Mineral resources, economic growth, and world populatic.
World population and world income can grow at any likely rate for the next 50 to 75 years, probably for longer, and mineral supplies will continue to keep pace with demand. Not, however, without environmental costs, without affecting Third World development, and, perhaps most important, without ignoring critical questions of power. In what might be termed the revisionist form of the limits to growth thesis, Aurelio Peccei and Alexander King, cofounders of the Club of Rome, seem to be saying that the forecasts of doom themselves are unimportant but they symbolize critical problems of the nature and uses of power in the modern world (30): . . . the Club of Rome is questioning the quality of growth and its distribution around the world. . . . We know that the present structure of the world is obsolete. . . . Both private and state capitalism are stale . . . we have to develop something else. Surely, continually increasing rates of mineral production are symptoms of this obsolete power structure, a result of the fact that, ultimately, population growth and monetary income growth lead to demands for natural resources that necessitate their being found and produced regardless of the implications. Since such higher rates of production are geologically and economically sustainable, we should choose among alternative paths of growth, and hence among alternative rates of mineral resource development, according to what we like or dislike about these implications. The key information will not be found in tables comparing reserves and consumption but in preferences and ethics.


Left ventricular chamber size predicts the race time of Japanese participants in a 100 km ultramarathon.
As a subanalysis of an echocardiographic study performed on 291 Japanese participants in a 100 km ultramarathon, to estimate predictors of race time. A total of 247 male participants in a 100 km ultramarathon (age 20-73 years) were examined by echocardiography. Correlations between age, body surface area, monthly running distance, or echocardiographic variables and the race time were examined. According to simple regression analysis, age (r = 0.299, p < 0.0001), monthly running distance (r = -0.388, p < 0.0001), left ventricular end diastolic diameter (r = -0.300, p < 0.0001), and left ventricular end systolic diameter (r = -0.325, p < 0.0001) correlated significantly with the race time. When multiple regression analysis was performed, age (f = 2.364), monthly running distance (f = -0.113), and left ventricular end systolic diameter (f = -2.361) remained significant predictors of the race time. Left ventricular diameter predicts the race time for a 100 km ultramarathon, in addition to age and amount of training.


PYHIN1 regulates pro-inflammatory cytokine induction rather than innate immune DNA sensing in airway epithelial cells.
Animal cells use pattern-recognition receptors (PRRs) to detect specific pathogens. Pathogen detection mounts an appropriate immune response, including interferon and cytokine induction. The intracellular PRR-signaling pathways that detect DNA viruses have been characterized, particularly in myeloid cells. In these pathways, cGMP-AMP synthase (cGAS) and the pyrin and HIN domain family member (PYHIN) protein interferon-γ-inducible protein 16 (IFI16) detect DNA and signal via stimulator of interferon genes protein (STING). However, although airway epithelial cells are frontline sentinels in detecting pathogens, information on how they respond to DNA viruses is limited, and the roles of PYHIN proteins in these cells are unknown. Here, we examined expression and activities of cGAS, STING, and PYHINs in human lung epithelial cells. A549 epithelial cells, commonly used for RNA-sensing studies, failed to respond to DNA because they lacked STING expression, and ectopic STING expression restored a cGAS-dependent DNA response in these cells. In contrast, NuLi-1 immortalized human bronchial epithelial cells did express STING, which was activated after DNA stimulation and mediated DNA-dependent gene induction. PYHIN1, which like IFI16 has been proposed to be a viral DNA sensor, was the only PYHIN protein expressed in both airway epithelial cell types. However, rather than having a role in DNA sensing, PYHIN1 induced proinflammatory cytokines in response to interleukin-1 (IL-1) or tumor necrosis factor α (TNFα) stimulation. Of note, PYHIN1, via its HIN domain, directly induced IL-6 and TNFα transcription, revealing that PYHIN proteins play a role in proinflammatory gene induction in airway epithelial cells.


Emergency ABO-incompatible liver transplant secondary to fulminant hepatic failure: outcome, role of TPE and review of the literature.
The increasing demand for solid organ transplants has brought to light the need to utilize organs in critical situations despite ABO-incompatibility. However, these transplantations are complicated by pre-existing ABO antibodies which may be potentially dangerous and makes the transplantation prone to failure due to rejection with resulting necrosis or intrahepatic biliary complications. We report the clinical outcome of an emergency ABO-incompatible liver transplant (due to fulminant hepatic failure with sudden and rapidly deteriorating mental status) using a modified therapeutic plasma exchange (TPE) protocol. The recipient was O-positive with an initial anti-B titer of 64 and the cadaveric organ was from a B-positive donor. The patient underwent initial TPE during the peri-operative period, followed by a series of postoperative daily TPE, and later a third series of TPE for presumptive antibody-mediated rejection. The latter two were performed in conjunction with the use of IVIg and rituximab. The recipient's anti-B titer was reduced and maintained at 8 or less 8 months post-op. However, an elevation of transaminases 3 months post-transplant triggered a biopsy which was consistent with cellular rejection and with weak C4d positive staining suggestive of antibody mediated rejection. Additional plasma exchange procedures were performed. The patient improved rapidly after modification of her immunosuppression regimen and treatment with plasma exchange. This case illustrates that prompt and aggressive plasma exchange, in conjunction with immunosuppression, is a viable approach to prevent and treat antibody mediated transplant rejection in emergency ABO-incompatible liver transplant.


Hydrogen sulphide protects against NSAID-enteropathy through modulation of bile and the microbiota.
Hydrogen sulphide is an important mediator of gastrointestinal mucosal defence. The use of non-steroidal anti-inflammatory drugs (NSAIDs) is significantly limited by their toxicity in the gastrointestinal tract. Particularly concerning is the lack of effective preventative or curative treatments for NSAID-induced intestinal damage and bleeding. We evaluated the ability of a hydrogen sulphide donor to protect against NSAID-induced enteropathy. Intestinal ulceration and bleeding were induced in Wistar rats by oral administration of naproxen. The effects of suppression of endogenous hydrogen sulphide synthesis or administration of a hydrogen sulphide donor (diallyl disulphide) on naproxen-induced enteropathy was examined. Effects of diallyl disulphide on small intestinal inflammation and intestinal microbiota were also assessed. Bile collected after in vivo naproxen and diallyl disulphide administration was evaluated for cytotoxicity in vitro using cultured intestinal epithelial cells. Suppression of endogenous hydrogen sulphide synthesis by β-cyano-L-alanine exacerbated naproxen-induced enteropathy. Diallyl disulphide co-administration dose-dependently reduced the severity of naproxen-induced small intestinal damage, inflammation and bleeding. Diallyl disulphide administration attenuated naproxen-induced increases in the cytotoxicity of bile on cultured enterocytes, and prevented or reversed naproxen-induced changes in the intestinal microbiota. Hydrogen sulphide protects against NSAID-enteropathy in rats, in part reducing the cytotoxicity of bile and preventing NSAID-induced dysbiosis.


Caring touch--patients' experiences in an anthroposophic clinical context.
This study describes the phenomenon of caring touch from the patients' perspective in an anthroposophic clinical context where caring touch is often used to promote health and alleviate suffering. The aim of the study was to explore and phenomenologically describe the phenomenon of caring touch from the patients' perspectives. The study has been carried out with a Reflective Lifeworld Research approach in order to understand and describe human existential phenomena. Ten female patients were interviewed in an anthroposophic clinic in Sweden. The findings show how caring touch has multifaceted meanings and makes the patients' feel present and anchored in a meaningful context. The patients' feel that they are seen, accepted and confirmed. Furthermore, touch creates a caring space where the patients become receptive for care and has the power to alleviate the patients' suffering, as well as to frighten and cause or worsen the suffering. In order to take advantage of the caring potential, the patient needs to be invited to a respectful and sensitive form of touch. An interpersonal flexible space is necessary where the touch can be effective, and where a dynamic interplay can develop. In conclusion, caring touch is an opportunity for carers to support well-being and health. The carers need to approach their patients in both a sensitive and reflective way. A caring science perspective can serve as a help to further understand touch as a unique caring act.


Bradyarrhythmias in acute myocardial infarction: should thrombolysis lower the decision threshold for temporary pacing?
Both acute myocardial infarction and reperfusion therapy with thrombolytic agents may be associated with bradyarrhythmias, and there may be a case for 'prophylactic' insertion of a temporary pacing wire in selected patients. We describe 4 patients in whom clinical decisions had to be made concerning the appropriateness and timing of temporary pacing, and discuss the implications for modern guidelines on the indications for pacing in such a setting.


A noninvasive portable acoustic diagnostic system to differentiate ischemic from hemorrhagic stroke.
To determine if a noninvasive brain acoustic monitor can differentiate acoustic responses from "normal patients" and ischemic from hemorrhagic stroke patients. A laptop-sized passive acoustic monitoring system acquires arterial-pressure-generated signals during a 15-second monitoring session from sensors placed at the radial artery and on the fore-head. The arterial pulse waveform from the head is compared with that of the arterial waveform to generate the time-domain signal comparison. Frequency domain signals from each area are also compared. The study involved patients with diagnosis of first stroke who could be monitored within 12 hours of symptom onset and normal subjects who provided informed consent. Individuals with history of brain injury, stroke, or other brain disease were excluded. Twelve normal subjects and 6 ischemic stroke, 2 transient ischemic attack (TIA), and 3 hemorrhagic stroke patients were monitored. Frequency response analysis identified uniform frequency responses in normal subjects. The signal in ischemic stroke patients was characterized by a divergence of the radial and cranial frequency response between 10 and 50 Hz of 10 dB or greater. In intracerebral hemorrhage patients, a divergence was seen below 10 Hz but not in the band above 10 Hz. TIA patients were monitored after symptom resolution and showed a divergence <10 dB in both bands, similar to normal subjects. In a pilot study using a noninvasive monitor, the authors detected a potential to differentiate between normal subjects and those with cerebral ischemia or hemorrhage.


Gas bubbles in fossil amber as possible indicators of the major gas composition of ancient air.
Gases trapped in Miocene to Upper Cretaceous amber were released by gently crushing the amber under vacuum and were analyzed by quadrupole mass spectrometry. After discounting the possibility that the major gases N(2), O(2), and CO(2) underwent appreciable diffusion and diagenetic exchange with their surroundings or reaction with the amber, it has been concluded that in primary bubbles (gas released during initial breakage) these gases represent mainly original ancient air modified by the aerobic respiration of microorganisms. Values of N(2)/(CO(2) + O(2)) for each time period give consistent results despite varying O(2)/CO(2) ratios that presumably were due to varying degrees of respiration. This allows calculation of original oxygen concentrations, which, on the basis of these preliminary results, appear to have changed from greater than 30 percent O(2) during one part of the Late Cretaceous (between 75 and 95 million years ago) to 21 percent during the Eocene-Oligocene and for present-day samples, with possibly lower values during the Oligocene-Early Miocene. Variable O(2) levels over time in general confirm theoretical isotope-mass balance calculations and suggest that the atmosphere has evolved over Phanerozoic time.


Mass spectrometry-based protein footprinting characterizes the structures of oligomeric apolipoprotein E2, E3, and E4.
The three common isoforms of apolipoprotein E (ApoE) differ at two sites in their 299 amino acid sequence; these differences modulate the structure of ApoE to affect profoundly the isoform associations with disease. The ε4 allele in particular is strongly associated with Alzheimer's disease. The study of the structural effects of these mutation sites in aqueous media is hampered by the aggregation proclivity of each ApoE isoform. Hence, understanding the differences between isoforms has thus far relied on lower resolution biophysical measurements, mutagenesis, homology studies, and the use of truncated ApoE variants. In this study, we report two comparative studies of the ApoE family by using the mass spectrometry-based protein footprinting methods of FPOP and glycine ethyl ester (GEE) labeling. The first experiment examines the three full-length WT isoforms in their tetrameric state and finds that the overall structures are similar, with the exception of M108 in ApoE4 which is more solvent-accessible in this isoform than in ApoE2 and ApoE3. The second experiment provides clear evidence, from a comparison of the footprinting results of the wild-type proteins and a monomeric mutant, that several residues in regions 183-205 and 232-251 are involved in self-association.


A pharmacokinetic and dosing study of intravenous insulin-like growth factor-I and IGF-binding protein-3 complex to preterm infants.
In preterm infants, low levels of insulin like growth factor 1 (IGF-I) have been associated with impaired growth and retinopathy of prematurity. Our objective was to study safety and pharmacokinetics of i.v. administered rhIGF-I with its binding protein 3 (rhIGFBP-3) to preterm infants. At 3 d chronological age, an i.v. 3 h infusion of rhIGF-I/rhIGFBP-3 was administered followed by serial measurements of IGF-I and IGFBP-3. Infants were evaluated for physiologic safety measurements. The individual dose of rhIGF-I ranged from 1 to 12 microg/kg. The study was conducted at Queen Silvia Children's Hospital, Gothenburg, Sweden, between January and November 2007. Five patients (3 F) with mean (range) post menstrual age 27 wk (26-29) and birth weight 1022 g (810-1310) participated. IGF-I and IGFBP-3 levels before infusion were median (range) 18 (12-28) and 771 (651-1047) ng/mL, respectively. Immediately after study drug infusion, serum IGF-I and IGFBP-3 levels were 38 (25-59) and 838 (754-1182) ng/mL, respectively. Median (range) half-life for IGF-I and IGFBP-3 was 0.79 (0.59-1.42) and 0.87 (0.85-0.94) hours, respectively. Blood glucose, insulin, sodium, potassium, and physiologic safety measures were within normal ranges. The rhIGF-I/rhIGFBP-3 equimolar proportion was effective in increasing serum IGF-I levels and administration under these study conditions was safe and well tolerated.


Somatosensory stimulation to improve hand and upper limb function after stroke-a systematic review with meta-analyses.
Background Somatosensory stimulation may have a positive impact on recovery of motor function by maintaining cortical representation of the hand and acting to prime the motor system for movement. Objective Determine the efficacy of somatosensory stimulation on upper limb motor function after stroke. Methods Five electronic databases (MEDLINE, CINAHL, Embase, PEDro and OT Seeker) were searched from inception to October 2016. Included studies were English-language randomized controlled trials where a sensory intervention was applied below the elbow to improve upper limb motor control of adults after stroke. One outcome needed to measure arm function at an impairment or activity level. Study selection and quality assessment (using the PEDro scale) were independently conducted by two reviewers. Meta-analysis was completed where there was sufficient homogeneity between trials. Results Fifteen articles were included reporting data from 14 randomized controlled trials (627 participants). There was low-quality evidence from four trials that sensory electrical stimulation did not improve upper limb activity compared to placebo (SMD 0.4, 95%CI -0.07 to 0.87, I2 38%) and moderate-quality evidence from three trials that it did not improve motor impairment (MD 3.45 units, 95%CI -1.47 to 8.36, I2 35%). Low-quality evidence from two trials demonstrated that therapist-delivered sensory stimulation did not improve upper limb activity (SMD 0.25, 95%CI -0.20 to 0.69, I2 0%) compared to usual care. Conclusion Current low- to moderate-quality evidence suggests somatosensory stimulation is not effective in improving upper limb motor impairment or activity after stroke.


Fish oil ameliorates trimethylamine N-oxide-exacerbated glucose intolerance in high-fat diet-fed mice.
Trimethylamine N-oxide (TMAO), a component commonly present in seafood, has been found to have a harmful impact on glucose tolerance in high-fat diet (HFD)-fed mice. However, seafood also contains fish oil (FO), which has been shown to have beneficial effects on metabolism. Here, we investigated the effect of FO on TMAO-induced impaired glucose tolerance in HFD-fed mice. Male C57BL/6 mice were randomly assigned to the high fat (HF), TMAO, and fish oil groups. The HF group was fed a diet containing 25% fat, the TMAO group was fed the HFD plus 0.2% TMAO, and the FO group was fed the HFD plus 0.2% TMAO and 2% fish oil for 12 weeks. After 10 weeks of feeding, oral glucose tolerance tests were performed. Dietary FO improved the fasting glucose level, the fasting insulin level, HOMA-IR value, QUICKI score and ameliorated TMAO-induced exacerbated impaired glucose tolerance in HFD-fed mice. These effects were associated with the expression of genes related to the insulin signalling pathway, glycogen synthesis, gluconeogenesis, and glucose transport in peripheral tissues. Dietary fish oil also decreased TMAO-aggravated adipose tissue inflammation. Our results suggested that dietary FO ameliorated TMAO-induced impaired glucose tolerance, insulin signal transduction in peripheral tissue, and adipose tissue inflammation in HFD-fed mice.


HDAC6: physiological function and its selective inhibitors for cancer treatment.
Acetylation and deacetylation of histones are important in regulating gene expression and play a key role in modification of gene transcription. Specific HDACs isoforms can be regarded as a target for cancer therapy avoiding side-effects, HDAC6 with a unique physiological function and structure has become a hot issue recently. The unique isoform HDAC6 is involved in tumorigenesis, development and metastasis through tubulin, HSP90, invasin and ubiquitin-protein. Here we review the structure elements, biological function, and recent selective inhibitors of HDAC6, and study the structure-activity and structure-selectivity relationship.


Comparisons between anthropometric indices for predicting the metabolic syndrome in Japanese.
Most definitions of the metabolic syndrome (MS) employ waist circumference as an indicator of central obesity. However, several reports, mainly from Asia, argue that other indices, for example the waist/height ratio, are superior to waist circumference for identifying subjects with cardiovascular risk factors. We therefore investigated correlations between the predictive power of several anthropometric indices and risk factor accumulation (RFA) defined by the existence of two or more disorders among hypertension, dyslipidemia (high triglycerides and/or low levels of high density lipoprotein cholesterol) and fasting hyperglycemia; each of which is a component of MS. We conducted a cross-sectional analysis using data from a part of the Japan Public Health Center-based Cohort. A total of 315 men and 314 women, 51 to 70 years of age were examined for variables including waist and hip circumferences, blood pressure, fasting plasma glucose and lipids at an annual health check-up. The prevalence of RFA increased almost linearly in parallel with increasing waist circumference up to 95 cm. Receiver operating characteristic analysis demonstrated that waist circumference was better than waist/ height ratio, waist/hip ratio and BMI at predicting RFA; but the differences were not statistically significant. However, even in the case of waist circumference, no clear cut-off point yields sufficiently high sensitivity and specificity simultaneously. The predictive power of waist circumference was not inferior to those of other indices. Therefore, waist circumference is practically the most convenient measure for predicting MS because of its simplicity.


A robust multiscale B-spline function decomposition for estimating motion transparency.
Motion transparency phenomena in image sequences are frequent, but classical methods of motion estimation are unable to deal with them. This paper describes a method for estimating optical flow by a generalization of the brightness constancy assumption to additive transparencies. The brightness constancy assumption is obtained by setting constant velocity fields during three images of a sequence. Thus, by a Taylor development to its second order, we reach an extension of the optical flow constraint equation. Since the equation is nonlinear, the Levenberg-Marquardt algorithm is used. In order to suppress the unavoidable aperture problem, a global model based on B-spline basis functions is applied with the aim of constraining optical flows. This description of motion allows us to work on a coarse to fine estimation of artificial image sequences that shows good convergence properties. It is also applied to natural image sequences.


Outcomes With Ultrafiltration Among Hospitalized Patients With Acute Heart Failure (from the National Inpatient Sample).
Acute heart failure (HF) management is a complex and often involves a delicate balance of both cardiac and renal systems. Although pharmacologic diuresis is a mainstay of the pharmacologic management of decompensated HF, ultrafiltration (UF) represents a nonpharmacologic approach in the setting of diuretic resistance. We conducted a cross-sectional analysis of the 2009 through 2014 hospitalization data from the National Inpatient Sample. The study population consisted of hospitalizations with a discharge Diagnosis Related Groups of HF who were older than 18 years of age, did not have end-stage kidney disease, acute kidney injury and had not undergone hemodialysis or hemofiltration. There were 6,174 hospitalizations which included UF among the 7,799,915 hospitalizations for HF. Hospitalizations which included UF were among patients significantly younger in age (68.1 ± 1.0 vs 73.8 ± 0.1 years), male (61.9% vs 47.7%), and with higher prevalence of co-morbid conditions including chronic kidney disease (58% vs 31%), diabetes mellitus (53% vs 42%), and higher rates of co-morbidity (Charlson comorbidity score ≥2, 92% vs 80%). All-cause mortality was significantly higher among hospitalizations which included an UF (4.68% vs 2.24%). Hospitalizations with UF had a longer mean length of stay (6.2 vs 4.3 days, p <0.01) average total charges ($42,035 vs 24,867 USD, p <0.01) as compared with those without UF. Hospitalizations with UF were associated with a greater adjusted odds of all-cause mortality (odds ratio: 3.36, [95% confidence interval 1.76,6.40]), greater than DRG-level target length of stay (odds ratio, 2.46; [95 confidence interval 1.65,3.67]), and a 72% increase in the average hospital charges. In conclusion, hospitalizations which included UF identified a subgroup of HF patients with more co-morbid conditions who are at higher risk of mortality and increased resource burden in terms of length of stay and costs. These findings also highlight that the need for UF may identify patients who are most likely to benefit from a multidisciplinary cardiorenal approach to alter the trajectory of their disease.


Neutrophil Immunomodulatory Activity of Nerolidol, a Major Component of Essential Oils from Populus balsamifera Buds and Propolis.
Propolis is a resinous mixture of substances collected and processed from various botanical sources by honeybees. Black poplar (Populus balsamifera L.) buds are one of the primary sources of propolis. Despite their reported therapeutic properties, little is known about the innate immunomodulatory activity of essential oils from P. balsamifera and propolis. In the present studies, essential oils were isolated from the buds of P. balsamifera and propolis collected in Montana. The main components of the essential oil from P. balsamifera were E-nerolidol (64.0%), 1,8-cineole (10.8%), benzyl benzoate (3.7%), α-terpinyl acetate (2.7%), α-pinene (1.8%), o-methyl anisol (1.8%), salicylaldehyde (1.8%), and benzyl salicylate (1.6%). Likewise, the essential oil from propolis was enriched with E-nerolidol (14.4%), cabreuva oxide-VI (7.9%), α-bisabolol (7.1%), benzyl benzoate (6.1%), β-eudesmol (3.6%), T-cadinol (3.1%), 2-methyl-3-buten-2-ol (3.1%), α-eudesmol (3.0%), fokienol (2.2%), nerolidol oxide derivative (1.9%), decanal (1.8%), 3-butenyl benzene (1.5%), 1,4-dihydronaphthalene (1.5%), selina-4,11-diene (1.5%), α-cadinol (1.5%), linalool (1.4%), γ-cadinene (1.4%), 2-phenylethyl-2-methyl butyrate (1.4%), 2-methyl-2-butenol (1.3%), octanal (1.1%), benzylacetone (1.1%), and eremoligenol (1.1%). A comparison between P. balsamifera and propolis essential oils demonstrated that 22 compounds were found in both essential oil samples. Both were enriched in E-nerolidol and its derivatives, including cabreuva oxide VI and nerolidol oxides. P. balsamifera and propolis essential oils and pure nerolidol activated Ca2+ influx in human neutrophils. Since these treatments activated neutrophils, the essential oil samples were also evaluated for their ability to down-regulate the neutrophil responses to subsequent agonist activation. Indeed, treatment with P. balsamifera and propolis essential oils inhibited subsequent activation of these cells by the N-formyl peptide receptor 1 (FPR1) agonist fMLF and the FPR2 agonist WKYMVM. Likewise, nerolidol inhibited human neutrophil activation induced by fMLF (IC50 = 4.0 μM) and WKYMVM (IC50 = 3.7 μM). Pretreatment with the essential oils and nerolidol also inhibited human neutrophil chemotaxis induced by fMLF, again suggesting that these treatments down-regulated human neutrophil responses to inflammatory chemoattractants. Finally, reverse pharmacophore mapping predicted several potential kinase targets for nerolidol. Thus, our studies have identified nerolidol as a potential anti-inflammatory modulator of human neutrophils.


Nitric oxide specifically reduces the permeability of Cx37-containing gap junctions to small molecules.
Gap junction intercellular communication (GJIC) plays a significant role in the vascular system. Regulation of GJIC is a dynamic process, with alterations in connexin (Cx) protein expression and post-translational modification as contributing mechanisms. We hypothesized that the endothelial autacoid nitric oxide (NO) would reduce dye coupling in human umbilical vein endothelial cells (HUVECs). In our subsequent experiments, we sought to isolate the specific Cx isoform(s) targeted by NO or NO-activated signaling pathways. Since HUVEC cells variably express three Cx (Cx37, Cx40, and Cx43), this latter aim required the use of transfected HeLa cells (HeLaCx37, HeLaCx43), which do not express Cx proteins in their wild type form. Dye coupling was measured by injecting fluorescent dye (e.g., Alexa Fluor 488) into a single cell and determining the number of stained adjacent cells. Application of the NO donor SNAP (2 microM, 20 min) reduced dye coupling in HUVEC by 30%. In HeLa cells, SNAP did not reduce dye transfer of cells expressing Cx43, but decreased the dye transfer from Cx37-expressing cells to Cx43-expressing cells by 76%. The effect of SNAP on dye coupling was not mediated via cGMP. In contrast to its effect on dye coupling, SNAP had no effect on electrical coupling, measured by a double patch clamp in whole cell mode. Our results demonstrate that NO inhibits the intercellular transfer of small molecules by a specific influence on Cx37, suggesting a potential role of NO in controlling certain aspects of vascular GJIC.


Evaluation of the resistance of transgenic potato plants expressing various levels of Cry3A against the Colorado potato beetle (Leptinotarsa decemlineata Say) in the laboratory and field.
The Colorado potato beetle (CPB), Leptinotarsa decemlineata Say, is a destructive pest. The CPB is a quarantine pest in China, but has now invaded the Xinjiang Uygur Autonomous Region and is continuing to spread eastwards. To control the damage and overspreading, transgenic potato plants expressing Cry3A toxin were developed, and their resistance to CPB was evaluated by bioassays in the laboratory and field in 2009, 2010 and 2011. The insect resistance of the high-dose (HD) transgenic lines was significantly greater than the middle-dose (MD) and low-dose (LD) transgenic lines regarding leaf consumption, biomass accumulation and mortality. The HD and MD transgenic lines showed 100% mortality when inoculated with first- and second-instar larvae; however, the LD transgenic lines showed about 50% mortality. The HD transgenic lines exhibited a significantly higher yield than the MD and LD transgenic lines owing to their high CPB resistance. Commercially available transgenic potato plants with above 0.1% Cry3A of total soluble protein and NT control refugia could control damage, delay adaptation and halt dispersion eastwards. The two HD transgenic lines developed in this study, PAH1 and PAH2, are ideal for use as cultivars or germplasm to breed new cultivars.


FtsZ fiber bundling is triggered by a conformational change in bound GTP.
Polymer formation by the essential FtsZ protein plays a crucial role in the cytokinesis of most prokaryotes. Lateral associations between these FtsZ polymers to form bundles or sheets are widely predicted to be extremely important for FtsZ function in vivo. We have carried out a study in vitro of FtsZ polymer formation and bundling using linear dichroism (LD) to assess structural properties of the polymers. We demonstrate proof-of-principle experiments to show that LD can be used as a technique to follow FtsZ polymerization, and we present the LD spectra of FtsZ polymers. Our subsequent examination of FtsZ polymer bundling induced by calcium reveals a substantial increase in the LD signal indicative of increased polymer length and rigidity. We also detect a specific conformational change in the guanine moiety associated with bundling, whereas the conformation and configuration of the FtsZ monomers within the polymer remain largely unchanged. We demonstrate that other divalent cations can induce this conformational change in FtsZ-bound GTP coincident with polymer bundling. Therefore, we present "flipping" of the guanine moiety in FtsZ-bound GTP as a mechanism that explains the link between reduced GTPase activity, increased polymer stability, and polymer bundling.


Effect of pegylated interferon therapy on intrahepatic recurrence after curative treatment of hepatitis C virus-related hepatocellular carcinoma.
We wished to determine whether pegylated interferon (PEG-IFN) therapy after curative treatment of hepatocellular carcinoma (HCC) prevents a recurrence of HCC. Thirty-seven HCC patients with hepatitis C virus (HCV) infection who were treated with PEG-IFN after curative treatment (PEG-IFN group) and 145 controls without IFN therapy (non-IFN group) were enrolled. The overall survival and recurrence-free survival rates were compared between the groups, and the predisposing factors for recurrence and survival were analyzed. The rates were also examined by propensity score (PS) matched analysis that could minimize selection biases. The median follow-up period was 3.7 years. The 5-year survival rate in the PEG-IFN group (91%) was significantly higher than that in the non-IFN group (56%; P < 0.01). The rate of the second recurrence but not that of the first recurrence of HCC in the sustained virological responder (SVR) group was lower than that in the non-IFN group (P = 0.03). Improvement of survival by PEG-IFN and low rate of second recurrence in the SVR group were also observed in PS matched analysis. Multivariate analysis revealed that PEG-IFN therapy and high serum albumin were good prognostic factors for survival. Although low serum albumin and large and multiple tumors were risk factors for the first recurrence, non-SVR and low serum albumin were risk factors for the second recurrence. PEG-IFN-therapy after curative treatment of HCC improved the rate of survival, and SVR was found to be closely correlated with the prevention of recurrence.


Biological variability of albumin excretion rate and albumin-to-creatinine ratio in hypertensive type 2 diabetic patients.
The importance of measuring microalbuminuria is well established. However, only scanty data are available concerning the biological variability of albumin excretion in type 2 diabetic subjects. We report our experience from a large clinical trial of a new antihypertensive drug (Lercanidipine) designed to reduce albumin excretion and blood pressure in type 2 diabetic patients with hypertension and microalbuminuria. Eighty seven patients with persistent microalbuminuria were studied within 1 year of the clinical trial. The measurements were performed on blood and timed urine samples frozen at -80 degrees C and shipped to a central laboratory unit. Preliminary experiments were performed to assess albumin stability in urine under various conditions (4 degrees C, -20 degrees C and -80 degrees C), particularly with regard to the albumin/creatinine ratio. Urine samples can be stored up to 3 weeks at 4 degrees C or up to 2 months at -80 degrees C. The biological variability of the albumin excretion rate was 25.7%, while that of the albumin/creatinine ratio was 13.4%. These data are useful in defining the analytical goals of imprecision for microalbuminuria (CV = 13% for albumin, and CV = 6% for albumin/creatinine ratio). No correlation between albumin/creatinine ratio and HbA1c was found in the cohort of 61 microalbuminuric patients who completed the trial. The results of this study confirm that the albumin/ creatinine ratio is much more suitable for monitoring albumin excretion in longitudinal studies than the albumin excretion rate.


G0 function of BCL2 and BCL-xL requires BAX, BAK, and p27 phosphorylation by Mirk, revealing a novel role of BAX and BAK in quiescence regulation.
BCL2 and BCL-x(L) facilitate G(0) quiescence by decreasing RNA content and cell size and up-regulating p27 protein, but the precise mechanism is not understood. We investigated the relationship between cell cycle regulation and the anti-apoptosis function of BCL2 and BCL-x(L). Neither caspase inhibition nor abrogation of mitochondria-dependent apoptosis by BAX and BAK deletion fully recapitulated the G(0) effects of BCL2 or BCL-x(L), suggesting that mechanisms in addition to anti-apoptosis are involved in the cell cycle arrest function of BCL2 or BCL-x(L). We found that BCL2 and BCL-x(L) expression in bax(-/-) bak(-/-) cells did not confer cell cycle effects, consistent with the G(0) function of BCL2 and BCL-x(L) being mediated through BAX or BAK. Stabilization of p27 in G(0) in BCL2 or BCL-x(L) cells was due to phosphorylation of p27 at Ser(10) by the kinase Mirk. In bax(-/-) bak(-/-) cells, total p27 and p27 phosphorylated at Ser(10) were elevated. Re-expression of BAX in bax(-/-) bak(-/-) cells and silencing of BAX and BAK in wild type cells confirmed that endogenous BAX and BAK modulated p27. These data revealed a novel role for BAX and BAK in the regulation of G(0) quiescence.


"If only had I known": a qualitative study investigating a treatment of patients with a hip fracture with short time stay in hospital.
Hip fractures are amongst the leading causes of admission to an orthopaedic ward. Systematized pathways with reduced admission time have become increasingly common as an essential tool for quality development and to improve efficiency in the hospital setting. The aim of this study was to clarify if the patients feel empowered and able to perform self-care after short time stay in hospital (STSH) due to a hip fracture. The study used descriptive phenomenology to describe experiences of the pathway. Field studies were conducted in hospitals and in the patients' homes. Interviews were performed with 10 patients recruited from two wards at a Danish University hospital, 4 family members and 15 health professionals from three hospitals. The open attitude of reflective lifeworld research guided the analysis. The findings revealed that patients felt unprepared and insecure about their future, but also had a strong desire to be in charge of their own lives. Of all the patients interviewed, none had any recollection of the information given to them by health professionals during their hospital admission. This study demonstrates that empowerment of patients with hip fractures is not adequately achieved in the pathway with STSH.


Prediction of Novel Inhibitors of the Main Protease (M-pro) of SARS-CoV-2 through Consensus Docking and Drug Reposition.
Since the outbreak of the COVID-19 pandemic in December 2019 and its rapid spread worldwide, the scientific community has been under pressure to react and make progress in the development of an effective treatment against the virus responsible for the disease. Here, we implement an original virtual screening (VS) protocol for repositioning approved drugs in order to predict which of them could inhibit the main protease of the virus (M-pro), a key target for antiviral drugs given its essential role in the virus' replication. Two different libraries of approved drugs were docked against the structure of M-pro using Glide, FRED and AutoDock Vina, and only the equivalent high affinity binding modes predicted simultaneously by the three docking programs were considered to correspond to bioactive poses. In this way, we took advantage of the three sampling algorithms to generate hypothetic binding modes without relying on a single scoring function to rank the results. Seven possible SARS-CoV-2 M-pro inhibitors were predicted using this approach: Perampanel, Carprofen, Celecoxib, Alprazolam, Trovafloxacin, Sarafloxacin and ethyl biscoumacetate. Carprofen and Celecoxib have been selected by the COVID Moonshot initiative for in vitro testing; they show 3.97 and 11.90% M-pro inhibition at 50 µM, respectively.


Prevalences of diabetes and impaired glucose regulation in a Danish population: the Inter99 study.
To determine the age- and sex-specific prevalence of impaired fasting glycemia, impaired glucose tolerance, screen-detected diabetes, and known diabetes in a Danish population aged 30-60 years and to examine the phenotype and the cardiovascular risk profile in individuals with impaired glucose regulation. In the Inter99 study, 13,016 inhabitants living in Copenhagen County were invited. All participants underwent anthropometric measurements, blood samples, and a 75-g standardized oral glucose tolerance test. The age-specific prevalences in men were as follows: impaired fasting glycemia: 1.4-16.3%; impaired glucose tolerance: 6.9-17.8%; screen-detected diabetes: 0.7-9.7%; and known diabetes: 0-5.8%. The corresponding figures in women were 0-5.1, 10.5-17.3, 0.6-6.3, and 0.5-9%. The prevalence of impaired glucose regulation increased with age. Among individuals with diabetes, 65.6% were previously undiagnosed; this proportion was highest in the youngest age-group (82% among 45-year-old men vs. 63% among 60-year-old men, and 70% among 45-year-old women vs. 52% among 60-year-old women). Mean BMI, waist, HbA(1c), systolic blood pressure, diastolic blood pressure, and total cholesterol were significantly higher (P < 0.0001) in the individuals with impaired glucose regulation compared with individuals with normal glucose tolerance. This study revealed that the prevalence of type 2 diabetes is high and that still two out of three individuals are undiagnosed, indicating a need for more attention to the disease in society.


A novel approach to monitor glucose metabolism using stable isotopically labelled glucose in longitudinal studies in mice.
The aetiology of insulin resistance is still an enigma. Mouse models are frequently employed to study the underlying pathology. The most commonly used methods to monitor insulin resistance are the HOMA-IR, glucose or insulin tolerance tests and the hyperinsulinemic euglycaemic clamp (HIEC). Unfortunately, these tests disturb steady state glucose metabolism. Here we describe a method in which blood glucose kinetics can be determined in fasted mice without noticeably perturbing glucose homeostasis. The method involves an intraperitoneal injection of a trace amount of [6,6-(2)H2]glucose and can be performed repeatedly in individual mice. The validity and performance of this novel method was tested in mice fed on chow or high-fat diet for a period of five weeks. After administering the mice with [6,6-(2)H2]glucose, decay of the glucose label was followed in small volumes of blood collected by tail tip bleeding during a 90-minute period. The total amount of blood collected was less than 120 μL. This novel approach confirmed in detail the well-known increase in insulin resistance induced by a high-fat diet. The mice showed reduced glucose clearance rate, and reduced hepatic and peripheral insulin sensitivity. To compensate for this insulin resistance, β-cell function was slightly increased. We conclude that this refinement of existing methods enables detailed information of glucose homeostasis in mice. Insulin resistance can be accurately determined while mechanistic insight is obtained in underlying pathology. In addition, this novel approach reduces the number of mice needed for longitudinal studies of insulin sensitivity and glucose metabolism.


Synovial sarcoma of the hand.
Synovial sarcoma of the hand is a very rate tumor in an equally unusual location with a difficult histology of a fibrosarcoma combined with synovial-like areas that resemble joint endothelial lining. It has a poor prognosis prior to the current combined treatment of surgical ablation, radiation to the surgical field, and chemotherapy for microscopic metastases. It has an unexplained natural history of very late recurrence and distant spread, often 10 to 20 years following primary treatment.


Homozygosity for a missense mutation in the 67 kDa isoform of glutamate decarboxylase in a family with autosomal recessive spastic cerebral palsy: parallels with Stiff-Person Syndrome and other movement disorders.
Cerebral palsy (CP) is an heterogeneous group of neurological disorders of movement and/or posture, with an estimated incidence of 1 in 1000 live births. Non-progressive forms of symmetrical, spastic CP have been identified, which show a Mendelian autosomal recessive pattern of inheritance. We recently described the mapping of a recessive spastic CP locus to a 5 cM chromosomal region located at 2q24-31.1, in rare consanguineous families. Here we present data that refine this locus to a 0.5 cM region, flanked by the microsatellite markers D2S2345 and D2S326. The minimal region contains the candidate gene GAD1, which encodes a glutamate decarboxylase isoform (GAD67), involved in conversion of the amino acid and excitatory neurotransmitter glutamate to the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). A novel amino acid mis-sense mutation in GAD67 was detected, which segregated with CP in affected individuals. This result is interesting because auto-antibodies to GAD67 and the more widely studied GAD65 homologue encoded by the GAD2 gene, are described in patients with Stiff-Person Syndrome (SPS), epilepsy, cerebellar ataxia and Batten disease. Further investigation seems merited of the possibility that variation in the GAD1 sequence, potentially affecting glutamate/GABA ratios, may underlie this form of spastic CP, given the presence of anti-GAD antibodies in SPS and the recognised excitotoxicity of glutamate in various contexts.


Immunohistochemical expression of SALL4 in hepatocellular carcinoma, a potential pitfall in the differential diagnosis of yolk sac tumors.
SALL4 is a transcription factor that serves as a marker of yolk sac tumor. Yolk sac tumor and hepatocellular carcinoma share histologic, serologic, and immunohistochemical features. Previous studies have shown lack of SALL4 expression in hepatocellular carcinoma, suggesting utility in this differential diagnosis. Sixty-nine samples of hepatocellular carcinoma were retrieved from surgical pathology archives and used to construct 9 tissue microarrays. A germ cell tumor tissue microarray containing 10 yolk sac tumors was used for comparison. Extent, intensity, and pattern of nuclear SALL4 expression were assessed in each spot. Mean percentage of expression was calculated for each tumor and used during analysis. Optimal discriminatory extent of expression cutoff was determined by receiver operating characteristic curve analysis. Other potential discriminatory markers including Hep Par1 were also evaluated. Forty-six percent (32/69) of hepatocellular carcinoma and all yolk sac tumors revealed at least focal expression of SALL4. A unique punctuate/clumped pattern of nuclear staining was present in 94% (30/32) of hepatocellular carcinoma, whereas all yolk sac tumors displayed a diffuse finely granular nuclear staining pattern. A 25% extent of SALL4 expression cutoff was found to be optimal for the distinction of yolk sac tumor from hepatocellular carcinoma yielding a sensitivity of 100%, specificity of 92.8%, and a positive predictive value of 66.6% for yolk sac tumor diagnosis. The addition of Hep Par1 increased the specificity (99%) and positive predictive value (90%). This is the first report of SALL4 expression in hepatocellular carcinoma. Our finding should be taken into consideration in the differential diagnosis of hepatocellular carcinoma and yolk sac tumor. The unique punctuate/clumped pattern seen in hepatocellular carcinoma cases could be of further discriminatory value.


Potassium currents in human myogenic cells from healthy and congenital myotonic dystrophy foetuses.
The whole-cell patch clamp technique was used to record potassium currents in in vitro differentiating myoblasts isolated from healthy and myotonic dystrophy type 1 (DM1) foetuses carrying 2000 CTG repeats. The fusion of the DM1 myoblasts was reduced in comparison to that of the control cells. The dystrophic muscle cells expressed less voltage-activated K(+) (delayed rectifier and non-inactivating delayed rectifier) and inward rectifier channels than the age-matched control cells. However, the resting membrane potential was not significantly different between the control and the DM1 cells. After four days in a differentiation medium, the dystrophic cells expressed the fast-inactivating transient outward K(+) channels, which were not observed in healthy cells. We suggest that the low level of potassium currents measured in differentiated DM1 cells could be related to their impaired fusion.


What are the dangers of biological therapy discontinuation or dose reduction strategies when treating rheumatoid arthritis?
Treatment with biological DMARDs (bDMARDs) has meant that remission or low disease activity (LDA) is now a realistic goal for patients with rheumatoid arthritis (RA). However, as in the case of all long-term therapies, potential side-effects give rise to concern. The main reasons for withdrawing or tapering bDMARDs are safety and the sustainability of national healthcare systems. Given these data our review has been focused on important question: whether conventional, including steroids, or bDMARDs can be reduced or even stopped in patients with stable established RA or early RA. Areas covered: The studies included in the evaluation had to be RCTs, observational studies, systematic reviews evaluating the withdrawing or tapering bDMARDs in RA patients who have been on long-term treatment and have achieved remission or LDA. A search was made in the MEDLINE and EMBASE databases from 1980 to May 2016. Expert commentary: There is curently no standardised way of identifying the patients for whom reducing bDMARD therapy is appropriate. Clinical experience and data from de-escalation studies suggest that patients with RA in sustained remission are the best target population for studying drug-tapering regimens, and that LDA should not be considered an adequate indication for bDMARD de-escalation because it could hide a persistent amount of inflammation.


Multi-variate model of T cell clonotype competition and homeostasis.
Diversity of the naive T cell repertoire is maintained by competition for stimuli provided by self-peptides bound to major histocompatibility complexes (self-pMHCs). We extend an existing bi-variate competition model to a multi-variate model of the dynamics of multiple T cell clonotypes which share stimuli. In order to understand the late-time behaviour of the system, we analyse: (i) the dynamics until the extinction of the first clonotype, (ii) the time to the first extinction event, (iii) the probability of extinction of each clonotype, and (iv) the size of the surviving clonotypes when the first extinction event takes place. We also find the probability distribution of the number of cell divisions per clonotype before its extinction. The mean size of a new clonotype at quasi-steady state is an increasing function of the stimulus available to it, and a decreasing function of the fraction of stimuli it shares with other clonotypes. Thus, the probability of, and time to, extinction of a new clonotype entering the pool of T cell clonotypes is determined by the extent of competition for stimuli it experiences and by its initial number of cells.


The effect of population bottlenecks on mutation rate evolution in asexual populations.
In the absence of recombination, a mutator allele can spread through a population by hitchhiking with beneficial mutations that appear in its genetic background. Theoretical studies over the past decade have shown that the survival and fixation probability of beneficial mutations can be severely reduced by population size bottlenecks. Here, we use computational modelling and evolution experiments with the yeast S. cerevisiae to examine whether population bottlenecks can affect mutator dynamics in adapting asexual populations. In simulation, we show that population bottlenecks can inhibit mutator hitchhiking with beneficial mutations and are most effective at lower beneficial mutation supply rates. We then subjected experimental populations of yeast propagated at the same effective population size to three different bottleneck regimes and observed that the speed of mutator hitchhiking was significantly slower at smaller bottlenecks, consistent with our theoretical expectations. Our results, thus, suggest that bottlenecks can be an important factor in mutation rate evolution and can in certain circumstances act to stabilize or, at least, delay the progressive elevation of mutation rates in asexual populations. Additionally, our findings provide the first experimental support for the theoretically postulated effect of population bottlenecks on beneficial mutations and demonstrate the usefulness of studying mutator frequency dynamics for understanding the underlying dynamics of fitness-affecting mutations.


Detection and quantification of adulteration in sandalwood oil through near infrared spectroscopy.
The confirmation of authenticity of essential oils and the detection of adulteration are problems of increasing importance in the perfumes, pharmaceutical, flavor and fragrance industries. This is especially true for 'value added' products like sandalwood oil. A methodical study is conducted here to demonstrate the potential use of Near Infrared (NIR) spectroscopy along with multivariate calibration models like principal component regression (PCR) and partial least square regression (PLSR) as rapid analytical techniques for the qualitative and quantitative determination of adulterants in sandalwood oil. After suitable pre-processing of the NIR raw spectral data, the models are built-up by cross-validation. The lowest Root Mean Square Error of Cross-Validation and Calibration (RMSECV and RMSEC % v/v) are used as a decision supporting system to fix the optimal number of factors. The coefficient of determination (R(2)) and the Root Mean Square Error of Prediction (RMSEP % v/v) in the prediction sets are used as the evaluation parameters (R(2) = 0.9999 and RMSEP = 0.01355). The overall result leads to the conclusion that NIR spectroscopy with chemometric techniques could be successfully used as a rapid, simple, instant and non-destructive method for the detection of adulterants, even 1% of the low-grade oils, in the high quality form of sandalwood oil.


Albumin-mediated selenium transfer by a selenotrisulfide relay mechanism.
In this study, we demonstrated a human serum albumin (HSA)-mediated selenium transfer; the selenium exported from red blood cells (RBCs) was bound to HSA through the selenotrisulfide and then transferred into the hepatocyte. After the treatment of the RBCs with selenite, the selenium efflux from the RBCs occurred in an HSA concentration-dependent manner. Pretreatment of HSA with iodoacetamide almost completely inhibited the selenium efflux from the RBC to the HSA solution. The selenium efflux experiment was carried out in an HSA solution (45 mg/mL), and subsequently the HSA solution was subjected to gel permeation chromatographic separation. The peak fraction of the selenium content was consistent with that of the HSA. The selenium bound to HSA in this solution was completely eliminated by a treatment with penicillamine (Pen), which resulted in the generation of penicillamine selenotrisulfide, PenSSeSPen. The selenium efflux from the RBCs was also occurred in a Pen solution, and PenSSeSPen was observed in the resulting Pen solution. The selenium exported from the RBC was thought to bind to the HSA via a selenotrisulfide linkage with its single free thiol. A model of the selenium-bound HSA was prepared by the reaction of the HSA with PenSSeSPen. The selenium from PenSSeSPen can bind to HSA by a thiol exchange between Pen and the free thiol of HSA, which produces the selenotrisulfide-containing HSA (HSA-SSeSPen). When HSA-SSeSPen was incubated with isolated rat hepatocytes, the selenium content in the hepatocytes increased along with its decrease in the incubation medium. To verify the results from the model experiments using HSA-SSeSPen, we conducted the HSA-mediated selenium transfer experiment from RBC treated with selenite to the hepatocytes. The selenotrisulfide-containing HSA was able to transport the selenium into the hepatocyte. Overall, the selenium transfer from the RBC to the hepatocytes involves a relay mechanism of thiol exchange that occurs between the selenotrisulfide and thiol compounds (selenotrisulfide relay mechanism: R-SSeS-R + HSA-SH --> HSA-SSeS-R + R'-SH --> R-SSeS-R').


Leukocytosis and enhanced susceptibility to endotoxemia but not atherosclerosis in adrenalectomized APOE knockout mice.
Hyperlipidemic apolipoprotein E (APOE) knockout mice show an enhanced level of adrenal-derived anti-inflammatory glucocorticoids. Here we determined in APOE knockout mice the impact of total removal of adrenal function through adrenalectomy (ADX) on two inflammation-associated pathologies, endotoxemia and atherosclerosis. ADX mice exhibited 91% decreased corticosterone levels (P<0.001), leukocytosis (WBC count: 10.0 ± 0.4 x 10E9/L vs 6.5 ± 0.5 x 10E9/L; P<0.001) and an increased spleen weight (P<0.01). FACS analysis on blood leukocytes revealed increased B-lymphocyte numbers (55 ± 2% vs 46 ± 1%; P<0.01). T-cell populations in blood appeared to be more immature (CD62L+: 26 ± 2% vs 19 ± 1% for CD4+ T-cells, P<0.001 and 58 ± 7% vs 47 ± 4% for CD8+ T-cells, P<0.05), which coincided with immature CD4/CD8 double positive thymocyte enrichment. Exposure to lipopolysaccharide failed to increase corticosterone levels in ADX mice and was associated with a 3-fold higher (P<0.05) TNF-alpha response. In contrast, the development of initial fatty streak lesions and progression to advanced collagen-containing atherosclerotic lesions was unaffected. Plasma cholesterol levels were decreased by 35% (P<0.001) in ADX mice. This could be attributed to a decrease in pro-atherogenic very-low-density lipoproteins (VLDL) as a result of a diminished hepatic VLDL secretion rate (-24%; P<0.05). In conclusion, our studies show that adrenalectomy induces leukocytosis and enhances the susceptibility for endotoxemia in APOE knockout mice. The adrenalectomy-associated rise in white blood cells, however, does not alter atherosclerotic lesion development probably due to the parallel decrease in plasma levels of pro-atherogenic lipoproteins.


Boreal feather mosses secrete chemical signals to gain nitrogen.
The mechanistic basis of feather moss-cyanobacteria associations, a main driver of nitrogen (N) input into boreal forests, remains unknown. Here, we studied colonization by Nostoc sp. on two feather mosses that form these associations (Pleurozium schreberi and Hylocomium splendens) and two acrocarpous mosses that do not (Dicranum polysetum and Polytrichum commune). We also determined how N availability and moss reproductive stage affects colonization, and measured N transfer from cyanobacteria to mosses. The ability of mosses to induce differentiation of cyanobacterial hormogonia, and of hormogonia to then colonize mosses and re-establish a functional symbiosis was determined through microcosm experiments, microscopy and acetylene reduction assays. Nitrogen transfer between cyanobacteria and Pleurozium schreberi was monitored by secondary ion mass spectrometry (SIMS). All mosses induced hormogonia differentiation but only feather mosses were subsequently colonized. Colonization on Pleurozium schreberi was enhanced during the moss reproductive phase but impaired by elevated N. Transfer of N from cyanobacteria to their host moss was observed. Our results reveal that feather mosses likely secrete species-specific chemo-attractants when N-limited, which guide cyanobacteria towards them and from which they gain N. We conclude that this signalling is regulated by N demands of mosses, and serves as a control of N input into boreal forests.


Visual impairment due to undiagnosed refractive error in working age adults in Britain.
Detection and treatment of undiagnosed refractive error (RE), with its attendant functional consequences, is a priority of VISION 2020, the global initiative against avoidable visual disability. The authors investigated the frequency of visual impairment due to undiagnosed RE and its associations with vision-related quality of life (VRQOL), general health and social circumstances in a contemporary and nationally representative population of British working-age adults. 9271 members of the 1958 British birth cohort had visual acuity and VRQOL assessed at 44/45 years. The authors compared those with undiagnosed RE with those with diagnosed RE, defining undiagnosed RE as >or=0.2 logMAR units/2 lines acuity improvement in both eyes with pinhole in individuals without current or prior optical treatment or ophthalmic history. 144/9271 (1.6%) individuals had undiagnosed and 3513/9271 (37.9%) diagnosed RE. 18% (24/144) of those with undiagnosed RE were classifiable as visually impaired. Individuals with undiagnosed RE were more likely to have a manual (vs non-manual) occupation and to be separated, divorced or widowed, and less likely to be in social or professional organisations. There is also some evidence that they are more likely to express concern, embarrassment and frustration about their eyesight and worry about coping with life. A significant proportion of working age adults in Britain appear to have undiagnosed but visually significant RE. Improvements in existing opportunities for detecting RE in adults could benefit these individuals during their working lives and avoid the serious adverse consequences associated with vision impairment in later life.


A manipulation of carotenoid metabolism influence biomass partitioning and fitness in tomato.
Improving yield, nutritional value and tolerance to abiotic stress are major targets of current breeding and biotechnological approaches that aim at increasing crop production and ensuring food security. Metabolic engineering of carotenoids, the precursor of vitamin-A and plant hormones that regulate plant growth and response to adverse growth conditions, has been mainly focusing on provitamin A biofortification or the production of high-value carotenoids. Here, we show that the introduction of a single gene of the carotenoid biosynthetic pathway in different tomato cultivars induced profound metabolic alterations in carotenoid, apocarotenoid and phytohormones pathways. Alterations in isoprenoid- (abscisic acid, gibberellins, cytokinins) and non-isoprenoid (auxin and jasmonic acid) derived hormones together with enhanced xanthophyll content influenced biomass partitioning and abiotic stress tolerance (high light, salt, and drought), and it caused an up to 77% fruit yield increase and enhanced fruit's provitamin A content. In addition, metabolic and hormonal changes led to accumulation of key primary metabolites (e.g. osmoprotectants and antiaging agents) contributing with enhanced abiotic stress tolerance and fruit shelf life. Our findings pave the way for developing a new generation of crops that combine high productivity and increased nutritional value with the capability to cope with climate change-related environmental challenges.


PLANETARY SCIENCE: Saturn Wins Satellite Title With New Moons.
This week an international team of astronomers announced the discovery of four new moons of Saturn, restoring the ringed planet to its status as commander of the largest retinue of satellites in the solar system. Their appearance should help researchers understand not just how the new moons were formed but also how the giant planets themselves came to be.


[Quality assurance and review in general practice].
Local procedures for quality assurance are needed to provide safe and reliable health care services. Fjellsiden Health Centre has since 1997 developed a system for quality assurance, which includes an annual review of selected quality items. This article presents the basic elements of the system, supplemented by experiences gained from its implementation. A local manual for essential procedures is the basis for the quality system. Other quality assurance activities are weekly practice meetings based on an annual plan for professional updating, including assessment of new guidelines, audits, cross-disciplinary meetings; reviews of "nearly-mistakes", resuscitation training, user surveys, and surveillance of the working environment. Specified routines are available for information safety. Local medication and equipment are regularly reviewed. Lab quality is regulated by a special system. A simple checklist based on locally developed specifications--relevant and vital issues that can be operationalized and assessed in a simple way--is used for annual quality review. The checklist specifications have lead to discussions about what is good enough and why. It has been easy to compile and summarize the data used for the annual review. We have experienced that our dedication to relevance, reality, and flexible format has contributed to giving quality assurance a natural place in a busy general practice office.


Topiramate attenuates exaggerated acoustic startle in an animal model of PTSD.
Exaggerated acoustic startle is a prominent symptom of post-traumatic stress disorder (PTSD); however, its physiological basis is not well understood, and there are few available treatments. Neurobiological research has suggested that anti-kindling agents and/or glutamate antagonists can attenuate the acoustic startle response (ASR) in animal models. The anticonvulsant topiramate is an AMPA antagonist that also demonstrates potent anti-kindling effects and may, therefore, have promise in treating trauma-enhanced ASR. To evaluate the ability of topiramate to attenuate stress-induced increases in ASR in a previously validated animal model of PTSD. Male Sprague-Dawley rats ( n=36) served as controls or received single prolonged stress (SPS). SPS consisted of 2 h restraint, forced swim and ether anesthesia, then a 7-day "undisturbed" period. Animals then received vehicle, 10 mg/kg or 30 mg/kg of topiramate orally, twice daily for 7 days. ASR was assessed for all animals before and after the study, in light and dark environments. SPS produced a sustained increase in the ASR in both environments, an effect that was significantly reduced by topiramate. Meanwhile the ASR of control animals remained unaffected by topiramate. The current results provide one of the few demonstrations of a single stress episode producing sustained enhancement of ASR. In addition, topiramate demonstrates promise in treating exaggerated acoustic startle symptoms in PTSD or other stress-related disorders.


[Value of varicography in the preoperative assessment of lower limb varicosities (author's transl)].
The author's experience of a 100 pilot cases revives the role of varicography for the preoperative evaluation of varicose veins in the lower limbs. This procedure consists of directly injecting the contrast medium into the varicose network. The technique is described in full details, also with several recommendations aimed at preventing potential side effects. The main advantages of direct varicography over "downstream" ascending phlebography include: 1 degrees clearer opacification of the connections between the varicose plexuses, the deep venous line and the paraaxial surface routes; 2 degrees more reliable detection of any deep- seated incompetence. Varicography seems to be particularly useful for the reevaluation of varicose veins after surgical failure; for studying perineal varicosities; and for finding out the source of external varicose veins at the thigh or lower leg.


Committee opinion No. 534: well-woman visit.
The annual health assessment ("annual examination") is a fundamental part of medical care and is valuable in promoting prevention practices, recognizing risk factors for disease, identifying medical problems, and establishing the clinician–patient relationship. The annual health assessment should include screening, evaluation and counseling, and immunizations based on age and risk factors. The interval for specific individual services and the scope of services provided may vary in different ambulatory care settings. The performance of a physical examination is a key part of an annual health assessment visit, and the components of that examination may vary depending on the patient's age, risk factors, and physician preference. The American College of Obstetricians and Gynecologists explains the need for annual assessments and provides guidelines regarding some important elements of the annual examination; specifically, when to perform pelvic examinations in asymptomatic women, including when to start internal pelvic and speculum examinations, and when to initiate formal clinical breast examinations.


Strain increases airway smooth muscle contractile and cytoskeletal proteins in vitro.
Mechanical stress contributes to lung development and the progression of some lung diseases, although its effects on individual lung cells are unknown. Because increased airway smooth muscle (ASM) is found in lung diseases where abnormal stress is present, we determined if strain (change in resting length) causes ASM hypertrophy independently of other in vivo influences. Cultured canine ASM cells were subjected to two levels of cyclic deformational strain for 14 days and compared with nonstrained cells by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and Western blotting. Cells subjected to 16-30% strain demonstrated increases in total cellular protein, myosin, myosin light chain kinase (MLCK), and desmin, whereas the cellular contents of actin, vimentin, and tubulin were similar. Changes in myosin appeared mostly due to the smooth muscle isoform, whereas nonmuscle myosin was unchanged. The increases in myosin and MLCK were disproportionate to increases in total protein, suggesting selective changes in contractile proteins. These relative increases in content of proteins were not as pronounced with 0-16% strain, suggesting a graded response. These data suggest that strain per se can increase the contractile proteins of ASM cells independently of other in vivo factors and modulates cultured cell phenotype to a more differentiated state, since it increases smooth muscle-specific proteins, such as smooth muscle myosin isoforms and desmin.


Predicting healthy and unhealthy behaviors through physical education: A self-determination theory-based longitudinal approach.
The aim of this study was to evaluate the relations between three dimensions of the structured teaching environment (promotion of theoretical knowledge, physical learning, and health improvement) in physical education (PE) and the adoption of health-related behaviors by students. The study adopted a two-occasion longitudinal design based on self-determination theory (SDT). PE students (N = 654, mean age = 16.13, SD = .77) completed measures of perceived structured teaching environment, satisfaction of basic psychological needs and motivation for PE, and healthy (physical activity, sport participation, and healthy eating) and unhealthy (consumption of tobacco, alcohol, and drugs) behaviors at the beginning and end of the first year of post-compulsory secondary education. Path analysis of the proposed relations among variables supported SDT tenets and showed positive relations between the three dimensions of the structured teaching environment, the satisfaction of basic psychological needs, and autonomous motivation in PE. Autonomous motivation contributed to an explanation of variance in two healthy behaviors, physical activity and sport participation. However, no relation was found among motivation in PE, healthy eating, and consumption of tobacco, alcohol, and drugs. These results show negligible trans-contextual influence of SDT motivational factors in PE on other healthy behaviors beyond physical activity.


Factors driving anticoagulant selection in patients with atrial fibrillation in the United States.
With the introduction of novel oral anticoagulants (NOACs), the factors driving anticoagulant selection in atrial fibrillation (AF) in real-world practice are unclear. The goal was to examine whether and to what extent utilization has been driven by predictions of stroke risk (treatment benefit), bleeding risk (treatment harm), or prescription benefits' coverage. We extracted a cohort of patients with nonvalvular AF initiating anticoagulation from October 2010 to December 2012 from a large US database of commercial and Medicare supplement claims. Multivariable regression examined associations between ischemic stroke (CHA2DS2-VASc) and bleeding (Anticoagulation and Risk Factors in Atrial Fibrillation [ATRIA]) risk scores and benefits' generosity (proportion of costs covered by patients relative to total) with warfarin and novel oral anticoagulant (NOAC) selection and also between dabigatran and rivaroxaban. C-statistics and partial chi-square statistics were used to assess the variation explained. Of 70,498 patients initiating anticoagulation, 29.9% and 7.9% used dabigatran and rivaroxaban, respectively. Compared with warfarin, patients were less likely to receive an NOAC with high ischemic stroke risk (CHA2DS2-VASc ≥2; adjusted relative risk [aRR] 0.75, 95% confidence interval [CI] 0.72 to 0.77) and high bleeding risk (ATRIA ≥5; aRR 0.66, 95% CI 0.64 to 0.69) but more likely with good benefits' generosity (≤20% of costs borne by patient; aRR 2.03, 95% CI 1.92 to 2.16). Prescription generosity explained almost twice the model variation as either risk score. Compared with dabigatran, patients were more likely to fill rivaroxaban with high bleeding risk (aRR 1.16, 95% CI 1.09 to 1.24). In conclusion, patients with greater bleeding and ischemic stroke risk were more likely to initiate warfarin, but generous benefits more strongly predicted NOAC usage and drove more selection.


Successful transfection of genes using AAV-2/9 vector in swine coronary and peripheral arteries.
Gene therapy has attracted attention for its potential to treat several cardiovascular diseases. The use of adeno-associated viral (AAV) vectors to facilitate therapeutic gene transfer to suppress intimal hyperplasia is a promising concept. The objective of this study was to analyze the in vivo transduction of a novel recombinant AAV-2/9 vector with SM22α promoter, containing β-galactosidase gene (LacZ) or green fluorescent protein (GFP) as reporter genes, to the medial layer smooth muscle cells (SMCs) of swine coronary and peripheral arteries. The AAV-2/9 vector containing SM22α (1 × 10(13) pfu) were administered into carotid/femoral/coronary arteries of domestic swine using irrigating balloon catheter-based gene delivery. Following gene transfer, cryosections of arteries were processed for X-Gal and GFP analysis. Fluorescence microscopy and Western blotting were done to analyze the GFP expression in the SMCs. LacZ mRNA expression was visualized in the medial layer 7 d after vector administration. The GFP expression was detected at day 7 and lasted for at least 2 mo showing the longer-lasting expression of the AAV-2/9 vector. Control arteries did not show any expression of GFP or LacZ. There was no significant effect of AAV-2/9 viral transduction on serum amylase, fibrinogen, and serum CRP levels. These finding support the use of AAV-2/9 as a vector to effectively transduce a gene in SMCs of coronary and peripheral arteries without causing inflammation.


Pathogenesis and management of postoperative ileus.
Postoperative ileus (POI) is a predictable delay in gastrointestinal (GI) motility that occurs after abdominal surgery. Probable mechanisms include disruption of the sympathetic/parasympathetic pathways to the GI tract, inflammatory changes mediated over multiple pathways, and the use of opioids for the management of postoperative pain. Pharmacologic treatment of postoperative ileus continues to be problematic as most agents are unreliable and unsubstantiated with robust clinical trials. The selective opioid antagonist alvimopan has shown promise in reducing POI, but needs more rigorous investigation. Clinician interventions proven to be of benefit include laparoscopy, thoracic epidural anesthesia, avoidance of opioids, and early feeding. Early ambulation may also contribute to early resolution of POI; however, routine nasogastric decompression plays no role and may increase complications. Multimodal care plans remain the mainstay of treatment for POI.


Gastrodin exerts robust neuroprotection in the postischemic brain via its protective effect against Zn2+-toxicity and its anti-oxidative effects in astrocytes.
Gastrodin (GAS) is a predominant bioactive constituent of the Chinese herbal medicine Tianma (Gastrodia elata Blume). Many authors have reported GAS has the beneficial effect on diverse diseases of the CNS, including epilepsy, Alzheimer's disease, Parkinson's disease, and cerebral ischemia. Here, we report GAS exhibited a robust neuroprotective effect in an Sprague-Dawley rat model of stroke (transient middle cerebral artery occlusion, tMCAO), and show that the underlying molecular mechanism involves its protective effect against Zn2+-toxicity and its anti-oxidative effects in astrocytes. Intraperitoneal administration of GAS (40 mg/kg) after MCAO reduced mean infarct volume to 30.1 ± 5.9% of that of MCAO controls and this neuroprotective effect was accompanied by neurological function recoveries which was measured using modified neurological severity score (mNSS). Interestingly, GAS induced up-regulation and nuclear translocation of Nrf2, and subsequently increased the expressions of anti-oxidative genes, such as, HO-1 and GCLM, in astrocytes. Furthermore, GAS co- or pre-treatment markedly suppressed Zn2+-induced cell death caused by excessive ROS production and PARP-1 induction. We found that GAS suppressed p67 expression and PAR formation in astrocytes, which might underlie the anti- Zn2+-toxicity and anti-oxidative effects of GAS in astrocytes. These findings indicate GAS protects astrocytes from Zn2+-induced toxicity and oxidative stress and these effects contribute to its neuroprotective effects in the postischemic brain.


Liver transplantation in Greek children: 15 years experience.
Liver transplantation (LT) is the only available live-saving procedure for children with irreversible liver failure. This paper reports our experience from the follow-up of 16 Greek children with end-stage liver failure who underwent a LT. Over a period of 15 years, 16 pediatric liver recipients received follow up after being subjected to OLT (orthotopic liver transplantation) due to end-stage liver failure. Nine children initially presented with extrahepatic biliary atresia, 2 with acute liver failure after toxic mushroom ingestion, 2 with intrahepatic cholestasis, 2 with metabolic diseases and one with hepatoblastoma. Ten children received a liver transplant in the Organ Transplantation Unit of Aristotle University of Thessaloniki and the rest in other transplant centers. Three transplants came from a living-related donor and 13 from a deceased donor. Six children underwent immunosuppressive treatment with cyclosporine, mycophenolate mofetil and corticosteroids, and 7 with tacrolimus, mycophenolate mofetil and corticosteroids. Three out of 16 children died within the first month after the transplantation due to post-transplant complications. Three children presented with acute rejection and one with chronic organ rejection which was successfully managed. Five children presented with cytomegalovirus infection, 5 with Epstein-Barr virus, 2 with HSV(1,2), 2 with ParvoB19 virus, 2 with varicella-zoster virus and one with C. Albicans infection. One child presented with upper gastrointestinal hemorrhage and one with small biliary paucity. A satisfying outcome was achieved in most cases, with good graft function, except for the patient with small biliary paucity who required re-transplantation.The long-term clinical course of liver transplanted children is good under the condition that they are attended in specialized centers.


Lossless compression of video using temporal information.
In this paper, we consider the problem of lossless compression of video by taking into account temporal information. Video lossless compression is an interesting possibility in the line of production and contribution. We propose a compression technique which is based on motion compensation, optimal three-dimensional (3-D) linear prediction and context based Golomb-Rice entropy coding. The proposed technique is compared with 3-D extensions of the JPEG-LS standard for still image compression. A compression gain of about 0.8 bit/pel with respect to static JPEG-LS, applied on a frame-by-frame basis, is achievable at a reasonable computational complexity.


[The size and volume of the kidneys in nutria during postnatal ontogenesis].
Kidneye size and volume, absolute and relative mass, and tissue density was determined in 50 male and female nutria of different age groups (1 day, 2, 4, 5, 7.5 months and 1 year). It was found that in females the relative mass of the kidneys decreased with age, while in males this tendency remained only until the age of 7.5 months. In females from 1 day up to 1 year, the mass and the volume of the right kidney increased 11.44 and 11.25 times, its length and width - increased 2.16 and 2.59 times and its thickness - 2.07 times. In the left kidney, the corresponding indicators increased 11.69, 11.04, 2.14, 2.65 and 2.01 times. In males, from 1 day up to 1 year, the mass and the volume of the right kidney increases 19.49 and 16. 14 times, the length and the width increased 2.69 and 3.11 times and its thickness - 2.38 times. In the left kidney, the corresponding indicators increased 18.52, 16.83, 2.56, 2.98 and 2.72 times. The greatest increase in the indicators studied of the kidneys in female and male nutria took place from birth up to the age of 2 months. It was found that the density of the kidney tissue was the highest at 4.5 months. In the left and right kidneys in female nutria, its value varied from 1.09+/-0,03 to 1.12+/-0.02 g/cm3 respectively, while in the males it changed from 1,04+/-0.01 to 1.08+/-0.02 g/cm3.


Effects of the repeated distribution of sainfoin hay on the resistance and the resilience of goats naturally infected with gastrointestinal nematodes.
Due to the high prevalence of anthelmintic resistance in goats, the need to explore novel approaches to control nematodes and to reduce the exclusive reliance on chemotherapy is strongly demanded in this host species. In sheep, several studies have shown that the consumption of tannin-rich legume forages was associated with positive effects on host resilience and resistance to parasite infection. In goats, studies on such interactions between tanniferous plants and nematode infections remain few. The objectives of the current study were to examine under natural conditions the effects of consumption of sainfoin hay by goats on the parasite populations and on host resilience. Eighteen adult cull goats naturally infected with Haemonchus contortus, Teladorsagia circumcincta and Trichostrongylus colubriformis were used in the study. At the start of the assay, the goats were allocated into two groups, balanced according to weight and the levels of egg excretion. The two groups grazed separate pastures for 3 months with similar stocking rates. Goats from group S received each month indoors, for 7 days, sainfoin hay and control goats (group C) received hay of ryegrass. The diets in both groups were made isoenergetic and isoproteic and the refusals measured. Individual parasitological and pathophysiological measurements were performed fortnightly in order to compare host resistance and resilience. At the end of the study, five goats per group were necropsied. The distribution of sainfoin was associated with: (1) a higher consumption of hay; (2) significant, lower levels of nematode egg excretion which was associated with a decrease in worm fertility but no change in worm population; however, the number of intestinal worms was reduced by 50% in group S; (3) a better host resilience. In particular, after 2 months of grazing, two control goats died and half of the remaining animals needed to be treated whereas this was not the case in group S. These differences were related to significant changes in pepsinogen and phosphate values (PCV) but not in pepsinogen and phosphate concentrations. These results demonstrate that a repeated distribution of sainfoin hay to grazing goats might be beneficial in regard of pasture contamination and host resilience. They suggest that administration of sainfoin hay might represent a valuable alternative and adjunct to reduce nematode infections in dairy goat flock.


Assessment of sonographic venous peak systolic velocity in detecting hemodialysis arteriovenous graft stenosis.
There is no single effective means of assessing arteriovenous access function, although monitoring hemodialysis venous pressure (VP) or measuring access recirculation may be of some benefit. The present study assesses prospectively the efficacy of following the peak systolic velocity (PSV) as a single measure to detect arteriovenous graft (AVG) stenosis. PSV was measured in 12 patients after new AVG placement and at approximately 2-month intervals. Angiography was also performed after new graft placement and when PSV was elevated to greater than 200 cm/sec, hemodialysis access VP increased to greater than 150 mm Hg on three consecutive readings, or access recirculation increased to greater than 11%. PSV was then compared with results from angiography, VP monitoring, and access recirculation. The 12 patients underwent 34 PSV studies, followed by angiography on 25 occasions. Each patient underwent at least one angiogram. Each abnormal PSV value was confirmed with the finding of stenosis on angiogram, except for two patients with PSVs greater than 400 cm/sec and normal angiography results. VP and recirculation were not elevated. During this period, two patients developed thrombosis of the AVG, and two patients underwent angioplasty with improvement in PSV. We conclude that elevations in PSV measured at the venous anastomosis are an effective means of screening for AVG stenosis, AVG stenosis can occur early after AVG placement, and elevated VP and recirculation are late findings in AVG dysfunction.


Biocompatibility and effect on osteogenesis of poly(ortho ester) compared to poly(DL-lactic acid).
Implantation of demineralized bone induces new bone formation by the action of contained growth factors, of which bone morphogenetic proteins are of prime importance. A biodegradable polymer may be used as a carrier for demineralized bone particles or recombinant bone growth factors to prevent displacement of the implant, preserve its volume and shape, and assure sustained release of the incorporated active components. A polymer for this use should be biocompatible and completely absorbed without interfering with the osteogenesis. We investigated the host-tissue response and effect on demineralized bone-induced bone formation by two biodegradable polymers, a poly(ortho ester) and an amorphous low-molecular poly(DL-lactic acid). Both polymers had a plastic consistency, could easily be molded, and adhered well to the demineralized bone particles. Demineralized bone particles were implanted alone and in combination with each of the polymers in the abdominal muscles of 45 male Wistar rats. Four weeks after the operation the implants were recovered and subjected to (85)Sr uptake analysis to quantify bone formation and histologic examination. The poly(ortho ester) provoked little inflammation; it was largely absorbed by 4 weeks, and no qualitative or quantitative effect on bone formation was found. The poly(DL-lactic acid) provoked a chronic inflammation with multinuclear giant cells, macrophages with engulfed material, and proliferating fibroblasts; part of the material was still present, and the bone formation was inhibited.


Enhanced susceptibility of obese mice to glycidamide-induced sperm chromatin damage without increased oxidative stress.
Diet-induced obesity is known to impair male reproduction and may aggravate the male reproductive toxicity of the food contaminant acrylamide. Exposure of male mice to acrylamide induces paternally mediated pre- and post-implantation losses because of spermatozoal toxicity and these effects are potentiated in mice fed a high-fat diet. Glycidamide - an acrylamide metabolite - is the primary mediator of reproductive effects in males. The mechanisms causing the interaction between diet and acrylamide are not clear. However, diet-induced obesity is associated with oxidative stress in male reproductive tissues which might contribute to increased germ cell susceptibility. In this study, we investigated whether a moderate diet-induced obesity regimen could interfere with glycidamide-induced spermatozoal toxicity and increase oxidative stress. For this purpose, sperm chromatin integrity, oxidised DNA and protein levels, transcript levels of oxidative stress responsive genes and glycidamide-induced DNA and haemoglobin adducts were analysed in samples from male mice exposed to a high-fat diet for 6 weeks in combination with a single glycidamide exposure 7 days prior to sacrifice. We found that glycidamide-induced sperm DNA fragmentation was markedly higher in obese than in lean mice. However, the levels of oxidised DNA and/or protein in blood, liver and testicular tissue was lower in obese than in lean mice. Accompanying the reduced level of oxidised macromolecules, the transcript levels of several oxidative stress-related genes were altered in the liver and testis from obese mice suggesting induction of an antioxidant response in these animals. The haemoglobin-glycidamide adduct levels were higher in obese than in lean animals, whereas obesity did not seem to increase the level of glycidamide-induced DNA adducts. These findings show that a moderate diet-induced obesity regimen may potentiate glycidamide-induced sperm cells toxicity and suggest that the increase in glycidamide-induced sperm toxicity observed in obese mice does not depend on overt oxidative stress.


Molecular basis of passive stress relaxation in human soleus fibers: assessment of the role of immunoglobulin-like domain unfolding.
Titin (also known as connectin) is the main determinant of physiological levels of passive muscle force. This force is generated by the extensible I-band region of the molecule, which is constructed of the PEVK domain and tandem-immunoglobulin segments comprising serially linked immunoglobulin (Ig)-like domains. It is unresolved whether under physiological conditions Ig domains remain folded and act as "spacers" that set the sarcomere length at which the PEVK extends or whether they contribute to titin's extensibility by unfolding. Here we focused on whether Ig unfolding plays a prominent role in stress relaxation (decay of force at constant length after stretch) using mechanical and immunolabeling studies on relaxed human soleus muscle fibers and Monte Carlo simulations. Simulation experiments using Ig-domain unfolding parameters obtained in earlier single-molecule atomic force microscopy experiments recover the phenomenology of stress relaxation and predict large-scale unfolding in titin during an extended period (> approximately 20 min) of relaxation. By contrast, immunolabeling experiments failed to demonstrate large-scale unfolding. Thus, under physiological conditions in relaxed human soleus fibers, Ig domains are more stable than predicted by atomic force microscopy experiments. Ig-domain unfolding did not become more pronounced after gelsolin treatment, suggesting that the thin filament is unlikely to significantly contribute to the mechanical stability of the domains. We conclude that in human soleus fibers, Ig unfolding cannot solely explain stress relaxation.


Attention control and the attention schema theory of consciousness.
In the attention schema theory (AST), the brain constructs a schematic, simplified model of attention. The model is associated with three cognitive processes: a model of one's own attention contributes to the endogenous control of attention, a model of the attention of others contributes to theory of mind, and the contents of these models leads to the common human claim that we contain a non-physical consciousness or awareness inside us. Because AST is a control-engineering style theory, it can make specific predictions in complex situations. Here, over six experiments, we examined interactions between attention and awareness to test predictions of AST. Participants performed a visual task in which a cue stimulus affected their attention, as measured by their reactions to a subsequent target stimulus. The task measured both exogenous attention drawn to the cue and endogenous attention directed to a target location predicted by the cue. When participants were not aware that the cue predicted the target, both exogenous and endogenous attention effects remained. In contrast, when participants were not visually aware of the cue itself, the exogenous attention effect remained and the endogenous effect was impaired. In an additional two experiments, when participants learned an implicit shift of attention, the learning generalized from trained spatial locations to adjacent, untrained locations. Each of these findings matched predictions of AST. The results support the interpretation that attention control relies partly on an internal model that is responsible for claims of awareness.


Ollier's Disease. An assessment of angular deformity, shortening, and pathological fracture in twenty-one patients.
A retrospective review of twenty-one patients with Ollier's disease showed that the lesion involved the femur and tibia most frequently, and that those bones accounted for the large majority of clinical problems. Angular deformities were common; 80 per cent of the affected femora had clinically significant varus or valgus angulation in the distal part and 42 per cent of the affected tibiae had proximal or distal deformity. The apex of the angulation, when present, was metaphyseal, with the concavity on the side that was more extensively involved by the enchondromas. Osteotomies were done frequently to correct angulation; all healed well. Deformity in the distal part of the femur frequently required repeat osteotomy to achieve a straight bone at skeletal maturity, The extent of shortening, which always was present in the involved limb, closely paralleled the extent of involvement, The discrepancies in limb lengths prior to surgical treatment averaged 9.8 centimeters (range, 4.3 to 35.7 centimeters). Epiphyseal arrest, when appropriately timed, was effective in correcting or limiting the discrepancies, but partial (medial or lateral) epiphyseal arrest to correct angular deformity was ineffective. Diaphyseal lengthening was done on six occasions, once in the femur and five times in the tibia and fibula, with good results. Fourteen pathological fractures occurred in seven of the twenty-one patients, and all healed uneventfully with conservative treatment.


[Prevalence of malnutrition and influence of oral nutritional supplementation on nutritional status in institutionalized elderly].
Nutritional supplementation might be an effective strategy for improving the nutritional status and the quality of life of institutionalized fragile elderly. The prevalence of malnutrition and its relation with disease, and the influence of dietary supplementation by means of oral formulas on the nutritional status of elderly nursing home residents were assessed. Two studies were carried out, one a cross-sectional survey in 31 subjects and the other a longitudinal-sectional survey in 19 subjects, both groups living in a public nursing home in the city of Murcia (SE Spain). Body mass index (BMI), serum albumin concentration (ALB) and geriatric nutritional risk index (GNRI) were assessed as markers of potential malnutrition. Illnesses were ascertained from medical records. The prevalence of malnutrition of the total collective was high (39%), and especially in the fragile subjects (50%). The administration of oral nutritional supplements in the usual diet for 12 months significantly increased ALB and GNRI, and had no effect on body weigh and BMI. Jointly, these effects decreased the in the number of subjects at high nutritional risk and increased the number of subjects with a low or zero risk of malnutrition. The administration of oral nutritional supplements in the usual diet of this elderly collective is an effective clinical strategy in nutritional therapy.


Focal Macroscopic Cortical Lesions in Cerebral Autosomal-Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy.
Cortical microinfarcts and secondary cortical degeneration have been demonstrated in cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a severe monogenic cerebral small vessel disease. The aim of this study was to determine whether focal macroscopic cortical lesions can be detected using a specific in vivo magnetic resonance imaging approach. Three-dimensional T1 magnetic resonance imaging scans were obtained in 28 nondemented nondisabled CADASIL patients and 29 age- and sex-matched controls. The cortical mantle of patients and controls were extracted using Brainvisa by an experienced user and then evaluated during a dedicated reading session by a second reader after removing the white matter to stay blind to the clinical status. Thereafter, confirmed focal macroscopic cortical lesions were characterized using all available imaging data, including 7-T magnetic resonance imaging in some patients. Three focal macroscopic cortical lesions were confirmed in 3 of 28 patients (11%) but none in controls. All lesions were observed in the close vicinity of severe signal changes in the underlying white matter. Focal macroscopic cortical lesions can be detected using specific magnetic resonance imaging approaches in CADASIL patients long before the end stage of the disorder. The underlying mechanisms and precise clinical consequences of these cortical changes still need to be determined.


Strong coupling between resonators and spin ensembles in the presence of exchange couplings.
Molecular qubits are extensively tunable, in contrast to other spin qubits. The use of spin ensembles as quantum repeaters in quantum communication relies on strong coupling between photon and spin modes. Here we show that the effective coupling strength depends on the magnetic interactions between the spins in the ensemble.