Evaluation of the Research Diagnostic Criteria for Temporomandibular Disorders for the recognition of an anterior disc displacement with reduction.
The aim of this Focus Article is to review critically the Research Diagnostic Criteria for Temporomandibular Disorders (RDC/TMD) for the recognition of an anterior disc displacement with reduction (ADDR) in the temporomandibular joint (TMJ). This evaluation is based upon the experience gained through the careful analysis of mandibular movement recordings of hundreds of patients and controls with or without an ADDR. Clinically, it is a challenge to discriminate between the two most prevalent internal derangements of the TMJ: ADDR and symptomatic hypermobility. It is due to the very nature of these derangements that they both show clicking on opening and closing (reciprocal clicking), making reciprocal clicking not a distinguishing feature between these disorders. However, there is a difference in timing of their opening and closing clicks. Unfortunately, it is not feasible to use this difference in timing clinically to distinguish between the two internal derangements, because it is the amount of mouth opening at the time of the clicking which is clinically noted, not the condylar translation. Two other criteria proposed by the RDC/TMD for the recognition of an ADDR are the 5-mm difference in mouth opening at the time of the opening and closing clicks, and the detection of joint sounds on protrusion or laterotrusion in case of non?reciprocal clicking. These, however, run the risk of false-positive or negative results and therefore have no great diagnostic value. Instead, it is recommended that the elimination of clicking on protrusive opening and closing be examined in order to distinguish ADDRs from symptomatic hypermobility.


A randomized, controlled dose-ranging study of risedronate in children with moderate and severe osteogenesis imperfecta.
Moderate to severe osteogenesis imperfecta is associated with multiple fractures in childhood. There are no published data regarding the effects of third-generation bisphosphonates in these children. This randomized study investigated which of three different doses of risedronate was most effective in reducing fracture incidence. We randomly assigned 53 children with moderate to severe osteogenesis imperfecta to receive 0.2, 1, or 2 mg/kg per week of risedronate. We assessed safety, fracture incidence, and bone measurement outcomes at 3, 6, 12, 18, and 24 months. At 24 months, 69% of children assigned 0.2 mg/kg per week had had new fractures compared with 44% receiving 1 mg/kg per week and 75% receiving 2 mg/kg per week. Poisson regression with age and prior fracture as covariates showed that there was no difference in incident nonvertebral fracture between groups. Fracture rate diminished in each group during the trial compared with previous the 2 years (p = .005). Lumbar spine bone mineral density increased significantly (p = .009) only in the 2 mg/kg per week group. Long bone bowing deformities reduced more in children receiving 1 or 2 mg/kg per week of risedronate [odds ratio (OR) 0.67, 95% confidence interval (CI) 0.48-0.93 per unit increase in risedronate dose, p = .015]. There were no serious adverse events. Bone mass increased and bowing deformities reduced with increasing risedronate dose. Children suffered fewer fractures irrespective of risedronate dose. The most appropriate dose of risedronate for children with moderate to severe osteogenesis imperfecta in this study was 2 mg/kg per week.


Vaccine-preventable illness in U.S. children 1980-1992.
For at least a decade after the licensure of vaccines to prevent major childhood diseases, incidence of these diseases decreased. However, in the mid-to-late-1980s, four major childhood illnesses showed increases in the number of cases and the case rate, and the United States experienced epidemics of measles, mumps, rubella and whooping cough. The measles epidemic was the most severe of the four with over 55,000 cases, 11,000 hospitalizations, and 130 deaths reported across the country between 1989 and 1991. Children were hit the hardest by these epidemics. Predating these epidemics was a decline in the immunization levels of 2-year-olds. This decline coincided with vaccine price increases, an increase in the percentage of children in poverty and a decline in the rate of poor children receiving Aid to Families with Dependent Children (AFDC) and Medicaid. An estimated 100,000 excess cases of disease resulted from the low levels of immunization and consequent epidemics. While immunization rates have increased in recent years, it is important to continue our progress in this area in order to protect children from vaccine-preventable infectious diseases.


Effects of insoles and additional shock absorption foam on the cushioning properties of sport shoes.
The purpose of this study was to investigate the effects of insoles and additional shock absorption foam on the cushioning properties of various sport shoes with an impact testing method. Three commercial sport shoes were used in this study, and shock absorption foam (TPE5020; Vers Tech Science Co. Ltd., Taiwan) with 2-mm thickness was placed below the insole in the heel region for each shoe. Eight total impacts with potential energy ranged from 1.82 to 6.08 J were performed onto the heel region of the shoe. The order of testing conditions was first without insole, then with insole, and finally interposing the shock absorption foam for each shoe. Peak deceleration of the striker was measured with an accelerometer attached to the striker during impact. The results of this study seemed to show that the insole or additional shock absorption foam could perform its shock absorption effect well for the shoes with limited midsole cushioning. Further, our findings showed that insoles absorbed more, even up to 24-32% of impact energy under low impact energy. It seemed to indicate that insoles play a more important role in cushioning properties of sport shoes under a low impact energy condition.


Antioxidant activity of seagrasses of the Mandapam coast, India.
In the search for new sources of safe and inexpensive antioxidants, the leaves of eight species of seagrasses were screened for antioxidant properties. Most of the seagrasses were evaluated for the first time for their antioxidant activities. Total phenolic content and in vitro antioxidant activity using, 2,2-diphenyl-1-picrylhydrozyl (DPPH) radical scavenging capacity and FRAP assay. The leaves of Halophila stipulacea (Forssk.) Aschers showed high levels of phenols (1.398 ± 0.055 mg GAE/g) and high reducing power (46.289 ± 1.002) in terms of mg GAE/g. Similarly, H. pinifolia exhibited high total antioxidant activity (132.38, 75.027 mg AscAE/g) and a high percentage of DPPH radical scavenging activity (68.14%). The TAA and FRAP assays showed positive and significantly high correlation (R2 = 0.646). The total phenolic content in the seagrass extracts showed a better correlation with reducing power (R2 = 0.597) than the DPPH radical-scavenging activity (R2 = 0.495). The antioxidant capacities of the seagrasses showed potential rich sources of natural antioxidants. Further studies are necessary for isolation and characterization of the active antioxidant compounds, which can be used to treat various oxidative stress-related diseases.


Synthetic and model computational studies of molar rotation additivity for interacting chiral centers: a reinvestigation of van't Hoff's principle.
When plane-polarized light impinges on a solution of optically active molecules, the polarization of the light that emerges is rotated. This simple phenomenon arises from the interaction of light with matter and is well understood, in principle, van't Hoff's rule of optical superposition correlates the molar rotation with the individual contributions to optical activity of isolated centers of asymmetry. This straightforward empirical additivity rule is rarely used for structure elucidation nowadays because of its limitations in the assessment of conformationally restricted or interacting chiral centers. However, additivity can be used successfully to assign the configuration of complex natural products such as hennoxazole A if appropriate synthetic partial structures are available. Therefore, van't Hoff's principle is a powerful stereochemical complement to natural products' total synthesis. The quest for reliable quantitative methods to calculate the angle of rotation a priori has been underway for a long time. Both classical and quantum methods for calculating molar rotation have been developed. Of particular practical importance for determining the absolute structure of molecules by calculation is the manner in which interactions between multiple chiral centers in a single molecule are included, leading to additive or non-additive optical rotation angles. This problem is addressed here using semi-empirical electronic structure models and the Rosenfeld equation.


Cyberbiosecurity: A Call for Cooperation in a New Threat Landscape.
The life sciences now interface broadly with information technology (IT) and cybersecurity. This convergence is a key driver in the explosion of biotechnology research and its industrial applications in health care, agriculture, manufacturing, automation, artificial intelligence, and synthetic biology. As the information and handling mechanisms for biological materials have become increasingly digitized, many market sectors are now vulnerable to threats at the digital interface. This growing landscape will be addressed by cyberbiosecurity, the emerging field at the convergence of both the life sciences and IT disciplines. This manuscript summarizes the current cyberbiosecurity landscape, identifies existing vulnerabilities, and calls for formalized collaboration across a swath of disciplines to develop frameworks for early response systems to anticipate, identify, and mitigate threats in this emerging domain.


Analysis of mode stability in a concave mirror vertical-cavity surface-emitting laser with an oxide aperture.
We applied the Fox-Li resonator theory to analyze the mode stability of concave mirror surface-emitting lasers. The numerical modeling incorporates the oxide aperture in the simple classical cavity by adding a non-uniform phase shifting layer to the flat mirror side. The calculation shows that there is a modal loss difference between the fundamental mode and the competing modes. The amount of loss difference depends upon cavity length and the thickness of the oxide aperture. In addition to loss difference, modal gain difference plays a key role in discriminating between the fundamental mode and the higher order transverse modes. The modal gain difference heavily depends upon the size of the oxide aperture and the field intensity distribution. To summarize, the geometry of the concave cavity affects the mode profile and the unique field profile of each transverse mode makes a difference in both modal loss and gain. Finally, this leads to a side-mode suppression.


On the Design of Food Effect Studies in Adults for Extrapolating Oral Drug Absorption Data to Infants: an Exploratory Study Highlighting the Importance of Infant Food.
In the present investigation, it was explored whether food effect on drug absorption in adults is similar with the food effect after administration of an infant meal with the drug product to adults. After confirming lack of pharmaceutical and pharmacokinetic interaction, a paracetamol suspension and an ibuprofen suspension were co-administered to eight healthy adults on a crossover basis in three different occasions, i.e. in the fasted state (as defined by regulatory agencies, fasted conditions), in the fed state (as defined by regulatory agencies, fed conditions) and under conditions simulating the fed state in infants (infant fed conditions). Unlike under fed conditions, under infant fed conditions early exposure was significantly lower than under fasted conditions for both paracetamol and ibuprofen. Also, for ibuprofen, Cmax values under infant fed conditions were significantly higher than under fed conditions. These data suggest that, even for drugs with non-problematic absorption administered in simple dosage forms, food effects in infants may not be adequately evaluated if the protocol suggested by regulatory agencies is applied. The usefulness of the methodology employed in the present investigation for simulating the fed state in infants deserves further evaluation. Until then, food effects in infants should be considered cautiously or be evaluated in infants.


Lipid-Reactive T Cells in Immunological Disorders of the Lung.
Regulation of T cell-mediated immunity in the lungs is critical for prevention of immune-related lung disorders and for host protection from pathogens. While the prevalent view of pulmonary T cell responses is based on peptide recognition by antigen receptors, called T cell receptors (TCR), on the T cell surface in the context of classical major histocompatibility complex (MHC) molecules, novel pathways involving the presentation of lipid antigens by cluster of differentiation 1 (CD1) molecules to lipid-reactive T cells are emerging as key players in pulmonary immune system. Whereas, genetic conservation of group II CD1 (CD1d) in mouse and human genomes facilitated numerous in vivo studies of CD1d-restricted invariant natural killer T (iNKT) cells in lung diseases, the recent development of human CD1-transgenic mice has made it possible to examine the physiological roles of group I CD1 (CD1a-c) molecules in lung immunity. Here, we discuss current understanding of the biology of CD1-reactive T cells with a specific focus on their roles in several pulmonary disorders.


A Candidate-Gene Approach Identifies Novel Associations Between Common Variants in/Near Syndromic Obesity Genes and BMI in Pediatric and Adult European Populations.
We hypothesized that monogenic syndromic obesity genes are also involved in the polygenic variation of BMI. Single-marker, tag single nucleotide polymorphism (tagSNP) and gene-based analysis were performed on common variants near 54 syndromic obesity genes. We used publicly available data from meta-analyses of European BMI genome-wide association studies conducted by the Genetic Investigation of ANthropometric Traits (GIANT) Consortium and the UK Biobank (UKB) (N = 681,275 adults). A total of 33 loci were identified, of which 19 of 33 (57.6%) were located at SNPs previously identified by the GIANT Consortium and UKB meta-analysis, 11 of 33 (33.3%) were located at novel SNPs, and 3 of 33 (9.1%) were novel genes identified with gene-based analysis. Both single-marker and tagSNP analyses mapped the previously identified 19 SNPs by the GIANT Consortium and UKB meta-analysis. Gene-based analysis confirmed 15 of 19 (78.9%) of the novel SNPs' associated genes. Of the 11 novel loci, 8 were identified with single-marker analysis and the remaining 3 were identified with tagSNP analysis. Gene-based analysis confirmed 4 of 11 (36.3%) of these loci. Meta-analysis with the Early Growth Genetics (EGG) Consortium (N = 35,668 children) was conducted post hoc for top SNPs, confirming 17 of 33 (51.5%) loci, of which 5 were novel. This study supports evidence for a continuum between rare monogenic syndromic and common polygenic forms of obesity.


The omega-3 index as a risk factor for coronary heart disease.
Because blood concentrations of n-3 (or omega-3) fatty acids (FAs) (eicosapentaenoic and docosahexaenoic acids) are a strong reflection of dietary intake, it is proposed that a n-3 FA biomarker, the omega-3 index (erythrocyte eicosapentaenoic acid plus docosahexaenoic acid), be considered as a potential risk factor for coronary heart disease mortality, especially sudden cardiac death. The omega-3 index fulfills many of the requirements for a risk factor including consistent epidemiologic evidence, a plausible mechanism of action, a reproducible assay, independence from classic risk factors, modifiability, and, most important, the demonstration that raising levels will reduce risk for cardiac events. Measuring membrane concentrations of n-3 FAs is a rational approach to biostatus assessment as these FAs appear to exert their beneficial metabolic effects because of their actions in membranes. They alter membrane physical characteristics and the activity of membrane-bound proteins, and, once released by intracellular phospholipases from membrane stores, they can interact with ion channels, be converted into a wide variety of bioactive eicosanoids, and serve as ligands for several nuclear transcription factors, thereby altering gene expression. The omega-3 index compares very favorably with other risk factors for sudden cardiac death. Proposed omega-3 index risk zones are (in percentages of erythrocyte FAs): high risk, <4%; intermediate risk, 4-8%; and low risk, >8%. Before assessment of n-3 FA biostatus can be used in routine clinical evaluation of patients, standardized laboratory methods and quality control materials must become available.


Do solar cycles influence giant cell arteritis and rheumatoid arthritis incidence?
To examine the influence of solar cycle and geomagnetic effects on the incidence of giant cell arteritis (GCA) and rheumatoid arthritis (RA). We used data from patients with GCA (1950-2004) and RA (1955-2007) obtained from population-based cohorts. Yearly trends in age-adjusted and sex-adjusted incidence were correlated with the F10.7 index (solar radiation at 10.7 cm wavelength, a proxy for the solar extreme ultraviolet radiation) and AL index (a proxy for the westward auroral electrojet and a measure of geomagnetic activity). Fourier analysis was performed on AL, F10.7, and GCA and RA incidence rates. The correlation of GCA incidence with AL is highly significant: GCA incidence peaks 0-1 year after the AL reaches its minimum (ie, auroral electrojet reaches a maximum). The correlation of RA incidence with AL is also highly significant. RA incidence rates are lowest 5-7 years after AL reaches maximum. AL, GCA and RA incidence power spectra are similar: they have a main peak (periodicity) at about 10 years and a minor peak at 4-5 years. However, the RA incidence power spectrum main peak is broader (8-11 years), which partly explains the lower correlation between RA onset and AL. The auroral electrojets may be linked to the decline of RA incidence more strongly than the onset of RA. The incidences of RA and GCA are aligned in geomagnetic latitude. AL and the incidences of GCA and RA all have a major periodicity of about 10 years and a secondary periodicity at 4-5 years. Geomagnetic activity may explain the temporal and spatial variations, including east-west skewness in geographic coordinates, in GCA and RA incidence, although the mechanism is unknown. The link with solar, geospace and atmospheric parameters need to be investigated. These novel findings warrant examination in other populations and with other autoimmune diseases.


Comparative accuracy of mammography and ultrasound in women with breast symptoms according to age and breast density.
Breast cancer is the most common cancer and the second most common cause of death from cancer in women.The aim of this studywas to determine which is more accurate imaging test mammography or ultrasound for diagnosis of breast cancer based on the women's age and breast density. We examined 546 patients with breast symptoms, by clinical breast examination, mammography and ultrasound. A total of 546 breast lesions were examined by histopathology analyses. Histopathology results revealed the presence of 259 invasive cancers, and 287 benign lesions. Sensitivity varied significantly with age and breast density. In the 259 women who had both tests, ultrasound had a higher sensitivity than mammography in women younger than 45 years, whereas mammography had a higher sensitivity than ultrasound in women older than 60 years. The sensitivity according to age was 52,1% for mammography and 72,6% for ultrasound. The specificity according to age was 88, 5% for ultrasound and 73, 9% for mammography. Comparing the sensitivity of mammography and ultrasound according to the breast density indicates that mammographic sensitivity was 82,2% among women with predominantly fatty breast, but 23.7% in women with heterogeneous dense breasts, with the increase of fibro glandular density the level of sensitivity with mammography decreases, while ultrasonographic sensitivity was 71,1% among women with predominantly fatty breast and 57,0% for heterogeneous dense breasts. Our data indicate that sensitivity and specificity of ultrasound was statistically significantly greater than mammography in patients with breast symptoms for the detection of breast cancer and benign lesions particularly in dense breast and in young women.


Comparison of DFT and lock-in amplifier features and search for optimal electrode positions in SSVEP-based BCI.
Brain-computer interfaces (BCIs) based on steady-state visual evoked potentials (SSVEPs) have been investigated increasingly in the last years. This type of brain signals resulting from repetitive flicker stimulation has the same fundamental frequency as the stimulation including higher harmonics. This study investigated how the classification accuracy of a 4-class BCI system can be improved by localizing individual electroencephalogram (EEG) recording positions. In the current work, a 4-class SSVEP-based BCI system was set up. Ten subjects participated and EEG was recorded from 21 channels overlying occipital areas. Features were extracted by applying Discrete Fourier transformation and a lock-in analyzer system. A simple one versus the rest classifier was applied to compare methods and localize individual electrode positions. It was shown that the use of three SSVEP-harmonics recorded from individual channels yielded significantly higher classification accuracy compared to one harmonic and to the standard positions O1 and O2. Furthermore, the application of a simple one versus the rest classifier and the use of a lock-in analyzer system lead to a higher classification accuracy (mean+/-S.D., about 74+/-16%) in a 4-class BCI compared to the commonly used Discrete Fourier transformation (DFT, 62+/-14%). By applying a screening procedure, the optimal electrode positions for bipolar derivations can be detected. Furthermore, information about subject's specific 'resonance-like' frequency regions can be obtained by observing higher harmonics of the SSVEPs.


Targeting the hypoxic fraction of tumours using hypoxia-activated prodrugs.
The presence of a microenvironment within most tumours containing regions of low oxygen tension or hypoxia has profound biological and therapeutic implications. Tumour hypoxia is known to promote the development of an aggressive phenotype, resistance to both chemotherapy and radiotherapy and is strongly associated with poor clinical outcome. Paradoxically, it is recognised as a high-priority target and one of the therapeutic strategies designed to eradicate hypoxic cells in tumours is a group of compounds known collectively as hypoxia-activated prodrugs (HAPs) or bioreductive drugs. These drugs are inactive prodrugs that require enzymatic activation (typically by 1 or 2 electron oxidoreductases) to generate cytotoxic species with selectivity for hypoxic cells being determined by (1) the ability of oxygen to either reverse or inhibit the activation process and (2) the presence of elevated expression of oxidoreductases in tumours. The concepts underpinning HAP development were established over 40 years ago and have been refined over the years to produce a new generation of HAPs that are under preclinical and clinical development. The purpose of this article is to describe current progress in the development of HAPs focusing on the mechanisms of action, preclinical properties and clinical progress of leading examples.


Induction of tumor cell apoptosis by a proteasome deubiquitinase inhibitor is associated with oxidative stress.
b-AP15 is a recently described inhibitor of the USP14/UCHL5 deubiquitinases (DUBs) of the 19S proteasome. Exposure to b-AP15 results in blocking of proteasome function and accumulation of polyubiquitinated protein substrates in cells. This novel mechanism of proteasome inhibition may potentially be exploited for cancer therapy, in particular for treatment of malignancies resistant to currently used proteasome inhibitors. The aim of the present study was to characterize the cellular response to b-AP15-mediated proteasome DUB inhibition. We report that b-AP15 elicits a similar, but yet distinct, cellular response as the clinically used proteasome inhibitor bortezomib. b-AP15 induces a rapid apoptotic response, associated with enhanced induction of oxidative stress and rapid activation of Jun-N-terminal kinase 1/2 (JNK)/activating protein-1 signaling. Scavenging of reactive oxygen species and pharmacological inhibition of JNK reduced b-AP15-induced apoptosis. We further report that endoplasmic reticulum (ER) stress is induced by b-AP15 and is involved in apoptosis induction. In contrast to bortezomib, ER stress is associated with induction of α-subunit of eukaryotic initiation factor 2 phosphorylation. The findings establish that different modes of proteasome inhibition result in distinct cellular responses, a finding of potential therapeutic importance. Our data show that enhanced oxidative stress and ER stress are major determinants of the strong apoptotic response elicited by the 19S DUB inhibitor b-AP15.


APOE and the risk of PD with or without dementia in a population-based study.
To study the association between APOE genotype and PD with or without dementia. The study formed part of the Rotterdam Study, a prospective, population-based cohort study on the frequency, etiology, and prognosis of chronic diseases. The cohort examined for PD consisted of 6,969 independently living or institutionalized inhabitants from a suburb of Rotterdam, the Netherlands, aged 55 years or older. All participants were screened at baseline (1990 to 1993) and at follow-up (1993 to 1994) for symptoms of parkinsonism by study physicians; screen positives received a diagnostic workup by a neurologist. APOE genotyping was available for 107 PD patients (26 with and 81 without dementia) and 4,805 non-PD control subjects. The presence of at least one epsilon2 allele significantly increased the risk of PD (OR = 1.7; 95% CI, 1.0 to 2.8). When we looked separately for demented and nondemented PD patients as compared with nonparkinsonian controls, APOE did not appear to be associated with PD without dementia, but both the epsilon2 and the epsilon4 allele increased the risk of PD with dementia (OR = 5.6; 95% CI, 2.0 to 15.2 and OR = 3.6; 95% CI, 1.3 to 9.9). The risk of dementia for epsilon4 allele carriers was not significantly different for persons with or without PD. However, the epsilon2 allele strongly increased the risk of dementia in patients with PD (interaction p < 0.007). In the elderly the APOE-epsilon2 allele increases the risk of PD and, in particular, the risk of PD with dementia.


Effects of low-volume walking programme and vitamin E supplementation on oxidative damage and health-related variables in healthy older adults.
Both exercise and vitamin E supplementation have been shown to reduce oxidative stress and cardiovascular disease risk in older adults, and when combined there is evidence suggesting that they act synergistically. The currently recommended amount of exercise for older adults is 150 min/week of moderate-intensity exercise; however, the minimum amount of exercise necessary to achieve health benefits is not known. The purpose of this study was to investigate the effects of 12 weeks of participation in a low-volume walking exercise programme (i.e. 90 min/week) combined with daily vitamin E supplementation on thiobarbituric acid reactive substances (TBARS) and oxidised low-density lipoprotein (LDL) concentrations in older adults. The participants were recruited from the following four groups separately: 1) control (CG, n = 14), 2) vitamin E supplementation (SG, n = 10), 3) walking (WG, n = 7), or 4) walking + supplementation (WSG, n = 7). In the CG, participants were advised to maintain their normal lifestyle during the study. Participants in both the SG and WSG received 450 IU (300 mg) /day of α-tocopherol for 12 weeks. The exercise programme for the WG and WSG consisted of two 30-60 minute sessions weekly for 12 weeks (average walking time was 44.5 ± 1.6 min/session). Blood samples were collected at baseline and at 12 weeks. Delta plasma oxidised LDL concentrations did not differ among four groups (One-factor ANOVA, P = 0.116). However, negative delta plasma TBARS, a marker of oxidative damage, concentrations were observed in the WG, WSG and SG relative to the CG at the end of the study period (One-factor ANOVA, P = 0.001; post hoc tests; CG compared with WG, WSG and SG, P = 0.005; P = 0.021; P = 0.024, respectively). These findings suggest that a low-volume of physical activity and/or vitamin E supplementation may be an effective intervention strategy for reducing TBARS concentrations of older adults. UMIN000008304.


The path to safe and accessible anaesthesia care.
The increasing focus on and importance of surgical care in achieving universal health coverage requires the development of safe and accessible anaesthesia services. Increasing access to care by supporting the necessary inputs to the anaesthesia system, including medications, equipment and personnel, must be accompanied by processes that support high-quality care, including support for education, and guidelines for standards, and training. As safe, high-quality care requires an integrated approach, each element must be supported together, i.e., in an integrated manner to ensure that anaesthesia care reaches those who need it, and in the safest possible manner. Several important efforts have been undertaken globally to address and foster these elements, and resources to guide these processes exist for low- and middle-income countries to improve them. This review highlights both the needs and resources for safe and high-quality care that patients deserve.


Elevation of plasma neurotensin in the dumping syndrome.
1. The pathophysiology of the dumping syndrome is poorly understood. Plasma levels of four small intestinal hormones have been measured after an oral glucose provocation test in 19 patients with dumping symptoms and in matched controls. 2. Plasma levels of neurotensin, a newly discovered highly potent, hypotensive ileal peptide, were significantly increased in symptomatic patients compared with those of controls [20 min rise of 43 +/- 6.0 (mean +/- SEM) pmol/l in 19 symptomatic patients, 8.0 +/- 5.5 pmol/l in 20 postoperative symptom-free patients, and 4.1 +/- 3.5 pmol/l in 20 pre-operative patients with duodenal ulcer, P < 0.01]. 3. The rise in enteroglucagon was greater than normal but of similar magnitude to that seen in several other gastrointestinal conditions not associated with dumping symptoms. 4. The release of both gastric inhibitory peptide and motilin did not differ significantly from that of controls.


Application of novel PCR-based methods for detection, quantitation, and phylogenetic characterization of Sutterella species in intestinal biopsy samples from children with autism and gastrointestinal disturbances.
Gastrointestinal disturbances are commonly reported in children with autism and may be associated with compositional changes in intestinal bacteria. In a previous report, we surveyed intestinal microbiota in ileal and cecal biopsy samples from children with autism and gastrointestinal dysfunction (AUT-GI) and children with only gastrointestinal dysfunction (Control-GI). Our results demonstrated the presence of members of the family Alcaligenaceae in some AUT-GI children, while no Control-GI children had Alcaligenaceae sequences. Here we demonstrate that increased levels of Alcaligenaceae in intestinal biopsy samples from AUT-GI children result from the presence of high levels of members of the genus Sutterella. We also report the first Sutterella-specific PCR assays for detecting, quantitating, and genotyping Sutterella species in biological and environmental samples. Sutterella 16S rRNA gene sequences were found in 12 of 23 AUT-GI children but in none of 9 Control-GI children. Phylogenetic analysis revealed a predominance of either Sutterella wadsworthensis or Sutterella stercoricanis in 11 of the individual Sutterella-positive AUT-GI patients; in one AUT-GI patient, Sutterella sequences were obtained that could not be given a species-level classification based on the 16S rRNA gene sequences of known Sutterella isolates. Western immunoblots revealed plasma IgG or IgM antibody reactivity to Sutterella wadsworthensis antigens in 11 AUT-GI patients, 8 of whom were also PCR positive, indicating the presence of an immune response to Sutterella in some children. Autism spectrum disorders affect ~1% of the population. Many children with autism have gastrointestinal (GI) disturbances that can complicate clinical management and contribute to behavioral problems. Understanding the molecular and microbial underpinnings of these GI issues is of paramount importance for elucidating pathogenesis, rendering diagnosis, and administering informed treatment. Here we describe an association between high levels of intestinal, mucoepithelial-associated Sutterella species and GI disturbances in children with autism. These findings elevate this little-recognized bacterium to the forefront by demonstrating that Sutterella is a major component of the microbiota in over half of children with autism and gastrointestinal dysfunction (AUT-GI) and is absent in children with only gastrointestinal dysfunction (Control-GI) evaluated in this study. Furthermore, these findings bring into question the role Sutterella plays in the human microbiota in health and disease. With the Sutterella-specific molecular assays described here, some of these questions can begin to be addressed.


Prednisolone induces the Wnt signalling pathway in 3T3-L1 adipocytes.
Synthetic glucocorticoids are potent anti-inflammatory drugs but show dose-dependent metabolic side effects such as the development of insulin resistance and obesity. The precise mechanisms involved in these glucocorticoid-induced side effects, and especially the participation of adipose tissue in this are not completely understood. We used a combination of transcriptomics, antibody arrays and bioinformatics approaches to characterize prednisolone-induced alterations in gene expression and adipokine secretion, which could underlie metabolic dysfunction in 3T3-L1 adipocytes. Several pathways, including cytokine signalling, Akt signalling, and Wnt signalling were found to be regulated at multiple levels, showing that these processes are targeted by prednisolone. These results suggest that mechanisms by which prednisolone induce insulin resistance include dysregulation of wnt signalling and immune response processes. These pathways may provide interesting targets for the development of improved glucocorticoids.


The bovine papillomavirus 1 E2 protein contains two activation domains: one that interacts with TBP and another that functions after TBP binding.
The E2 transactivator of bovine papillomavirus type-1 is unable to activate minimal promoters in vivo that contain only E2 binding sites and a TATA box. This block can be overcome by over-expression of human TATA binding protein (TBP) or by the addition of either SP1 binding sites or an initiator element to the promoter, suggesting that the binding of TFIID may normally be a rate-limiting step for activation by E2. Surprisingly, purified E2 and TBP bind co-operatively to DNA in vitro when the sites are closely spaced. E2 does not affect the on rate of association but reduces the off rate. The E2 region responsible for this effect is located in the hinge region that links the classic transactivation and DNA binding domains. We demonstrate that the TBP stabilizing domain contributes in vivo to co-operativity with co-expressed TBP and to activation of the major late minimal promoter (MLP) containing E2 sites. In contrast, promoters with SP1 sites are activated to wild-type levels by such a mutant. This promoter specificity is also evident in vitro. A truncated E2 mutant, lacking the classic transactivation domain but containing the TBP stabilizing domain, stimulates transcription of the MLP in vitro, but does not activate promoters with SP1 sites. In conclusion, our results show that the E2 transactivation domain has a modular structure. We have identified one domain which probably acts at an early step in the assembly of the pre-initiation complex and which is involved in reducing the dissociation rate of bound TBP in vitro. The classic N-terminal activation domain of E2 might affect one or several step(s) in the assembly of the preinitiation complex occurring after the binding of TFIID.


Has UK guidance affected general practitioner antibiotic prescribing for otitis media in children?
Since 1997, UK guidance has advocated limiting antibiotic prescribing for otitis media. It is not known whether this has influenced general practitioner prescribing practice. Aims and objectives To investigate the trends in diagnoses and antibiotic prescribing for otitis media in children in relation to guidance. We used the General Practice Research Database to conduct time-trend analyses of diagnoses and antibiotic prescribing for otitis media in 3 months to 15 years old, between 1990 and 2006. A total of 1 210 237 otitis media episodes were identified in 464 845 children; two-thirds (68%; 818 006) received antibiotics. Twenty-two percent (267 335) were classified as acute, 85% (227 335) of which received antibiotics. Overall, antibiotic prescribing for otitis media declined by 51% between 1995 and 2000. Much of this reduction predated guidance. During this period, prescribing for otitis media coded as acute increased by 22%. Children diagnosed with acute otitis media were more likely to receive antibiotics than otitis media not coded as acute (P < 0.05). From 2000 prescribing plateaued, despite publication of further guidance. Otitis media diagnoses consistently paralleled prescribing. The reduction in antibiotic prescribing for otitis media predated guidance. The simultaneous decrease in prescribing for non-acute otitis media and increase for acute otitis media suggest diagnostic transfer, possibly to justify the decision to treat.


Genetic incompatibility drives sex allocation and maternal investment in a polymorphic finch.
Genetic compatibility may drive individual mate choice decisions because of predictable fitness effects associated with breeding with incompatible partners. In Gouldian finches (Erythrura gouldiae), females paired with genetically incompatible males of alternative color morphs overproduce sons, presumably to reduce investment in inviable daughters. We also observed a reduced overall investment in clutch size, egg size, and care to offspring resulting from incompatible matings. Within-female experimental pairings demonstrate that female birds have the ability to adaptively adjust the sex of their eggs and allocate resources on the basis of partner quality. Female Gouldian finches thus make cumulative strategic allocation decisions to minimize the costs of poor-quality pairings when faced with a genetically incompatible partner.


High-Quality Immunohistochemical Stains Through Computational Assay Parameter Optimization.
Accurate profiling of tumors using immunohistochemistry (IHC) is essential in cancer diagnosis. The inferences drawn from IHC-stained images depend to a great extent on the quality of immunostaining, which is in turn affected strongly by assay parameters. To optimize assay parameters, the available tissue sample is often limited. Moreover, with current practices in pathology, exploring the entire assay parameter space is not feasible. Thus, the evaluation of IHC stained slides is conventionally a subjective task, in which diagnoses are commonly drawn on images that are suboptimal. In this work, we introduce a framework to analyze IHC staining quality and its sensitivity to process parameters. To that extent, first histopathological sections are segmented automatically. Then, machine learning techniques are employed to extract disease-specific staining quality metrics (SQMs) targeting a quantitative assessment of staining quality. Finally, an approach to efficiently analyze the parameter space is introduced to infer sensitivity to process parameters. We present results on microscale IHC tissue samples of five breast tumor classes, based on disease state and protein expression. A disease-type classification F1-score of 0.82 and a contrast-level classification F1-score of 0.95 were achieved. With the proposed SQMs, an area under the curve of 0.85 was achieved on average over different disease types. Our methodology provides a promising step in automatically evaluating and quantifying staining quality of IHC stained tissue sections, and it can potentially standardize immunostaining across diagnostic laboratories.


Phenotype of glutathione S-transferase Mu (GSTM1) and susceptibility to malignant melanoma. MMM group. Multidisciplinary Malignant Melanoma Group.
The isoenzyme Mu of glutathione S-transferase (GSTM1) is dominantly inherited, and the prevalence of this isoenzyme in the population is about 60%. The lack of GSTM1 has been linked with cancer risk. The frequency of the phenotypes of this isoenzyme in melanoma (MM) patients (n = 197) is reported here. A significantly higher proportion of individuals in the control group (n = 147) had measurable GSTM1 than MM patients (59.1% vs 42%, P = 0.002); there was a higher proportion of positive phenotypes in general among women than among men. Odds ratio analysis indicated that individuals with this polymorphic variant have an approximately 2-fold risk of developing these cancers. GSTM1 phenotype distribution depends on age, smoking habit and tumour pathology. A group of MM patients with dysplastic naevi was also studied.


In vitro assessment of lidocaine release from aqueous and oil solutions and from preformed and in situ formed aqueous and oil suspensions. Parenteral depots for intra-articular administration.
In vitro drug release rates from aqueous and oil solutions as well as preformed and in situ formed aqueous and oil suspensions intended for intra-articular delivery have been investigated using the rotating dialysis cell model. Using lidocaine as a model drug substance the release kinetics from aqueous and oil suspensions have been compared and the sustained release properties from such suspensions formed in situ has been evaluated. The appearance of lidocaine in the acceptor phase after instillation of preformed and in situ formed aqueous and oil suspensions into the small aqueous donor compartment applied to zero-order kinetics as long sufficient amounts of solid lidocaine remained in the donor cell. The obtained data indicate that oil solutions and oil suspensions of lidocaine possess prolonged release properties equal to or better than those of aqueous counterparts. Also the release properties of preformed aqueous and oil suspensions are identical to such suspension types formed in situ. The present in vitro model appears useful in quality control and formulation development in the field of parenteral depots.


Interactions between Fragmented Seagrass Canopies and the Local Hydrodynamics.
The systematic creation of gaps within canopies results in fragmentation and the architecture of fragmented canopies differs substantially from non-fragmented canopies. Canopy fragmentation leads to spatial heterogeneity in hydrodynamics and therefore heterogeneity in the sheltering of canopy communities. Identifying the level of instability due to canopy fragmentation is important for canopies in coastal areas impacted by human activities and indeed, climate change. The gap orientation relative to the wave direction is expected to play an important role in determining wave attenuation and sheltering. Initially we investigated the effect of a single transversal gap within a canopy (i.e. a gap oriented perpendicular to the wave direction) on hydrodynamics, which was compared to fully vegetated canopies (i.e. no gaps) and also to bare sediment. The wave velocity increased with gap width for the two canopy densities studied (2.5% and 10% solid plant fraction) reaching wave velocities found over bare sediments. The turbulent kinetic energy (TKE) within the gap also increased, but was more attenuated by the adjacent vegetation than the wave velocity. As expected, denser canopies produced a greater attenuation of both the wave velocity and the turbulent kinetic energy within an adjacent gap, compared to sparse canopies. Using non-dimensional analysis and our experimental data, a parameterization for predicting TKE in a canopy gap was formulated, as a function of easily measured variables. Based on the experimental results, a fragmented canopy model was then developed to determine the overall mixing level in such canopies. The model revealed that canopies with large gaps present more mixing than canopies with small gaps despite having the same total gap area in the canopy. Furthermore, for the same total gap area, dense fragmented canopies provide more shelter than sparse fragmented canopies.


Sexual identity and HIV status influence the relationship between internalized stigma and psychological distress in black gay and bisexual men.
Experiences of internalized homophobia and HIV stigma in young Black gay and bisexual men (GBM) may lead to psychological distress, but levels of distress may be dependent upon their sexual identity or HIV status. In this study, we set out to explore the associations between psychological distress, sexual identity, and HIV status in young Black GBM. Participants were 228 young Black GBM who reported on their psychological distress, their HIV status, and their sexual identity. Results indicated that internalized homophobia was significantly related to psychological distress for gay men, but not for bisexual men. HIV stigma was related to psychological stress for HIV-positive men, but not for HIV-negative men. Results indicate a need for more nuanced examinations of the role of identity in the health and well-being of men who have sex with men.


Transcriptomic analysis of peritoneal cells in a mouse model of sepsis: confirmatory and novel results in early and late sepsis.
The events leading to sepsis start with an invasive infection of a primary organ of the body followed by an overwhelming systemic response. Intra-abdominal infections are the second most common cause of sepsis. Peritoneal fluid is the primary site of infection in these cases. A microarray-based approach was used to study the temporal changes in cells from the peritoneal cavity of septic mice and to identify potential biomarkers and therapeutic targets for this subset of sepsis patients. We conducted microarray analysis of the peritoneal cells of mice infected with a non-pathogenic strain of Escherichia coli. Differentially expressed genes were identified at two early (1 h, 2 h) and one late time point (18 h). A multiplexed bead array analysis was used to confirm protein expression for several cytokines which showed differential expression at different time points based on the microarray data. Gene Ontology based hypothesis testing identified a positive bias of differentially expressed genes associated with cellular development and cell death at 2 h and 18 h respectively. Most differentially expressed genes common to all 3 time points had an immune response related function, consistent with the observation that a few bacteria are still present at 18 h. Transcriptional regulators like PLAGL2, EBF1, TCF7, KLF10 and SBNO2, previously not described in sepsis, are differentially expressed at early and late time points. Expression pattern for key biomarkers in this study is similar to that reported in human sepsis, indicating the suitability of this model for future studies of sepsis, and the observed differences in gene expression suggest species differences or differences in the response of blood leukocytes and peritoneal leukocytes.


Genetic Analysis of Metalaxyl Insensitivity Loci in Phytophthora infestans Using Linked DNA Markers.
ABSTRACT Previous studies indicated that incompletely dominant loci determine insensitivity by oomycetes to phenylamide fungicides such as metalaxyl. To compare the bases of insensitivity in different strains of the late blight pathogen, Phytophthora infestans, crosses were performed between sensitive isolates and isolates from Mexico, the Netherlands, and the United Kingdom that displayed varying levels of insensitivity. Segregation analyses indicated that metalaxyl insensitivity was determined primarily by one locus in each isolate, and that two of the isolates were heterozygous and the other homozygous for the insensitive allele. Metalaxyl insensitivity was also affected by the segregation of additional loci of minor effect. DNA markers linked to insensitivity were obtained by bulked segregant analysis using random amplified polymorphic DNA (RAPD) markers and the Dutch and Mexican crosses. By studying the linkage relationships between these markers and the insensitivity in each cross by RAPD or restriction fragment length polymorphism analysis, it appeared that the same chromosomal locus conferred insensitivity in the Mexican and Dutch isolates. However, a gene at a different chromosomal position was responsible for insensitivity in the British isolate.


Molecular characterization of apricot germplasm from an old stone collection.
Increasing germplasm erosion requires the recovery and conservation of traditional cultivars before they disappear. Here we present a particular case in Spain where a thorough prospection of local fruit tree species was performed in the 1950s with detailed data of the origin of each genotype but, unfortunately, the accessions are no longer conserved in ex situ germplasm collections. However, for most of those cultivars, an old stone collection is still preserved. In order to analyze the diversity present at the time when the prospection was made and to which extent variability has been eroded, we developed a protocol in apricot (Prunus armeniaca L.) to obtain DNA from maternal tissues of the stones of a sufficient quality to be amplified by PCR. The results obtained have been compared with the results from the profiles developed from apricot cultivars currently conserved in ex situ germplasm collections. The results highlight the fact that most of the old accessions are not conserved ex situ but provide a tool to prioritize the recovery of particular cultivars. The approach used in this work can also be applied to other plant species where seeds have been preserved.


High-activity catechol-O-methyltransferase allele is more prevalent in polysubstance abusers.
Allelic variants at the catechol-O-methyltransferase (COMT) locus are candidates to contribute to genetic components of interindividual differences in vulnerability to substance abuse. COMT plays a prominent role in dopaminergic circuits important for drug reward, and COMT alleles encode enzymes whose activities vary from three- to four-fold. We compared COMT allele frequencies in control research volunteers reporting insignificant lifetime use of addictive substances with those in volunteers reporting substantial polysubstance use. Homozygosity for the high-activity COMT allele was found in 18% of controls, 31% of volunteers with high lifetime substance use, and 39% meeting DSMIII-R substance abuse criteria [odds ratio (relative risks) 2.0 (control vs. use; 95% confidence interval 1.2-3.5; P < 0.013) and 2.8 (control vs. DSM; 1.3-6.1; P < 0.008)]. Individuals with the high-activity COMT variant may have greater genetic vulnerability to drug abuse.


West Nile virus transmission through organ transplantation in north-eastern Italy: a case report and implications for pre-procurement screening.
West Nile virus (WNV) transmission through organ transplantation occurs rarely and screening of organ donors for WNV infection remains controversial. This report describes the case of WNV encephalitis in a kidney recipient and the case of asymptomatic WNV infection in the organ donor, both observed at Treviso Hospital, northeastern Italy. After briefly reviewing the literature, we discuss the implications for WNV screening. We reviewed medical, laboratory and epidemiological records at our hospital, and the literature concerning cases of organ-transmitted WNV infections and WNV screening of organ donors in Italy and worldwide. The kidney recipient was the first confirmed case of WNV infection notified in northeastern Italy in 2011, and the first case of WNV infection in a cluster of four transplant recipients who acquired the infection from a common organ donor. The organ donor, whose WNV infection was only retrospectively diagnosed by IgM detection, represents the index case of a WNV outbreak in the Treviso Province. Screening of her blood prior to organ recovery did not show detectable levels of WNV nucleic acid with the use of quantitative real-time polymerase chain reaction. This report emphasizes that transplant-acquired WNV neuroinvasive disease can be particularly severe. We suggest that pre-procurement screening of organ donors by testing blood with both WNV IgM capture ELISA and a sensitive nucleic acid testing should be adopted during the transmission season in the present Italian epidemiological setting.


Ameliorative effect of ginseng extract on phthalate and bisphenol A reprotoxicity during pregnancy in rats.
Phthalates (such as DEHP) and bisphenol A (BPA) are widely used chemicals in plastics manufacturing and exert public health concerns as endocrine disrupters. This study was designed to investigate the deleterious effect of DEHP and BPA on endocrine profile of pregnant female rats and the combined treatment with ginseng extract (Panax ginseng). Seventy-two pregnant rats were divided into six groups (control, ginseng, DEHP, BPA, Gin + DEHP, and Gin + BPA), 12 females per each group. The drugs were supplemented from pregnancy day 0 until day 20. Determination of serum sex hormones (testosterone, progesterone, and estradiol) were determined on days 4, 10, and 20 of pregnancy. mRNA transcripts of STAR, HSD17B3, CYP17, AKT1, and PTEN were relatively quantified against ACTB in the ovary and placenta of days 10 and 20 pregnant females by relative quantitative polymerase-chain reaction (RQ-PCR). DEHP and BPA significantly decreased the endocrine profile of testosterone, progesterone, and estradiol of days 10 and 20 of pregnant females. Combined administration of these chemicals along with ginseng extracts has returned the hormones to normal levels when compared with the control group. The ovarian and placental CYP17 and HSD17B3 mRNA transcripts showed variable expression pattern in both tissues and they were significantly affected by DEHP and BPA administration, concomitantly correlating to STAR, AKT1, PTEN, progesterone, and testosterone levels on pregnancy days 10 and 20. The results confirm the reprotoxicity of DEHP and BPA as endocrine disruptors and indicate that ginseng could be used to alleviate the toxic effects of these chemicals.


SARS-CoV-2 and Health Care Worker Protection in Low-Risk Settings: a Review of Modes of Transmission and a Novel Airborne Model Involving Inhalable Particles.
Since the beginning of the COVID-19 pandemic, there has been intense debate over SARS-CoV-2's mode of transmission and appropriate personal protective equipment for health care workers in low-risk settings. The objective of this review is to identify and appraise the available evidence (clinical trials and laboratory studies on masks and respirators, epidemiological studies, and air sampling studies), clarify key concepts and necessary conditions for airborne transmission, and shed light on knowledge gaps in the field. We find that, except for aerosol-generating procedures, the overall data in support of airborne transmission-taken in its traditional definition (long-distance and respirable aerosols)-are weak, based predominantly on indirect and experimental rather than clinical or epidemiological evidence. Consequently, we propose a revised and broader definition of "airborne," going beyond the current droplet and aerosol dichotomy and involving short-range inhalable particles, supported by data targeting the nose as the main viral receptor site. This new model better explains clinical observations, especially in the context of close and prolonged contacts between health care workers and patients, and reconciles seemingly contradictory data in the SARS-CoV-2 literature. The model also carries important implications for personal protective equipment and environmental controls, such as ventilation, in health care settings. However, further studies, especially clinical trials, are needed to complete the picture.


Endoscopic hologram interferometry using fiber optics.
Basic and practical problems on the formation of fringes in endoscopic hologram interferometry using fiber optics have been studied in connection with medical diagnosis of living body cavities, nondestructive testing of inner parts of machines, etc. It is pointed out that fiber bundles instead of single fibers can be used to transmit high power laser light for object illumination to prevent the light path break induced by the high power density of concentrated laser light. The effects of extended source illumination by the fiber bundle, image transmission through the ordered fiber bundle, and fiber bundle movement on the fringe visibility were investigated.


Randomized controlled trial of primary care physician motivational interviewing versus brief advice to engage adolescents with an Internet-based depression prevention intervention: 6-month outcomes and predictors of improvement.
We believe that primary care physicians could play a key role in engaging youth with a depression prevention intervention. We developed CATCH-IT (Competent Adulthood Transition with Cognitive Behavioral and Interpersonal Training), which is an adolescent Internet-based behavior change model. We conducted a randomized comparison of two approaches in engaging adolescents with the Internet intervention: primary care physician (PCP) motivational interview + CATCH-IT Internet program (MI) vs PCP brief advice + CATCH-IT Internet program (BA). The participants (N = 84) were recruited by screening for risk of depression in 13 primary care practices. We compared depressive disorder outcomes between groups and within groups over 6 months and examined the potential predictors and moderators of outcomes across both study arms. Depressive symptom scores declined from baseline to 6 weeks with these statistically significant reductions sustained at the 6 months follow-up in both groups. No significant interactions with treatment condition were found. However, by 6 months, the MI group demonstrated significantly fewer depressive episodes and reported less hopelessness as compared with the BA group. Hierarchical linear modeling regressions showed higher ratings of ease of use of the Internet program predicting lower depressive symptom levels over 6 months. In conclusion, a primary care/Internet-based intervention model among adolescents demonstrated reductions in depressed mood over 6 months and may result in fewer depressive episodes.


The Relationship between Magnesium and Endothelial Function in End-Stage Renal Disease Patients on Hemodialysis.
Chronic kidney disease (CKD) patients tend to have higher serum magnesium values than healthy population due to their positive balance of magnesium in kidney. Recent studies found that magnesium level is positively correlated with endothelial function. Therefore, this study was conducted to define the relationship between magnesium level and endothelial dysfunction in end stage renal disease (ESRD) patients on hemodialysis (HD). A total of 27 patients were included in this cross-sectional study. Iontophoresis with laser-Doppler flowmetry, flow mediated dilation (FMD), and carotid intima-media thickness were measured. Patients' average serum magnesium levels were measured over previous three months, including the examination month. Pearson's correlation coefficient analysis and multivariate regression model were used to define the association between magnesium and endothelial function. In the univariate analysis, higher magnesium levels were associated with better endothelium-dependent vasodilation (EDV) of the FMD in ESRD patients on HD (r=0.516, p=0.007). When the participants were divided into two groups according to the median magnesium level (3.47 mg/dL), there was a significant difference in EDV of FMD (less than 3.47 mg/dL, 2.8±1.7%; more than 3.47 mg/dL, 5.1±2.0%, p=0.004). In multivariate analysis, magnesium and albumin were identified as independent factors for FMD (β=1.794, p=0.030 for serum magnesium; β=3.642, p=0.012 for albumin). This study demonstrated that higher serum magnesium level may be associated with better endothelial function in ESRD patients on HD. In the future, a large, prospective study is needed to elucidate optimal range of serum magnesium levels in ESRD on HD patients.


NN2211: a long-acting glucagon-like peptide-1 derivative with anti-diabetic effects in glucose-intolerant pigs.
Glucagon-like peptide-1 (GLP-1) is an effective anti-diabetic agent, but its metabolic instability makes it therapeutically unsuitable. This study investigated the pharmacodynamics of a long-acting GLP-1 derivative (NN2211: (Arg(34)Lys(26)-(N- epsilon -(gamma-Glu(N-alpha-hexadecanoyl)))-GLP-1(7-37)), after acute and chronic treatment in hyperglycaemic minipigs. During hyperglycaemic glucose clamps, NN2211 (2 micrograms kg(-1) i.v.) treated pigs required more (P < 0.005) glucose than control animals (5.8 +/- 2.1 vs. 2.9 +/- 1.8 mg kg(-1) min(-1)). Insulin excursions were higher (P < 0.01) after NN2211 (15,367 +/- 5,438 vs. 9,014 +/- 2,952 pmol l(-1) min), and glucagon levels were suppressed (P < 0.05). Once-daily injections of NN2211 (3.3 micrograms kg(-1) s.c.) reduced the glucose excursion during an oral glucose tolerance test, to 59 +/- 15% of pre-treatment values by 4 weeks (P < 0.05), without measurable changes in insulin responses. Fructosamine concentrations were unaltered by vehicle, but decreased (from 366 +/- 187 to 302 +/- 114 micromol l(-1), P = 0.14) after 4 weeks of NN2211. Gastric emptying was reduced (P < 0.05) by NN2211. NN2211 acutely increases glucose utilization during a hyperglycaemic glucose clamp and chronic treatment results in better daily metabolic control. Therefore, NN2211, a GLP-1 derivative that can be administered once daily, holds promise as a new anti-diabetic drug with a minimal risk of hypoglycaemia.


Risk Factors for the Requirement of Antenatal Insulin Treatment in Gestational Diabetes Mellitus.
Poor maternal glycemic control increases maternal and fetal risk for adverse outcomes, and strict management of gestational diabetes mellitus (GDM) is recommended to prevent neonatal and maternal complications. However, risk factors for the requirement of antenatal insulin treatment (AIT) are not well-investigated in the pregnant women with GDM. We enrolled 37 pregnant women with GDM and investigated the risk for AIT by comparing the patients with AIT (AIT group; n = 10) and without insulin therapy (Diet group; n = 27). The 1-h and 2-h plasma glucose levels and the number of abnormal values in 75 g OGTT were significantly higher in AIT group compared with Diet group. By logistic regression analysis, plasma glucose level at 1-h was significant predictor for AIT and the odds ratios were 1.115 (1.004-1.239) using forward selection method and 1.192 (1.006-1.413) using backward elimination method. There were no significant differences in obstetrical outcomes and neonatal complications. 1-h plasma glucose levels in 75 g OGTT are useful parameters in predicting the requirement for AIT in GDM. Both maternal and neonatal complications are comparable in GDM patients with and without insulin therapy.


Interventions for dissociated vertical deviation.
The term "strabismus" describes misalignment of the eyes. One or both eyes may deviate inward, outward, upward, or downward. Dissociated vertical deviation (DVD) is a well-recognized type of upward drifting of one or both eyes, which can occur in children or adults. DVD often develops in the context of infantile- or childhood-onset horizontal strabismus, either esotropia (inward-turning) or exotropia (outward-turning). For some individuals, DVD remains controlled and can only be detected during clinical testing. For others, DVD becomes spontaneously "manifest" and the eye drifts up of its own accord. Spontaneously manifest DVD can be difficult to control and often causes psychosocial concerns. Traditionally, DVD has been thought to be asymptomatic, although some individuals have double vision. More recently it has been suggested that individuals with DVD may also suffer from eyestrain. Treatment for DVD may be sought either due to psychosocial concerns or because of these symptoms. The standard treatment for DVD is a surgical procedure; non-surgical treatments are offered less commonly. Although there are many studies evaluating different management options for the correction of DVD, a lack of clarity remains regarding which treatments are most effective. The objective of this review was to determine the effectiveness and safety of various surgical and non-surgical interventions in randomized controlled trials of participants with DVD. We searched CENTRAL (which contains the Cochrane Eyes and Vision Trials Register) (2015, Issue 8), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to August 2015), EMBASE (January 1980 to August 2015), PubMed (1948 to August 2015), Latin American and Caribbean Health Sciences Literature Database (LILACS) (1982 to August 2015), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com) (last searched 3 February 2014), ClinicalTrials.gov (www.clinicaltrials.gov), and the WHO International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 3 August 2015. We included randomized controlled trials (RCTs) of surgical and non-surgical interventions for the correction of DVD. We used standard procedures expected by Cochrane. Two review authors independently completed eligibility screening, data abstraction, 'Risk of bias' assessment, and grading of the evidence. We found four RCTs eligible for inclusion in this review (248 eyes of 151 participants between the ages of 6 months to 22 years). All trials were assessed as having unclear risk of bias overall due to insufficient reporting of study methods. One trial was conducted in Canada and compared anteriorization of the inferior oblique muscle with resection versus anteriorization of the inferior oblique muscle alone; one in the USA compared superior rectus recession with posterior fixation suture versus superior rectus recession alone; and two in the Czech Republic compared anteriorization of the inferior oblique muscle versus myectomy of the inferior oblique muscle.Only one trial reported data that allowed analysis of the primary outcome for this review, the proportion of participants with treatment success. The difference between inferior oblique anteriorization plus resection versus inferior oblique anteriorization alone was uncertain when measured at least four months postoperatively (risk ratio 1.13, 95% confidence interval 0.60 to 2.11, 30 participants, very low-quality evidence). Three trials measured the magnitude of hyperdeviation, but did not provide sufficient data for analysis. All four trials reported a relatively low rate of adverse events; hypotropia, limited elevation, and need for repeat surgery were reported as adverse events associated with some of the surgical interventions. No trials reported any other secondary outcome specified for our review. The four trials included in this review assessed the effectiveness of five different surgical procedures for the treatment of DVD. Nevertheless, insufficient reporting of study methods and data led to methodological concerns that undermine the conclusions of all studies. There is a pressing need for carefully executed RCTs of treatment for DVD in order to improve the evidence for the optimal management of this condition.


Estimating the accuracy of polymerase chain reaction-based tests using endpoint dilution.
Polymerase chain reaction (PCR)-based tests for various microorganisms or target DNA sequences are generally acknowledged to be highly "sensitive," yet the concept of sensitivity is ill-defined in the literature on these tests. We propose that sensitivity should be expressed as a function of the number of target DNA molecules in the sample (or specificity, when the target number is 0). However, estimating this "sensitivity curve" is problematic, since it is difficult to construct samples with a fixed number of targets. Nonetheless, using serially diluted replicate aliquots of a known concentration of the target DNA sequence, we show that it is possible to disentangle random variations in the number of target DNA molecules from the underlying test sensitivity. We develop parametric, nonparametric, and semiparametric (spline-based) models for the sensitivity curve. The methods are compared on a new test for M. genitalium.


Improving foot care for people with diabetes mellitus--a randomized controlled trial of an integrated care approach.
To evaluate a model of integrated diabetic footcare, for identification and clinical management of the high risk diabetic foot, centred on the primary care-based diabetic annual review. A pragmatic randomized controlled study was undertaken with matched cluster randomization of practices from 10 towns drawn from mid and east Devon responsible for the care of 1,939 people with diabetes (age > or =18 years). Outcome measures were patients' attitudes regarding the value and importance of footcare, patients' footcare knowledge, healthcare professionals' footcare knowledge and pattern of service utilization. Attitudes towards footcare improved in both intervention and control groups (mean percentage change 3.91, 0.68) with a significant difference in change of 3.18 (95% confidence interval (CI) 1.29-5.07) between the groups. Patients' knowledge about diabetic foot problems improved significantly in both groups (mean percentage change 1.09, 1.32) but with no significant difference in change: -0.09 (95% CI -1.81-1.63) between groups. Health professionals' knowledge scores improved in the intervention group (mean percentage change 13.2; P < 0.001). No improvement was seen in the control group (mean percentage change -0.2; P = 0.1) with a significant difference in change of 13.46 (95% CI 8.30-18.62) between groups. Appropriate referrals from intervention practices to the specialized foot clinic rose significantly (P = 0.05) compared with control practices (P = 0.14). Provision of integrated care arrangements for the diabetic foot has a positive impact on primary care staffs' knowledge and patients' attitudes resulting in an increased number of appropriate referrals to acute specialist services.


Baclofen effects on alcohol seeking, self-administration and extinction of seeking responses in a within-session design in baboons.
Baclofen, a gamma-aminobutyric acidB receptor agonist, is currently under investigation as a potential treatment to prevent relapse to drinking in alcohol-dependent persons. In the current study, two groups of baboons were trained under a chained schedule of reinforcement (CSR), with three linked components, which were each correlated with different response requirements and cues. Fulfilling the requirement in the second link initiated the third link where either alcohol (n = 4) or a preferred non-alcoholic beverage (Tang, n = 5) was available for self-administration; failure to complete the response requirement in Link 2 ended the session (no access to alcohol or Tang). Seeking responses in Link 2 were used as indices of the motivational processes thought to be involved in relapse. The effects of baclofen (0.1-2.4 mg/kg) were examined under conditions with alcohol or Tang access and under extinction. Under the CSR, baclofen (1.8 and 2.4 mg/kg) significantly decreased (P < 0.05) alcohol self-administration responses and total g/kg alcohol intake. In contrast, only the highest dose of baclofen (2.4 mg/kg) reduced Tang self-administration and consumption. Under within-session extinction conditions, baclofen (1.8 and 2.4 mg/kg) facilitated extinction of responding for both alcohol and Tang, particularly during the first 10 minutes of extinction. Baclofen may be effective in reducing craving and alcohol drinking, although the facilitation of extinction and suppression of both alcohol and Tang self-administration by baclofen suggests these effects may be related to a more general suppression of consummatory and conditioned behaviors.


Efficacy of tumor-infiltrating lymphocytes in the treatment of hepatic metastases arising from transgenic intraocular tumors in mice.
The purpose of this study was to determined if tumor-infiltrating lymphocytes (TIL) isolated from transgenic intraocular tumors were capable of preventing the development of spontaneous hepatic metastases. Tumor-infiltrating lymphocytes were isolated from intraocular tumors in immunocompetent mice and were examined for cytolytic activity in vitro. The antigenic phenotypes of the TIL were determined by in situ immunohistology. Cultured TIL were transferred adoptively to immunoincompetent, intraocular, tumor-bearing recipients to determine the efficacy of TIL in preventing spontaneous liver metastases. Cultured TIL displayed remarkable cytolytic activity in vitro and antimetastatic properties after adoptive transfer into immunoincompetent, athymic nude mice and anti-CD4/CD8-treated euthymic FVB/N mice. Hepatic metastases developed in only 2 of 10 athymic nude mice that subsequently received TIL, whereas metastases developed in all 10 control mice. Similar results were found in anti-CD4/CD8-treated FVB/N mice. Hepatic metastases did not develop in any of the 10 mice treated with TIL, whereas extensive metastatic foci developed in all 10 untreated FVB/N control mice. The efficacy of TIL therapy was manifested also by significant prolongation of host survival times. Tumor-infiltrating lymphocytes isolated from intraocular tumors can be expanded in vitro and can exert antimetastatic effects in vivo.


Characterization, cloning and immunogenicity of antigens released by lung-stage larvae of Schistosoma mansoni.
Lung-stage schistosomula are the target of protective immunity in mice vaccinated with attenuated cercariae of Schistosoma mansoni. Therefore, proteins present at this developmental stage, and in particular those which are secreted, are a potential source of novel vaccine candidates. However, little information is available about such molecules. Here we describe the cDNA clones identified by screening expression libraries with serum raised against proteins released by lung-stage schistosomula. In total, 11 different cDNA species were identified, 6 of which have been described previously in S. mansoni; these included fructose 1,6-bisphosphate aldolase and Sm21.7 which together accounted for two-thirds of all positive clones. Of the 5 newly described schistosome genes, 1 cDNA had a high degree of homology to the s5a subunit of 26S proteasomes, most significant being with the human protein. The remaining 4 clones showed no significant homologies to any genes sequenced previously. Fructose 1,6-bisphosphate aldolase, Sm21.7, the proteasome homologue and 1 unknown clone (A26) have been expressed in a bacterial expression system and serum produced against each recombinant protein. Immunolocalization showed fructose 1,6-bisphosphate aldolase, Sm21.7 and the proteasome homologue to be most abundant in muscle cells whilst clone A26 was distributed throughout many tissues, but was most abundant in the tegument. Analysis of the cellular immune responses of vaccinated mice showed 3 of the 4 expressed clones to be highly immunogenic, inducing the secretion of large quantities of the Th1-type cytokine interferon gamma.


Clinical practice guidelines for Clostridium difficile infection in adults: 2010 update by the society for healthcare epidemiology of America (SHEA) and the infectious diseases society of America (IDSA).
Since publication of the Society for Healthcare Epidemiology of America position paper on Clostridium difficile infection in 1995, significant changes have occurred in the epidemiology and treatment of this infection. C. difficile remains the most important cause of healthcare-associated diarrhea and is increasingly important as a community pathogen. A more virulent strain of C. difficile has been identified and has been responsible for more-severe cases of disease worldwide. Data reporting the decreased effectiveness of metronidazole in the treatment of severe disease have been published. Despite the increasing quantity of data available, areas of controversy still exist. This guideline updates recommendations regarding epidemiology, diagnosis, treatment, and infection control and environmental management.


Strain rate acceleration yields a better index for evaluating left ventricular contractile function as compared with tissue velocity acceleration during isovolumic contraction time: an in vivo study.
Our study aimed to investigate whether strain rate acceleration (SRA) during isovolumic contraction time (IVCT) could serve as a sensitive indicator of myocardial function. A total of 8 sheep underwent occlusion of left anterior descending coronary artery or diagonal branches and 2 sheep underwent left circumflex coronary artery occlusion to create septal, apical, or basal segment myocardial ischemia 19 to 27 weeks before the study. Baseline, volume-loading, dobutamine, and metoprolol infusion were used to produce 4 hemodynamic stages for each sheep. Doppler tissue imaging was acquired using a 5-MHz probe (GE/VingMed Vivid Five, GE Medical Systems, Milwaukee, Wis) on open-chest animals using the liver as a standoff at the apex. Using software (EchoPac, GE Medical Systems), SRA during IVCT was calculated and compared with tissue velocity acceleration (TVA) during IVCT from areas located in the normal and ischemic zones. Also, invasively monitored left ventricle dP/dt was measured as reference contractile function. Both TVA and SRA during IVCT showed higher values for normal tissue than for ischemic area (P <.0001). SRA for normal wall segments changed significantly during the 4 stages (P =.01) with corresponding changes on high-fidelity left ventricular pressure catheters (r = 0.92). TVA over normal segments showed no significant change (P =.29) in the 4 hemodynamic stages. Both TVA and SRA of the ischemic segments showed no significant change with pharmacologic maneuvers or loading conditions. SRA and TVA during IVCT are both useful indicators for detecting abnormal heart wall motion. However, SRA tends to be more sensitive than TVA for differentiating the response to stress conditions.


Linearity evaluation in absorbance detection: the use of light-emitting diodes for on-capillary detection in capillary electrophoresis.
A model which takes into account both stray light and polychromatic light was used to predict and evaluate linearity in on-capillary detection in capillary electrophoresis (CE). According to the model the stray light is the major factor which determines linearity under typical CE operating conditions. By calculating theoretical absorbance versus concentration plots, the influence of different levels of stray light and polychromatic light on linearity is demonstrated. Experimentally, six light-emitting diodes (LEDs) in the range from 563 to 654 nm were examined as light sources for on-capillary detection in CE. Fitting theoretical curves to measured linearity plots enabled determination of the values of both effective path length and stray light for a particular detection system. The detector linearity for the four LEDs was compared to mercury and tungsten lamps used with interference filters. For potassium permanganate as the test compound, the linear range for a 563 nm LED was two times greater than that for a mercury lamp operated at 546 nm. The relatively poor linearity of the mercury lamp detector is explained by its high level of stray light. The noise of the LED563-based detector was the same as for the mercury lamp, whereas the other LEDs of higher light intensity gave approximately half the noise of the mercury lamp. The lowest noise level of 3 x 10(-5) AU was obtained for the LED at 554 nm (determined at a detector time constant of 0.1 s).


A C-terminal peptide of the GIRK1 subunit directly blocks the G protein-activated K+ channel (GIRK) expressed in Xenopus oocytes.
1. In order to find out the functional roles of cytosolic regions of a G protein-activated, inwardly rectifying potassium channel subunit we studied block of GIRK channels, expressed in Xenopus laevis oocytes, by synthetic peptides in isolated inside-out membrane patches. 2. A peptide (DS6) derived from the very end of the C-terminus of GIRK1 reversibly blocked GIRK activity with IC50 values of 7.9 +/- 2.0 or 3.5 +/- 0.5 micrograms ml-1 (corresponding to 3.7 +/- 0.9 or 1.7 +/- 0.2 mumol l-1) for GIRK1/GIRK5 or GIRK1/GIRK4 channels, respectively. 3. Dose dependency studies of GIRK activation by purified beta gamma subunits of the G protein (G beta gamma) showed that DS6 block of GIRK channels is not the result of competition of the peptide with functional GIRK channels for the available G beta gamma. 4. Burst duration of GIRK channels was reduced, whereas long closed times between bursts were markedly increased, accounting for the channel block observed. 5. Block by the DS6 peptide was slightly voltage dependent, being stronger at more negative potentials. 6. These data support the hypothesis that the distal part of the carboxy-terminus of GIRK1 is a part of the intrinsic gate that keeps GIRK channels closed in the absence of G beta gamma.


Paeoniflorin ameliorates interferon-alpha-induced neuroinflammation and depressive-like behaviors in mice.
Long-term treatment with high-dose Interferon-alpha (IFN-α) has resulted in depression in 30-50% of the patients. Paeoniflorin may ameliorate the IFN-α-induced depression; however, the underlying mechanism is less studied. Here, we investigated the prophylactic antidepressant and anti-neuroinflammatory effects of paeoniflorin on the behaviors and specific emotion-related regions of the brain in mice with IFN-α-induced depression. A series of behavior assessments were conducted to identify the depressive state after subcutaneously IFN-α injections and with or without intragastrically paeoniflorin administration in C57BL/6J mice. Levels of many inflammatory-related cytokines in serum, mPFC, vHi and amygdala were determined by cytokine array analysis. Furthermore, microglia and astrocyte activation in these three regions were evaluated by immunohistochemistry. We found that the mice which were subcutaneously injected IFN-α 15×106 IU/kg for 4 successive weeks to mimic an IFN-α-induced depression model had distinct inflammatory changes in the amygdala. Interestingly, 4-week 20 mg/kg or 40 mg/kg paeoniflorin pretreatments reversed the depressive-like behaviors and the abnormal inflammatory cytokine levels in the serum, mPFC, vHi and amygdala. These cytokines were not limited to the commonly reported IL-6, IL-1β and TNF-α, but also IL-9, IL-10, IL-12, and MCP-1. Besides, the increased density of microglia in IFN-α-treated mice was reversed by paeoniflorin in these three brain areas. Taken together, our data suggest that paeoniflorin can reverse the long-term, high-dose IFN-α-induced depressive-like behaviors that were associated with local distinct neuroinflammation in the mPFC, vHi and particularly the amygdala. Paeoniflorin might have a preventive therapeutic potential in IFN-α-induced depression.


Neutrophil recruitment and bacterial clearance correlated with LPS responsiveness in local gram-negative infection.
The inflammatory response to Gram-negative infection was studied in LPS responder and nonresponder C3H mice. Twenty-four hours after ascending E. coli urinary tract infection, an influx of neutrophils into the urine was observed in C3H/HeN mice (Lpsn,Lpsn); no significant neutrophil influx occurred in C3H/HeJ mice (Lpsd,Lpsd) at this time. A second peak of urinary neutrophil excretion was observed in both strains of mice approximately 6 days post-infection. The first, but not the second peak was inducible by inoculation with formalin-killed E. coli but not by Gram-positive bacteria. This finding suggested that the first peak is triggered by LPS, whereas the second peak emanates from other bacterial components which activate both LPS responder and nonresponder mice. The first peak of the inflammatory response was inversely related to bacterial clearance. C3H/HeJ mice (Lpsd,Lpsd) retained about 2000-fold more E. coli in the kidneys than C3H/HeN mice (Lpsn,Lpsn). The infection persisted despite the late-occurring influx of neutrophils in C3H/HeJ mice. These results suggest that an inflammatory response to LPS is required for the elimination of a local Gram-negative infection.


Performance trade-offs and ageing in the 'world's greatest athletes'.
The mechanistic foundations of performance trade-offs are clear: because body size and shape constrains movement, and muscles vary in strength and fibre type, certain physical traits should act in opposition with others (e.g. sprint versus endurance). Yet performance trade-offs are rarely detected, and traits are often positively correlated. A potential resolution to this conundrum is that within-individual performance trade-offs can be masked by among-individual variation in 'quality'. Although there is a current debate on how to unambiguously define and account for quality, no previous studies have partitioned trait correlations at the within- and among-individual levels. Here, we evaluate performance trade-offs among and within 1369 elite athletes that performed in a total of 6418 combined-events competitions (decathlon and heptathlon). Controlling for age, experience and wind conditions, we detected strong trade-offs between groups of functionally similar events (throwing versus jumping versus running) occurring at the among-individual level. We further modelled individual (co)variation in age-related plasticity of performance and found previously unseen trade-offs in throwing versus running performance that manifest through ageing. Our results verify that human performance is limited by fundamental genetic, environmental and ageing constraints that preclude the simultaneous improvement of performance in multiple dimensions. Identifying these constraints is fundamental to understanding performance trade-offs and predicting the ageing of motor function.


Confocal and conventional immunofluorescence and ultrastructural localisation of intracellular strength-giving components of human amniochorion.
Key cytoskeletal polypeptides of human fetal membranes have been localised at subcellular level using confocal and conventional indirect immunofluorescence microscopy. Correlation with electron microscope data has allowed us to examine how cellular compartments of this multilaminar tissue maintain their mechanical integrity until the time of membrane rupture at parturition. Evidence is presented for myofibroblastic characteristics of cells in both the fibroblast and reticular layers which may therefore have tension-generating, position-adjustment and wound-healing roles in the amniochorion. Desmin and vimentin are coexpressed in these cells, but a small localised population of cells in the fibroblast layer contains vimentin alone. An interaction of cytokeratin filaments with nuclei and desmosomes of amniotic epithelium in vivo is demonstrated, indicating that nuclei of cells of ectodermal origin are integrated into a mechanical structure extending throughout the tissue as a whole. Cells of the basal 1 or 2 layers of trophoblast have been shown to have a more extensive and better integrated cytoskeletal organisation than those overlying and forming the boundary with decidua. Structures within the trophoblast, identified previously as degenerate villi, contain cells with intermediate filaments with similar immunofluorescence properties to those of the neighbouring reticular layer and thus may represent papillae that prevent shearing at this interface.


Predictors of psychopathology in young adults referred to mental health services in childhood or adolescence.
For children referred to mental health services future functioning may be hampered. To examine stability and prediction of behavioural and emotional problems from childhood into adulthood. A referred sample (n = 789) aged 4-18 years was followed up after a mean of 10.5 years. Scores derived from the Child Behavior Checklist, Youth Self-Report and Teacher Report Form were related to equivalent scores for young adults from the Young Adult Self-Report and Young Adult Behavior Checklist. Correlations between first contact (T1) and follow-up (T2) scores were 0.12-0.53. Young adult psychopathology was predicted by corresponding T1 problem scores. Social problems and anxious/depressed scores were predictors of general problem behaviour. Problem behaviour of children and adolescents referred to outpatient mental health services is highly predictive of similar problem behaviour at young adulthood. Stability is higher for externalizing than for internalizing behaviour and for intra-informant than for inter-informant information. Stabilities are similar across gender. To obtain a comprehensive picture of the young adult's functioning, information from related adults may prove valuable.


On the mechanism of unidirectional killing in mixtures of two cytotoxic T lymphocytes. Unidirectional polarization of cytoplasmic organelles and the membrane-associated cytoskeleton in the effector cell.
In mixtures of two CTL of the type a anti-b and b anti-c, only the latter is lysed; i.e., killing is unidirectional. Here, we show that two profound types of changes occur in the effector CTL but not in the target CTL upon formation of couples between them. One is that the microtubule organizing center (and presumably the Golgi apparatus that is invariably colocalized with it) is reoriented inside the effector CTL to face the bound target CTL. This unidirectional reorientation, it is proposed, serves to direct putative cytotoxic secretory components derived from the Golgi apparatus of the effector cell to the site of cell-cell binding. The second unidirectional change is in the membrane-associated cytoskeleton of the effector CTL in the area of target cell binding. The cytoskeletal protein talin, but not any of four other such proteins assayed, is highly concentrated at the contacting membrane of the effector CTL, while it is uniformly distributed over the entire membrane of the bound target CTL. This localized, massive cytoskeletal reorganization may reflect a mechanism to protect the membrane of the effector CTL from the effects of putative cytotoxic components secreted by the effector cell into the intercellular space between it and the target cell.


There and back again; historical perspective and future directions for Vaccinium breeding and research studies.
The genus Vaccinium L. (Ericaceae) contains a wide diversity of culturally and economically important berry crop species. Consumer demand and scientific research in blueberry (Vaccinium spp.) and cranberry (Vaccinium macrocarpon) have increased worldwide over the crops' relatively short domestication history (~100 years). Other species, including bilberry (Vaccinium myrtillus), lingonberry (Vaccinium vitis-idaea), and ohelo berry (Vaccinium reticulatum) are largely still harvested from the wild but with crop improvement efforts underway. Here, we present a review article on these Vaccinium berry crops on topics that span taxonomy to genetics and genomics to breeding. We highlight the accomplishments made thus far for each of these crops, along their journey from the wild, and propose research areas and questions that will require investments by the community over the coming decades to guide future crop improvement efforts. New tools and resources are needed to underpin the development of superior cultivars that are not only more resilient to various environmental stresses and higher yielding, but also produce fruit that continue to meet a variety of consumer preferences, including fruit quality and health related traits.


Detection of Chlamydia trachomatis in rapidly produced McCoy cell monolayers.
The 24-hour delay between seeding coverslips with cells and inoculating samples for culture of chlamydiae was reduced to less than 1 hour by using coverslips which had been pre-treated with glutaraldehyde-activated gamma-aminopropyl-triethoxysilane. Treated coverslips were not toxic for McCoy cells and even one year after treatment monolayers formed rapidly on them. Furthermore, all of 13 Chlamydia trachomatis serotypes and one C. psittaci strain tested produced inclusions in such cell monolayers. In comparative tests, when there were large numbers of inclusions, more were always seen in conventionally produced monolayers than in monolayers on treated coverslips. However, when there were few inclusions, more were seen in the latter monolayers, a phenomenon observed with unpassaged chlamydiae in clinical specimens as well as in laboratory-passaged strains. The rapid method is, therefore, as sensitive for isolating chlamydiae as using conventionally produced monolayers.


Current and emerging treatment options for a patient with a second relapse of Hodgkin's lymphoma.
Hodgkin's lymphoma (HL) is largely a curable disease with excellent prognosis. The standard of care in patients with relapsed disease has been to try salvage chemotherapy followed by an autologous stem cell transplantation (ASCT). Managing the patients who relapse after ASCT, is challenging. With the approval of targeted therapies such as PD-1 inhibitors, brentuximab vedotin, the outcomes have improved greatly. Areas covered: This review summarizes the current data available on the newer therapies as well as the present strategies used to treat patients with relapsed HL after an autologous stem cell transplantation. Expert commentary: The approval of brentuximab vedotin and PD-L1 inhibitors has ushered in a new era of targeted therapy in HL. There are currently several targeted therapies under investigation, particularly in the setting of relapsed disease. The current challenges faced are how best to integrate these newer therapies into the existing treatment regimens, finding a right combination with minimal toxicities, role of allogenic transplant in the era of targeted therapy.


Authentication labels based on guided-mode resonant filters.
A guided-mode resonance (GMR) filter with wide angular tolerances is experimentally demonstrated as an authentication label illuminated with unpolarized white light. The proposed filter, based on a free-standing silicon nitride membrane suspended on a silicon substrate, is fabricated by using anisotropic wet etching to remove the substrate beneath the silicon nitride layer. Both grating and waveguide structures without a lower cladding layer, i.e., a substrate, are fabricated simultaneously on a silicon nitride membrane. Since the silicon nitride is transparent within the spectra of visible and infrared light, such suspended-membrane-type GMR filters are well suited for applications within the visible spectrum. Moreover, the high refractive index of silicon nitride allows the proposed filters to have strongly modulated gratings and an immunity to high angular deviation. The measured reflection resonance has an angular tolerance up to +/-5 degrees under normal incidence for the wavelength of 629.5 nm.


Bracket bond strength dependence on light power density.
In order to reduce curing time for bracket bonding with light-cured composites, manufacturers increase the power density (PD) of light sources. The present study aims at investigating the relationship between PD and shear bond strength (SBS) at short exposure time. Stainless steel brackets were bonded to bovine incisors using light-cured adhesive. Six groups of 20 incisors each were exposed to 4s of halogen light with different PD increasing from 500 to 3000 mW/cm(2) in steps of 500 mW/cm(2). Two more groups were exposed to a PD of 3000 mW/cm(2) for 6s (n=15) and 8s (n=19), thus simulating non-available PD of 4500 and 6000 mW/cm(2) for 4s. A halogen lamp with a PD of 1000 mW/cm(2) was used for 40s in the control group (n=15). After storage for 24h at 37 degrees C in water, SBS and adhesive remnant index (ARI) were recorded. SBS was significantly different among groups (ANOVA, p<0.001). SBS comparable to the control group could only be achieved with a PD of at least 3000 mW/cm(2). An exponential model described the relationship between SBS and PD. The best-fit curve based on this model reached 85% of the highest possible SBS at approximately 4000 mW/cm(2). ARI scores showed that higher PD was associated with better adhesion at the bracket/adhesive interface. Our findings show the SBS dependence on PD, and thus provide a valuable tool for the development of light-curing systems. An exponential model suggests that SBS enters a region of saturation and cannot be improved significantly by further increasing PD.