Randomized double-blind comparison of cetirizine and fexofenadine after pollen challenge in the Environmental Exposure Unit: duration of effect in subjects with seasonal allergic rhinitis.
There is published evidence that cetirizine has a longer duration of effect than fexofenadine. This study compared duration of effect and other measures of efficacy of cetirizine, 10 mg; fexofenadine, 180 mg; and placebo in allergic subjects exposed to pollen in the Environmental Exposure Unit. Eligible subjects (n = 575) were exposed to ragweed pollen (day 1, 7 hours; day 2, 5 hours) and randomized in double-blind fashion to once-daily cetirizine, 10 mg; fexofenadine, 180 mg; or placebo. The total symptom severity complex (TSSC) score, the primary efficacy variable, was based on four rhinoconjunctivitis symptoms rated at 20-minute intervals. Treatment evaluation was divided into three periods: period 1 TSSC, average of 15 scores obtained 0-5 hours after the first dose; period 2 TSSC, average of 9 scores obtained 21-24 hours after the first dose; and period 3 TSSC, average of 6 scores obtained 0-2 hours after the second dose. The primary efficacy end point was the change from baseline TSSC at period 2. Baseline TSSC was the final pretreatment score on day 1 and was 9.7 for cetirizine, 9.8 for fexofenadine, and 9.7 for placebo. For the primary efficacy end point, the reduction in baseline TSSC at period 2 was greater for cetirizine (-3.6) compared with fexofenadine (-2.7; p < 0.001) and placebo (-2.0; p < 0.001), representing a 33% greater reduction for cetirizine versus fexofenadine. Cetirizine continued to reduce TSSC more than fexofenadine (-5.2 versus -4.6; p = 0.017) and placebo (-3.9; p < 0.001) (period 3). Similar efficacy was observed in period 1 for both active treatments. Treatment-related adverse events were similar in all groups with an incidence of somnolence of 1.3% for both active medications. In conclusion, cetirizine produced a 33% greater reduction in SAR symptoms over the 21- to 24-hour interval after the first dose and for 40 minutes after the second dose, indicating a superior and longer duration of effect, which is relevant because both are once-daily medications. Onset of action was comparable and both treatments were safe and well tolerated.


Sodium regulation of agonist binding at opioid receptors. II. Effects of sodium replacement on opioid binding in guinea pig cortical membranes.
We have examined the effects of sodium on the binding of opioid agonists to mu-, delta-, and kappa-receptors in guinea pig cortical membranes. Concentration curves for sodium indicated that maximal inhibition of mu binding by this cation was about 60% and maximal inhibition for delta binding was about 70%, whereas that for kappa binding was only about 20%. The concentration of sodium required for half-maximal inhibition of binding to all three sites was about 10-30 mM, corresponding to the intracellular sodium concentration. The nature of the sodium effect was further characterized by saturation analysis of binding to each of the three receptor types by comparing results obtained in the presence of 120 mM sodium with those obtained with equimolar replacement of sodium by another cation. Two radiolabeled agonists with different structural characteristics were tested for each binding site. In the presence of sodium, the affinity of the labeled agonists for mu sites was approximately 2-3-fold less than in its absence, but the density of binding sites was not changed. At kappa sites, sodium reduced agonist affinity slightly but, again, did not alter the number of binding sites. In contrast, sodium reduced the apparent density of delta-binding sites while leaving the agonist affinity unchanged. Competition against antagonist binding to delta sites indicated that, in the presence of sodium, a higher proportion of sites was in a lower affinity state, as reflected by the biphasic nature of the agonist displacement curve. In contrast, the effect of sodium on displacement of antagonist from mu sites was to of sodium on displacement of antagonist from mu sites was to lower the affinity of the agonist. Competition against antagonist binding to kappa sites also showed a reduction in agonist affinity by sodium, but no change in number of receptors. The results indicate that sodium may differentially regulate agonist binding to opioid receptor types and that this regulation may occur at an intracellular site. The kappa site appears to be less sensitive to sodium than the mu and delta sites.


Retrospective Analysis of CA19-9 Decrease in Patients with Metastatic Pancreatic Carcinoma Treated with FOLFIRINOX or Gemcitabine in a Randomized Phase III Study (ACCORD11/PRODIGE4).
Carbohydrate antigen 19-9 (CA19-9) is a sensitive and specific serum marker in pancreatic cancer. Our retrospective analysis aims to evaluate CA19-9 decrease in patients with metastatic pancreatic cancer treated in ACCORD11/PRODIGE4 (FOLFIRINOX vs. gemcitabine). A total of 342 patients were treated. CA19-9 was measured at 8 weeks (±2) in 160 patients from a total of 282 with abnormal CA19-9 values at baseline (gemcitabine arm, n = 75; FOLFIRINOX arm, n = 85). In the present study, 8-week CA19-9 decrease or greater CA19-9 decrease according to the 20 and 90% thresholds were analyzed. Progression-free survival (PFS) and overall survival (OS) were estimated in each subgroup. In the FOLFIRINOX arm, patients with an 8-week CA19-9 decrease or greater CA19-9 decrease ≥20% showed improved median OS, PFS, and objective response rate. In the overall study population, median OS and PFS were significantly improved in patients with an 8-week CA19-9 decrease ≥20% (vs. <20%). The 8-week CA19-9 decrease was predictive of PFS (interaction test significant according to treatment arm; p = 0.006). An 8-week CA19-9 decrease ≥20% is a prognostic factor for OS and PFS. The 8-week CA19-9 decrease (20% threshold) is predictive of PFS. It could help to evaluate the efficacy of FOLFIRINOX and gemcitabine regimens.


Relation between lead in surface tooth enamel, blood, and saliva from children residing in the vicinity of a non-ferrous metal plant in Belgium.
Two groups of schoolchildren between seven and 12 years old residing in the vicinity of a non-ferrous industrial plant and exposed to lead (Pb) at a concentration that could cause health problems, were monitored. Concentrations of Pb in blood (blood-Pb), which were determined at regular six monthly intervals, were related to the Pb concentrations in surface tooth enamel (enamel-Pb). Acid etch biopsy samples of surface enamel were taken at the end of the five year study period in the first group (A) and after two years in the second group (B). Salivary Pb (saliva-Pb) concentrations were determined for the first study group on the same day that the enamel biopsies were performed. Calibration of the data was necessary--that is, blood-Pb concentration with respect to age and sex and enamel-Pb concentration with respect to etch depth and age. The blood-Pb concentrations declined with time. Surface enamel Pb concentrations correlated with blood-Pb concentration for the period starting with the pre-eruptive development of the incisors, related to blood-Pb concentration for a long time, and corresponded partly to the exposure at the time of pre-eruptive development and/or eruption. Through the correlation with enamel-Pb concentration, the seasonal behaviour of blood-Pb concentration became apparent. Saliva-Pb concentrations related to blood-Pb concentrations only in the short term.


Recovery of polarimetric Stokes images by spatial mixture models.
A Bayesian approach for joint restoration and segmentation of polarization encoded images is presented with emphasis on both physical admissibility and smoothness of the solution. Two distinct models for the sought polarized radiances are used: (i) the polarized light at each site of the image is described by its Stokes vector, which directly follows a mixture of truncated Gaussians, explicitly assigning zero probability to inadmissible configurations and (ii) polarization at each site is represented by the coherency matrix, which is parameterized by a set of variables assumed to be generated by a spatially varying mixture of Gaussians. Application on real and synthetic images using the proposed methods assesses the pertinence of the approach.


Anchor Hole Placement for Bankart Repairs and Its Interaction With Variable Size Hill-Sachs Defects-Minimizing Risk of Glenoid Rim Fractures.
As the use of glenoid suture anchors in arthroscopic and open reconstruction, for instability after Bankart lesions of the shoulder, increases, an emerging problem has been the incidence of glenoid rim fractures through suture drill holes. Very little is known regarding the effect of the Hill-Sachs lesion on the glenoid's susceptibility to fracture and how drill hole location can further affect this. This study used finite element modeling techniques to investigate the risk of fracture of the glenoid rim in relation to variable sized Hill-Sachs defects impacting on the anterior glenoid edge with suture anchor holes placed in varying positions. The distribution of Von Mises (VM) stresses and the factor of safety (FOS) for each of the configurations were calculated. The greatest peak in VM stresses was generated when the glenoid was loaded with a small Hill-Sachs lesion. The VM stresses were lessened and the FOS increased (reducing likelihood of failure) with increasing size of the Hill-Sachs lesion. Placement of the suture drill holes at 2 mm from the glenoid rim showed the highest risk of failure; and when combined with a medium sized Hill-Sachs lesion, which matched the central line of the drill holes, a potentially clinically significant configuration was presented. The results of this study are useful in assisting the surgeon in understanding the interaction between the Hill-Sachs lesion size and the placement of suture anchors with the purpose of minimizing the risk of subsequent rim fracture with new injury.


Retinal projections in the freshwater butterfly fish, Pantodon buchholzi (Osteoglossoidei). I. Cytoarchitectonic analysis and primary visual pathways.
The freshwater butterfly fish, Pantodon buchholzi, is a member of the most primitive radiation of teleosts. The retinofugal projections were studied in this fish with autoradiographic and horseradish peroxidase (HRP) methods, and the cytoarchitecture of the retinorecipient regions in the diencephalon and pretectum was analyzed with Bodian-, cresylecht-violet- and acetylcholinesterase-reacted sections. The rostral diencephalon of Pantodon contains a large retinorecipient nucleus, not previously identified in any other fish, i.e. nucleus rostrolateralis. Other nuclei that are described correspond to those previously recognized in other species. The majority of retinorecipient nuclei are positive for acetylcholinesterase, particularly those in the pretectum, as has been found in other species of teleosts. Most of the retinofugal fibers decussate in the optic chiasm. Some fibers project via the axial optic tract to preoptic nuclei and a region in the rostral hypothalamus. Fibers leave the medial optic tract to terminate in nucleus rostrolateralis and in dorsal and ventral thalamic nuclei, accessory optic and tubercular nuclei, periventricular and central pretectal nuclei, and sparsely in the deep tectal fascicle and terminal field. Dorsal optic tract fibers project to the dorsal accessory optic nucleus, superficial and central pretectal nuclei, and superficial and deep tectal layers. Ventral optic tract fibers project to the superficial pretectum, accessory optic nuclei, posterior tuberculum, nucleus corticalis in the central pretectum, and superficial tectal layer. Fibers that remain in the ipsilateral optic tract project to most of the targets reached by contralaterally projecting fibers. A few fibers in the contralateral medial optic tract redecussate via the posterior commissure to reach the ipsilateral periventricular pretectum. No labeled retinopetal cells caudal to the olfactory bulb were identified in any of the HRP cases.


Screening for cardiovascular risk in patients with severe mental illness in primary care: a comparison with patients with diabetes.
People with severe mental illness (SMI) have a higher risk of developing cardiovascular disease (CVD) compared with the general population. Clinical guidelines recommend annual screening for CVD risk factors with appropriate lifestyle counselling. Aims To establish the proportion of patients with SMI being screened for CVD risk factors in their primary care practice compared with those with diabetes and determine whether people with SMI receive lifestyle advice. METHOD DESIGN: a retrospective audit. five primary care centres in Northampton, England. three hundred and eighty-six patients with SMI and 1875 with diabetes. Just over a fifth of patients with SMI received a full CVD screen compared with the 96% of those with diabetes (OR = 90.37; 95% CI = 64.53-126.55, p < 0.01). Fifty-seven per cent of the SMI patients were given smoking advice but only 13% and 14% received guidance regarding diet and exercise, respectively. On average of each patient with SMI received fewer than two (from four) screening interventions and less than one (from three) components of lifestyle advice. In primary care, the number of people with SMI receiving screening for CVD risk is much lower than those with diabetes.


Femtosecond laser-assisted endothelial keratoplasty: a laboratory model.
To evaluate the ability of a 40-kHz femtosecond laser in performing posterior stromal ablation for endothelial keratoplasty. Human corneoscleral rims were mounted on an artificial anterior chamber. After corneal pachymetry, the femtosecond laser was used to create a donor lenticule by using a variety of diameter ablations, 150 microm from the Descemet membrane. After ablation, the donor lenticule was peeled from the posterior surface and examined under light and scanning electron microscopy. Grading of ease of peeling and removing of the donor lenticule was assessed. The 40-kHz laser was able to produce effective dissection at low power in the posterior stroma. Modification of laser parameter settings was needed to improve the quality of stromal bed ablation. Double pass ablation of the bed significantly improved ease of peeling and removing of the donor lenticule. This was corroborated by smoother ablations on light and scanning electron microscopy. However, multiple pass ablations did not improve vertical rim dissections, which were satisfactory when single passes were used. Femtosecond laser-assisted endothelial keratoplasty is a viable alternative to microkeratome-assisted endothelial keratoplasty. Customized nomograms are needed for deep stromal ablation.


Impact of lower urinary tract symptoms on quality of life using Functional Assessment Cancer Therapy scale.
To assess the impact of lower urinary tract symptoms (LUTS) on general quality-of-life (QOL) measures in an outpatient setting. A total of 1546 male patients aged 51 years or older and scoring more than 11 in the International Prostate Symptom Score completed the general version of the Functional Assessment Cancer Therapy, the Benign Prostatic Hyperplasia Impact Index, and additional questions. Previous prostatic surgery and neurourologic conditions were exclusion criteria, but the use of urologic medication was not. LUTS and QOL were significantly related to age, with older patients presenting with more symptoms and worse QOL. In addition, the results showed negative correlations between LUTS and QOL. The division of the severity groups according to the International Prostate Symptom Score showed that patients from the severe group reported significantly worse QOL compared with the moderate group. The 32% variance in the FACT-G was explained by the International Prostate Symptom Score items, controlling for age. Nocturia combined with incomplete bladder emptying were the strongest predictors of QOL. LUTS have considerable impact on the general well-being of the patient. Combined with age, they can explain up to 30% of the variance in QOL. Nocturia and incomplete emptying are the most troublesome symptoms.


FGFR inhibitor AZD4547 can enhance sensitivity of esophageal squamous cell carcinoma cells with epithelial‑mesenchymal transition to gefitinib.
Activation of fibroblast growth factor receptor (FGFR) signaling occurs in various cancers, including esophageal squamous cell carcinoma (ESCC), however, the effect of targeting FGFR in ESCC is not clear. Herein, we examined the phosphorylation level of FGFR1Y654 (p‑FGFR1) in ESCC cell lines and tumor tissues, as well as the cancer cell killing effects of gefitinib and FGFR inhibitor AZD4547 in combination form or alone in ESCC cells. Immunohistochemistry staining was used to detect the expression level of p‑FGFR1 in 87 ESCC specimens. The effects of gefitinib and FGFR inhibitor AZD4547 on ESCC cells were analyzed by CCK‑8 assay, flow cytometry and western blotting assays. Twenty‑six patients diagnosed with esophageal squamous cell carcinoma (ESCC) (29.9%) were observed with a high level of p‑FGFR1. The proportion of lesions located in the lower segment of the esophagus was significantly higher in the high p‑FGFR1 level group (26.9 vs. 8.2%, P=0.003). The IC50 values of gefitinib alone and in combination with 500 nM AZD4547 were 22.9±2.1 and 4.13±0.12 µM in TE10 cells, and 9.85±5.5 and 3.21±0.76 µM in EC9706 cells, respectively. The combination of AZD4547 and gefitinib induced robust apoptosis and decreased clone formation ability compared to gefitinib monotherapy in the TE10 cells. TE10 cells exhibited a mesenchymal phenotype, with a higher level of p‑FGFR1 and p‑AKT than that in EC9706 cells. AZD4547 and gefitinib co‑treatment resulted in a significant decrease in the level of p‑AKT in TE10 cells and a complete inhibition of phosphorylation of ERK1/2 in EC9706 cells. Collectively, AZD4547 can improve sensitivity of ESCC cells to gefitinib.


Targeting the alternative bile acid synthetic pathway for metabolic diseases.
The gut microbiota is profoundly involved in glucose and lipid metabolism, in part by regulating bile acid (BA) metabolism and affecting multiple BA-receptor signaling pathways. BAs are synthesized in the liver by multi-step reactions catalyzed via two distinct routes, the classical pathway (producing the 12α-hydroxylated primary BA, cholic acid), and the alternative pathway (producing the non-12α-hydroxylated primary BA, chenodeoxycholic acid). BA synthesis and excretion is a major pathway of cholesterol and lipid catabolism, and thus, is implicated in a variety of metabolic diseases including obesity, insulin resistance, and nonalcoholic fatty liver disease. Additionally, both oxysterols and BAs function as signaling molecules that activate multiple nuclear and membrane receptor-mediated signaling pathways in various tissues, regulating glucose, lipid homeostasis, inflammation, and energy expenditure. Modulating BA synthesis and composition to regulate BA signaling is an interesting and novel direction for developing therapies for metabolic disease. In this review, we summarize the most recent findings on the role of BA synthetic pathways, with a focus on the role of the alternative pathway, which has been under-investigated, in treating hyperglycemia and fatty liver disease. We also discuss future perspectives to develop promising pharmacological strategies targeting the alternative BA synthetic pathway for the treatment of metabolic diseases.


Analysis of phenolics in wine by high performance thin-layer chromatography with gradient elution and high resolution plate imaging.
Health benefits of wine, especially with red wine, have been linked to the presence of a wide range of phenolic antioxidants. Thus, the aim of this study was to develop a simple, high performance thin layer chromatographic (HPTLC) method combined with high resolution digital plate images to visually compare multiple wine samples simultaneously on a single chromatographic plate and to quantify levels of gallic acid, caffeic acid, resveratrol and rutin, as representatives of the four different classes of phenolics found in wines. We also wanted to investigate the contribution of the investigated phenolic compounds to the total polyphenolic content (TPC) and total antioxidant capacity (TAC) of the wine samples. The average concentrations of caffeic acid, gallic acid, resveratrol, and rutin in the red wines were 2.15, 30.17, 0.59 and 2.47 mg/L respectively with their concentration below limit of quantification in the white wine samples. The highest concentration of resveratrol and rutin is found in the Cabernet and Shiraz wine samples. The amounts of gallic acid are correlated with TPC (r=0.58). Italian wines have the highest correlation between TPC and TAC (r=0.99) although they do not contain detectable amounts of resveratrol, they contain significant amount of rutin. Therefore, antioxidant properties might be associated with the presence of flavanols in these wines.


Maintenance of smoking cessation.
Relapse is a frequently encountered problem in smoking cessation. With a cognitive-behavioral model of the relapse process, we can describe high-risk situations where smoking first recurs, the process by which people end up in these situations, and typical responses to violations of abstinence. The model posits that individuals are actively coping with situation-specific urges to smoke that result from prior conditioning. Individuals' beliefs in their ability to cope with urges are critical. Clinical strategies based on the model include assessment of risk profiles, understanding and anticipating high-risk situations, debriefing and reinterpreting lapses in abstinence, and limiting risk through lifestyle changes. These strategies can be incorporated into brief medical office visits. Recommended procedures include systematic but brief assessment, encouragement, goal setting, planning for risk, reinterpreting lapses, recommendations for lifestyle changes, and follow-up appointments.


Simultaneous Compared With Interval Medical Abortion Regimens Where Home Use Is Restricted.
To evaluate outcomes with simultaneous administration of mifepristone and misoprostol for medical abortion at 63 days of gestation or less in the year after its implementation in a British clinic system. We conducted a retrospective cohort study using deidentified data from the electronic booking and complications databases and medical records of women who underwent medical abortion at British Pregnancy Advisory Service. Our primary outcome was treatment success with simultaneous dosing compared with a regimen with a 24- to 48-hour interval between medications. We defined success as complete abortion without surgical evacuation and without continuing pregnancy. To assess relative regimen effectiveness while accounting for self-assignment to simultaneous or interval dosing, we modeled the probability of treatment success using logistic regression with propensity score adjustment for demographic and clinical characteristics. Secondary outcomes were reasons for abortion failure and clinically significant adverse events (hospital admission, blood transfusion, intravenous antibiotic administration). Of 28,901 women treated between May 2015 and April 2016, 85% chose simultaneous dosing. Overall success rates were high with both regimens but lower with simultaneous than with interval dosing (94.5% vs 97.1%, respectively, adjusted relative risk 0.973, 95% CI 0.967-0.979). For both regimens, success rates were lower at higher gestational ages, but the relative effectiveness of simultaneous dosing did not vary significantly with gestational age (P=.268). Surgical intervention rates for continuing pregnancy were lowest at 49 days of gestation or less (1.4% simultaneous vs 0.2% interval, P<.001) and highest at 57-63 days of gestation (5.0% and 2.2%, P<.001). The rate of clinically significant adverse events was 0.2% and did not differ by regimen (P=.972). Simultaneous administration of mifepristone and misoprostol is 97% as effective as a 24- to 48-hour interval at all gestational ages 63 days or less with no increase in the risk of clinically significant adverse events. Pragmatic use of simultaneous dosing is reasonable given the small difference in effectiveness.


Interleukin 1-induced calcium signalling in chondrocytes requires focal adhesions.
The cytokine interleukin 1 (IL-1) is an important mediator of connective-tissue destruction in arthritic joints but the mechanisms by which IL-1 mediates signal transduction in chondrocytes is poorly understood. Previous results have indicated that IL-1 receptors co-localize with focal adhesions [Qwarnstrom, Page, Gillis and Dower (1988) J. Biol. Chem. 263, 8261-8269], discrete adhesive domains of cells that function in cell attachment and possibly in signal transduction. We have determined whether focal adhesions restrict IL-1-induced Ca2+ signalling in primary cultures of bovine chondrocytes. In cells grown for 24 h on fibronectin, the basal intracellular Ca2+ ion concentration ([Ca2+]i) was 100+/-3 nM. Optimal increases of [Ca2+]i above baseline were induced by 10 nM IL-1 (183+/-30 nM above baseline). There was no significant difference between cells plated on fibronectin or type II collagen (P>0.2; 233+/-90 nM above baseline). Ca2+ transients were significantly decreased by the inclusion of 0.5 mM EGTA in the bathing buffer (74+/-11 nM above baseline), and 1 microM thapsigargin completely blocked Ca2+ transients. Cells plated on poly-(l-lysine) or suspended cells showed no Ca2+ increases, whereas cells grown on fibronectin exhibited IL-1-induced Ca2+ responses that corresponded temporally to the time-dependent cell spreading after plating on fibronectin. Cells plated on poly-(l-lysine) and incubated with fibronectin-coated beads exhibited vinculin staining in association with the beads. In identical cell preparations, IL-1 induced a 136+/-39 nM increase of [Ca2+]i above baseline in response to 10 nM IL-1beta. There were no IL-1-induced Ca2+ increases when cells on poly-(l-lysine) were incubated with fibronectin-coated beads for only 15 min at 37 degrees C, in cells maintained for 3 h at 4 degrees C, in cells incubated with BSA beads for 3 h at 37 degrees C, or in cells pretreated with cytochalasin D. Labelling of IL-1 receptors with 125I-IL-1beta showed 3-fold more specific labelling of focal adhesion complexes in cells incubated with fibronectin-coated beads compared with cells incubated with BSA-coated beads, indicating that IL-1 receptor binding or the number of IL-1 receptors was increased in focal adhesions. These results indicate that, in chondrocytes, IL-1-induced Ca2+ signalling is dependent on focal adhesion formation and that focal adhesions recruit IL-1 receptors by redistribution in the cell membrane.


Brain structural correlates of psychopathic traits in elite female combat-sports athletes.
Psychopathy is characterized by glibness and superficial charm, as well as a lack of empathy, guilt and remorse, and is often accompanied by antisocial behaviour. The cerebral bases of this syndrome have been mostly studied in violent subjects or those with a criminal history. However, the antisocial component of psychopathy is not central to its conceptualization, and in fact, psychopathic traits are present in well-adjusted, non-criminal individuals within the general population. Interestingly, certain psychopathy characteristics appear to be particularly pronounced in some groups or professions. Importantly, as these so-called adaptive or successful psychopaths do not show antisocial tendencies or have significant psychiatric comorbidities, they may represent an ideal population to study this trait. Here, we investigated such a group, specifically elite female judo athletes, and compared them with matched non-athletes. Participants completed psychopathy, anger, perspective-taking and empathic concern questionnaires and underwent structural magnetic resonance imaging (MRI). Grey matter volume (GMV) was computed using voxel-based morphometry from the T1-weighted images. Athletes scored significantly higher in primary psychopathy and anger and lower in empathy and perspective taking. They also exhibited smaller GMV in the right temporal pole, left occipital cortex and left amygdala/hippocampus. GMV values for the latter cluster significantly correlated with primary psychopathy scores across both groups. These results confirm and extend previous findings to a little-studied population and provide support for the conceptualization of psychopathy as a dimensional personality trait which not only is not necessarily associated with antisocial behaviour but may potentially have adaptive value.


Escherichia coli Attenuation by Fe Electrocoagulation in Synthetic Bengal Groundwater: Effect of pH and Natural Organic Matter.
Technologies addressing both arsenic and microbial contamination of Bengal groundwater are needed. Fe electrocoagulation (Fe-EC), a simple process relying on the dissolution of an Fe(0) anode to produce Fe(III) precipitates, has been shown to efficiently remove arsenic from groundwater at low cost. We investigated Escherichia coli (E. coli) attenuation by Fe-EC in synthetic Bengal groundwater as a function of Fe dosage rate, total Fe dosed, pH, and presence of natural organic matter (NOM). A 2.5 mM Fe dosage simultaneously achieved over 4-log E. coli attenuation and arsenic removal from 450 to below 10 μg/L. E. coli reduction was significantly enhanced at pH 6.6 compared to pH 7.5, which we linked to the decreased rate of Fe(II) oxidation at lower pH. 3 mg/L-C of NOM (Suwanee River fulvic acid) did not significantly affect E. coli attenuation. Live-dead staining and comparisons of Fe-EC with chemical coagulation controls showed that the primary mechanism of E. coli attenuation is physical removal with Fe(III) precipitates, with inactivation likely contributing as well at lower pH. Transmission electron microscopy showed that EC precipitates adhere to and bridge individual E. coli cells, resulting in large bacteria-Fe aggregates that can be removed by gravitational settling. Our results point to the promising ability of Fe-EC to treat arsenic and bacterial contamination simultaneously at low cost.


Triple A syndrome--clinical aspects and molecular genetics.
The triple A syndrome or Allgrove syndrome (MIM*231550) is characterized by adrenocorticotropic hormone (ACTH) resistant Adrenal insufficiency, Achalasia of the cardia and Alacrima. In addition to the main features, patients frequently suffer from neurological disturbances. Dermatological abnormalities such as palmoplantar hyperkeratosis as well as other signs like short stature, microcephaly and osteoporosis point to the multisystemic character of the disorder. The molecular defect of the autosomal recessively inherited triple A syndrome is not known. We initially performed a systematic genome linkage scan in eight triple A families and were able to map the syndrome to a 6 cM interval on human chromosome 12q13 near the type II keratin gene cluster. A refinement of the triple A critical region was achieved by detailed haplotype analysis in a further 37 families from different ethnic backgrounds. There was no indication of genetic heterogeneity. The achalasia-alacrima (AA) syndrome which has been defined as a distinct clinical entity (MIM 200440) is most likely a variant of the triple A syndrome as shown by haplotype analysis in three AA families. We constructed a high-resolution BAC/PAC-based transcript map of the region which will greatly facilitate the identification of the triple A syndrome gene. The considerable intra- and interfamilial variability of the severity of the disorder implies a variable expression of an impaired pleiotropically acting gene.


Abiogenic hydrocarbon production at lost city hydrothermal field.
Low-molecular-weight hydrocarbons in natural hydrothermal fluids have been attributed to abiogenic production by Fischer-Tropsch type (FTT) reactions, although clear evidence for such a process has been elusive. Here, we present concentration, and stable and radiocarbon isotope, data from hydrocarbons dissolved in hydrogen-rich fluids venting at the ultramafic-hosted Lost City Hydrothermal Field. A distinct "inverse" trend in the stable carbon and hydrogen isotopic composition of C1 to C4 hydrocarbons is compatible with FTT genesis. Radiocarbon evidence rules out seawater bicarbonate as the carbon source for FTT reactions, suggesting that a mantle-derived inorganic carbon source is leached from the host rocks. Our findings illustrate that the abiotic synthesis of hydrocarbons in nature may occur in the presence of ultramafic rocks, water, and moderate amounts of heat.


Single-Port Robotic Inguinal Lymph Node Dissection for Penile Cancer.
Inguinal lymph node dissection (ILND) is an essential component in the diagnosis, management, and treatment of penile cancer. Recent advances in minimally invasive surgery may play an important role in decreasing the adverse effects and complications of lymph node dissections. We present our technique utilizing a single-port (SP) robot assisted laparoscopic bilateral ILND in a patient with pT3N2Mx penile cancer s/p partial penectomy and sentinel lymph node biopsy. We present a case of a 64-year-old man who underwent a radical penectomy for previously diagnosed penile cancer. Pathology report showed invasive squamous cell carcinoma of the penis. In accordance with NCCN guidelines, we performed a bilateral inguinal and pelvic lymph node dissection using robotic assisted SP laparoscopy with the DaVinci Single-Site platform. Our methods are detailed in this technical report. Total operative time was 3 hours and 38 minutes in duration with minimal blood loss (<20 mL). A 3 cm inguinal lymph node was excised and positive for malignancy without involvement of other nodes. The patient was discharged 90 minutes after recovery in PACU without narcotics and returned to normal bowel function within 6 hours. We present a successful surgical outcome of a SP robotic ILND in treating a patient with T3N2M0 penile cancer. At the time of publication, the patient is cancer-free with no palpable lymphadenopathy on exam. Utilization of the SP DaVinci system may soon become the standard of care in select cases as it is currently the least invasive approach and is associated with lower morbidity and mortality.


The role of dopamine in the accumbens core in the expression of Pavlovian-conditioned responses.
The role of dopamine in reward is a topic of debate. For example, some have argued that phasic dopamine signaling provides a prediction-error signal necessary for stimulus-reward learning, whereas others have hypothesized that dopamine is not necessary for learning per se, but for attributing incentive motivational value ('incentive salience') to reward cues. These psychological processes are difficult to tease apart, because they tend to change together. To disentangle them we took advantage of natural individual variation in the extent to which reward cues are attributed with incentive salience, and asked whether dopamine (specifically in the core of the nucleus accumbens) is necessary for the expression of two forms of pavlovian-conditioned approach behavior--one in which the cue acquires powerful motivational properties (sign-tracking) and another closely related one in which it does not (goal-tracking). After acquisition of these conditioned responses (CRs), intra-accumbens injection of the dopamine receptor antagonist flupenthixol markedly impaired the expression of a sign-tracking CR, but not a goal-tracking CR. Furthermore, dopamine antagonism did not produce a gradual extinction-like decline in behavior, but maximally impaired expression of a sign-tracking CR on the very first trial, indicating the effect was not due to new learning (i.e. it occurred in the absence of new prediction-error computations). The data support the view that dopamine in the accumbens core is not necessary for learning stimulus-reward associations, but for attributing incentive salience to reward cues, transforming predictive conditional stimuli into incentive stimuli with powerful motivational properties.


Selective efficacy and safety of first line and non front line antineoplasic agent combinations determined with individualized assays on colorectal cancer primary cultures.
To evaluate the efficacy of first-line and not-conventional antineoplastic drug combinations in colorectal adenocarcinoma primary cultures (CRAC PCs). The efficacy and safety of 21 drug combinations (DCs) were evaluated using a simplified adenosine triphosphate-based chemotherapy response assay (sATP-CRA). The efficacy of each DC was reported as the percentage of cell death (PCD) produced on each of 12 CRAC-PCs, and the safety of each DC was evaluated as a safety window (SW). The SW was calculated as the quotient of PCD-CRAC PC/PCD-hMSC-TA (human mesenchymal stem cells derived from adipose tissue). Nine DCs contained 5-fluorouracil and oxaliplatin, and 1-3 non-front line drugs (NFLDs [carboplatin, doxorubicin, cisplatin, aspirin, or 3,3' diindolylmethane]). The other 11 DCs only contained 2-4 NFLDs. The efficacy and safety each DC were highly variable and depended on each CRAC PC and DC. The usefulness of DCs was considered as a combination of PCD >20 and an SW >0.6: 13 /21 DCs (62%) met the requirements of efficacy and safety on 7/12 CRAC PCs (58.3%). The resistance to 5-fluorouracil/oxaliplatin of CRAC PCs and the usefulness of seven new DCs strongly suggest the convenience of performing ex vivo individualized assays to evaluate DCs, and implement new and more useful treatments, instead of submitting patients to standardized chemotherapies in a blinded manner. Approaches such as this and properly evaluated in clinical assays could increase the life expectancy of patients with cancer and improve their quality of life.


The repeatability of serum carotenoid, retinoid, and tocopherol concentrations in specimens of blood collected 15 years apart.
Community-wide programs to collect blood for a research serum bank were carried out in Washington County, Maryland in 1974 and 1989. Of the 8395 persons who participated in both programs, 64 were controls in a nested case-control study of the association of antioxidant micronutrients with subsequent breast cancer, and 30 and 166 were controls in similar studies of lung and prostate cancer. Assay results for five carotenoids, two retinoids, and two tocopherols in samples of blood collected 15 years apart were thus available for comparisons of micronutrient concentrations. The mean Spearman rank order correlation coefficient for all comparisons was 0.44, with two coefficients greater than 0.60 and two less than 0.30. Blood pressure readings at the two blood collections had a mean rank order correlation coefficient of 0.46. Because blood pressure readings in 1974 were shown to be significantly predictive of atherosclerosis 15-18 years later, the present results suggest that ranked concentrations of antioxidant micronutrients from a single sample are sufficiently representative to be used as predictors of subsequent concentrations and are thus suitable for assessment as risk factors for subsequent illnesses.


Immunostimulatory, but not antiendotoxin, activity of lipid X is due to small amounts of contaminating N,O-acylated disaccharide-1-phosphate: in vitro and in vivo reevaluation of the biological activity of synthetic lipid X.
Lipid X, a precursor in the biosynthesis of lipid A, has been claimed to possess most of the immunostimulatory activity but none of the toxicity of endotoxin. However, recent work shows that synthetic lipid X can be contaminated with small amounts of N,O-acylated disaccharide-1-phosphate (H. Aschauer, A. Grob, J. Hildebrandt, E. Schuetze, and P. Steutz, J. Biol. Chem. 265:9159-9164, 1990). Because the impurities themselves exhibit immunostimulatory properties, it was necessary to establish whether chemically pure synthetic lipid X exhibits any of the endotoxinlike biological activities previously attributed to the native compound extracted from the Escherichia coli MN7 mutant. In the present study, two batches of synthetic lipid X were used: batch A contained the contaminating disaccharide, and batch B was pure lipid X. Batch A, previously believed to be pure on the basis of spectroscopic and microanalysis data, induced murine peritoneal macrophages to secrete tumor necrosis factor, interleukin-1, and prostaglandin E2 at a minimal dose of 10 micrograms/ml in vitro. Batch B, further purified by Sephadex LH 20 chromatography, was found virtually inactive in these in vitro assays. Furthermore, batch A was pyrogenic in rabbits at a dose of 0.05 mg/kg, whereas batch B was not pyrogenic at doses of up to greater than or equal to 2 mg/kg. However, both batches were equally tolerated by galactosamine-loaded mice at doses of up to 100 mg/kg. Surprisingly, while only batch A protected neutropenic mice against lethal infection with Pseudomonas aeruginosa (50% effective dose, 12.4 mg/kg), both batches were equally protective against infection with herpes simplex virus type 1 in mice and guinea pigs, even when lipid X was administered therapeutically. Interestingly, both batches of lipid X blocked endotoxin-induced expression of monocyte procoagulant activity and priming of human neutrophils for superoxide anion release. Similarly, both batches protected galactosamine-sensitized mice from otherwise lethal endotoxemia when administered prophylactically or simultaneously with the lipopolysaccharide challenge. Thus, our findings suggest that chemically pure lipid X (batch B) is devoid of the immunostimulatory properties of lipid A or endotoxin. Rather, it behaves as a competitive inhibitor of lipopolysaccharide. We conclude, therefore, that previous studies which attributed immunostimulatory activities to any batch of synthetic lipid X should be interpreted with caution.


[Hypertension in general practice in Switzerland].
Arterial hypertension is a leading problem in general practice. Nevertheless, reliable epidemiological and outcome data on hypertensive patients obtained directly from GPs are scarce. We report some results of our GP cohort "HccHs" of the Institute of general practice Basel. Swiss GPs fill in relevant baseline and follow-up data of their own hypertensive patients in an internnn based questionnaire The first results show a good blood pressure control. 94% of 950 patients receive antihypertensive drug treatment. 24-hour-blood pressure-measurement is helpful for baseline diagnosis and in drug treated hypertensive patients. 24-hour-blood pressure-measurement identifies patients with elevated office but normal 24-hour blood pressure with good prognosis.


Peripheral and central arterial pressure and its relationship to vascular target organ damage in carotid artery, retina and arterial stiffness. Development and validation of a tool. The Vaso risk study.
Ambulatory blood pressure monitoring (ABPM) shows a better correlation to target organ damage and cardiovascular morbidity-mortality than office blood pressure. A loss of arterial elasticity and an increase in carotid artery intima-media thickness (IMT) has been associated with increased cardiovascular morbidity-mortality. Tools have been developed that allow estimation of the retinal arteriovenous index but not all studies coincide and there are contradictory results in relation to the evolution of the arteriosclerotic lesions and the caliber of the retinal vessels. The purpose of this study is to analyze the relationship between peripheral and central arterial pressure (clinic and ambulatory) and vascular structure and function as evaluated by the carotid artery intima-media thickness, retina arteriovenous index, pulse wave velocity (PWV) and ankle-brachial index in patients with and without type 2 diabetes. In turn, software is developed and validated for measuring retinal vessel thickness and automatically estimating the arteriovenous index. A cross-sectional study involving a control group will be made, with a posterior 4-year follow-up period in primary care. The study patients will be type 2 diabetics, with a control group of non-diabetic individuals. Consecutive sampling will be used to include 300 patients between 34-75 years of age and no previous cardiovascular disease, one-half being assigned to each group. age, gender, height, weight and abdominal circumference. Lipids, creatinine, microalbuminuria, blood glucose, HbA1c, blood insulin, high sensitivity C-reactive protein and endothelial dysfunction markers. Clinic and ambulatory blood pressure monitoring. Carotid ultrasound to evaluate IMT, and retinography to evaluate the arteriovenous index. ECG to assess left ventricle hypertrophy, ankle-brachial index, and pulse wave analysis (PWA) and pulse wave velocity (PWV) with the Sphigmocor System. We hope to obtain information on the correlation of different ABPM-derived parameters and PWA to organ target damage--particularly vascular structure and function evaluated from the IMT and PWV--and endothelial dysfunction in patients with and without type 2 diabetes. We also hope to demonstrate the usefulness of the instrument developed for the automated evaluation of retinal vascularization in the early detection of alterations in vascular structure and function and in the prognosis of middle-term cardiovascular morbidity. Clinical Trials.gov Identifier: NCT01325064.


P2X7 Receptor Signaling in Stress and Depression.
Stress exposure is considered to be the main environmental cause associated with the development of depression. Due to the limitations of currently available antidepressants, a search for new pharmacological targets for treatment of depression is required. Recent studies suggest that adenosine triphosphate (ATP)-mediated signaling through the P2X7 receptor (P2X7R) might play a prominent role in regulating depression-related pathology, such as synaptic plasticity, neuronal degeneration, as well as changes in cognitive and behavioral functions. P2X7R is an ATP-gated cation channel localized in different cell types in the central nervous system (CNS), playing a crucial role in neuron-glia signaling. P2X7R may modulate the release of several neurotransmitters, including monoamines, nitric oxide (NO) and glutamate. Moreover, P2X7R stimulation in microglia modulates the innate immune response by activating the NLR family pyrin domain containing 3 (NLRP3) inflammasome, consistent with the neuroimmune hypothesis of MDD. Importantly, blockade of P2X7R leads to antidepressant-like effects in different animal models, which corroborates the findings that the gene encoding for the P2X7R is located in a susceptibility locus of relevance to depression in humans. This review will discuss recent findings linked to the P2X7R involvement in stress and MDD neuropathophysiology, with special emphasis on neurochemical, neuroimmune, and neuroplastic mechanisms.


[Radionuclide radiation monitoring].
Radionuclide radiation monitors used nowadays can operate fairly well in measuring the parameters of the radiation type for which they are intended and calibrated. However, in many cases (particularly in emergency situations) the detector is exposed at a time to several types of radiation. Under such conditions its readings may be noticeably influenced by concomitant radiation. In view of this fact interpretation of the measurement data is embarrassing. Bearing this in mind, it is advisable that the available monitors be modernized and new ones be devised for mixed radiation with the common equivalent surface thickness amounting to 1 g/cm2 of tissue equivalent substance.


Radiographic and clinical outcomes following combined lateral lumbar interbody fusion and posterior segmental stabilization in patients with adult degenerative scoliosis.
A hybrid approach of minimally invasive lateral lumbar interbody fusion (LLIF) followed by supplementary open posterior segmental instrumented fusion (PSIF) has shown promising early results in the treatment of adult degenerative scoliosis. Studies assessing the impact of this combined approach on correction of segmental and regional coronal angulation, sagittal realignment, maximum Cobb angle, restoration of lumbar lordosis, and clinical outcomes are needed. The authors report their results of this approach for correction of adult degenerative scoliosis. Twenty-six patients underwent combined LLIF and PSIF in a staged fashion. The patient population consisted of 21 women and 5 men. Ages ranged from 40 to 77 years old. Radiographic measurements including coronal angulation, pelvic incidence, lumbar lordosis, and sagittal vertical axis were taken preoperatively and 1 year postoperatively in all patients. Concurrently, the visual analog score (VAS) for back and leg pain, the Oswestry Disability Index (ODI), and Short Form-36 (SF-36) Physical Component Summary (PCS) and Mental Component Summary (MCS) scores were used to assess clinical outcomes in 19 patients. At 1-year follow-up, all patients who underwent combined LLIF and PSIF achieved statistically significant mean improvement in regional coronal angles (from 14.9° to 5.8°, p < 0.01) and segmental coronal angulation at all operative levels (p < 0.01). The maximum Cobb angle was significantly reduced postoperatively (from 41.1° to 15.1°, p < 0.05) and was maintained at follow-up (12.0°, p < 0.05). The mean lumbar lordosis-pelvic incidence mismatch was significantly improved postoperatively (from 15.0° to 6.92°, p < 0.05). Although regional lumbar lordosis improved (from 43.0° to 48.8°), it failed to reach statistical significance (p = 0.06). The mean sagittal vertical axis was significantly improved postoperatively (from 59.5 mm to 34.2 mm, p < 0.01). The following scores improved significantly after surgery: VAS for back pain (from 7.5 to 4.3, p < 0.01) and leg pain (from 5.8 to 3.1, p < 0.01), ODI (from 48 to 38, p < 0.01), and PCS (from 27.5 to 35.0, p = 0.01); the MCS score did not improve significantly (from 43.2 to 45.5, p = 0.37). There were 3 major and 10 minor complications. A hybrid approach of minimally invasive LLIF and open PSIF is an effective means of achieving correction of both coronal and sagittal deformity, resulting in improvement of quality of life in patients with adult degenerative scoliosis.


High degree of interlaboratory reproducibility of human immunodeficiency virus type 1 protease and reverse transcriptase sequencing of plasma samples from heavily treated patients.
We assessed the reproducibility of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) and protease sequencing using cryopreserved plasma aliquots obtained from 46 heavily treated HIV-1-infected individuals in two laboratories using dideoxynucleotide sequencing. The rates of complete sequence concordance between the two laboratories were 99.1% for the protease sequence and 99.0% for the RT sequence. Approximately 90% of the discordances were partial, defined as one laboratory detecting a mixture and the second laboratory detecting only one of the mixture's components. Only 0.1% of the nucleotides were completely discordant between the two laboratories, and these were significantly more likely to occur in plasma samples with lower plasma HIV-1 RNA levels. Nucleotide mixtures were detected at approximately 1% of the nucleotide positions, and in every case in which one laboratory detected a mixture, the second laboratory either detected the same mixture or detected one of the mixture's components. The high rate of concordance in detecting mixtures and the fact that most discordances between the two laboratories were partial suggest that most discordances were caused by variation in sampling of the HIV-1 quasispecies by PCR rather than by technical errors in the sequencing process itself.


Sleep effects of Ketogenic diet in pediatric patients with migraine: Preliminary data of a prospective study.
Ketogenic dietary therapies' effects on sleep have been poorly investigated up to date. Preliminary results of a prospective study aimed at evaluating possible sleep changes in pediatric patients with migraine treated with classic ketogenic diet are presented. Included patients were aged 14-18 years and had a diagnosis of chronic migraine. A customized classic ketogenic diet was drawn up for all patients and all participants underwent neurological, nutritional and subjective and objective sleep assessment at baseline and after three months of follow-up (standardized sleep questionnaires, polysomnography, actigraphy). The majority of patients reported an improvement in migraine symptoms and quality of life. As far as sleep effects, a possible sleep stabilization was evidenced according to actigraphic data, and polysomnographic data showed a slight increase in total sleep time and sleep efficiency together with a reduction in waking time during night and a trend of NREM stage 1 decrease and REM increase. Future analyses on a broader population are needed to shed light on the ketogenic dietary therapies' effects on sleep and future research should be devoted to identify influence of possible individual and diet characteristics, and biochemical related changes.


[Assessment of the spiritual needs of patients in palliative care].
The appraisal and the right diagnostics of all needs and problems of patients, including the spiritual needs, are unavoidable for increase of the quality of the all-embracing nursing care. In the case of satisfying of the needs of the patients, it is important to have view the person as a unity of thebody and the soul. Identification and satisfying of the spiritual needs are not uncomplicated; moreover, spirituality does not have a target--ed and clear definition. In the palliative care, the solution and saturation of spiritual needs have a great priority, and it can be the key aspect of psychological activity. Also, medical experts are becoming aware of the meaning of spirituality as the part of psychological contentment more and more. Smaller importance is attached to measurement of spiritual needs, and in many medical institutions ends at the case history with the questions: "Are you a believer?", "Do you have any spiritual needs?". Spirituality and religion are very personal matters of every human. Many patients turn to religion to find answers to difficult questions while others find support through the spiritual beliefs outside the scope of organized religion. Mistaking of meanings of the spirituality and religionism can lead to many misunderstandings. The basic condition for the right diagnostics and satisfaction of spiritual needs are the definition of the used terms and using of standardized measurement devices in the clinical praxis. The target of summarizing study was to define the term of spirituality, to describe a lot of measurement devices these are suitable for the evaluation of human spiritual needs. For methodology for acquiring of the results of research works that are concerned with the questions of spiritual needs in case of the incurable patients, the following databases were used (2005-2013): EBSCO, Bibliographia Medica Čechoslovaca, Google Scholar, Solen - www.solen.cz, Profese on-line as the source of the data. The choice of studies were as follows the systematic overview, the summarizing essay, the qualitative and quantitative study.


Using Potential Outcomes to Understand Causal Mediation Analysis: Comment on.
In this commentary, we demonstrate how the potential outcomes framework can help understand the key identification assumptions underlying causal mediation analysis. We show that this framework can lead to the development of alternative research design and statistical analysis strategies applicable to the longitudinal data settings considered by Maxwell, Cole, and Mitchell (2011).


Predictors of 30-day mortality in patients diagnosed with hepatic encephalopathy on admission to the emergency department.
The aim of this study is to compare the laboratory findings and disease severity scores of patients diagnosed with hepatic encephalopathy (HE) in the emergency department (ED) to predict 30-day mortality. The patients over 18 years old and diagnosed HE in the ED of a tertiary hospital were included in the study. Demographic and clinical characteristics, laboratory parameters, predisposing causes and outcomes of the patients included in the study were recorded in the data form. Severity of liver disease was assessed by Child Pugh Score (CPS), End-stage liver disease model (MELD), MELD-Na and MELD-Lactate scores. Two hundred fifty-four patients diagnosed with HE were included in the study. 59.1% of the patients were male. The mean age of the patients was 65.2 ± 12.6 years. The mortality rate of the patients was 47.2%. When the receiver operating characteristic (ROC) analysis, which determines the predictive properties of laboratory parameters and disease severity scores, was examined, the area under curve value of the MELD-Lactate score (0.858 95% CI 0.812-0.904, P < 0.001) was the highest. Binary logistic regression analysis for the estimation of patients' 30-day mortality showed that CPS and MELD-Lactate scores and blood ammonia and B-type natriuretic peptide levels were independent predictors of mortality. According to the study data, MELD-Lactate and BNP levels in patients diagnosed with HE in the ED may help the clinician in the prediction of 30-day mortality in the early period.


Prognostic Utility of Multivariate Morphometry in Schizophrenia.
Background: Voxel-based morphometry studies have repeatedly highlighted the presence of distributed gray matter changes in schizophrenia, but to date, it is not clear if clinically useful prognostic information can be gleaned from structural imaging. The suspected association between gray matter volume (GMV) and duration of psychotic illness, antipsychotic exposure, and symptom severity also limits the prognostic utility of morphometry. We address the question of whether morphometric information from patients with drug-naive first-episode psychosis can predict the linear trajectory of symptoms following early antipsychotic intervention using a longitudinal design. Method: Sixty-two first-episode, drug-naive patients with schizophrenia underwent brain magnetic resonance imaging scans at baseline, treated with antipsychotics, and rescanned after 1-year follow-up. Positive and Negative Syndrome Scale (PANSS) was used to assess their clinical manifestations. A multivariate approach to detect covariance-based network-like spatial components [Source Based Morphometry (SBM)] was performed to analyze the GMV. Paired t tests were used to study changes in the loading coefficients of GMV in the spatial components between two time points. The reduction in PANSS scores between the baseline (T0) and 1-year follow-up (T1) expressed as a ratio of the baseline scores (reduction ratio) was computed for positive, negative, and disorganization symptoms. Separate multiple regression analyses were conducted to predict the longitudinal change in symptoms (treatment response) using the loading coefficients of spatial components that differed between T0 and T1 with age, gender, duration of illness, and antipsychotic dose as covariates. We also tested the putative "toxicity" effects of baseline symptom severity on the GMV at 1 year using multiple regression analysis. Results: Of the 30 spatial components of gray matter extracted using SBM, loading coefficients of anterior cingulate cortex (ACC), insula and inferior frontal gyrus (IFG), superior temporal gyrus (STG), middle temporal gyrus (MTG), precuenus, and dorsolateral prefrontal cortex (DLPFC) reduced with time in patients. Specifically, the lower volume of insula and IFG at baseline predicted a lack of improvement in positive and disorganization symptoms. None of the symptom severity scores (positive, negative, or disorganization) at baseline independently predicted the reduced GMV at 1 year. Conclusions: The baseline deficit in a covariance-based network-like spatial component comprising of insula and IFG is predictive of the clinical course of schizophrenia. We do not find any evidence to support the notion of symptoms per se being neurotoxic to gray matter tissue. If judiciously combined with other available predictors of clinical outcome, multivariate morphometric information can improve our ability to predict prognosis in schizophrenia.


Mitochondrial cyclophilin-D as a critical mediator of ischaemic preconditioning.
It has been suggested that mitochondrial reactive oxygen species (ROS), Akt and Erk1/2 and more recently the mitochondrial permeability transition pore (mPTP) may act as mediators of ischaemic preconditioning (IPC), although the actual interplay between these mediators is unclear. The aim of the present study is to determine whether the cyclophilin-D (CYPD) component of the mPTP is required by IPC to generate mitochondrial ROS and subsequently activate Akt and Erk1/2. Mice lacking CYPD (CYPD-/-) and B6Sv129 wild-type (WT) mice were used throughout. We have demonstrated that under basal conditions, non-pathological mPTP opening occurs (indicated by the percent reduction in mitochondrial calcein fluorescence). This effect was greater in WT cardiomyocytes compared with CYPD-/- ones (53 ± 2% WT vs. 17 ± 3% CYPD-/-; P < 0.01) and was augmented by hypoxic preconditioning (HPC) (70 ± 9% WT vs. 56 ± 1% CYPD-/-; P < 0.01). HPC reduced cell death following simulated ischaemia-reperfusion injury in WT (23.2 ± 3.5% HPC vs. 43.7 ± 3.2% WT; P < 0.05) but not CYPD-/- cardiomyocytes (19.6 ± 1.4% HPC vs. 24.4 ± 2.6% control; P > 0.05). HPC generated mitochondrial ROS in WT (four-fold increase; P < 0.05) but not CYPD-/- cardiomyocytes. HPC induced significant Akt phosphorylation in WT cardiomyocytes (two-fold increase; P < 0.05), an effect which was abrogated by ciclosporin-A (a CYPD inhibitor) and N-2-mercaptopropionyl glycine (a ROS scavenger). Finally, in vivo IPC of adult murine hearts resulted in significant phosphorylation of Akt and Erk1/2 in WT but not CYPD-/- hearts. The CYPD component of the mPTP is required by IPC to generate mitochondrial ROS and phosphorylate Akt and Erk1/2, major steps in the IPC signalling pathway.


Critical biomechanical and clinical insights concerning tissue protection when positioning patients in the operating room: A scoping review.
An optimal position of the patient during operation may require a compromise between the best position for surgical access and the position a patient and his or her tissues can tolerate without sustaining injury. This scoping review analysed the existing, contemporary evidence regarding surgical positioning-related tissue damage risks, from both biomechanical and clinical perspectives, focusing on the challenges in preventing tissue damage in the constraining operating room environment, which does not allow repositioning and limits the use of dynamic or thick and soft support surfaces. Deep and multidisciplinary aetiological understanding is required for effective prevention of intraoperatively acquired tissue damage, primarily including pressure ulcers (injuries) and neural injuries. Lack of such understanding typically leads to misconceptions and increased risk to patients. This article therefore provides a comprehensive aetiological description concerning the types of potential tissue damage, vulnerable anatomical locations, the risk factors specific to the operative setting (eg, the effects of anaesthetics and instruments), the complex interactions between the tissue damage risk and the pathophysiology of the surgery itself (eg, the inflammatory response to the surgical incisions), risk assessments for surgical patients and their limitations, and available (including emerging) technologies for positioning. The present multidisciplinary and integrated approach, which holistically joins the bioengineering and clinical perspectives, is unique to this work and has not been taken before. Close collaboration between bioengineers and clinicians, such as demonstrated here, is required to revisit the design of operating tables, support surfaces for surgery, surgical instruments for patient stabilisation, and for surgical access. Each type of equipment and its combined use should be evaluated and improved where needed with regard to the two major threats to tissue health in the operative setting: pressure ulcers and neural damage.


Titanium-enriched hydroxyapatite-gelatin scaffolds with osteogenically differentiated progenitor cell aggregates for calvaria bone regeneration.
Adequate bony support is the key to re-establish both function and esthetics in the craniofacial region. Autologous bone grafting has been the gold standard for regeneration of problematic large bone defects. However, poor graft availability and donor-site complications have led to alternative bone tissue-engineering approaches combining osteoinductive biomaterials and three-dimensional cell aggregates in scaffolds or constructs. The goal of the present study was to generate novel cell aggregate-loaded macroporous scaffolds combining the osteoinductive properties of titanium dioxide (TiO2) with hydroxyapatite-gelatin nanocomposites (HAP-GEL) for regeneration of craniofacial defects. Here we investigated the in vivo applicability of macroporous (TiO2)-enriched HAP-GEL scaffolds with undifferentiated and osteogenically differentiated multipotent adult progenitor cell (MAPC and OD-MAPC, respectively) aggregates for calvaria bone regeneration. The silane-coated HAP-GEL with and without TiO2 additives were polymerized and molded to produce macroporous scaffolds. Aggregates of the rat MAPC were precultured, loaded into each scaffold, and implanted to rat calvaria critical-size defects to study bone regeneration. Bone autografts were used as positive controls and a poly(lactic-co-glycolic acid) (PLGA) scaffold for comparison purposes. Preimplanted scaffolds and calvaria bone from pig were tested for ultimate compressive strength with an Instron 4411(®) and for porosity with microcomputerized tomography (μCT). Osteointegration and newly formed bone (NFB) were assessed by μCT and nondecalcified histology, and quantified by calcium fluorescence labeling. Results showed that the macroporous TiO2-HAP-GEL scaffold had a comparable strength relative to the natural calvaria bone (13.8±4.5 MPa and 24.5±8.3 MPa, respectively). Porosity was 1.52±0.8 mm and 0.64±0.4 mm for TiO2-HAP-GEL and calvaria bone, respectively. At 8 and 12 weeks postimplantation into rat calvaria defects, greater osteointegration and NFB were significantly present in the TiO2-enriched HAP-GEL constructs with OD-MAPCs, compared to the undifferentiated MAPC-loaded constructs, cell-free HAP-GEL with and without titanium, and PLGA scaffolds. The tissue-engineered TiO2-enriched HAP-GEL constructs with OD-MAPC aggregates present a potential useful therapeutic approach for calvaria bone regeneration.


Poliovirus-specific polypeptides in infected HeLa cells analysed by isoelectric focusing and 2D-analysis.
Analysis of poliovirus-infected cells by isoelectric focusing in urea resolves at least 25 bands. Combination of isoelectric focusing and sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE) in a two-dimensional analysis (2D-analysis) revealed a much better resolution than each method separately. By 2D-analysis most of the bands could be correlated with the known poliovirus-specific polypeptides generated in the infected cell. With this technique it was possible to determine the apparent isoelectric point (pI) of the identified poliovirus polypeptides. They are in the range from pH 5.6 for polypeptide 7d to pH 8.8 for polypeptide X, which is the most basic found so far.


Effect of 0.25 ppm ozone exposure on pulmonary damage induced by bleomycin.
To study the effect of ozone in a chronically damaged lung, we used a bleomycin (BLM) induced pulmonary fibrosis model. Both endotracheal instillation of BLM and O3 exposure both produce lung inflammation and fibrosis. Oxidative stress would be a common mechanism of damage for both BLM and O3. Our aim was to assess lung injury induced by 5 and 60 days of intermittent exposure to 0.25 ppm O3 in rats with bleomycin-induced pulmonary fibrosis. Thirty-day-old Sprague Dawley rats were endotracheally instilled with BLM (1 U/100 g body weight) and, 30 days later, exposed to 0.25 ppm 03 (0.25 ppm 4 h per day, 5 days a week). Histopatology controls were instilled with saline and breathing room air. Histopathological evaluation of lungs was done 5 and 60 days after O3 exposure. BLM-induced lung damage did not change after 60 days of intermittent O3 exposure. Five days of O3 exposure increased the mean score of BLM-induced pulmonary inflammation and fibrosis (p=0.06). Frequency of bronchopneumonia increased from 1/7 to 6/6 (p <0.001), suggesting that a short-term exposure to O3 in a previously damaged lung might be a risk factor for developing further lung injury.


The antithrombotic activity of EP224283, a neutralizable dual factor Xa inhibitor/glycoprotein IIbIIIa antagonist, exceeds that of the coadministered parent compounds.
EP224283 combines in a single molecule idraparinux and tirofiban, which allows obtaining a predictable and sustained antiplatelet effect through the transfer of the pharmacokinetics properties of idraparinux to the anti-αIIbβ3 antagonist. The activity can be instantaneously neutralized by injection of avidin, a specific antidote. We have tested the effects of this new profile anticoagulant in various thrombosis models. The antithrombotic effect of EP224283 was compared with those of the parent compounds used alone or in association at doses achieving low to moderate inhibition of platelet aggregation ex vivo. In a model of systemic thromboembolism independent of thrombin generation, tirofiban and EP224283 had similar effects at equimolar doses. On the other hand, EP224283 was more potent than tirofiban or idraparinux under thrombin-dependent conditions. In a ferric chloride-induced thrombosis model, EP224283 was more potent than either parent compound or their combination. Similar results were obtained after atherosclerotic plaque rupture in ApoE(-/-) mice. Thus, the dual action of EP224283 exceeds that of the parent compounds used in combination. A possible explanation is that EP224283 could concentrate antithrombin inside the thrombus by binding to αIIbβ3 through the tirofiban moiety, as shown by immunolabeling of the occluded vessel. No prolongation of the bleeding time was observed at doses achieving strong antithrombotic effects, suggesting that low to moderate αIIbβ3 inhibition combined with factor Xa inhibition minimizes the bleeding risk. The favorable antithrombotic profile of EP224283 together with its possible neutralization by avidin makes it an interesting drug candidate for the treatment and prevention of acute ischemic events.


Rectal cancer: comparison of accuracy of local-regional staging with two- and three-dimensional preoperative 3-T MR imaging.
To compare the local-regional staging accuracy of the conventional two-dimensional (2D) T2-weighted imaging protocol and of the three-dimensional (3D) T2-weighted imaging protocol for preoperative magnetic resonance (MR) imaging in rectal cancer patients. This retrospective study was approved by the institutional review board, and a waiver of informed consent was obtained. A review was conducted of 109 preoperative 3-T MR images obtained with 2D and 3D T2-weighted imaging protocols in rectal cancer patients. Two radiologists independently assessed the radiologic findings for T and N category lesions, conspicuity of tumor margin, and image quality of 2D and 3D data. Interactive multiplanar reconstruction was performed for 3D data analysis. The linear weighted kappa values for T2-weighted imaging staging results (2D and 3D data) and histopathologic staging results were calculated and compared. Wilcoxon signed rank test was performed to compare tumoral conspicuity and overall image quality. T category lesion staging accuracy values for 2D and 3D data, respectively, were 66.0% and 67.0% for reviewer 1 (P = .465) and 63.3% and 56.9% for reviewer 2 (P = .402). N category lesion staging accuracy values for 2D and 3D T2-weighted images, respectively, were 64.2% and 57.8% for reviewer 1 (P = .427) and 47.7% and 62.4% for reviewer 2 (P = .666). Tumor conspicuity was better for 2D T2-weighted imaging, but no significant difference in image quality was observed. Preoperative MR imaging in rectal cancer patients for staging with conventional 2D and multiplanar reconstruction 3D T2-weighted imaging protocols showed no significant differences in accuracy of T and N category staging and overall image quality, as determined by degree of artifact. However, the 3D T2-weighted imaging protocol had limitations in regard to lesion conspicuity.


Long-term beta blockers for stable angina: systematic review and meta-analysis.
To assess the effects of long-term beta blockers in patients with stable angina. We reviewed the literature up to June 2010 from CENTRAL, MEDLINE, EMBASE, CBM, and CNKI for randomized controlled trials. The appropriate data were meta-analysed using Revman 5.0. Twenty-six trials including 6108 patients were identified. The treatment with beta blockers has significantly decreased all-cause mortality when compared with no control (OR 0.40, 95% CI 0.20 to 0.79), but has had no statistically differences when compared with placebo (OR 0.92, 95% CI 0.62 to 1.38) and with calcium-channel blocker (CCB) (OR0.84, 95% CI 0.49 to 1.44). This was similar in patients with fatal and non-fatal acute myocardial infarction when compared with placebo (OR 0.82, 95% CI 0.57 to 1.17) or CCB (OR 1.08, 95% CI 0.71 to 1.66); on revascularization and quality of life. The beta blockers reduced the incident of unstable angina compared to no treatment (OR 0.14, 95% CI0.07 to 0.29), but increased unstable angina compared to placebo (OR 3.32, 95% CI 1.50 to 7.36). There was a significant reduction of nitrate consumption when beta blockers were compared with CCBs (OR 1.18, 95% CI 1.54 to 0.82),but not with placebo and trimetazidine. There was no significant difference in angina attack between each group. Side effects in beta blocker were similar with ones in controls. Beta blockers may decrease the death and unstable angina when compared with no treatment, but no more effective than other anti-anginal agents on prophylaxis of myocardial ischaemia in stable angina patients.


Effect of steric restriction on the intracortical distribution of microspheres in the dog kidney.
The effect on the intracortical distribution of microspheres and radioactivity caused by steric hindrance of the free movement of spheres into afferent arterioles are described by two mathematical models. The results are compared with corresponding experimental data obtained in six kidneys from normotensive dogs. The first model (A) assumes that spheres are distributed as blood flow, regardless of their size, except for those having diameters greater than that of an afferent arteriole and which do not enter this vessel. The second model (B) includes the Ferry correction. The experimental data show that the percent recovery of spheres with diameters of 20-25 mum was significantly greater in the outer cortex and significantly less in the juxtamedullary cortex than recovery of the smaller spheres, and that the distribution of spheres with diameters of 10 mum to about 17 mum seems uninfluenced by the sphere size. The experimental results we have obtained fit best with model A. We found that according to both models steric restriction is a factor of major importance in relation to the intracortical distribution of spheres, and the analysis shows that the blood flow in the inner part of the renal cortex is grossly underestimated by the method of isotope labeled microspheres when diameters of 15 +/- 5 mum are used in the dog. Furthermore we found that dilation of the afferent arterioles will change the steric hindrance so that a redistribution of spheres and radioactivity may occur without any redistribution of blood flow. It is suggested that the results interpreted as redistribution of blood flow can be explained as due to altered steric hindrance alone, i.e., as a methodological artifact.


Evaluation of Three Commercial Backpack Sprayers with Aqualuer® 20-20 Against Caged Adult Aedes Aegypti.
Three commercially available backpack sprayers were evaluated with Aqualuer® 20-20 (20.6% permethrin, active ingredient; 20.6% piperonyl butoxide, technical) against caged adult Aedes aegypti in semifield trials in northeastern Florida. Two battery-powered sprayers, Birchmeier and Hudson, were compared with the standard hand-pump SOLO 425 sprayer, which is currently used in pest management operations. Physical characteristics, droplet analysis, and overall ease of use were documented. Multiple dilutions of the insecticide were also evaluated. The results indicated that the Birchmeier sprayer was the preferable machine in terms of its physical characteristics and operator use. There was no significant difference in percent mortality of the test mosquitoes between the sprayers. Multiple dilutions ranging from 1:9 to 1:1050 of the insecticide resulted in greater than 80% mean mortality.


Cisplatin, etoposide and either bleomycin or ifosfamide in the treatment of disseminated germ cell tumors: final analysis of an intergroup trial.
Various staging systems have been proposed for disseminated germ cell neoplasms. The Indiana University staging system was based on clinical and radiographic findings only, whereas the newly created International Germ Cell Cancer Collaborative Group (IGCCCG) staging system also utilized serum markers as a prognostic factor. This study updated the intergroup trial that compared the standard therapy of bleomycin, etoposide, and cisplatin (BEP) with etoposide, ifosfamide, and cisplatin (VIP) in advanced germ cell tumors and reanalyzed the results using the IGCCCG staging system. From October 1987 to April 1992, 304 patients with advanced-stage germ cell tumors (using the Indiana University staging system) were randomized to receive four cycles of BEP or VIP. Two hundred and eighty-six patients were eligible and fully evaluable. With a median follow-up of 7.3 years, 283 of the 286 evaluable patients from the Eastern Cooperative Oncology Group protocol, E3887, were reclassified using the IGCCCG staging system. Progression-free survival (PFS), overall survival (OS), and toxicity were assessed for the treatment arms. With a longer follow-up of 7.3 years and using the Indiana University staging system, the PFS rates were 64% versus 58% and the OS rates were 69% versus 67% in the VIP and BEP arms, respectively. For patients reclassified with the IGCCCG staging system, the PFS rates were 81%, 72%, and 54% and the OS rates were 89%, 81%, and 60% for good, intermediate, and poor-risk patients, respectively. Differences in OS (VIP, 62%; BEP, 57%) and PFS (VIP, 56%; BEP, 49%) for the subset of patients reclassified as poor risk by the IGCCCG staging system were not significantly different. More toxicity, primarily hematologic toxicity, occurred on the VIP arm. With a median follow-up of 7.3 years and with a reclassification based on the IGCCCG, OS and PFS rates were comparable between BEP and VIP. Toxicity, primarily hematologic, was modestly greater with the ifosfamide-containing arm. The VIP regimen may be considered a treatment alternative for patients with underlying pulmonary disease. In most patients with poor and intermediate-risk germ cell tumors, four cycles of BEP remain the standard therapy.


Breast self-examination in adolescents.
Although serious breast lesions are unusual in adolescence, girls should learn how to perform breast self-examination. This will enable them to detect abnormal growths or galactorrhea. It will also encourage them to establish an important lifelong practice while they are young. Respect for the patient's modesty during the course of the demonstration is essential.


Phylogeny of teleost connexins reveals highly inconsistent intra- and interspecies use of nomenclature and misassemblies in recent teleost chromosome assemblies.
Based on an initial collecting of database sequences from the gap junction protein gene family (also called connexin genes) in a few teleosts, the naming of these sequences appeared variable. The reasons could be (i) that the structure in this family is variable across teleosts, or (ii) unfortunate naming. Rather clear rules for the naming of genes in fish and mammals have been outlined by nomenclature committees, including the naming of orthologous and ohnologous genes. We therefore analyzed the connexin gene family in teleosts in more detail. We covered the range of divergence times in teleosts (eel, Atlantic herring, zebrafish, Atlantic cod, three-spined stickleback, Japanese pufferfish and spotted pufferfish; listed from early divergence to late divergence). The gene family pattern of connexin genes is similar across the analyzed teleosts. However, (i) several nomenclature systems are used, (ii) specific orthologous groups contain genes that are named differently in different species, (iii) several distinct genes have the same name in a species, and (iv) some genes have incorrect names. The latter includes a human connexin pseudogene, claimed as GJA4P, but which in reality is Cx39.2P (a delta subfamily gene often called GJD2like). We point out the ohnologous pairs of genes in teleosts, and we suggest a more consistent nomenclature following the outlined rules from the nomenclature committees. We further show that connexin sequences can indicate some errors in two high-quality chromosome assemblies that became available very recently. Minimal consistency exists in the present practice of naming teleost connexin genes. A consistent and unified nomenclature would be an advantage for future automatic annotations and would make various types of subsequent genetic analyses easier. Additionally, roughly 5% of the connexin sequences point out misassemblies in the new high-quality chromosome assemblies from herring and cod.


Accident-injury organization: Canadian overview.
Trauma from motor vehicle accidents is a major health-care problem, resulting in enormous economic losses to the country, and is second only to heart disease as a reason for hospitalization in Canada. Funding fro research and accident-injury programs is critically low. National and provincial trauma registries must be developed to provide data that can be used appropriately to plan and monitor the strategy of accident health-care and prevention programs. Manitoba, which has in place a trauma registry, has a province-wide trauma system comprising two comprehensive trauma units and seven regional centres located strategically in the catchment areas of the major centres. A comparison of the performance of this system with that of hospitals in Baltimore has shown that the Manitoba system provides an equal level of care. The author recommends that a trauma system be established that a trauma system be established in regions of one to two million population. Each region should have one to three comprehensive trauma services and a number of regional trauma services, each strategically located. With appropriate funding for trauma care, the proposed system would pay for itself.


Enhanced excitability induced by ionizing radiation in the kindled rat.
Evidence derived from both clinical and experimental investigations has suggested an influence of ionizing radiation on focal epileptogenicity. To better characterize this influence we applied focal ionizing radiation to a kindled epileptic focus in the rat amygdala. The right and left basolateral amygdala and right frontal cortex were implanted with concentric bipolar electrodes. Rats were kindled through a minimum of 10 stage 5 seizures by afterdischarge-threshold electrostimulation of the left amygdala, after which generalized seizure thresholds were determined prior to irradiation. The left amygdala was exposed to single-fraction central-axis doses of either 18 or 25 Gy using a beam-collimated (60)Co source (1.25 MeV). Generalized seizure thresholds were then redetermined at weekly intervals for 10 weeks and at monthly intervals for an additional 3 months. We observed no significant changes in seizure threshold during the postirradiation interval; however, we did observe persistent changes in seizure dynamics manifesting within the first week postirradiation. These consisted of an increased tendency for seizure activity to propagate into brain stem circuits during the primary ictus (i.e., "running fits") and an increased tendency for secondary convulsions to emerge postictally. These effects involving seizure dynamics have not been reported previously and appear to represent a radiation-induced disinhibition of one or more neural circuits. The disparity between these effects and earlier reports of seizure-suppressive effects resulting from analogous radiation exposures is discussed in relation to kindling and status epilepticus-induced pathogenesis within the hippocampus.


Intravascular plastic catheters. How they potentiate tumor necrosis factor release and exacerbate complications associated with sepsis.
We tested the hypothesis that long-term intravascular cannulation exacerbates the harmful effects of an infectious challenge. Four groups of rats were initially studied: rats without intravascular catheters or infection (group 1), rats without catheters with a polymicrobial infection (group 2), rats with catheters but no infection (group 3), and rats with catheters and infection (group 4). Infected animals had an increased mortality and generated a significantly increased tumor necrosis factor response compared with noninfected animals. Animals with catheters and infection generated far less cardiac output than animals from the other three groups. No histologic changes differentiated the four groups. Therefore, the presence of a sterile intravascular catheter significantly increases cardiac dysfunction and mortality rates in rats with chronic bacteremia. These results suggest that intravascular plastic catheters potentiate the destructive cascade of events produced by the host in response to bacteremia.


Changes in background blood-brain barrier integrity between lacunar and cortical ischemic stroke subtypes.
Lacunar stroke is associated with endothelial dysfunction and histologically with intrinsic cerebral microvascular disease of unknown cause. Endothelial dysfunction could impair blood-brain barrier integrity. We assessed background blood-brain barrier leakage in patients with lacunar ischemic stroke compared with cortical stroke controls. We recruited patients with lacunar or mild cortical ischemic stroke and assessed generalized cerebral blood-brain barrier leak with MRI and intravenous gadolinium at least 1 month after stroke. We used detailed image processing to compare signal change before and for 30 minutes postcontrast throughout gray matter, white matter, and cerebrospinal fluid with summary analyses and general linear modeling. Among 48 patients (29 lacunar, 19 cortical), postcontrast enhancement was significantly higher in cerebrospinal fluid (P=0.04, Mann-Whitney U), and nonsignificantly higher in white matter, in lacunar than in cortical strokes, with no difference in gray matter. General linear modeling confirmed significantly greater postcontrast enhancement in cerebrospinal fluid in lacunar patients than in cortical controls (t=3.37, P<0.0008). These preliminary data suggest that the blood-brain barrier may be dysfunctional throughout subcortical white matter (white matter drains via interstitial spaces to cerebrospinal fluid) in patients with lacunar stroke. Further studies are required to confirm these findings and determine whether abnormal blood-brain barrier might predate development of lacunar disease. Blood-brain barrier dysfunction may be an important mechanism for brain damage in cerebral microvascular disease.


Stereoselective quantification of methadone and a d(6)-labeled isotopomer using high performance liquid chromatography-atmospheric pressure chemical ionization mass-spectrometry: application to a pharmacokinetic study in a methadone maintained subject.
There is evidence that the apparent oral clearance of rac-methadone is induced during the early phase of methadone maintenance treatment. However, it is not known if this is due to changes in bioavailability or if this phenomenon is stereoselective. This knowledge can be obtained by administering a dose of stable-labeled methadone at selected times during ongoing treatment. Therefore, the authors developed a stereoselective high performance liquid chromatography-atmospheric pressure chemical ionization mass-spectrometry assay for the quantification of the enantiomers of methadone and a d(6)-labeled isotopomer. The compounds were quantified in a single assay after liquid-liquid extraction and stereoselective high performance liquid chromatograph with atmospheric pressure chemical ionization-mass spectrometry detection. The following ions were monitored: m/z 310.15 for unlabeled methadone; m/z 316.15 for methadone-d(6); and m/z 313.15 for the methadone-d(3) (internal standard). Calibration curves ranged from 0.5 to 75 ng/mL for each compound. Extraction recovery was approximately 80% for all analytes, without evidence of differences between the unlabeled and stable-labeled compounds or concentration dependency. Minor ion promotion was observed (<15%) but this was identical for all analytes including the d(3)-labeled internal standard, with peak area ratios in extracted samples identical to control injections. The isotopomers did not alter each others' ionisation, even at 10:1 concentration ratios, and 10-fold diluted samples were within 10% of the nominal concentration. Assay performance was acceptable, with interassay and intra-assay bias and precision <10% for all compounds, including the upper and lower limits of quantitation. In conclusion, the assay was successfully applied to quantify the concentration of the methadone enantiomers of both orally administered unlabeled methadone and an intravenous 5 mg dose of methadone-d(6) in a patient receiving chronic oral methadone maintenance therapy.


The development of temperament and maternal perception of child: A cross-cultural examination in the United States and Japan.
Previous research shows cross-cultural differences in adult personality and child temperament, yet the developmental origin of these cultural differences remains unclear. To understand a potential role of socialization grounded in cultural values, this study investigated culturally specific maternal perceptions of child and children's development of temperament in the U.S. and Japan. Maternal perception of child was assessed via maternal interview in the U.S. (n = 42) and Japan (n = 40). Six months after the interview, child's temperament was assessed. Cross-cultural differences in maternal perception of child and child's temperament, and the relation between the two were analyzed. US-American infants scored higher on the surgency/extraversion trait than Japanese infants, whereas Japanese infants scored higher on the negative affectivity/neuroticism trait than US-American infants. US-American mothers used more positive evaluation and private/autonomy descriptions of their infants, whereas Japanese mothers used more negative evaluation and context-specific descriptions of their infants by making references to other people, time, or location. Child's negative affectivity trait was closely related to maternal perception of child's social/context characteristics and negative evaluations. The findings provide support for the socio-cultural framework of temperament development and suggest an important consideration of cultural factors when designing educational and parenting programs.


Neuroplasticity in cigarette smokers is altered under withdrawal and partially restituted by nicotine exposition.
Nicotine improves cognitive functions by modulating neuroplasticity and cortical excitability in nonsmoking subjects. As shown recently, the positive effect of nicotine on cognition might at least partially be caused by a focusing effect of nicotine on neuroplasticity in these subjects. Concordant to this, smokers under nicotine withdrawal show reduced cognitive abilities, which are at least partially restituted by nicotine consumption. We aimed to explore the neurophysiological foundation of these effects by exploring nonfocal and focal plasticity-inducing protocols in human smokers under nicotine withdrawal and exposition. Focal, synapse-specific plasticity was induced by paired associative stimulation (PAS), while nonfocal plasticity was induced by transcranial direct current stimulation (tDCS). Each subject (12) received placebo and nicotine patches combined with one of the stimulation protocols to the primary motor cortex. Corticospinal excitability was monitored by transcranial magnetic stimulation-induced motor-evoked potential amplitudes. In smokers during nicotine withdrawal, facilitatory plasticity induced by tDCS and PAS was abolished, but restituted by nicotine. In contrast, excitability-diminishing plasticity was not affected by nicotine withdrawal. Under nicotine, the inhibitory aftereffects of PAS were delayed and prolonged, while the tDCS-generated excitability reduction was abolished. Thus, absent facilitatory plasticity in smokers during nicotine withdrawal is restituted by nicotine, favoring the deficit-compensating hypothesis of nicotine consumption. These results might shed further light on the proposed mechanism of nicotine on cognition and attention, which might be connected to nicotine addiction and probability of relapse in smokers.


The effects of vagus nerve stimulation on cognitive performance in patients with treatment-resistant depression.
Chronic vagus nerve stimulation (VNS) is effective in the management of treatment-resistant epilepsy. Open-trial evidence suggests that VNS has clinically significant antidepressant effects in some individuals who experience treatment-resistant major depressive episodes. However, limited information regarding the effects of VNS on neurocognitive performance exists. The primary aim of this study was to determine whether VNS leads to neurocognitive deterioration. A neuropsychological battery was administered to 27 patients with treatment-resistant depression before and after 10 weeks of VNS. Thirteen neurocognitive tests sampled the domains of motor speed, psychomotor function, language, attention, memory, and executive function. No evidence of deterioration in any neurocognitive measure was detected. Relative to baseline, improvement in motor speed (finger tapping), psychomotor function (digit-symbol test), language (verbal fluency), and executive functions (logical reasoning, working memory, response inhibition, or impulsiveness) was found. For some measures, improved neurocognitive performance correlated with the extent of reduction in depressive symptoms, but VNS output current was not related to changes in cognitive performance. Vagus nerve stimulation in treatment-resistant depression may result in enhanced neurocognitive function, primarily among patients who show clinical improvement. Controlled investigation is needed to rule out the contribution of practice effects.


Characteristics in childhood and adolescence associated with future multiple sclerosis risk in men: cohort study.
Associations with multiple sclerosis (MS) of living conditions in childhood and characteristics in adolescence including physical fitness, cognitive function and psychological stress resilience were investigated. A cohort of male Swedish residents born 1952-1956 who were included in the Swedish Military Conscription Register was used to create a nested case-control study comprising 628 MS cases and 6187 controls matched on birth year, county of residence and vital status at time of diagnosis. Conscription examination records were linked with other national register data. Conditional logistic regression was used to evaluate associations with MS subsequent to the conscription examination. Men with MS were less likely to be from more crowded households in childhood (>two persons per room) with an adjusted odds ratio of 0.67 (95% confidence interval 0.51-0.86, P = 0.023). They had lower physical working capacity in adolescence with adjusted odds ratio of 0.94 (95% confidence interval 0.89-0.99, P = 0.026). Cognitive function and stress resilience scores displayed no significant differences between cases and controls. Parental occupation in childhood and body mass index in adolescence were not associated with future MS risk. The inverse association of MS risk with higher levels of household crowding may reflect environmental factors such as the pattern of exposure to microorganisms. Lower physical fitness in men at MS risk may indicate a protective effect of exercise or could be due to prodromal disease activity, although there was no association with cognitive function. Poor psychological stress resilience (and thus risk of chronic stress arousal) was not associated with MS.


Perspective: a practical approach to defining professional practice gaps for continuing medical education.
The Accreditation Council for Continuing Medical Education mandates that continuing medical education (CME) be developed around professional practice gaps. Accordingly, CME course directors must identify the intended learners, assess learners' needs, identify gaps in knowledge, and evaluate their CME activities. Writing gap statements is challenging for CME course directors because there is not a universally accepted format for writing these statements. The authors describe a practical approach to defining gaps for CME accreditation, which involves four steps indicated by the mnemonic LASO (learner, assessment, standard, outcomes): (1) define the learner population's characteristics, (2) create a learning needs assessment, (3) determine if the standard is met, and (4) state educational outcome for the CME activity. Based on this model, the difference between the practice standard and the current practice represents the gap in practice. The LASO approach has assisted in making CME content learner centered, relevant, and measurable at the authors' institution. The authors anticipate that LASO will be able to provide all CME course directors with a practical approach to defining educational gaps for CME accreditation.