Selective targeting by preS1 domain of hepatitis B surface antigen conjugated with phosphorylcholine-based amphiphilic block copolymer micelles as a biocompatible, drug delivery carrier for treatment of human hepatocellular carcinoma with paclitaxel.
Using dithioester-capped 2-methacryloyloxyethyl phosphorylcholine (MPC) as a macro chain transfer agent, a diblock copolymer was synthesized with n-butyl methacrylate (BMA) as hydrophobic core-forming blocks. The MPC-BMA unit was copolymerized with an immobilizable unit, p-nitrophenylcarbonyloxyethyl methacrylate (NPMA). The NPMA moiety then was modified by the addition of preS1 domain of hepatitis B surface antigen (HBsAg). This micelle-forming nanoparticle, the poly (MPC-co-BMA-co-NPMA) (PMBN) conjugated with preS1 enables solubilization of paclitaxel (PTX) with increased hepatotropism. The 50% inhibitory concentration (IC(50)) values of PTX and PTX/PMBN-preS1 against the human hepatocellular carcinoma cell line, HepG2, were 1,008 and 131 nM, respectively (p < 0.05). Conjugation of preS1 to PMBN enhanced strongly the synergistic inhibitory effect of paclitaxel on HepG2 cells in vitro, whereas such a change in IC(50) was not detected against the human squamous cell carcinoma cell line, A431. Tumor growth rates of a HepG2 xenograft in Balb/c nude mice after intraperitoneal injection of PTX, PTX/PMBN and PTX/PMBN-preS1 were +97.9%, -74.3% and -96.2%*, respectively (*p < 0.05 versus PTX). The local paclitaxel levels after administration of the PMBN-preS1 conjugate were determined in the xenografts by high-performance liquid chromatography and were 8 times higher than that after administration of paclitaxel alone. No side effects attributable to PMBN-preS1 were observed histologically in vital organs, and body weight loss was significantly less in the PTX/PMBN-preS1 group. These studies demonstrate that PMBN-preS1 may be used as a human hepatocyte-specific drug delivery carrier without serious adverse effects.


In Vitro Susceptibility Testing of Bedaquiline against Mycobacterium abscessus Complex.
We performed bedaquiline broth microdilution susceptibility testing using Clinical and Laboratory Standards Institute (CLSI) guidelines on 104 nonduplicate isolates of Mycobacterium abscessus complex [M. abscessus subsp. abscessus (76); M. abscessus subsp. massiliense (10); M. abscessus subsp. bolletii (2); and M. abscessus subsp. abscessus-M. abscessus subsp. massiliense hybrid, i.e., M. abscessus subsp. abscessus by rpoB gene and M. abscessus subsp. massiliense by erm(41) gene (16)]. All isolates from patients not known to have been on bedaquiline prior had MIC values of ≤0.25 μg/ml. The bedaquiline MIC50 value for all 76 isolates of M. abscessus subsp. abscessus and 16 isolates of M. abscessus subsp. abscessus-M. abscessus subsp. massiliense hybrid was 0.06 μg/ml. The MIC50 and MIC90 values for 10 isolates of M. abscessus subsp. massiliense were 0.12 μg/ml. Only two isolates of M. abscessus subsp. bolletii were tested with bedaquiline MICs of 0.06 μg/ml. Our study suggests that oral bedaquiline may have potential use in the treatment of disease caused by the M. abscessus complex. Combination therapy with other agents (imipenem, cefoxitin, amikacin, and/or tigecycline) is recommended.


Insulin receptor autoimmunity and insulin resistance.
The frequency of insulin receptor autoantibodies (IR-ab) was determined among adolescents and young adults with documented insulin resistance syndrome (IRS) with and without concomitant autoimmunity. The study population was comprised of 61 patients with obesity, acanthosis nigricans and insulin resistance (simple IRS); 12 with IRS and other autoimmune problems (lupus erythematosus, rheumatoid arthritis, dermatomyositis) (type B insulin resistance); six with autoimmune polyglandular syndrome type 2; and 40 healthy controls. Using our newly developed radiobinding assay system, we found no control positive while 25% of the patients with type B IRS (3/12) were positive, as expected. However, we found that 9.8% of the patients with simple IRS (6/61) were also reproducibly positive. All the latter patients with positive IR-ab were female with ovarian hyperandrogenism. The phenotype of those affected was otherwise unremarkably different from those without IR-ab. Our findings suggest that autoimmunity to insulin receptors may be causal in IRS especially for females with ovarian hyperandrogenism, and that IR-ab may be found in IRS besides those previously defined by the type B phenotype. Determining the level of IR-ab in childhood onset IRS may provide mechanistic insights into the genesis of insulin resistance and lead to novel treatment approaches.


The role of fear-avoidance cognitions and behaviors in patients with chronic tinnitus.
The current study investigated the role of fear-avoidance-a concept from chronic pain research-in chronic tinnitus. A self-report measure the "Tinnitus Fear-Avoidance Cognitions and Behaviors Scale (T-FAS)" was developed and validated. Furthermore, the role of fear-avoidance behavior as mediator of the relationship between anxiety sensitivity and tinnitus handicap was investigated. From a clinical setting, N = 373 patients with chronic tinnitus completed questionnaires assessing tinnitus handicap (Tinnitus Handicap Inventory), anxiety, depression (Hospital Anxiety and Depression Scale), anxiety sensitivity (Anxiety Sensitivity Index-3), personality factors (Big Five Inventory-10), and fear-avoidance. To analyze the psychometric properties, principal component analysis with parallel component extraction and correlational analyses were used. To examine a possible mediating effect, hierarchical regression analysis was applied. The principal component analysis resulted in a three-factor solution: Fear-avoidance Cognitions, Tinnitus-related Fear-Avoidance Behavior, and Ear-related Fear-Avoidance Behavior. Internal consistency was satisfactory for the total scale and all subscales. High correlations between tinnitus-related handicap scales, depressive and anxiety symptoms, and the T-FAS were found, whereas associations with personality factors were low. Moreover, results indicate a significant partial mediation of fear-avoidance behaviors in the relationship between anxiety sensitivity and the cognitive dimension of tinnitus handicap. Results show that fear-avoidance behavior plays an important role in tinnitus handicap. More attention should be paid to this concept in research and clinical practice of psychotherapy for chronic tinnitus.


Microbial transformations of isophorone by Alternaria alternata and Neurospora crassa.
Isophorone (3,5,5-trimethyl-2-cyclohexen-1-one), a monoterpene, and the structurally related 1,8-cineole and camphor, have demonstrated a protective effect against cancer, biological activity against a variety of microorganisms, and anti-oxidant properties. The derivatization of isophorone is, therefore, an important field of xenobiochemistry, pharmacology and toxicology. The aim of this study was to obtain derivatives of isophorone through microbial biotransformation and evaluate the biotransformation metabolites as potential antimicrobial agents. Incubation of isophorone with the fungi Alternaria alternata and Neurospora crassa afforded 4a-hydroxy- and 7-hydroxy-isophorone as transformation metabolites. The antimicrobial activities of isophorone and the metabolites were evaluated in vitro both by using agar dilution and microdilution methods. However, no significant antibacterial activity was observed when compared with those of standard substances.


Salivary Biomarkers for Detection of Oral Squamous Cell Carcinoma in a Taiwanese Population.
This study evaluated the discriminatory power of salivary transcriptomic and proteomic biomarkers in distinguishing oral squamous cell carcinoma cases from controls and potentially malignant oral disorders (PMOD). A total of 180 samples (60 OSCC patients, 60 controls, and 60 PMOD patients) were used in the study. Seven transcriptomic markers (IL8, IL1β, SAT1, OAZ1, DUSP1, S100P, and H3F3A) were measured using qPCR, and two proteomic markers (IL8 and IL1β) were evaluated by ELISA. Among 7 transcriptomic markers, transcript level of DUSP1 was significantly lower in OSCC patients than in controls and PMOD patients. Between the proteomic markers, the protein concentration of IL8 and IL1β was significantly higher in OSCC patients than controls and dysplasia patients. Univariate fractional polynomial (FP) models revealed that salivary IL8 protein (IL8p) has the highest AUC value between OSCC patients and controls (0.74) and between OSCC and PMOD patients (0.72). Applying a 2-marker FP model, salivary IL8p combined with IL1β gave the best AUC value for discrimination between OSCC patients and controls, as well as the IL8p combined with H3F3A mRNA, which gave the best AUC value for discrimination between OSCC and PMOD patients. Multivariate models analysis combining salivary analytes and risk factor exposure related to oral carcinogenesis formed the best combinatory variables for differentiation between OSCC versus PMOL (AUC = 0.80), OSCC versus controls (AUC = 0.87), and PMOD versus controls (AUC = 0.78). The combination of transcriptomic and proteomic salivary markers is of great value for oral cancer detection and differentiation from PMOD patients and controls. Clin Cancer Res; 22(13); 3340-7. ©2016 AACR.


Results of the combined U.S. multicenter postapproval study of the Nit-Occlud PDA device for percutaneous closure of patent ductus arteriosus.
To report the results of the Nit-Occlud PDA prospective postapproval study (PAS) along with a comparison to the results of the pivotal and continued access trials. The Nit-Occlud PDA (PFM Medical, Cologne, Germany), a nitinol coil patent ductus arteriosus (PDA) occluder, was approved by the Food and Drug Administration in 2013. The PAS enrolled a total of 184 subjects greater than 6 months of age, weighing at least 5 kg, with PDAs less than 4 mm by angiography at 11 centers. Patients were followed prospectively at 2 months, 12 months, and 24 months postprocedure. These outcomes were compared to the 357 subjects enrolled in the pivotal and continued access protocols. Efficacy and safety data were reported. Among 184 subjects enrolled for the PAS between 2014 and 2017, 180 (97.8%) had successful device implantation. After 12 months, 98.7% (150/152) had trivial or no residual shunt by echocardiography and two subjects had only small residual shunts. There were three device embolizations that were all retrieved by snare without clinical consequence. Together with the pivotal and continued access study, 97.4% (449/461) had complete echocardiographic closure at 12 months in 541 enrolled subjects. The composite success was 94.4%. There were no mortalities and no serious device-related adverse events. The Nit-Occlud PDA is a safe and effective device for closure of a small to moderate sized PDA. There were no serious device-related adverse events in a large cohort of three clinical trials.


Development of mass spectrometry-based shotgun method for proteome analysis of 500 to 5000 cancer cells.
A shotgun proteome analysis method and its performance for protein identification from 500 to 5000 cells are described. Sample preparation, which was done in one tube, involved the use of a surfactant (NP-40) for cell lysis, followed by acetone precipitation of the proteins. The resulting protein pellet was washed with cold acetone to remove remaining surfactant, and the pellet was then solubilized in NH(4)HCO(3). After trypsin digestion of the proteins, the digest was analyzed by the use of nanoflow liquid chromatography (LC) quadrupole time-of-flight mass spectrometry (QTOF MS). Sample injection and gradient speed in running LC QTOF MS were optimized. It was shown that this method could identify an average (n = 3) of 167 +/- 21, 237 +/- 30, 491 +/- 63, and 619 +/- 59 proteins from 500, 1000, 2500, and 5000 MCF-7 breast cancer cells, respectively. To demonstrate the potential use of this method for generating proteome profile from circulating tumor cells (CTCs) isolated from human blood, a healthy human blood sample was spiked with MCF-7 cells, and this mixture was processed and then subjected to antibody tagging of the MCF-7 cells. The tagged cells were sorted and collected using flow cytometry. The proteome profiles of small numbers of cells isolated in this way were found to be similar to those of the original MCF-7 cells, suggesting the possibility of the use of this method for cell typing of CTCs.


Acute- and chronic-phase chronic myelogenous leukemia colony-forming units are highly sensitive to the growth inhibitory effects of c-myb antisense oligodeoxynucleotides.
We have previously demonstrated that malignant hematopoietic colony-forming units (CFUs) may be purged from normal CFU by exposure to c-myb antisense oligodeoxynucleotides (oligomers). This novel strategy appeared particularly promising for patients with chronic myelogenous leukemia (CML) in blast crisis, since in some cases complete elimination of bcr-abl-expressing cells was accomplished. We have examined 11 additional patients, including seven in chronic phase, in order to extend these initial observations. We sought in particular to determine if elimination of bcr-abl-expressing clones was a usual event. Exposure of CML cells to c-myb antisense oligomers resulted in inhibition of CFU-granulocyte, macrophage (CFU-GM)-derived colony formation in eight of 11 (73%) cases evaluated. Inhibition was antisense sequence-specific, dose-dependent, ranged between 58% and 93%, and was statistically significant (P less than or equal to .03) in seven of the eight cases. In two cases, CFU-granulocyte, erythrocyte, monocyte, megakaryocyte (CFU-GEMM)-derived colony formation was also examined and found to be inhibited by the c-myb antisense oligomers in a sequence-specific manner. To determine whether CML CFU had been reduced or eliminated after exposure to the antisense oligomers, we examined cells in the residual colonies for bcr-abl mRNA expression using a reverse transcription-polymerase chain reaction detection technique (RT-PCR). Eight cases were evaluated and in each case where antisense myb inhibited growth, bcr-abl expression as detected by RT-PCR was either greatly decreased or nondetectable. No residual leukemic CFU were demonstrable on replating of treated cells. These results suggest that c-myb antisense oligomers substantially inhibit the growth and survival of CML CFU in both chronic and blast phase of disease. They may therefore prove useful for both ex vivo and in vivo treatment of CML.


pH and amphiphilic structure direct supramolecular behavior in biofunctional assemblies.
Supramolecular self-assembly offers promising new ways to control nanostructure morphology and respond to external stimuli. A pH-sensitive self-assembled system was developed to both control nanostructure shape and respond to the acidic microenvironment of tumors using self-assembling peptide amphiphiles (PAs). By incorporating an oligo-histidine H6 sequence, we developed two PAs that self-assembled into distinct morphologies on the nanoscale, either as nanofibers or spherical micelles, based on the incorporation of the aliphatic tail on the N-terminus or near the C-terminus, respectively. Both cylinder and sphere-forming PAs demonstrated reversible disassembly between pH 6.0 and 6.5 upon protonation of the histidine residues in acidic solutions. These PAs were then characterized and assessed for their potential to encapsulate hydrophobic chemotherapies. The H6-based nanofiber assemblies encapsulated camptothecin (CPT) with up to 60% efficiency, a 7-fold increase in CPT encapsulation relative to spherical micelles. Additionally, pH-sensitive nanofibers showed improved tumor accumulation over both spherical micelles and nanofibers that did not change morphologies in acidic environments. We have demonstrated that the morphological transitions upon changes in pH of supramolecular nanostructures affect drug encapsulation and tumor accumulation. Our findings also suggest that these supramolecular events can be tuned by molecular design to improve the pharmacologic properties of nanomedicines.


Effects of wolf mortality on livestock depredations.
Predator control and sport hunting are often used to reduce predator populations and livestock depredations, but the efficacy of lethal control has rarely been tested. We assessed the effects of wolf mortality on reducing livestock depredations in Idaho, Montana and Wyoming from 1987-2012 using a 25 year time series. The number of livestock depredated, livestock populations, wolf population estimates, number of breeding pairs, and wolves killed were calculated for the wolf-occupied area of each state for each year. The data were then analyzed using a negative binomial generalized linear model to test for the expected negative relationship between the number of livestock depredated in the current year and the number of wolves controlled the previous year. We found that the number of livestock depredated was positively associated with the number of livestock and the number of breeding pairs. However, we also found that the number of livestock depredated the following year was positively, not negatively, associated with the number of wolves killed the previous year. The odds of livestock depredations increased 4% for sheep and 5-6% for cattle with increased wolf control--up until wolf mortality exceeded the mean intrinsic growth rate of wolves at 25%. Possible reasons for the increased livestock depredations at ≤25% mortality may be compensatory increased breeding pairs and numbers of wolves following increased mortality. After mortality exceeded 25%, the total number of breeding pairs, wolves, and livestock depredations declined. However, mortality rates exceeding 25% are unsustainable over the long term. Lethal control of individual depredating wolves may sometimes necessary to stop depredations in the near-term, but we recommend that non-lethal alternatives also be considered.


The effect of altering head length on corrosion using a material loss method.
Corrosion at head neck taper junctions in total hip arthroplasty has increasingly been reported in the literature. Debate persists as to the exact causes and clinical significance of corrosion. Increased offset and head length has been correlated with an increased risk of tribocorrosion due to an adverse mechanical environment. The purpose of this study is to assess the effect of head length on corrosion of a metal-on-polyethylene articulation. Retrievals from a single institution of 28-mm cobalt chromium alloy heads with a 12/14 taper from a single manufacturer were studied. Corrosion of femoral head bores were studied utilising a material loss method. Testing was performed using co-ordinate measuring for maximum linear wear depth. 56 heads were examined with lengths of either -3, 0, +4 or +8 mm and all had been in situ for a minimum of 2 years. There were no significant differences in mean maximum linear wear depth (MLWD) (p = 0.6545). There was no correlation found between MLWD and the time implants were in situ (Spearman coefficient -0.1157) and no significant difference seen between high or standard offset stems (p = 0.1336). In contrast to studies using qualitative methodologies, there was no correlation between head length and material loss when confined to a 28-mm head. Broad application of this outcome should be cautioned against as this study examined 1 taper construct and a metal-on-polyethylene articulation.


Mapping ethical and social aspects of cancer biomarkers.
Cancer biomarkers represent a revolutionary advance toward personalised cancer treatment, promising therapies that are tailored to subgroups of patients sharing similar generic traits. Notwithstanding the optimism driving this development, biomarkers also present an array of social and ethical questions, as witnessed in sporadic debates across different literatures. This review article seeks to consolidate these debates in a mapping of the complex terrain of ethical and social aspects of cancer biomarker research. This mapping was undertaken from the vantage point offered by a working cancer biomarker research centre called the Centre for Cancer Biomarkers (CCBIO) in Norway, according to a dialectic move between the literature and discussions with researchers and practitioners in the laboratory. Starting in the lab, we found that, with the exception of some classical bioethical dilemmas, researchers regarded many issues relative to the ethos of the biomarker community; how the complexity and uncertainty characterising biomarker research influence their scientific norms of quality. Such challenges to the ethos of cancer research remain largely implicit, outside the scope of formal bioethical enquiry, yet form the basis for other social and ethical issues. Indeed, looking out from the lab we see how questions of complexity, uncertainty and quality contribute to debates around social and global justice; undermining policies for the prioritisation of care, framing the stratification of those patients worthy of treatment, and limiting global access to this highly sophisticated research. We go on to discuss biomarker research within the culturally-constructed 'war on cancer' and highlight an important tension between the expectations of 'magic bullets' and the complexity and uncertainty faced in the lab. We conclude by arguing, with researchers in the CCBIO, for greater reflexivity and humility in cancer biomarker research and policy.


Atomic force microscopy application in biological research: a review study.
Atomic force microscopy (AFM) is a three-dimensional topographic technique with a high atomic resolution to measure surface roughness. AFM is a kind of scanning probe microscope, and its near-field technique is based on the interaction between a sharp tip and the atoms of the sample surface. There are several methods and many ways to modify the tip of the AFM to investigate surface properties, including measuring friction, adhesion forces and viscoelastic properties as well as determining the Young modulus and imaging magnetic or electrostatic properties. The AFM technique can analyze any kind of samples such as polymers, adsorbed molecules, films or fibers, and powders in the air whether in a controlled atmosphere or in a liquid medium. In the past decade, the AFM has emerged as a powerful tool to obtain the nanostructural details and biomechanical properties of biological samples, including biomolecules and cells. The AFM applications, techniques, and -in particular- its ability to measure forces, are not still familiar to most clinicians. This paper reviews the literature on the main principles of the AFM modality and highlights the advantages of this technique in biology, medicine, and- especially- dentistry. This literature review was performed through E-resources, including Science Direct, PubMed, Blackwell Synergy, Embase, Elsevier, and Scholar Google for the references published between 1985 and 2010.


An analysis of saturable absorbers.
This paper contains an analysis of the behavior of saturable filters, based on models with simple energy level structures. In this analysis, the effects of possible excited state absorption at the irradiating wavelength are considered and are shown to give rise to a nonsaturable component of the absorption coefficient. Expressions for the steady-state transmission of an optically thick saturable absorber, and for the temporal response of an optically thin absorber, are derived. The question of homogeneous vs inhomogeneous broadening of the absorption line is discussed, and it is suggested that spectral hole burning may occur in a thermally broadened line at a sufficiently high irradiance level. The desirable features of a saturable absorber for use in a Q-switched laser system are briefly described, and it is shown how the usual rate equations for a laser system may be amended to include the effects of an intracavity saturable filter.


2-(fluorine-18)-fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography after breast conserving surgery: Correlation with molecular markers of breast cancer.
To investigate the role of 2-(fluorine-18)-fluoro-2-deoxy-D-glucose ((18)F-FDG) positron emission tomography/computed tomography (PET/CT) early after breast-conserving surgery (BCS) in patients with breast cancer (BC) and whether we can determine which molecular biomarkers of breast carcinoma put the patients at risk. This retrospective study involved 88 patients with histologically proven T1 or T2 BC, who were treated with BCS and underwent (18)F-FDG PET/CT study. The correlation between biological markers (estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2 [HER2], and Ki-67) of the primary tumor and (18)F-FDG PET/CT findings was analyzed. (18)F-FDG PET/CT demonstrated the presence of BC disease (locoregional disease [LRD], distant metastases, or contralateral BC) in 26 of 88 patients (29.5%). Regarding immunohistochemical profiles, BC expressing high levels of Ki-67 were associated with an increased percentage of LRD, which was the major recurrence pattern on (18)F-FDG PET/CT. Although the BC disease was observed more commonly in patients with HER2 positivity compared to those of HER2 negative, the difference did not reach statistical significance. The patients with T2 tumor or a higher histopathological grade had a higher percentage of BC disease. This study demonstrated that patients with early stage BC treated with BCS have a remarkable risk of the presence of BC even early after surgery, and there was a clinically important relationship between (18)F-FDG PET/CT findings and biological markers of BC. These findings suggest that high-risk molecular biomarkers (Ki-67, HER2) can be taken into account in the decision-making the process for both preoperative imaging and planning of the surgical approach.


The branch-site test of positive selection is surprisingly robust but lacks power under synonymous substitution saturation and variation in GC.
Positive selection is widely estimated from protein coding sequence alignments by the nonsynonymous-to-synonymous ratio ω. Increasingly elaborate codon models are used in a likelihood framework for this estimation. Although there is widespread concern about the robustness of the estimation of the ω ratio, more efforts are needed to estimate this robustness, especially in the context of complex models. Here, we focused on the branch-site codon model. We investigated its robustness on a large set of simulated data. First, we investigated the impact of sequence divergence. We found evidence of underestimation of the synonymous substitution rate for values as small as 0.5, with a slight increase in false positives for the branch-site test. When dS increases further, underestimation of dS is worse, but false positives decrease. Interestingly, the detection of true positives follows a similar distribution, with a maximum for intermediary values of dS. Thus, high dS is more of a concern for a loss of power (false negatives) than for false positives of the test. Second, we investigated the impact of GC content. We showed that there is no significant difference of false positives between high GC (up to ∼80%) and low GC (∼30%) genes. Moreover, neither shifts of GC content on a specific branch nor major shifts in GC along the gene sequence generate many false positives. Our results confirm that the branch-site is a very conservative test.


Charging behavior of single-stranded DNA polyelectrolyte brushes.
DNA monolayers are widely used in fundamental and applied genomics and are versatile experimental models for elucidating the behavior of charged polymers at interfaces. The physical behavior of these systems is to a large extent governed by their internal ionic microenvironment, which is investigated here for layers of end-tethered, single-stranded DNA oligonucleotides (DNA brushes). Retention of counterions by the DNA brush manifests as lowered susceptibility of the interfacial capacitance to external salt conditions. A physical model based on concepts adapted from polymer science was used to further elucidate the connection between monolayer organization and its charging behavior. The data indicate a reorganization of the monolayer with changes in ionic strength and strand coverage that is consistent with that expected for a polyelectrolyte brush. A method for electrochemical quantification of strand coverage, based on shift of reduction potential for redox counterions associated with the DNA monolayer, is also described. These results provide guidance for development of label-free electrochemical diagnostics employing DNA monolayers and formulate a description of monolayer behavior within a polymer science framework.


Relationship between Insurance Type and Discharge Disposition From the Emergency Department of Young Children Diagnosed with Physical Abuse.
To describe the disposition of young children diagnosed with physical abuse in the emergency department (ED) setting and identify factors associated with the decision to discharge young abused children. We performed a retrospective cross-sectional study of children less than 2 years of age diagnosed with physical abuse in the 2006-2012 Nationwide Emergency Department Sample. National estimates were calculated accounting for the complex survey design. We developed a multivariable logistic regression model to evaluate the relationship between payer type and discharge from the ED compared with admission with adjustment for patient and hospital factors. Of the 37 655 ED encounters with a diagnosis of physical abuse among children less than 2 years of age, 51.8% resulted in discharge, 41.2% in admission, 4.3% in transfer, 0.3% in death in the ED, and 2.5% in other. After adjustment for age, sex, injury type, and hospital characteristics (trauma designation, volume of young children, and hospital region), there were differences in discharge decisions by payer and injury severity. The adjusted percentage discharged of publicly insured children with minor/moderate injury severity was 56.2% (95% CI 51.6, 60.7). The adjusted percentages discharged were higher for both privately insured children at 69.9% (95% CI 64.4, 75.5) and self-pay children at 72.9% (95% CI 67.4, 78.4). The adjusted percentages discharged among severely injured children did not differ significantly by payer. The majority of ED visits for young children diagnosed with abuse resulted in discharge. The notable differences in disposition by payer warrant further investigation.


Lactobacillus rhamnosus GG supplementation during critical windows of gestation influences immune phenotype in Swiss albino mice offspring.
Probiotic supplementation during critical windows of gestation might have a significant influence on the infant's immune phenotype. Swiss albino mice (F0 generation) aged 31 days were supplemented orally with probiotic Lactobacillus rhamnosus GG (LGG); and the supplementation was continued throughout mating, gestation and lactation. The pups (F1 generation) born to them were separated post weaning and received either the same probiotic supplementation as their mothers or were denied supplementation postnatally. Neutrophil phagocytic ability, splenocyte proliferation, immunoglobulins and cytokines were determined in both F0 and F1 pups. In addition, antibody response against hepatitis-B surface antigen (HBsAg) was determined in F1 pups. Probiotic supplementation had no effect on the neutrophil phagocytic ability and splenocyte proliferation index. The serum immunoglobulin G (IgG) and secretory IgA (s-IgA) among the probiotic supplemented group of F0 generation were significantly (P<0.05) higher compared to the controls. Similarly, the mean concentration of interleukin (IL)-10, IL-17 and interferon gamma (IFN-γ) among F0 probiotic group were significantly higher (P<0.05) compared to the control. Prenatal and postnatal probiotic supplementation in F1 pups led to similar results as F0 dams. Prenatal probiotic supplementation in F1 pups led to significantly (P<0.05) higher serum IgG (55.15 ± 1.35 ng/ml) and intestinal s-IgA (77.9 ± 2.86 ng/mg protein) concentration when compared to the control. Similarly, IFN-γ concentration increased (P<0.05) with prenatal probiotic supplementation compared to the control. However, IL-10 and IL-17 concentrations of prenatal probiotic supplemented F1 pups were comparable to the control. As for the antibody response to HBsAg, prenatal probiotic supplementation led to enhanced HBsAg antibody response (471.4 ± 3.97 U/ml) compared to the control. LGG affected the immune regulation and immune responses favourably in mothers and offspring. In addition, some of the beneficial effects of prenatal LGG supplementation extended into postnatal life of the offspring, thus suggesting possible immunoprogramming effect of LGG.


Diabetes prevalence, incidence and mortality in First Nations and other people in Ontario, 1995-2014: a population-based study using linked administrative data.
Diabetes mellitus is an established health concern in First Nations communities and is associated with complex influences of colonization. This study, a partnership between First Nations and academic researchers, was undertaken to determine patterns of diabetes prevalence, incidence and mortality in Ontario. Using health services and population data from Ontario for 1995 to 2014, linked with the federal Indian Register, we calculated age- and sex-adjusted annual estimates of diabetes prevalence, incidence and mortality for First Nations people (living within and outside First Nations communities) and other people in Ontario. We also examined age- and sex-specific crude diabetes prevalence. Between 1995 and 2014, the prevalence of diabetes increased and the incidence decreased somewhat in all populations. Both prevalence and incidence were substantially higher among First Nations people than among other people in Ontario. In particular, First Nations women had higher prevalence than other women (4.2% v. 1.6% for ages 20-34 yr and 17.6% v. 6.0% for ages 35-49 yr). The lifetime risk of diabetes was higher among First Nations people than among other people in Ontario (57.0%, 95% confidence interval [CI] 56.3%-57.6% v. 44.5%, 95% CI 44.4%-44.6%). Over time, all-cause mortality for those with diabetes declined but remained consistently higher for First Nations people than for other people in Ontario. Diabetes is more common among First Nations people than among other people in Ontario, particularly at younger ages and in women. First Nations-led approaches to address the high prevalence of diabetes in younger First Nations women have the potential to improve metabolic health across generations.


Crystal structures and proposed structural/functional classification of three protozoan proteins from the isochorismatase superfamily.
We have determined the crystal structures of three homologous proteins from the pathogenic protozoans Leishmania donovani, Leishmania major, and Trypanosoma cruzi. We propose that these proteins represent a new subfamily within the isochorismatase superfamily (CDD classification cd004310). Their overall fold and key active site residues are structurally homologous both to the biochemically well-characterized N-carbamoylsarcosine-amidohydrolase, a cysteine hydrolase, and to the phenazine biosynthesis protein PHZD (isochorismase), an aspartyl hydrolase. All three proteins are annotated as mitochondrial-associated ribonuclease Mar1, based on a previous characterization of the homologous protein from L. tarentolae. This would constitute a new enzymatic activity for this structural superfamily, but this is not strongly supported by the observed structures. In these protozoan proteins, the extended active site is formed by inter-subunit association within a tetramer, which implies a distinct evolutionary history and substrate specificity from the previously characterized members of the isochorismatase superfamily. The characterization of the active site is supported crystallographically by the presence of an unidentified ligand bound at the active site cysteine of the T. cruzi structure.


Rotating polarization spectroscopy for single nano-antenna characterization.
We report on a novel micro-spectroscopic technique to quantitatively measure the extinction cross-section σ(ext) of few and single linearly polarizing nano-antennas. This technique relies on rotating the linear polarization of a monochromatic laser beam at a frequency ω(1) while optically chopping the incident beam at ω(2) and using lock-in detection with a switched reference frequency input to measure the amount of scattered and absorbed power. The amount of power removed from the beam corresponds to σ(ext) of the polarizing nano-structure. Furthermore, this technique is easy to integrate into existing microscopy or micro-photoluminescence setups and does not depend on the sample's temperature.


Occurrence of stroke in a nonhuman primate model of cerebrovascular disease.
A relation between hypertension, atherosclerosis, and stroke is well documented in humans. We report a similar relation in two hypertensive cynomolgus monkeys with severe cerebral atherosclerosis. In our primate model hypertension is induced by surgical coarctation of the aorta. These monkeys, when fed an atherogenic diet, develop severe cerebrovascular atherosclerosis. In this setting two monkeys developed spontaneous cerebral hemispheric strokes that occurred during treatment of hypertension. Since the strokes were topographically related to severe atherosclerotic narrowing of cerebral arteries and occurred without evidence of either thrombosis or embolization, they are presumed to be related to disturbances of blood flow. In both humans and animals cerebral perfusion is autoregulated to a constant flow over a wide range of mean arterial blood pressures. In hypertension both the upper and lower limits of autoregulation are increased. With treatment of hypertension readaptation to more normal levels is reported to be inconsistent and slow to develop. It is therefore postulated that the strokes in these two monkeys were due to hypoperfusion as a result of the combination of pharmacologic reduction in blood pressure and severe occlusive atherosclerosis.


Mechanical circulatory support with the Impella 5.0 device for postcardiotomy cardiogenic shock: a three-center experience.
Postcardiotomy cardiogenic shock (PCCS) is associated with high mortality rates, despite full conventional treatment. Although the results of treatment with surgically implantable ventricular assist devices have been encouraging, the invasiveness of this treatment limits its applicability. Several less invasive devices have been developed, including the Impella system. The objective of this study was to describe our three-center experience with the Impella 5.0 device in the setting of PCCS. From January 2004 through December 2010, a total of 46 patients were diagnosed with treatment-refractory PCCS and treated with the Impella 5.0 percutaneous left ventricular assist device at three european heart centers. Baseline and follow-up characteristics were collected retrospectively and entered into a dedicated database. Within the study cohort of 46 patients, mean logistic and additive EuroSCORES were 24 ± 19 and 10 ± 4. The majority of patients underwent coronary artery bypass grafting (48%) or combined surgery (33%). Half of all patients had been treated with an intra-aortic balloon pump before 5.0-implantation, 1 patient had been treated with an Impella 2.5 device. All patients were on mechanical ventilation and intravenous inotropes. The Kaplan-Meier estimate of overall 30-day survival was 39.5%. Thirty-day survival rates for patients with PCCS, refractory to aggressive conventional treatment and treated with the Impella 5.0 device, are comparable to those reported in studies evaluating surgically implantable VADs, whereas the Impella system is much less invasive. Therefore, mechanical circulatory support with the Impella 5.0 device is a suitable treatment modality for patients with severe PCCS.


Characterization of single airborne particle extinction using the tunable optical trap-cavity ringdown spectroscopy (OT-CRDS) in the UV.
We integrated a rigid optical trap into a tunable pulsed cavity ringdown spectroscopy (OT-CRDS) system to characterize the extinction of single airborne particles in the UV spectral region (306-315 nm). Single solid particles from a multi-walled carbon nanotube (MWCNT), Bermuda grass smut spore, carbon microsphere, and blackened polyethylene microsphere were trapped in air based on the photophoretic force. The improved OT-CRDS system was highly sensitive and able to resolve extinctions of single particles from different materials and sizes at a given wavelength. Further, we successfully manipulated the number of particles, e.g., 1, 2 or more particles, in the trap and measured their distinguishable extinctions using the OT-CRDS. We also show that the particle size and extinction have a good linear correlation from the measurements of 24 single MWCNT particles. Material- and wavelength-dependent extinctions of the four types of airborne particles were also characterized. Results reveal that single airborne particles regardless of their differences in material and size, due to their heterogeneous morphology, have individual-particle dependent extinctions and that dependence can be resolved and characterized using the OT-CRDS technique.


Topography and refractometry of nanostructures using spatial light interference microscopy.
Spatial light interference microscopy (SLIM) is a novel method developed in our laboratory that provides quantitative phase images of transparent structures with a 0.3 nm spatial and 0.03 nm temporal accuracy owing to the white light illumination and its common path interferometric geometry. We exploit these features and demonstrate SLIM's ability to perform topography at a single atomic layer in graphene. Further, using a decoupling procedure that we developed for cylindrical structures, we extract the axially averaged refractive index of semiconductor nanotubes and a neurite of a live hippocampal neuron in culture. We believe that this study will set the basis for novel high-throughput topography and refractometry of man-made and biological nanostructures.


Consistent negative response of US crops to high temperatures in observations and crop models.
High temperatures are detrimental to crop yields and could lead to global warming-driven reductions in agricultural productivity. To assess future threats, the majority of studies used process-based crop models, but their ability to represent effects of high temperature has been questioned. Here we show that an ensemble of nine crop models reproduces the observed average temperature responses of US maize, soybean and wheat yields. Each day >30 °C diminishes maize and soybean yields by up to 6% under rainfed conditions. Declines observed in irrigated areas, or simulated assuming full irrigation, are weak. This supports the hypothesis that water stress induced by high temperatures causes the decline. For wheat a negative response to high temperature is neither observed nor simulated under historical conditions, since critical temperatures are rarely exceeded during the growing season. In the future, yields are modelled to decline for all three crops at temperatures >30 °C. Elevated CO2 can only weakly reduce these yield losses, in contrast to irrigation.


Embedding of cortical representations by the superficial patch system.
Pyramidal cells in layers 2 and 3 of the neocortex of many species collectively form a clustered system of lateral axonal projections (the superficial patch system--Lund JS, Angelucci A, Bressloff PC. 2003. Anatomical substrates for functional columns in macaque monkey primary visual cortex. Cereb Cortex. 13:15-24. or daisy architecture--Douglas RJ, Martin KAC. 2004. Neuronal circuits of the neocortex. Annu Rev Neurosci. 27:419-451.), but the function performed by this general feature of the cortical architecture remains obscure. By comparing the spatial configuration of labeled patches with the configuration of responses to drifting grating stimuli, we found the spatial organizations both of the patch system and of the cortical response to be highly conserved between cat and monkey primary visual cortex. More importantly, the configuration of the superficial patch system is directly reflected in the arrangement of function across monkey primary visual cortex. Our results indicate a close relationship between the structure of the superficial patch system and cortical responses encoding a single value across the surface of visual cortex (self-consistent states). This relationship is consistent with the spontaneous emergence of orientation response-like activity patterns during ongoing cortical activity (Kenet T, Bibitchkov D, Tsodyks M, Grinvald A, Arieli A. 2003. Spontaneously emerging cortical representations of visual attributes. Nature. 425:954-956.). We conclude that the superficial patch system is the physical encoding of self-consistent cortical states, and that a set of concurrently labeled patches participate in a network of mutually consistent representations of cortical input.


Comparison between the palatal configurations in complete and incomplete unilateral cleft lip and palate infants under 18 months of age.
The purpose of this study was to examine the three-dimensional characteristics of the palatal configurations in incomplete unilateral cleft lip and palate (UCLP) patients and to determine whether there are differences in the effect of early orthopedic treatment between complete and incomplete UCLP patients. Eight infants with incomplete UCLP and 12 infants with complete UCLP, selected at random, wore Hotz plates, and 8 other infants with complete UCLP did not. Palatal impressions were taken of these patients immediately after birth and at 1, 2, 3, 4 (just before cheiloplasty), 6, and 18 months of age (just before palatoplasty). Using our measuring system, the palatal casts were measured and compared three-dimensionally. The palate of the incomplete UCLP patients measured immediately after birth, compared with complete UCLP, showed: (1) smaller posterior arch width; (2) sagittal arch length did not differ; (3) incisal point was located more mesially; (4) the gap between the alveolar arch forms of the major and minor segments was smaller; and (5) the curvature of the palatal surface forward the nasal cavity in the minor segment was less. At 18 months of age, the following characteristics could be observed: (1) the difference observed at birth in the posterior arch width between the incomplete and complete UCLP infants vanished; (2) a significant difference in the location of the incisal point was observed only between the incomplete UCLP infants and the complete UCLP infants with a Hotz plate; and (3) the curvature was less in the incomplete UCLP infants than in the complete UCLP infants. Furthermore, the morphological change of the palatal surface was less in the incomplete UCLP infants than in the complete UCLP infants. This suggested that any influence of the Hotz appliance might be less in incomplete UCLP than in complete UCLP.


Attentional activation of the cerebellum independent of motor involvement.
The cerebellum traditionally has been viewed as a neural device dedicated to motor control. Although recent evidence shows that it is involved in nonmotor operations as well, an important question is whether this involvement is independent of motor control and motor guidance. Functional magnetic resonance imaging was used to demonstrate that attention and motor performance independently activate distinct cerebellar regions. These findings support a broader concept of cerebellar function, in which the cerebellum is involved in diverse cognitive and noncognitive neurobehavioral systems, including the attention and motor systems, in order to anticipate imminent information acquisition, analysis, or action.


Embryonic striatal grafts restore bi-directional synaptic plasticity in a rodent model of Huntington's disease.
Embryonic striatal grafts integrate with the host striatal circuitry, forming anatomically appropriate connections capable of influencing host behaviour. In addition, striatal grafts can influence host behaviour via a variety of non-specific, trophic and pharmacological mechanisms; however, direct evidence that recovery is dependent on circuit reconstruction is lacking. Recent studies suggest that striatal grafts alleviate simple motor deficits, and also that learning of complex motor skills and habits can also be restored. However, although the data suggest that such 're-learning' requires integration of the graft into the host striatal circuitry, little evidence exists to demonstrate that such integration includes functional synaptic connections. Here we demonstrate that embryonic striatal grafts form functional connections with the host striatal circuitry, capable of restoring stable synaptic transmission, within an excitotoxic lesion model of Huntington's disease. Furthermore, such 'functional integration' of the striatal graft enables the expression of host-graft bi-directional synaptic plasticity, similar to the normal cortico-striatal circuit. These results indicate that striatal grafts express synaptic correlates of learning, and thereby provide direct evidence of functional neuronal circuit repair, an essential component of 'functional integration'.


The characteristics and effectiveness of Question Prompt List interventions in oncology: a systematic review of the literature.
Question Prompt Lists (QPLs) have been used extensively in the oncology setting to improve communication, psychological and/or cognitive outcomes. In this systematic review, the objectives were to (a) examine the methodological quality of QPL interventions, (b) review the effectiveness of QPL interventions on communication, psychological and/or cognitive outcomes of cancer patients, (c) gain more insight into the characteristics of QPL interventions (e.g., the number and content of questions, and the mode of delivery) and (d) explore whether the effectiveness of QPL interventions might be explained by their characteristics. A systematic literature search was conducted in PsycINFO, Medline, CINAHL and CENTRAL. Empirical studies that investigated the use and effectiveness of QPL interventions in an oncology setting were included. The methodological quality of the included studies was assessed using the Cochrane method. Sixteen articles met the inclusion criteria. Results indicated evidence for the effectiveness of QPL interventions in enhancing patient participation (i.e., question asking). Furthermore, there was evidence that QPL interventions can influence psychological outcomes (i.e., anxiety at follow-up) and cognitive outcomes (i.e., recall of information). The majority of QPL interventions were given to patients before their consultation in hardcopy. In most studies, QPLs were combined with other intervention components. It is suggested that characteristics of a QPL intervention (i.e., the number of questions on a QPL and provider training) can influence its effectiveness. Question Prompt List interventions are effective in improving communication, psychological and cognitive outcomes of cancer patients.


Confabulation in schizophrenia: a neuropsychological study.
Confabulation has been documented in schizophrenia, but its neuropsychological correlates appear to be different from those of confabulation in neurological disease states. Forty-five schizophrenic patients and 37 controls were administered a task requiring them to recall fables. They also underwent testing with a range of memory and executive tasks. The patients with schizophrenia produced significantly more confabulations than the controls. After correcting for multiple comparisons, confabulation was not significantly associated with memory impairment, and was associated with impairment on only one of eight executive measures, the Brixton Test. Confabulation scores were also associated with impairment on two semantic memory tests. Confabulation was correlated with intrusion errors in recall, but not false positive errors in a recognition task. The findings suggest that confabulation in schizophrenia is unrelated to the episodic memory impairment seen in the disorder. However, the association with a circumscribed deficit in executive function could be consistent with a defective strategic retrieval account of confabulation similar to that of Moscovitch and co-workers, interacting with defective semantic memory.


Pharmaceuticals and personal care products in effluent matrices: A survey of transformation and removal during wastewater treatment and implications for wastewater management.
Pharmaceuticals and personal care products (PPCPs) represent pollutants of emerging concern, originating in surface and drinking waters largely from their persistence in wastewater effluent. Accordingly, a wealth of recent investigations has examined PPCP fate during wastewater treatment, focusing on their removal during conventional (e.g., activated sludge) and advanced (e.g., ozonation and membrane filtration) treatment processes. Here, we compile nearly 1500 data points from over 40 published sources pertaining to influent and effluent PPCP concentrations measured at pilot- and full-scale wastewater treatment facilities to identify the most effective series of technologies for minimizing effluent PPCP levels. Available data suggest that at best a 1-log(10) concentration unit (90%) of PPCP removal can be achieved at plants employing only primary and secondary treatment, a performance trend that is maintained over the range of reported PPCP influent concentrations (ca. 0.1-10(5) ng L(-1)). Relatively few compounds (15 of 140 PPCPs considered) are consistently removed beyond this threshold at facilities using solids removal and conventional activated sludge (CAS), and most PPCPs are removed to a far lesser extent. Further, increases in CAS hydraulic retention time or sludge retention time do not appreciably increase removal beyond this limit. In contrast, plants employing advanced treatment methodologies, particularly ozonation and/or membranes, remove the vast majority of PPCPs beyond 1-log(10) concentration unit and oftentimes to levels below analytical detection limits in effluent. Data also indicate that passive approaches for tertiary treatment (e.g., wetlands and lagoons) represent promising options for PPCP removal. We conclude by addressing future challenges and frontiers in wastewater management posed by PPCPs including analytical needs for their real-time measurement, energy demands associated with advanced treatment technologies, and byproducts arising from transformation of PPCPs during treatment.


Circadian rhythms of blood minerals during adolescence.
Sequential blood sampling every 30 min was performed in six adolescent males. Samples were analyzed for serum phosphate [Pi), total calcium (CaT), and blood ionized calcium (Ca++) concentrations. A circadian (24-h) pattern was observed for each mineral: 1) Ca++ concentrations followed a U-shaped curve with a peak at 11 AM and a trough at 3:30 PM; 2) CaT concentrations followed a W-shaped curve with maxima at 11 and 1 AM and troughs at 5 AM and 6 PM; and 3) Pi concentrations followed an M-shaped curve with peaks at 4 PM and 3:30 AM. The overall mineral patterns were similar in shape to those previously described in adult males. In contrast, however, the amplitude of the Pi fluctuations were considerably greater in the adolescents compared with that in adults (3.0 mg/dl versus 1.2 mg/dl). The Ca++ pattern diverged from the CaT pattern during the nocturnal phase to an extent that neither pattern could be predicted from the other. Ultradian rhythms were found in some of the time series mineral data sets; however, no single frequency encompassed all subjects for each circulating mineral.


Regulation of 17-AAG-induced apoptosis: role of Bcl-2, Bcl-XL, and Bax downstream of 17-AAG-mediated down-regulation of Akt, Raf-1, and Src kinases.
17-allylamino-demethoxy geldanamycin (17-AAG) inhibits the chaperone function of heat shock protein-90 (Hsp-90) and promotes the proteasomal degradation of its misfolded client proteins. Here, we demonstrate that treatment of the human acute myeloid leukemia HL-60 cells with 17-AAG attenuates the intracellular levels of a number of Hsp-90 client proteins, including Akt, c-Raf-1, and c-Src. Also, 17-AAG induced the mitochondrial release and cytosolic accumulation of cytochrome c (cyt c) and second mitochondria-derived activator of caspases (Smac)/DIABLO, resulting in the activation of caspase-9 and caspase-3 and apoptosis. Treatment with 17-AAG triggered the B-cell lymphoma-2 (Bcl-2)-associated X protein (Bax) conformational change associated with apoptosis, while Bax-deficient cells were resistant to 17-AAG-induced apoptosis. In addition, in HL-60/Bcl-2 and HL-60/Bcl-xL cells, which ectopically express Bcl-2 and Bcl-xL respectively, 17-AAG-induced Bax conformational change, cytosolic accumulation of cyt c and Smac/DIABLO, and apoptosis were markedly inhibited. Although the rate of 17-AAG-mediated decline in Akt, c-Raf-1, and c-Src levels was blunted, the total decline was not compromised in HL-60/Bcl-2 and HL-60/Bcl-xL cells. Cotreatment with HA14-1, a nonpeptidic ligand that can bind and inhibit the antiapoptotic activity of Bcl-2, significantly overcame the resistance to 17-AAG-induced apoptosis in HL-60/Bcl-2 cells. Together, these findings indicate that although 17-AAG treatment causes the levels of a number of survival-signaling protein kinases to decline, the downstream engagement of the mitochondrial pathway of apoptosis is regulated by the activity of the Bcl-2 family of proteins. Also, neutralizing the antiapoptotic effect of Bcl-2 would further enhance the antileukemia activity of 17-AAG.


A novel Lawsonia intracellularis autotransporter protein is a prominent antigen.
Investigation of antigenic determinants of the microaerophilic obligate intracellular bacterium Lawsonia intracellularis using a mass spectrometry approach identified a novel bacterial protein present in an extract of cell culture medium aspirated from heavily infected in vitro cell cultures. Western immunoblotting analysis of SDS-PAGE-resolved proteins using immune sera pooled from L. intracellularis-infected pigs revealed the presence of a strongly immunoreactive band of ∼ 72 kDa. Liquid chromatography-electrospray ionization-tandem mass spectrometry analysis of this component and database mining using a fully annotated L. intracellularis genome sequence and the comprehensive GenBank prokaryotic genomic database highlighted the presence of a protein that shares little sequence similarity with other prokaryotic proteins and appears to be highly species specific. Detailed bioinformatic analyses identified the protein as member of the autotransporter protein family of surface-exposed proteins, and the designation LatA (Lawsonia autotransporter protein A) is suggested. Recognition of recombinant LatA on Western blots by a panel of sera from infected and control pigs corresponded 100% with a commercial serodiagnostic that relies on in vitro culture of this fastidious organism. LatA therefore represents a potential candidate for the development of a rapid and species-specific serodiagnostic reagent.


Simultaneous occurrence of nonepileptic and epileptic seizures during a single period of in-patient video-electroencephalographic monitoring.
Epilepsy and psychogenic nonepileptic seizures (PNES) can coexist and may present in two forms: sequential and simultaneous. In sequential presentations, epileptic seizures (ES) are treated and PNES emerge later. Simultaneous recording of ES and PNES by video-electroencephalogram (vEEG) is less well described. We retrospectively reviewed all patients diagnosed with PNES by vEEG following standard seizure induction practices over a 21-month period. Within this cohort, we established the prevalence of coexisting epilepsy using clinical and electrographic data acquired from our epilepsy-specific patient record. We identified patients with simultaneous PNES and ES recorded during a single vEEG admission, establishing the frequency and emergent timing of each type. Of our 262 monitored patients, 59 were diagnosed with PNES. Nineteen of the patients with PNES had coexisting epilepsy (prevalence rate of 7.3% or 32% of those with PNES). Sixteen patients had PNES and ES recorded during the same admission, and the remaining three patients had sequential PNES following successful treatment of ES. PNES occurred earlier (mean, within 1.21 days), with ES occurring later (mean, within 4.86 days). The simultaneous occurrence of PNES and ES recorded during a single admission is more common than previously reported. Identifying this group of patients may require a significantly longer period of vEEG monitoring and a detailed analysis of each individual's historical seizure events.


Human resources for refraction services in Central Nepal.
Uncorrected refractive error is a public health problem globally and in Nepal. Planning of refraction services is hampered by a paucity of data. This study was conducted to determine availability and distribution of human resources for refraction, their efficiency, the type and extent of their training; the current service provision of refraction services and the unmet need in human resources for refraction in Central Nepal. This was a descriptive cross-sectional study. All refraction facilities in the Central Region were identified through an Internet search and interviews of key informants from the professional bodies and parent organisations of primary eye centres. A stratified simple random sampling technique was used to select 50 per cent of refraction facilities. The selected facilities were visited for primary data collection. Face-to-face interviews were conducted with the managers and the refractionists available in the facilities using a semi-structured questionnaire. Data was collected in 29 centres. All the managers (n=29; response rate 100 per cent) and 50 refractionists (Response rate 65.8 per cent) were interviewed. Optometrists and ophthalmic assistants were the main providers of refraction services (n=70, 92.11 per cent). They were unevenly distributed across the region, highly concentrated around urban areas. The median number of refractions per refractionist per year was 3,600 (IQR: 2,400 - 6,000). Interviewed refractionists stated that clients' knowledge, attitude and practice related factors such as lack of awareness of the need for refraction services and/or availability of existing services were the major barriers to the output of refraction services. The total number of refractions carried out in the Central Region per year was 653,176. An additional 170 refractionists would be needed to meet the unmet need of 1,323,234 refractions. The study findings demand a major effort to develop appropriately trained personnel when planning refraction services in the Central Region and in Nepal as a whole. The equitable distribution of the refractionists, their community-outreach services and awareness raising activities should be emphasised.


Relating fitness to long-term environmental variations in natura.
Quantifying links between ecological processes and adaptation dynamics in natura remains a crucial challenge. Many studies have documented the strength, form and direction of selection, and its variations in space and time, but only a few managed to link these variations to their proximal causes. This step is, however, crucial, if we are to understand how the variation in selective pressure affects adaptive allele dynamics in natural settings. We used data from a long-term survey (about 30 years) monitoring the adaptation to insecticides of Culex pipiens mosquitoes in Montpellier area (France), focusing on three resistance alleles of the Ester locus. We used a population genetics model taking temporal and spatial variations in selective pressure into account, to assess the quantitative relationships between variations in the proximal agent of selection (amounts of insecticide sprayed) and the fitness of resistance alleles. The response to variations in selective pressure was fast, and the alleles displayed different fitness-to-environment relationships: the analyses revealed that even slight changes in insecticide doses could induce changes in the strength and direction of selection, thus changing the fitness ranking of the adaptive alleles. They also revealed that selective pressures other than the insecticides used for mosquito control affected the resistance allele dynamics. These fitness-to-environment relationships, fast responses and continuous evolution limit our ability to predict the outcome of adaptive allele dynamics in a changing environment, but they clearly contribute to the maintenance of polymorphism in natural populations. Our study also emphasizes the necessity of long-term surveys in evolutionary ecology.


Hydrophilic interaction liquid chromatography in the separation of glycopeptides and their isomers.
The analysis of intact glycopeptides is a challenge because of the structural variety of the complex conjugates. In this work, we used separation involving hydrophilic interaction liquid chromatography using a superficially porous particle HALO® penta-HILIC column with tandem mass spectrometric detection for the analysis of N-glycopeptides of hemopexin. We tested the effect of the mobile phase composition on retention and separation of the glycopeptides. The results indicated that the retention of the glycopeptides was the combination of partitioning and adsorption processes. Under the optimized conditions, our HILIC method showed the ability to efficiently separate the glycoforms of the same peptide backbone including separation of the isobaric glycoforms. We achieved efficient separation of core and outer arm linked fucose of bi-antennary and tri-antennary glycoforms of the SWPAVGNCSSALR peptide and bi-antennary glycoform of the ALPQPQNVTSLLGCTH peptide, respectively. Moreover, we demonstrated the separation of antennary position of sialic acid linked via α2-6 linkage of the monosialylated glycopeptides. Glycopeptide isomers are often differentially associated with various biological processes. Therefore, chromatographic separation of the species without the need for an extensive sample preparation appears attractive for their identification, characterization, and reliable quantification.


Patient outcome as a measure of quality of nursing home care.
One thousand males transferred from a general medical hospital into 40 community nursing homes were classified by their physicians as to expectations of outcome within six months and measured on physical functioning at the time of their transfer. They were followed up six months later and retested on functional status. Subjects were classified on follow-up as improved, the same deteriorated, or dead. They were also classified as discharged from the nursing home, still in the home, or readmitted to the hospital. Nursing homes were measured every six months on structural variables. Outcomes of the patients were related to the nursing home characteristics by multivariate analysis of variance, controlling for expected outcome, age, and diagnoses of cancer and chronic brain disease. Homes with more RN hours per patient were associated with patients being alive, improved, and discharged from the home. Better ratings on meal services were related to being alive and improved. A higher professional staff-to-patient ratio, better medical records, and more services were related to being discharged from the nursing home.


Genetics and Mechanism of Resistance to Meloidogyne arenaria in Peanut Germplasm.
Segregation of resistance to Meloidogyne arenaria in six BCF peanut breeding populations was examined in greenhouse tests. Chi-square analysis indicated that segregation of resistance was consistent with resistance being conditioned by a single gene in three breeding populations (TP259-3, TP262-3, and TP271-2), whereas two resistance genes may be present in the breeding populations TP259-2, TP263-2, and TP268-3. Nematode development in clonally propagated lines of resistant individuals of TP262-3 and TP263-2 was compared to that of the susceptible cultivar Florunner. Juvenile nematodes readily penetrated roots of all peanut genotypes, but rate of development was slower (P = 0.05) in the resistant genotypes than in Florunner. Host cell necrosis indicative of a hypersensitive response was not consistently observed in resistant genotypes of either population. Three RFLP loci linked to resistance at distances of 4.2 to 11.0 centiMorgans were identified. Resistant and susceptible alleles for RFLP loci R2430E and R2545E were quite distinct and are useful for identifying individuals homozygous for resistance in segregating populations.


On the importance of the clinician-educator. Dermatology fellowship for academic clinician teachers.
Within each academic dermatology department there usually exists one clinician who is viewed as the "gold standard" against which diagnostic and therapeutic acumen are measured. As a patient with a puzzling disorder is discussed at rounds, it is to this master that the final word falls, whose recommendation for treatment gets the nod; it is to his or her words that people remain quiet and listen intently. They are commonly also the leading teachers in the medical centers, passing on to succeeding generations the factual knowledge, spiced with bits of philosophy, ethics, and anecdote, that helps to ensure the development of dermatology residents into superb practitioners. They are often the ones most responsible for generating medical student interest in our specialty. Such individuals in our current lingo are "clinician-educators," the rock residents depend on to provide role models to emulate in the diagnosis, care, and treatment of our patients and to whom the community looks to for help in caring for their patients with the most difficult diagnoses.


Differential kidney proteome profiling in a murine model of renal fibrosis under treatment with mycophenolate mofetil.
The aim of this study was to investigate the effect of mycophenolate mofetil (MMF) using differential kidney proteome profiling of COL4A3-deficient mice as a model of progressive renal disease. Histological evaluation of kidney sections was performed. Total protein lysate from kidneys of placebo- and MMF-treated COL4A3-deficient mice was studied for significant differences in protein abundance using 2-dimensional electrophoresis and mass spectrometry. While tubulointerstitial fibrosis in COL4A3-deficient mice was inhibited by MMF, 19 proteins in the kidneys were regulated: 12 with lower (ATPO, TAGL2, CAH1, TPD52, VA0D1, SERPH, GNAL, PSB6, EF1D, OTUB1, NDUS8, and NAPSA) and 7 with higher (ACADM, ACY3, CK054, ACTB/G, ACTB, UBP5, and ACY1) spot intensity. Nine differentially expressed proteins showed interaction potential (ATPO, TPD52, PSB6, EF1D, OTUB1, NAPSA, ACTB, ACTG, and UBP5). The identified proteins take part in different signaling pathways. With the highest probability, the VEGF signaling pathway (TAGL2, EF1D, and ACTB) and hypoxia (CAH1, PSB6, and ACTG) were influenced by MMF in fibrotic conditions. Moreover, MMF may modulate antifibrotic and apoptotic pathways as well as epithelial-mesenchymal transition (EMT). Different signaling pathways may be influenced by MMF therapy. These results suggest an inhibitory effect of MMF on renal EMT in COL4A3-deficient mice. Further studies are necessary to validate these findings.


Liquid Chromatography Coupled to High-Resolution Mass Spectrometry for the Confirmation of Caribbean Ciguatoxin-1 as the Main Toxin Responsible for Ciguatera Poisoning Caused by Fish from European Atlantic Coasts.
Ciguatera poisoning (CP) is a common seafood intoxication mainly caused by the consumption of fish contaminated by ciguatoxins. Recent studies showed that Caribbean ciguatoxin-1 (C-CTX1) is the main toxin causing CP through fish caught in the Northeast Atlantic, e.g., Canary Islands (Spain) and Madeira (Portugal). The use of liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) combined with neuroblastoma cell assay (N2a) allowed the initial confirmation of the presence of C-CTX1 in contaminated fish samples from the abovementioned areas, nevertheless the lack of commercially available reference materials for these particular ciguatoxin (CTX) analogues has been a major limitation to progress research. The EuroCigua project allowed the preparation of C-CTX1 laboratory reference material (LRM) from fish species (Seriola fasciata) from the Madeira archipelago (Portugal). This reference material was used to implement a liquid chromatography coupled to high-resolution mass spectrometry (LC-HRMS) for the detection of C-CTX1, acquisition of full-scan as well as collision-induced mass spectra of this particular analogue. Fragmentation pathways were proposed based on fragments obtained. The optimized LC-HRMS method was then applied to confirm C-CTX1 in fish (Bodianus scrofa) caught in the Selvagens Islands (Portugal).


A postmodern Pandora's box: anti-vaccination misinformation on the Internet.
The Internet plays a large role in disseminating anti-vaccination information. This paper builds upon previous research by analyzing the arguments proffered on anti-vaccination websites, determining the extent of misinformation present, and examining discourses used to support vaccine objections. Arguments around the themes of safety and effectiveness, alternative medicine, civil liberties, conspiracy theories, and morality were found on the majority of websites analyzed; misinformation was also prevalent. The most commonly proposed method of combating this misinformation is through better education, although this has proven ineffective. Education does not consider the discourses supporting vaccine rejection, such as those involving alternative explanatory models of health, interpretations of parental responsibility, and distrust of expertise. Anti-vaccination protestors make postmodern arguments that reject biomedical and scientific "facts" in favour of their own interpretations. Pro-vaccination advocates who focus on correcting misinformation reduce the controversy to merely an "educational" problem; rather, these postmodern discourses must be acknowledged in order to begin a dialogue.


Carotid Near-Occlusion: A Comprehensive Review, Part 1--Definition, Terminology, and Diagnosis.
Carotid near-occlusion is distal ICA luminal collapse beyond a tight stenosis, where the distal lumen should not be used for calculating percentage stenosis. Near-occlusion with full ICA collapse is well-known, with a threadlike lumen. However, near-occlusion without collapse is often subtle and can be overlooked as a usual severe stenosis. More than 10 different terms have been used to describe near-occlusion, sometimes causing confusion. This systematic review presents what is known about carotid near-occlusion. In this first part, the foci are definition, terminology, and diagnosis.


Proning in Non-Intubated (PINI) in Times of COVID-19: Case Series and a Review.
It has been well known for decades that prone positioning (PP) improves oxygenation. However, it has gained widespread acceptance only in the last few years since studies have shown significant survival benefit. Many centers have established prone ventilation in their treatment algorithm for mechanically ventilated patients with severe acute respiratory distress syndrome (ARDS). Physiologically, PP should also benefit awake, non-intubated patients with acute hypoxemic respiratory failure. However, proning in non-intubated (PINI) patients did not gain any momentum until a few months ago when the Coronavirus disease 2019 (COVID-19) pandemic surged. A large number of sick patients overwhelmed the health care system, and many centers faced a dearth of ventilators. In addition, outcomes of patients placed on mechanical ventilation because of COVID-19 infection have been highly variable and often dismal. Hence, increased focus has shifted to using various strategies to prevent intubation, such as PINI. There is accumulating evidence that PINI is a low-risk intervention that can be performed even outside intensive care unit with minimal assistance and may prevent intubation in certain patients with ARDS. It can also be performed safely at smaller centers and, therefore, may reduce the patient transfer to larger institutions that are overwhelmed in the current crisis. We present a case series of 2 patients with acute hypoxemic respiratory failure who experienced significant improvements in oxygenation with PP. In addition, the physiology of PP is described, and concerns such as proning in obese and patient's anxiety are addressed; an educational pamphlet that may be useful for both patients and health care providers is provided.


The Impact of Age and Sex in DLBCL: Systems Biology Analyses Identify Distinct Molecular Changes and Signaling Networks.
Potential molecular alterations based on age and sex are not well defined in diffuse large B-cell lymphoma (DLBCL). We examined global transcriptome DLBCL data from The Cancer Genome Atlas (TCGA) via a systems biology approach to determine the molecular differences associated with age and sex. Collectively, sex and age revealed striking transcriptional differences with older age associated with decreased metabolism and telomere functions and female sex was associated with decreased interferon signaling, transcription, cell cycle, and PD-1 signaling. We discovered that the key genes for most groups strongly regulated immune function activity. Furthermore, older females were predicted to have less DLBCL progression versus older males and young females. Finally, analyses in systems biology revealed that JUN and CYCS signaling were the most critical factors associated with tumor progression in older and male patients. We identified important molecular perturbations in DLBCL that were strongly associated with age and sex and were predicted to strongly influence tumor progression.


State trends in premiums and deductibles, 2003-2010: the need for action to address rising costs.
Rapidly rising health insurance costs continue to strain the budgets of U.S. families and employers. This issue brief analyzes changes in private employer-based health premiums and deductibles for all states from 2003 to 2010, and finds total premiums for family coverage increased 50 percent across states and employee annual share of premiums increased by 63 percent over these seven years. At the same time, per-person deductibles doubled in large, as well as small, firms. If premium trends continue at the rate prior to enactment of the Affordable Care Act, the average premium for family coverage will rise 72 percent by 2020, to nearly $24,000. Health reform offers the potential to reduce insurance cost growth while improving financial protections. If efforts succeed in slowing annual premium growth by 1 percentage point, by 2020 employers and families together would save $2,161 annually for family coverage, compared with projected premiums at historical rates of increase.


Alterations in gene expression induced by cyclic mechanical stress in trabecular meshwork cells.
To investigate the changes in gene expression induced by cyclic mechanical stress (CMS) in trabecular meshwork (TM) cells. Human TM cultures from three donors were plated on type I collagen-coated flexible silicone bottom plates and subjected to 15% stretching, one cycle per second for 6 h. Non-stressed parallel control cultures were incubated under the same conditions in the absence of CMS. Total RNA from each culture was amplified (1 round of amplification) and hybridized to Operon Human Oligo Arrays version 3.0 (35 K probes). Differences in gene expression induced by CMS were analyzed using Genespring 7.2. quantitative polymerase chain reaction (Q-PCR) was used to confirm changes in the expressions of 12 selected genes. The effects of chemical inhibitors for p38, ERK (extracellular signal-regulated kinase), JNK (Jun N-terminal kinase), PKA (protein kinase A), PI3K (phosphoinositide 3-kinase), and P2 (purinergic 2) receptors on the induction of MMP3 (matrix metalloproteinase 3), HSP70 (heat shock protein 70), ECSM1 (endothelial cell specific molecule 1), BMP2 (bone morphogenetic protein 2), VEGFC (vascular endothelial growth factor C), and IL-8 (interleukin 8) were evaluated in porcine TM cells subjected to the same regime of CMS as that used in human cells. CMS induced extensive gene expression changes (664 genes, p < or = 0.05) twofold or higher in cultured TM cells. Many of these changes were related to extracellular matrix (ECM) synthesis and remodeling including the upregulation of two metalloproteinases (MMP3 and MMP10). Cytoskeleton and cell adhesion genes were also affected by CMS as well as genes known to be involved in cellular protection against stress including several members of the HSP70 family. Inhibition of PI3K/AKT and P2 receptors pathways significantly reduced the induction of MMP3 and IL-8 whereas the inhibition of the PKA/cAMP pathway decreased ECSM1 and BMP2. CMS activated many genes that could influence the aqueous humor outflow facility, specifically genes involved in ECM synthesis and remodeling (e.g. MMPs), cytoskeletal organization, and cell adhesion. Induction of MMP3 has the potential to increase the aqueous humor outflow facility and could be part of a homeostatic mechanism involved in the maintenance of normal intraocular pressure (IOP) levels. Other observed changes are more likely to be related to general cellular responses to stress (e.g., HSP70, ECSM1, and BMP2). Although these latter changes may initially help to repair mechanical damage, some of them such as the induction of BMP2 could eventually increase tissue rigidity and compromise the ability of the TM to maintain normal levels of outflow resistance.


Calcium channel blocker ingestion: an evidence-based consensus guideline for out-of-hospital management.
In 2003, U.S. poison control centers were consulted after 9650 ingestions of calcium channel blockers (CCBs), including 57 deaths. This represents more than one-third of the deaths reported to the American Association of Poison Control Centers' Toxic Exposure Surveillance System database that were associated with cardiovascular drugs and emphasizes the importance of developing a guideline for the out-of-hospital management of calcium channel blocker poisoning. The objective of this guideline is to assist poison center personnel in the appropriate out-of-hospital triage and initial management of patients with suspected ingestions of calcium channel blockers. An evidence-based expert consensus process was used to create this guideline. This guideline applies to ingestion of calcium channel blockers alone and is based on an assessment of current scientific and clinical information. The expert consensus panel recognizes that specific patient care decisions may be at variance with this guideline and are the prerogative of the patient and the health professionals providing care, considering all of the circumstances involved. The panel's recommendations follow. The grade of recommendation is in parentheses. 1) All patients with stated or suspected self-harm or the recipient of a potentially malicious administration of a CCB should be referred to an emergency department immediately regardless of the amount ingested (Grade D). 2) Asymptomatic patients are unlikely to develop symptoms if the interval between the ingestion and the call is greater than 6 hours for immediate-release products, 18 hours for modified-release products other than verapamil, and 24 hours for modified-release verapamil. These patients do not need referral or prolonged observation (Grade D). 3) Patients without evidence of self-harm should have further evaluation, including determination of the precise dose ingested, history of other medical conditions, and the presence of co-ingestants. Ingestion of either an amount that exceeds the usual maximum single therapeutic dose or an amount equal to or greater than the lowest reported toxic dose, whichever is lower (see Table 5), would warrant consideration of referral to an emergency department (Grade D). 4) Do not induce emesis (Grade D). 5) Consider the administration of activated charcoal orally if available and no contraindications are present. However, do not delay transportation in order to administer charcoal (Grade D). 6) For patients who merit evaluation in an emergency department, ambulance transportation is recommended because of the potential for life-threatening complications. Provide usual supportive care en route to the hospital, including intravenous fluids for hypotension. Consider use of intravenous calcium, glucagon, and epinephrine for severe hypotension during transport, if available (Grade D). 7) Depending on the specific circumstances, follow-up calls should be made to determine outcome at appropriate intervals based on the clinical judgment of the poison center staff (Grade D).


Network curvature as a hallmark of brain structural connectivity.
Although brain functionality is often remarkably robust to lesions and other insults, it may be fragile when these take place in specific locations. Previous attempts to quantify robustness and fragility sought to understand how the functional connectivity of brain networks is affected by structural changes, using either model-based predictions or empirical studies of the effects of lesions. We advance a geometric viewpoint relying on a notion of network curvature, the so-called Ollivier-Ricci curvature. This approach has been proposed to assess financial market robustness and to differentiate biological networks of cancer cells from healthy ones. Here, we apply curvature-based measures to brain structural networks to identify robust and fragile brain regions in healthy subjects. We show that curvature can also be used to track changes in brain connectivity related to age and autism spectrum disorder (ASD), and we obtain results that are in agreement with previous MRI studies.


A pivotal role for NF-κB in the macrophage inflammatory response to the myeloperoxidase oxidant hypothiocyanous acid.
Atherosclerosis is characterised by the infiltration of macrophages at sites of inflammation within the vessel wall and the release of myeloperoxidase (MPO), which forms hypochlorous acid (HOCl) and hypothiocyanous acid (HOSCN). HOCl is a damaging oxidant implicated in the development of atherosclerosis. Preferential formation of HOSCN occurs under conditions where thiocyanate ions are elevated, as is the case in smokers. HOSCN reacts selectively with thiols, which can result in more enzyme inactivation and damage than HOCl at susceptible sites, which may contribute to atherosclerosis in smokers. In this study, we show that exposure of macrophages to HOSCN results in a time- and dose-dependent increase in the mRNA expression and release of pro-inflammatory cytokines and chemokines, including monocyte chemotactic protein 1, tumour necrosis factor alpha, and interleukins 6, 8 and 1β. At high oxidant concentrations (>200 μM), a significant loss of cellular thiols and increased cell death is observed. HOSCN-induced cytokine/chemokine expression and cell death were decreased on pharmacological inhibition of nuclear factor kappa B. These data highlight a pathway by which HOSCN could promote inflammation and the development of atherosclerosis, in the presence of supra-physiological levels of the precursor thiocyanate, which are achievable by cigarette smoking.


The role of the NADPH oxidase NOX2 in prion pathogenesis.
Prion infections cause neurodegeneration, which often goes along with oxidative stress. However, the cellular source of reactive oxygen species (ROS) and their pathogenetic significance are unclear. Here we analyzed the contribution of NOX2, a prominent NADPH oxidase, to prion diseases. We found that NOX2 is markedly upregulated in microglia within affected brain regions of patients with Creutzfeldt-Jakob disease (CJD). Similarly, NOX2 expression was upregulated in prion-inoculated mouse brains and in murine cerebellar organotypic cultured slices (COCS). We then removed microglia from COCS using a ganciclovir-dependent lineage ablation strategy. NOX2 became undetectable in ganciclovir-treated COCS, confirming its microglial origin. Upon challenge with prions, NOX2-deficient mice showed delayed onset of motor deficits and a modest, but significant prolongation of survival. Dihydroethidium assays demonstrated a conspicuous ROS burst at the terminal stage of disease in wild-type mice, but not in NOX2-ablated mice. Interestingly, the improved motor performance in NOX2 deficient mice was already measurable at earlier stages of the disease, between 13 and 16 weeks post-inoculation. We conclude that NOX2 is a major source of ROS in prion diseases and can affect prion pathogenesis.


Analysis of phenotypic evolution in Dictyostelia highlights developmental plasticity as a likely consequence of colonial multicellularity.
Colony formation was the first step towards evolution of multicellularity in many macroscopic organisms. Dictyostelid social amoebas have used this strategy for over 600 Myr to form fruiting structures of increasing complexity. To understand in which order multicellular complexity evolved, we measured 24 phenotypic characters over 99 dictyostelid species. Using phylogenetic comparative methods, we show that the last common ancestor (LCA) of Dictyostelia probably erected small fruiting structures directly from aggregates. It secreted cAMP to coordinate fruiting body morphogenesis, and another compound to mediate aggregation. This phenotype persisted up to the LCAs of three of the four major groups of Dictyostelia. The group 4 LCA co-opted cAMP for aggregation and evolved much larger fruiting structures. However, it lost encystation, the survival strategy of solitary amoebas that is retained by many species in groups 1-3. Large structures, phototropism and a migrating intermediate 'slug' stage coevolved as evolutionary novelties within most groups. Overall, dictyostelids show considerable plasticity in the size and shape of multicellular structures, both within and between species. This probably reflects constraints placed by colonial life on developmental control mechanisms, which, depending on local cell density, need to direct from 10 to a million cells into forming a functional fructification.


[Anal intraepithelial neoplasia].
Anal intraepithelial lesions are caused by chronic infection with oncogenic types of human papillomavirus. Their incidence and prevalence are increasing, especially among patients with HIV infection. Their natural history is not well known, but high-grade intraepithelial lesions seem to have an important risk to progress to squamous cell carcinoma. Their treatment can be achieved by many ways (surgery, coagulation, imiquimod, etc.) but there is a high rate of recurrent lesions. Pretherapeutic evaluation should benefit from high-resolution anoscopy. Periodic physical examination and anal cytology may probably be interesting for screening the disease among patients with risk factors. Vaccine against oncogenic types of papillomavirus may prevent the development of anal intraepithelial neoplasia.


Safety and efficacy of vaginal birth after cesarean attempts at or beyond 40 weeks of gestation.
To compare rates of vaginal birth after cesarean (VBAC) failure and major complications in women attempting VBAC before and after the estimated date of delivery (EDD) METHODS: This was a 5-year retrospective cohort study in 17 university and community hospitals of women with at least 1 prior cesarean delivery. Women who attempted VBAC before the EDD were compared with those at or beyond 40 weeks of gestation. Logistic regression analyses were performed to assess the relationship between delivery beyond the EDD and VBAC failure or complication rate. A total of 11,587 women in the cohort attempted VBAC. Women past 40 weeks of gestation were more likely to have a failed VBAC. After controlling for confounders, the increased risk of a failed VBAC beyond 40 weeks remained significant (31.3% compared with 22.2%, odds ratio 1.36, 95% confidence interval 1.24-1.50). The risk of uterine rupture (1.1% compared with 1.0%) or overall morbidity (2.7% compared with 2.1%) was not significantly increased in the women attempting VBAC beyond the EDD. When the cohort was defined as 41 weeks or more of gestation, the risk of a failed VBAC was again significantly increased (35.4% compared with 24.3%, odds ratio 1.35, 95% confidence interval 1.20-1.53), but the risk of uterine rupture or overall morbidity was not increased. Women beyond 40 weeks of gestation can safely attempt VBAC, although the risk of VBAC failure is increased.


Urinary excretion of arsenic following rice consumption.
Patterns of arsenic excretion were followed in a cohort (n = 6) eating a defined rice diet, 300 g per day d.wt. where arsenic speciation was characterized in cooked rice, following a period of abstinence from rice, and other high arsenic containing foods. A control group who did not consume rice were also monitored. The rice consumed in the study contained inorganic arsenic and dimethylarsinic acid (DMA) at a ratio of 1:1, yet the urine speciation was dominated by DMA (90%). At steady state (rice consumption/urinary excretion) ∼40% of rice derived arsenic was excreted via urine. By monitoring of each urine pass throughout the day it was observed that there was considerable variation (up to 13-fold) for an individual's total arsenic urine content, and that there was a time dependent variation in urinary total arsenic content. This calls into question the robustness of routinely used first pass/spot check urine sampling for arsenic analysis.


Social sources of women's emotional difficulty after abortion: lessons from women's abortion narratives.
The experiences of women who have negative emotional outcomes, including regret, following an abortion have received little research attention. Qualitative research can elucidate these women's experiences and ways their needs can be met and emotional distress reduced. Twenty-one women who had emotional difficulties related to an abortion participated in semi-structured, in-depth telephone interviews in 2009. Of these, 14 women were recruited from abortion support talklines; seven were recruited from a separate research project on women's experience of abortion. Transcripts were analyzed using the principles of grounded theory to identify key themes. Two social aspects of the abortion experience produced, exacerbated or mitigated respondents' negative emotional experience. Negative outcomes were experienced when the woman did not feel that the abortion was primarily her decision (e.g., because her partner abdicated responsibility for the pregnancy, leaving her feeling as though she had no other choice) or did not feel that she had clear emotional support after the abortion. Evidence also points to a division of labor between women and men regarding pregnancy prevention, abortion and childrearing; as a result, the majority of abortion-related emotional burdens fall on women. Experiencing decisional autonomy or social support reduced respondents' emotional distress. Supporting a woman's abortion decision-making process, addressing the division of labor between women and men regarding pregnancy prevention, abortion and childrearing, and offering nonjudgmental support may guide interventions designed to reduce emotional distress after abortion.


An obsessive-compulsive view of obesity and its treatment.
It was hypothesized that some obese individuals who are obsessed with food and who eat compulsively may not respond to the stimulus control techniques widely used in treating obesity. Sixty-eight participants were administered a measure of obsessive tendencies and randomly assigned to three treatment modalities: (a) Exposure and response prevention; (b) Stimulus control; (c) Control. Results indicated that participants who scored high on the Eating Obsessive Compulsive questionnaire (EOC) maintained weight loss significantly better with exposure and response prevention (ERP) training than did either the stimulus control or the control group. It was concluded that for the obsessive-compulsive eater, ERP training is the treatment of choice.


A laser-assisted infrared scanning technique for evaluating bonded connections on beam lead microcircuits.
An argon ion laser and an ir microscope have been combined to function as a unique combination for non- destructively testing the quality of bonded connections in microcircuits of the beam lead type. A microcircuit is heated with the focused beam from the laser and scanned with the microscope to determine the temperature pattern. Nonbonded microcircuits, poorly bonded microcircuits, and a multiplicity of adjacent poorly bonded leads have been detected by using this scanner. Preliminary results have indicated that a single nonbonded connection in an array of well bonded connections may be detected. An analytical check by computer analysis demonstrates the validity of the experimental data.


PRAS40 prevents development of diabetic cardiomyopathy and improves hepatic insulin sensitivity in obesity.
Diabetes is a multi-organ disease and diabetic cardiomyopathy can result in heart failure, which is a leading cause of morbidity and mortality in diabetic patients. In the liver, insulin resistance contributes to hyperglycaemia and hyperlipidaemia, which further worsens the metabolic profile. Defects in mTOR signalling are believed to contribute to metabolic dysfunctions in diabetic liver and hearts, but evidence is missing that mTOR activation is causal to the development of diabetic cardiomyopathy. This study shows that specific mTORC1 inhibition by PRAS40 prevents the development of diabetic cardiomyopathy. This phenotype was associated with improved metabolic function, blunted hypertrophic growth and preserved cardiac function. In addition PRAS40 treatment improves hepatic insulin sensitivity and reduces systemic hyperglycaemia in obese mice. Thus, unlike rapamycin, mTORC1 inhibition with PRAS40 improves metabolic profile in diabetic mice. These findings may open novel avenues for therapeutic strategies using PRAS40 directed against diabetic-related diseases.