Identification and characterization of antigenic determinants of Mycobacterium leprae that react with antibodies in sera of leprosy patients.
Antigenic determinants of Mycobacterium leprae were identified by screening a lambda gt11::M. leprae genomic library with two separate pools of sera from leprosy patients. A total of 45 recombinant clones were detected with pooled sera from 21 lepromatous (LL) leprosy patients and 5 additional clones specified polypeptides that reacted with antibodies in pooled sera from 30 borderline tuberculoid or tuberculoid leprosy patients. The recombinant clones that specified antigenic determinants that reacted with sera from LL patients were condensed into eight groups on the basis of DNA hybridization experiments among the M. leprae DNA insert fragments. In addition, 11 of the 45 recombinant clones did not hybridize to members of the eight groups nor to one another; these represent unique recombinant clones. None of the recombinant clones identified by screening with sera from tuberculoid leprosy patients hybridized to each other or to any of the 45 LL recombinant clones. The polypeptides specified by the recombinant clones were usually fusion proteins with beta-galactosidase, ranging in size from 117 to 175 kilodaltons (kDa). Members of hybridization group III specified nonfusion proteins of 45 kDa. Only members of hybridization group I reacted with any of 30 monoclonal antibodies prepared against M. leprae proteins; recombinant proteins from these clones reacted with a single monoclonal antibody directed against the M. leprae 65-kDa protein. Thus, at least 22 new antigenic determinants of M. leprae have been identified on the basis of their reactivity to antibodies in sera from LL patients or sera from tuberculoid leprosy patients or both.


Direct-potential-fit analyses yield improved empirical potentials for the ground X (1)Σ(+)(g) state of Be2.
We have performed new direct-potential-fit (DPF) analyses of the rotationally resolved A (1)Π(u)(ν'=2,3;J' =1,2)→X(1)Σ(+)(g) (ν" ∈[0,11];J" ∈[0,3]) stimulated emission pumping spectra of Be2 [J. M. Merritt, V. E. Bondybey, and M. C. Heaven, Science 324, 1548 (2009)] using two quite different analytical potential energy functions that incorporate the correct theoretically known long-range behaviour in different ways. These functions are: the damped Morse/long-range potential [R. J. Le Roy, C. C. Haugen, J. Tao, and H. Li, Mol. Phys. 109, 435 (2011)], and the Chebyshev polynomial expansion potential [L. Busevica, I. Klincare, O. Nikolayeva, M. Tamanis, R. Ferber, V. V. Meshkov, E. A. Pazyuk, and A. V. Stolyarov, J. Chem. Phys. 134, 104307 (2011)]. In contrast with the expanded Morse oscillator potential determined in the original DPF analysis of Merritt et al. [Science 324, 1548 (2009)], both of these functions unambiguously support the existence of the v″ = 11 last vibrational levels which is bound by only ∼0.5 cm(-1), and they give equivalent, essentially exact predictions for this level when using the original data set which ended at v″ = 10. These empirical potentials predict an equilibrium distance of re = 2.445(5) Å and a well depth of D(e) = 934.9(0.4) cm(-1), values which agree (within the uncertainties) with the best ab initio estimates of 2.444(10) Å and 935(10) cm(-1), respectively [J. Koput, Phys. Chem. Chem. Phys. 13, 20311 (2011)].


Experimental autoimmune encephalomyelitis (EAE) as a model for multiple sclerosis (MS).
Experimental autoimmune encephalomyelitis (EAE) is the most commonly used experimental model for the human inflammatory demyelinating disease, multiple sclerosis (MS). EAE is a complex condition in which the interaction between a variety of immunopathological and neuropathological mechanisms leads to an approximation of the key pathological features of MS: inflammation, demyelination, axonal loss and gliosis. The counter-regulatory mechanisms of resolution of inflammation and remyelination also occur in EAE, which, therefore can also serve as a model for these processes. Moreover, EAE is often used as a model of cell-mediated organ-specific autoimmune conditions in general. EAE has a complex neuropharmacology, and many of the drugs that are in current or imminent use in MS have been developed, tested or validated on the basis of EAE studies. There is great heterogeneity in the susceptibility to the induction, the method of induction and the response to various immunological or neuropharmacological interventions, many of which are reviewed here. This makes EAE a very versatile system to use in translational neuro- and immunopharmacology, but the model needs to be tailored to the scientific question being asked. While creating difficulties and underscoring the inherent weaknesses of this model of MS in straightforward translation from EAE to the human disease, this variability also creates an opportunity to explore multiple facets of the immune and neural mechanisms of immune-mediated neuroinflammation and demyelination as well as intrinsic protective mechanisms. This allows the eventual development and preclinical testing of a wide range of potential therapeutic interventions.


Induction of in vitro heart block is not restricted to affinity purified anti-52 kDa Ro/SSA antibody from mothers of children with neonatal lupus.
The ability of affinity purified anti-52 kDa Ro/SSA antibody from patients without obstetric history of neonatal lupus to cause heart block using an experimental model was investigated. IgG-enriched fractions from sera of 20 systemic lupus erythematosus (SLE) and one Sjögren's syndrome (SS) all positives for anti-Ro/SSA antibodies as detected by CIE, were perfused on isolated whole rabbit hearts. Only six (29%) samples induced A-V block, five of them presenting low anti-Ro/SSA titre. All of them recognized the 52 kDa isoform on ELISA whereas only one had a concomitant binding to the 60 kDa protein. Moreover, affinity purified antibodies from two sera previously known to induce A-V block were obtained by affinity chromatography using a column containing the full-length 52 kDa Ro/SSA fusion protein. Paired eluate and effluent devoid of anti-52 kDa activity from the same patient were individually perfused in whole hearts. The ability to cause cardiac blockade was restricted to the affinity anti-52 kDa eluates. In addition, anti-52 kDa eluates from three IgG fractions that primarily failed to induce blockade remained ineffective. The present study has added to our knowledge that affinity anti-52 kDa Ro/SSA antibodies from mothers with healthy infants are capable of causing in vitro cardiac conduction disturbances. A prospective follow up of these patients will better delineate the clinical usefulness of this experimental model.


[Idiopathic gastric rupture in toddler: case report].
Idiopathic gastric rupture is rare in children. Most of them occur in newborn. The authors report the case of a 2-year-old female toddler with no significant medical records. Clinical picture began 48 h before with abdominal pain, nausea and vomiting. She was admitted to the Emergency Room in poor general condition, with abdominal distension and rebound tenderness. Laparotomy was performed immediately show-ing multiple perforations in the posterior wall of the stomach. Partial gastrectomy was performed. Afterwards, she was admitted to ICU in shock. She received mechanical ventilation, intravenous fluid administration (260 ml/kg in 12 h), vasoactive support and antibacterial therapy (cefotaxime and metronidazole). Laboratory showed leukopenia and thrombocytopenia. Etiological study was entirely negative for toxic and drug consumption. Collagen disease was ruled out and serum level of gastrin was normal. Her post operative course was characterized by persistent fever caused by left subphrenic collection (positive culture for Candida galabrata). Peritoneal lavage via laparotomy and percutaneous drainage of the residual collections were performed. She completed 3 weeks of antibacterial and antifungal therapies with adequate outcome. Her follow-up in 12 months was uneventful.


Effects of mouthwashes on Knoop hardness and surface roughness of dental composites after different immersion times.
The aim of this in vitro study was to evaluate the effect of different mouthwashes on superficial roughness and Knoop hardness of two resin composites. Eighty specimens (6 mm Ø and 2 mm height) were prepared and divided into eight experimental groups (n = 10) according to the resin composites (4 Seasons and Esthet X), and storage solutions (G1 - Distilled water; G2 - Colgate Plax Overnight; G3 - Colgate Plax Alcohol Free; and G4 - Colgate Plax Whitening). The initial hardness and roughness readings (T1) were measured and then the specimens were stored in 2 mL of mouthwash for 12 h (T2) and 24 h (T3). The data were analyzed with repeat-measures two-way ANOVA and Tukey's test (α = 5%). Regardless of the type of solution and time of exposure, there was no statistical difference for roughness between the resins (p = 0.44). G4 and G8 presented higher roughness means than G1, G3, G5 and G7, after 12 and 24 hours of immersion. For Knoop microhardness analysis, there was a significant reduction for all groups after 12 hours and 24 hours. We conclude that the mouthwashes containing hydrogen peroxide and/or alcohol decrease the microhardness of the resins tested; however, the mouthwash containing hydrogen peroxide had a higher deleterious effect on roughness.


An update on antiepileptic drugs and suicide: are there definitive answers yet?
In 2008, the Food and Drug Administration (FDA) issued a warning that any and all antiepileptic drugs (AEDs) might increase the risk of suicidal ideation, suicide attempt, and completed suicide. Considerable confusion and concern followed regarding the use of these drugs, in general, and specifically for people with epilepsy. Recently, four publications examined suicidality and AED use among several databases and illustrated how biases affect the findings. None of the studies was able to control completely for the indication for which the AEDs were prescribed or to account for the varying intensities with which different specialists monitoring patients for suicidality. Though multiple analyses were conducted for many AEDs, no study controlled for the numerous comparisons made. The result is a multitude of contradictions in the findings across studies and even within studies, with no study providing clear or convincing support for the FDA conclusions. This review attempts to clarify the methodological issues in assessing potential associations between AED use and suicidality.


Ambroxol Hydrochloride Improves Motor Functions and Extends Survival in a Mouse Model of Familial Amyotrophic Lateral Sclerosis.
Amyotrophic lateral sclerosis (ALS) is a multifactorial and fatal neurodegenerative disease. Growing evidence connects sphingolipid metabolism to the pathophysiology of ALS. In particular, levels of ceramides, glucosylceramides, and gangliosides are dysregulated in the central nervous system and at the neuromuscular junctions of both animal models and patients. Glucosylceramide is the main precursor of complex glycosphingolipids that is degraded by lysosomal (GBA1) or non-lysosomal (GBA2) glucocerebrosidase. Here, we report that GBA2, but not GBA1, activity is markedly increased in the spinal cord, of SOD1G86R mice, an animal model of familial ALS, even before disease onset. We therefore investigated the effects of ambroxol hydrochloride, a known GBA2 inhibitor, in SOD1G86R mice. A presymptomatic administration of ambroxol hydrochloride, in the drinking water, delayed disease onset, protecting neuromuscular junctions, and the number of functional spinal motor neurons. When administered at disease onset, ambroxol hydrochloride delayed motor function decline, protected neuromuscular junctions, and extended overall survival of the SOD1G86R mice. In addition, ambroxol hydrochloride improved motor recovery and muscle re-innervation after transient sciatic nerve injury in non-transgenic mice and promoted axonal elongation in an in vitro model of motor unit. Our study suggests that ambroxol hydrochloride promotes and protects motor units and improves axonal plasticity, and that this generic compound is a promising drug candidate for ALS.


Radial artery hypertrophy occurs in coronary atherosclerosis and is independent of blood pressure.
Endothelial dysfunction, believed to underlie the structural changes of atherosclerosis, is a systemic phenomenon. Despite this, the radial artery has been considered as devoid of atherosclerosis and is commonly used as a conduit in coronary artery bypass grafting (CABG). Recently, histological study has shown intimal hyperplasia and other structural changes consistent with early atherosclerosis in the radial artery. The objective of the present study was to determine if structural changes in the radial artery could be detected in vivo in patients with coronary atherosclerosis. Using high resolution echo-tracking, measurements of radial artery internal diameter, wall thickness and wall cross-sectional area were made in 25 patients awaiting CABG and in 20 controls. Digital and brachial blood pressures were also recorded. Mean arterial pressures did not differ between the patient and control groups. All measures of wall thickness were greater in the patient than the control group. Neither current arterial pressures nor past history of hypertension correlated with wall thickness. Using a model of analysis of covariance, coronary artery disease was the best single predictor of intima-media thickness, R(2)=48%, n=44, P<0.0005. We concluded that increased radial artery wall thickness can be demonstrated in vivo in patients with coronary atherosclerosis. This is a novel observation which seems to be independent of blood pressure, and is consistent both with the hypothesis of systemic endothelial dysfunction leading to systemic structural changes and also to the recent histological evidence for atherosclerotic changes in this vessel.


c-Src-mediated phosphorylation of the epidermal growth factor receptor on Tyr845 and Tyr1101 is associated with modulation of receptor function.
Accumulating evidence indicates that interactions between the epidermal growth factor receptor (EGFR) and the nonreceptor tyrosine kinase c-Src may contribute to an aggressive phenotype in multiple human tumors. Previous work from our laboratory demonstrated that murine fibroblasts which overexpress both these tyrosine kinases display synergistic increases in DNA synthesis, soft agar growth, and tumor formation in nude mice, and increased phosphorylation of the receptor substrates Shc and phospholipase gamma as compared with single overexpressors. These parameters correlated with the ability of c-Src and EGFR to form an EGF-dependent heterocomplex in vivo. Here we provide evidence that association between c-Src and EGFR can occur directly, as shown by receptor overlay experiments, and that it results in the appearance of two novel tyrosine phosphorylations on the receptor that are seen both in vitro and in vivo following EGF stimulation. Edman degradation analyses and co-migration of synthetic peptides with EGFR-derived tryptic phosphopeptides identify these sites as Tyr845 and Tyr1101. Tyr1101 lies within the carboxyl-terminal region of the EGFR among sites of receptor autophosphorylation, while Tyr845 resides in the catalytic domain, in a position analogous to Tyr416 of c-Src. Phosphorylation of Tyr416 and homologous residues in other tyrosine kinase receptors has been shown to be required for or to increase catalytic activity, suggesting that c-Src can influence EGFR activity by mediating phosphorylation of Tyr845. Indeed, EGF-induced phosphorylation of Tyr845 was increased in MDA468 human breast cancer cells engineered to overexpress c-Src as compared with parental MDA 468 cells. Furthermore, transient expression of a Y845F variant EGFR in murine fibroblasts resulted in an ablation of EGF-induced DNA synthesis to nonstimulated levels. Together, these data support the hypothesis that c-Src-mediated phosphorylation of EGFR Tyr845 is involved in regulation of receptor function, as well as in tumor progression.


[Work-related chronic respiratory diseases--current diagnosis].
Bronchial asthma, COPD and extrinsic allergic alveolitis are respiratory diseases that can be also acquired through occupational exposure. However, the definitive identification of an occupational disease is difficult because the symptoms do not exclusively appear in direct connection with noxious workplace substances but rather also appear in the leisure time. It is still important to make an early and clear correlation in order to establish preventive measures at the workplace if necessary.


Getting by in the community: lessons from frail elders.
This study explores how functionally impaired, elderly persons are able to remain in the community without home- and community- based care (HCBC) under the Medicaid program. Using HCBC administrative data, Medicare data, and survey data, we find the nonparticipants in the community appear to get by through a combination of reliance on informal care, use of Medicare home care, and going without needed services. Despite their efforts to manage their care in the community, non-participants were significantly more likely than the participants to enter a nursing home during the six months following assessment. While our analysis does not allow us to attribute the higher nursing home entry to the absence of HCBC services with certainty, the finding does raise questions about whether the elements of the HCBC program that discourage participation may save Medicaid dollars in the short-run at the expense of future Medicaid costs from more rapid nursing home entry.


Dynamics of dendritic cell maturation are identified through a novel filtering strategy applied to biological time-course microarray replicates.
Dendritic cells (DC) play a central role in primary immune responses and become potent stimulators of the adaptive immune response after undergoing the critical process of maturation. Understanding the dynamics of DC maturation would provide key insights into this important process. Time course microarray experiments can provide unique insights into DC maturation dynamics. Replicate experiments are necessary to address the issues of experimental and biological variability. Statistical methods and averaging are often used to identify significant signals. Here a novel strategy for filtering of replicate time course microarray data, which identifies consistent signals between the replicates, is presented and applied to a DC time course microarray experiment. The temporal dynamics of DC maturation were studied by stimulating DC with poly(I:C) and following gene expression at 5 time points from 1 to 24 hours. The novel filtering strategy uses standard statistical and fold change techniques, along with the consistency of replicate temporal profiles, to identify those differentially expressed genes that were consistent in two biological replicate experiments. To address the issue of cluster reproducibility a consensus clustering method, which identifies clusters of genes whose expression varies consistently between replicates, was also developed and applied. Analysis of the resulting clusters revealed many known and novel characteristics of DC maturation, such as the up-regulation of specific immune response pathways. Intriguingly, more genes were down-regulated than up-regulated. Results identify a more comprehensive program of down-regulation, including many genes involved in protein synthesis, metabolism, and housekeeping needed for maintenance of cellular integrity and metabolism. The new filtering strategy emphasizes the importance of consistent and reproducible results when analyzing microarray data and utilizes consistency between replicate experiments as a criterion in both feature selection and clustering, without averaging or otherwise combining replicate data. Observation of a significant down-regulation program during DC maturation indicates that DC are preparing for cell death and provides a path to better understand the process. This new filtering strategy can be adapted for use in analyzing other large-scale time course data sets with replicates.


Corrigendum to: Integrated transcriptomics and metabolomics reveal induction of hierarchies of resistance genes in potato against late blight.
Late blight caused by Phytophthora infestans is a devastating disease affecting potato production worldwide. The quantitative resistance is durable, but the underlying molecular and biochemical mechanisms are poorly understood, limiting its application in breeding. Integrated transcriptomics and metabolomics approach was used for the first time to study the hierarchies of molecular events occurring, following inoculation of resistant and susceptible potato genotypes with P. infestans. RNA sequencing revealed a total of 4216 genes that were differentially expressed in the resistant than in the susceptible genotype. Genes that were highly expressed and associated with their biosynthetic metabolites that were highly accumulated, through metabolic pathway regulation, were selected. Quantitative real-time PCR was performed to confirm the RNA-seq expression levels. The induced leucine-rich repeat receptor-like kinases (LRR-RLKs) are considered to be involved in pathogen recognition. These receptor genes are considered to trigger downstream oxidative burst, phytohormone signalling-related genes, and transcription factors that regulated the resistance genes to produce resistance related metabolites to suppress the pathogen infection. It was noted that several resistance genes in metabolic pathways related to phenylpropanoids, flavonoids, alkaloids and terpenoid biosynthesis were strongly induced in the resistant genotypes. The pathway specific gene induction provided key insights into the metabolic reprogramming of induced defence responses in resistant genotypes.


Pathophysiology of post-gastrectomy hypoglycaemia.
The blood glucose and plasma insulin response to oral glucose and slow intravenous infusion of glucose was determined in seven patients who had undergone partial gastrectomy or gastroenterostomy. Similar studies were conducted in normal subjects; in these experiments oral glucose administration was replaced by infusion of glucose direct into the jejunum in order to simulate the rapid gastric emptying which occurs after gastric surgery.Peak insulin levels were much higher after oral or intrajejunal glucose, though peak blood glucose levels were higher after intravenous glucose. Despite the high insulin levels occurring with oral administration the late fall in blood glucose below fasting levels was not significantly greater after oral or intrajejunal glucose than after intravenous administration of the sugar. This does not support the concept that hyperinsulinaemia alone is responsible for reactive hypoglycaemia.


Long non-coding RNAs as surrogate indicators for chemical stress responses in human-induced pluripotent stem cells.
In this study, we focused on two biological products as ideal tools for toxicological assessment: long non-coding RNAs (lncRNAs) and human-induced pluripotent stem cells (hiPSCs). lncRNAs are an important class of pervasive non-protein-coding transcripts involved in the molecular mechanisms associated with responses to cellular stresses. hiPSCs possess the capabilities of self-renewal and differentiation into multiple cell types, and they are free of the ethical issues associated with human embryonic stem cells. Here, we identified six novel lncRNAs (CDKN2B-AS1, MIR22HG, GABPB1-AS1, FLJ33630, LINC00152, and LINC0541471_v2) that respond to model chemical stresses (cycloheximide, hydrogen peroxide, cadmium, or arsenic) in hiPSCs. Our results indicated that the lncRNAs responded to general and specific chemical stresses. Compared with typical mRNAs such as p53-related mRNAs, the lncRNAs highly and rapidly responded to chemical stresses. We propose that these lncRNAs have the potential to be surrogate indicators of chemical stress responses in hiPSCs.


Enlargement or reduction of digital images with minimum loss of information.
The purpose of this paper is to derive optimal spline algorithms for the enlargement or reduction of digital images by arbitrary (noninteger) scaling factors. In our formulation, the original and rescaled signals are each represented by an interpolating polynomial spline of degree n with step size one and Delta, respectively. The change of scale is achieved by determining the spline with step size Delta that provides the closest approximation of the original signal in the L(2)-norm. We show that this approximation can be computed in three steps: (i) a digital prefilter that provides the B-spline coefficients of the input signal, (ii) a resampling using an expansion formula with a modified sampling kernel that depends explicitly on Delta, and (iii) a digital postfilter that maps the result back into the signal domain. We provide explicit formulas for n=0, 1, and 3 and propose solutions for the efficient implementation of these algorithms. We consider image processing examples and show that the present method compares favorably with standard interpolation techniques. Finally, we discuss some properties of this approach and its connection with the classical technique of bandlimiting a signal, which provides the asymptotic limit of our algorithm as the order of the spline tends to infinity.


Five-year results: the initial clinical trial of MammoSite balloon brachytherapy for partial breast irradiation in early-stage breast cancer.
Patients with early-stage invasive ductal breast cancer were prospectively evaluated using MammoSite RTS balloon brachytherapy (RTS Cytyc Corp, Marlborough, MA) as the sole modality for delivering accelerated partial breast irradiation to the lumpectomy bed with breast-conserving surgery. This report presents the 5-year results of the treated patients. From May 2000 to October 2001, 70 patients were enrolled in this prospective study. Forty-three patients completed accelerated partial breast irradiation with MammoSite brachytherapy following lumpectomy and axillary staging. Thirty-six patients have been followed for a median of 5.5 years (mean 65.2 months). Criteria for entry into the study were unifocal invasive ductal carcinoma, tumor size < or = 2 cm, age > or = 45 years, absence of extensive intraductal component, cavity size > or = 3 cm in 1 dimension, node-negative, and final margins negative per National Surgical Adjuvant Breast and Bowel Project definition. A minimum balloon-to-skin surface distance of 5 mm was required. A dose of 34 Gy was delivered in 10 fractions over 5 days prescribed to 1 cm from the applicator surface using iridium-192 high-dose-rate brachytherapy. Data on infection, seromas, cosmetic outcome, and toxicities were collected at 3 and 6 months and at yearly intervals. Local recurrences, both true recurrences in the lumpectomy bed and failures outside the initially treated target volume (elsewhere failures), were recorded. Contralateral breast failure rates were noted. The catheter was not implanted in 16 of the 70 enrolled patients due to cavity size not amenable to balloon placement (n = 10), ineligible by criteria (n = 4), and skin spacing (n = 2). Fifty-four patients were implanted and 43 were successfully treated with MammoSite balloon brachytherapy. Reasons for catheter explantation in 11 patients were poor cavity conformance in 7, inadequate skin spacing in 2, positive node in 1 and age less than 45 years in 1. Of the 43 patients who completed treatment, the infection rate was 9.3%. Seroma formation occurred in 32.6% of patients, of which 12% were symptomatic requiring aspiration. Asymptomatic fat necrosis was identified in 4 of the 43 patients, noted from time of catheter removal at 11, 14, 42, and 63 months. Good-excellent cosmetic outcomes were achieved in 83.3% of the 36 patients with more than 5 years of follow-up. Cosmetic outcomes were improved, with increased skin spacing having statistical significance at skin spacing > or = 7 mm. The only serious adverse events were 2 infections: mastitis and abscess. Seven of the 43 treated patients have been discontinued from follow-up. None had a local recurrence recorded at last visit. Reasons for exit from the study were death from metastatic disease (n = 3), lost to follow-up (n = 2), and placed in hospice for other medical conditions (n = 2). No local recurrences (either at the tumor bed or elsewhere in the breast) or regional recurrences have occurred in the 36 patients who have been followed for a median of 5.5 years. No contralateral cancers have developed. MammoSite balloon brachytherapy as a sole modality for delivering radiation to the tumor bed has been successful in achieving excellent local control in this initial clinical study of patients with early-stage invasive ductal breast cancer. This has been achieved with minimal toxicities and good-excellent cosmetic outcomes in 83.3%. Accelerated partial breast irradiation using the MammoSite balloon in a carefully selected group of patients has demonstrated 5-year local recurrence results comparable to those achieved with conventional whole breast radiation therapy and interstitial catheter brachytherapy as reported at 5-year data points in studies of these treatment modalities. Poor cavity conformance and inadequate skin distance were the main factors limiting use of the MammoSite device. Extended follow-up will be required to determine the long-term efficacy of this treatment modality.


Pseudoinsulinoma. Alimentary tract hypoglycemia revisited.
Knowing that hypoglycemia and inappropriate plasma insulin levels and insulin-glucose ratios can occur after gastric surgery may prevent unwarranted exploration for insulinoma in patients with alimentary tract hypoglycemia (ATH). Absolute differentiation may be achieved by comparing the insulin-glucose ratios obtained during a 72-hour fast with those obtained during an oral glucose tolerance test. The treatment of ATH is primarily medical, surgery being reserved for those patients in whom diet and drug therapy fails. For such medically intractable patients , reversal of a 10-cm segment of jejunum at the gastroenteric stoma is highly effective in controlling the symptoms of hypoglycemia.


Robust recursive least squares learning algorithm for principal component analysis.
A learning algorithm for the principal component analysis is developed based on the least-square minimization. The dual learning rate parameters are adjusted adaptively to make the proposed algorithm capable of fast convergence and high accuracy for extracting all principal components. The proposed algorithm is robust to the error accumulation existing in the sequential principal component analysis (PCA) algorithm. We show that all information needed for PCA can be completely represented by the unnormalized weight vector which is updated based only on the corresponding neuron input-output product. The updating of the normalized weight vector can be referred to as a leaky Hebb's rule. The convergence of the proposed algorithm is briefly analyzed. We also establish the relation between Oja's rule and the least squares learning rule. Finally, the simulation results are given to illustrate the effectiveness of this algorithm for PCA and tracking time-varying directions-of-arrival.


Enhanced catalytic oxidation ability of ternary layered double hydroxides for organic pollutants degradation.
Co(2+) and Cu(2+) substituted MgAl layered double hydroxides with an M(2+)/M(3+) atomic ratio of 2.0 were synthesized by a co-precipitation method and fully characterized using various techniques including powder X-ray diffraction, ICP-AES analysis, FT-IR, DR UV-Vis spectroscopy, N2 adsorption-desorption and transmission electron microscopy. The materials revealed a good crystallinity with no phase impurity and successful substitution of cobalt and copper ions in the framework of binary LDH with the target ratio of metals in the sheet. The adsorption characteristics (kinetic and isotherm) and the catalytic oxidation of organic pollutants, methylene blue (cationic dye) and orange II (anionic) were carried out to investigate a potential use of LDH materials as catalysts. In particular, Co3Cu1Al2 LDH exhibited an excellent catalytic activity towards catalytic dye degradation, especially for orange II with good stability and reusability over several times. Furthermore, this LDH material showed good catalytic performance for several chlorophenol compounds, suggesting its practical application in wastewater treatment. Therefore, layered double hydroxides substituted with Co(2+) and Cu(2+) could be promising candidates in various applications, such as the abatement of organic pollutants.


Performance of a tool to identify different types of self-reported sexual risk among women attending a contraception and sexual health clinic: results of a cross-sectional survey.
A clinical prediction rule (CPR) using psychosocial questions was previously derived to target sexual healthcare in general practice by identifying women at risk of unintended pregnancy (UIP) and sexually transmitted infections (STIs). This psychosocial CPR may help target resources within contraception and sexual health (CASH) services. This study investigated how well it predicted recent self-reported risk of UIP and STI acquisition among women attending a CASH clinic. Female patients aged 16-44 years attending a CASH clinic in South-East England were offered a questionnaire on arrival. This comprised psychosocial questions, and others addressing three sexual risks: (1) two or more male sexual partners in the last year (2+P), (2) risk of STI acquisition through most recent partner and (3) risk of UIP in the last 6 months. A CPR score was calculated for each participant and cross-tabulated against self-report of each sexual risk to estimate CPR sensitivity and specificity. The psychosocial questions predicting 2+P had sensitivity 83.2% (95% CI 79.3% to 86.5%) and specificity 56.1% (95% CI 51.3%-60.6%). Those predicting combined 2+P and/or risk of STI acquisition through most recent partner had a sensitivity of 89.1% (95% CI 85.7%-91.8%) and specificity of 43.7% (95% CI 39.0%-48.5%). Questions predicting risk of UIP in the last 6 months had a sensitivity of 82.5% (95% CI 78.6%-86.0%) and specificity of 48.3% (95% CI 43.4%-53.1%). The CPR demonstrated good sensitivity but low specificity, so may be suited to triaging or stratifying which interventions to offer CASH patients and by which mode (eg, online vs face-to-face). Further investigation of causal links between psychosocial factors and sexual risk is warranted to support development of psychosocial interventions for this patient group.


Protein kinase D3 sensitizes RAF inhibitor RAF265 in melanoma cells by preventing reactivation of MAPK signaling.
RAS mutations occur in more than 30% of all human cancers but efforts to directly target mutant RAS signaling as a cancer therapy have yet to succeed. As alternative strategies, RAF and MEK inhibitors have been developed to block oncogenic signaling downstream of RAS. As might be expected, studies of these inhibitors have indicated that tumors with RAS or BRAF mutations display resistance RAF or MEK inhibitors. In order to better understand the mechanistic basis for this resistance, we conducted a RNAi-based screen to identify genes that mediated chemoresistance to the RAF kinase inhibitor RAF265 in a BRAF (V600E) mutant melanoma cell line that is resistant to this drug. In this way, we found that knockdown of protein kinase D3 (PRKD3) could enhance cell killing of RAF and MEK inhibitors across multiple melanoma cell lines of various genotypes and sensitivities to RAF265. PRKD3 blockade cooperated with RAF265 to prevent reactivation of the MAPK signaling pathway, interrupt cell cycle progression, trigger apoptosis, and inhibit colony formation growth. Our findings offer initial proof-of-concept that PRKD3 is a valid target to overcome drug resistance being encountered widely in the clinic with RAF or MEK inhibitors.


The Metabolic Syndrome Does Not Affect Development of Collateral Circulation in the Poststenotic Swine Kidney.
The collateral circulation is important in maintenance of blood supply to the ischemic kidney distal to renal artery stenosis (RAS). Obesity metabolic syndrome (MetS) preserves renal blood flow (RBF) in the stenotic kidney, but whether this is related to an increase of collateral vessel growth is unknown. We hypothesized that MetS increased collateral circulation around the renal artery. Twenty-one domestic pigs were randomly divided into unilateral RAS fed an atherogenic (high-fat/high-fructose, MetS-RAS) or standard diet, or controls (n = 7 each). RBF, glomerular filtration rate (GFR), and the peristenotic collateral circulation were assessed after 10 weeks using multidetector computed tomography (CT) and the intrarenal microcirculation by micro-CT. Vascular endothelial growth factor (VEGF) expression was studied in the renal artery wall, kidney, and perirenal fat. Renal fibrosis and stiffness were examined by trichrome and magnetic resonance elastography. Compared with controls, RBF and GFR were decreased in RAS, but not in MetS-RAS. MetS-RAS formed peristenotic collaterals to the same extent as RAS pigs but induced greater intrarenal microvascular loss, fibrosis, stiffness, and inflammation. MetS-RAS also attenuated VEGF expression in the renal tissue compared with RAS, despite increased expression in the perirenal fat. MetS does not interfere with collateral vessel formation in the stenotic kidney, possibly because decreased renal arterial VEGF expression offsets its upregulation in perirenal fat, arguing against a major contribution of the collateral circulation to preserve renal function in MetS-RAS. Furthermore, preserved renal function does not protect the poststenotic kidney from parenchymal injury.


Experimental model of the formation of pelvic adhesions by videolaparoscopic in female rabbits.
To verify the frequency of postsurgical pelvic adhesion formation in an experimental animal model using videolaparoscopy. Experimental study in a sample of 11 non-pregnant female rabbits, aged 5 to 7 months. After general anesthesia, access to the abdominal cavity was performed by an open puncture technique, with 10mm optics, placing two other 5 mm trochars under direct visualization, in the iliac fossae. Then a fragment of peritoneum was resected, followed by electrocauterization. In 21 days, the videolaparoscopy was repeated, and adhesion formation and score was looked at, with biopsies at the surgical site. 54 % of adhesion formation was observed, and the median score of adhesions was 6 (minimum of 3 and maximum of 10), all of them found in the bladder and the anterior abdominal wall. The method used presents a high frequency of intra-abdominal adhesion formation.


The spatial ecology of free-ranging domestic pigs (Sus scrofa) in western Kenya.
In many parts of the developing world, pigs are kept under low-input systems where they roam freely to scavenge food. These systems allow poor farmers the opportunity to enter into livestock keeping without large capital investments. This, combined with a growing demand for pork, especially in urban areas, has led to an increase in the number of small-holder farmers keeping free range pigs as a commercial enterprise. Despite the benefits which pig production can bring to a household, keeping pigs under a free range system increases the risk of the pig acquiring diseases, either production-limiting or zoonotic in nature. This study used Global Positioning System (GPS) technology to track free range domestic pigs in rural western Kenya, in order to understand their movement patterns and interactions with elements of the peri-domestic environment. We found that these pigs travel an average of 4,340 m in a 12 hr period and had a mean home range of 10,343 m(2) (range 2,937-32,759 m(2)) within which the core utilisation distribution was found to be 964 m(2) (range 246-3,289 m(2)) with pigs spending on average 47% of their time outside their homestead of origin. These are the first data available on the home range of domestic pigs kept under a free range system: the data show that pigs in these systems spend much of their time scavenging outside their homesteads, suggesting that these pigs may be exposed to infectious agents over a wide area. Control policies for diseases such as Taenia solium, Trypanosomiasis, Trichinellosis, Toxoplasmosis or African Swine Fever therefore require a community-wide focus and pig farmers require education on the inherent risks of keeping pigs under a free range system. The work presented here will enable future research to incorporate movement data into studies of disease transmission, for example for the understanding of transmission of African Swine Fever between individuals, or in relation to the life-cycle of parasites including Taenia solium.


Nephrolithiasis: recent advances in therapy.
The stone-forming process includes crystal formation, crystal aggregation, and retention time to allow growth. The crystal-forming process, in turn, is influenced by the pH of the urine, the solute load, and inhibitors of crystallization. Idiopathic stone disease is characterized by recurrent formation of calcium oxalate, calcium phosphate, and hydroxyapatite stones without an apparent underlying cause. Treatment of idiopathic stone disease has been aimed at decreasing the solute concentration, increasing the solubility of calcium phosphate, or interfering with extension of the crystal lattice.


Analysis of children with peripheral lymphadenopathy.
In this study, the clinical and laboratory features of children with lymphadenopathy were evaluated. Over a 3-year period, 126 patients were referred to the clinic for lymphadenopathy. Twenty-eight of cases have diseases mimicking lymphadenopathy; 98 (mean age: 86+/-55 months) have lymphadenopathy. Localized, limited, and generalized involvement was found in 52%, 30%, and 18% of patients. The most common localization was the head and neck region. The causes of lymphadenopathy were benign diseases in 75 patients. Sixty percent were reactive lymphadenopathy, 39% were lymphadenitis. Lymphadenitis was more frequently localized and bigger than 3 cm compared with reactive adenopathy (p=.02, p=.004). Twenty-three patients have malignant diseases whose mean age was higher than others (p=.002). The enlargement of supraclavicular nodes was more likely due to malignant disease (p=.001). The risk of malignant disease was higher in patients who had generalized lymphadenopathy, lymph nodes bigger than 3 cm, hepatosplenomegaly, and high lactate dehydrogenase levels. In conclusion, this study pointed out the important clues for the differential diagnosis, which were present in the history, physical, and laboratory findings.


Synthesis and application of molecularly imprinted polymer on selective solid-phase extraction for the determination of monosulfuron residue in soil.
A novel sample clean-up procedure using molecularly imprinted polymer as the solid-phase extraction material for the determination of monosulfuron residue in soil samples has been developed. The molecularly imprinted polymer (MIP) was synthesized by non-covalent method with monosulfuron as the template. The selectivity and affinity of the MIP was evaluated by equilibrium adsorption and HPLC experiments, which demonstrated that the MIP has specific affinity for the template. The template-MIP interaction was studied by investigating the influence of different mobile phases on the retention of the template, which provided basic knowledge for the selection of the washing and elution solutions in the molecularly imprinted solid-phase extraction (MISPE) process. The study indicated that polar organic solvents with hydrogen bonding abilities have stronger eluting strength for the monosulfuron. After the MISPE procedure, a clean baseline was obtained in the HPLC quantification analysis. The recoveries of the method using the combination of MISPE and HPLC were above 93% and the R.S.D. was less than 3.2% in the soil sample determinations. Low detection limit (0.08 microg g(-1), when defined as 3 times of the noise) was also obtained in the method evaluation study.


Storage of aerobic granular sludge embedded in agar and its reactivation by real wastewater.
Aerobic granular sludge (AGS) was preserved using an agar embedding method to maintain its stability. No obvious damage was imposed on the granular appearance during 30 days of cold and dry storage, but the granular microstructure had an uneven surface with a large number of holes. The results were consistent with the extinction of microbial communities and the monitored consumption of extracellular polymeric substances, in which granular specific oxygen utilization rate and mixed liquor volatile suspended solids/mixed liquor suspended solids ratio, respectively, decreased by 72.4% and 62.5% during storage. A mass conversation calculation indicated that the loss of granular mass was 1.6393 g. An offensive odour was smelled during storage, and the results indicated that a material transformation and mitigation were involved between AGS and the gas phase. Although the granular structure was destroyed to a certain extent, no obvious damage was imposed on the granular skeleton during storage. After it was aerated again after a feeding with real wastewater, the residual skeleton served as a carrier for the rapid proliferation of microorganisms, and good granular properties were obtained after 11 days of reactivation.


Persistent erythema multiforme associated with Epstein-Barr virus infection.
Erythema multiforme (EM) is a common, self-limiting condition. Recurrent EM is a well-recognised variant, often associated with herpes simplex virus infection. It is frequently managed with prophylactic aciclovir. Anecdotal reports suggest that recurrent EM may be associated with the use of corticosteroids. Persistent EM, however, is a rare variant, with few cases reported in the literature. It has a protracted course often with atypical and inflammatory lesions. It has been associated with occult viral infections, particularly Epstein-Barr Virus (EBV), as well as inflammatory bowel disease and malignancy. We report a case of EM associated with EBV infection.


What Is Appropriate Upper Endoscopic Interval Among Dyspeptic Patients With Previously Normal Endoscopy? A Multicenter Study With Bayesian Change Point Analysis.
Appropriate interval for performing follow-up endoscopy among dyspeptic patients without abnormal findings on previous endoscopy is unclear. We analyzed the multicenter-collected data from the Korean Society of Neurogastroenterology and Motility. We collected clinical data of the patients who visited the gastroenterology department and underwent 2 or more sessions of upper endoscopy during 2012-2017 at 6 university hospitals in Korea. Patients with endoscopic interval between 90 days and 760 days were included. For those with multiple endoscopic sessions, only the first 2 were analyzed. Positive outcome was defined as adenoma or cancer in the upper gastrointestinal tract. To identify the point of change and estimate the properties of the stochastic process before and after the change, we used Bayesian regression with Metropolis-Hastings algorithm. There were 1595 patients. Mean age was 58.8 years (standard deviation, 12.8). Median interval of endoscopy was 437 days (standard deviation, 153). On follow-up endoscopy, there were 12 patients (0.75%) who had neoplasia (4 with gastric cancer and 8 with gastric adnoma). As with the prior hypothesis, we presumed the change point (CP) of increase in frequency of organic lesion as 360 days. After random-walk Metropolis-Hastings sampling with Markov-Chain Monte Carlo iterations of 5000, the CP was 560 days (95% credible interval, 139-724). Estimated average of frequency of dysplastic lesions increased by a factor of 4.4 after the estimated CP. To rule out dysplastic lesions among dyspeptic patients who had previously normal endoscopy, a 2-year interval could be offered as follow-up interval for repeat upper endoscopy.


Crisis of Antimicrobial Resistance in China: Now and the Future.
The crisis of antimicrobial resistance is worsening and has become a major public safety problem in China, seriously endangering human and animal health and ecological environment. Gram-negative bacterial resistance in China is severe: the related pathogens mainly include carbapenem-resistant Acinetobacter, Pseudomonas aeruginosa and Klebsiella pneumoniae. Surging antimicrobial consumption and irrational use of antimicrobials are the main causes of resistance. In China, a variety of strategies are implemented to control the antimicrobial resistance in hospitals, agriculture and environment. However, there is still a long way to go to strengthen the drug resistance surveillance, to reduce the emergence of drug-resistant bacteria, and to find new antimicrobials and therapies for drug-resistant bacteria. Controlling the antimicrobial resistance crisis takes great efforts from the whole society.


Aging prisoners' treatment selection: does prospect theory enhance understanding of end-of-life medical decisions?
With the rapid growth in the older inmate population and the economic impact of end-of-life treatments within the cash-strapped prison system, consideration should be given to inmate treatment preferences. We examined end-of-life treatment preferences and days of desired life for several health scenarios among male inmates incarcerated primarily for murder. Inmates over the age of 45 who passed a cognitive screening completed face-to-face interviews (N = 94; mean age = 57.7; SD = 10.68). We found a 3-way interaction indicating that the effect of parole expectation on desire for life-sustaining treatment varied by race/ethnicity and treatment. Minority inmates desired cardiopulmonary resuscitation or feeding tubes only if they believed that they would be paroled. The model predicting desire for palliative care was not significant. Future days of desired life were related to prospective health condition, fear of death, negative affect, and trust in prison health care. Caucasian inmates expressed a desire for more days of life out of prison, whereas minority inmates did not differ in days of desired life either in or out of prison. Minorities wanted more days of life than Caucasians but only if they believed that they would be paroled. End-of-life care for the burgeoning inmate population is costly, and active life-sustaining treatments may not be desired under certain conditions. Specifically, expectation of parole but not current functional ability interacts with future illness condition in explaining inmates' desire for active treatment or days of desired life in the future.


Lytic gene expression is frequent in HSV-1 latent infection and correlates with the engagement of a cell-intrinsic transcriptional response.
Herpes simplex viruses (HSV) are significant human pathogens that provide one of the best-described examples of viral latency and reactivation. HSV latency occurs in sensory neurons, being characterized by the absence of virus replication and only fragmentary evidence of protein production. In mouse models, HSV latency is especially stable but the detection of some lytic gene transcription and the ongoing presence of activated immune cells in latent ganglia have been used to suggest that this state is not entirely quiescent. Alternatively, these findings can be interpreted as signs of a low, but constant level of abortive reactivation punctuating otherwise silent latency. Using single cell analysis of transcription in mouse dorsal root ganglia, we reveal that HSV-1 latency is highly dynamic in the majority of neurons. Specifically, transcription from areas of the HSV genome associated with at least one viral lytic gene occurs in nearly two thirds of latently-infected neurons and more than half of these have RNA from more than one lytic gene locus. Further, bioinformatics analyses of host transcription showed that progressive appearance of these lytic transcripts correlated with alterations in expression of cellular genes. These data show for the first time that transcription consistent with lytic gene expression is a frequent event, taking place in the majority of HSV latently-infected neurons. Furthermore, this transcription is of biological significance in that it influences host gene expression. We suggest that the maintenance of HSV latency involves an active host response to frequent viral activity.


N-methyl-D-aspartate receptor subtype mediated bidirectional control of p38 mitogen-activated protein kinase.
N-methyl-d-aspartate receptor (NMDAR) stimulation activates many downstream mechanisms involved in both cell survival and cell death. The manner in which the NMDAR regulates one of these pathways, the p38 mitogen-activated protein kinase (p38) pathway, is currently unknown. In the present study, we have defined a developmental-, concentration-, and time-dependent phosphorylation and subsequent dephosphorylation of p38. In cultured hippocampal neurons 7-8 days in vitro (DIV7-8), NMDAR stimulation leads to a concentration-dependent increase in p38 phosphorylation (phospho-p38). However, in more mature neurons (>DIV17) application of NMDA produces concentration-dependent effects, such that low concentrations result in sustained increases in phospho-p38 levels, and high concentrations dephosphorylate p38 within 5 min. Conantokin G, an antagonist of NR1/2A/2B and NR1/2B receptors, inhibits p38 phosphorylation, while NR1/2B-specific antagonists prevent the rapid dephosphorylation of p38 without affecting p38 activation. Furthermore, inhibition of calcineurin prevents the activation of p38, whereas inhibition of phosphoinositide 3-kinase (PI3K) prevents the rapid dephosphorylation of p38. Our results support the presence of subtype-dependent pathways regulating p38 activation and deactivation: one involves NR1/2A/2B receptors activating calcineurin and resulting in p38 phosphorylation, and the other utilizes NR1/2B receptors binding to and activating PI3K and leading to the dephosphorylation of p38 in a manner involving both NR1/2A/2B receptor activation and tyrosine phosphorylation of NR2B. The ability of NMDAR subtype-specific mechanisms to regulate p38 has implications for NMDAR-mediated synaptic plasticity, gene regulation, and excitotoxicity.


Preparation and evaluation of fexofenadine microemulsions for intranasal delivery.
To enhance the solubility and bioavailability of poorly absorbable fexofenadine, microemulsion system composed of oil, surfactant and co-surfactant was developed for intranasal delivery. Phase behavior, particle size, viscosity and solubilization capacity of the microemulsion system were characterized. Histopathology and in vivo nasal absorption of the optimized microemulsion formulations were also investigated in rats. A single isotropic region was found in the pseudo-ternary phase diagrams developed at various ratios with Lauroglycol 90 as oil, Labrasol as surfactant and Plurol Oleique CC49 or its mixture with PEG-400 (1:1) as cosurfactant. An increase in the microemulsion region in pseudo-ternary phase systems was observed with increased surfactant concentration. The optimized microemulsion formulations showed higher solubulization of fexofenadine, i.e., F1 (22.64 mg/mL) and F2 (22.98 mg/mL), compared to its intrinsic water solubility (1.51 mg/mL). Nasal absorption of fexofenadine from these microemulsions was found to be fairly rapid. Tmax was observed within 5 min after intranasal administration at 1.0 mg/kg dose, and the absolute bioavailability (0-4 h) was about 68% compared to the intravenous administration in rats. Our results suggested that these microemulsion formulations could be used as an effective intranasal dosage form for the rapid-onset delivery of fexofenadine


Tadalafil Improves Nocturia and Nocturia-Related Quality of Life in Patients with Benign Prostatic Hyperplasia (KYU-PRO Study).
Tadalafil improves lower urinary tract symptoms (LUTS) including nocturia. However, the effect of tadalafil on the nocturia-related quality of life (QoL) is still unknown. The effects of tadalafil on nocturia and nocturia-related QoL were evaluated prospectively in patients with benign prostatic hyperplasia (BPH) as a multicenter study. Eligible men were ≥40 years with nocturia ≥2 and a prostate volume ≥20 mL. Patients were asked to complete a self-report questionnaire on the International Prostate Symptom Score (IPSS), the Nocturia Quality of Life questionnaire (N-QoL) and the International Index of Erectile Function 5 (IIEF5). Urinary frequency volume charts (FVCs) were also evaluated. These measures were evaluated at baseline, and after 4, 8, and 12 weeks of tadalafil administration (5 mg once daily). Thirty-one patients with a mean age of 74 years, a mean prostate volume of 31 mL, and a mean prostate-specific antigen level of 2.8 ng/mL were included. Treatment with tadalafil significantly improved their nocturia after 4 weeks, and these improvements were maintained for the 12-week treatment period. Total N-QoL score in new patients and several N-QoL items (inadequate sleep at night and overall bother) in all patients improved significantly after tadalafil treatment. FVCs revealed a significant improvement in the number of hours of undisturbed sleep (HUS) after treatment with tadalafil. No serious adverse events were observed. This study indicates that tadalafil 5 mg once daily improves nocturia, nocturia-related QoL, and HUS in BPH patients with nocturia. These results suggest that tadalafil can offer a clinically meaningful treatment option for BPH patients with nocturia.


Cold Plasma Treatment of Sunflower Seeds Modulates Plant-Associated Microbiome and Stimulates Root and Lateral Organ Growth.
Cold atmospheric pressure (CP) plasma irradiation of seeds has been shown to promote plant growth, but the molecular basis of this phenomenon is poorly understood. In our study, optimum irradiation of common sunflower seeds using a dielectric barrier discharge CP device stimulated growth of sunflower lateral organs and roots by 9-14% compared to the control. Metagenomic analysis revealed that the structure of plant-associated bacterial assembly was greatly modified upon CP treatment and could be attributed to the antimicrobial effect of CP-generated reactive species. The treatment resulted in the domination of spore forming Mycobacterium sp. in the above-ground tissues of the seedlings. While the overall bacterial diversity in the roots was barely affected, the CP-induced shift in microbial composition is the likely basis for the observed seedling root growth stimulation and the long-term effect on lateral organ growth and could be mediated by increase in water uptake and/or direct root signaling. Low amplitude protein abundance differences were detected in the roots of the emerging seedlings that are characteristic to low intensity stress stimuli response and could be linked to the changes in plant-associated microbiome upon CP treatment.


Kirschner Wire and Bone Cement is a Viable Alternative to Reconstruction of Large Iliac Bone Defects After Strut Bone Graft Harvesting.
A retrospective study. To assess the safety and efficacy of iliac crest defect reconstruction using Kirschner wire (K-wire)/polymethylmethacrylate (PMMA) versus traditional autologous rib graft reconstruction. The iliac crest has been the preferred donor site for strut bone graft for various spinal fusion surgeries. Seventy-three patients (44 males and 29 females; average age: 57.2 y) were divided into 2 groups: the rib group (35 patients) and the K-wire/PMMA group (38 patients). All operations involved anterior spinal interbody fusion. Patients were followed-up, on average, for 34.2 months using plain radiographs and both pain and cosmesis visual analog scales (VAS) to assess the clinical results after surgery. Almost all patients had pain VAS scores of ≤1 and grade 1 cosmesis VAS scores with no significant difference between the 2 groups in terms of either pain or cosmesis (P=1.00 and 0.505, respectively). In addition, few complications were noted in both groups. Radiographic complications in the rib group and the K-wire group numbered 4 (11%) and 2 (5%), respectively; however, did not significantly differ between the 2 groups (P=0.418). One case required intraoperative revision of the length of the K-wire and 1 case needed reoperation for iliac ring fracture and K-wire migration. An additional case required revision due to a bad fall. K-wire and bone cement reconstruction is an effective and safe alternative method for large iliac bone defect repair when autologous rib graft is not available.


Homozygous and compound heterozygous mutations in the FBN1 gene: unexpected findings in molecular diagnosis of Marfan syndrome.
Marfan syndrome (MFS) is an autosomal-dominant connective tissue disorder usually associated with heterozygous mutations in the gene encoding fibrillin-1 (FBN1). Homozygous and compound heterozygous cases are rare events and have been associated with a clinical severe presentation. Report unexpected findings of homozygosity and compound heterozygosity in the course of molecular diagnosis of heterozygous MFS and compare the findings with published cases. In the context of molecular diagnosis of heterozygous MFS, systematic sequencing of the FBN1 gene was performed in 2500 probands referred nationwide. 1400 probands carried a heterozygous mutation in this gene. Unexpectedly, among them four homozygous cases (0.29%) and five compound heterozygous cases (0.36%) were identified (total: 0.64%). Interestingly, none of these cases carried two premature termination codon mutations in the FBN1 gene. Clinical features for these carriers and their families were gathered and compared. There was a large spectrum of severity of the disease in probands carrying two mutated FBN1 alleles, but none of them presented extremely severe manifestations of MFS in any system compared with carriers of only one mutated FBN1 allele. This observation is not in line with the severe clinical features reported in the literature for four homozygous and three compound heterozygous probands. Homozygotes and compound heterozygotes were unexpectedly identified in the course of molecular diagnosis of MFS. Contrary to previous reports, the presence of two mutated alleles was not associated with severe forms of MFS. Although homozygosity and compound heterozygosity are rarely found in molecular diagnosis, they should not be overlooked, especially among consanguineous families. However, no predictive evaluation of severity should be provided.


Stress and premenstrual symptoms among Korean women studying in the U.S. and South Korea: A longitudinal web-based study.
Premenstrual symptoms have been reported to be highly correlated with levels of perceived stress; however, the magnitude of the relationship remains unclear. The purpose of the study was to identify the relationships among perceived stress, acculturative stress, and premenstrual symptoms. The study used a 10-week longitudinal web-based design. A total of 98 female Korean international students studying in the U.S. and 89 Korean domestic students studying in South Korea were recruited using convenience sampling. Data collection was conducted between November 2014 and February 2015. The participants completed 10 weekly web-based surveys. Data were analyzed through descriptive analyses, linear multivariable mixed model regressions, t-tests, and hierarchical multiple regressions. The levels of both perceived stress and menstrual-related symptoms were higher during the premenstrual phase in Korean international students than in domestic students (p < .001). In Korean international students, perceived stress (β = 0.30; p < .001) and acculturative stress (β = 0.26; p < .01) were the most strongly related factors to the severity of premenstrual symptoms. Although perceived stress was significantly related to the symptoms in Korean domestic students, a history of sexual abuse was the strongest related factor (β = -0.28; p < .001). Because stress is a potentially modifiable factor, understanding its relationship to premenstrual symptoms can contribute to relieving these symptoms.


Release from native root herbivores and biotic resistance by soil pathogens in a new habitat both affect the alien Ammophila arenaria in South Africa.
Many native communities contain exotic plants that pose a major threat to indigenous vegetation and ecosystem functioning. Therefore the enemy release hypothesis (ERH) and biotic resistance hypothesis (BRH) were examined in relation to the invasiveness of the introduced dune grass Ammophila arenaria in South Africa. To compare plant-soil feedback from the native habitat in Europe and the new habitat in South Africa, plants were grown in their own soil from both Europe and South Africa, as well as in sterilised and non-sterilised soils from a number of indigenous South African foredune plant species. While the soil feedback of most plant species supports the ERH, the feedback from Sporobolus virginicus soil demonstrates that this plant species may contribute to biotic resistance against the introduced A. arenaria, through negative feedback from the soil community. Not only the local plant species diversity, but also the type of plant species present seemed to be important in determining the potential for biotic resistance. As a result, biotic resistance against invasive plant species may depend not only on plant competition, but also on the presence of plant species that are hosts of potential soil pathogens that may negatively affect the invaders. In conclusion, exotic plant species such as A. arenaria in South Africa that do not become highly invasive, may experience the ERH and BRH simultaneously, with the balance between enemy escape versus biotic resistance determining the invasiveness of a species in a new habitat.


Comparison of in vitro tensile bond strengths of luting cements to metallic and tooth-colored posts.
The aim of this study was to compare the tensile bond strength of tooth-colored ceramic and carbon-fiber post materials as well as titanium and stainless steel post materials luted with three different kinds of luting cements. Disks of alloy post materials were polished with 600-grit SiC paper, air abraded, and ultrasonically cleaned. Ceramic surfaces were pretreated with hydrofluoric acid and silanized. Panavia F, Vitremer, and ProTec Cem cements were bonded to the post specimens and placed in a humidor for 24 hours. Specimens were placed in a jig, and the debonding values were obtained using a universal testing machine. Means and standard deviations were analyzed by two-way ANOVA. Panavia F provided the highest bond strengths for all types of post materials. ProTec Cem bonded more strongly to stainless steel and titanium than to zirconium oxide. Vitremer results were the lowest. Bonds to carbon-fiber post materials were weaker than to metallic post materials, but stronger than to zirconium oxide. In general, higher bond strengths resulted in a higher percentage of cohesive failures.


[Community knowledge about stroke. A survey in the District of Wesel, Germany (2002)].
Community knowledge of stroke signs and risk factors in Germany is poor, while lacking knowledge is an important cause for delays in hospital admission. In the Wesel district (North Rhine-Westphalia) the local health conference put this issue on its agenda and initiated a phone survey. The aim was to assess community knowledge of stroke symptoms and risk factors as well as self-reported prevalence of established risk factors; in addition, the role of information on stroke risk provided to patients by the general practitioner (GP) was to be estimated. The study population was defined as comprising all residents in the district of Wesel between 18 and 87 years of age (approx. 385,000 people). The sample of 1,089 persons was drawn randomly and the telephone survey was carried out by the CATI-Laboratory (Computer Assisted Telephone Interviews) at the Institute of Public Health (lögd, Bielefeld) between 18 February and 28 March 2002. A total of 1,089 people were interviewed, of whom 31.9% knew no symptom, 25.7% could name one symptom, 23.8% two symptoms and 18.6% knew three or more correct signs. Weakness/paralysis was named most frequently by 43.6% of the respondents. The majority of respondents named smoking as a risk factor (59.6%), while hypertension was mentioned by 39.4% of the participants. Among 555 respondents aged 45 years and older, 75.1% said they had never received a GP's advice on stroke risk, while 75.3% among these persons reported to have at least one risk factor. The present study shows a persistent lack of community knowledge about stroke. It is recommended that knowledge be improved especially with regard to (a) proper action: "stroke is a medical emergency-call the emergency telephone code 112", (b) symptoms and warning signs and (c) major stroke risk factors, especially high blood pressure. Moreover, information and advice on stroke should play a bigger part in the doctor's daily practice; patients should be made aware of their stroke risks and ways of prevention.


Personal exposure to mixtures of volatile organic compounds: modeling and further analysis of the RIOPA data.
Emission sources of volatile organic compounds (VOCs*) are numerous and widespread in both indoor and outdoor environments. Concentrations of VOCs indoors typically exceed outdoor levels, and most people spend nearly 90% of their time indoors. Thus, indoor sources generally contribute the majority of VOC exposures for most people. VOC exposure has been associated with a wide range of acute and chronic health effects; for example, asthma, respiratory diseases, liver and kidney dysfunction, neurologic impairment, and cancer. Although exposures to most VOCs for most persons fall below health-based guidelines, and long-term trends show decreases in ambient emissions and concentrations, a subset of individuals experience much higher exposures that exceed guidelines. Thus, exposure to VOCs remains an important environmental health concern. The present understanding of VOC exposures is incomplete. With the exception of a few compounds, concentration and especially exposure data are limited; and like other environmental data, VOC exposure data can show multiple modes, low and high extreme values, and sometimes a large portion of data below method detection limits (MDLs). Field data also show considerable spatial or interpersonal variability, and although evidence is limited, temporal variability seems high. These characteristics can complicate modeling and other analyses aimed at risk assessment, policy actions, and exposure management. In addition to these analytic and statistical issues, exposure typically occurs as a mixture, and mixture components may interact or jointly contribute to adverse effects. However most pollutant regulations, guidelines, and studies remain focused on single compounds, and thus may underestimate cumulative exposures and risks arising from coexposures. In addition, the composition of VOC mixtures has not been thoroughly investigated, and mixture components show varying and complex dependencies. Finally, although many factors are known to affect VOC exposures, many personal, environmental, and socioeconomic determinants remain to be identified, and the significance and applicability of the determinants reported in the literature are uncertain. To help answer these unresolved questions and overcome limitations of previous analyses, this project used several novel and powerful statistical modeling and analysis techniques and two large data sets. The overall objectives of this project were (1) to identify and characterize exposure distributions (including extreme values), (2) evaluate mixtures (including dependencies), and (3) identify determinants of VOC exposure. METHODS VOC data were drawn from two large data sets: the Relationships of Indoor, Outdoor, and Personal Air (RIOPA) study (1999-2001) and the National Health and Nutrition Examination Survey (NHANES; 1999-2000). The RIOPA study used a convenience sample to collect outdoor, indoor, and personal exposure measurements in three cities (Elizabeth, NJ; Houston, TX; Los Angeles, CA). In each city, approximately 100 households with adults and children who did not smoke were sampled twice for 18 VOCs. In addition, information about 500 variables associated with exposure was collected. The NHANES used a nationally representative sample and included personal VOC measurements for 851 participants. NHANES sampled 10 VOCs in common with RIOPA. Both studies used similar sampling methods and study periods. Specific Aim 1. To estimate and model extreme value exposures, extreme value distribution models were fitted to the top 10% and 5% of VOC exposures. Health risks were estimated for individual VOCs and for three VOC mixtures. Simulated extreme value data sets, generated for each VOC and for fitted extreme value and lognormal distributions, were compared with measured concentrations (RIOPA observations) to evaluate each model's goodness of fit. Mixture distributions were fitted with the conventional finite mixture of normal distributions and the semi-parametric Dirichlet process mixture (DPM) of normal distributions for three individual VOCs (chloroform, 1,4-DCB, and styrene). Goodness of fit for these full distribution models was also evaluated using simulated data. Specific Aim 2. Mixtures in the RIOPA VOC data set were identified using positive matrix factorization (PMF) and by toxicologic mode of action. Dependency structures of a mixture's components were examined using mixture fractions and were modeled using copulas, which address correlations of multiple components across their entire distributions. Five candidate copulas (Gaussian, t, Gumbel, Clayton, and Frank) were evaluated, and the performance of fitted models was evaluated using simulation and mixture fractions. Cumulative cancer risks were calculated for mixtures, and results from copulas and multivariate lognormal models were compared with risks based on RIOPA observations. Specific Aim 3. Exposure determinants were identified using stepwise regressions and linear mixed-effects models (LMMs). Specific Aim 1. Extreme value exposures in RIOPA typically were best fitted by three-parameter generalized extreme value (GEV) distributions, and sometimes by the two-parameter Gumbel distribution. In contrast, lognormal distributions significantly underestimated both the level and likelihood of extreme values. Among the VOCs measured in RIOPA, 1,4-dichlorobenzene (1,4-DCB) was associated with the greatest cancer risks; for example, for the highest 10% of measurements of 1,4-DCB, all individuals had risk levels above 10(-4), and 13% of all participants had risk levels above 10(-2). Of the full-distribution models, the finite mixture of normal distributions with two to four clusters and the DPM of normal distributions had superior performance in comparison with the lognormal models. DPM distributions provided slightly better fit than the finite mixture distributions; the advantages of the DPM model were avoiding certain convergence issues associated with the finite mixture distributions, adaptively selecting the number of needed clusters, and providing uncertainty estimates. Although the results apply to the RIOPA data set, GEV distributions and mixture models appear more broadly applicable. These models can be used to simulate VOC distributions, which are neither normally nor lognormally distributed, and they accurately represent the highest exposures, which may have the greatest health significance. Specific Aim 2. Four VOC mixtures were identified and apportioned by PMF; they represented gasoline vapor, vehicle exhaust, chlorinated solvents and disinfection byproducts, and cleaning products and odorants. The last mixture (cleaning products and odorants) accounted for the largest fraction of an individual's total exposure (average of 42% across RIOPA participants). Often, a single compound dominated a mixture but the mixture fractions were heterogeneous; that is, the fractions of the compounds changed with the concentration of the mixture. Three VOC mixtures were identified by toxicologic mode of action and represented VOCs associated with hematopoietic, liver, and renal tumors. Estimated lifetime cumulative cancer risks exceeded 10(-3) for about 10% of RIOPA participants. The dependency structures of the VOC mixtures in the RIOPA data set fitted Gumbel (two mixtures) and t copulas (four mixtures). These copula types emphasize dependencies found in the upper and lower tails of a distribution. The copulas reproduced both risk predictions and exposure fractions with a high degree of accuracy and performed better than multivariate lognormal distributions. Specific Aim 3. In an analysis focused on the home environment and the outdoor (close to home) environment, home VOC concentrations dominated personal exposures (66% to 78% of the total exposure, depending on VOC); this was largely the result of the amount of time participants spent at home and the fact that indoor concentrations were much higher than outdoor concentrations for most VOCs. In a different analysis focused on the sources inside the home and outside (but close to the home), it was assumed that 100% of VOCs from outside sources would penetrate the home. Outdoor VOC sources accounted for 5% (d-limonene) to 81% (carbon tetrachloride [CTC]) of the total exposure. Personal exposure and indoor measurements had similar determinants depending on the VOC. Gasoline-related VOCs (e.g., benzene and methyl tert-butyl ether [MTBE]) were associated with city, residences with attached garages, pumping gas, wind speed, and home air exchange rate (AER). Odorant and cleaning-related VOCs (e.g., 1,4-DCB and chloroform) also were associated with city, and a residence's AER, size, and family members showering. Dry-cleaning and industry-related VOCs (e.g., tetrachloroethylene [or perchloroethylene, PERC] and trichloroethylene [TCE]) were associated with city, type of water supply to the home, and visits to the dry cleaner. These and other relationships were significant, they explained from 10% to 40% of the variance in the measurements, and are consistent with known emission sources and those reported in the literature. Outdoor concentrations of VOCs had only two determinants in common: city and wind speed. Overall, personal exposure was dominated by the home setting, although a large fraction of indoor VOC concentrations were due to outdoor sources. City of residence, personal activities, household characteristics, and meteorology were significant determinants. Concentrations in RIOPA were considerably lower than levels in the nationally representative NHANES for all VOCs except MTBE and 1,4-DCB. Differences between RIOPA and NHANES results can be explained by contrasts between the sampling designs and staging in the two studies, and by differences in the demographics, smoking, employment, occupations, and home locations. (ABSTRACT TRUNCATED)


Escalation of extracorporeal life support as a bridge to lung transplantation in end-stage lung disease.
Extracorporeal membrane oxygenation (ECMO) as a bridge to lung transplant (LTx) is not uncommon, but it is not commonplace yet. We present a case of a 45-year-old man with cystic fibrosis with recent deterioration in lung function who was initially supported with veno-venous (VV) ECMO. However, he subsequently required conversion to veno-veno-arterial (VVA) ECMO. After 21 days of support, he underwent double lung transplantation, with an uneventful postoperative course. This case shows that, in patients with end-stage respiratory failure awaiting lung transplantation, extracorporeal life support may require escalation to improve gas exchange and address circulatory requirements.


Inhibition of pseudomonas strains in two soft contact lens soaking solutions.
Ten Pseudomonas aeruginosa and six Pseudomonas cepacia strains recently isolated from infected patients were tested for susceptibility to the antimicrobial activity of two commercially-available soft contact lens soaking solutions. No strain showed evidence of viability after two hours but survivors were found in both solutions after one-half hour and in one solution after one hour. The solution most effective in inhibiting the Pseudomonas strains contained chlorhexidine and disodium edetate but each solution was effective in reducing heavy inocula of both species within the times recommended by the manufacturers.


Privileged hydration sites in aromatic side chains: effect on conformational equilibrium.
Water interaction with peptide chains is one of the key structure stabilizing factors in an aqueous environment. Because of its strong polar character, water can bind to both anionic and cationic sites via electrostatic interactions. It can also act as a hydrogen-bond donor or acceptor according to its interactions with different polar groups in the backbone and side chains of peptides and proteins. Based on density functional theory calculations, the present report aims at illustrating the most energetically favorable interaction sites of aromatic side chains of phenylalanine, tyrosine, tryptophan, and histidine (neutral and protonated species) with surrounding water molecules. It was shown that beyond the strong interactions occurring between water and the aromatic ring acceptor/donor sites, such as O-H, N-H and -N[double bond, length as m-dash] groups, weaker interactions with π-electron clouds should also be considered. The latter type of binding, hereafter referred to as Hwπ interaction, involves one of the water hydrogen atoms (Hw) pointing toward the aromatic ring. Upon comparison between the theoretical data obtained from a purely implicit hydration model, i.e. a polarized solvent continuum, and those collected from a mixture of implicit and explicit hydration models, it has been shown that the explicit water molecule binding to aromatic rings affects the relative energies of the rotamers generated by the two side chain torsion angles (χ1 and χ2).


Competitive adsorption on gold nanoparticles for human papillomavirus 16 L1 protein detection by LDI-MS.
The detection of the HPV L1 protein provides information about the infection status of the virus, reflects the replication status of the HPV virus in cervical cells, and helps understand the regression and progress of cervical lesions. Herein, we report a novel laser desorption ionization mass spectrometry (LDI MS) method for the sensitive detection of the HPV 16 L1 protein, based on non-covalent competitive adsorption between the HPV 16 L1 aptamer and melamine on gold nanoparticles (AuNPs). The intensity of the MS signal corresponding to the mass tag shows a linear relationship with the HPV 16 L1 concentration in the range 2-80 ng mL-1, with a limit of detection (LOD) of 58.8 pg mL-1. Using this method, the HPV 16 L1 protein is quantitatively analyzed in both clinical and vaccine samples. The described method is simple and has high sensitivity and good reliability.


The variational gaussian approximation revisited.
The variational approximation of posterior distributions by multivariate gaussians has been much less popular in the machine learning community compared to the corresponding approximation by factorizing distributions. This is for a good reason: the gaussian approximation is in general plagued by an Omicron(N)(2) number of variational parameters to be optimized, N being the number of random variables. In this letter, we discuss the relationship between the Laplace and the variational approximation, and we show that for models with gaussian priors and factorizing likelihoods, the number of variational parameters is actually Omicron(N). The approach is applied to gaussian process regression with nongaussian likelihoods.


Proteinuria can predict short-term prognosis in critically ill cirrhotic patients.
Increasing evidence supports that proteinuria is a useful tool in several clinical situations. Cirrhotic patients with proteinuria admitted to intensive care units (ICUs) have high mortality rates. This study analyzed the outcomes of critically ill cirrhotic patients and determined the prognostic value of proteinuria. A total of 230 cirrhotic patients were admitted to the ICU of a hospital in Taiwan between March 2008 and February 2011. We prospectively collected data, including demographic parameters and clinical characteristics, of patients on day 1 of admission to the ICU and analyzed these variables as predictors of mortality. The overall ICU, hospital, and 90-day mortality rates were 54%, 60%, and 63%, respectively. The patients with proteinuria had higher rates of acute kidney injury (84% vs. 53%, P<0.001), ICU death (60% vs. 25%, P<0.001), and 90-day mortality (79% vs. 40%, P<0.001). Patients with proteinuria had a hazard ratio for 90-day mortality of 2.800 (P<0.001; 95% CI, 1.927-4.069). Multivariate analysis showed that proteinuria and the Sequential Organ Failure Assessment score were predictors of short-term prognosis. Proteinuria in critically ill cirrhotic patients is associated with increased complications of liver cirrhosis, ICU mortality, and poor short-term prognosis.


Physical activity after inpatient occupational rehabilitation: Secondary outcomes of two randomized controlled trials.
To assess whether inpatient multicomponent occupational rehabilitation, including physical activity (PA), increases the PA level of participants more than an outpatient program without PA, and whether changes in PA are associated with future work outcomes. A total of 265 participants were included in one of two randomized clinical trials. Participants had been sick listed 2-12 months with a musculo-skeletal, psychological, or general/unspecified diagnosis. We measured PA by questionnaires at the start of the programs and at 3, 6, and 12 months of follow-up. Between-group differences in PA were assessed using linear mixed models. Associations between change in PA and future work outcomes were assessed by logistic and linear regression. There was no difference in change in PA between the inpatient and outpatient programs during 12 months of follow-up. We did not find any associations between the amount of PA and future work outcomes. However, intensity of PA was positively associated with return to work (RTW); participants reporting increased vigorous PA had an odds ratio (OR) for RTW of 4.1 (95% confidence interval [CI] 1.1-15.7) whereas participants reporting consistently high intensity of PA had an OR of 3.1 (95% CI 1.0-9.7), compared to participants reporting low-intensity PA. Inpatient occupational rehabilitation, including PA, did not increase PA-level in the follow-up period more than a less comprehensive program without PA. The amount of PA was not associated with future work outcomes. However, vigorous PA showed a positive association with RTW.


Potential cost-effectiveness of a new infant tuberculosis vaccine in South Africa--implications for clinical trials: a decision analysis.
Novel tuberculosis vaccines are in varying stages of pre-clinical and clinical development. This study seeks to estimate the potential cost-effectiveness of a BCG booster vaccine, while accounting for costs of large-scale clinical trials, using the MVA85A vaccine as a case study for estimating potential costs. We conducted a decision analysis from the societal perspective, using a 10-year time frame and a 3% discount rate. We predicted active tuberculosis cases and tuberculosis-related costs for a hypothetical cohort of 960,763 South African newborns (total born in 2009). We compared neonatal vaccination with bacille Calmette-Guérin alone to vaccination with bacille Calmette-Guérin plus a booster vaccine at 4 months. We considered booster efficacy estimates ranging from 40% to 70%, relative to bacille Calmette-Guérin alone. We accounted for the costs of Phase III clinical trials. The booster vaccine was assumed to prevent progression to active tuberculosis after childhood infection, with protection decreasing linearly over 10 years. Trial costs were prorated to South Africa's global share of bacille Calmette-Guérin vaccination. Vaccination with bacille Calmette-Guérin alone resulted in estimated tuberculosis-related costs of $89.91 million 2012 USD, and 13,610 tuberculosis cases in the birth cohort, over the 10 years. Addition of the booster resulted in estimated cost savings of $7.69-$16.68 million USD, and 2,800-4,160 cases averted, for assumed efficacy values ranging from 40%-70%. A booster tuberculosis vaccine in infancy may result in net societal cost savings as well as fewer active tuberculosis cases, even if efficacy is relatively modest and large scale Phase III studies are required.


Bullous pemphigoid autoantibodies are markers of corneal epithelial hemidesmosomes.
Sera from patients with bullous pemphigoid (BP) contain autoantibodies that bind to the BP antigen, which is a component of the epithelial-stromal junction of the cornea. Previous studies, employing direct immunoelectron microscopy (IEM) on perilesional skin of patients have localized the BP antigen to the lamina lucida. On this basis, studies of corneal epithelial-stromal adhesion and wound healing have employed BP antigen as a marker of the lamina lucida of the corneal basement membrane zone (BMZ). The authors used indirect IEM with BP autoantibodies on frozen sections of cornea and found that the majority of the BP antigen is intracellular and is closely associated with the corneal epithelial hemidesmosome. Only a small amount of BP antigen appears to be extracellular, limited to the portion of the lamina lucida directly beneath individual hemidesmosomes. When rabbit corneal epithelium is extracted and analyzed by Western immunoblotting, BP autoantibodies recognize two polypeptides of molecular weights of 240 and 180 kilodaltons, which comigrate with BP antigens extracted from epidermis. BP autoantibodies are a specific marker of corneal epithelial hemidesmosomes and can be used as a probe to identify and study the role of hemidesmosomes in epithelial-stromal adhesion.


Storage and retrieval of THz-bandwidth single photons using a room-temperature diamond quantum memory.
We report the storage and retrieval of single photons, via a quantum memory, in the optical phonons of a room-temperature bulk diamond. The THz-bandwidth heralded photons are generated by spontaneous parametric down-conversion and mapped to phonons via a Raman transition, stored for a variable delay, and released on demand. The second-order correlation of the memory output is g((2))(0)=0.65±0.07, demonstrating a preservation of nonclassical photon statistics throughout storage and retrieval. The memory is low noise, high speed and broadly tunable; it therefore promises to be a versatile light-matter interface for local quantum processing applications.


Hugo Münsterberg's attack on the application of scientific psychology.
No individual in the early history of American psychology is more identified with the promotion of applied psychology than Hugo Münsterberg, whose books and articles on applied topics such as industrial psychology, forensic psychology, psychotherapy, and educational psychology made him one of the most visible psychologists of his day. But there is an earlier chapter to Münsterberg's life that tells a very different story of a Münsterberg opposed to application. The story begins in 1898 when he wrote an article for an American magazine in which he told teachers that the findings of experimental psychology had no relevance for education, setting off a firestorm of controversy among his colleagues in psychology and education. This article describes Münsterberg's early denigration of applied psychology and his subsequent transformation as applied psychologist. Reasons for that transformation are discussed as well as issues involving the stigma associated with applied psychology and the popularization of psychology.


A clinical overview of pheochromocytomas/paragangliomas and carcinoid tumors.
Pheochromocytomas/paragangliomas are rare tumors; most are sporadic. Biochemical proof of disease is better with measurement of plasma metanephrines and less cumbersome than determinations in urine; its implementation is expanding. Anatomical imaging with computed tomography or magnetic resonance imaging should be followed by functional (nuclear medicine) imaging: chromaffin tumor-specific methods are preferred. Treatment is surgical; for nonoperable disease other options are available. Overall 5-year survival is 50%. Carcinoid tumors derive from serotonin-producing enterochromaffin cells in the fore-, mid- or hindgut. Biochemical screening (and follow-up) is done with measurements of 5-hydroxyindoloacetic acid in urine. For most carcinoids, functional imaging is better than other modalities in localizing primary tumors. Surgery is the treatment of choice; nonresectable tumors are treated with somatostatin analogs or chemotherapy. Overall 5-year survival for patients with carcinoids is 67%.


Patient-reported outcomes with nivolumab in advanced solid cancers.
Patients with recurrent or metastatic cancer commonly suffer from debilitating toxicity associated with conventional treatment modalities, as well as disease-related symptoms, often with a concomitant negative impact on health-related quality of life (HRQoL). Patient-reported outcomes (PROs) provide important insights into the patient experience in clinical trials. Nivolumab is a programmed death-1 receptor inhibitor that extends survival in patients with recurrent or metastatic disease in multiple tumor types. In this review, we summarize published PRO analyses from eight phase II-IV clinical trials with nivolumab for the treatment of melanoma, non-small cell lung cancer, renal cell carcinoma (RCC), and squamous cell carcinoma of the head and neck (SCCHN). Symptom burden, physical functioning, and HRQoL were measured using generic, cancer-specific, and tumor type-specific validated PRO instruments. Nivolumab showed sustained stabilization across all tumor types and, in some cases, clinically meaningful improvement in HRQoL, whereas standard of care therapies often led to deteriorations. Exploratory analyses found a positive correlation between baseline HRQoL scores and overall survival in RCC, and between baseline HRQoL scores and healthcare resource utilization in SCCHN, suggesting that patient-reported symptoms at treatment initiation may have clinical value. In the era of value-based oncology care, stakeholders are increasingly interested in PRO findings to guide clinical, regulatory, and reimbursement decisions. However, missing data remain a significant challenge in PRO analyses, including in nivolumab trials. Future clinical trials in immuno-oncology should incorporate PRO data collection, including beyond treatment discontinuation or trial completion to assess the long-term effects of treatment on HRQoL.


Clinical validity: Combinatorial pharmacogenomics predicts antidepressant responses and healthcare utilizations better than single gene phenotypes.
In four previous studies, a combinatorial multigene pharmacogenomic test (GeneSight) predicted those patients whose antidepressant treatment for major depressive disorder resulted in poorer efficacy and increased health-care resource utilizations. Here, we extended the analysis of clinical validity to the combined data from these studies. We also compared the outcome predictions of the combinatorial use of allelic variations in genes for four cytochrome P450 (CYP) enzymes (CYP2D6, CYP2C19, CYP2C9 and CYP1A2), the serotonin transporter (SLC6A4) and serotonin 2A receptor (HTR2A) with the outcome predictions for the very same subjects using traditional, single-gene analysis. Depression scores were measured at baseline and 8-10 weeks later for the 119 fully blinded subjects who received treatment as usual (TAU) with antidepressant standard of care, without the benefit of pharmacogenomic medication guidance. For another 96 TAU subjects, health-care utilizations were recorded in a 1-year, retrospective chart review. All subjects were genotyped after the clinical study period, and phenotype subgroups were created among those who had been prescribed a GeneSight panel medication that is a substrate for either CYP enzyme or serotonin effector protein. On the basis of medications prescribed for each subject at baseline, the combinatorial pharmacogenomic (CPGx™) GeneSight method categorized each subject into either a green ('use as directed'), yellow ('use with caution') or red category ('use with increased caution and with more frequent monitoring') phenotype, whereas the single-gene method categorized the same subjects with the traditional phenotype (for example, poor, intermediate, extensive or ultrarapid CYP metabolizer). The GeneSight combinatorial categorization approach discriminated and predicted poorer outcomes for red category patients prescribed medications metabolized by CYP2D6, CYP2C19 and CYP1A2 (P=0.0034, P=0.04 and P=0.03, respectively), whereas the single-gene phenotypes failed to discriminate patient outcomes. The GeneSight CPGx process also discriminated health-care utilization and disability claims for these same three CYP-defined medication subgroups. The CYP2C19 phenotype was the only single-gene approach to predict health-care outcomes. Multigenic combinatorial testing discriminates and predicts the poorer antidepressant outcomes and greater health-care utilizations by depressed subjects better than do phenotypes derived from single genes. This clinical validity is likely to contribute to the clinical utility reported for combinatorial pharmacogenomic decision support.