Early efficacy of CABG care delivery in a low procedure-volume community hospital: operative and midterm results.
The Leapfrog Group recommended that coronary artery bypass grafting (CABG) surgery should be done at high volume hospitals (>450 per year) without corresponding surgeon-volume criteria. The latter confounds procedure-volume effects substantially, and it is suggested that high surgeon-volume (>125 per year) rather than hospital-volume may be a more appropriate indicator of CABG quality. We assessed 3-year isolated CABG morbidity and mortality outcomes at a low-volume hospital (LVH: 504 cases) and compared them to the corresponding Society of Thoracic Surgeons (STS) national data over the same period (2001-2003). All CABGs were performed by 5 high-volume surgeons (161-285 per year). "Best practice" care at LVH -- including effective practice guidelines, protocols, data acquisition capabilities, case review process, dedicated facilities and support personnel -- were closely modeled after a high-volume hospital served by the same surgeon-team. Operative mortality was similar for LVH and STS (OM: 2.38% vs. 2.53%), and the corresponding LVH observed-to-expected mortality (O/E = 0.81) indicated good quality relative to the STS risk model (O/E<1). Also, these results were consistent irrespective of risk category: O/E was 0, 0.9 and 1.03 for very-low risk (<1%), low risk (1-3%) and moderate-to-high risk category (>3%), respectively. Postoperative leg wound infections, ventilator hours, renal dysfunction (no dialysis), and atrial fibrillation were higher for LVH, but hospital stay was not. The unadjusted Kaplan-Meier survival for the LVH cohort was 96%, 94%, and 92% at one, two, and three years, respectively. Our results demonstrated that high quality CABG care can be achieved at LVH programs if 1) served by high volume surgeons and 2) patient care procedures similar to those of large programs are implemented. This approach may prove a useful paradigm to ensure high quality CABG care and early efficacy at low volume institutions that wish to comply with the Leapfrog standards.


[Hydrodynamic properties of exopolysaccharide-acrylamide copolymer].
The method for producing copolymer EPAA of exopolysaccharide (EPS)--polyacrylamide (PAA) has been presented which was based on microbial exopolysaccharides (enposane, xampane), their mixture and model EPS (xanthane sigma, rodopol P-23). The copolymer was produced by acrylamide polymerization in 1-2% water solutions of polysaccharides, the concentration of acrylamide in the reaction mixture being 4.7-2% and that of polysaccharides 0.1-1% of the weight. Hydrodynamic parameters of the studied polymers have been determined, their heterogenity as to molecular-weight characteristics has been demonstrated. Molecular-weight distribution of copolymers showed that the content of low-molecular fractions decreased, thus the Mw values were (0.08-0.2) x 10(6) Da in contrast to that of exopolysaccharides possessing Mw (1.2-0.4) x 10(6) Da and of polyacrylamide possessing Mw within (2-30) x 10(6) Da. The value of efficient viscosity of copolymers ranged from 120 to 131 mPa.s that was lower than that of polyacrylamide (500 mPa.s), and higher than that of exopolysaccharides (42 mPa.s), and it depended on the sample, raw material, production conditions. A possibility has been shown to produce a new copolymer based on microbial polysaccharides enposane and xampane in the process of acrylamide polymerization. It has been found out that the studied copolymers EPAA differ from initial ones as to their hydrodynamical properties, which determines their preference: better solubility, good glueing properties, prolonged term of preservation, resistance to bacterial pollution.


Development of a measure of informed choice suitable for use in low literacy populations.
To assess the reliability and validity of a simplified questionnaire-based measure of informed choice in populations with low literacy. The measure comprises (a) knowledge about the test and (b) attitudes towards undergoing the test. Responses to (a) and (b) together with information on test uptake, are used to classify choices as informed or uninformed. A cross-sectional study of 79 pregnant women (46 women with higher, and 33 with lower education levels) completed a simplified questionnaire, a standardised questionnaire and a semi-structured interview about antenatal sickle cell and thalassaemia (SCT) screening. The measures used were: (a) informed choice, based on knowledge about the test, attitudes towards undergoing the test, and uptake of the test and (b) ease of completion measures. The simplified measures of knowledge and attitudes were able to distinguish between women classified according to interview responses as having good or poor knowledge (knowledge scores 6.8 versus 3.2, p<0.001), and positive or negative attitudes towards undergoing the test (attitude scores 20.6 versus 16.2, p=0.023). There was no difference in rates of informed choice derived from the simplified or standardised measures (54% versus 51%, 95% CI difference -11 to 19). Women with lower levels of education found the simplified questionnaire easier to complete than the standardised version (11.0 versus 9.6, p=0.009). Those with higher levels of education found no difference in ease of completion between the two versions of the questionnaire (11.8 versus 11.6, p=0.54). A simplified questionnaire-based measure of informed choice in antenatal SCT screening is as reliable and valid as a more complex standardised version and for those with less education, easier to complete. The simplified questionnaire-based measure of informed choice is suitable for use in populations with low and high levels of education.


Pathogenic T cell responses against aquaporin 4.
Inflammatory lesions in the central nervous system of patients with neuromyelitis optica are characterized by infiltration of T cells and deposition of aquaporin-4-specific antibodies and complement on astrocytes at the glia limitans. Although the contribution of aquaporin-4-specific autoantibodies to the disease process has been recently elucidated, a potential role of aquaporin-4-specific T cells in lesion formation is unresolved. To address this issue, we raised aquaporin-4-specific T cell lines in Lewis rats and characterized their pathogenic potential in the presence and absence of aquaporin-4-specific autoantibodies of neuromyelitis optica patients. We show that aquaporin-4-specific T cells induce brain inflammation with particular targeting of the astrocytic glia limitans and permit the entry of pathogenic anti-aquaporin-4-specific antibodies to induce NMO-like lesions in spinal cord and brain. In addition, transfer of aquaporin-4-specific T cells provoked mild (subclinical) myositis and interstitial nephritis. We further show that the expression of the conformational epitope, recognized by NMO patient-derived aquaporin-4-specific antibodies is induced in kidney cells by the pro-inflammatory cytokine gamma-interferon. Our data provide further support for the view that NMO lesions may be induced by a complex interplay of T cell mediated and humoral immune responses against aquaporin-4.


[Regulation of behavior in the period between the world wars: Robert Musil and Kurt Lewin].
The paper attempts to reconstruct the proto-cybernetic concept of regulation which emerged in early 20th century both in biology and psychology, and was critically reflected in literature. The basic premise is that Kurt Lewin's field-theoretical psychology played a crucial role in the development of behavioral self-regulation concepts. The goal is to show (1) that Lewin's early experiments and theories were based on the idea of a dynamic process of self-regulation determined by the actors and their personal motivation and interaction, (2) that this concept of self-regulation functioned as a camouflage for power-strategies that aimed to regulate and optimize the economic production and social reproduction processes, (3) that in Robert Musil's fragmentary, 'fringing' novel The Man without Qualities the attempt to optimize the social and economic behavior and to establish a homeostatic state proved to be a complete failure. As a notable result, this 'literary test' of behavioral self-regulation revealed the violence and imbalance of power inherent in this concept of self-regulation and its practical implementation.


Tenseness relaxed by vocalizing, illustrated by horses (Equus caballus) whinnying.
Animal calls are commonly considered indicators of a sudden change in their arousal state. However, reports evidencing associated internal physiological changes are rare. By homology with human "emotional" vocal productions (e.g., laughter and crying), we predicted that animal vocal productions may result in relaxing tenseness or excitement. In this study, 15 stallions equipped with a heart rate monitor were presented a mare at some distance so as to prevent contact, thereby increasing the males' arousal. Stallions' heart rates increased just before whinnying but returned to baseline rates while vocalizing. We found that sudden changes of a caller's arousal state could be associated with vocalizing, and this opens new lines for noninvasive research concerning the self-regulation of emotional via vocal production in humans and animals.


Prospective Evaluation of Precision Multimodal Gallbladder Surgery Navigation: Virtual Reality, Near-infrared Fluorescence, and X-ray-based Intraoperative Cholangiography.
We aimed to prospectively evaluate NIR-C, VR-AR, and x-ray intraoperative cholangiography (IOC) during robotic cholecystectomy. Near-infrared cholangiography (NIR-C) provides real-time, radiation-free biliary anatomy enhancement. Three-dimensional virtual reality (VR) biliary anatomy models can be obtained via software manipulation of magnetic resonance cholangiopancreatography, enabling preoperative VR exploration, and intraoperative augmented reality (AR) navigation. Fifty-eight patients were scheduled for cholecystectomy for gallbladder lithiasis. VR surgical planning was performed on virtual models. At anesthesia induction, indocyanine green was injected intravenously. AR navigation was obtained by overlaying the virtual model onto real-time images. Before and after Calot triangle dissection, NIR-C was obtained by turning the camera to NIR mode. Finally, an IOC was performed. The 3 modality performances were evaluated and image quality was assessed with a Likert-scale questionnaire. The three-dimensional VR planning enabled the identification of 12 anatomical variants in 8 patients, of which only 7 were correctly reported by the radiologists (P = 0.037). A dangerous variant identified at VR induced a "fundus first" approach. The cystic-common bile duct junction was visualized before Calot triangle dissection at VR in 100% of cases, at NIR-C in 98.15%, and in 96.15% at IOC.Mean time to obtain relevant images was shorter with NIR-C versus AR (P = 0.008) and versus IOC (P = 0.00000003). Image quality scores were lower with NIR-C versus AR (P = 0.018) and versus IOC (P < 0.0001). This high-tech protocol illustrates the multimodal imaging of biliary anatomy towards precision cholecystectomy. Those visualization techniques could complement to reduce the likelihood of biliary injuries (NCT01881399).


Resident peritoneal NK cells.
In this study, we describe a new population of NK cells that reside in the normal, uninflamed peritoneal cavity. Phenotypically, they share some similarities with the small population of CD49b(-), CD27(+) immature splenic NK cells, as well as liver NK cells, but they differ in their expression of CD62L, TRAIL, and EOMES. Functionally, the peritoneal NK cells resemble the immature splenic NK cells in their production of IFN-γ, GM-CSF, and TNF-α and in the killing of YAC-1 target cells. We also found that the peritoneum induces different behavior in mature and immature splenic NK cells. When transferred i.v. into RAGγc knockout mice, both populations undergo homeostatic proliferation in the spleen, but only the immature splenic NK cells are able to reach the peritoneum. When transferred directly into the peritoneum, the mature NK cells survive but do not divide, whereas the immature NK cells proliferate profusely. These data suggest that the peritoneum is not only home to a new subset of tissue-resident NK cells, but that it differentially regulates the migration and homeostatic proliferation of immature versus mature NK cells.


[Not Available].
D. Salet-Lizée, S. Alsary Ovarian cancer often invades regional lymph nodes but the patterns of involvement are variable; spread to para-aortic and pelvic lymph nodes can be unilateral, contralateral or bilateral. For staging purposes, complete lymph node dissection seems more reasonable and effective than simple lymph node sampling. In early stage disease, lymph node dissection has both diagnostic and therapeutic value allowing identification and optimal management of Stage IIIc tumors with retroperitoneal spread; it may also have direct therapeutic value by removing retroperitoneal micrometastatic disease including cell clones which may be resistant to chemotherapy. Therefore, complete lymph node dissection is recommended in early-stage disease with the exception of stage I mucinous ovarian cancer. In advanced-stage disease, lymph node involvement is an additional factor of poor prognosis correlating with increased tumor aggressivity. Optimal debulking resection of all visible tumor offers the best chance for a prolonged disease-free interval if patient condition permits and morbidity can be limited. Survival benefit for complete lymph node dissection has not been evaluated by randomized controlled trials; but several non-randomized studies and two long-term prospective trials have shown objective improvement in disease-free survival and improved quality of life when debulking surgery leaves no residual tumor larger than 1 cm.


Preventing Improper Disposal of Healthcare Facility Waste Containing RAM.
Non-hazardous waste management facilities, which are not authorized to receive licensable radioactive material (RAM), periodically find contaminated waste in shipments from local healthcare facilities. As a consequence, many healthcare facilities are cited each year for losing control and/or improperly disposing of RAM at unauthorized disposal sites. Healthcare radiation safety professionals must ensure that effective measures are in place at their facilities to prevent RAM from inadvertently being included with non-radioactive waste shipments. The objective of this article is to assist in developing and implementing procedures to properly monitor and dispose of waste containing RAM. This article discusses, among other topics, the installation of portal monitors containing both visual and audible alarms to screen medical waste, instruction to individuals handling medical waste and emergency response procedures.


Sensory Attenuation in Sport and Rehabilitation: Perspective from Research in Parkinson's Disease.
People with Parkinson's disease (PD) experience motor symptoms that are affected by sensory information in the environment. Sensory attenuation describes the modulation of sensory input caused by motor intent. This appears to be altered in PD and may index important sensorimotor processes underpinning PD symptoms. We review recent findings investigating sensory attenuation and reconcile seemingly disparate results with an emphasis on task-relevance in the modulation of sensory input. Sensory attenuation paradigms, across different sensory modalities, capture how two identical stimuli can elicit markedly different perceptual experiences depending on our predictions of the event, but also the context in which the event occurs. In particular, it appears as though contextual information may be used to suppress or facilitate a response to a stimulus on the basis of task-relevance. We support this viewpoint by considering the role of the basal ganglia in task-relevant sensory filtering and the use of contextual signals in complex environments to shape action and perception. This perspective highlights the dual effect of basal ganglia dysfunction in PD, whereby a reduced capacity to filter task-relevant signals harms the ability to integrate contextual cues, just when such cues are required to effectively navigate and interact with our environment. Finally, we suggest how this framework might be used to establish principles for effective rehabilitation in the treatment of PD.


False positive diagnostic tests and coronary angiographic findings in 105 presumably healthy males.
Among 2014 presumably healthy males aged 40-59 years coronary heart disease (CHD) was suggested in 115 in the presence of one or more of the following criteria: 1) a WHO-questionnaire on angina pectoris positive on interview, 2) typical angina during a near maximal bicycle exercise test, 3) a positive exercise ECG during and/or post exercise, 4) a Minnesota Code 1.1 on a resting ECG. Diagnostic coronary angiography was offered to all 115 CHD-suspect cases. Six refused angiography and four others were excluded. Of the remaining 105, thirty-six had less than 50% obstruction of any major coronary artery (34.3%). Eighteen (17.1%) had single, 25 (23.8%) had double and 26 (24.8%) had triple vessel disease. In 62 of the 69 with pathologic angiograms at least one obstruction greater than or equal to 75% was found. Eighty percent of the cases with proven CHD were greater than or equal to 50 years. All CHD-suggestive criteria had approximately the same diagnostic performance regardless of age, i.e., approximately one false positive/two true positives. Except for one retroperitoneal hematoma no complications to angiography occurred.


Eukaryotic class II cyclobutane pyrimidine dimer photolyase structure reveals basis for improved ultraviolet tolerance in plants.
Ozone depletion increases terrestrial solar ultraviolet B (UV-B; 280-315 nm) radiation, intensifying the risks plants face from DNA damage, especially covalent cyclobutane pyrimidine dimers (CPD). Without efficient repair, UV-B destroys genetic integrity, but plant breeding creates rice cultivars with more robust photolyase (PHR) DNA repair activity as an environmental adaptation. So improved strains of Oryza sativa (rice), the staple food for Asia, have expanded rice cultivation worldwide. Efficient light-driven PHR enzymes restore normal pyrimidines to UV-damaged DNA by using blue light via flavin adenine dinucleotide to break pyrimidine dimers. Eukaryotes duplicated the photolyase gene, producing PHRs that gained functions and adopted activities that are distinct from those of prokaryotic PHRs yet are incompletely understood. Many multicellular organisms have two types of PHR: (6-4) PHR, which structurally resembles bacterial CPD PHRs but recognizes different substrates, and Class II CPD PHR, which is remarkably dissimilar in sequence from bacterial PHRs despite their common substrate. To understand the enigmatic DNA repair mechanisms of PHRs in eukaryotic cells, we determined the first crystal structure of a eukaryotic Class II CPD PHR from the rice cultivar Sasanishiki. Our 1.7 Å resolution PHR structure reveals structure-activity relationships in Class II PHRs and tuning for enhanced UV tolerance in plants. Structural comparisons with prokaryotic Class I CPD PHRs identified differences in the binding site for UV-damaged DNA substrate. Convergent evolution of both flavin hydrogen bonding and a Trp electron transfer pathway establish these as critical functional features for PHRs. These results provide a paradigm for light-dependent DNA repair in higher organisms.


Prospective observational study to evaluate NOTSS (Non-Technical Skills for Surgeons) for assessing trainees' non-technical performance in the operating theatre.
Most surgical assessment has been aimed at technical proficiency. However, non-technical skills also affect patient safety and clinical effectiveness. The NOTSS (Non-Technical Skills for Surgeons) assessment instrument was developed specifically to assess the non-technical skills of individual surgeons in the operating theatre. This study evaluated NOTSS as a real-world assessment, with a mix of minimally trained assessors. The evaluation criteria were feasibility, validity and psychometric reliability. In a standard evaluation of NOTSS, 56 anaesthetists, 39 scrub nurses, two surgical care practitioners and three independent assessors provided 715 assessments of 404 surgical cases of 15 index procedures across six specialties performed by 85 surgical trainees. The assessment was feasible, but important implementation challenges were highlighted. Most respondents considered the method valid, but with reservations about assessing cognition. The factor structure of scores, and their positive relationships with other measures of experience and performance, supported validity. Trainees' non-technical skill scores were relatively procedure-independent and achieved good reliability (generalizability coefficient 0·8 or more) when six to eight assessors observed one case each. Minimally trained assessors, who are typically present in operating theatres, were sufficiently discriminating and consistent in their judgements of trainee surgeons' non-technical skills to provide reliable scores based on an achievable number of observations.


Validation of the Short-Form Health Literacy Questionnaire (HLS-SF12) and Its Determinants among People Living in Rural Areas in Vietnam.
Background: Health literacy (HL) is an important factor in improving health inequalities in poor and marginalized groups. Assessing comprehensive HL is critical. In this study, we validated the use of a comprehensive short-form HL survey tool (HLS-SF12) and examined the determinants of HL among people in rural areas. Methods: A cross-sectional study was conducted in July 2019 on 440 people residing in mountainous areas in Vietnam. Health literacy was measured using the HLS-SF12. Personal characteristics were also collected. We analyzed data using confirmatory factor analysis, internal consistency analysis, and regression analysis. Results: The questionnaire demonstrated a good construct validity with satisfactory goodness-of-fit indices and item-scale convergent validity. The tool was reliable and homogeneous with Cronbach's alpha = 0.79, with no floor/ceiling effects. People who were married had lower HL (regression coefficient B = -3.12; 95% confidence interval (CI) = -5.69, -0.56; p = 0.017) compared with those who never married. Higher education attainment (B = 3.41 to 10.44; p < 0.001), a better ability to pay for medication (B = 4.17 to 9.89; p < 0.001), and a tendency to view health-related TV/radio more often (B = 5.23 to 6.15; p < 0.001) were associated with higher HL. Conclusions: The HLS-SF12 is a valid survey tool for the evaluation of HL in rural populations. A number of personal characteristics were strongly associated with HL.


Role of intestinal circadian genes in alcohol-induced gut leakiness.
Several studies have indicated that endotoxemia is the required co-factor for alcoholic steatohepatitis (ASH) that is seen in only about 30% of alcoholics. Recent studies have shown that gut leakiness that occurs in a subset of alcoholics is the primary cause of endotoxemia in ASH. The reasons for this differential susceptibility are not known. Since disruption of circadian rhythms occurs in some alcoholics and circadian genes control the expression of several genes that are involved in regulation of intestinal permeability, we hypothesized that alcohol induces intestinal hyperpermeability by stimulating expression of circadian clock gene proteins in the intestinal epithelial cells. We used Caco-2 monolayers grown on culture inserts as an in vitro model of intestinal permeability and performed Western blotting, permeability, and siRNA inhibition studies to examine the role of Clock and Per2 circadian genes in alcohol-induced hyperpermeability. We also measured PER2 protein levels in intestinal mucosa of alcohol-fed rats with intestinal hyperpermeability. Alcohol, as low as 0.2%, induced time dependent increases in both Caco-2 cell monolayer permeability and in CLOCK and PER2 proteins. SiRNA specific inhibition of either Clock or Per2 significantly inhibited alcohol-induced monolayer hyperpermeability. Alcohol-fed rats with increased total gut permeability, assessed by urinary sucralose, also had significantly higher levels of PER2 protein in their duodenum and proximal colon than control rats. Our studies: (i) demonstrate a novel mechanism for alcohol-induced intestinal hyperpermeability through stimulation of intestinal circadian clock gene expression, and (ii) provide direct evidence for a central role of circadian genes in regulation of intestinal permeability.


Locomotion: the cost of gastropod crawling.
The power of locomotion of a terrestrial slug rises linearly with crawling speed. The metabolic cost of movement is 904 joules per kilogram per meter, considerably more than that reported for other forms of locomotion. This high cost is primarily attributable to the production of the pedal mucus by which the slug adheres to the substratum.


Consequences of drought severity for tropical live oak (Quercus oleoides) in Mesoamerica.
In two Costa Rican and three Honduran sites that vary in rainfall and soil properties, we used natural isotopes, a soil water balance model, and broad-scale climate-based drought indices to study shifts in water use with ontogeny from seedlings to mature tropical live oak (Quercus oleoides) trees. Water use patterns help to explain persistence of this broadly distributed species in Mesoamerica and to evaluate likely threats of ongoing climate changes. At the end of the dry season, soil δ18 O profiles can be described by one-phase exponential decay curves. Minimum values reflect geographic origins of the last significant rain event, and curvature is inversely related to canopy closure, demonstrating its role in controlling topsoil evaporation. Partitioning of soil water sources for transpiration was analyzed with a mixing model. In the Costa Rican sites, in a relatively dry year, saplings and mature trees took up water from the upper soil. In a relatively wet year in the Honduran sites, we observed deeper water extraction. In all sites, soil storage dampens extreme variation in water availability. The size dependence of water uptake with larger stems exploiting deeper layers is translated into variation in bulk leaf δ13 C-based water use efficiency (WUE) with the exception of mature trees. From 1932 to 2015, drought severity was evaluated with the Standardized Precipitation Evapotranspiration Index (SPEI) concurrently with simulations of the soil water balance model. Drought occurrence increased, regardless of the time period, averaged across 6, 12, or 24 months. All ontogenetic stages in all populations experienced frequent water limitation. We found evidence for linear trends toward aridification with increases of return periods of drought for October SPEI-24 declining from 42 to 6 yr in Costa Rica and from 21 to 7 yr in Honduras and recent occurrence of multiyear droughts from 2013 to 2016. October SPEI-12 and SPEI-24 were significantly related to the Oceanic Niño Indices demonstrating that local inter-annual variations in drought severity in Mesoamerica are modulated by large-scale climate forces. Drought severity in the near-term future depends on the extent to which the Pacific will adopt a more La Niña-like vs. a more El Niño-like state under ongoing climatic changes.


The selection of a model microalgal species as biomaterial for a novel aquatic phytotoxicity assay.
A phytotoxicity assay based on the ToxY-PAM dual-channel yield analyser has been developed and successfully incorporated into field assessments for the detection of phytotoxicants in water. As a means of further exploring the scope of the assay application and of selecting a model biomaterial to complement the instrument design, nine algal species were exposed to four chemical substances deemed of priority for water quality monitoring purposes (chlorpyrifos, copper, diuron and nonylphenol ethoxylate). Inter-species differences in sensitivity to the four toxicants varied by a factor of 1.9-100. Measurements of photosystem-II quantum yield using these nine single-celled microalgae as biomaterial corroborated previous studies which have shown that the ToxY-PAM dual-channel yield analyser is a highly sensitive method for the detection of PS-II impacting herbicides. Besides Phaeodactylum tricornutum, the previously applied biomaterial, three other species consistently performed well (Nitzschia closterium, Chlorella vulgaris and Dunaliella tertiolecta) and will be used in further test optimisation experiments. In addition to sensitivity, response time was evaluated and revealed a high degree of variation between species and toxicants. While most species displayed relatively weak and slow responses to copper, C. vulgaris demonstrated an IC10 of 51 microgL-1, with maximum response measured within 25 minutes and inhibition being accompanied by a large decrease in fluorescence yield. The potential for this C. vulgaris-based bioassay to be used for the detection of copper is discussed. There was no evidence that the standard ToxY-PAM protocol, using these unicellular algae species, could be used for the detection of chlorpyrifos or nonylphenol ethoxylate at environmentally relevant levels.


β-Lactoglobulin Elevates Insulin and Glucagon Concentrations Compared with Whey Protein-A Randomized Double-Blinded Crossover Trial in Patients with Type Two Diabetes Mellitus.
Whey protein is an insulinotropic fraction of dairy that reduces postprandial glucose levels in patients with type 2 diabetes mellitus (T2DM). We have recently shown that β-lactoglobulin (BLG), the largest protein fraction of whey, elevates insulin concentrations compared with iso-nitrogenous whey protein isolate (WPI) in healthy individuals. We therefore hypothesized that BLG pre-meals would lower glucose levels compared with WPI in patients with T2DM. We investigated 16 participants with T2DM using a randomized double-blinded cross-over design with two pre-meal interventions, (i) 25 g BLG and (ii) 25 g WPI prior to an oral glucose tolerance test (OGTT), followed by four days of continuous glucose monitoring (CGM) at home. BLG increased concentrations of insulin with 10%, glucagon with 20%, and glucose with 10% compared with WPI after the OGTT (all p < 0.05). Both BLG and WPI reduced the interstitial fluid (ISF) glucose concentrations (using CGM) with 2 mM and lowered glycemic variability with 10-15%, compared with tap-water (p < 0.05), and WPI lowered the ISF glucose with 0.5 mM compared with BLG from 120 min and onwards (p < 0.05). In conclusion, BLG pre-meals resulted in higher insulin, glucagon, and glucose concentrations compared with WPI in participants with T2DM. Pre-meal servings of WPI remains the most potent protein in terms of lowering postprandial glucose excursions.


Suppression of glioblastoma angiogenicity and tumorigenicity by inhibition of endogenous expression of vascular endothelial growth factor.
The development of new capillary networks from the normal microvasculature of the host appears to be required for growth of solid tumors. Tumor cells influence this process by producing both inhibitors and positive effectors of angiogenesis. Among the latter, the vascular endothelial growth factor (VEGF) has assumed prime candidacy as a major positive physiological effector. Here, we have directly tested this hypothesis in the brain tumor, glioblastoma multiforme, one of the most highly vascularized human cancers. We introduced an antisense VEGF expression construct into glioblastoma cells and found that (i) VEGF mRNA and protein levels were markedly reduced, (ii) the modified cells did not secrete sufficient factors so as to be chemoattractive for primary human microvascular endothelial cells, (iii) the modified cells were not able to sustain tumor growth in immunodeficient animals, and (iv) the density of in vivo blood vessel formation was reduced in direct relation to the reduction of VEGF secretion and tumor formation. Moreover, revertant cells that recovered the ability to secrete VEGF regained each of these tumorigenic properties. These results suggest that VEGF plays a major angiogenic role in glioblastoma.


Distribution, expression and germ line transmission of exogenous DNA sequences following microinjection into Xenopus laevis eggs.
We analysed the fate, expression and germ line transmission of exogenous DNA which was microinjected into fertilized eggs of Xenopus laevis. DNA was injected into fertilized eggs within 1 h following fertilization. The injected DNA was dispersed around the site of injection and became localized to cleavage nuclei by stage 6. Injected DNA persisted in the tissues of 6- to 8-month-old frogs and exhibited a mosaic pattern of distribution with regard to the presence or absence and copy number between different tissues. We detected the exogenous DNA sequences in 60% of injected frogs. Restriction digestion analysis of this DNA suggested that it is not rearranged and was organized as head-to-tail multimers. The copy number varied from 2 to 30 copies/cell in various tissues of the same frog. Plasmid pSV2CAT which contains the prokaryotic gene coding for chloramphenicol acetyl transferase (CAT) enzyme linked to the SV40 early gene promoter was expressed in 50% of the animals containing the gene. The pattern of expression, however, varied between different animals and could not be correlated with copy number. We also showed that the exogenous DNA sequences were transmitted through the male germ line and that each offspring contained the gene integrated into a different region of the genome.


The combined impact of testosterone and Western-style diet on endometriosis severity and progression in rhesus macaques†.
Polycystic ovary syndrome (PCOS) is associated with irregular menstrual cycles, hyperandrogenemia, and obesity. It is currently accepted that women with PCOS are also at risk for endometriosis, but the effect of androgen and obesity on endometriosis has been underexplored. The goal of this study was to determine how testosterone (T) and an obesogenic diet impact the progression of endometriosis in a nonhuman primate (NHP) model. Female rhesus macaques were treated with T (serum levels approximately 1.35 ng/ml), Western-style diet (WSD; 36% of calories from fat compared to 16% in standard monkey chow) or the combination (T + WSD) at the time of menarche as part of a longitudinal study for ~7 years. Severity of endometriosis was determined based on American Society for Reproductive Medicine (ASRM) revised criteria, and staged 1-4. Stages 1 and 2 were associated with extent of abdominal adhesions, while stages 3 and 4 were associated with presence of chocolate cysts. The combined treatment of T + WSD resulted in earlier onset of endometriosis and more severe types associated with large chocolate cysts compared to all other treatments. There was a strong correlation between glucose clearance, homeostatic model assessment for insulin resistance (HOMA-IR), and total percentage of body fat with presence of cysts, indicating possible indirect contribution of hyperandrogenemia via metabolic dysfunction. An RNA-seq analysis of omental adipose tissue revealed significant impacts on a number of inflammatory signaling pathways. The interactions between obesity, hyperandrogenemia, and abdominal inflammation deserve additional investigation in NHP model species.


MUS81 promotes common fragile site expression.
Fragile sites are chromosomal loci with a propensity to form gaps or breaks during early mitosis, and their instability is implicated as being causative in certain neurological disorders and cancers. Recent work has demonstrated that the so-called common fragile sites (CFSs) often impair the faithful disjunction of sister chromatids in mitosis. However, the mechanisms by which CFSs express their fragility, and the cellular factors required to suppress CFS instability, remain largely undefined. Here, we report that the DNA structure-specific nuclease MUS81-EME1 localizes to CFS loci in early mitotic cells, and promotes the cytological appearance of characteristic gaps or breaks observed at CFSs in metaphase chromosomes. These data indicate that CFS breakage is an active, MUS81-EME1-dependent process, and not a result of inadvertent chromatid rupturing during chromosome condensation. Moreover, CFS cleavage by MUS81-EME1 promotes faithful sister chromatid disjunction. Our findings challenge the prevailing view that CFS breakage is a nonspecific process that is detrimental to cells, and indicate that CFS cleavage actually promotes genome stability.


[Removal of monomeric 239Pu from bones and liver by liposome-encapsulated pentacin].
Dependence of monomeric 239Pu removal from the liver and skeleton by liposome-encapsulated pentacine on dose and concentration of encapsulated chelate was studied in rats. It has been shown that the liposome-encapsulated pentacine (LP) removed 1.5-2.5 times as much 239Pu as free chelate (FP). Dose-effect dependences were logarithmic. The distinction between LP and FP in 239Pu removal from the liver was maximum when chelate had been used in a dose of 50 mumol/kg, with the dose effect upon injection in a large number of liposomes (200 mumol of lipids/kg) being 1.8 times as high as upon injection in smaller number of liposomes (50 mumol/kg). LP doses varying from 100 to 400 mumol/kg, there were no differences between two types of LP; with a LP dose of 400 mumol/kg its action is a bit stronger than that of the chelate. The distinction between LP and FP in 239Pu removal from the skeleton is the greatest with chelate doses exceeding 100 mumol/kg. The use of liposomes in combination with concentrated chelate solution is more effective. Possible interpretation of the features revealed are discussed.


Pathogenicity of avian reoviruses: examination of six isolates and a vaccine strain.
Six avian reovirus isolates and a vaccine reovirus strain were compared for invasiveness, virulence, and pathological characteristics upon infection of day-old specific-pathogen-free chicks by the footpad, subcutaneous, and oral routes of inoculation. No significant differences were noted regarding the ability of individual isolates to infect target tissues. However, virulence (measured as the 50% lethal dose) among the isolates varied markedly from 2 x 10(5) to less than 10 PFU per chick for the most virulent isolate; between the parental wild-type virus and the derivative vaccine virus strain, a million-fold (10(6)) difference in virulence was demonstrated. All strains revealed, with considerable variation, arthrogenic potential.


Mutation patterns of the reverse transcriptase and protease genes in human immunodeficiency virus type 1-infected patients undergoing combination therapy: survey of 787 sequences.
The aim of the present study was to evaluate the resistance-associated mutations in 302 human immunodeficiency virus type 1 (HIV-1)-infected patients receiving combination therapy and monitored in Marseille, France, hospitals from January 1997 to June 1998. In the reverse transcriptase (RT) gene, the most frequent mutations were found at codons 215 (53%), 41 (34%), and 67, 70, 184, and 210 (>20%). One deletion and two insertions in the beta3-beta4 hairpin loop of the finger subdomain (codon 69) were detected. Interesting associations and/or exclusions of specific mutations were observed. In 96% of RT genes, a mutation at codon 70 (most frequently, K70R) was associated with a wild-type genotype at position 210 (P < 10(-5)). Similarly, a mutation at codon 210 (most frequently, L210W) was generally associated with mutations at codons 41 (92%) and 215 (96%) but not at codon 219 (16%) or codon 70 (4%) (P < 10(-5)). In the protease gene, the most prevalent mutations were at codons 63 (84%), followed by codons 10, 36, 71, 77, and 93 (ca. 20%). As for RT, pairwise associations of mutations were observed. Analysis of the mutation patterns for patients with undetectable HIV-1 loads revealed a high proportion (65%) of wild-type RT genotypes but only 18% wild-type protease genotypes. For patients with high viral loads (>100,000 copies/ml), more than 50% of the RT and protease genes displayed three or more mutations. The significant correlation between the level of viremia in plasma and the number of resistance mutations in the protease (P = 0.007) and RT (P = 0.00078) genes strengthens the importance of defining the genotype of the predominant HIV-1 quasispecies before initiating antiretroviral therapy.


An Investigation of Diabetes Knowledge Levels Between Newly Diagnosed Type 2 Diabetes Patients in Galway, Ireland and New York, USA: A Cross-Sectional Study.
Management of diabetes mellitus (DM) involves podiatrists as the primary practitioners engaged in prevention and treatment of lower limb pathology. Patients must first possess adequate knowledge to engage in effective self-management. A knowledge assessment of a DM cohort has never before been conducted in Ireland. The primary research objective was to determine the existence of gaps in specific areas of DM-related knowledge between type 2 DM (T2DM) patients in Galway (GW) and New York (NY). A cross-sectional study compared DM-related knowledge levels between 2 cohorts over a 10-week period. Participants were recently (<3 years) diagnosed with T2DM, were based in general podiatry clinics in GW or NY and had no current or previous diabetic foot ulceration (DFU) or other DM-related foot pathology. Participants were recruited by convenience sampling. A purpose-designed 28-item closed questionnaire was completed by both cohorts to assess knowledge differences. Fifty-two subjects were recruited (GW, n = 32; NY, n = 20). The mean age was 61 ± 10 years; 56% were male. Significant differences were found between cohorts relating to individual questions; specifically regarding knowledge of glycemic control (P = .002) and frequency of self-monitoring of blood glucose (P = .003). Inappropriate foot care practices across both cohorts were highlighted. No significant intercohort differences in particular survey sections were identified. The scores in the systemic and podiatric sections of the questionnaire highlight patterns of common health misconceptions and some highly inappropriate foot care practices respectively across the entire sample. In particular, the dearth of patient awareness regarding uncontrolled blood glucose and its relationship to DFU development, amputation, and associated morbidity is shown to be an area of concern; this must be addressed a priori.


Rapid host adaptation by extensive recombination.
Experimental investigations into virus recombination can provide valuable insights into the biochemical mechanisms and the evolutionary value of this fundamental biological process. Here, we describe an experimental scheme for studying recombination that should be applicable to any recombinogenic viruses amenable to the production of synthetic infectious genomes. Our approach is based on differences in fitness that generally exist between synthetic chimaeric genomes and the wild-type viruses from which they are constructed. In mixed infections of defective reciprocal chimaeras, selection strongly favours recombinant progeny genomes that recover a portion of wild-type fitness. Characterizing these evolved progeny viruses can highlight both important genetic fitness determinants and the contribution that recombination makes to the evolution of their natural relatives. Moreover, these experiments supply precise information about the frequency and distribution of recombination breakpoints, which can shed light on the mechanistic processes underlying recombination. We demonstrate the value of this approach using the small single-stranded DNA geminivirus, maize streak virus (MSV). Our results show that adaptive recombination in this virus is extremely efficient and can yield complex progeny genomes comprising up to 18 recombination breakpoints. The patterns of recombination that we observe strongly imply that the mechanistic processes underlying rolling circle replication are the prime determinants of recombination breakpoint distributions found in MSV genomes sampled from nature.


DNA sensor's selectivity enhancement and protection from contaminating nucleases due to a hydrated ionic liquid.
The thermodynamic stability of certain mismatched base pairs has made the development of DNA sequence sensing systems challenging. Thus, the stability of fully matched and mismatched DNA oligonucleotides in the hydrated ionic liquid choline dihydrogen phosphate (choline dhp) was investigated. Mismatched base pairs were significantly destabilized in choline dhp relative to those in aqueous buffer. A molecular beacon that forms a triplex with a conserved HIV-1 sequence was then designed and tested in choline dhp. The molecular beacon specifically detected the target duplex via triplex formation at concentrations as low as 1 pmol per 10 μL with 10,000-fold sequence selectivity. Moreover, the molecular beacon was protected from a contaminating nuclease in choline dhp, and DNAs in aqueous solutions were not sufficiently stable for practical use.


Effects of arsenite on estrogen receptor-alpha expression and activity in MCF-7 breast cancer cells.
To determine whether arsenite has estrogen-like activities, the effects of this compound on estrogen receptor-alpha (ERalpha) and other estrogen-regulated genes were measured in the human breast cancer cell line MCF-7. Treatment of cells with 1 microM arsenite resulted in a 60% decrease in the amount of ERalpha and in a parallel decrease of 40% in ERalpha messenger RNA. Progesterone receptor concentration increased 22-fold after arsenite treatment. pS2 messenger RNA also increased 2. 1-fold after treatment. The induction of progesterone receptor and pS2 was blocked by the antiestrogen ICI-182,780. In transient cotransfection experiments of wild-type ERalpha and an estrogen response element-reporter construct, arsenite stimulated chloramphenicol acetyltransferase (CAT) activity. In growth assays, arsenite significantly stimulated the proliferation of MCF-7 cells compared with cells grown in estrogen-depleted medium. Addition of an antiestrogen blocked growth stimulation by arsenite. In binding assays, arsenite blocked the binding of estradiol to ERalpha (Ki = 5 +/- 0.5 nM; n = 3), suggesting that the compound interacts with the hormone-binding domain of the receptor. To determine whether interaction of arsenite with the hormone-binding domain results in receptor activation, COS-1 cells were transiently cotransfected with the chimeric receptors GAL-ER, which contains the hormone-binding domain of ERalpha and the DNA-binding domain of the transcription factor GAL4, and a GAL4-responsive CAT reporter gene. Treatment of cells with estradiol or arsenite resulted in a 4-fold increase in CAT activity. The effects of arsenite on the chimeric receptor were blocked by the antiestrogen, suggesting that arsenite activates ERalpha through an interaction with the hormone-binding domain of the receptor. Transfection assays with ERalpha mutants identified C381, C447, H524, and N532 as interaction sites of arsenite with the hormone-binding domain.


Depth inversion with a 3D structure influences brightness perception.
Whether or not depth perception influences brightness and/or lightness perception has been repeatedly discussed, and some studies have emphasized its importance. In addition, a small number of studies have empirically tested and shown the effect of depth inversion, such as seen in the Mach card illusion, on perceived lightness, and they interpreted such results in terms of lightness constancy. However, how perceived brightness changes contingent on depth inversion remains unexplained. Therefore, this study used the matching method to examine changes in brightness perception when depth inversion is observed. We created and used a three-dimensional (3D) concave object, composed of three sides made of card stock, which could be perceived as having two different shapes in 3D; it could be perceived as a horizontal concave object, corresponding to its actual physical structure, and as a convex standing object, similar in shape to a building. Participants observed this object as both a concave object and as a convex object, and judged the brightness of its surfaces during each observation. Our results show that the perception of the brightness of the object's surfaces clearly changed depending on the perception of depth. When the object was seen as convex, one part of the surface was perceived as darker than when the object was seen as concave, but the other part of the surface remained unchanged. Here we discuss the relationship between depth perception and brightness perception in terms of perceptual organization.


Dynamic message-passing equations for models with unidirectional dynamics.
Understanding and quantifying the dynamics of disordered out-of-equilibrium models is an important problem in many branches of science. Using the dynamic cavity method on time trajectories, we construct a general procedure for deriving the dynamic message-passing equations for a large class of models with unidirectional dynamics, which includes the zero-temperature random-field Ising model, the susceptible-infected-recovered model, and rumor spreading models. We show that unidirectionality of the dynamics is the key ingredient that makes the problem solvable. These equations are applicable to single instances of the corresponding problems with arbitrary initial conditions and are asymptotically exact for problems defined on locally treelike graphs. When applied to real-world networks, they generically provide a good analytic approximation of the real dynamics.


Management of severe anterior open-bite in an adult patient using miniscrews as skeletal anchorage.
Anterior open bite is often caused by a downward rotation of the mandible and/or by excessive eruption of the posterior teeth. In such cases, it is difficult to establish absolute anchorage for molar intrusion by traditional orthodontic mechanics. This is a case report of successful treatment of a severe anterior open bite using miniscrew anchorage. A female patient of 20 yrs presented with symmetrical frontal facial appearance, increased anterior facial height, convex profile and incompetent lips. Dentally, she had lost both mandibular first molars due to caries and both maxillary first molars were extruded. She had class II canine relationship, 5 mm overjet, 5 mm anterior open bite, 3 mm mandibular midline diastema and a spacing of 2 mm in the maxillary arch. The treatment objectives were to correct the anterior open bite and establish ideal overjet and overbite and to restore the mandibular first molars with fixed prosthesis. Titanium miniscrews (1.3 mm diameter and 9 mm length) were implanted bilaterally in the maxillary arch between the second premolar and the first molar, and an intrusion force was applied with NiTi closed coil springs for 8 months. After molar intrusion, the same screws were used for en masse retraction of the entire dentition (third molars were extracted) for 4 months. The results showed that, after an active treatment of 20 months, the maxillary molars were intruded about 4 mm each and good occlusion was achieved. In conclusion, the miniscrews were very useful in the non-surgical management of adult anterior open bite cases.


Effect of different surface treatments and multimode adhesive application on the Weibull characteristics, wettability, surface topography and adhesion to CAD/CAM lithium disilicate ceramic.
This paper aims to evaluate the effect of different surface treatments on surface topography, wettability, and shear bond strength of resin cement to glass ceramic. For SBS test, 32 blocks (7x7x2 mm) of lithium disilicate were obtained and randomly divided into eight groups (four blocks per group) according to each surface treatment (HF 20 s, 60 s, 120 s + silanization/S or Scotch Bond Universal/ SBU) and the Monobond Etch & Prime - MEP application followed or not by SBU. On each treated surface ceramic block, up to four dual-curing resin cement cylinders were prepared and light-cured for 40s (N=120/n=15). The specimens were thermocycled (10,000 cycles, 5-55°C, 30 s) and the SBS test (50KgF, 0.5 mm/min) was performed. Furthermore, failure analysis, wettability, AFM, and SEM were carried out. SBS data (MPa) were analyzed using Student's t-test, two-way ANOVA, Tukey's test (5%) and Weibull's analysis. For HF experimental groups, two-way ANOVA presented the factors "etching time" and "bonding agent" as significant (p<0.05). After silane application, the HF groups presented similar bond strength. SBU application compromised the SBS, except for 120s etching time (HF120sS: 23.39ᵃ±6.48 MPa; HF120sSBU: 18.76ᵃ±8.81MPa). For MEP groups, SBU application did not significantly affect the results (p=0.41). The MEP group presented the highest Weibull modulus (4.08A) and they were statistically different exclusively from the HF20sSBU (0.58B). The HF 20s, 60s, 120 s followed by silane, promoted similar resin-bond strength to ceramic and the SBU application after HF or MEP did not increase the SBS.


Molecular characterization of lung dysplasia induced by c-Raf-1.
Lung cancer is a multistage process with poor prognosis and high morbidity. Importantly, the genetics of dysplasia, a facultative cancer, at the edge of malignant transformation is unknown. We employed laser microdissection to harvest c-Raf1- induced dysplastic as opposed to transgenic but otherwise morphologically unaltered epithelium and compared findings to non-transgenic lung. We then employed microarrays to search genome wide for gene regulatory networks. A total of 120 and 287 genes were significantly regulated, respectively. Dysplasia was exclusive associated with up-regulation of genes coding for cell growth and proliferation, cell-to-cell signalling and interaction, lipid metabolism, development, and cancer. Likewise, when dysplasia was compared with non-transgenic cells up-regulation of cancer associated genes, tight junction proteins, xenobiotic defence and developmental regulators was observed. Further, in a comparison of the data sets of dysplasia vs transgenic and dysplasia vs non-transgenic 114 genes were regulated in common. We additionally confirmed regulation of some genes by immunohistochemistry and therefore demonstrate good concordance between gene regulation and coded protein. Our study identified transcriptional networks at successive stages of tumor-development, i.e. from histological unaltered but transgenic lungs to nuclear atypia. Our SP-C/c-raf transgenic mouse model revealed interesting and novel candidate genes and pathways that provide clues on the mechanism forcing respiratory epithelium into dysplasia and subsequently cancer, some of which might also be useful in the molecular imaging and flagging of early stages of disease.


A recombinant immunotoxin derived from a humanized epithelial cell adhesion molecule-specific single-chain antibody fragment has potent and selective antitumor activity.
Epithelial cell adhesion molecule (Ep-CAM) is a tumor-associated antigen overexpressed in many solid tumors but shows limited expression in normal epithelial tissues. To exploit this favorable expression pattern for targeted cancer therapy, an Ep-CAM-specific recombinant immunotoxin was developed and its antitumor activity investigated. The immunotoxin 4D5MOCB-ETA was developed by genetically fusing a truncated form of Pseudomonas aeruginosa exotoxin A (ETA) (ETA(252-608)KDEL) to the highly stable humanized single-chain antibody fragment (scFv) 4D5MOCB. Cytotoxicity of 4D5MOCB-ETA was measured in cell growth and leucine incorporation assays in vitro. Tumor localization and antitumor activity were assessed in athymic mice bearing established human tumor xenografts. Fusion of the toxin moiety to the scFv did neither affect its thermal stability nor its antigen-binding affinity. In vitro, 4D5MOCB-ETA potently and specifically inhibited protein synthesis and reduced the viability of Ep-CAM-positive carcinoma cells of diverse histological origins with IC(50)s ranging from 0.005 to 0.2 pM. Upon systemic administration in mice, 4D5MOCB-ETA showed similar organ distribution as the scFv 4D5MOCB and preferentially localized to Ep-CAM-positive tumor xenografts with a tumor:blood ratio of 5.4. The potent antitumor activity of 4D5MOCB-ETA was demonstrated by its ability to strongly inhibit the growth and induce regression of relatively large tumor xenografts derived from lung, colon, or squamous cell carcinomas. We describe for the first time the development of a fully recombinant Ep-CAM-specific immunotoxin and demonstrate its potent activity against solid tumors of various histological origins. 4D5MOCB-ETA is currently being evaluated in a Phase I study in patients with refractory squamous cell carcinoma of the head and neck.


Effects of orlistat and its relationship with nitric oxide in the small intestinal mucosa.
Nitric oxide (NO) is known to be a messenger molecule that plays an important role in physiological and pathological conditions. It is synthesized by an enzyme called nitric oxide synthase (NOS). Inducible NOS (iNOS), one of the three isomers of NOS, has both protective and toxic properties. In this study, the role of NO has been evaluated by gastrointestinal symptoms induced by orlistat which is used in obesity treatment. Orlistat was given to Wistar rats with and without iNOS inhibition. The effects of orlistat and inhibition of NOS were studied. Glucose, urea, alanine transaminase (ALT), and gamma glutamil transpeptidase (GGT) were descreased after short- and long- term orlistat applications. Dexamethasone increased level of these enzymes. Cholesterol and triglyceride were increased in all experimental groups than the controls. This increment was more severe in animals received orlistat and dexamethasone together. Small intestinal tissue also were researched histologically and NADPH-diaphorase (NADPH-d) histochemistrically. Orlistat caused histological damages in brush border membranes, connective tissues of villi, and lymphocyte migration also increased. Dexamethasone treatment prevented these damages partially while orlistat increased the NOS distribution in the tissue sections. Dexamethasone, which is an iNOS inhibitor, decreased NADPH-d histochemistry. There was a similiar NOS distribution both in the control and orlistat+dexamethasone group. Hence, we concluded that long- term trials with orlistat and similar drugs are needed.


Increased reactive oxygen species contribute to high NaCl-induced activation of the osmoregulatory transcription factor TonEBP/OREBP.
The signaling pathways leading to high NaCl-induced activation of the transcription factor tonicity-responsive enhancer binding protein/osmotic response element binding protein (TonEBP/OREBP) remain incompletely understood. High NaCl has been reported to produce oxidative stress. Reactive oxygen species (ROS), which are a component of oxidative stress, contribute to regulation of transcription factors. The present study was undertaken to test whether the high NaCl-induced increase in ROS contributes to tonicity-dependent activation of TonEBP/OREBP. Human embryonic kidney 293 cells were used as a model. We find that raising NaCl increases ROS, including superoxide. N-acetylcysteine (NAC), an antioxidant, and MnTBAP, an inhibitor of superoxide, reduce high NaCl-induced superoxide activity and suppress both high NaCl-induced increase in TonEBP/OREBP transcriptional activity and high NaCl-induced increase in expression of BGT1mRNA, a transcriptional target of TonEBP/OREBP. Catalase, which decomposes hydrogen peroxide, does not have these effects, whether applied exogenously or overexpressed within the cells. Furthermore, NAC and MnTBAP, but not catalase, blunt high NaCl-induced increase in TonEBP/OREBP transactivation. N(G)-monomethyl-l-arginine, a general inhibitor of nitric oxide synthase, has no significant effect on either high NaCl-induced increase in superoxide or TonEBP/OREBP transcriptional activity, suggesting that the effects of ROS do not involve nitric oxide. Ouabain, an inhibitor of Na-K-ATPase, attenuates high NaCl-induced superoxide activity and inhibits TonEBP/OREBP transcriptional activity. We conclude that the high NaCl-induced increase in ROS, including superoxide, contributes to activation of TonEBP/OREBP by increasing its transactivation.


[Color properties of the receptive fields of visual cortex neurons in the squirrel].
The colour-sensitive properties of the visual cortex neurons were studied in the squirrel. All the neurons responded to achromatic, green and blue visual stimuli; responses to red stimuli were slight or absent. According to responses to patterned visual stimuli the neurons were classified as non-selective, directionally-selective and orientation-selective (simple and complex). No colour-opponent properties were revealed in any of these neuronal groups: neuronal responses were qualitatively the same to achromatic, green and blue stimuli, and the receptive fields organization was independent of the stimulus colour. These data are discussed with respect to the fact of presence of colour-opponent cells in the retina and lateral geniculate nucleus of squirrel.


Biochemical markers in cancer of the breast.
Currently, one could summarize this area by saying that we appear to be in a situation where three relatively nonspecific tests detect the majority of patients with metastatic disease, as well as those post-operative patients who are at high risk of relapse. The critical test of their utility for segregating those at risk for relapse from those who are not at high risk will need to be done in a highly select subgroup, e.g., N- patients. Two of these tests, CEA and hCG, also appear to be useful indicators for predicting the probability of responding to combination chemotherapy in metastatic disease. The development and further testing of potentially more specific markers to replace or add to the current matrix is now in progress, Casein, which is a product of the milk synthesis pathway of breast tissue, represents a potentially more specific test than any of those studied to date. HENDRICK and FRANCHIMONT, 1974, have found elevated levels in 21 of 26, or 81%, of patients with metastatic disease, and 8 of 11, or 73%, of patients preoperatively. The test may also reflect the tumor burden since the proportion of patients with elevated levels dropped to 41-50% postoperatively. Further results with this marker are awaited with interest. Other tests such as ferritin, hydroxyproline, or the development of tumor antigen associated immunospecific assays could increase both the specificity and sensitivity of the tests utilized in this field of investigation. Injecting the use of both single marker tests and matrix approaches into routine clinical use in the postoperative setting now appears to be ready for more critical testing. Their use in diagnostic or screening settings, which is the ultimate goal, also needs to be evaluated. Finally, from the practising clinician's viewpoint the data in this discussion should be considered preliminary. It constitutes a status report. Although there is evidence that CEA and hCG are prognostic in metastatic disease, and that subclinical disease is detectable, larger and more tightly controlled studies will be necessary before their routine clinical use can be recommended in breast cancer patients.


[Surgical treatment of renal hyperparathyroidism. Experience in 71 patients].
Surgery is an effective method for the management of renal hyperparathyroidism. To report the clinical presentation and results of surgical treatment of renal hyperparathyroidism. Retrospective analysis of 58 patients aged 46 ± 11 years with secondary hyperparathyroidism (HPT2) and 13 patients aged 53 ± 11 years with tertiary hyperparathyroidism (HPT3), operated at a clinical hospital. In 55 cases (77.4%) the indications for surgery were complications of excess parathyroid hormone (PTH) and in 16 patients (22.6%) a failure of medical treatment. Total parathyroidectomy with intraoperative measurement of PTH (PTHop) plus a forearm parathyroid autograft was performed in 54 (93.1%) patients with HPT2 and in all patients with HPT3. PTHop decreased ≥ 75% in 51 patients (88%) with HPT2 and in 9 patients (69.2%) with HPT3, respectively. Cure of the disease was achieved in 52 (89.7%) and 11 (84.6%) patients with HPT2 and 3, respectively. Median follow-up was 41 months. Five (9.6%) patients with HPT2 and two patients (18.2%) with HPT3 had a recurrence of the disease. In patients with renal hyperparathyroidism, the primary indication for surgery was the presence of complications of PTH excess. A drop in PTHop ≥ 75% from baseline predicts healing in 98% and 100% of cases with secondary or tertiary HPT respectively. Surgery was a safe and effective treatment in both groups.


Hospital-acquired conjunctivitis in a neonatal intensive care unit: Bacterial etiology and susceptibility patterns.
Our study investigates the causative pathogens of hospital-acquired conjunctivitis in our neonatal intensive care unit and their susceptibility patterns. Coagulase-negative Staphylococcus was the most common bacterium, 22.1% of all isolates. The frequency of the pathogens changed during neonates' stay; Klebsiella pneumoniae (from 18% to 6.9%) and Escherichia coli (from 16% to 4.8%) decreased, whereas methicillin-susceptible Staphylococcus aureus (from 4% to 12.7%) and Enterococcus spp (from 1% to 5.3%) increased. Gram-positive cocci showed high resistant patterns. Our study indicates that the distribution of bacteria causing hospital-acquired conjunctivitis in our neonates shifted from gram-negative to gram-positive microorganisms during their neonatal intensive care unit stay. The resistance patterns are worrisome among gram-positive cocci.


Anti-inflammatory Effects of Enhanced Recovery Programs on Early-Stage Colorectal Cancer Surgery.
Postoperative ileus (POI) is observed in 20-30% of patients undergoing colorectal cancer surgery, despite enhanced recovery programs (ERPs). Cyclooxygenase (COX)-2 is identified as a key enzyme in POI, but other arachidonic acid pathway enzymes have received little attention despite their potential as selective targets to prevent POI. The objectives were to compare the expression of arachidonic acid metabolism (AAM) enzymes (1) between patients who underwent colorectal cancer surgery and followed an ERP or not (NERP), (2) and between ERP patients who experimented POI or not and (3) to determine the ability of antagonists of these pathways to modulate contractile activity of colonic muscle. This was a translational study. Main outcome measures were gastrointestinal motility recovery data, mRNA expressions of key enzymes involved in AAM (RT-qPCR) and ex vivo motility values of the circular colon muscle. Twenty-eight prospectively included ERP patients were compared to eleven retrospectively included NERP patients that underwent colorectal cancer surgery. ERP reduced colonic mucosal COX-2, microsomal prostaglandin E synthase (mPGES1) and hematopoietic prostaglandin D synthase (HPGDS) mRNA expression. mPGES1 and HPGDS mRNA expression were significantly associated with ERP compliance (respectively, r2 = 0.25, p = 0.002 and r2 = 0.6, p < 0.001). In muscularis propria, HPGDS mRNA expression was correlated with GI motility recovery (p = 0.002). The pharmacological inhibition of mPGES1 increased spontaneous ex vivo contractile activity in circular muscle (p = 0.03). The effects of ERP on GI recovery are correlated with the compliance of ERP and could be mediated at least in part by mPGES1, HPGDS and COX-2. Furthermore, mPGES1 shows promise as a therapeutic target to further reduce POI duration among ERP patients.


The Effects of Abortion Decision Rightness and Decision Type on Women's Satisfaction and Mental Health.
Background A case series report based on the Turnaway Study has previously concluded that 99% of women with a history of abortion will continue to affirm satisfaction with their decisions to abort. Those findings have been called into question due to a low participation rate (31%) and reliance on a single yes/no assessment of decision satisfaction. Aim To utilize more sensitive scales in assessing decision satisfaction and the associated mental health outcomes women attribute to their abortions. Method A retrospective survey was completed by 1,000 females, aged 41-45, living in the United States. The survey instrument included 11 visual analog scales for respondents to rate their personal preferences and outcomes they attributed to their abortion decisions. A categorical question allowed women to identify if their abortions were wanted and consistent with their own values and preferences, inconsistent with their values and preferences, unwanted, or coerced. Linear regression models were tested to identify which of three decision scales best predicted positive or negative emotions, effects on mental health, emotional attachment, personal preferences, moral conflict, and other factors relevant to an assessment of satisfaction with a decision to abort. Results Of 226 women reporting a history of abortion, 33% identified it as wanted, 43% as accepted but inconsistent with their values and preferences, and 24% as unwanted or coerced. Only wanted abortions were associated with positive emotions or mental health gains. All other groups attributed more negative emotions and mental health outcomes to their abortions. Sixty percent reported they would have preferred to give birth if they had received more support from others or had more financial security. Conclusions Perceived pressure to abort is strongly associated with women attributing more negative mental health outcomes to their abortions. The one-third of women for whom abortion is wanted and consistent with their values and preferences are most likely over-represented in studies initiated at abortion clinics. More research is needed to understand better the experience of the two-thirds of women for whom abortion is unwanted, coerced, or otherwise inconsistent with their own values and preferences.


A systems approach to implementation of eLearning in medical education: five MEPI schools' journeys.
How should eLearning be implemented in resource-constrained settings? The introduction of eLearning at four African medical schools and one school of pharmacy, all part of the Medical Education Partnership Initiative (MEPI) eLearning Technical Working Group, highlighted the need for five factors essential for successful and sustainable implementation: institutional support; faculty engagement; student engagement; technical expertise; and infrastructure and support systems. All five MEPI schools reported strengthening technical expertise, infrastructure, and support systems; four schools indicated that they were also successful in developing student engagement; and three reported making good progress in building institutional support. Faculty engagement was the one core component that all five schools needed to enhance.


Encopresis in the school-aged child.
This paper defines encopresis, identifies associated characteristics and clinical presentation, and describes diagnosis and treatment plans. The use of a case study illustrates how encopresis may be encountered by the school nurse. Health promotion issues and prevention concepts are examined as possible means of facilitating prevention and management of encopresis in the school-aged child.


The breakdown of lipid reserves in the endosperm of germinating castor beans.
1. Lipid extracts were obtained from castor-bean endosperm tissue at various times during germination and, after purification, the total lipid content was determined. Quantitative measurements of the triglyceride and phospholipid content together with the fatty acid composition were made. 2. The total lipid content of the endosperm rapidly decreased during germination; after 10 days less than 20% of the original weight of lipid remained. In contrast, the phospholipid content (initially less than 0.5% of the total lipid) increased slightly during this time. The fatty acid composition and the relative proportions of the triglyceride species of the total lipid extract remained constant during 10 days of germination. 3. Gibberellic acid (0.3 mM) markedly stimulated the rate of lipid breakdown but did not alter either the fatty acid composition or the relative proportion of triglyceride species. 4. The embryo had little effect on lipid metabolism in the endosperm tissue; only after 6 days of germination were differences observed in the rate of fat utilization in the presence and absence of the embryo.


Parents' and health-care providers' perspectives on side- effects of childhood cancer treatment in Indonesia.
Efficacy of childhood cancer treatment in low-income countries may be impacted by parents' and health-care providers' perspectives on chemotherapy-related side-effects. This study explores prevalence and severity of side-effects in childhood cancer, and compares health beliefs about side-effects between parents and health-care providers, and between nurses and doctors in Indonesia. Semi-structured questionnaires were filled in by 40 parents and 207 health-care providers in an academic hospital. Parents exporessed a desire to receive more information about side-effects (98%) and worried about this aspect of treatment (90%), although side-effects were less severe than expected (66%). The most frequent was behavior alteration (98%) and the most severe was hair loss. Only 26% of parents consulted doctors about side-effects. More parents, compared to health-care providers, believed that medicines work better when side-effects are more severe (p<0.001), and accepted severe side-effects (p=0.021). More health-care providers, compared to parents, believed that chemotherapy can be stopped or the dosage altered when there are side-effects (p=0.011). More nurses, compared to doctors, stated that side-effects were unbearable (p=0.004) and made them doubt efficacy of treatment (p<0.001). Behavior alteration is the most frequent and hair loss the most severe side-effect. Apparent discrepancies in health beliefs about side-effects exist between parents and health-care providers. A sustainable parental education program about side-effects is recommended. Health-care providers need to update and improve their knowledge and communication skills in order to give appropriate information. Such measures may improve outcome of childhood cancer treatment in low-income countries, where adherence to therapy is a major issue.


SARS-CoV-2 infection triggers pro-atherogenic inflammatory responses in human coronary vessels.
COVID-19 patients present higher risk for myocardial infarction (MI), acute coronary syndrome, and stroke for up to 1 year after SARS-CoV-2 infection. While the systemic inflammatory response to SARS-CoV-2 infection likely contributes to this increased cardiovascular risk, whether SARS-CoV-2 directly infects the coronary vasculature and attendant atherosclerotic plaques to locally promote inflammation remains unknown. Here, we report that SARS-CoV-2 viral RNA (vRNA) is detectable and replicates in coronary atherosclerotic lesions taken at autopsy from patients with severe COVID-19. SARS-CoV-2 localizes to plaque macrophages and shows a stronger tropism for arterial lesions compared to corresponding perivascular fat, correlating with the degree of macrophage infiltration. In vitro infection of human primary macrophages highlights that SARS-CoV-2 entry is increased in cholesterol-loaded macrophages (foam cells) and is dependent, in part, on neuropilin-1 (NRP-1). Furthermore, although viral replication is abortive, SARS-CoV-2 induces a robust inflammatory response that includes interleukins IL-6 and IL-1β, key cytokines known to trigger ischemic cardiovascular events. SARS-CoV-2 infection of human atherosclerotic vascular explants recapitulates the immune response seen in cultured macrophages, including pro-atherogenic cytokine secretion. Collectively, our data establish that SARS-CoV-2 infects macrophages in coronary atherosclerotic lesions, resulting in plaque inflammation that may promote acute CV complications and long-term risk for CV events.


Spinocerebellar ataxia type 1 with multiple system degeneration and glial cytoplasmic inclusions.
Spinocerebellar ataxia type 1 (SCA1) is a dominantly inherited progressive neurological disorder characterized by neuronal degeneration and reactive gliosis in the cerebellum, brainstem, spinocerebellar tracts, and dorsal columns. Multiple system atrophy is a sporadic progressive neurological disorder with degeneration and gliosis in the basal ganglia, cerebellum, brainstem, and spinal autonomic nuclei, and with argyrophilic glial cytoplasmic inclusions. We describe 4 members of a family with the SCA1 mutation and a dominantly inherited progressive ataxia in which autopsy examination of 1 member showed neuropathological changes typical of multiple system atrophy, including glial cytoplasmic inclusions. In this patient, magnetic resonance imaging revealed marked brainstem and cerebellar volume loss and mild supratentorial generalized volume loss. Positron emission tomography with [18F]fluorodeoxyglucose revealed widespread hypometabolism in a pattern found in sporadic multiple system atrophy and not in dominantly inherited olivopontocerebellar atrophy. Positron emission tomography with [11C]flumazenil revealed normal benzodiazepine receptor distribution volumes, similar to those seen in sporadic multiple system atrophy. Two other family members still living had similar changes in the imaging studies. The findings in this family suggest that the SCA1 gene mutation can result in a disorder similar to multiple system atrophy, both clinically and neuropathologically.


Propagation properties of longitudinal leaky surface waves on lithium tetraborate.
Theoretical and experimental results of longitudinal leaky surface waves with a higher phase velocity than that of ordinary leaky surface waves and a low propagation loss on lithium tetraborate (LBO) are investigated in detail. They propagate along the surface with a phase velocity close to that of longitudinal bulk wave, slightly radiating two kinds of shear bulk waves (or one shear bulk wave in the case that one of two shear wave terms is uncoupled) into the solid. Most surface components of the mode consist of a longitudinal wave term and an electromagnetic wave term. The detailed propagation properties of the longitudinal leaky surface waves on LBO with the Euler angles (phi, theta, 90 degrees ) are investigated theoretically and experimentally. The (011) cut of LBO was found to be desirable for higher frequency SAW devices. One of the reasons why that mode on LBO has a low propagation loss is also discussed.


Treatment-associated leukemia following testicular cancer.
Men with testicular cancer are at an increased risk of leukemia, but the relationship to prior treatments is not well characterized. The purpose of our study was to describe the risk of leukemia following radiotherapy and chemotherapy for testicular cancer. Within a population-based cohort of 18 567 patients diagnosed with testicular cancer (from 1970 through 1993), a case-control study of leukemia was undertaken. Radiation dose to active bone marrow and type and cumulative amount of cytotoxic drugs were compared between 36 men who developed leukemia and 106 matched control patients without leukemia. Conditional logistic regression was used to estimate the relative risk of leukemia associated with specific treatments. All P values are two-sided. Radiotherapy (mean dose to active bone marrow, 12.6 Gy) without chemotherapy was associated with a threefold elevated risk of leukemia. Risk increased with increasing dose of radiation to active bone marrow (P for trend =.02), with patients receiving radiotherapy to the chest as well as to the abdominal/pelvic fields accounting for much of the risk at higher doses. Radiation dose to active bone marrow and the cumulative dose of cisplatin (P for trend =.001) were both predictive of excess leukemia risk in a model adjusted for all treatment variables. The estimated relative risk of leukemia at a cumulative dose of 650 mg cisplatin, which is commonly administered in current testicular cancer treatment regimens, was 3.2 (95% confidence interval = 1.5-8.4); larger doses (1000 mg) were linked with statistically significant sixfold increased risks. Past treatments for testicular cancer are associated with an increased risk of leukemia, with evidence for dose-response relationships for both radiotherapy and cisplatin-based chemotherapy. Statistically nonsignificant excesses are estimated for current radiotherapy regimens limited to the abdomen and pelvis: Among 10 000 patients given a treatment dose of 25 Gy and followed for 15 years, an excess of nine leukemias is predicted; cisplatin-based chemotherapy (dose, 650 mg) might result in 16 cases of leukemia. The survival advantage provided by current radiotherapy and chemotherapy regimens for testicular cancer far exceeds the small absolute risk of leukemia.


Pharmacologic Therapy of Diabetes and Overall Cancer Risk and Mortality: A Meta-Analysis of 265 Studies.
Different anti-diabetic medications (ADMs) may modify cancer risk and mortality in patients with diabetes. We conducted a systematic review and meta-analysis to estimate the magnitude of association and quality of supporting evidence for each ADM. A total of 265 studies (44 cohort studies, 39 case-control studies, and 182 randomized controlled trials (RCT)) were identified, involving approximately 7.6 million and 137,540 patients with diabetes for observational studies and RCTs, respectively. The risk of bias overall was moderate. Meta-analysis demonstrated that the use of metformin or thiazolidinediones was associated with a lower risk of cancer incidence (RR = 0.86, 95% CI 0.83-0.90, I(2) = 88.61%; RR = 0.93, 95% CI 0.91-0.96, I(2) = 0.00% respectively). On the other hand, insulin, sulfonylureas and alpha glucosidase inhibitor use was associated with an increased risk of cancer incidence (RR = 1.21, 95% CI 1.08-1.36, I(2) = 96.31%; RR = 1.20, 95% CI 1.13-1.27, I(2) = 95.02%; RR = 1.10, 95% CI 1.05-1.15, I(2) = 0.00% respectively). Use of other types of ADMs was not significantly associated with cancer risk. This study indicates that some ADMs may modify the risk of cancer in individuals with diabetes. Knowledge of this risk may affect the choice of ADM in individuals concerned about cancer or at increased risk for cancer.


Adipocytokines and ischemic stroke: differential associations between stroke subtypes.
Experimental studies have indicated that adipocytokines are associated with vascular diseases with regard to the pathology of atherosclerotic plaque. We hypothesized that the strength of the associations between adipocytokines and stroke would differ between ischemic stroke subtypes. A total of 96 acute ischemic stroke patients (within 5 days from onset) and 48 non-stroke subjects were analyzed in this study. Stroke patients were comprised of 26 strokes due to large artery atherosclerosis (LAA) and 72 non-LAA strokes. Venous blood from all participants was drawn after an overnight fast, and serum levels of leptin, adiponectin and resistin were measured by multiple sandwich immunoassay techniques. Compared with non-LAA strokes, patients with LAA strokes had lower levels of serum adiponectin (6.4 ± 3.1 vs. 8.5 ± 3.9 μg/mL; P=0.04), and a higher level of leptin-to-adiponectin ratio (L:A ratio; 1.6 ± 1.4 vs. 0.9 ± 0.9; P<0.01). Multinomial logistic regression analyses showed that, although none of the adipocytokines was associated with non-LAA strokes, lower adiponectin (adjusted OR, 0.79 per 1-μg/mL increase; 95% CI, 0.64-0.98), higher leptin (aOR, 1.12 per 1-ng/mL increase; 95% CI, 1.004-1.25) and higher L:A ratio (aOR, 2.93 per 1-quartile increase; 95% CI, 1.39-6.15) showed significant associations with increased odds of having LAA stroke, compared to non-stroke subjects. From our study, we documented that leptin and adiponectin had differential association patterns with ischemic stroke according to the stroke subtype. Careful consideration of the heterogeneity of stroke subtypes would be warranted in studying the utility of biomarkers including adipocytokines.


Successful simultaneous retrieval of two dislodged and entangled intracoronary stents using distal balloon inflating technique.
Stent loss in coronary arteries is a rare complication of coronary intervention. Furthermore, the entanglement of a lost stent with a second previously deployed stent leading to a very complicated scenario has not been reported previously. In this case, we are presenting the first case report of a stent loss due to the entanglement of a stent with the ostial part of the second already deployed side branch stent leading to distortions of the second stent and entrapment. This is also the first case report describing the successful and simultaneous retrieval of both the lost and entangled deployed stents percutaneously using the distal inflating balloon technique.


The intubating laryngeal mask airway with and without fiberoptic guidance.
We conducted this feasibility study using the intubating laryngeal mask airway (ILMA) and a polyvinyl chloride tracheal tube to compare success rates, hemodynamic effects, and postoperative morbidity with two methods of tracheal intubation. After ethics approval and informed consent, 90 healthy ASA physical status I or II women with normal airways were enrolled in the randomized, controlled study. After a standardized inhaled anesthesia induction protocol, tracheal intubations using ILMA with fiberoptic guidance (ILMA-FOB) and ILMA inserted blindly without fiberoptic guidance (ILMA-Blind) were compared with the control group of direct laryngoscopy (laryngoscopy group). All 90 patients were successfully ventilated. For tracheal intubation, success rates were equal in all three groups (97%). Total intubation times were longer for the ILMA-FOB group (77 s versus 48.5 s for laryngoscopy and 53.5 s for ILMA-Blind). The laryngoscopy group had a larger increase in mean arterial blood pressure to tracheal intubation. There were no differences in postoperative sore throat or hoarseness among the groups. In conclusion, success rates are equally high for tracheal intubation using ILMA-Blind and ILMA-FOB techniques in women with normal airways. The intubating laryngeal mask airway (ILMA) can be used as a primary airway for oxygenation and ventilation. Both methods of tracheal intubation using the ILMA were equally successful. Postoperative morbidity in the ILMA groups was similar to that in the laryngoscopy group. For women with normal airways, both the ILMA inserted blindly and the ILMA with fiberoptic guidance are suitable alternatives to laryngoscopy for tracheal intubation.


Retinal glucose metabolism in mice lacking the L-glutamate/aspartate transporter.
The conventional view that glucose is the substrate for neuronal energy metabolism has been recently challenged by the "lactate shuttle" hypothesis in which glutamate cycling in glial cells drives all neuronal glucose metabolism. According to this view, glutamate released by activated retinal neurons is transported into Müller (glial) cells where it triggers glycolysis. The lactate released by Müller cells serves as the energy substrate for neuronal metabolism. Because the L-Glutamate/aspartate transporter (GLAST) is the predominant, Na+-dependent, glutamate transporter expressed by Müller cells, we have used GLAST-knockout (GLAST -/-) mice to examine the relationship between lactate release and GLAST activity in the retina. We found that glucose uptake and lactate production by the GLAST -/- mouse retina was similar to that observed in the wild type mouse retina. Furthermore, addition of 1 mM glutamate and NH4Cl to the incubation medium did not further stimulate glucose uptake in either case. When lactate release was measured in the presence of the lactate uptake inhibitor, alpha-cyano-4-hydroxycinnamate, there was no significant change in the amount of lactate released by retinas from GLAST -/- mice compared to the wild type. Finally, lactate release was similar under both dark and light conditions. These results show that lactate production and release is not altered in retinas of GLAST -/- mice, which suggests that metabolic coupling between photoreceptors and Müller cells is not mediated by the glial glutamate transporter, GLAST.


Temporarily Out of Order: Temporal Perspective Taking in Language in Children With Autism Spectrum Disorder.
Clinical reports suggest that children with autism spectrum disorder (ASD) struggle with time perception, but few studies have investigated this. This is the first study to examine these children's understanding of before and after. These temporal conjunctions have been argued to require additional cognitive effort when conjoining two events in a clause order that is incongruent with their order in time. Given the suggested time perception impairment and well-established cognitive deficits of children with ASD, we expected them to have difficulties interpreting temporal conjunctions, especially in an incongruent order. To investigate this, the interpretation of before and after in congruent and incongruent orders was examined in 48 children with ASD and 43 typically developing (TD) children (age 6-12). Additional tasks were administered to measure Theory of Mind (ToM), working memory (WM), cognitive inhibition, cognitive flexibility, IQ, and verbal ability. We found that children with ASD were less accurate in their interpretation of temporal conjunctions than their TD peers. Contrary to our expectations, they did not have particular difficulties in an incongruent order. Furthermore, older children showed better overall performance than younger children. The difference between children with ASD and TD children was explained by WM, ToM, IQ, and verbal ability, but not by cognitive inhibition and flexibility. These cognitive functions are more likely to be impaired in children with ASD than in TD children, which could account for their poorer performance. Thus, the cognitive factors found to affect the interpretation of temporal language in children with ASD are likely to apply in typical development as well. Sufficient WM capacity and verbal ability may help children to process complex sentences conjoined by a temporal conjunction. Additionally, ToM understanding was found to be related to children's interpretation of temporal conjunctions in an incongruent order, indicating that perspective taking is required when events are presented out of order. We conclude from this that perspective-taking abilities are needed for the interpretation of temporal conjunctions, either to shift one's own perspective as a hearer to another point in time, or to shift to the perspective of the speaker to consider the speaker's linguistic choices.


Effects of oxygen on exertional dyspnoea and exercise performance in patients with chronic obstructive pulmonary disease.
The results of studies on the oxygen response in patients with COPD should provide important clues to the pathophysiology of exertional dyspnoea. We investigated the exercise responses to hyperoxia in relation to dyspnoea profile, as well as cardiopulmonary, acidotic and sympathetic parameters in 35 patients with stable COPD (mean FEV(1) 46% predicted). This was a single-blind trial, in which patients breathed 24% O(2) or compressed air (CA) in random order during two incremental cycle exercise tests. PaO(2) and PaCO(2) were higher (P < 0.0001 and P < 0.05, respectively) at each exercise point while patients were breathing 24% O(2) compared with CA. At a standardized time point near peak exercise, use of O(2) resulted in reduced plasma lactate and plasma noradrenaline concentrations (P < 0.01). Peak minute ventilation/indirect maximum voluntary ventilation was similar while breathing 24% O(2) and CA. At peak exercise, the dyspnoea score, pH and plasma noradrenaline concentrations were similar while breathing 24% O(2) and CA. The dyspnoea-ratio (%) of Δoxygen uptake (peak minus resting oxygen uptake) curve reached a break point that occurred at a similar exercise point while breathing 24% O(2) or CA. Regardless of whether they breathed CA or 24% O(2) , patients with COPD did not develop ventilatory compensation for exertional acidosis, and the pH values measured were similar. Hyperoxia during a standardized exercise protocol did not alter the pattern of exertional dyspnoea in these patients, compared with breathing CA, although hyperoxia resulted in miscellaneous effects.


A regulatory region from the mouse Hox-2.2 promoter directs gene expression into developing limbs.
To characterize cis-acting regulatory elements of the murine homeobox gene, Hox-2.2, transgenic mouse lines were generated that contained the LacZ reporter gene under the control of different fragments from the presumptive Hox-2.2 promoter. A promoter region of 3600 base pairs (bp) was identified, which reproducibly directed reporter gene expression into specific regions of developing mouse embryos. At 8.5 days postcoitum (p.c.) reporter gene activity was detected in posterior regions of the lateral mesoderm and, in subsequent developmental stages, expression of the LacZ gene was restricted to specific regions of the developing limb buds and the mesenchyme of the ventrolateral body region. This pattern of Hox-2.2-LacZ expression was found in all transgenic embryos that have been generated with the 3.6 kb promoter fragment (two founder embryos and embryos from five transgenic lines). In addition, embryos from two transgenic mouse lines expressed the reporter gene at low levels in the developing central nervous system (CNS). Our results are consistent with the idea that in addition to their presumptive role in CNS and vertebrae development, Hox-2.2 gene products are involved in controlling pattern formation in developing limbs.


Neurostimulation in People with Oropharyngeal Dysphagia: A Systematic Review and Meta-Analyses of Randomised Controlled Trials-Part I: Pharyngeal and Neuromuscular Electrical Stimulation.
Objective. To assess the effects of neurostimulation (i.e., neuromuscular electrical stimulation (NMES) and pharyngeal electrical stimulation (PES)) in people with oropharyngeal dysphagia (OD). Methods. Systematic literature searches were conducted to retrieve randomised controlled trials in four electronic databases (CINAHL, Embase, PsycINFO, and PubMed). The methodological quality of included studies was assessed using the Revised Cochrane risk-of-bias tool for randomised trials (RoB 2). Results. In total, 42 studies reporting on peripheral neurostimulation were included: 30 studies on NMES, eight studies on PES, and four studies on combined neurostimulation interventions. When conducting meta analyses, significant, large and significant, moderate pre-post treatment effects were found for NMES (11 studies) and PES (five studies), respectively. Between-group analyses showed small effect sizes in favour of NMES, but no significant effects for PES. Conclusions. NMES may have more promising effects compared to PES. However, NMES studies showed high heterogeneity in protocols and experimental variables, the presence of potential moderators, and inconsistent reporting of methodology. Therefore, only conservative generalisations and interpretation of meta-analyses could be made. To facilitate comparisons of studies and determine intervention effects, there is a need for more randomised controlled trials with larger population sizes, and greater standardisation of protocols and guidelines for reporting.


Randomized study of valacyclovir as prophylaxis against cytomegalovirus reactivation in recipients of allogeneic bone marrow transplants.
Oral valacyclovir for cytomegalovirus (CMV) prophylaxis in bone marrow transplantation (BMT) was investigated in a randomized, double-blind, acyclovir-controlled, multicenter clinical trial in recipients of allogeneic BMT who were CMV seropositive (or donor positive) before transplantation and were aged 13 years or older. Patients were randomized before BMT. All initially received intravenous acyclovir (500 mg/m(2)) 3 times daily until day 28 after transplantation or after discharge, then oral valacyclovir (2 g) or acyclovir (800 mg) 4 times daily until week 18 after transplantation. Evidence of CMV infection, CMV disease, and death were documented for 22 weeks. Primary end points were time to CMV infection (detection of CMV in blood, broncho-alveolar lavage) or CMV disease and survival. Preemptive CMV therapy was permitted. Seven hundred twenty-seven patients were evaluable for efficacy. After the administration of intravenous acyclovir, valacyclovir was significantly more effective than oral acyclovir in reducing the incidence of CMV infection. CMV infection or disease developed in 102 (28%) valacyclovir patients, compared with 143 (40%) acyclovir patients (HR, 0.59; 95% CI, 0.46-0.76; P <.0001). Survival did not differ between treatments (76% and 75% in the valacyclovir and acyclovir groups, respectively). The safety of oral valacyclovir was similar to that of high-dose oral acyclovir. Valacyclovir was more effective than acyclovir in preventing CMV reactivation in BMT recipients and showed a similar safety profile. CMV disease incidence was low, and no differences were observed between oral valacyclovir and acyclovir. Survival was similar in each group. Valacyclovir prophylaxis provides a clinically valuable intervention but must be part of an overall strategy for CMV prevention in BMT.