the immensely diverse gut microbiota in the pathogenesis of obesity and diabetes. Several mechanisms have been proposed including altered glucose and fatty acid metabolism, hepatic fatty acid storage, and modulation of glucagon-like peptide (GLP)-1. Importantly, the relationship between unhealthy diet and a modified gut microbiota composition observed in diabetic or obese subjects has been recognized. Similarly, the role of diet rich in polyphenols and plant polysaccharides in modulating gut bacteria and its impact on diabetes and obesity have been the subject of investigation by several research groups. Gut microbiota are also responsible for the extensive metabolism of polyphenols thus modulating their biological activities. The aim of this review is to shed light on the composition of gut microbes, their health importance and how they can contribute to diseases as well as their modulation by polyphenols and polysaccharides to control obesity and diabetes. In addition, the role of microbiota in improving the oral bioavailability of polyphenols and hence in shaping their antidiabetic and antiobesity activities will be discussed.


A divergent approach to the synthesis of iGb3 sugar and lipid analogues via a lactosyl 2-azido-sphingosine intermediate.
Isoglobotrihexosylceramide (iGb3, 1) is an immunomodulatory glycolipid that binds to CD1d and is presented to the T-cell receptor (TCR) of invariant natural killer T (iNKT) cells. To investigate how modifications to the lipid tail or terminal sugar residue of iGb3 influence iNKT cell activity, we developed an efficient and divergent synthetic route that provided access to both sugar and lipid iGb3 analogues which utilised a lactosyl 2-azido-sphingosine derivative as a common intermediate. In this way, iGb3 (1) and the unprecedented analogues 6'''-deoxy-iGb3-sphingosine 2, 6'''-deoxy-iGb3-sphinganine 3, C12 N-acyl iGb3 4 and C20:2 N-acyl iGb3 5 were prepared so that key structure-activity relationships can be explored.


An MEG-based brain-computer interface (BCI).
Brain-computer interfaces (BCIs) allow for communicating intentions by mere brain activity, not involving muscles. Thus, BCIs may offer patients who have lost all voluntary muscle control the only possible way to communicate. Many recent studies have demonstrated that BCIs based on electroencephalography (EEG) can allow healthy and severely paralyzed individuals to communicate. While this approach is safe and inexpensive, communication is slow. Magnetoencephalography (MEG) provides signals with higher spatiotemporal resolution than EEG and could thus be used to explore whether these improved signal properties translate into increased BCI communication speed. In this study, we investigated the utility of an MEG-based BCI that uses voluntary amplitude modulation of sensorimotor mu and beta rhythms. To increase the signal-to-noise ratio, we present a simple spatial filtering method that takes the geometric properties of signal propagation in MEG into account, and we present methods that can process artifacts specifically encountered in an MEG-based BCI. Exemplarily, six participants were successfully trained to communicate binary decisions by imagery of limb movements using a feedback paradigm. Participants achieved significant mu rhythm self control within 32 min of feedback training. For a subgroup of three participants, we localized the origin of the amplitude modulated signal to the motor cortex. Our results suggest that an MEG-based BCI is feasible and efficient in terms of user training.


Streptococcal toxic shock syndrome in southern Taiwan.
This report outlines our experience with streptococcal toxic shock syndrome (STSS) at the Veterans General Hospital-Kaohsiung during the period October 1990 to November 1993. Group A streptococci were isolated from blood or normally sterile tissue in association with hypotension and multi-organ failure in the eight cases studied. A primary focus of infection was identified in seven cases, including pneumonia (1), septic arthritis (1) and soft-tissue infections (5). The remaining patient suffered from hyperglycemic hyperosmolar non-ketotic coma and Group A streptococcal bacteremia, without an obvious focus of infection. There were four cases of bacteremia. Clinical complications included acute renal failure in all eight cases, disseminated intravascular coagulation in five cases, liver involvement in two cases, adult respiratory distress syndrome in one case and soft-tissue necrosis in five cases. All isolates were sensitive to penicillin, and most patients were treated with intravenous penicillin G, with or without other antibiotics (gentamicin or clindamycin). Of the six patients with soft-tissue infection, two underwent amputation of the infected limb, and one patient underwent sono-guided pigtail drainage of psoas muscle abscess. Three of the patients died. STSS may be uncommon in Taiwan, but it is not rare. Early recognition of STSS (facilitated by Gram stain and culture), prompt debridement and drainage, and adequate antibiotic treatment with penicillin or clindamycin, or both, are necessary for control of such lethal infections.


Magnetic bead-based salivary peptidome profiling for periodontal-orthodontic treatment.
Patients with periodontitis seek periodontal-orthodontic treatment to address certain functional and aesthetic problems. However, little is known of the effect of periodontitis on orthodontic treatment. Thus, we compared the differences in peptide mass fingerprints of orthodontic patients with and without periodontitis by MALDI-TOF MS using a magnetic bead-based peptidome analysis of saliva samples. In this way, we aimed to identify and explore a panel of differentially-expressed specific peptides. Saliva samples from 24 patients (eight orthodontic patients without periodontitis, eight with periodontitis and another eight with periodontitis but no orthodontic treatment) were analyzed, and peptide mass fingerprints were created by scanning MS signals using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) combined with magnetic beads. Nine mass peaks showed significant differences. Orthodontic patients in the group without periodontal disease showed higher mass peaks for seven peptides of the nine, whereas the mass peaks for the other two peptides were higher in the periodontal-orthodontic patients. Besides, these differentially-expressed peptides were sequenced. The elucidated candidate biomarkers indicated interactions between periodontal condition and orthodontic treatment and their contributions to the changes of saliva protein profiles. Our results provide novel insight into the altered salivary protein profile during periodontal-orthodontic treatment, and may lead to the development of a therapeutic monitoring strategy for periodontics and orthodontics.


The management of splenic artery aneurysms: experience with 23 cases.
Splenic artery aneurysms (SAA) are rare clinical entities that carry the risk of rupture and fatal hemorrhage. They are being detected with increased frequency and often cause a clinical dilemma, particularly when small lesions occur in compromised patients. This paper relates our experience in the management of SAA over a 14-year period. We analyzed data from the medical charts and radiological images of all patients diagnosed with SAA at Emory University Hospital from December 1979 to January 1993. A search of medical records discovered 23 patients who experienced 44 SAAs during the time period under study. Twelve patients had multiple SAAs, most of them in the distal third of the artery. Seven had SAAs > 2 cm in diameter. Modalities used to diagnose SAA included Doppler ultrasound in 9 patients, computerized tomography in 10, and arteriography in 21. Sixteen patients had portal hypertension. Splenomegaly was present in 13 of those with portal hypertension. Aneurysm excision and splenectomy were carried out emergently on 2 patients and electively on 1. Aneurysm ligation was performed on 3 patients. One patient underwent embolization of the lesion. Sixteen asymptomatic patients whose aneurysms were < 2 cm in diameter were treated expectantly for a mean period of 3 years. One patient who received active treatment died. There were no documented deaths attributable to SAA among patients treated by observation. Six patients in this group died of unrelated causes. The longest follow-up was 7 years. We support current criteria that call for active treatment of symptomatic or enlarging SAAs, with particular emphasis on treating women anticipating pregnancy and patients undergoing orthotopic liver transplantations. For most other cases, expectant treatment is acceptable.


Hyperammonemia-mediated autophagy in skeletal muscle contributes to sarcopenia of cirrhosis.
Hyperammonemia and sarcopenia (loss of skeletal muscle) are consistent abnormalities in cirrhosis and portosystemic shunting. We have shown that muscle ubiquitin-proteasome components are not increased with hyperammonemia despite sarcopenia. This suggests that an alternative mechanism of proteolysis contributes to sarcopenia in cirrhosis. We hypothesized that autophagy could be this alternative pathway since we observed increases in classic autophagy markers, increased LC3 lipidation, beclin-1 expression, and p62 degradation in immunoblots of skeletal muscle protein in cirrhotic patients. We observed similar changes in these autophagy markers in the portacaval anastamosis (PCA) rat model. To determine the mechanistic relationship between hyperammonemia and autophagy, we exposed murine C(2)C(12) myotubes to ammonium acetate. Significant increases in LC3 lipidation, beclin-1 expression, and p62 degradation occurred by 1 h, whereas autophagy gene expression (LC3, Atg5, Atg7, beclin-1) increased at 24 h. C(2)C(12) cells stably expressing GFP-LC3 or GFP-mCherry-LC3 constructs showed increased formation of mature autophagosomes supported by electron microscopic studies. Hyperammonemia also increased autophagic flux in mice, as quantified by an in vivo autophagometer. Because hyperammonemia induces nitration of proteins in astrocytes, we quantified global muscle protein nitration in cirrhotic patients, in the PCA rat, and in C(2)C(12) cells treated with ammonium acetate. Increased protein nitration was observed in all of these systems. Furthermore, colocalization of nitrated proteins with GFP-LC3-positive puncta in hyperammonemic C(2)C(12) cells suggested that autophagy is involved in degradation of nitrated proteins. These observations show that increased skeletal muscle autophagy in cirrhosis is mediated by hyperammonemia and may contribute to sarcopenia of cirrhosis.


Duplications of hox gene clusters and the emergence of vertebrates.
The vertebrate body plan is characterized by an increased complexity relative to that of all other chordates and large-scale gene amplifications have been associated with key morphological innovations leading to their remarkable evolutionary success. Here, we use compound full Hox clusters deletions to investigate how Hox genes duplications may have contributed to the emergence of vertebrate-specific innovations. We show that the combined deletion of HoxA and HoxB leads to an atavistic heart phenotype, suggesting that the ancestral HoxA/B cluster was co-opted to help in diversifying the complex organ in vertebrates. Other phenotypic effects observed seem to illustrate the resurgence of ancestral (plesiomorphic) features. This indicates that the duplications of Hox clusters were associated with the recruitment or formation of novel cis-regulatory controls, which were key to the evolution of many vertebrate features and hence to the evolutionary radiation of this group.


Chronic illness management and health literacy: an overview.
Poor literacy skills can severely compromise effective chronic illness management by the patient. Practitioners' awareness of the prevalence of low health literacy, or the ability to understand and appropriately act on healthcare instructions, among their patients is a first step toward making changes in the practice to ensure patients understand how to manage their chronic illnesses. Researchers and clinicians in the health literacy field gathered recently at a national health literacy conference and shared techniques used and studied in their practices to aid in more effective provider-patient communications and to help improve outcomes and successful patient management of their chronic illnesses.


Estimation of district-level under-5 mortality in Zambia using birth history data, 1980-2010.
Birth history data-the primary source of data on under-5 mortality in developing countries-are infrequently used for subnational estimates due to concerns over small sample sizes. In this study we consider different methods for analyzing birth history data in combination with various small area models. We construct a simulation environment to assess the performance of different combinations of birth history methods and small area models in terms of bias, efficiency, and coverage. We find that performance is highly dependent on the birth history method applied and how temporal trends are accounted for. We estimated trends in district-level under-5 mortality in Zambia from 1980 to 2010 using the best-performing model. We find that under-5 mortality is highly variable within Zambia: there was a 1.8-fold difference between the lowest and highest levels in 2010, and declines over the period 1980 to 2010 ranged from less than 5% to more than 50%.


High-density lipoprotein cholesterol associated with change in coronary plaque lipid burden assessed by near infrared spectroscopy.
Little is known about the relation between serum lipid parameters and serial change in plaque composition using in vivo coronary imaging. The aim of this study was to examine the association between serum lipids and change in coronary plaque lipid burden assessed by near-infrared spectroscopy (NIRS). We performed serial NIRS-intravascular ultrasound studies in 49 patients who underwent coronary angiography for an acute coronary syndrome (ACS) or stable ischemic symptoms. Univariable and multivariable linear regression analyses were applied to evaluate the relationship between serum lipid parameters and change in lipid core burden index at the 4-mm maximal segment (max LCBI4mm). Mean patient age was 61 ± 9 y, 29% were women, 35% had an ACS clinical presentation, 78% received statin therapy at baseline, and median low-density lipoprotein cholesterol, high-density lipoprotein cholesterol (HDL-C), total cholesterol and triglyceride levels were 101, 43, 174 and 133 mg/dL, respectively. During a median follow-up period of 13 months, max LCBI4mm significantly decreased from 277 to 194 (p = 0.001). On univariable analysis, the percent change in HDL-C negatively associated with the change in max LCBI4mm (β = -3.19, p = 0.004). There were no significant associations between the other lipid parameters and change in max LCBI4mm. On multivariable analysis, percent change in HDL-C remained significantly associated with the change in max LCBI4mm (p = 0.002). Change in HDL-C, but not other lipids parameters, associated with changes in coronary plaque lipid burden assessed by NIRS. These findings highlight the potential therapeutic importance of high-density lipoprotein on serial change in plaque composition.


Support for the prion hypothesis for inheritance of a phenotypic trait in yeast.
A cytoplasmically inherited genetic element in yeast, [PSI+], was confirmed to be a prionlike aggregate of the cellular protein Sup35 by differential centrifugation analysis and microscopic localization of a Sup35-green fluorescent protein fusion. Aggregation depended on the intracellular concentration and functional state of the chaperone protein Hsp104 in the same manner as did [PSI+] inheritance. The amino-terminal and carboxy-terminal domains of Sup35 contributed to the unusual behavior of [PSI+]. [PSI+] altered the conformational state of newly synthesized prion proteins, inducing them to aggregate as well, thus fulfilling a major tenet of the prion hypothesis.


The critical need for accurately defining digital ulcers in scleroderma.
Digital ulcers are one of the key predictors of disease progression and quality of life in patients with systemic sclerosis. Choosing the right treatment for the individual patient begins at developing a consensus among clinicians of what constitutes a digital ulcer. The aim of this editorial is to describe the high unmet need for a standardized method of defining digital ulcers, which is a major challenge not only for treatment, but also for development of new therapies. We discuss the potential role of ultrasound in the development of a validated definition of digital ulcers in systemic sclerosis.


Early mesozoic coexistence of amniotes and hepadnaviridae.
Hepadnaviridae are double-stranded DNA viruses that infect some species of birds and mammals. This includes humans, where hepatitis B viruses (HBVs) are prevalent pathogens in considerable parts of the global population. Recently, endogenized sequences of HBVs (eHBVs) have been discovered in bird genomes where they constitute direct evidence for the coexistence of these viruses and their hosts from the late Mesozoic until present. Nevertheless, virtually nothing is known about the ancient host range of this virus family in other animals. Here we report the first eHBVs from crocodilian, snake, and turtle genomes, including a turtle eHBV that endogenized >207 million years ago. This genomic "fossil" is >125 million years older than the oldest avian eHBV and provides the first direct evidence that Hepadnaviridae already existed during the Early Mesozoic. This implies that the Mesozoic fossil record of HBV infection spans three of the five major groups of land vertebrates, namely birds, crocodilians, and turtles. We show that the deep phylogenetic relationships of HBVs are largely congruent with the deep phylogeny of their amniote hosts, which suggests an ancient amniote-HBV coexistence and codivergence, at least since the Early Mesozoic. Notably, the organization of overlapping genes as well as the structure of elements involved in viral replication has remained highly conserved among HBVs along that time span, except for the presence of the X gene. We provide multiple lines of evidence that the tumor-promoting X protein of mammalian HBVs lacks a homolog in all other hepadnaviruses and propose a novel scenario for the emergence of X via segmental duplication and overprinting of pre-existing reading frames in the ancestor of mammalian HBVs. Our study reveals an unforeseen host range of prehistoric HBVs and provides novel insights into the genome evolution of hepadnaviruses throughout their long-lasting association with amniote hosts.


[A comparative evaluation of amphotericin pharmacokinetics in the skin and subcutaneous fatty tissue when used dermally and by phonophoresis].
During the combined use of the ointment with amphotericin B and ultrasound after 1, 3, 24, 48 and 72 hours there was detected a higher content of the drug in the skin and the subcutaneous fatty tissue as compared with the epicutaneous application of the ointment without ultrasound. The drug contents in the insonified and non-insonified samples increased by the 3rd hour after the application except the insonified skin, where the maximal values were noted after 1 hour; subsequently (after 24, 48 and 72 hours) amphotericin B concentration gradually decreased. It remained significantly higher in the insonified samples than in the non-insonified ones. The data ground the expediency of using the ointment with amphotericin B in combination with ultrasound in candidosis that is one of the ways of increasing the effectiveness of treatment of this disease.


Regression of in-water radiometric profile data.
This study addresses the regression of in-water radiometric profile data with the objective of investigating solutions to minimize uncertainties of derived products like subsurface radiance and irradiance (L(u0) and E(d0)) and diffuse attenuation coefficients. Analyses are conducted using radiometric profiles generated through Monte Carlo simulations and field measurements. A nonlinear NL approach is presented as an alternative to the standard linear method LN. Results indicate that the LN method, relying on log-transformed data, tends to underestimate regression results with respect to NL operating on non-transformed data. The log-transformation is thus identified as the source of biases in data products. Observed differences between LN and NL regression results for L(u0) are of the order of 1-2%, that is well below the target uncertainty for data products from in situ measurements (i.e., 5%). For E(d0), instead, differences can easily exceed 5% as a result of more pronounced light focusing and defocusing effects due to wave perturbations. This work also remarks the importance of applying the multi-cast measurement scheme as a mean to increase the precision of data products.


Pathology of deaths associated with "ecstasy" and "eve" misuse.
To study the postmortem pathology associated with ring substituted amphetamine (amphetamine derivatives) misuse. The postmortem findings in deaths associated with the ring substituted amphetamines 3,4-methylenedioxymethyl-amphetamine (MDMA, ecstasy) and 3,4-methylenedioxyethylamphetamine (MDEA, eve) were studied in seven young white men aged between 20 and 25 years. Striking changes were identified in the liver, which varied from foci of individual cell necrosis to centrilobular necrosis. In one case there was massive hepatic necrosis. Changes consistent with catecholamine induced myocardial damage were seen in five cases. In the brain perivascular haemorrhagic and hypoxic changes were identified in four cases. Overall, the changes in four cases were the same as those reported in heart stroke, although only two cases had a documented history of hyperthermia. Of these four cases, all had changes in their liver, three had changes in their brains, and three in their heart. Of the other three cases, one man died of fulminant liver failure, one of water intoxication and one probably from a cardiac arrhythmia associated with myocardial fibrosis. These data suggest that there is more than one mechanism of damage in ring substituted amphetamine misuse, injury being caused by hyperthermia in some cases, but with ring substituted amphetamines also possibly having a toxic effect on the liver and other organs in the absence of hyperthermia.


Prevention of dentine erosion by brushing with anti-erosive toothpastes.
This in vitro study aimed to investigate the preventive effect of brushing with anti-erosive toothpastes compared to a conventional fluoride toothpaste on dentine erosion. Bovine dentine specimens (n=12 per subgroup) were eroded in an artificial mouth (6 days, 6×30 s/day) using either citric acid (pH:2.5) or a hydrochloric acid/pepsin solution (pH:1.6), simulating extrinsic or intrinsic erosive conditions, respectively. In between, the specimens were rinsed with artificial saliva. Twice daily, the specimens were brushed for 15 s in an automatic brushing machine at 2.5 N with a conventional fluoride toothpaste slurry (elmex, AmF) or toothpaste slurries with anti-erosive formulations: Apacare (NaF/1% nHAP), Biorepair (ZnCO3-HAP), Chitodent (Chitosan), elmex Erosionsschutz (NaF/AmF/SnCl2/Chitosan), mirasensitive hap (NaF/30% HAP), Sensodyne Proschmelz (NaF/KNO3). Unbrushed specimens served as control. Dentine loss was measured profilometrically and statistically analysed using two-way and one-way ANOVA followed by Scheffe's post hoc tests. RDA-values of all toothpastes were determined, and linear mixed models were applied to analyse the influence of toothpaste abrasivity on dentine wear (p<0.05). Dentine erosion of unbrushed specimens amounted to 5.1±1.0 μm (extrinsic conditions) and 12.9±1.4 μm (intrinsic conditions). All toothpastes significantly reduced dentine erosion by 24-67% (extrinsic conditions) and 21-40% (intrinsic conditions). Biorepair was least effective, while all other toothpastes were not significantly different from each other. Linear mixed models did not show a significant effect of the RDA-value of the respective toothpaste on dentine loss. Toothpastes with anti-erosive formulations reduced dentine erosion, especially under simulated extrinsic erosive conditions, but were not superior to a conventional fluoride toothpaste.


Control of mRNA export and translation termination by inositol hexakisphosphate requires specific interaction with Gle1.
The unidirectional translocation of messenger RNA (mRNA) through the aqueous channel of the nuclear pore complex (NPC) is mediated by interactions between soluble mRNA export factors and distinct binding sites on the NPC. At the cytoplasmic side of the NPC, the conserved mRNA export factors Gle1 and inositol hexakisphosphate (IP(6)) play an essential role in mRNA export by activating the ATPase activity of the DEAD-box protein Dbp5, promoting localized messenger ribonucleoprotein complex remodeling, and ensuring the directionality of the export process. In addition, Dbp5, Gle1, and IP(6) are also required for proper translation termination. However, the specificity of the IP(6)-Gle1 interaction in vivo is unknown. Here, we characterize the biochemical interaction between Gle1 and IP(6) and the relationship to Dbp5 binding and stimulation. We identify Gle1 residues required for IP(6) binding and show that these residues are needed for IP(6)-dependent Dbp5 stimulation in vitro. Furthermore, we demonstrate that Gle1 is the primary target of IP(6) for both mRNA export and translation termination in vivo. In Saccharomyces cerevisiae cells, the IP(6)-binding mutants recapitulate all of the mRNA export and translation termination defects found in mutants depleted of IP(6). We conclude that Gle1 specifically binds IP(6) and that this interaction is required for the full potentiation of Dbp5 ATPase activity during both mRNA export and translation termination.


Evaluation of Enrichment for Reptiles in Zoos.
Studies on environmental enrichment for reptiles are lacking in the scientific literature. Although the literature reflects a limited take on reptile enrichment in the zoological community, it may not be the case in reality as enrichment is generally considered an important aspect of the care of nonhuman animals in captivity. This project investigated the current state of reptile enrichment as it is being used in zoos. Although respondents were disproportionately accredited by the Association of Zoos and Aquariums, the results showed many forms of enrichment being used for reptiles in zoos and happening at much greater levels than what has been suggested in the scientific literature. There were significant differences between a) reptile groups for each form of enrichment, and b) enrichment forms within each reptile group, except with the use of natural enrichment devices and structural/habitat design, which did not differ across all reptile groups. Enrichment goals, assessment methods, and sources of information for reptile enrichment used by zoos suggest the need for more scientific publications for facilities to make evidence-based decisions to improve the welfare of reptiles in captivity.


Self-Assembly and Collagen-Stimulating Activity of a Peptide Amphiphile Incorporating a Peptide Sequence from Lumican.
The self-assembly and bioactivity of a peptide amphiphile (PA) incorporating a 13-residue sequence derived from the last 13 amino acids of the C-terminus of lumican, C16-YEALRVANEVTLN, attached to a hexadecyl (C16) lipid chain have been examined. Lumican is a proteoglycan found in many types of tissue and is involved in collagen fibril organization. A critical aggregation concentration (cac) for the PA was determined through pyrene fluorescence measurements. The structure of the aggregates was imaged using electron microscopy, and twisted and curved nanotapes were observed. In situ small-angle X-ray scattering and fiber X-ray diffraction reveal that these tapes contain interdigitated bilayers of the PA molecules. FTIR and circular dichroism spectroscopy and fiber X-ray diffraction indicate that the lumican sequence in the PA adopts a β-sheet secondary structure. Cell assays using human dermal fibroblasts show that below the cac the PA displays good biocompatibility and also stimulates collagen production over a period of 3 weeks, exceeding a 2-fold enhancement for several concentrations. Thus, this PA has promise in future biological applications, in particular, in tissue engineering.


Risk of lymphoid neoplasms in a Swedish population-based cohort of 337,437 patients undergoing appendectomy.
Appendectomy remains one of the most common surgical procedures, but possible long-term consequences for health and disease are incompletely investigated. The appendix forms part of the secondary lymphoid system and appendectomy has been associated with increased risks of hematolymphoproliferative malignancies in some studies. We examined the risk of lymphoid neoplasms in a large cohort of 337,437 appendectomised patients <60 years of age in Sweden 1975-2009. We estimated relative risks of non-Hodgkin lymphoma (NHL) and major subtypes, Hodgkin lymphoma (HL), chronic lymphocytic leukaemia (CLL), myeloma, and acute lymphoblastic leukaemia (ALL) versus the general population using standardised incidence ratios (SIRs) with 95% confidence intervals (CIs). There was no increased risk of NHL (SIR = 0.97, 95%CI 0.88-1.06), major NHL subtypes, CLL (SIR = 0.87, 95%CI 0.70-1.06), myeloma (SIR = 1.14, 95%CI 0.96-1.33) or ALL (SIR = 1.10, 95%CI 0.80-1.47) following appendectomy. An increased risk of HL was observed among patients diagnosed with appendicitis (SIR = 1.29, 95%CI 1.07-1.54, p=0.007), especially individuals aged <20 years at surgery (SIR = 1.43, 95%CI 1.11-1.82), and for the nodular sclerosis subtype of HL (SIR = 1.55, 95%CI 1.01-2.27). A marginally increased risk of myeloma was noted among men, but the association was limited to the first few years of follow-up. Appendectomy is not associated with any notable increase in risk of lymphoid neoplasms. A small increased risk of HL following appendicitis (rather than appendectomy per se) could reflect a true association, or shared susceptibility to infection/inflammation among individuals prone to develop HL. The association observed for myeloma may be explained by chance or surveillance bias.


Acoustic force measurements on polymer-coated microbubbles in a microfluidic device.
This work presents an acoustofluidic device for manipulating coated microbubbles, designed for the simultaneous use of optical and acoustical tweezers. A comprehensive characterization of the acoustic pressure in the device is presented, obtained by the synergic use of different techniques in the range of acoustic frequencies where visual observations showed aggregation of polymer-coated microbubbles. In absence of bubbles, the combined use of laser vibrometry and finite element modelling supported a non-invasive measurement of the acoustic pressure and an enhanced understanding of the system resonances. Calibrated holographic optical tweezers were used for direct measurements of the acoustic forces acting on an isolated microbubble, at low driving pressures, and to confirm the spatial distribution of the acoustic field. This allowed quantitative acoustic pressure measurements by particle tracking, using polystyrene beads, and an evaluation of the related uncertainties. This process facilitated the extension of tracking to microbubbles, which have a negative acoustophoretic contrast factor, allowing acoustic force measurements on bubbles at higher pressures than optical tweezers, highlighting four peaks in the acoustic response of the device. Results and methodologies are relevant to acoustofluidic applications requiring a precise characterization of the acoustic field and, in general, to biomedical applications with microbubbles or deformable particles.


Nanoscale imaging of buried structures via scanning near-field ultrasound holography.
A nondestructive imaging method, scanning near-field ultrasound holography (SNFUH), has been developed that provides depth information as well as spatial resolution at the 10- to 100-nanometer scale. In SNFUH, the phase and amplitude of the scattered specimen ultrasound wave, reflected in perturbation to the surface acoustic standing wave, are mapped with a scanning probe microscopy platform to provide nanoscale-resolution images of the internal substructure of diverse materials. We have used SNFUH to image buried nanostructures, to perform subsurface metrology in microelectronic structures, and to image malaria parasites in red blood cells.


Characteristics of patients with Guillain Barre Syndrome at a tertiary care centre in Pakistan, 1995-2003.
To study the clinical presentation, hospital course and outcome of patients admitted with Guillain Barre Syndrome (GBS) to a tertiary care hospital in Karachi, Pakistan. The charts of patients conforming to International Classification of Diseases (ICD) code 9.0, for GBS, from September 1995 to January 2003 were reviewed. Clinical data was recorded on a standardized questionnaire, which included patients' age, sex, antecedent events, neurological signs and symptoms and ventilation requirement. The hospital course was analyzed, including nosocomial infections, therapy given and the functional status of patients, using the Rankin scale (0-6). Standard SPSS 11.5 software (Windows) was used for data analysis. Thirty-four cases of GBS were admitted to the hospital during the study period, with an age range of 3 to 70 years. The mean age for disease onset was 35.2 years for female patients, compared to 30 years for males; the male/female ratio was 1.6:1.Gastrointestinal infections (12/22, 54.6%) were the most common antecedent event, followed by upper respiratory tract infections (9/22, 40.9%) and skin lesions (1/22, 4.5%). Most patients developed GBS within one month of the preceding infection. Cranial nerve abnormalities (30/34, 88.2%), autonomic dysfunction (21/34, 61.8%) and respiratory failure requiring intubation (19/34, 55.9%) were also common. The median Rankin score of patients at admission, and at 30 and 60 days thereafter was 5, 4 and 3.5 respectively. The in-patient mortality was 1 of 34 (2.4%). We found that GBS occurred at all ages and was slightly more common in males. Majority of patients had an antecedent history of infection and had severe disease on presentation. The patients were treated with either plasmapheresis or intravenous immunoglobulins and there was no significant difference in outcome in the two groups. Despite severe persistent disability, in-hospital mortality was low.


Compromised autophagy and neurodegenerative diseases.
Most neurodegenerative diseases that afflict humans are associated with the intracytoplasmic deposition of aggregate-prone proteins in neurons and with mitochondrial dysfunction. Autophagy is a powerful process for removing such proteins and for maintaining mitochondrial homeostasis. Over recent years, evidence has accumulated to demonstrate that upregulation of autophagy may protect against neurodegeneration. However, autophagy dysfunction has also been implicated in the pathogenesis of various diseases. This Review summarizes the progress that has been made in our understanding of how perturbations in autophagy are linked with neurodegenerative diseases and the potential therapeutic strategies resulting from the modulation of this process.


Medical and environmental risk factors for sporadic frontotemporal dementia: a retrospective case-control study.
A retrospective case-control study was carried out on 80 patients with sporadic frontotemporal dementia and 124 age, sex, and surrogate informant matched controls with respect to various medical and environmental risk factors. Head trauma was associated with an odds ratio of 3.3 (95% confidence interval (CI), 1.3 to 8.1). Although recall bias may play a role, the frontal lobes are known to be especially vulnerable to even mild head trauma. Thyroid disease was associated with a 2.5 times increased risk of frontotemporal dementia (95% CI, 0.9 to 7.9), which was not statistically significant (p = 0.09) owing to limited power. As altered thyroid hormone status has been observed before in frontotemporal dementia, future studies will be important to confirm this observation.


Macroscopic quantum effects in nanometer-scale magnets.
Quantum tunneling, the passage of a microscopic system from one state to another by way of a classically forbidden path, is theoretically possible in the macroscopic world. One can now make direct observations of such macroscopic quantum tunneling in very small magnetic structures. This is possible because of significant advances both in the ability to obtain magnetic systems of almost any desirable size, shape, and composition and in the development of superconducting instrumentation for the detection of extremely weak magnetic signals. As an example, measurements on magnetic horse spleen ferritin proteins with the predictions of quantum tunneling theory are discussed and shown.


Extraction of naturally occurring cannabinoids: an update.
Organic molecules that interact with the cannabinoid receptors are called cannabinoids, which can be endogenous, natural or synthetic compounds. They possess similar pharmacological properties as produced by the plant, Cannabis sativa L. Before cannabinoids can be analysed, they need to be extracted from the matrices. To review literature on the methods and protocols for the extraction of naturally occurring cannabinoids. An extensive literature search was performed incorporating several databases, notably, Web of Knowledge, PubMed and Google Scholar, and other relevant published materials. The keywords used in the search, in various combinations, with cannabinoids and extraction being present in all combinations, were Cannabis, hemp, cannabinoids, Cannabis sativa, marijuana, and extraction. In addition to classical maceration with organic solvents, e.g. ethanol, pressurised solvent extraction, solvent heat reflux, Soxhlet extraction, supercritical fluid extraction, ultrasound-assisted extraction and microwave-assisted extraction, are routinely used nowadays for the extraction of cannabinoids from plant materials and cannabis consumer products. For the extraction of cannabinoids from biological samples, e.g. human blood, and also from food and beverages, and wastewater, solid-phase extraction and its variants, as well as liquid-liquid extraction are commonly used. Parameters for extraction can be optimised by response surface methodology or other mathematical modelling tools. There are at least six US patents on extraction of cannabinoids available to date. Irrespective of the extraction method, extraction temperature, extraction time and extraction pressure play a vital role in overall yield of extraction. Solvent polarity can also be an important factor in some extraction methods.


New Methodology for an Expert-Designed Map From International Classification of Diseases (ICD) to Abbreviated Injury Scale (AIS) 3+ Severity Injury.
There has been a longstanding desire for a map to convert International Classification of Diseases (ICD) injury codes to Abbreviated Injury Scale (AIS) codes to reflect the severity of those diagnoses. The Association for the Advancement of Automotive Medicine (AAAM) was tasked by European Union representatives to create a categorical map classifying diagnoses codes as serious injury (Abbreviated Injury Scale [AIS] 3+), minor/moderate injury (AIS 1/2), or indeterminate. This study's objective was to map injury-related ICD-9-CM (clinical modification) and ICD-10-CM codes to these severity categories. Approximately 19,000 ICD codes were mapped, including injuries from the following categories: amputations, blood vessel injury, burns, crushing injury, dislocations/sprains/strains, foreign body, fractures, internal organ, nerve/spinal cord injury, intracranial, laceration, open wounds, and superficial injury/contusion. Two parallel activities were completed to create the maps: (1) An in-person expert panel and (2) an electronic survey. The panel consisted of expert users of AIS and ICD from North America, the United Kingdom, and Australia. The panel met in person for 5 days, with follow-up virtual meetings to create and revise the maps. Additional qualitative data were documented to resolve potential discrepancies in mapping. The electronic survey was completed by 95 injury coding professionals from North America, Spain, Australia, and New Zealand over 12 weeks. ICD-to-AIS maps were created for: ICD-9-CM and ICD-10-CM. Both maps indicated whether the corresponding AIS 2005/Update 2008 severity score for each ICD code was AIS 3+, 1/2, or indeterminable. Though some ICD codes could be mapped to multiple AIS codes, the maximum severity of all potentially mapped injuries determined the final severity categorization. The in-person panel consisted of 13 experts, with 11 Certified AIS specialists (CAISS) with a median of 8 years and an average of 15 years of coding experience. Consensus was reached for AIS severity categorization for all injury-related ICD codes. There were 95 survey respondents, with a median of 8 years of injury coding experience. Approximately 15 survey responses were collected per ICD code. Results from the 2 activities were compared, and any discrepancies were resolved using additional qualitative and quantitative data from the in-person panel and survey results, respectively. Robust maps of ICD-9-CM and ICD-10-CM injury codes to AIS severity categories (3+ versus <3) were successfully created from an in-person panel discussion and electronic survey. These maps provide a link between the common ICD diagnostic lexicons and the AIS severity coding system and are of value to injury researchers, public health scientists, and epidemiologists using large databases without available AIS coding.


Distinct mechanisms for induction and tolerance regulate the immediate early genes encoding interleukin 1β and tumor necrosis factor α.
Interleukin-1β and Tumor Necrosis Factor α play related, but distinct, roles in immunity and disease. Our study revealed major mechanistic distinctions in the Toll-like receptor (TLR) signaling-dependent induction for the rapidly expressed genes (IL1B and TNF) coding for these two cytokines. Prior to induction, TNF exhibited pre-bound TATA Binding Protein (TBP) and paused RNA Polymerase II (Pol II), hallmarks of poised immediate-early (IE) genes. In contrast, unstimulated IL1B displayed very low levels of both TBP and paused Pol II, requiring the lineage-specific Spi-1/PU.1 (Spi1) transcription factor as an anchor for induction-dependent interaction with two TLR-activated transcription factors, C/EBPβ and NF-κB. Activation and DNA binding of these two pre-expressed factors resulted in de novo recruitment of TBP and Pol II to IL1B in concert with a permissive state for elongation mediated by the recruitment of elongation factor P-TEFb. This Spi1-dependent mechanism for IL1B transcription, which is unique for a rapidly-induced/poised IE gene, was more dependent upon P-TEFb than was the case for the TNF gene. Furthermore, the dependence on phosphoinositide 3-kinase for P-TEFb recruitment to IL1B paralleled a greater sensitivity to the metabolic state of the cell and a lower sensitivity to the phenomenon of endotoxin tolerance than was evident for TNF. Such differences in induction mechanisms argue against the prevailing paradigm that all IE genes possess paused Pol II and may further delineate the specific roles played by each of these rapidly expressed immune modulators.


Revealing the spin-vibronic coupling mechanism of thermally activated delayed fluorescence.
Knowing the underlying photophysics of thermally activated delayed fluorescence (TADF) allows proper design of high efficiency organic light-emitting diodes. We have proposed a model to describe reverse intersystem crossing (rISC) in donor-acceptor charge transfer molecules, where spin-orbit coupling between singlet and triplet states is mediated by one of the local triplet states of the donor (or acceptor). This second order, vibronically coupled mechanism describes the basic photophysics of TADF. Through a series of measurements, whereby the energy ordering of the charge transfer (CT) excited states and the local triplet are tuned in and out of resonance, we show that TADF reaches a maximum at the resonance point, substantiating our model of rISC. Moreover, using photoinduced absorption, we show how the populations of both singlet and triplet CT states and the local triplet state change in and out of resonance. Our vibronic coupling rISC model is used to predict this behaviour and describes how rISC and TADF are affected by external perturbation.


Patterning of fast and slow fibers within embryonic muscles is established independently of signals from the surrounding mesenchyme.
During embryonic development, and before functional innervation, a highly stereotypic pattern of slow- and fast-contracting primary muscle fibers is established within individual muscles of the limbs, from distinct populations of myoblasts. A difference between the fiber-type pattern found within chicken and quail pectoral muscles was exploited to investigate the contributions of somite-derived myogenic precursors and lateral plate-derived mesenchymal stroma to the establishment of muscle fiber-type patterns. Chimeric chicken/quail embryos were constructed by reciprocal transplantation of somites or lateral plate mesoderm at stages prior to muscle formation. Muscle fibers derived from quail myogenic precursors that had migrated into chicken stroma showed a quail pattern of mixed fast- and slow-contracting muscle fibers. Conversely, chicken myogenic precursors that had migrated into quail stroma showed a chicken pattern of nearly exclusive fast muscle fiber formation. These results demonstrate in vivo an intrinsic commitment to fiber-type on the part of the myoblast, independent of extrinsic signals it receives from the mesenchymal stroma in which it differentiates.


Integrating Patient Safety Education in the Undergraduate Nursing Curriculum: A Discussion Paper.
This paper explores the opportunities and challenges for integrating patient safety education in undergraduate nursing curriculum. Four dimensions of undergraduate nursing education are examined: National accreditation of nursing programs, building a competency-based nursing education, a model of nursing education and building faculty capacity in patient safety education and research. Incorporating patient safety in a nursing curriculum can be "institutionalized" by making it a pre-requisite for granting program accreditation. At the operational level, transforming undergraduate nursing education to incorporate inquiry-based learning and moving toward competency-based patient safety education are two key requirements for engaging the students with patient safety science. Building faculty capacity who are experts in both patient safety teaching and research remains a key challenge that needs to be addressed to enable a shift in the patient safety "mindset" for future nursing workforce. Efforts to introduce patient safety in nursing education are both necessary and timely, and should accommodate students' unique needs and cultural context.


Learning from errors: students' and instructors' practices, attitudes, and beliefs.
In some educational contexts, such as during assessments, it is essential to avoid errors. In other contexts, however, generating an error can foster valuable learning opportunities. For instance, generating errors can improve memory for correct answers. In two surveys conducted at three large public universities in North America, we investigated undergraduate students' and instructors' awareness of the pedagogical benefits of generating errors, as well as related practices, attitudes, and beliefs. Surveyed topics included the incorporation of errors into learning activities, opinions about the consequences of studying errors, and approaches to feedback. Many students had an aversion towards making errors during learning and did not use opportunities to engage in errorful generation, yet studied or analysed errors when they occurred. Many instructors had a welcoming attitude towards errors that occur during learning, yet varied in providing students with resources that facilitate errorful generation. Overall, these findings reveal the prevalence of an ambivalent approach to errors: Students and instructors avoid generating errors but prioritise learning from them when they occur. These results have important implications for the implementation of pretesting, productive failure, and other error-focused learning techniques in educational contexts.


Science of rugby league football: a review.
The purpose of this paper is to provide a comprehensive review of the science of rugby league football at all levels of competition (i.e. junior, amateur, semi-professional, professional), with special reference to all discipline-specific scientific research performed in rugby league (i.e. physiological, psychological, injury epidemiology, strength and conditioning, performance analysis). Rugby league football is played at junior and senior levels in several countries worldwide. A rugby league team consists of 13 players (6 forwards and 7 backs). The game is played over two 30 - 40 min halves (depending on the standard of competition) separated by a 10 min rest interval. Several studies have documented the physiological capacities and injury rates of rugby league players. More recently, studies have investigated the physiological demands of competition. Interestingly, the physiological capacities of players, the incidence of injury and the physiological demands of competition all increase as the playing standard is increased. Mean blood lactate concentrations of 5.2, 7.2 and 9.1 mmol . l(-1) have been reported during competition for amateur, semi-professional and professional rugby league players respectively. Mean heart rates of 152 beats . min(-1) (78% of maximal heart rate), 166 beats . min(-1) (84% of maximal heart rate) and 172 beats . min(-1) (93% of maximal heart rate) have been recorded for amateur, semi-professional and junior elite rugby league players respectively. Skill-based conditioning games have been used to develop the skill and fitness of rugby league players, with mean heart rate and blood lactate responses during these activities almost identical to those obtained during competition. In addition, recent studies have shown that most training injuries are sustained in traditional conditioning activities that involve no skill component (i.e. running without the ball), whereas the incidence of injuries while participating in skill-based conditioning games is low. Collaborative research among the various sport science disciplines is required to identify strategies to reduce the incidence of injury and enhance the performance of rugby league players. An understanding of the movement patterns and physiological demands of different positions at all standards of competition would allow the development of strength and conditioning programmes to meet the precise requirements of these positions. Finally, studies investigating the impact of improvements in physiological capacities (including the effect of different strength and conditioning programmes) on rugby league playing performance are warranted.


Traumatic cervical spine injuries in childhood and adolescence.
Of 84 consecutive children and adolescents with traumatic cervical spine injuries treated over a 10-year period, 61 (73%) were available for review. Age ranged from the newborn period to 17 years. Analysis of injury type revealed four groups of roughly equal incidence: atlantoaxial rotary subluxation, upper cervical fracture or dislocation, lower cervical injury, and spinal cord injury without radiographic abnormality. Forty-four percent of patients incurred a neurologic injury. Falling from a height was the most common mechanism of injury. Apart from patients with complete neurologic deficits, the prognosis for these injuries is good.


Continuous synthesis of hollow silver-palladium nanoparticles for catalytic applications.
Hollow bimetallic nanoparticles exhibit unique surface plasmonic properties, enhanced catalytic activities and high photo-thermal conversion efficiencies amongst other properties, however, their research and further deployment are currently limited by their complicated multi-step syntheses. This paper presents a novel approach for their continuous synthesis with controllable and tuneable sizes and compositions. This robust manufacturing tool, consisting of coiled flow inverter (CFI) reactors connected in series, allows for the first time the temporal and spatial separation of the initial formation of silver seeds and their subsequent galvanic displacement reaction in the presence of a palladium precursor, leading to the full control of both steps separately. We have also demonstrated that coupling the galvanic replacement and co-reduction leads to a great kinetic enhancement of the system leading to a high yield process of hollow bimetallic nanoparticles, directly applicable to other metal combinations.


Generation and characterization of B7-H4/B7S1/B7x-deficient mice.
Members of the B7 family of cosignaling molecules regulate T-cell proliferation and effector functions by engaging cognate receptors on T cells. In vitro and in vivo blockade experiments indicated that B7-H4 (also known as B7S1 or B7x) inhibits proliferation, cytokine production, and cytotoxicity of T cells. B7-H4 binds to an unknown receptor(s) that is expressed on activated T cells. However, whether B7-H4 plays nonredundant immune regulatory roles in vivo has not been tested. We generated B7-H4-deficient mice to investigate the roles of B7-H4 during various immune reactions. Consistent with its inhibitory function in vitro, B7-H4-deficient mice mounted mildly augmented T-helper 1 (Th1) responses and displayed slightly lowered parasite burdens upon Leishmania major infection compared to the wild-type mice. However, the lack of B7-H4 did not affect hypersensitive inflammatory responses in the airway or skin that are induced by either Th1 or Th2 cells. Likewise, B7-H4-deficient mice developed normal cytotoxic T-lymphocyte reactions against viral infection. Thus, B7-H4 plays a negative regulatory role in vivo but the impact of B7-H4 deficiency is minimal. These results suggest that B7-H4 is one of multiple negative cosignaling molecules that collectively provide a fine-tuning mechanism for T-cell-mediated immune responses.


Global white matter abnormalities in schizophrenia: a multisite diffusion tensor imaging study.
Emerging evidence implicates white matter (WM) abnormalities in the pathophysiology of schizophrenia. However, there is considerable heterogeneity in the presentation of WM abnormalities in the existing studies. The object of this study was to evaluate WM integrity in a large sample of patients with first-episode (FE) and chronic schizophrenia in comparison to matched control groups. Our goal was to assess whether WM findings occurred early in the illness or whether these abnormalities developed with the illness over time. Participants included 114 patients with schizophrenia (31 FE and 83 chronic patients) and 138 matched controls. High-resolution structural and diffusion tensor images were obtained on all participants. Measures of fractional anisotropy (FA) were calculated for the 4 cortical lobes and the cerebellum and brain stem. FA was significant lower in patients vs controls in the whole brain and individually in the frontal, parietal, occipital, and temporal lobes. FA was not significantly different in the brain stem or cerebellum. FA differences were significant only in patients with chronic schizophrenia and not in the FE group. We found global differences in the WM microstructure in patients with chronic but not FE schizophrenia. These findings suggest progressive alterations in WM microstructure.


Mercury concentration in the eggs of four Canadian Arctic-breeding shorebirds not predicted based on their population statuses.
Methylmercury is a toxic form of mercury which persists in food webs for long periods of time and biomagnifies up successive trophic levels. Shorebirds breeding in the Arctic are exposed to methylmercury, derived from both natural and anthropogenic sources, when they ingest their invertebrate prey. Populations of many shorebird species are believed to be declining and one hypothesis for these declines is that they are due to detrimental effects of contaminants, including methylmercury. To test this hypothesis, we assessed mercury contamination in eggs of four Canadian Arctic-breeding shorebird species: black-bellied plover (Pluvialis squatarola), ruddy turnstone (Arenaria interpres), semipalmated plover (Charadrius semipalmatus) and white-rumped sandpiper (Calidris fuscicollis). Black-bellied plovers and ruddy turnstones are declining in the western hemisphere, whereas white-rumped sandpipers and semipalmated plovers have stable or slightly increasing populations. We found no relationship between egg mercury concentration and population trend for these four shorebird species. Intraspecific variation in mercury concentration was high. Notably, the mercury concentrations were much higher than levels found in a previous study of eggs of the same shorebird species from this same site, suggesting that mercury contamination may be subject to substantial inter-annual variation in the Canadian Arctic food web.


Frequency of and risk factors for epistaxis associated with exercise-induced pulmonary hemorrhage in horses: 251,609 race starts (1992-1997).
To determine the frequency of epistaxis during or after racing among racehorses and identify factors associated with development of epistaxis. Retrospective study. 247,564 Thoroughbred and 4,045 Anglo-Arab race starts. Race start information (breed, age, sex, racing distance, and race type) was obtained for Thoroughbred and Anglo-Arab horses racing in Japan Racing Association-sanctioned races between 1992 and 1997. All horses that raced were examined by a veterinarian within 30 minutes of the conclusion of the race; any horse that had blood at the nostrils was examined with an endoscope. If blood was observed in the trachea, epistaxis related to exercise-induced pulmonary hemorrhage (EIPH) was diagnosed. Epistaxis related to EIPH was identified following 369 race starts (0.15%). Frequency of EIPH-related epistaxis was significantly associated with race type, age, distance, and sex. Epistaxis was more common following steeplechase races than following flat races, in older horses than in horses that were 2 years old, following races < or =1,600 m long than following races between 1,601 and 2,000 m long, and in females than in sexually intact males. For horses that had an episode of epistaxis, the recurrence rate was 4.64%. Results suggested that frequency of EIPH-related epistaxis in racehorses is associated with the horse's age and sex, the type of race, and the distance raced. The higher frequency in shorter races suggests that higher intensity exercise of shorter duration may increase the probability of EIPH.


Diaphragmatic intramuscular pressure in relation to tension, shortening, and blood flow.
We used an in situ isolated diaphragmatic preparation in anesthetized dogs to relate intramuscular pressure (IMP) to the blood flow, tension, and shortening of the diaphragm. In this preparation, the diaphragm shortens in a fashion similar to the intact diaphragm. Tension was measured by transducers attached to the left costal margin, which was detached from the rib cage and abdomen; IMP was measured by a miniature transducer placed between muscle fibers; length was measured by sonomicrometry; and diaphragmatic blood flow was monitored by measuring left phrenic arterial flow. In protocol 1, the relationships between tension, shortening, and IMP were assessed by stimulating the diaphragm for 2 s at various frequencies. Tension and shortening increased with increasing stimulation frequency up to 50 Hz with no change thereafter. Tension was linearly related to IMP. Similarly, there was a linear relationship between the degree of shortening and IMP; however, the slopes varied considerably between dogs. In protocol 2, the diaphragm was paced intermittently (12 trains/min, duty cycle of 0.5) with a gradual increase in stimulation frequency. Blood flow during contraction phase rose slightly at low tension and then declined significantly when tension exceeded 30% of maximum, whereas relaxation-phase flow increased with the increase in tension. IMP rose linearly with the increase in tension, and the IMP, at the point where contraction-phase flow became severely limited, was 50 +/- 14 mmHg (mean +/- SE). We conclude the following. 1) IMP is linearly related to tension and shortening; however, because tension and shortening changed simultaneously during contractions, the independent relationship of either tension or shortening and IMP remained untested.(ABSTRACT TRUNCATED AT 250 WORDS)


Collective behavior.
The resurgence of interest in collective behavior is in large part due to tools recently made available for conducting laboratory experiments on groups, statistical methods for analyzing large data sets reflecting social interactions, the rapid growth of a diverse variety of online self-organized collectives, and computational modeling methods for understanding both universal and scenario-specific social patterns. We consider case studies of collective behavior along four attributes: the primary motivation of individuals within the group, kinds of interactions among individuals, typical dynamics that result from these interactions, and characteristic outcomes at the group level. With this framework, we compare the collective patterns of noninteracting decision makers, bee swarms, groups forming paths in physical and abstract spaces, sports teams, cooperation and competition for resource usage, and the spread and extension of innovations in an online community. Some critical issues surrounding collective behavior are then reviewed, including the questions of "Does group behavior always reduce to individual behavior?""Is 'group cognition' possible?" and "What is the value of formal modeling for understanding group behavior?"


Longitudinal changes in glucocorticoid metabolism are associated with later development of adverse metabolic phenotype.
Dysregulation of enzymes that control local tissue steroid metabolism has been implicated in the pathogenesis of obesity and insulin resistance; however, longitudinal changes in glucocorticoid metabolism have not been investigated. This study was performed to evaluate the role of glucocorticoid metabolism in the development of insulin resistance and obesity and to identify biomarkers for future development of metabolic disease. This was a prospective longitudinal observation study conducted over 5 years. A 24-h collection was used to serially analyze urinary glucocorticoid and mineralocorticoid metabolites in 57 obese and overweight patients with no prior diagnosis of diabetes mellitus, recruited from the community. Baseline higher 5α-reductase (5αR) activity, but not 11β-hydroxysteroid dehydrogenase type 1 activity, was predictive of increased fasting insulin at final visit (11.4 compared with 7.4 mU/l in subjects with lower 5αR activity, P<0.05), area under the curve insulin response to oral glucose tolerance test (176.7 compared with 89.1 mU/l.h, P<0.01), and homeostasis model assessment (HOMA2-IR; 1.3 compared with 0.8, P<0.01). Higher total glucocorticoid production was associated with abnormal glucose tolerance and increased BMI. During this study, systolic blood pressure increased (equivalent to ∼1 mmHg/year), as did plasma sodium levels; this evidence of increased mineralocorticoid activity was associated with increased aldosterone metabolites and decreased 11β-hydroxysteroid dehydrogenase type 2 activity. Increased 5αR activity and glucocorticoid secretion rate over time are linked with the development of metabolic disease, and may represent targets for therapeutic intervention, which merits further study.


Advanced endografting techniques: snorkels, chimneys, periscopes, fenestrations, and branched endografts.
The anatomy of aortic aneurysms from the proximal neck to the access vessels may create technical challenges for endovascular repair. Upwards of 30% of patients with abdominal aortic aneurysms (AAA) have unsuitable proximal neck morphology for endovascular repair. Anatomies considered unsuitable for conventional infrarenal stent grafting include short or absent necks, angulated necks, conical necks, or large necks exceeding size availability for current stent grafts. A number of advanced endovascular techniques and devices have been developed to circumvent these challenges, each with unique advantages and disadvantages. These include snorkeling procedures such as chimneys, periscopes, and sandwich techniques; "homemade" or "back-table" fenestrated endografts as well as manufactured, customized fenestrated endografts; and more recently, physician modified branched devices. Furthermore, new devices in the pipeline under investigation, such as "off-the-shelf" fenestrated stent grafts, branched stent grafts, lower profile devices, and novel sealing designs, have the potential of solving many of the aforementioned problems. The treatment of aortic aneurysms continues to evolve, further expanding the population of patients that can be treated with an endovascular approach. As the technology grows so do the number of challenging aortic anatomies that endovascular specialists take on, further pushing the envelope in the arena of aortic repair.


Stereotactic body radiation therapy: a comprehensive review.
Stereotactic body radiation therapy (SBRT) is a novel technique that takes advantage of the technologic advancements in image guidance and radiation dose delivery to direct ablative doses to tumors with acceptable toxicity that was not previously achievable with conventional techniques. SBRT requires a high degree of confidence in tumor location provided by high quality diagnostic and near real-time imaging studies for accurate treatment delivery and precise assessment of physiologic tumor motion. In addition, stringent dosimetric parameters must be applied, paying close attention to the spatial arrangement of functional subunits in the adjacent normal tissues, to optimize clinical outcomes. Phase I/II trials for tumors of the lung, liver, spine, pancreas, kidney, and prostate provide evidence that the potent doses delivered with SBRT may provide results that rival surgery while avoiding the typical morbidities associated with that invasive approach. Further clinical study in the form of multi-institutional Phase II trials is currently underway, and ultimately collaborative efforts on a national level to support Phase III trials will be necessary, to firmly establish SBRT as a comparable noninvasive alternative to surgery.


An articulatory view of Kinyarwanda coronal harmony.
Coronal harmony in Kinyarwanda causes alveolar fricatives to become postalveolar preceding a postalveolar fricative within a stem. Alveolar and postalveolar stops, affricates and palatals block coronal harmony, but the flap and non-coronal consonants are reported to be transparent. Kinematic data on consonant production in Kinyarwanda were collected using electromagnetic articulography. The mean angle for the line defined by receivers placed on the tongue tip and blade was calculated over the consonant intervals. Mean angle reliably distinguished alveolar and postalveolar fricatives, with alveolars showing a lower tip relative to blade. Mean angle during transparent non-coronal consonants showed a higher tip relative to blade than in contexts without harmony, and the mean angle during transparent [m] was not significantly different than during postalveolar fricatives. This is consistent with a model where Kinyarwanda coronal harmony extends a continuous tip-blade gesture, causing it to be present during 'transparent' segments, but without perceptible effect.


Root cause analysis of laboratory turnaround times for patients in the emergency department.
Laboratory investigations are essential to patient care and are conducted routinely in emergency departments (EDs). This study reports the turnaround times at an academic, tertiary care ED, using root cause analysis to identify potential areas of improvement. Our objectives were to compare the laboratory turnaround times with established benchmarks and identify root causes for delays. Turnaround and process event times for a consecutive sample of hemoglobin and potassium measurements were recorded during an 8-day study period using synchronized time stamps. A log transformation (ln [minutes + 1]) was performed to normalize the time data, which were then compared with established benchmarks using one-sample t tests. The turnaround time for hemoglobin was significantly less than the established benchmark (n = 140, t = -5.69, p < 0.001) and that of potassium was significantly greater (n = 121, t = 12.65, p < 0.001). The hemolysis rate was 5.8%, with 0.017% of samples needing recollection. Causes of delays included order-processing time, a high proportion (43%) of tests performed on patients who had been admitted but were still in the ED waiting for a bed, and excessive laboratory process times for potassium. The turnaround time for hemoglobin (18 min) met the established benchmark, but that for potassium (49 min) did not. Root causes for delay were order-processing time, excessive queue and instrument times for potassium and volume of tests for admitted patients. Further study of these identified causes of delays is required to see whether laboratory TATs can be reduced.


Cell type-dependent induction of DNA damage by 1800 MHz radiofrequency electromagnetic fields does not result in significant cellular dysfunctions.
Although IARC clarifies radiofrequency electromagnetic fields (RF-EMF) as possible human carcinogen, the debate on its health impact continues due to the inconsistent results. Genotoxic effect has been considered as a golden standard to determine if an environmental factor is a carcinogen, but the currently available data for RF-EMF remain controversial. As an environmental stimulus, the effect of RF-EMF on cellular DNA may be subtle. Therefore, more sensitive method and systematic research strategy are warranted to evaluate its genotoxicity. To determine whether RF-EMF does induce DNA damage and if the effect is cell-type dependent by adopting a more sensitive method γH2AX foci formation; and to investigate the biological consequences if RF-EMF does increase γH2AX foci formation. Six different types of cells were intermittently exposed to GSM 1800 MHz RF-EMF at a specific absorption rate of 3.0 W/kg for 1 h or 24 h, then subjected to immunostaining with anti-γH2AX antibody. The biological consequences in γH2AX-elevated cell type were further explored with comet and TUNEL assays, flow cytometry, and cell growth assay. Exposure to RF-EMF for 24 h significantly induced γH2AX foci formation in Chinese hamster lung cells and Human skin fibroblasts (HSFs), but not the other cells. However, RF-EMF-elevated γH2AX foci formation in HSF cells did not result in detectable DNA fragmentation, sustainable cell cycle arrest, cell proliferation or viability change. RF-EMF exposure slightly but not significantly increased the cellular ROS level. RF-EMF induces DNA damage in a cell type-dependent manner, but the elevated γH2AX foci formation in HSF cells does not result in significant cellular dysfunctions.


Identification of Genetic Factors that Modify Clinical Onset of Huntington's Disease.
As a Mendelian neurodegenerative disorder, the genetic risk of Huntington's disease (HD) is conferred entirely by an HTT CAG repeat expansion whose length is the primary determinant of the rate of pathogenesis leading to disease onset. To investigate the pathogenic process that precedes disease, we used genome-wide association (GWA) analysis to identify loci harboring genetic variations that alter the age at neurological onset of HD. A chromosome 15 locus displays two independent effects that accelerate or delay onset by 6.1 years and 1.4 years, respectively, whereas a chromosome 8 locus hastens onset by 1.6 years. Association at MLH1 and pathway analysis of the full GWA results support a role for DNA handling and repair mechanisms in altering the course of HD. Our findings demonstrate that HD disease modification in humans occurs in nature and offer a genetic route to identifying in-human validated therapeutic targets in this and other Mendelian disorders.


OMGene: mutual improvement of gene models through optimisation of evolutionary conservation.
The accurate determination of the genomic coordinates for a given gene - its gene model - is of vital importance to the utility of its annotation, and the accuracy of bioinformatic analyses derived from it. Currently-available methods of computational gene prediction, while on the whole successful, frequently disagree on the model for a given predicted gene, with some or all of the variant gene models often failing to match the biologically observed structure. Many prediction methods can be bolstered by using experimental data such as RNA-seq. However, these resources are not always available, and rarely give a comprehensive portrait of an organism's transcriptome due to temporal and tissue-specific expression profiles. Orthology between genes provides evolutionary evidence to guide the construction of gene models. OMGene (Optimise My Gene) aims to improve gene model accuracy in the absence of experimental data by optimising the consistency of multiple sequence alignments of orthologous genes from multiple species. Using RNA-seq data sets from plants, mammals, and fungi, considering intron/exon junction representation and exon coverage, and assessing the intra-orthogroup consistency of subcellular localisation predictions, we demonstrate the utility of OMGene for improving gene models in annotated genomes. We show that significant improvements in the accuracy of gene model annotations can be made, both in established and in de novo annotated genomes, by leveraging information from multiple species.


Caldolase, a chelator-insensitive extracellular serine proteinase from a Thermus spp.
An extracellular alkaline serine proteinase from Thermus strain ToK3 was isolated and purified to homogeneity by (NH4)2SO4 precipitation followed by ion-exchange chromatography on DEAE-cellulose and QAE-Sephadex, affinity chromatography on N alpha-benzyloxycarbonyl-D-phenylalanyl-triethylenetetraminyl-Sepha rose 4B and gel-filtration chromatography on Sephadex G-75. The purified enzyme had a pI of 8.9 and an Mr determined by gel-permeation chromatography of 25,000. The specific activity was about 37,700 proteolytic units/mg with casein as substrate, and the pH optimum was 9.5. Proteolytic activity was inhibited by low concentrations of di-isopropyl phosphorofluoridate and phenylmethanesulphonyl fluoride, but was unaffected by EDTA, EGTA, o-phenanthroline, N-ethyl-5-phenylisoxazolium-3'-sulphonate, N alpha-p-tosyl-L-phenylalanylchloromethane, N alpha-p-tosyl-L-lysylchloromethane, trypsin inhibitors and pepstatin A. The enzyme contained approx. 10% carbohydrate and four disulphide bonds. No Ca2+, Zn2+ or free thiol groups were detected. It hydrolysed several native and dye-linked proteins and synthetic chromogenic peptides and esters. The enzyme was very thermostable (half-life values were 840 min at 80 degrees C, 45 min at 90 degrees C and 5 min at 100 degrees C). The enzyme was unstable at low ionic strength: after 60 min at 75 degrees C in 0.1 M-Tris/acetate buffer, pH 8, only 20% activity remained, compared with no loss in 0.1 M-Tris/acetate buffer, pH 8, containing 0.4 M-NaCl.


A model system for assessing and comparing the ability of exon microarray and tag sequencing to detect genes specific for malignant B-cells.
Malignant cells in tumours of B-cell origin account for 0.1% to 98% of the total cell content, depending on disease entity. Recently, gene expression profiles (GEPs) of B-cell lymphomas based on microarray technologies have contributed significantly to improved sub-classification and diagnostics. However, the varying degrees of malignant B-cell frequencies in analysed samples influence the interpretation of the GEPs. Based on emerging next-generation sequencing technologies (NGS) like tag sequencing (tag-seq) for GEP, it is expected that the detection of mRNA transcripts from malignant B-cells can be supplemented. This study provides a quantitative assessment and comparison of the ability of microarrays and tag-seq to detect mRNA transcripts from malignant B-cells. A model system was established by eight serial dilutions of the malignant B-cell lymphoma cell line, OCI-Ly8, into the embryonic kidney cell line, HEK293, prior to parallel analysis by exon microarrays and tag-seq. We identified 123 and 117 differentially expressed genes between pure OCI-Ly8 and HEK293 cells by exon microarray and tag-seq, respectively. There were thirty genes in common, and of those, most were B-cell specific. Hierarchical clustering from all dilutions based on the differentially expressed genes showed that neither technology could distinguish between samples with less than 1% malignant B-cells from non-B-cells. A novel statistical concept was developed to assess the ability to detect single genes for both technologies, and used to demonstrate an inverse proportional relationship with the sample purity. Of the 30 common genes, the detection capability of a representative set of three B-cell specific genes--CD74, HLA-DRA, and BCL6 - was analysed. It was noticed that at least 5%, 13% and 22% sample purity respectively was required for detection of the three genes by exon microarray whereas at least 2%, 4% and 51% percent sample purity of malignant B-cells were required for tag-seq detection. A sample purity-dependent loss of the ability to detect genes for both technologies was demonstrated. Taq-seq, in comparison to exon microarray, required slightly less malignant B-cells in the samples analysed in order to detect the two most abundantly expressed of the selected genes. The results show that malignant cell frequency is an important variable, with fundamental impact when interpreting GEPs from both technologies.


Measurement of negative symptoms in schizophrenia.
This article focuses on the measurement of 'negative symptoms'. Standardized scales used to rate negative symptoms are reviewed and compared, as are the individual items which comprise them. The overlap of negative symptoms, akinesia, and depression is explored, and means are suggested to improve the precision of defining and measuring negative symptoms. Flat affect is the only item present in all negative symptom scales and may overlap with depression and akinesia. Inappropriate affect and attentional disturbance should not be considered negative symptoms. Poverty of speech and anhedonia lack unified definitions, and in some scales, they can also be confounded with depression and akinesia. The psychometric properties of most scales have not been sufficiently studied. The lack of long-term studies of stability of the supposedly enduring negative symptoms is especially worrisome. Carpenter's deficit syndrome consisting of non-secondary negative symptoms lasting more than one year is a promising new step to try and address some of these problems.


Patient education for preventing diabetic foot ulceration.
Ulceration of the feet, which can result in loss of limbs and even death, is one of the major health problems for people with diabetes mellitus. To assess the effects of patient education on the prevention of foot ulcers in patients with diabetes mellitus. We searched The Cochrane Wounds Group Specialised Register (searched 03 September 2014); The Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2014, Issue 8). Prospective randomised controlled trials (RCTs) that evaluated educational programmes for preventing foot ulcers in people with diabetes mellitus. Two review authors independently undertook data extraction and assessment of risk of bias. Primary end points were foot ulceration or ulcer recurrence and amputation. Of the 12 RCTs included, the effect of patient education on primary end points was reported in only five. Pooling of outcome data was precluded by marked, mainly clinical, heterogeneity. One of the RCTs showed reduced incidence of foot ulceration (risk ratio (RR) 0.31, 95% confidence interval (CI) 0.14 to 0.66) and amputation (RR 0.33, 95% CI 0.15 to 0.76) during one-year follow-up of diabetes patients at high risk of foot ulceration after a one-hour group education session. However, one similar study, with lower risk of bias, did not confirm this finding (RR amputation 0.98, 95% CI 0.41 to 2.34; RR ulceration 1.00, 95% CI 0.70 to 1.44). Three other studies, also did not demonstrate any effect of education on the primary end points, but were most likely underpowered. Patients' foot care knowledge was improved in the short term in five of eight RCTs in which this outcome was assessed, as was patients' self-reported self-care behaviour in the short term in seven of nine RCTs. Callus, nail problems and fungal infections improved in only one of five RCTs. Only one of the included RCTs was at low risk of bias. In some trials, foot care knowledge and self reported patient behaviour seem to be positively influenced by education in the short term. Yet, based on the only two sufficiently powered studies reporting the effect of patient education on primary end points, we conclude that there is insufficient robust evidence that limited patient education alone is effective in achieving clinically relevant reductions in ulcer and amputation incidence.


Metabolism of intravenously administered dipeptides in rats: effects on amino acid pools, glucose concentration and insulin and glucagon secretion.
1. Studies were performed to investigate the metabolic fate of dipeptides when administered intravenously in rats. Glycyl-leucine, glycylglycine or glycylsarcosine was injected into the jugular vein. The plasma disappearance rate after the peak plasma concentrations was most rapid for glycyl-leucine and least rapid for glycylsarcosine. 2. During urine collection for 40 min, trace amounts of glycyl-leucine and glycylglycine and 13% of the injected glycylsarcosine were excreted. 3. Neither glycylglycine nor glycyl-leucine was detected in the liver, muscle, intestinal mucosa or renal cortex, but concentrations of glycine or leucine, or both, in these tissues were increased after each injection. In contrast, glycylsarcosine was recovered in all these tissues with concentrations in the renal cortex being far greater than in any other tissue, but sarcosine was found only in the renal cortex and intestinal mucosa. 4. The changes in plasma concentrations of free amino acids, glucose and glucagon, and tissue concentrations of free amino acids, were similar after the intravenous administration of glycyl-leucine and an equimolar mixture of free glycine and leucine. However, the amount of insulin secreted during the 40 min after glycyl-leucine injection was 1-6 times that produced after the injection of the corresponding amino acid mixture. 5. Results show that, within the present experimental conditions, the intravenous administration of dipeptides is as effective as that of the corresponding free amino acids in enriching the tissue pools of amino acids. It is suggested that efficient hydrolysis by cellular enzymes prohibits accumulation of intact dipeptides in body tissues.


Arthrodesis for failed knee arthroplasty. A report of 20 cases.
Twenty consecutive patients treated by arthrodesis for failed knee arthroplasty are reviewed. Eight hinged, five stabilised and seven compartmental prostheses were removed, for infection (15 cases), loosening (4) and instability (1). One patient refused a second-stage operation but the remainder gained sound fusion. Infected knees had a two-stage procedure with temporary insertion of gentamicin-loaded beads after removal of the prosthesis; all infections healed. Six arthrodeses using a Hoffmann-Vidal external fixator resulted in two temporary failures. One Ace-Fischer external fixation was successful. Of 10 primary attempts at arthrodesis with an intramedullary Küntscher nail, nine were successful; the tenth fused after two more attempts by the same method. The two failures of external fixation and two failures after Charnley single-frame compression done elsewhere were successfully fused with intramedullary nails. Delayed union in three cases fused after prolonged fixation and repeated bone grafts. The indications for and methods of arthrodesis after failed knee arthroplasty are discussed.


Prediction mechanisms in motor and auditory areas and their role in sound perception and language understanding.
Is the meaning of an expected stimulus manifest in brain activity even before it appears? Although theories of predictive coding see anticipatory activity as crucial for the understanding of brain function, few studies have explored neurophysiologically manifest semantic predictions. Here, we report predictive negative-going potentials before the onset of action (i.e. whistle and hand clap) and non-action (i.e. pure tone, water drop) sounds. These prediction potentials (PP) indexed the meaning of action-related sounds. Dependent on the body-part-relationship of sound stimuli, neural sources were relatively more prominent in dorsal or ventral motor areas. In contrast, meaningless sounds (pure tones) activated predictive sources in temporal areas close to the auditory cortex; complex environmental sounds induced an anticipatory positivity broadly distributed over the scalp. We also found a systematic relationship between predictive activity and a Mismatch Negativity (MMN) like response to unexpected meaningful words which were presented as rare deviant stimuli amongst frequently repeated sounds. This deviant-elicited potential indexed semantic priming between action sounds and action-related words and semantic mismatch (prediction error). These results suggest a systematic link between perceptual/semantic prediction and matching mechanisms in the processing of sounds and words.


The effect of type 2 diabetes risk loci on insulin requirements in type 1 diabetes.
To analyze the correlation between insulin requirements of type 1 diabetic (T1D) patients and genotype at type 2 diabetes (T2D) risk loci, obtained in our genome-wide association study. From a database of detailed insulin dosing of 567 patients, we selected 177 for whom we also had genome-wide genotyping data. Using PLINK software, we examined the association between insulin requirement as a quantitative trait and nineteen T2D risk loci. Out of 19 single-nucleotide polymorphisms (SNPs), rs13266634 on chromosome 8 and rs7901695 on chromosome 10 showed nominal significance of association (p < 0.05). The first SNP is nonsynonymous (325 Arg>Trp) and maps to the SLC30A8 gene encoding the β-cell-specific ZnT8 zinc transporter, while the second is an intronic SNP in TCF7L2, the strongest known T2D association. Both loci exert their effect on β-cells and, in both, the T2D risk allele is associated with lower insulin requirements. We identified two T2D susceptibility loci that modulate insulin requirements in T1D patients. Our results are consistent with the association of lower insulin secretion with higher insulin sensitivity. To explain the continuation of this correlation after β-cell destruction, we hypothesize an epigenetic mechanism that alters insulin responsiveness in T1D patients based on β-cell function in early life. Such knowledge may allow a more precise approach to treatment.


Results of modern therapy for patients with mediastinal nonseminomatous germ cell tumors.
The aim of this study was to determine the effects of independent prognostic variables, such as prechemotherapy tumor markers, the extent of disease at diagnosis, the tumor markers postchemotherapy (PC), and the pathology of the PC residual mass on the overall survival of patients with primary mediastinal nonseminomatous germ cell tumors (PMNSGCT). The authors undertook a retrospective review of 39 patients with PMNSGCT between 1983 and 1997 who received their initial chemotherapy at Indiana University and 36 additional patients referred for PC resection. All patients received chemotherapy based on the combination of cisplatin and etoposide. The median follow-up was 22 months (range, 12-144 months). The prechemotherapy tumor markers did not affect overall survival. Extent of disease (mediastinal only vs. visceral metastases) was an important prognostic factor for survival in univariate analysis (P = 0.042). Sixty-two of 75 patients underwent PC resection of residual disease. Fifteen of the 62 patients achieved a CR with chemotherapy alone, as the PC resection revealed only necrosis. Fourteen of these 15 patients continuously had no evidence of disease (NED). Forty-seven of the 62 patients had NED with chemotherapy and PC resection, including 31 with teratoma and 16 with carcinoma. However, 11 of 31 with teratoma and 11 of 16 with carcinoma subsequently relapsed. Although 18 patients had elevated tumor markers at the time of PC resection, 6 of 18 had only necrosis and 4 had teratoma. The PC tumor markers did not affect survival. The pathology of the resected specimen was the most significant predictor of survival in multivariate analysis (P < 0.001). Twenty-eight of 39 patients (71.8%) with PMNSGCT treated at Indiana University achieved NED status, but only 16 (41%) continuously had NED. Twenty of 36 (55.5%) referred for resection continuously had NED. Disease confined to the mediastinum and necrosis in the PC specimen were important prognostic factors for survival.


Effects of PSA Removal from NCAM on the Critical Period Plasticity Triggered by the Antidepressant Fluoxetine in the Visual Cortex.
Neuronal plasticity peaks during critical periods of postnatal development and is reduced towards adulthood. Recent data suggests that windows of juvenile-like plasticity can be triggered in the adult brain by antidepressant drugs such as Fluoxetine. Although the exact mechanisms of how Fluoxetine promotes such plasticity remains unknown, several studies indicate that inhibitory circuits play an important role. The polysialylated form of the neural cell adhesion molecules (PSA-NCAM) has been suggested to mediate the effects of Fluoxetine and it is expressed in the adult brain by mature interneurons. Moreover, the enzymatic removal of PSA by neuroaminidase-N not only affects the structure of interneurons but also has been shown to play a role in the onset of critical periods during development. We have here used ocular dominance plasticity in the mouse visual cortex as a model to investigate whether removal of PSA might influence the Fluoxetine-induced plasticity. We demonstrate that PSA removal in the adult visual cortex alters neither the baseline ocular dominance, nor the fluoxetine-induced shift in the ocular dominance. We also show that both chronic Fluoxetine treatment and PSA removal independently increase the basal FosB expression in parvalbumin (PV) interneurons in the primary visual cortex. Therefore, our data suggest that although PSA-NCAM regulates inhibitory circuitry, it is not required for the reactivation of juvenile-like plasticity triggered by Fluoxetine.


Strong parasitoid-mediated selection in experimental populations of aphids.
Clonal diversity in asexual populations may be maintained if different clones are favoured under different environmental conditions. For aphids, parasitoids are an important variable of the biotic environment. To test whether parasitoids can mediate selection among host clones, we used experimental populations consisting of 10 clones of the peach-potato aphid, Myzus persicae, and allowed them to evolve for several generations either without parasitoids or in the presence of two species of parasitoid wasps. In the absence of parasitoids, strong shifts in clonal frequencies occurred, mostly in favour of clones with high rates of increase. The parasitoid Diaeretiella rapae hardly affected aphid densities but changed the outcome of competition by favouring one entirely resistant clone and disfavouring a highly susceptible clone. Aphidius colemani, the more infective parasitoid, strongly reduced aphid densities and dramatically changed host clonal frequencies. The most resistant clone, not a successful clone without parasitoids, became totally dominant. These results highlight the potential of temporal or spatial variation in parasitoid densities to maintain clonal diversity in their aphid hosts.


Heritable risk factors associated with language impairments.
There is a strong genetic contribution to children's language and literacy impairments. The aim of this study was to determine which aspects of the phenotype are familial by comparing 34 parents of probands with language/literacy impairments and 33 parents of typically developing probands. The parents responded to questionnaires regarding previous history for language/reading impairment and participated in psychometric testing. The psychometric test battery consisted of tests assessing non-verbal IQ, short-term memory, articulation, receptive grammar, reading abilities and spelling. Self-report measures demonstrated a higher prevalence of language and literacy impairments in parents of affected probands (32%) compared with parents of unaffected probands (6%). The two groups of parents differed significantly in their performance on the non-word repetition, oromotor and digit span tasks. Non-word repetition gave the best discrimination between the parent groups even when the data from the parents who actually were impaired as ascertained by direct testing or self-report were removed from the analyses. This suggests that non-word repetition serves as a marker of a family risk for language impairment. The paper concludes with a discussion of issues associated with ascertainment of specific language impairment (SLI).


End-to-End Distance Distributions of Flexible Molecules: Frequency-Domain Fluorescence Energy Transfer Measurements and Rotational Isomeric State Model Calculations.
We used frequency-domain measurements of fluorescence energy transfer to determine the end-to-end distance distribution of donor-acceptor (D-A) pairs linked by flexible alkyl chains. The length of the linker was varied from 11 to 28 atoms, and two different D-A pairs were used. In each case the D-A distributions were recovered from global analysis of measurements with different values for the Förster distance, which were obtained by collisional quenching of the donors. In all cases essentially the same distance distribution was recovered from the frequency-domain data for each value of the Förster distance. Additionally, these recovered distributions were also in agreement with those recovered from steady-state measurements of the energy-transfer efficiency for various Förster distances. We compared the experimentally recovered distance distributions with those calculated from the rotational isomeric state (RIS) model of Flory. The experimentally recovered distance distributions for the largest chain molecules were in agreement with the predictions of the RIS model. However, the experimental and RIS distributions were distinct for the shorter D-A pairs. The experimental distance distributions were not in agreement with the predictions of two simpler models, the freely jointed and the freely rotating chain models. Overall, these results demonstrate that the current resolution of distance distributions is adequate for comparison with the results of conformational modeling, which in turn should allow refinement of these models.