Small intestinal permeability is increased in diarrhoea predominant IBS, while alterations in gastroduodenal permeability in all IBS subtypes are largely attributable to confounders.
Intestinal permeability has been studied in small groups of IBS patients with contrasting findings. To assess intestinal permeability at different sites of the GI tract in different subtypes of well-characterised IBS patients and healthy controls (HC), and to assess potential confounding factors. IBS patients and HC underwent a multi-sugar test to assess site-specific intestinal permeability. Sucrose excretion and lactulose/rhamnose ratio in 0-5 h urine indicated gastroduodenal and small intestinal permeability, respectively. Sucralose/erythritol ratio in 0-24 h and 5-24 h urine indicated whole gut and colonic permeability, respectively. Linear regression analysis was used to assess the association between IBS groups and intestinal permeability and to adjust for age, sex, BMI, anxiety or depression, smoking, alcohol intake and use of medication. Ninety-one IBS patients, i.e. 37% IBS-D, 23% IBS-C, 33% IBS-M and 7% IBS-U and 94 HC were enrolled. Urinary sucrose excretion was significantly increased in the total IBS group [μmol, median (Q1;Q3): 5.26 (1.82;11.03) vs. 2.44 (0.91;5.85), P < 0.05], as well as in IBS-C and IBS-D vs. HC. However, differences attenuated when adjusting for confounders. The lactulose/rhamnose ratio was increased in IBS-D vs. HC [0.023 (0.013;0.038) vs. 0.014 (0.008;0.025), P < 0.05], which remained significant after adjustment for confounders. No difference was found in 0-24 and 5-24 h sucralose/erythritol ratio between groups. Small intestinal permeability is increased in patients with IBS-D compared to healthy controls, irrespective of confounding factors. Adjustment for confounders is necessary when studying intestinal permeability, especially in a heterogeneous disorder such as IBS.


Acute and long-term effects of psilocybin on energy balance and feeding behavior in mice.
Psilocybin and other serotonergic psychedelics have re-emerged as therapeutics for neuropsychiatric disorders, including addiction. Psilocybin induces long-lasting effects on behavior, likely due to its profound ability to alter consciousness and augment neural connectivity and plasticity. Impaired synaptic plasticity in obesity contributes to 'addictive-like' behaviors, including heightened motivation for palatable food, and excessive food seeking and consumption. Here, we evaluate the effects of psilocybin on feeding behavior, energy metabolism, and as a weight-lowering agent in mice. We demonstrate that a single dose of psilocybin substantially alters the prefrontal cortex transcriptome but has no acute or long-lasting effects on food intake or body weight in diet-induced obese mice or in genetic mouse models of obesity. Similarly, sub-chronic microdosing of psilocybin has no metabolic effects in obese mice and psilocybin does not augment glucagon-like peptide-1 (GLP-1) induced weight loss or enhance diet-induced weight loss. A single high dose of psilocybin reduces sucrose preference but fails to counter binge-like eating behavior. Although these preclinical data discourage clinical investigation, there may be nuances in the mode of action of psychedelic drugs that are difficult to capture in rodent models, and thus require human evaluation to uncover.


Ketamine - reves et realites.
Ketamine is an anaesthetic used in human medicine and veterinary practice, synthesised on 1962 and marketed on 1970 in France. Recreational uses were described during 1992 in the medical communauty and in 1996 in the dance settings. The chemical name of ketamine is 2 - (2chlorophenyl) 2-(methylamine)-cyclohexanone, an aryl cyclohexylamine, structurally related to phencyclidine. Ketamine is known under the following street names : Keta K, Kate, Special K, Vitamine K, la Golden, la Vétérinaire. Ketamine is used intranasally, orally and intramusculary in recreational use. Ketamine is manufactured by the chemical industry. Due to the complicated synthesis, it is sold illicitly for recreational use. Ketamine is a dissociative drug, and the user enters in a psychedelic dream with hallucinations, floating sensation, feeling of dissociation of the mind from the body. The dream is forgotten, the user fulls in reality with loss of self control, risk of acute intoxication. In long term exposure, tolerance, dependence, withdrawal signs and flash back are described. Ketamine trademarks are subject to control in France through medicine legislation Ketamine and its salts are subject to control under the national legislation on narcotics and psychotropics substance. From September 2001, the theft of medical and veterinary trademarks have to be declared to police, care health authority Pharmacy control authority and French Health Products Safety Agency.


Postherpetic Nevocentric Erythema Multiforme.
A previously healthy 35-year-old Caucasian woman presented with abrupt onset of erythematous, mildly pruritic plaques surrounding the majority of the nevi present on her neck, chest, back, and upper and lower extremities. She denied history of any recent systemic illnesses and was not taking any medications. On further questioning, the patient reported a recent episode of recurrent herpes labialis 2 weeks prior. The patient has a Fitzpatrick type I skin type with more than 100 brown and reddish brown pigmented macules and papules over her entire body. Plaques ranged in size from 0.4 cm to 1.5 cm depending on the size of the corresponding nevus. The patient's skin was examined in its entirety, and there were no lesions suspicious for melanoma. Two biopsies were performed from the patient's back: one from the nevus itself and another from the surrounding erythematous plaque. The nevocentric erythematous plaques were visible for approximately 1 week at which time they gradually disappeared without treatment. As these areas improved, the patient noticed targetoid lesions on the dorsal hands without associated nevi. Two weeks later, the targetoid lesions had spontaneously resolved.


Relationship between symptoms of depression, functional health status, and chronic disease among a residential sample of African Americans.
Depression and psychological distress often go unrecognized and untreated in primary care settings. The association between depression, socioeconomic status, and chronic disease underscore the importance of incorporating mental health education and screening into community-based health initiatives. This is particularly critical for African Americans who bear a disproportionate burden of poverty and chronic disease. This descriptive study assessed associations between symptoms of depression, socioeconomic status, healthcare utilization, physical and mental health functioning, and reactions to race among a sample of low-income African Americans. Consistent with the findings of previous research, respondents with symptoms of depression reported lower levels of physical and mental health functioning, and perceived that they had been treated worse by others at work, and had worse healthcare experiences than those of other races. Community-based programs for reducing disparities in physical illness may need to address the burden of undiagnosed and untreated depression in order to become optimally effective.


A spitting image: specializations in archerfish eyes for vision at the interface between air and water.
Archerfish are famous for spitting jets of water to capture terrestrial insects, a task that not only requires oral dexterity, but also the ability to detect small camouflaged prey against a visually complex background of overhanging foliage. Because detection of olfactory, auditory and tactile cues is diminished at air-water interfaces, archerfish must depend almost entirely on visual cues to mediate their sensory interactions with the aerial world. During spitting, their eyes remain below the water's surface and must adapt to the optical demands of both aquatic and aerial fields of view. These challenges suggest that archerfish eyes may be specially adapted to life at the interface between air and water. Using microspectrophotometry to characterize the spectral absorbance of photoreceptors, we find that archerfish have differentially tuned their rods and cones across their retina, correlated with spectral differences in aquatic and aerial fields of view. Spatial resolving power also differs for aquatic and aerial fields of view with maximum visual resolution (6.9 cycles per degree) aligned with their preferred spitting angle. These measurements provide insight into the functional significance of intraretinal variability in archerfish and infer intraretinal variability may be expected among surface fishes or vertebrates where different fields of view vary markedly.


Effect of antibiotic treatment on Mycoplasma hyopneumoniae detection and infectious potential.
Mycoplasma hyopneumoniae (M. hyopneumoniae) causes significant economic losses in the swine industry. Antibiotics with activity against Mycoplasma spp. are employed for disease mitigation and pathogen elimination. However, veterinarians are often challenged with the detection of M. hyopneumoniae by PCR after antibiotic treatment, thus raising the question whether the bacterium is still infectious. The objective of this study was to evaluate the effect of tulathromycin treatment on M. hyopneumoniae detection and infectious potential during the acute and chronic phases of infection. For each infection phase, one age-matched naïve gilt was placed in contact with one M. hyopneumoniae infected gilt that was either treated with tulathromycin, treated and vaccinated, or non-treated, for 14 days. Four replicates per treatment group were performed for each infection phase. A numerical reduction in relative bacterial load was observed in acutely treated gilts compared to non-treated gilts. The rate at which naïve gilts became infected with M. hyopneumoniae was numerically reduced when co-housed with treated, acutely infected gilts compared to those housed with non-treated, infected gilts. During the chronic infection phase, M. hyopneumoniae was detected by PCR in more than 50 % of treated infected gilts and persisted for up to three months post-treatment. Transmission was not detected in all treatment groups however, the possibility that the pathogen was infectious could not be completely ruled out. Further research focused on assessing M. hyopneumoniae detection and viability post-treatment is necessary to guide control and elimination efforts.


Adaptive changes of pyruvate oxidation in perfused heart during adrenergic stimulation.
Pyruvate oxidation was studied in isolated guinea pig hearts perfused under various conditions of work and stimulated by norepinephrine. Hearts metabolized pyruvate alone or in combination with 3-hydroxybutyrate or acetate as substrate. [1-14C]-pyruvate-dependent 14CO2 release into the venous effluent (MVpyr) was, like myocardial oxygen consumption (MVO2), directly related to aortic pressure or filling pressure. At high aortic pressures, ventricular pressure development and not work performance was the major determinant of MVO2 and thus MVpyr. With 1 mM pyruvate as sole substrate, 0.08 microM norepinephrine produced parallel changes in hemodynamic performance, MVO2. MVpyr, and pyruvate dehydrogenase complex (PDC) activity (active form). Similar and dose-dependent effects of norepinephrine were observed during infusion of 5 mM DL-3-hydroxybutyrate as cosubstrate. When 1 mM acetate was applied, MVpyr was also dependent on work performance and norepinephrine stimulation. However, in perfusions with 25 mM potassium chloride, norepinephrine did not enhance hemodynamic function or MVO2 and hence PDC activity and MVpyr. Thus regulation of the PDC in catecholamine-stimulated heart appears to be linked predominantly to myocardial energy demand even when alternative energy-providing substrates are utilized.


Production and Identification of Wheat-Agropyron cristatum 2P Translocation Lines.
Agropyron cristatum (L.) Gaertn. (2n = 28, PPPP), a wild relative of common wheat, possesses many potentially valuable traits that can be transferred to common wheat through breeding programs. The wheat-A. cristatum disomic addition and translocation lines can be used as bridge materials to introduce alien chromosomal segments to wheat. Wheat-A. cristatum 2P disomic addition line II-9-3 was highly resistant to powdery mildew and leaf rust, which was reported in our previous study. However, some translocation lines induced from II-9-3 have not been reported. In this study, some translocation lines were induced from II-9-3 by 60Co-γ irradiation and gametocidal chromosome 2C and then identified by cytological methods. Forty-nine wheat-A. cristatum translocation lines were obtained and various translcoation types were identified by GISH (genomic in situ hybridization), such as whole-arm, segmental and intercalary translocations. Dual-color FISH (fluorescent in situ hybridization) was applied to identify the wheat chromosomes involved in the translocations, and the results showed that A. cristatum 2P chromosome segments were translocated to the different wheat chromosomes, including 1A, 2A, 3A, 4A, 5A, 6A, 7A, 3B, 5B, 7B, 1D, 4D and 6D. Many different types of wheat-A. cristatum alien translocation lines would be valuable for not only identifying and cloning A. cristatum 2P-related genes and understanding the genetics and breeding effects of the translocation between A. cristatum chromosome 2P and wheat chromosomes, but also providing new germplasm resources for the wheat genetic improvement.


Early referral for 24-h esophageal pH monitoring may prevent unnecessary treatment with acid-reducing medications.
Gastroesophageal reflux disease (GERD) affects nearly 25 % of adults; however, an objective diagnosis is rarely established. We hypothesized that patients' symptoms and response to acid-reducing therapy are poor predictors of the outcome of 24-h esophageal pH monitoring. A review of 24-h esophageal pH monitoring studies performed at an ambulatory tertiary care center between 2004 and 2011 was performed. Demographics, type of GERD symptoms, and duration and response to acid-reducing medications before referral for pH monitoring were collected. DeMeester score, symptom sensitivity index (SSI), and symptom index (SI) were tabulated and compared with the patients' symptoms and response to medical therapy. One hundred patients were included. Of all reported symptoms, only heartburn was more common in patients with positive DeMeester scores, but there were no correlations between any symptoms and SSI or SI scores. Sixty-nine percent of patients with esophageal symptoms had a positive DeMeester score compared with only 29 % of patients with extraesophageal symptoms (P < 0.01). Esophageal symptoms and endoscopic evidence of GERD significantly increased the likelihood of having a positive DeMeester score, but they had no influence on SSI or SI scores. There was no correlation between response to acid-reducing medications and DeMeester, SSI, or SI scores. A total of 536 person-years of acid-reducing medications were prescribed to the study population, of which 151 (28 %) were prescribed to patients who had a negative pH study. Extraesophageal symptoms and response to empiric trials of acid-reducing medications are poor predictors of the presence of GERD and the DeMeester score is more likely to identify GERD in patients who met other empiric diagnostic criteria than SSI or SI. Early referral for 24-h esophageal pH monitoring may avoid lengthy periods of unnecessary medical therapy.


Factors influencing adherence to treatment in older adults with hypertension.
Hypertension (HT) is considered to be the most common disorder in the general population. Demographic data indicate that older adults commonly suffer from HT. Older age is one of the key factors affecting the adherence of patients with HT. The main purpose was to identify demographic, socioeconomic, and clinical factors that affect adherence in older adults with HT. This cross-sectional study included 150 patients (84 women and 66 men) with mean age of 72.1 years. The Hill-Bone Compliance to High Blood Pressure Therapy Scale (Hill-Bone CHBPTS) was used to evaluate the adherence to therapeutic recommendations for HT. The mean score obtained by the patients in the Hill-Bone CHBPTS was 20.19 (SD±4.05). The linear regression model showed the independent predictors of the total score (P<0.05): 1) age, each subsequent year of life raises the total score by an average of 0.2 points; 2) gender, males raise it by an average of 1.34 points compared to females; 3) education, a secondary, higher, or higher professional education lowers it by an average of 1.75 points compared to a primary education or no education; and 4) living with the family, having familial support lowers it by an average of 1.91 points compared to living alone or in an organized institution. Our study has shown that the variables of age, education level, and living with the family were statistically significant in explaining the adherence rates. Health care professionals should pay more attention to older HT patients who have a low level of education and who experience the lack of social support. There is a need for a tailored education among this group of patients to better understand and adhere to medication treatment.


Ibuprofen Blunts Ventilatory Acclimatization to Sustained Hypoxia in Humans.
Ventilatory acclimatization to hypoxia is a time-dependent increase in ventilation and the hypoxic ventilatory response (HVR) that involves neural plasticity in both carotid body chemoreceptors and brainstem respiratory centers. The mechanisms of such plasticity are not completely understood but recent animal studies show it can be blocked by administering ibuprofen, a nonsteroidal anti-inflammatory drug, during chronic hypoxia. We tested the hypothesis that ibuprofen would also block the increase in HVR with chronic hypoxia in humans in 15 healthy men and women using a double-blind, placebo controlled, cross-over trial. The isocapnic HVR was measured with standard methods in subjects treated with ibuprofen (400 mg every 8 hrs) or placebo for 48 hours at sea level and 48 hours at high altitude (3,800 m). Subjects returned to sea level for at least 30 days prior to repeating the protocol with the opposite treatment. Ibuprofen significantly decreased the HVR after acclimatization to high altitude compared to placebo but it did not affect ventilation or arterial O2 saturation breathing ambient air at high altitude. Hence, compensatory responses prevent hypoventilation with decreased isocapnic ventilatory O2-sensitivity from ibuprofen at this altitude. The effect of ibuprofen to decrease the HVR in humans provides the first experimental evidence that a signaling mechanism described for ventilatory acclimatization to hypoxia in animal models also occurs in people. This establishes a foundation for the future experiments to test the potential role of different mechanisms for neural plasticity and ventilatory acclimatization in humans with chronic hypoxemia from lung disease.


Quantifying the potential persuasive returns to political microtargeting.
Much concern has been raised about the power of political microtargeting to sway voters' opinions, influence elections, and undermine democracy. Yet little research has directly estimated the persuasive advantage of microtargeting over alternative campaign strategies. Here, we do so using two studies focused on U.S. policy issue advertising. To implement a microtargeting strategy, we combined machine learning with message pretesting to determine which advertisements to show to which individuals to maximize persuasive impact. Using survey experiments, we then compared the performance of this microtargeting strategy against two other messaging strategies. Overall, we estimate that our microtargeting strategy outperformed these strategies by an average of 70% or more in a context where all of the messages aimed to influence the same policy attitude (Study 1). Notably, however, we found no evidence that targeting messages by more than one covariate yielded additional persuasive gains, and the performance advantage of microtargeting was primarily visible for one of the two policy issues under study. Moreover, when microtargeting was used instead to identify which policy attitudes to target with messaging (Study 2), its advantage was more limited. Taken together, these results suggest that the use of microtargeting-combining message pretesting with machine learning-can potentially increase campaigns' persuasive influence and may not require the collection of vast amounts of personal data to uncover complex interactions between audience characteristics and political messaging. However, the extent to which this approach confers a persuasive advantage over alternative strategies likely depends heavily on context.


Simulation of semidilute polymer solutions in planar extensional flow via conformationally averaged Brownian noise.
The dynamics and rheology of semidilute polymer solutions in strong flows are of great practical relevance. Processing applications can in principle be designed utilizing the relationship between nonequilibrium polymer conformations and the material properties of the solution. However, the interplay between concentration, flow, hydrodynamic interactions (HIs), and topological interactions which govern semidilute polymer dynamics is challenging to characterize. Brownian dynamics (BD) simulations are particularly valuable as a way to directly visualize how molecular interactions arise in these systems and are quantitatively comparable to single-molecule experiments. However, such simulations are often computationally intractable and are limited by the need to calculate the correlated Brownian noise via decomposition of the diffusion tensor. Previously, we have introduced an iterative conformational averaging (CA) method for BD simulations which bypasses these limitations by preaveraging the HI and Brownian noise in an iterative procedure. In this work, we generalize the CA method to flowing semidilute solutions by introducing a conformation dependent diffusion tensor and a strain dependent approximation to the conformationally averaged Brownian noise. We find that this approach nearly quantitatively reproduces both transient and steady state polymer dynamics and rheology while achieving an order of magnitude computational acceleration. We then utilize the CA method to investigate the concentration and flow rate dependence of polymer dynamics in planar extensional flows. Our results are consistent with previous experimental and simulation studies and provide a detailed view of broad conformational distributions in the semidilute regime. We observe interconversion between stretched and coiled states at steady state, which we conjecture occur due to the effect of concentration on the conformation dependent polymer drag. Additionally, we observe transient flow-induced intermolecular hooks in the startup of flow which lead to diverse and unique stretching pathways.


Inhibition of glutathione synthesis with propargylglycine enhances N-acetylmethionine protection and methylation in bromobenzene-treated Syrian hamsters.
The finding that liver necrosis caused by the environmental glutathione (GSH)-depleting chemical, bromobenzene (BB) is associated with marked impairment in O- and S-methylation of BB metabolites in Syrian hamsters raises questions concerning the role of methyl deficiency in BB toxicity. N-Acetylmethionine (NAM) has proven to be an effective antidote against BB toxicity when given after liver GSH has been depleted extensively. The mechanism of protection by NAM may occur via a replacement of methyl donor and/or via an increase of GSH synthesis. If replacement of the methyl donor is an important process, then blocking the resynthesis of GSH in the methyl-repleted hamsters should not decrease NAM protection. This hypothesis was examined in this study. Propargylglycine (PPG), an irreversible inhibitor of cystathionase, was used to inhibit the utilization of NAM for GSH resynthesis. Two groups of hamsters were pretreated with an intraperitoneal (ip) dose of PPG (30 mg/kg) or saline 24 h before BB administration (800 mg/kg, ip). At 5 h after BB treatment, an ip dose of NAM (1200 mg/kg) was given. Light microscopic examinations of liver sections obtained 24 h after BB treatment indicated that NAM provided better protection (P < 0.05) in the PPG + BB + NAM group than in the BB + NAM group. Liver GSH content, however, was lower in the PPG + BB + NAM group than in the BB + NAM group. The Syrian hamster has a limited capability to N-deacetylated NAM. The substitution of NAM with methionine (Met; 450 mg/kg) resulted in a higher level of GSH in the BB + Met group than in the BB + NAM group (P < 0.05). The enhanced protection by PPG in the PPG + BB + NAM group was accompanied by higher (P < 0.05) urinary excretions of specificO- and S-methylated bromothiocatechols than in the BB + NAM group. The results suggest that NAM protection occurs primarily via a replacement of the methyl donor and that methyl deficiency occurring in response to GSH repletion plays a potential role in BB toxicity.


[Violence against women and family medicine].
prevalence of violence against women in Mexico fluctuate within 30 to 60%, but health and court administration institutions' numbers are under real ones, they only include extreme violence or pressed charges against them aggressor. To asses the level of knowledge on the norms and procedures for the attention of domestic violence in family practitioners workers of the Instituto Mexicano del Seguro Social in Colima, México. A cross-sectional study was conducted during the September-December 2005 period. The indicator was obtained of a self-administered questionnaire. The data collection instrument was design to asses the level of knowledge in five areas: definition, norms, classification, risk factors and domestic violence indicators. An knowledge index was constructed and analyzed using frequencies distribution and percentages. The age average was 41 years; medical practice 20 years. 72% men, 28% women; 91% had sentimental couple; 53% was family medicine specialist and 2% mastery; 53% worked in the morning shift and 47% in the evening one. The 91% didn't know the Mexican official norm; 91% without training on domestic violence, 74% ignored the types that exist; 76% ignored the cycles; 63% didn't register it as diagnostic in the clinical file; 52% know that the integral attention health registration leaf has a specific item for this problem. The average of guessed right answers was of 19 (range 15-24). The level of knowledge on the norms and procedures for the attention of domestic violence in family practitioners workers of the Instituto Mexicano del Seguro Social in Colima, México; was low degree in 0%, moderate in 81% and highly in 19%.


Evidence for neuroprotective properties of human umbilical cord blood cells after neuronal hypoxia in vitro.
One of the most promising options for treatment of stroke using adult stem cells are human umbilical cord blood (HUCB) cells that were already approved for therapeutic efficacy in vivo. However, complexity of animal models has thus far limited the understanding of beneficial cellular mechanisms. To address the influence of HUCB cells on neuronal tissue after stroke we established and employed a human in vitro model of neuronal hypoxia using fully differentiated vulnerable SH-SY5Y cells. These cells were incubated under an oxygen-reduced atmosphere (O2< 1%) for 48 hours. Subsequently, HUCB mononuclear cells (MNC) were added to post-hypoxic neuronal cultures. These cultures were characterized regarding to the development of apoptosis and necrosis over three days. Based on this we investigated the therapeutic influence of HUCB MNC on the progression of apoptotic cell death. The impact of HUCB cells and hypoxia on secretion of neuroprotective and inflammatory cytokines, chemokines and expression of adhesion molecules was proved. Hypoxic cultivation of neurons initially induced a rate of 26% +/- 13% of apoptosis. Hypoxia also caused an enhanced expression of Caspase-3 and cleaved poly(ADP-ribose) polymerase (PARP). Necrosis was only detected in low amounts. Within the next three days rate of apoptosis in untreated hypoxic cultures cumulated to 85% +/- 11% (p < or = 0.001). Specific cytokine (VEGF) patterns also suggest anti-apoptotic strategies of neuronal cells. Remarkably, the administration of MNC showed a noticeable reduction of apoptosis rates to levels of normoxic control cultures (7% +/- 3%; p < or = 0.001). In parallel, clustering of administered MNC next to axons and somata of neuronal cells was observed. Furthermore, MNC caused a pronounced increase of chemokines (CCL5; CCL3 and CXCL10). We established an in vitro model of neuronal hypoxia that affords the possibility to investigate both, apoptotic neuronal cell death and neuroprotective therapies. Here we employed the therapeutic model to study neuroprotective properties of HUCB cells. We hypothesize that the neuroprotective effect of MNC was due to anti-apoptotic mechanisms related to direct cell-cell contacts with injured neuronal cells and distinct changes in neuroprotective, inflammatory cytokines as well as to the upregulation of chemokines within the co-cultures.


Control of the translational efficiency of beta-F1-ATPase mRNA depends on the regulation of a protein that binds the 3' untranslated region of the mRNA.
The expression of the nucleus-encoded beta-F1-ATPase gene of oxidative phosphorylation is developmentally regulated in the liver at both the transcriptional and posttranscriptional levels. In this study we have analyzed the potential mechanisms that control the cytoplasmic expression of beta-F1-ATPase mRNA during liver development. Remarkably, a full-length 3' untranslated region (UTR) of the transcript is required for its efficient in vitro translation. When the 3' UTR of beta-F1-ATPase mRNA is placed downstream of a reporter construct, it functions as a translational enhancer. In vitro translation experiments with full-length beta-F1-ATPase mRNA and with a chimeric reporter construct containing the 3' UTR of beta-F1-ATPase mRNA suggested the existence of an inhibitor of beta-F1-ATPase mRNA translation in the fetal liver. Electrophoretic mobility shift assays and UV cross-linking experiments allowed the identification of an acutely regulated protein (3'betaFBP) of the liver that binds at the 3' UTR of beta-F1-ATPase mRNA. The developmental profile of 3'betaFBP parallels the reported changes in the translational efficiency of beta-F1-ATPase mRNA during development. Fractionation of fetal liver extracts revealed that the inhibitory activity of beta-F1-ATPase mRNA translation cofractionates with 3'-UTR band-shifting activity. Compared to other tissues of the adult rat, kidney and spleen extracts showed very high expression levels of 3'betaFBP. Translation of beta-F1-ATPase mRNA in the presence of kidney and spleen extracts further supported a translational inhibitory role for 3'betaFBP. Mapping experiments and a deletion mutant of the 3' UTR revealed that the cis-acting element for binding 3'betaFBP is located within a highly conserved region of the 3' UTR of mammalian beta-F1-ATPase mRNAs. Overall, we have identified a mechanism of translational control that regulates the rapid postnatal differentiation of liver mitochondria.


Effects of Environmental Temperature on the Dynamics of Ichthyophoniasis in Juvenile Pacific Herring (Clupea pallasii).
The effects of temperature and infection by Ichthyophonus were examined in juvenile Pacific herring (Clupea pallasii) maintained under simulated overwinter fasting conditions. In addition to defining parameters for a herring bioenergetics model (discussed in Vollenweider et al. this issue), these experiments provided new insights into factors influencing the infectivity and virulence of the parasite Ichthyophonus. In groups of fish with established disease, temperature variation had little effect on disease outcome. Ichthyophonus mortality outpaced that resulting from starvation alone. In newly infected fish, temperature variation significantly changed the mortality patterns related to disease. Both elevated and lowered temperatures suppressed disease-related mortality relative to ambient treatments. When parasite exposure dose decreased, an inverse relationship between infection prevalence and temperature was detected. These findings suggest interplay between temperature optima for parasite growth and host immune function and have implications for our understanding of how Ichthyophonus infections are established in wild fish populations.


Effect of ischemic postconditioning on infarct size in patients with ST-elevation myocardial infarction treated by primary PCI results of the POSTEMI (POstconditioning in ST-Elevation Myocardial Infarction) randomized trial.
Reduction of infarct size by ischemic postconditioning (IPost) has been reported in smaller proof-of-concept clinical studies, but has not been confirmed in other smaller studies. The principle needs to be evaluated in larger groups of ST-elevation myocardial infarction (STEMI) patients before being implemented in clinical practice. This study assessed the effect of ischemic postcoditioning (IPost) on infarct size in patients with STEMI treated by primary percutaneous coronary intervention (PCI). Patients with first-time STEMI, <6 hours from symptom onset, referred to primary PCI were randomized to IPost or control groups. IPost was administered by 4 cycles of 1-minute reocclusion and 1-minute reperfusion, starting 1 minute after opening, followed by stenting. In the control group, stenting was performed immediately after reperfusion. The primary endpoint was infarct size measured by cardiac magnetic resonance after 4 months. A total of 272 patients were randomized. Infarct size (percent of left ventricular mass) after 4 months (median values and interquartile range) was 14.4% (7.7, 24.6) and 13.5% (8.1, 19.3) in the control group and IPost group, respectively (P=0.18). No significant impact of IPost was found when controlling for baseline risk factors of infarct size in a multivariate linear regression model (P=0.16). The effects of IPost on secondary endpoints, including markers of necrosis, myocardial salvage, and ejection fraction, as well as adverse cardiac events during follow-up, were consistently neutral. In contrast to several smaller trials reported previously, we found no significant effects of IPost on infarct size or secondary study outcomes. http://www.clinicaltrials.gov Unique identifier: NCT.No.PO1506.


Relation of heart rate parameters during exercise test to sudden death and all-cause mortality in asymptomatic men.
Heart rate (HR) profile during exercise predicts all-cause mortality. However, less is known about its relation to sudden (vs nonsudden) death in asymptomatic people. The relation of exercise HR parameters (HR at rest, target HR achievement, HR increase, and HR recovery) with sudden death, coronary heart disease (CHD) death, myocardial infarction, and all-cause mortality was assessed in 12,555 men who participated in MRFIT. Subjects were 35 to 57 years old without clinical CHD, but with higher than average Framingham risk. Trial follow-up was 7 years, and extended follow-up after the trial for all-cause mortality was 25 years. After adjusting for cardiac risk factors, having to stop exercise before achieving 85% of age-specific maximal HR was associated with increased risk of sudden death (hazard ratio 1.8, 95% confidence interval [CI] 1.3 to 2.5, p = 0.001), CHD death (hazard ratio 1.4, 95% CI 1.2 to 1.5, p <0.001), and all-cause mortality (hazard ratio 1.3, 95% CI 1.2 to 1.4, p <0.001). Increased HR at rest (p = 0.001), attenuated HR increase (p = 0.02), delayed HR recovery (p = 0.04), and exercise duration (p <0.0001) were independent predictors of all-cause death in the overall study population and also in the subgroup that achieved target HR. In conclusion, middle-aged men without clinical CHD who stopped exercise before reaching 85% of maximal HR had a higher risk of sudden death. Other exercise HR parameters and exercise duration predicted all-cause mortality.


Perceptual scale expansion: an efficient angular coding strategy for locomotor space.
Whereas most sensory information is coded on a logarithmic scale, linear expansion of a limited range may provide a more efficient coding for the angular variables important to precise motor control. In four experiments, we show that the perceived declination of gaze, like the perceived orientation of surfaces, is coded on a distorted scale. The distortion seems to arise from a nearly linear expansion of the angular range close to horizontal/straight ahead and is evident in explicit verbal and nonverbal measures (Experiments 1 and 2), as well as in implicit measures of perceived gaze direction (Experiment 4). The theory is advanced that this scale expansion (by a factor of about 1.5) may serve a functional goal of coding efficiency for angular perceptual variables. The scale expansion of perceived gaze declination is accompanied by a corresponding expansion of perceived optical slants in the same range (Experiments 3 and 4). These dual distortions can account for the explicit misperception of distance typically obtained by direct report and exocentric matching, while allowing for accurate spatial action to be understood as the result of calibration.


Role of the EGFR/Ras/Raf pathway in specification of photoreceptor cells in the Drosophila retina.
The Drosophila EGF receptor is required for differentiation of many cell types during eye development. We have used mosaic analysis with definitive null mutations to analyze the effects of complete absence of EGFR, Ras or Raf proteins during eye development. The Egfr, ras and raf genes are each found to be essential for recruitment of R1-R7 cells. In addition Egfr is autonomously required for MAP kinase activation. EGFR is not essential for R8 cell specification, either alone or redundantly with any other receptor that acts through Ras or Raf, or by activating MAP kinase. As with Egfr, loss of ras or raf perturbs the spacing and arrangement of R8 precursor cells. R8 cell spacing is not affected by loss of argos in posteriorly juxtaposed cells, which rules out a model in which EGFR acts through argos expression to position R8 specification in register between adjacent columns of ommatidia. The R8 spacing role of the EGFR was partially affected by simultaneous deletion of spitz and vein, two ligand genes, but the data suggest that EGFR activation independent of spitz and vein is also involved. The results prove that R8 photoreceptors are specified and positioned by distinct mechanisms from photoreceptors R1-R7.


Impacts of short-term food restriction on immune development in altricial house sparrow nestlings.
Food limitation is a common ecological scenario for nestling altricial birds, and reductions in growth and maintenance have been observed in resource-limited nestlings. Substantial development of the immune system occurs during the nestling period, yet the resource dependence of this immune development is understudied. We examined constitutive immune system development as well as acute-phase responses to lipopolysaccharide (LPS) injection after 48 h of food restriction in house sparrows at 7 and 13 d posthatch. We also examined nestlings that were restricted early (5-7 d) but refed and tested at 13 d posthatch to determine whether altered immune function and growth early in the nestling period were recovered upon return to adequate resource supply. Induced acute-phase protein response was reduced in food-restricted birds, yet no lasting reductions in acute-phase protein levels were observed in previously restricted nestlings that were challenged with LPS after refeeding. Food restriction did not significantly impact constitutive levels of complement-mediated lysis or circulating IgY antibodies. As a comparator to immune measures, we found that organ and tarsus size, as well as muscle size and citrate synthase enzyme activity (an index of muscle cellular aerobic capacity), were significantly reduced in food-restricted nestlings. Reductions in flight muscle mass and function persisted in birds refed after early food restriction, which may have contributed to persistent body temperature reductions observed in refed birds.


Healthcare data warehouse system supporting cross-border interoperability.
The free movement of European citizens across member states of the European Union adds an important level of complexity to strategic efforts of health interoperability. The use of electronic health data has been marked as an important strategic activity and policy to improve healthcare in European countries. Cross-border healthcare depends on the ability to set up shared practices with respect to patient data exchange across the countries. Data flow must comply with demanding security, legal and interoperability requirements, as defined by the European Patients Smart Open Services project specifications. The aim of this article is to propose a novel design of healthcare data warehouse based on the restructured Extract-Transform-Load process. We describe a portal framework that offers a comprehensive set of interoperability services to enable national e-Health platforms to set up cross-border health information networks compliant with European Patients Smart Open Services. The presented approach incorporates the technical and organizational interoperability by interconnecting Health Level Seven standard and Open National Contact Points framework in order to provide a modular, scalable and inter-operating architecture.


Interstitial Perfusion Culture with Specific Soluble Factors Inhibits Type I Collagen Production from Human Osteoarthritic Chondrocytes in Clinical-Grade Collagen Sponges.
Articular cartilage has poor healing ability and cartilage injuries often evolve to osteoarthritis. Cell-based strategies aiming to engineer cartilaginous tissue through the combination of biocompatible scaffolds and articular chondrocytes represent an alternative to standard surgical techniques. In this context, perfusion bioreactors have been introduced to enhance cellular access to oxygen and nutrients, hence overcoming the limitations of static culture and improving matrix deposition. Here, we combined an optimized cocktail of soluble factors, the BIT (BMP-2, Insulin, Thyroxin), and clinical-grade collagen sponges with a bidirectional perfusion bioreactor, namely the oscillating perfusion bioreactor (OPB), to engineer in vitro articular cartilage by human articular chondrocytes (HACs) obtained from osteoarthritic patients. After amplification, HACs were seeded and cultivated in collagen sponges either in static or dynamic conditions. Chondrocyte phenotype and the nature of the matrix synthesized by HACs were assessed using western blotting and immunohistochemistry analyses. Finally, the stability of the cartilaginous tissue produced by HACs was evaluated in vivo by subcutaneous implantation in nude mice. Our results showed that perfusion improved the distribution and quality of cartilaginous matrix deposited within the sponges, compared to static conditions. Specifically, dynamic culture in the OPB, in combination with the BIT cocktail, resulted in the homogeneous production of extracellular matrix rich in type II collagen. Remarkably, the production of type I collagen, a marker of fibrous tissues, was also inhibited, indicating that the association of the OPB with the BIT cocktail limits fibrocartilage formation, favoring the reconstruction of hyaline cartilage.


Characterization of MEC 14.7, a new monoclonal antibody recognizing mouse CD34: a useful reage for identifying and characterizing blood vessels and hematopoietic precursors.
Endothelial cell-specific molecules are potential targets for new therapeutic strategies in the control of inflammatory reactions, immune responses and neoangiogenesis. We describe the production and characterization of MEC 14.7, a monoclonal antibody directed to murine endothelial cells recognizing a glycosylated protein with an apparent molecular mass of about 100 kDa in cultured endothelioma cell lysate and about 80 kDa in lung lysate. MEC 14.7 antigen was selectively expressed by the endothelium in vivo, particularly in small vessels and neoformed capillaries and by developing vascular structures in embryonal bodies. Deglycosylation of the molecule with neuraminidase, O- and N-glycanase showed that the MEC 14.7 epitope is neuraminidase-sensitive. MEC 14.7 antigen was purified from lung lysates by chromatographic techniques, and sequenced internal peptides indicated it was identical with murine CD34. Thus the apparent molecular mass of CD34 is heterogeneous, depending on the glycosylation state in the different cell types. Immunomagnetic isolation and culture of MEC 14.7-positive bone marrow cells showed that this antibody recognizes hematopoietic progenitors (particularly myelomonocytic) and can be used in murine models of bone marrow reconstitution.


Heterodonty and ontogenetic shift dynamics in the dentition of the tiger shark Galeocerdo cuvier (Chondrichthyes, Galeocerdidae).
The lifelong tooth replacement in elasmobranch fishes (sharks, rays and skates) has led to the assemblage of a great number of teeth from fossil and extant species, rendering tooth morphology an important character for taxonomic descriptions, analysing phylogenetic interrelationships and deciphering their evolutionary history (e.g. origination, divergence, extinction). Heterodonty (exhibition of different tooth morphologies) occurs in most elasmobranch species and has proven to be one of the main challenges for these analyses. Although numerous shark species are discovered and described every year, detailed descriptions of tooth morphologies and heterodonty patterns are lacking or are only insufficiently known for most species. Here, we use landmark-based 2D geometric morphometrics on teeth of the tiger shark Galeocerdo cuvier to analyse and describe dental heterodonties among four different ontogenetic stages ranging from embryo to adult. Our results reveal rather gradual and subtle ontogenetic shape changes, mostly characterized by increasing size and complexity of the teeth. We furthermore provide the first comprehensive description of embryonic dental morphologies in tiger sharks. Also, tooth shapes of tiger sharks in different ontogenetic stages are re-assessed and depicted in detail. Finally, multiple cases of tooth file reversal are described. This study, therefore, contributes to our knowledge of dental traits across ontogeny in the extant tiger shark G. cuvier and provides a baseline for further morphological and genetic studies on the dental variation in sharks. Therefore, it has the potential to assist elucidating the underlying developmental and evolutionary processes behind the vast dental diversity observed in elasmobranch fishes today and in deep time.


Re-entry residency training: opportunities and obstacles.
To identify and quantify the reasons general practitioners and family physicians consider retraining and their reasons for not pursuing further training. Population-based mailed survey. British Columbia. Family physicians and general practitioners identified by the College of Physicians and Surgeons of British Columbia. Practising physicians' level of awareness of the University of British Columbia's re-entry training program, the number and demographic characteristics of those who had considered retraining, their specialties of interest, and the barriers and possible inducements to retraining. Only half of the survey respondents were aware of the re-entry training program at the University of British Columbia. A small but substantial number of practising general practitioners and family physicians were interested in taking specialty training from the Royal College of Physicians and Surgeons of Canada. While several training programs were particularly popular (ie, anesthesia and psychiatry--18.5% of respondents for each), almost every specialty training program was mentioned. Physicians identified the length and hours of training, financial issues, family issues, and the need for relocation as obstacles to retraining. The availability of part-time training, regional training, and return-of-service financial assistance were all identified as potential inducements. To meet the needs of practising physicians, re-entry training programs will need to consider flexibility, where feasible, with regard to choice of specialty, intensity, and location of postgraduate training.


Sex disparity in subsequent outcomes in survivors of coronary heart disease.
Evidence on sex differences in outcomes after developing coronary heart disease (CHD) has focused on recurrent CHD, all-cause mortality or revascularisation. We assessed sex disparities in subsequent major adverse cardiovascular events (MACE) in adults surviving their first-time CHD. Using a population-based cohort obtained from the Clinical Practice Research Datalink (CPRD GOLD) linked to hospitalisation and death records in the UK, we identified 143 702 adults (aged ≥18 years) between 1 January 1998 and 31 December 2017 with no prior history of MACE. MACE outcome was a composite of recurrent CHD, stroke, peripheral vascular disease, heart failure and cardiovascular-related mortality. Multivariable models (Cox and competing risks regressions) were used to assess differences between sexes. There were 143 702 adults with any incident CHD (either angina, myocardial infarction or coronary revascularisation). Women (n=63 078, 43.9%) were older than men (median age, 73 vs 66 years). First subsequent MACE outcome was observed in 91 706 (63.8%). Women had a significantly lower risk of MACE (hazard ratio (HR), 0.68 (95% CI 0.67 to 0.69); sub-hazard ratio (HRsd), 0.71 (0.70 to 0.72), respectively) and recurrent CHD (n=66 543, 46.3%) (HR, 0.60 (0.59 to 0.61); HRsd, 0.62 (0.61 to 0.63)) when compared with men after incident CHD. However, women had a significantly higher risk of stroke (n=5740, 4.0%) (HR, 1.26 (1.19 to 1.33); HRsd, 1.32 (1.25 to 1.39)), heart failure (n=7905, 5.5%) (HR, 1.09 (1.04 to 1.15); HRsd, 1.13 (1.07 to 1.18)) and all-cause mortality (n=29 503, 20.5%) (HR, 1.05 (1.02 to 1.07); HRsd, 1.11 (1.08 to 1.13)). After incident CHD, women have lower risk of composite MACE and recurrent CHD outcomes but higher risk of stroke, heart failure, and all-cause mortality compared with men.


SMLocalizer, a GPU accelerated ImageJ plugin for single molecule localization microscopy.
SMLocalizer combines the availability of ImageJ with the power of GPU processing for fast and accurate analysis of single molecule localization microscopy data. Analysis of 2D and 3D data in multiple channels is supported. Plugin freely available for Fiji and ImageJ2.0 through https://sourceforge.net/projects/smlocalizer/. Plugin also available for continuous updates through ImageJ update system, add http://sites.imagej.net/Cellular-Biophysics-KTH/ as update site in ImageJ. Java and CUDA source code freely available on the web at https://github.com/KristofferBernhem/SMlocalizer. email@example.com. Supplementary data are available at Bioinformatics online.


Psychological aspects of in vitro fertilization: a review.
This paper reviews psychological research within the context of in vitro fertilization (IVF). The focus will be on psychological reactions before entering an IVF-procedure, during an IVF-treatment, and after both unsuccessful and successful IVF. The effects of psychosocial factors on the treatment outcome after IVF and interventions on conception rates will also be discussed. Undergoing an IVF-treatment is an emotional and physical burden, for both the woman and her partner. Research results suggest that couples entering an IVF-treatment program are, in general, psychologically well adjusted. Concerning reactions during the treatment, both women and men experience waiting for the outcome of the IVF-treatment and an unsuccessful IVF. as most stressful. Common reactions during IVF are anxiety and depression, while after an unsuccessful IVF, feelings of sadness, depression and anger prevail. After a successful IVF-treatment, IVF-parents experience more stress during pregnancy than 'normal fertile' parents. Mothers with children conceived by IVF express a higher quality of parent child relationship than mothers with a naturally conceived child. Research further suggests that psychosocial factors, like ineffective coping strategies, anxiety and/or depression are associated with a lower pregnancy rate following IVF-procedures. In addition, support has been found suggesting that stress reduction through relaxation training or behavioral treatment improves conception rates.


Temporal dynamics of neurobehavioral hormone sensitivity in a scaled-down experimental model of early pregnancy and parturition.
The hormonal changes of pregnancy and parturition can trigger robust changes in affective state, particularly among patients with a history of postpartum depression. However, more work is needed to elucidate the temporal dynamics of symptom emergence. The current study explored how quickly hormone-sensitive (HS+) individuals can be differentiated from hormone-insensitive (HS-) controls in the context of a tightly controlled experimental hormone manipulation, and which symptoms demonstrate the most rapid, consistent, and largest response during this protocol. Participants were female, non-pregnant, and euthymic, with a history of DSM-5 major depressive episode with peripartum onset (n = 15) or parous healthy controls with no psychiatric history (n = 15). Perinatal hormonal changes were simulated by inducing hypogonadism, adding back estradiol (E2) and progesterone (P4) to reach first-trimester levels for 8 weeks, and then subsequently withdrawing both hormones. Those reporting a 30% or greater increase during addback or withdrawal on select subscales of the Inventory of Depression and Anxiety Symptoms (IDAS) were identified as HS+. Participants provided daily ratings of symptoms throughout the study via the Daily Record of Severity of Problems. Results indicated that HS+ participants could be differentiated from HS- participants early in the hormone protocol, with many symptoms showing significantly greater change from baseline within the first week of addback. Notably, the most rapid symptom increases were observed for Anger/Irritability, Mood Swings, Overwhelm, Lethargy, Increased Appetite, Joint and Muscle Pain, and Breast Tenderness, reaching 50% of peak group contrast within the first week of hormone addback. The largest group effects were observed for Anger/Irritability, followed by Fatigue and Anxiety, and the most consistent group effects were observed for Anger/Irritability, Interpersonal Conflict, Overwhelm, and Hopelessness. Findings support the role of reproductive hormones in the onset of perinatal affective disorders. The rapid emergence of anger and irritability in HS+ participants suggests that these symptoms may be early indicators of perinatal hormone sensitivity.


The existence of the borderline diagnosis: studies on diagnostic validity.
The author discusses the validity of the borderline concept in terms of the recent empirical research. Five phases of exploration are reviewed; namely, clinical descriptions, laboratory studies, delineation from other disorders, follow-up studies, and family studies. These data are related to the current status of the diagnosis for clinical practice and to areas warranting further research. The conclusions reached show initial support for the validity of the borderline diagnosis. Descriptively, the literature tends to characterize these patients as having impulsivity, heightened affect, mild psychotic reactions and disturbed close relationships. Speculation about possible etiologies is felt to be premature and the identification of meaningful subgroups of patients within this syndrome is not yet possible. Further research using the objective scales in well-defined samples is felt to be required, as are family and prospective follow-up studies.


Higher-band gap soliton formation in defocusing photonic lattices.
We report on the experimental observation of higher-band gap solitons in a one-dimensional photonic lattice possessing a defocusing saturable nonlinearity. Pure Floquet-Bloch modes of the first three bands are excited using a prism-coupler setup, and spatial gap solitons of different width are formed, the latter property being related to the increasing anomalous diffraction in the three bands and the fixed value of the nonlinearity in our lithium niobate sample.


Urinary concentrations of phthalates in couples planning pregnancy and its association with 8-hydroxy-2'-deoxyguanosine, a biomarker of oxidative stress: longitudinal investigation of fertility and the environment study.
Oxidative stress has been recognized as one of the most important contributors to infertility in both males and females. Exposure to many environmental chemicals, such as phthalates, has been shown to induce oxidative stress. In a longitudinal study designed to assess exposure to environmental chemicals and fecundity in couples who were planning pregnancy, 894 urine samples were collected from 469 couples from Michigan and Texas during 2005-2009. The concentrations of 14 phthalate metabolites and a marker of oxidative stress, 8-hydroxy-2'-deoxyguanosine (8-OHdG), were determined in these samples. Concentrations, profiles, and estimated daily intakes (DIs) of phthalates were positively associated with 8-OHdG. The median concentrations of monomethyl phthalate (mMP), monoethyl phthalate (mEP), mono(3-carboxypropyl) phthalate (mCPP), mono-n-butyl phthalate (mBP), mono(2-isobutyl) phthalate (miBP), monobenzyl phthalate (mBzP), Σ5mEHP (sum of five metabolites of di(2-ethylhexyl) phthalate (DEHP)) and Σ14phthalates (sum of 14 urinary phthalate metabolites) were 0.48, 85.2, 4.50, 7.66, 4.36, 3.80, 54.8, and 249 μg/g creatinine, respectively. The estimated DI values for DEHP in 39 individuals were above the U.S. Environmental Protection Agency's (EPA) reference dose (RfD) of 20 μg/kg-bw/day. The mean and median concentrations of 8-OHdG were 6.02 and 3.13 μg/g creatinine, respectively, which were significantly higher in females than in males. Statistically significant associations were found between 8-OHdG and urinary concentrations of mEP, and Σ5mEHP for females. Similarly, a significant association was found between 8-OHdG and DIs estimated for select phthalates. Our results suggested that phthalate exposure increases oxidative stress, which can be a mechanism for the diminished fertility observed in couples who were highly exposed to select phthalates.


A flow-dialysis method for obtaining relative measures of association constants in calmodulin-metal-ion systems.
A flow-dialysis apparatus suitable for the study of high-affinity metal-binding proteins has been utilized to study calmodulin-metal exchange as a measure of relative calmodulin-metal association constants. Calmodulin labelled with radioactive 153Gd was dialysed against buffer containing various competing metal ions. The rate of label exchange was monitored by a gamma-ray scintillation detector. Competing metals used were Ca2+ and Cd2+, and the lanthanides Gd3+, Eu3+, La3+ and Lu3+. All exchange processes were first-order, and two categories of metal were found: Ca2+ and Cd2+ in one, the lanthanides comprising the other. In addition calmodulin-metal complexes with radioactive 109Cd and 45Ca released the bound label without any competing metal being added to the buffer. The kinetics of this metal loss can be described by two consecutive first-order processes, and the fraction of label associated with each rate can be determined. Studies of phosphodiesterase activation by calmodulin show Cd2+ and calmodulin to cause 80% of the maximum activation found when Ca2+ and calmodulin are used.


Spontaneous self-intercalation of copper atoms into transition metal dichalcogenides.
Intercalated transition metal dichalcogenides (TMDs) have attracted substantial interest due to their exciting electronic properties. Here, we report a unique approach where copper (Cu) atoms from bulk Cu solid intercalate spontaneously into van der Waals (vdW) gaps of group IV and V layered TMDs at room temperature and atmospheric pressure. This distinctive phenomenon is used to develop a strategy to synthesize Cu species-intercalated layered TMD compounds. A series of Cu-intercalated 2H-NbS2 compounds were obtained with homogeneous distribution of Cu intercalates in the form of monovalent Cu (I), occupying the tetrahedral sites coordinated by S atoms within the interlayer space of NbS2. The Fermi level of NbS2 shifts up because of the intercalation of Cu, resulting in the improvement of electrical conductivity in the z-direction. On the other hand, intercalation of Cu into vdW gaps of NbS2 systematically suppresses the superconducting transition temperature (T c) and superconducting volume fraction.


A conversation with Oliver Smithies.
Professor Oliver Smithies is the Weatherspoon Eminent Distinguished Professor of Pathology and Laboratory Medicine at the University of North Carolina, Chapel Hill. Along with Mario Capecchi and Martin Evans, Oliver was awarded the Nobel Prize in Medicine in Physiology or Medicine in 2007 for his contributions to the development of gene targeting using homologous recombination in embryonic stem cells. This technique has had an immense impact on biomedical research over the past two decades. Professor Smithies has had a long and distinguished career as a researcher and mentor. Here, he provides an entertaining and enlightening discussion of his life in science.


Simultaneous determination of 4-tert-octylphenol, 4-nonylphenol and bisphenol A in Guanting Reservoir using gas chromatography-mass spectrometry with selected ion monitoring.
The wide occurrence of estrogenic compounds 4-tert-octylphenol, 4-nonylphenol, bisphenol A in surface water of Guanting Reservoir was successfully determined. The target compounds in water samples were preconcentrated by liquid-liquid extraction with dichloromethane, derivatized by trifluoroacetic anhydride, and quantified by gas chromatography-mass spectrometry(GC-MS) with selected ion monitoring (SIM). In the selected seven sampling sites (S1-S7), the concentration of NP in sample S7 was significantly higher than the other in reservoir. The status of pollution in S3 and S7 were much more serious. The concentrations of OP, NP and BPA were in the range of 44.5-48.8, 221.6-349.6 and 30.2-82.7 ng/L, respectively. The pollutants were mainly inputted from the upper river and released from sediments in Guanting Reservoir.


Thoracoscopic assessment of mediastinal tuberculous lymphadenitis in a 4-month-old child.
Isolated mediastinal tuberculous lymphadenitis is a relatively common entity in children, second in frequency after cervical localization. In the absence of an accompanying parenchymal lesion, mediastinal tuberculous lymphadenitis may pose a diagnostic dilemma on admission and must be distinguished from other causes of mediastinal masses. Bronchoscopy is suggested as a diagnostic tool where tuberculosis cannot be excluded by radiology or specific skin tests. Thoracotomy and excision is reported as necessary to treat the obstructive symptoms. In this report, the diagnostic and therapeutic feasibility of thoracoscopic mediastinal node biopsy in a 4-month-old presenting mediastinal tuberculous lymphadenitis is reported.


DNA methylation patterns and gene expression from amygdala tissue of mature Brahman cows exposed to prenatal stress.
Prenatal stress can alter postnatal performance and temperament of cattle. These phenotypic effects may result from changes in gene expression caused by stress-induced epigenetic alterations. Specifically, shifts in gene expression caused by DNA methylation within the brain's amygdala can result in altered behavior because it regulates fear, stress response and aggression in mammals Thus, the objective of this experiment was to identify DNA methylation and gene expression differences in the amygdala tissue of 5-year-old prenatally stressed (PNS) Brahman cows compared to control cows. Pregnant Brahman cows (n = 48) were transported for 2-h periods at 60 ± 5, 80 ± 5, 100 ± 5, 120 ± 5, and 140 ± 5 days of gestation. A non-transported group (n = 48) were controls (Control). Amygdala tissue was harvested from 6 PNS and 8 Control cows at 5 years of age. Overall methylation of gene body regions, promoter regions, and cytosine-phosphate-guanine (CpG) islands were compared between the two groups. In total, 202 genes, 134 promoter regions, and 133 CpG islands exhibited differential methylation (FDR ≤ 0.15). Following comparison of gene expression in the amygdala between the PNS and Control cows, 2 differentially expressed genes were identified (FDR ≤ 0.15). The minimal differences observed could be the result of natural changes of DNA methylation and gene expression as an animal ages, or because this degree of transportation stress was not severe enough to cause lasting effects on the offspring. A younger age may be a more appropriate time to assess methylation and gene expression differences produced by prenatal stress.


Micellization in vegetable oils: A structural characterisation.
The solubilisation of polar and polyphenol antioxidant in vegetable oils was studied. It was shown that the use of a polyglyceryl-3-diisostearate (PG3DS), a bio-sourced emulsifier well known in cosmetics, increases the yield of solubilisation thanks to some aggregation properties analysed using x-ray scattering technique. We show indeed that PG3DS forms reverse aggregates with a critical concentration that depends on the oil polarity. PG3DS reverse aggregates are elongated with a polar core and cannot be really swollen by addition of water. This supramolecular organisation allows however an efficient solubilisation of polar antioxidants in vegetable oils.


Mitotic arrest in Ptk(2) cells induced by microinjection of a rabbit antiserum and affinity-purified antibodies against a 66-kDa PtK(2) cell polypeptide.
Cell division was arrested by injection of a preimmune rabbit serum, B-61, into PtK(2) cells during interphase and prometaphase. Identical results were obtained by injection of whole B-61 antiserum and of antibodies affinity-purified from the serum against a 66-kDa PtK(2) cell polypeptide. When injected into interphase cells, the antibodies arrested further development and cell division. When injected into prometaphase and metaphase cells, spindles shortened and poles moved together at a rate of 0.2-0.4 mu m/min, approximately half the rate of anaphase A chromosome movements in normally dividing PtK(2) cells. Chromosomes decondensed and cells did not reenter division. Both whole antisera and affinity-purified antibodies stained antigens diffusely localized throughout the cytoplasm in dividing and interphase cells. These results suggest that the 66-kDa antigen is a nonspindle protein that may regulate mitotic progression in PtK(2) cells.


The effect of rapid maxillary expansion on conductive hearing loss.
The effects of rapid maxillary expansion (RME) on conductive hearing loss were investigated in 14 subjects (11 females and 3 males). The subjects ranged in age from 10 years 4 months to 16 years 9 months (mean age 12 years 11 months +/- 1 year 9 months) and had narrow maxillary arches and conductive hearing loss. Hearing levels were determined by means of pure-tone audiometric records. Three records were taken for each subject. The first was taken before RME, the second after sufficient midpalatal suture opening was achieved (mean = 15 days), and the third after the retention period (mean = 4.5 months). All the audiometric records were assessed by an otolaryngologist. Changes in both hearing level and air-bone gap were investigated by means of analysis of variance. It has been determined that hearing improved at a statistically significant level (P < 0.05) after the active treatment period, but that the improvement reversed at the end of the retention period. Five patients experienced significant and stable hearing improvement over the duration of this study.


Breast milk as the gold standard for protective nutrients.
In this introductory overview, I explore the observation that breast milk is the gold standard for protective nutrients fed to newborn infants and present clinical evidence of its strong protective effect against age-related infectious gastroenteritis. The composition of breast milk changes according to the newborn infant's needs for passive protection. In addition, substances in breast milk can actively stimulate development of the newborn's host defenses to provide continued mucosal protection after breastfeeding is terminated. Later I present several specific examples of the development of intestinal host defenses due to breastfeeding. An important function of early breastfeeding is its anti-inflammatory effect on the immature, excessive inflammatory response in newborns. Several components of breast milk can reduce the inflammatory response to stimuli in the newborn intestine. These include transforming growth factor (TGF)-beta, interleukin (IL)-10, erythropoietin, and lactoferrin. These components of breast milk can act individually or in concert to contain the neonatal immature anti-inflammatory response.


Genetic Diversity and Population Structure of Pythium irregulare from Soybean and Corn Production Fields in Ohio.
High levels of genetic diversity have been described within the Pythium irregulare complex from several host plants; however, little is known about the population structure in fields used for grain production. Therefore, the objective of this study was to evaluate the genetic diversity and population structure of 53 isolates baited from 28 soybean and corn production fields from 25 counties in Ohio. Genetic diversity was characterized based on sequence analysis of the internal transcribed spacer (ITS1-5.8S-ITS2) region and with 21 simple sequence repeat (SSR) markers. In addition, aggressiveness on soybean, optimum growth temperature, and sensitivity to metalaxyl fungicide were determined. ITS sequence analysis indicated that four isolates clustered with P. cryptoirregulare, whereas the remaining isolates clustered with P. irregulare that was subdivided into two groups (1 and 2). Cluster analysis of SSR data revealed a similar subdivision, which was also supported by structure analysis. The isolates from group 2 grew at a slower rate, but both groups of P. irregulare and P. cryptoirregulare recovered in this study had the same optimum growth at 27°C. Variability of aggressiveness and sensitivity toward metalaxyl fungicide was also observed among isolates within each group. The results from this study will help in the selection of isolates to be used in screening for resistance, assessment of fungicide efficacy, and disease management recommendations.


The myths of motivation: time for a fresh look at some received wisdom in the eating disorders?
The eating disorders typically involve poor motivation to change. This article reviews the evidence behind many of our beliefs about motivation and whether we need a different conceptual framework for understanding why patients commonly get "stuck." The outcome literature is reviewed, and demonstrates that there is little evidence that we are effective in enhancing motivation to induce changes in symptoms. Indeed, there are suggestions that commonly used models are unhelpful. Verbal expressions of motivation are not the best indicator of likely treatment response, and can best be understood as providing a "manifesto," which has functions that can obstruct recovery from the eating disorder. A behavioral analysis of motivation is likely to be more effective. Cognitive, emotional, and behavioral methods for enhancing motivation are outlined, with the aim of bypassing the motivational manifesto and encouraging positive therapeutic change.


Bone Mineral Density Changes during Weight Regain following Weight Loss with and without Exercise.
The purpose of this study was to compare changes in bone mineral density (BMD) over a 6 month follow up (period of weight regain) in overweight, postmenopausal women having previously completed a 6 month weight loss (WL) intervention with and without aerobic exercise (AEX). Women (BMI > 25 kg/m2) underwent VO2max and DEXA scans at baseline, after 6 months of WL or AEX + WL, and at 12 months ad libitum follow up. Both groups lost ~9% body weight from 0 to 6 months and regained ~2% from 6 to 12 months, while losing ~4% of appendicular lean mass (ALM) across the 12-month study duration. VO2max increased 10% from 0 to 6 months and declined 12% from 6 to 12 months for AEX + WL, with no changes for WL. Total body (p < 0.01) and total femur (p = 0.03) BMD decreased similar between groups across time (combined groups: 0-6 months: total body: -1.2% and total femur: -1.2%; 6-12 months: total body: -0.26% and total femur: -0.09%). Less ALM loss and greater VO2max increases during the WL phase were associated with attenuated BMD loss at various anatomical sites during periods of weight regain (6-12 months) p's < 0.05). Results suggest that BMD loss may continue following WL, despite weight regain. Further, this study adds to the literature by suggesting that preventing declines in muscle quality and function during WL may attenuate the loss of BMD during weight regain. Future studies are needed to identify mechanisms underlying WL-induced bone loss so that effective practices can be designed to minimize the loss of BMD during WL and weight maintenance in older women.


Plasma-collection plant has to overcome tainted-blood fallout in search for donors.
Canada's lack of self-sufficiency in blood products has led to the opening of a blood-plasma collection centre in Thunder Bay, Ont.--the first of its type in Canada. In convincing donors to donate plasma, the new centre had to overcome some lingering public concern about the safety of the blood-collection system.


Variation in measures of urea kinetics over four years in a single adult.
Urea kinetics was measured in a single woman on five occasions over four years by the prime/intermittent oral-dose method with [15N15N]-urea. On a nitrogen intake of 231 +/- 24 mg/kg/day, urea production was 198 +/- 22 mg/kg/day, with the urinary excretion of urea being 143 +/- 25 mg/kg/day. Urea hydrolysis and salvaging in the bowel was 55 +/- 6 mgN/kg/day. The coefficients of variation for production, 11 per cent, excretion, 18 per cent, and hydrolysis, 11 per cent, were similar to that for intake, 10 per cent, and substantially less than reported inter-individual variations from other studies. It is concluded that the method employed for measuring urea kinetics gives reproducible results and that the intra-individual variation in urea kinetics is much less than the inter-individual variation.


Testing the utility of internally transcribed spacer sequences in coral phylogenetics.
Reef-building corals often possess high levels of intraindividual and intraspecific ribosomal DNA (rDNA) variation that is largely polyphyletic between closely related species. Polyphyletic rDNA phylogenies coupled with high intraindividual rDNA variation have been taken as evidence of introgressive hybridization in corals. Interpreting the data is problematic because the rDNA cluster evolves in a complex fashion and polyphyletic lineages can be generated by a variety of processes--such as incomplete lineage sorting and slow concerted evolution--in addition to hybridization. Using the genetically characterized Caribbean Acropora hybridization system, we evaluate how well rDNA data perform in revealing patterns of recent introgressive hybridization in contrast to genetic data from four single-copy loci. While the rDNA data are broadly consistent with the unidirectional introgression seen in other loci, we show that the phylogenetic signature of recent introgressive hybridization is obscured in the Caribbean Acropora by ancient shared rDNA lineages that predate the divergence of the species.


Management of respiratory failure in severe neuroparalytic snake envenomation.
Fourteen patients with severe neuroparalytic snake envenomation, resulting in acute type II respiratory failure, admitted to respiratory critical care unit for mechanical ventilation during one year period, were studied. Ventilatory requirements, amount of anti snake venom (ASV) infused, period of neurological recovery and hospital survival were evaluated. All patients had severe manifestations such as ptosis, extraocular muscle paresis and limb weakness along with dyspnoea. Seven patients (50%) had additional complaints of dysphagia and dysphonia. ASV was administered to all, with a median requirement of 900 ml. Mechanical ventilation was required for a median duration of 17 hours and all except one patient, who had suffered irreversible hypoxic cerebral injury prior to resuscitation, survived with complete neurological recovery. We conclude, that the timely institution of ventilatory support and anti-venom therapy in such patients, is associated with an excellent outcome.


Changing the scale: slides and electron microscopy at the Virus Laboratory of the Pasteur Institute.
Slides are material objects, the daily existence of which cannot be diassociated from the practice of microscopy. But what happens to slides when the examination tool is no longer an optical apparatus but an electon microscope? This is the core issue this paper examines. The answer it proposes is that electron microscope slides are not slides in the classical sense of the word but complex arrangements of materials including plates, cards, photographs and notebooks, which constitute an imaginary "slide," an assemblage the status and existence of which is defined in reference to the heritage of optical microscopy. To illustrate this argument, the paper follows the experimental work of Odile Croissant, the first electron microscopist at the Pasteur Institute in Paris during the 1940s and 1950s when the practices of the new microscopy were introduced and calibrated.


Evaluation of fritless solid-phase extraction coupled on-line with capillary electrophoresis-mass spectrometry for the analysis of opioid peptides in cerebrospinal fluid.
Fritless SPE on-line coupled to CE with UV and MS detection (SPE-CE-UV and SPE-CE-MS) was evaluated for the analysis of opioid peptides. A microcartridge of 150 μm id was packed with a C18 sorbent (particle size > 50 μm), which was retained between a short inlet capillary and a separation capillary (50 μm id). Several experimental parameters were optimized by SPE-CE-UV using solutions of dynorphin A (DynA), endomorphin 1 (End1), and methionine-enkephaline (Met). A microcartridge length of 4 mm was selected, sample was loaded for 10 min at 930 mbar and the retained peptides were eluted with 67 nL of an acidic hydro-organic solution. Using SPE-CE-MS, peak area and migration time repeatabilities for the three opioid peptides were 12-27% and 4-5%, respectively. SPE recovery was lower for the less hydrophobic DynA (22%) than for End1 (66%) and Met (78%) and linearity was satisfactory in all cases between 5 and 60 ng/mL. The LODs varied between 0.5 and 1.0 ng/mL which represent an enhancement of two orders of magnitude when compared with CE-MS. Cerebrospinal fluid (CSF) samples spiked with the opioid peptides were analyzed to demonstrate the applicability to biological samples. Peak area and migration time repeatabilities were similar to the standard solutions and the opioid peptides could be detected down to 1.0 ng/mL.


Disclosing a diagnosis of cancer: considerations specific to gynecologic oncology patients.
To characterize gynecologic oncology patients' perceptions of the process of disclosure of a cancer diagnosis. We surveyed 100 gynecologic oncology patients between December 2011 and September 2012. An 83-item tool based on three validated assessment tools evaluated patient-centered factors, physician behavior and communication skills, and environmental factors. Associations between patients' satisfaction and these variables were analyzed using Wilcoxon rank-sum, Kruskal-Wallis, and Spearman's rho tests. Poisson regression was used to assess factors associated with patient's satisfaction. Twenty-four percent of patients were notified of their diagnosis by phone, 60% in the physician's office, and 16% in the hospital. Disclosure was performed by an obstetrician-gynecologist (58%), gynecologic oncologist (26%), primary care physician (8%), or other (8%). Fifty-two percent of all patients were accompanied by a support person. Higher patient satisfaction scores were associated with face-to-face disclosure (mean score 91% compared with over the phone 72%, P=.02), a private setting (mean score 92% compared with impersonal setting 72%, P=.004), and duration of the encounter of greater than 10 minutes (mean score 94% compared with less than 10 minutes 79%, P<.001). Multivariate analysis confirmed that both physician communication skills (P<.001) and patient-centered factors (eg, perception of physician sensitivity and empathy, opportunities to ask questions and express emotion, and set the pace of conversation; P=.013) were associated with higher patient satisfaction. Effective physician communication skills and patient-centered factors resulted in higher patient satisfaction with the gynecologic cancer diagnosis disclosure experience. II.


An unusual cause of dysphagia: thoracic aorta aneurysm.
The vascular structure related compression of esophagus is rather rare. Aberrant right subclavicular artery accounts for the majority of the rare entity, while the thoracic aorta aneurysm is a more dangerous type, called as dysphagia aortica. Delay in diagnosis and treatment of the dysphagia aortica predisposes to rupture and death. Herein, we reported a female patient with thoracic aorta aneurysm. A quick diagnosis by using chest contrast computed tomography (CT) scan and angiography of heart was made, and followed by emergent surgery. In the process, there was no delay on the diagnosis and treatment. The patient is going on well in the follow up.


The protein C pathway.
To examine the role of the protein C anticoagulant pathway in the regulation of microvascular thrombosis. The mechanisms by which inflammation impairs the function of this pathway are also reviewed; conversely, we will survey emerging knowledge of the multiple mechanisms by which the protein C anticoagulant pathway can control the inflammatory response. The information reviewed here was taken from the primary literature, including recent abstracts. All studies that bear directly on the interrelationship between the protein C anticoagulant pathway and inflammation were included, as was a summary of the initial clinical experience with protein C/activated protein C therapy in sepsis. The results from each of the experimental approaches are summarized. Clinical experience with protein C supplementation in sepsis, although promising, is still in the early stages of study. The protein C anticoagulant pathway is a major mechanism in controlling microvascular thrombosis. Protein C deficiency that can occur in sepsis facilitates thrombin generation in the microvasculature, probably augmenting inflammatory responses and contributing to endothelial cell dysfunction. Animal studies and preliminary clinical results suggest that protein C/activated protein C supplementation may be useful in reversing microvascular dysfunction.


Spatially discordant alternans in cardiac tissue: role of calcium cycling.
Spatially discordant alternans, where the action potential duration (APD) and intracellular calcium transient (Ca(i)) alternate with opposite phase in different regions of tissue, is known to promote wave break and reentry. However, this phenomenon is not completely understood. It is known that alternans at the cellular level can be caused by dynamical instabilities arising from either membrane voltage (V(m)) attributable to steep APD restitution or to calcium (Ca) cycling. Here, we used a mathematical model of intracellular Ca cycling, coupled with membrane ion currents, to investigate the dynamics of V(m) and Ca(i) transient alternans in an isolated cell, in two electrotonically coupled cells, and in 1D spatially homogeneous tissue. Our main finding is a novel instability mechanism in which the bidirectional coupling of V(m) and Ca(i) can drive the Ca(i) transient of two neighboring cells to be out of phase. This instability is manifested in cardiac tissue by the dynamical formation of spatially discordant alternans. In this case, Ca(i) transient alternans can reverse phase over a length scale of one cell, whereas APD alternans reverses phase over a much longer length scale set by the electrotonic coupling. We analyze this mechanism in detail and show that it is a robust consequence of experimentally established properties of the bidirectional coupling between Ca cycling and V(m) dynamics. Finally, we address the experimental relevance of these findings and suggest physiological conditions under which these patterns can be observed.


Similar Isokinetic Strength Preinjury and at Return to Sport after Hamstring Injury.
Side-to-side strength differences are often used in return to sport (RTS) decision making after hamstring injury. In football (soccer), there is little consensus, and a side-to-side difference of <10% is often suggested as a criterion. To date, no study has determined whether differences exist when comparing the strength of the injured limb at RTS with the preinjury level. The aims of this study were to compare the isokinetic strength at RTS with preinjury strength in the injured limb and to investigate the side-to-side differences at RTS. This study was based on a pooled group of patients participating in two single-site randomized controlled trials. All eligible professional male soccer players who suffered a hamstring injury confirmed by magnetic resonance imaging were included. The isokinetic strength of the injured limb at RTS was compared with preinjury screening tests, and the side-to-side difference was determined at both time points. In total, 41 hamstring injuries were included in the analyses. Side-to-side differences in isokinetic strength at RTS were similar to preinjury levels. At RTS, the average strength of the injured limb was >95% compared with preinjury strength. Overall, 63.4% of the players had a >10% negative strength difference (i.e., the injured limb being weaker), and 57.9% of the players had a >10% positive strength difference (i.e., the injured limb being stronger) in at least one of the five isokinetic variables. The distribution of isokinetic strength differences when comparing strength at RTS with preinjury measures was similar, urging clinical caution when interpreting these results. Small changes in the isokinetic strength of the injured limb at RTS compared with preinjury strength suggest that isokinetic cutoff values are not useful to guide the restoration of strength as a criterion for RTS after hamstring injury.


A remote patient monitoring system for congestive heart failure.
Congestive heart failure (CHF) is a leading cause of death in the United States affecting approximately 670,000 individuals. Due to the prevalence of CHF related issues, it is prudent to seek out methodologies that would facilitate the prevention, monitoring, and treatment of heart disease on a daily basis. This paper describes WANDA (Weight and Activity with Blood Pressure Monitoring System); a study that leverages sensor technologies and wireless communications to monitor the health related measurements of patients with CHF. The WANDA system is a three-tier architecture consisting of sensors, web servers, and back-end databases. The system was developed in conjunction with the UCLA School of Nursing and the UCLA Wireless Health Institute to enable early detection of key clinical symptoms indicative of CHF-related decompensation. This study shows that CHF patients monitored by WANDA are less likely to have readings fall outside a healthy range. In addition, WANDA provides a useful feedback system for regulating readings of CHF patients.


Soluble components of Utah Valley particulate pollution alter alveolar macrophage function in vivo and in vitro.
Water-soluble extracts of Utah Valley dust (UVD) have been found to cause inflammatory injury of the lung in both humans and rodents. The degree of lung damage found correlated with the metal content in the extracts. In the present study, extracts of a set of UVD PM(10) filters collected over a 3-yr span, varying in total metal content with yr 1 = yr 3 > yr 2, were used to assess effects on human alveolar macrophage (AM) function. The phagocytic activity and oxidative response of AM was investigated 24 h after segmental instillation of UVD, or after overnight in vitro culture of the extracts with AM. Using flow cytometry analysis, AM phagocytosis of fluorescently (FITC)-labeled Saccharomyces cerevisiae was inhibited following instillation of UVD1 (61%) but not by yr 2 and 3. Neither baseline oxidant activity nor phorbol ester-induced oxidant generation was affected by the dust extracts in vivo. Overnight culture of AM with UVD1 resulted in a significant decrease in the percentage of AM phagocytizing particles (30%), while no significant effect on this function was found with the other two extracts. Furthermore, only UVD1 caused an immediate oxidative response in AM, although both UVD1 and UVD3 inhibited oxidant activity in AM when the cells were incubated with the extracts overnight. The detrimental effects on AM host defenses could be due to apoptosis, which was evident in cells exposed to the UVD1 and to a much lesser extent with AM exposed to yr 2 and 3. The component(s) responsible for the toxic effects on AM in vitro were removed by pretreatment of the UVD extracts with a polycation chelating resin, chelex-100. However, since yr 1 and 3 are similar in their soluble metal content, but differ in their effects on AM phagocytosis, it is possible that the metals may not be the culprit in effects of particulate matter on AM host defense.


Discourse, Dissonance, and Dualities: How Drug Shortages Are Understood and Communicated Among Health Care Professionals.
Persistent drug shortages introduce challenges to clinicians and health care systems. We describe an exploratory qualitative study of key informants' perspectives, discourse, and experiences in confronting drug shortages. Semi-structured interviews were conducted with pharmacy directors and bedside clinicians at urban academic medical centers and surrounding community hospitals. Focused coding, reflexive review, and thematic analyses informed by constructionist grounded theory were employed. For some participants, the unpredictability of drug shortages created a siege mentality. Recognition of potentially related patient safety deficits also led to moral distress. Participants were often unprepared to make explicit allocation decisions nor openly discuss drug substitutions with patients. Despite these struggles; participants displayed resilience, and inter-professional teamwork, which eclipsed role constraints and medical hierarchical authority. Varied perspectives and responses are described.


Mechanical validation of whole bone composite femur models.
Composite synthetic models of the human femur have recently become commercially available as substitutes for cadaveric specimens. Their quick diffusion was justified by the advantages they offer as a substitute for real femurs. The present investigation concentrated on an extensive experimental validation of the mechanical behaviour of the whole bone composite model, compared to human fresh-frozen and dried-rehydrated specimens for different loading conditions. First, the viscoelastic behaviour of the models was investigated under simulated single leg stance loading, showing that the little time dependent phenomena observed tend to extinguish within a few minutes of the load application. The behaviour under axial loading was then studied by comparing the vertical displacement of the head as well as the axial strains, by application of a parametric descriptive model of the strain distribution. Finally, a four point bending test and a torsional test were performed to characterize the whole bone stiffness of the femur. In all these tests, the composite femurs were shown to fall well within the range for cadaveric specimens, with no significant differences being detected between the synthetic femurs and the two groups of cadaveric femurs. Moreover, the interfemur variability for the composite femurs was 20-200 times lower than that for the cadaveric specimens, thus allowing smaller differences to be characterized as significant using the same simple size, if the composite femurs are employed.


From α-arylation of olefins to acylation with aldehydes: a journey in regiocontrol of the Heck reaction.
The Pd-catalyzed Mizoroki-Heck reaction of olefins with aryl halides, more often simply called the Heck reaction, was recently recognized with the 2010 Nobel Prize in chemistry. Although highly selective with electron-deficient olefins, which generally yield the linear β-arylated product exclusively, the Heck reaction is less satisfactory with electron-rich olefins. This substrate typically generates a mixture of both α- and β-arylated regioisomeric products, hampering wider application of the reaction in chemical synthesis. Pioneering studies by a number of researchers revealed that high α-regioselectivity could be obtained under Pd-diphosphine catalysis either through (i) the substitution of aryl triflates for halides or (ii) the addition of stoichiometric silver or thallium salts when aryl halides are used. Under these conditions, the arylation is believed to proceed via an ionic pathway. However, silver introduces added cost, thallium salts are toxic, and triflates are generally commercially unavailable, base sensitive, and thermally labile. Believing that the ionic pathway would be promoted in an ionic medium, in the early 2000s, we attempted the Pd-catalyzed arylation of the benchmark electron-rich olefin butyl vinyl ether with aryl bromides in an imidazolium ionic liquid. We were delighted to observe that highly regioselective α-arylation could readily be accomplished, with no need for silver additives, thallium additives, or aryl triflates. A range of other electron-rich olefins has since been shown to be viable as well. The high α-selectivity probably results from the high ionic strength of the medium, which facilitates the dissociation of halide anions from the [L(2)Pd(Ar)X] intermediate, channeling the arylation into the ionic pathway. Hydrogen bonding interactions may also play a role, however. We subsequently discovered that the α-arylation can indeed be significantly accelerated by a hydrogen bond donor salt, in both ionic liquids and common solvents. Evidence shows that the concentration of the cationic Pd(II)-olefin species along the ionic pathway is increased as a result of hydrogen bonding between the hydrogen bond donor and the halide anion. More recently, we reported that cheaper and greener alcohols allow the Heck arylation of electron-rich olefins to proceed in a much faster, productive, and totally α-regioselective manner, circumventing the need for an ionic medium or hydrogen bond donor salt. In particular, aryl chlorides with diverse properties have been demonstrated to be viable substrates for the first time. Significantly, it appears that ethylene glycol facilitates both the oxidative addition of ArCl to Pd(0) and the subsequent dissociation of chloride from Pd(II). A closely related reaction, acylation of aryl halides with aldehydes, was also developed. Proceeding via the intermediacy of an electron-rich enamine, this Pd-pyrrolidine cooperative catalysis affords alkyl aryl ketones in a straightforward manner, extending the Heck reaction from olefins to aldehydes.


Extinction of Cocaine Seeking Requires a Window of Infralimbic Pyramidal Neuron Activity after Unreinforced Lever Presses.
The infralimbic cortex (IL) mediates extinction learning and the active suppression of cocaine-seeking behavior. However, the precise temporal relationship among IL activity, lever pressing, and extinction learning is unclear. To address this issue, we used activity-guided optogenetics in male Sprague Dawley rats to silence IL pyramidal neurons optically for 20 s immediately after unreinforced lever presses during early extinction training after cocaine self-administration. Optical inhibition of the IL increased active lever pressing during shortened extinction sessions, but did not alter the retention of the extinction learning as assessed in ensuing extinction sessions with no optical inhibition. During subsequent cued reinstatement sessions, rats that had previously received optical inhibition during the extinction sessions showed increased cocaine-seeking behavior. These findings appeared to be specific to inhibition during the post-lever press period because IL inhibition given in a noncontingent, pseudorandom manner during extinction sessions did not produce the same effects. Illumination alone (i.e., with no opsin expression) and food-seeking control experiments also failed to produce the same effects. In another experiment, IL inhibition after lever presses during cued reinstatement sessions increased cocaine seeking during those sessions. Finally, inhibition of the prelimbic cortex immediately after unreinforced lever presses during shortened extinction sessions decreased lever pressing during these sessions, but had no effect on subsequent reinstatement. These results indicate that IL activity immediately after unreinforced lever presses is necessary for normal extinction of cocaine seeking, suggesting that critical encoding of the new contingencies between a lever press and a cocaine reward occurs during that period.SIGNIFICANCE STATEMENT The infralimbic cortex (IL) contributes to the extinction of cocaine-seeking behavior, but the precise relationship among IL activity, lever pressing during extinction, and extinction learning has not been elucidated using traditional methods. Using a closed-loop optogenetic approach, we found that selective inhibition of the IL immediately after unreinforced lever pressing impaired within-session extinction learning and promoted the subsequent cued reinstatement of cocaine seeking. These studies suggest that IL activity immediately after the instrumental response during extinction learning of cocaine seeking encodes information required for such learning and that altering such activity produces long-lasting changes in subsequent measures of cocaine craving/relapse.