Bayesian statistical models for community annoyance survey data.
This paper demonstrates the use of two Bayesian statistical models to analyze single-event sonic boom exposure and human annoyance data from community response surveys. Each model is fit to data from a NASA pilot study. Unlike many community noise surveys, this study used a panel sample to collect multiple observations per participant instead of a single observation. Thus, a multilevel (also known as hierarchical or mixed-effects) model is used to account for the within-subject correlation in the panel sample data. This paper describes a multilevel logistic regression model and a multilevel ordinal regression model. The paper also proposes a method for calculating a summary dose-response curve from the multilevel models that represents the population. The two models' summary dose-response curves are visually similar. However, their estimates differ when calculating the noise dose at a fixed percent highly annoyed.


Human Biomonitoring of Lead Exposure.
After a chronic exposure, lead accumulates in the human body, especially in bones and teeth. Critical effects of lead affect the nervous system, reproduction, fertility as well as genotoxicity and carcinogenicity [1]. Analyses of lead concentrations in human biological material are performed using inductively coupled plasma mass spectrometry and atomic absorption spectrometry, but also electrochemical methods and X-ray fluorescence spectroscopy. The predominant sample matrices include blood and bone, as well as urine, hair, nail, and saliva. To characterize first biological effects, diverse parameters are discussed as "biomarkers of effect". These include δ-aminolevulinic acid dehydratase (ALAD) and erythrocyte porphyrins (EPs) in blood as well as δ-aminolevulinic acid (ALA) in urine and plasma and coproporphyrin in urine. However, biomarkers of effect alone are not sufficiently sensitive for an early detection of a health impairment caused by lead. In summary, lead in blood is the most prominent and best validated biomarker for a lead exposure. A recommended diagnostic strategy for revealing lead-induced effects is the determination of lead in whole blood combined with the analysis of different effect parameters like ALA and coproporphyrin in urine and ALAD and zinc protoporphyrin (ZPP) in blood.


Pharmacokinetics and metabolism of 5-125I-iodo-4'-thio-2'-deoxyuridine in rodents.
Pharmacokinetics and metabolite analysis of radioiodinated 5-iodo-4'-thio-2'-deoxyuridine (ITdU), a potential tumor cell proliferation-imaging agent, were investigated in rodents. Blood and urine metabolites of radiolabeled ITdU were analyzed by thin-layer chromatography in rats. Tissue fractionation studies in mice were also performed to investigate the incorporation of (125)I-ITdU into DNA. The blood distribution study suggested the influx of (125)I-ITdU into rat peripheral blood cells. The blood metabolism of (125)I-ITdU in vitro was negligible. Plasma analysis at 60 min after injection showed that 50% of the radioactivity was intact (125)I-ITdU. The plasma clearance of (125)I-ITdU showed a biexponential function with half-lives of 0.2 and 29.5 min, representing 94.2% and 5.8% of plasma (125)I-ITdU concentration, respectively. (125)I-ITdU was excreted in urine 86% intact at 3.5 h after injection. Extraction of the tissues demonstrated that >70% of the activity in the duodenum, spleen, and thymus was incorporated into DNA at 8 h after injection. On the other hand, <8% of the activity in the liver was in the DNA fraction at that time. These data demonstrate that (125)I-ITdU is less susceptible against catabolism and readily incorporated into DNA in proliferating tissues. Therefore, (125)I-ITdU may be useful in measuring DNA synthesis with SPECT.


[Botulinum toxin for the treatment of secretory disorders of the head and neck area].
Botulinum toxin can be used for the temporary blockade of secretory glands in the head and neck area. Botulinum toxin is increasingly the therapy of choice for the treatment of Frey's syndrome and gustatory tearing, and it is gaining attention for hypersalivation therapy. For nasal hypersecretion, this drug has a very specific use. In comparison to the treatment of skeletal muscles, the individual effect and its duration are more difficult to predict. All indications presented here are for off-label use; therefore, careful counseling and informed consent are necessary. With botulinum toxin, for several diseases, as new treatment options are opening up, well-founded knowledge about the indications and treatment course is important for the ENT surgeon.


Dipeptidyl aminopeptidase III of guinea-pig brain: specificity for short oligopeptide sequences.
A dipeptidyl aminopeptidase III-type activity has been purified from the cytoplasm of guinea-pig brain using arginyl-arginyl-7-amido-4 methylcoumarin as substrate. The enzyme was purified 754-fold relative to the crude homogenate and with a 12.7% recovery. The purified enzyme was found to have a relative molecular weight of 85,000 and consists of one polypeptide chain of relative molecular weight 80,000, on the basis of its migration on calibrated sodium dodecyl sulphate-polyacrylamide gel electrophoresis gel. It is highly sensitive to the presence of chelating agents, sulphydryl reactive agents, and the dipeptide Tyr-Tyr. Dithiothreitol (1 mM) reduced activity by 28%, and 36 and 65% inhibition was noted with phenylmethylsulphonyl fluoride and puromycin (both at 1 mM), respectively. Little or no inhibition was observed with bestatin, bacitracin, captopril, amastatin, and arphamenine B. The purified enzyme released dipeptide moieties from a wide range of peptides including enkephalin sequences and also angiotensin sequences up to the octapeptide angiotensin II. These sequences inhibited the hydrolysis of arginyl-arginyl-7-amido-4-methylcoumarin by dipeptidyl aminopeptidase III with Ki values in the micromolar range. No hydrolysis was observed with angiotensin I or with peptide sequences containing more than 10 amino acids. No hydrolysis was observed also with peptide sequences containing a Pro residue on either side of the sissile bond. Peptides containing less than four amino acids were not hydrolysed.


Links Between Education and Age at Marriage among Palestinian Women in Israel: Changes Over Time.
This study focuses on the link between education and marriage timing among Israeli-Palestinian women. Theoretical discussions on marriage timing center on the effect of the time women spend in educational institutions on their age at marriage, and on the change in the desirable traits of women in the marriage market. But most of these arguments overlook situations where significant changes in education take place alongside retention of traditional patriarchal values. Based on data from three population censuses - in 1983, 1995 and 2008-our results suggest that staying longer in schooling delays marriage, so women with less education are more likely to marry earlier than others. While young age is still considered an important characteristic in the Israeli-Palestinian marriage market, and women who delay marriage face a greater risk of remaining single, education becomes more important over the years so that postponing marriage becomes especially problematic for low-educated women. Our findings suggest that traditional norms and structural conditions together shape marriage timing.


[Regulation of the O-antigen polysaccharide chain length by Wzz- a review ].
The O-antigen of Gram-negative bacterium plays an important role in the signal identification, adhesion, immune evasion and other processes. There are three O-antigen polysaccharides biosynthesis mechanisms according to the type of the flippase that is involved. The Wzy-dependent mechanism is more commonly seen. In Wzy-dependent mechanism, the wzz gene is involved in regulating the length of O-antigen polysaccharide chain which can affect antigenicity of the pathogen and immune response of the host. Based on the crystal structure of Wzz (regulator of the O- antigen polysaccharides length) , different length of O-antigen chain can be obtained through molecular modification of the gene wzz. Conjugating O-antigen or its mutants of a pathogen to a carrier protein could help to develop a vaccine that have both a good target specificity and a strong immunogenicity. Therefore, it is important to understand the function, structure and mechanism of Wzz for the development and production of glycoconjugates vaccine.


PET imaging in differentiated thyroid cancer: where does it fit and how do we use it?
Positron emission tomography (PET) is a rapidly evolving imaging modality that has gained widespread acceptance in oncology, with several radionuclides applicable to thyroid cancer. Thyroid cancer patients have been studied most commonly using 18F-Fluorodeoxyglucose (FDG)-PET, with perhaps the greatest utility being the potential localization of tumor in differentiated thyroid cancer (DTC) patients who are radioiodine whole body scan (WBS) negative and thyroglobulin (Tg) positive. Also of value is the identification of patients unlikely to benefit from additional 131I therapy and identification of patients at highest risk of disease-specific mortality, which may prompt more aggressive therapy or enrollment in clinical trials. Emerging data suggest that PET/CT fusion studies provide increased accuracy and modify the treatment plan in a significant number of DTC cases when compared to PET images alone. However, studies documenting improvements in survival and tumor recurrence attributable to FDG-PET imaging in thyroid cancer patients are lacking. Specific case examples of thyroid cancer patients who appear to have benefited from FDG-PET imaging do exist, while less data are available in the setting of anaplastic or medullary thyroid carcinoma. This article reviews the utility and limitations of FDG-PET in DTC management, and offers practical recommendations.


Changes in Protein Expression and Lysine Acetylation Induced by Decreased Glutathione Levels in Astrocytes.
Astrocytes and neurons form a highly specialized functional unit, and the loss or gain of astrocytic functions can influence the initiation and progression of different neurodegenerative diseases. Neurons depend on the antioxidant protection provided by neighboring astrocytes. Glutathione (γ-l-glutamyl-l-cysteinyl-glycine) is a major component of the antioxidant system that defends cells against the toxic effects of reactive oxygen/nitrogen species. A decline in glutathione levels has been observed in aging and neurodegenerative diseases, and it aggravates the pathology in an amyotrophic lateral sclerosis-mouse model. Using a SILAC-based quantitative proteomic approach, we analyzed changes in global protein expression and lysine acetylation in primary astrocyte cultures obtained from wild-type mice or those deficient in the glutamate-cysteine ligase modifier subunit (GCLM). GCLM knockout astrocytes display an ∼80% reduction in total glutathione levels. We identified potential molecular targets and novel sites of acetylation that are affected by the chronic decrease in glutathione levels and observed a response mediated by Nrf2 activation. In addition, sequence analysis of peptides displaying increased acetylation in GCLM knockout astrocytes revealed an enrichment of cysteine residues in the vicinity of the acetylation site, which suggests potential crosstalk between lysine-acetylation and cysteine modification. Regulation of several metabolic and antioxidant pathways was observed at the level of protein expression and lysine acetylation, revealing a coordinated response involving transcriptional and posttranslational regulation.


NMRProcFlow: a graphical and interactive tool dedicated to 1D spectra processing for NMR-based metabolomics.
Concerning NMR-based metabolomics, 1D spectra processing often requires an expert eye for disentangling the intertwined peaks. The objective of NMRProcFlow is to assist the expert in this task in the best way without requirement of programming skills. NMRProcFlow was developed to be a graphical and interactive 1D NMR (1H & 13C) spectra processing tool. NMRProcFlow (http://nmrprocflow.org), dedicated to metabolic fingerprinting and targeted metabolomics, covers all spectra processing steps including baseline correction, chemical shift calibration and alignment. Biologists and NMR spectroscopists can easily interact and develop synergies by visualizing the NMR spectra along with their corresponding experimental-factor levels, thus setting a bridge between experimental design and subsequent statistical analyses.


Protein-protein association in polymer solutions: from dilute to semidilute to concentrated.
In a typical cell, proteins function in the crowded cytoplasmic environment where 30% of the space is occupied by macromolecules of varying size and nature. This environment may be simulated in vitro using synthetic polymers. Here, we followed the association and diffusion rates of TEM1-beta-lactamase (TEM) and the beta-lactamase inhibitor protein (BLIP) in the presence of crowding agents of varying molecular mass, from monomers (ethylene glycol, glycerol, or sucrose) to polymeric agents such as different polyethylene glycols (PEGs, 0.2-8 kDa) and Ficoll. An inverse linear relation was found between translational diffusion of the proteins and viscosity in all solutions tested, in accordance with the Stokes-Einstein (SE) relation. Conversely, no simple relation was found between either rotational diffusion rates or association rates (k(on)) and viscosity. To assess the translational diffusion-independent steps along the association pathway, we introduced a new factor, alpha, which corrects the relative change in k(on) by the relative change in solution viscosity, thus measuring the deviations of the association rates from SE behavior. We found that these deviations were related to the three regimes of polymer solutions: dilute, semidilute, and concentrated. In the dilute regime PEGs interfere with TEM-BLIP association by introducing a repulsive force due to solvophobic preferential hydration, which results in slower association than predicted by the SE relation. Crossing over from the dilute to the semidilute regime results in positive deviations from SE behavior, i.e., relatively faster association rates. These can be attributed to the depletion interaction, which results in an effective attraction between the two proteins, winning over the repulsive force. In the concentrated regime, PEGs again dramatically slow down the association between TEM and BLIP, an effect that does not depend on the physical dimensions of PEGs, but rather on their mass concentration. This is probably a manifestation of the monomer-like repulsive depletion effect known to occur in concentrated polymer solutions. As a transition from moderate to high crowding agent concentration can occur in the cellular milieu, this behavior may modulate protein association in vivo, thereby modulating biological function.


RANK ligand inhibition with denosumab for the management of osteoporosis.
Receptor activator of nuclear factor-kappaB ligand (RANKL) is a cytokine member of the tumour necrosis factor family that is the principal final mediator of osteoclastic bone resorption. It plays a major role in the pathogenesis of postmenopausal osteoporosis, as well bone loss associated with rheumatoid arthritis, metastatic cancer, multiple myeloma, aromatase inhibitor therapy and androgen deprivation therapy. Denosumab (AMG 162) is an investigational fully human monoclonal antibody with a high affinity and specificity for RANKL. By inhibiting the action of RANKL, denosumab reduces the differentiation, activity and survival of osteoclasts, thereby slowing the rate of bone resorption. Denosumab has been shown to increase bone mineral density (BMD) and reduce bone turnover in postmenopausal women with low BMD. Denosumab is a potential treatment for osteoporosis and other skeletal disorders.


Downward and Parallel Perspectives in an Experimental Study of Out-of-Body Experiences.
Out-of-body experiences (OBEs) have been reported in patients with neurological or psychiatric disorders. According to these reports, the patients looked down on their body from overhead. Based on this phenomenon, we adopted a downward perspective in an experimentally induced OBE paradigm and compared responses to an OBE questionnaire (sensations of OBE) with self-location mapping (feelings of body drift). The results revealed a correlation between the sensation of an OBE and self-location under the downward-perspective condition but not under the parallel-perspective condition; however, no significant difference was observed between the two conditions. Thus, the effect of perspective on OBE illusion that has been reported in clinical research of OBE did not affect the results obtained in previous studies inducing OBE.


Effects of Combining Medication and Pivotal Response Treatment on Aberrant Behavior in Children with Autism Spectrum Disorder.
Abstract: The purpose of this study was to investigate the effects of combined risperidone (RIS) and pivotal response treatment (PRT) on children with autism spectrum disorder (ASD). A total of 34 children diagnosed with ASD according to the Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-V) (mean age of 12.36 years) were randomly assigned to either of two groups; the first group (n = 17) received combined PRT-RIS while the second group (n = 17) received RIS only. Behavioral problems were evaluated with the Aberrant Behavior Checklist (ABC), whereas global improvement (GI) was measured with the Clinical Global Impressions (CGI). Assessment of ABC was performed before intervention, after intervention (12 weeks), and following 3 months of the intervention (follow-up). Total ABC scores were seen to decrease in both groups after 3 months, as compared with the scores prior to the interventions. Also, in both groups, mean scores of behavioral problems after the intervention were not significantly different from those prior to the intervention, in all subscales but the inappropriate speech (p < 0.001). However, both groups showed significant differences in mean scores of ABC subscales in both of the post-intervention evaluation stages. It was concluded that the combination of behavioral and drug interventions can further improve behavioral problems, ultimately improving patient's communication and social skills.


Platelet-based Detection of Nitric Oxide in Blood by Measuring VASP Phosphorylation.
Platelets are the blood components responsible for proper blood clotting. Their function is highly regulated by various pathways. One of the most potent vasoactive agents, nitric oxide (NO), can also act as a powerful inhibitor of platelet aggregation. Direct NO detection in blood is very challenging due to its high reactivity with cell-free hemoglobin that limits NO half-life to the millisecond range. Currently, NO changes after interventions are only estimated based on measured changes of nitrite and nitrate (members of the nitrate-nitrite-NO metabolic pathway). However precise, these measurements are rather difficult to interpret vis a vis actual NO changes, due to the naturally high baseline nitrite and nitrate levels that are several orders of magnitude higher than expected changes of NO itself. Therefore, the development of direct and simple methods that would allow one to detect NO directly is long overdue. This protocol addresses a potential use of platelets as a highly sensitive NO sensor in blood. It describes initial platelet rich plasma (PRP) and washed platelet preparations and the use of nitrite and deoxygenated red blood cells as NO generators. Phosphorylation of VASP at serine 239 (P-VASPSer239) is used to detect the presence of NO. The fact that VASP protein is highly expressed in platelets and that it is rapidly phosphorylated when NO is present leads to a unique opportunity to use this pathway to directly detect NO presence in blood.


Construct validity of the adolescent borderline personality disorder: a review.
Although the term borderline personality disorder (BPD) is used to describe adolescents in clinical settings, there is confusion as to what it comprises. To further elucidate that diagnosis, this article reviews its construct validity. Relevant publications appearing in PsychInfo (1872 to present) were reviewed for the purposes of this article. Thirty-six of the approximately sixty-five publications selected for consideration were included in this review. The construct validity of adolescent BPD is supported by internal consistency (comparable to that of adults), group differences (ie this diagnosis segregates BPD from non-BPD adolescents), convergent validity (ie multiple measures of this disorder measure the same pathology) and concurrent validity, whereby these youth manifest functional impairment and distress. By contrast, the adolescent BPD criteria manifest less construct validity than the adult diagnosis in that its criteria did not uniformly predict the overall diagnosis, and showed more criterion overlap with other personality disorders and a broader pattern of axis II comorbidity. Further diminishing its construct validity, factor analysis suggested that adolescent BPD was not a single entity, and its low predictive validity was demonstrated by little diagnostic stability through adolescence into adulthood.


Does evidence exist to include dietary therapy in the treatment of Crohn's disease?
Prescription drugs and surgery are two common medical therapies for Crohn's disease (CD), an inflammatory bowel disease that affects the GI tract. Unfortunately, certain drugs can cause serious side effects, and surgeries must often be repeated. No diet has been established to alleviate the pain and suffering of CD patients. This is curious given the fact that a higher prevalence of food sensitivities exist in this population of patients, and enteral nutrition is not only the first-line of therapy in Japan, but a known research method used to place the majority of CD patients into remission. Although not all patients respond equally to diet, many simply remove symptom-provoking foods, such as dairy, wheat, corn and certain fruits and vegetables. We suggest assisting these patients in their self-assessment of irritating and symptom-provoking foods by educating them in the use of a food-symptom diary followed by a customized elimination diet trialed for 2-4 weeks to determine if there is any benefit to the individual patient.


Road Safety Efficiency on Interurban Roads in Spain.
The slowdown in economic development caused by traffic accidents in Spain, together with the disparity in the risk of death or injury due to traffic accidents in its provinces, makes it necessary to evaluate their road safety performance. Therefore, the objectives of the present research are, on the one hand, to find out the level of road safety efficiency of Spanish provinces in the period 2014-2018. On the other hand, it is also aimed to determine to what extent the annual efficiency change is originated by pure changes in efficiency or by technological changes. To achieve both objectives, the nonparametric technique of Data Envelopment Analysis and the Malmquist Index have been used based on the consideration of the Safety Performance Indicators (SPI) as the inputs of the process. The research findings show changes in the level of road safety efficiency in each of the years of the study period. Thus, it is possible to identify a geographical delimitation of the causes that generate changes in efficiency in recent years. A contraction in efficiency and technological progress is identified in part of the Spanish provinces in the north, northeast, and south of Spain.


Volume-time curve of cardiac magnetic resonance assessed left ventricular dysfunction in coronary artery disease patients with type 2 diabetes mellitus.
Type 2 diabetes mellitus (DM2) may induce epicardial coronary artery diseases and left ventricular myocardial damaging as well. Left ventricular dysfunction was found in DM2. In this research, we compared the left ventricular dysfunction of coronary artery disease (CAD) patients with and without type 2 diabetes mellitus as well as normal controls using the volume-time curve of cardiac magnetic resonance (CMR). Sixty-one CAD patients (28 with DM2 and 33 without DM2) and 18 normal individuals were enrolled in this study. Left ventricular function parameters, including the end-diastolic and end-systolic volumes (EDV, ESV), stroke volume (SV) and ejection fraction (EF), and morphologic dimension parameters (end diastolic and systolic diameter (EDD and ESD), were measured and compared. Volume-time curve parameters, including the peak ejection rate (PER), peak ejection time (PET), peak filling rate (PFR), peak filling time from ES (PFT), peak ejection rate normalized to EDV (PER/EDV), and peak filling rate normalized to EDV (PFR/EDV), were derived automatically and compared. LVEF in the diabetic CAD group was markedly reduced when compared to the normal and CAD without DM2 groups (all p < 0.05). LVEDD of the diabetic CAD group was significantly enlarged compared to the normal and non-diabetic CAD groups (all p < 0.05). More importantly, the lowest parameters of the left ventricle volume time curve (i.e., PER, PFR, PER/EDV and PFR/EDV) were obtained in diabetic CAD patients (all p < 0.05). In diabetic CAD patients, logistic regression analysis indicated that PET, PFT and PFR/EDV were independent predictors of left ventricular dysfunction (odds ratio [OR]: 1.1208, 1.0161, and 0.0139, respectively). The sensitivity and specificity of PET were 81.2 and 90%, respectively, when the threshold value was greater than 164.4 msec; for PFT, the sensitivity and specificity were 87.5 and 95.0%, respectively (criterion >166.0 msec). Higher sensitivity (87.5%) and specificity (100.0%) were obtained for PFR/EDV (criterion ≤3.7EDV/s). Parameters that are derived from the volume-time curve on CMR, including PET, PFT and PFR/EDV, allow clinicians to predict left ventricular dysfunction in diabetic CAD subjects with a high degree of sensitivity and specificity.


Energy, protein, fat and carbohydrate intakes of underweight, normal weight and obese government office workers in an urban area.
Diet is one of the major factors contributing to the development of obesity, apart from heredity and energy balance. The objective of this cross-sectional study is to assess energy, carbohydrate, protein and fat intakes in relation to bodyweight status among government office workers in Kuala Lumpur. A total of 185 Malay men and 196 Malay women aged 18 and above were randomly selected as the study sample. Height and weight were taken to determine body mass index (BMI). The dietary profile was obtained by using 24-hour dietary recalls and food frequency methods. This was analysed to determine average nutrient intake per day. Other information was ascertained from tested and coded questionnaires. The subjects were categorised into three groups of bodyweight status namely underweight (BMI < 20 kg/m2), normal weight (BMI 20-25 kg/m2) and obese (BMI > 25 kg/m2). The prevalence of obesity was 37.8%. The study showed that the mean energy intake of the respondents was 1709 ± 637 kcal/day. The energy composition comprised of 55.7 ± 7.6% carbohydrates, 29.7 ± 21.7 % fat and 15.6 ± 3.8% protein. There was no significant difference in diet composition among the three groups. The findings indicate that normal weight and overweight individuals had a lower intake of calories and carbohydrates than the underweight individuals (p<0.05). However, there were no significant differences in fat intakes.


Penetrating Colon Trauma Outcomes in Black and White Males.
Racial disparities have been both published and disputed in trauma patient mortality, outcomes, and rehabilitation. In this study, the objective was to assess racial disparities in patients with penetrating colon trauma. The National Trauma Data Bank was searched for males aged ≥14years from 2010 through 2014 who underwent operative intervention for penetrating colon trauma. The primary outcomes for this study were stoma formation and transfer to rehabilitation; secondary outcomes were postoperative morbidity and mortality. Analyses were performed in 2016-2018. There were 7,324 patients identified (4,916 black, 2,408 white). Black and white patients underwent fecal diversion with stoma formation at a similar rate (19.6% vs 18.5%, p=0.28). Black patients were more likely than white patients to be uninsured (self-pay; 37.1% vs 29.9%) and more likely to be injured by firearms (88.3% vs 70.2%, p<0.001), but had a lower overall postoperative morbidity rate (52.6% vs 55.3%, p=0.04). The odds of stoma formation (OR=0.92, 95% CI=0.78, 1.09, p=0.35) and the odds of transfer to rehabilitation (OR=1.03, 95% CI=0.82, 1.30, p=0.78) were similar for black versus white patients. Black patients experienced similar rates of stoma formation and transfer to rehabilitation as white patients with penetrating colon trauma. Multivariate analysis confirmed expected findings that trauma severity increased the odds of receiving an ostomy and rehabilitation placement. The protocol-based management approach to emergency trauma care potentially decreases the risk for the racial biases that could lead to healthcare disparities. This article is part of a supplement entitled African American Men's Health: Research, Practice, and Policy Implications, which is sponsored by the National Institutes of Health.


The effect of financial crisis on the profile of the patients examined at the surgical emergencies of an academic institution in Greece.
Greece is suffering an economic recession of enormous magnitude, but whether its health has deteriorated as a result, has not yet been well established. We aim to present and analyze differences in demographics and clinical distribution of patients examined at the emergency room (ER) in the era of financial crisis. A retrospective data analysis of all patients that were examined to surgical ER, between January 1st 2008 and December 31st 2014, was conducted. We only analyzed and evaluated data for the years 2008, 2011 and 2014. We evaluated the etiology of the examination (main complaint of the patient), the gender, the ethnic origin, the age and the severity of the disease, whenever it was feasible. The diseases that presented differences that were statistically significant were analyzed in terms of medical, social and financial aspects. The number of patients being examined in the ER in 2011 was higher compared with that of 2014 and to 2008 respectively (P<0.05). Throughout the years, there was a decline in vascular emergencies (veins, arteries, AAA; P<0.05). An increased incidence of soft tissue infections (STIs) was also found (P<0.05). Finally, an increased incidence of anal diseases and patients with abdominal pain was also noted (P<0.05). Financial crisis seems to have a multivariable effect on epidemiology and clinical diversity of patients being examined in the ER.


Integrated Analysis of a Competing Endogenous RNA Network Reveals a Prognostic lncRNA Signature in Bladder Cancer.
Long non-coding RNAs (lncRNAs) act as competing endogenous RNAs (ceRNAs) to regulate mRNA expression through sponging microRNA in tumorigenesis and progression. However, following the discovery of new RNA interaction, the differentially expressed RNAs and ceRNA regulatory network are required to update. Our study comprehensively analyzed the differentially expressed RNA and corresponding ceRNA network and thus constructed a potentially predictive tool for prognosis. "DESeq2" was used to perform differential expression analysis. Two hundred and six differentially expressed (DE) lncRNAs, 222 DE miRNAs, and 2,463 DE mRNAs were found in this study. The lncRNA-mRNA interactions in the miRcode database and the miRNA-mRNA interactions in the starBase, miRcode, and mirTarBase databases were searched, and a competing endogenous RNA (ceRNA) network with 186 nodes and 836 interactions was subsequently constructed. Aberrant expression patterns of lncRNA NR2F1-AS1 and lncRNA AC010168.2 were evaluated in two datasets (GSE89006, GSE31684), and real-time polymerase chain reaction was also performed to validate the expression pattern. Furthermore, we found that these two lncRNAs were independent prognostic biomarkers to generate a prognostic lncRNA signature by univariate and multivariate Cox analyses. According to the lncRNA signature, patients in the high-risk group were associated with a poor prognosis and validated by an external dataset. A novel genomic-clinicopathologic nomogram to improve prognosis prediction of bladder cancer was further plotted and calibrated. Our study deepens the understanding of the regulatory ceRNA network and provides an easy-to-do genomic-clinicopathological nomogram to predict the prognosis in patients with bladder cancer.


Site of J chain attachment to human polymeric IgA.
A fragment containing J chain was released from human polymeric myeloma IgA protein by cyanogen bromide cleavage. The identity of the fragment was determined by its electrophoretic mobility and antigenic determinants. After purification by gel filtrations and DEAE-Sephadex chromatography, this fraction appeared similar (with respect to its amino acid and carbohydrate compositions and its peptide maps) to the J chain isolated from this IgA protein; the molecular weight was 17,000 +/- 100. Upon reduction and alkylation, with subsequent separation of peptides by gel filtration, three components were obtained: the largest component (molecular weight 13,400) corresponded to the N-terminal segment of J chain and contained a homoserine residue, the second corresponded to the C-terminal part of J chain with 13-18 amino acid residues, and the third corresponded to the C-terminal octapeptide of the alpha chain. The data indicate that J chain is attached to alpha chain(s) through the penultimate cysteine residue of the C-terminal octapeptide.


Determination of alpha-fetoprotein in human serum by a quartz crystal microbalance-based immunosensor.
Increased alpha-fetoprotein (AFP) in adult plasma is considered an early indication of hepatocellular carcinoma and teratoblastoma. The aim of this study was to develop a rapid method to measure AFP in human serum by use of a direct immunosensor based on a quartz crystal microbalance (QCM). A self-assembled monolayer prepared by the cystamine method was applied to immobilize anti-AFP monoclonal antibodies on the gold surface of a quartz crystal. The frequency shifts of the QCM were measured and related to AFP concentrations. The piazoimmunosensor used no labeled reagent and no pretreatment of samples. Ten cycles of measurements could be performed on the gold surface of the same crystal regenerated with a solution of glycine-HCl. A linear relationship existed between the frequency shifts (Hz) and the log values of AFP concentrations from 0.1 to 100 microg/L in buffer and human serum. When used for 15 days, the frequency shifts were all >95% of those on the response at the first day. The regression equation was y = 1.03x - 0.06 (S(y/x) = 3.92; r = 0.9987) for this QCM method and RIA in 29 clinical human serum samples. The QCM sensor can measure AFP in buffer and human serum and offers advantages of high specificity, reusability, low detection limit, no label or sample pretreatment, and low sample requirement. The assay format of the immunosensor was more rapid and simpler than conventional methods.


Humoral immune response to fibrillar beta-amyloid peptide.
The beta-amyloid peptide (Abeta) is a normal product of the proteolytic processing of its precursor (beta-APP). Normally, it elicits a very low humoral immune response; however, the aggregation of monomeric Abeta to form fibrillar Abeta amyloid creates a neo-epitope, to which antibodies are generated. Rabbits were injected with fibrillar human Abeta(1-42), and the resultant antibodies were purified and their binding properties characterized. The antibodies bound to an epitope in the first eight residues of Abeta and required a free amino terminus. Additional residues did not affect the affinity of the epitope as long as the peptide was unaggregated; the antibody bound Abeta residues 1-8, 1-11, 1-16, 1-28, 1-40, and 1-42 with similar affinities. In contrast, the antibodies bound approximately 1000-fold more tightly to fibrillar Abeta(1-42). Their enhanced affinity did not result from their bivalent nature: monovalent Fab fragments exhibited a similar affinity for the fibrils. Nor did it result from the particulate nature of the epitope: monomeric Abeta(1-16) immobilized on agarose and soluble Abeta(1-16) exhibited similar affinities for the antifibrillar antibodies. In addition, antibodies raised to four nonfibrillar peptides corresponding to internal Abeta sequences did not exhibit enhanced affinity for fibrillar Abeta(1-42). Antibodies directed to the C-terminus of Abeta bound poorly to fibrillar Abeta(1-42), which is consistent with models where the carboxyl terminus is buried in the interior of the fibril and the amino terminus is on the surface. When used as an immunohistochemical probe, the antifibrillar Abeta(1-42) IgG exhibited enhanced affinity for amyloid deposits in the cerebrovasculature. We hypothesize either that the antibodies recognize a specific conformation of the eight amino-terminal residues of Abeta, which is at least 1000-fold more favored in the fibril than in monomeric peptides, or that affinity maturation of the antibodies produces an additional binding site for the amino-terminal residues of an adjacent Abeta monomer. In vivo this specificity would direct the antibody primarily to fibrillar vascular amyloid deposits even in the presence of a large excess of monomeric Abeta or its precursor. This observation may explain the vascular meningeal inflammation that developed in Alzheimer's disease patients immunized with fibrillar Abeta. Passive immunization with an antibody directed to an epitope hidden in fibrillar Abeta and in the transmembrane region of APP might be a better choice in the search for an intervention to remove Abeta monomers without provoking an inflammatory response.


A comparison of in vitro culture of fetal nucleated erythroblasts from fetal chorionic villi and maternal peripheral blood for noninvasive prenatal diagnosis.
We tested the feasibility of the in vitro culture of fetal nucleated erythroblasts from maternal blood for noninvasive prenatal screening as a substitute for culturing fetal nucleated erythroblasts from fetal villi. Nucleated blood cells separated via Percoll from 52 samples of fetal villi and maternal peripheral blood were cultured with or without magnetic-activated cell sorting glycophorin A (MACS-GPA+), and detected by an anti-hemoglobin-epsilon (FITC) antibody. Gender of the epsilon-positive cells were identified by FISH and further confirmed by PCR of the villi karyotype. Developmental stages of nucleated erythroblasts from villi and blood with MACS-GPA+ were analyzed by Wright-Giemsa staining. In the maternal blood, epsilon-positive cells were found in 4 and 24 cultured samples with and without MACS-GPA+, respectively. Also, Y-signals were visualized in 3 out of 4 and in 15 out of 24 cases in the epsilon-positive cells. Although epsilon-positive cells were found in all villus samples irrespective of MACS-GPA+ sorting, Y-signals were visualized in 31 out of 52 cases. Proerythroblasts and basophilic erythroblasts occupied 7 and 1% in fetal and maternal samples (with MACS-GPA+), respectively. The in vitro culturing of fetal nucleated erythroblasts from maternal blood is not feasible with the current techniques for prenatal diagnosis, because the fetal nucleated erythroblast is not well developed in vitro. This may be attributed to the low proportion of these erythroblasts at an early stage in the fetal circulation and the low permeability of these cells to the maternal blood.


Differential vitreous dye diffusion following microplasmin or plasmin pre-treatment.
Plasmin and microplasmin are related enzymes that differ mainly in size. The differential effect of plasmin and microplasmin on vitreous structure, protein degradation, and dye diffusion through porcine vitreous was evaluated. The enzymatic effect was examined using a number of approaches on fresh porcine eyes: (1) structural integrity of vitreous after a 2-hr incubation using the electron microscope (EM); (2) effect on soluble proteins within the vitreous using gel electrophoresis after incubation at various time points over a 24-hr period; (3) fluorescein dye diffusion within the vitreous cavity measured over a 1-hr period following a 2-hr incubation. The chosen enzymatic activities for plasmin 0.5 IU and microplasmin 125 microg were within the clinical range, and were chosen for equipotence. A saline control was also used in all experiments. Significant structural changes were seen with both microplasmin and plasmin when examined by EM. Gel electrophoresis showed that microplasmin and plasmin digested the same proteins, mainly molecular weights above 50 kDa. The enzymatic effect was noticeable earlier in microplasmin-treated eyes and was more significant by the end of the incubation period. Differential fluorescein diffusion rates were seen between normal saline, plasmin, and microplasmin within the vitreous cavity. The greatest diffusion rate was seen with microplasmin and was statistically significantly higher than plasmin. Microplasmin and plasmin have a similar enzymatic effect on vitreous. However, an equipotent amount of microplasmin appears to have a more extended effect on vitreous gel. This may, in part, be related to its smaller size allowing it to diffuse more readily through the vitreous matrix.


Kaposi's sarcoma.
Pulmonary KS may occur in up to 20 to 25 per cent of patients with cutaneous KS. The presenting symptoms of pulmonary KS are indistinguishable from those of opportunistic pathogens that cause pneumonia. It most frequently presents with the symptoms of cough or dyspnea; however, fever, hemoptysis, and stridor have been reported to occur secondary to pulmonary KS. Roentgenographically, pulmonary KS may present as diffuse infiltrates, nodal disease, and/or pleural effusions. The diagnosis is established by a characteristic histologic pattern obtained from large pieces of tissue, that is, from open lung biopsy or autopsy rather than from transbronchial biopsy. No effective therapy for pulmonary KS exists; however, short-term palliation may be achieved with radiotherapy or combination chemotherapy. In a patient with known pulmonary KS who develops either new or changing symptoms or new roentgenographic findings, an attempt should be made to rule out an associated infectious process.


EFFECTS OF INTRINSIC AND EXTRINSIC FACTORS ON POPULATION FRAGMENTATION IN THREE SPECIES OF NORTH AMERICAN MINNOWS (TELEOSTEI: CYPRINIDAE).
Geographic patterns of genetic variation (mitochondrial DNA [mtDNA] and allozymes) were used to examine effects of intrinsic characteristics (e.g., vagility, habitat specificity, and reproductive behaviors) and extrinsic factors (e.g., climatic and geological history) on population fragmentation. The three species of cyprinid fishes examined (Tiaroga cobitis, Meda fulgida, and Agosia chrysogaster) occupied similar historical ranges within the lower Colorado River drainage, but differ in intrinsic characteristics conducive to population fragmentation. Relationships among populations were similar across species, reflecting common historical influences, but results indicate the distribution of variation among species is strongly affected by intrinsic characteristics. Variation within two species (T. cobitis and M. fulgida) is subdivided among populations, suggesting little gene flow among rivers. In contrast, similarity of A. chrysogaster populations throughout the Gila River drainage supports the hypothesis that levels of gene flow are high for this species. Levels of mtDNA divergence were much higher than expected for both T. cobitis and A. chrysogaster suggesting long-term isolation of geographic regions. These results indicate that both long-term and short-term extrinsic factors have shaped basic patterns of variation within these fishes; however, the intrinsic characteristics of each species have strongly affected the population genetic structure of these fishes.


Indications and effects of captopril therapy in childhood.
Chronic effects of captopril were studied in 29 patients (age, 4 months to 16 years; mean, 6.9 years) suffering from digitalis and diuretic resistant congestive heart failure (CHF) or hypertension of different etiology. Twenty two patients with CHF (13 dilated, 4 restrictive cardiomyopathy, 5 congenital heart defects) and 7 cases with hypertension were treated for 1 to 31 months (mean, 9 months). The dose of captopril varied from 1 to 3 mg/kg/day (mean, 2.2 mg) in CHF and from 1.1 to 6.8 mg/kg/day (mean, 3.7 mg) in hypertension. In CHF digoxin therapy was maintained while the dose of diuretics could be reduced or discontinued. In 4 severely hypertensive patients the addition of a diuretic or beta blockers was necessary. In CHF clinical improvement was observed in 13 patients (59%), while there was no response in 4 and 5 patients died. The survivors exhibited a significant decrease of the cardiothoracic index (p less than 0.05), the PEP/LVET ratio (p less than 0.05) and an increase of the echocardiographic linear ejection fraction (p less than 0.001). If hypertension was present, blood pressure decreased in all patients (p less than 0.05). Captopril was well tolerated by all patients except one who developed anaemia. This side effect disappeared after having discontinued the drug. These findings suggest that captopril is of benefit in controlling chronic CHF. Captopril alone or in combination with other drugs is effective in the management of severe hypertension.


[Are more girls than boys born in breech presentation compared with head presentation?].
In breech presentations a little more girls are born than boys, among head presentations there is a slight excess of boys. Among the factors favoring pelvic presentation birth weight has, according to present investigations, a decisive influence on the different sex relationship in the two presentations. Boys are little more common than girls in head presentation in the higher weight groups, in breech presentation in the upper and lower weight groups, while girls predominate in the middle weight groups. The absolute size of the middle weight groups in breech presentation causes the small excess of girls. A possible link with the slightly higher mortality of boys during the first year and its higher incidence in very high and very low weight groups are discussed as well as the dependence of the production of breech presentation on weight and mobility of the fetus.


PCDH19-related epilepsy is associated with a broad neurodevelopmental spectrum.
To characterize the features associated with PCDH19-related epilepsy, also known as "female-limited epilepsy." We analyzed data from participants enrolled in the PCDH19 Registry, focusing on the seizure-related, developmental, neurobehavioral, and sleep-related features. We evaluated variants for pathogenicity based on previous reports, population databases, and in silico predictions, and included individuals with pathogenic or potentially pathogenic variants. We performed a retrospective analysis of medical records and administered a targeted questionnaire to characterize current or past features in probands and genotype-positive family members. We included 38 individuals with pathogenic or potentially pathogenic variants in PCDH19: 21 de novo, 5 maternally inherited, 7 paternally inherited, and 5 unknown. All 38 had epilepsy; seizure burden varied, but typical features of clustering of seizures and association with fever were present. Thirty individuals had intellectual disability (ID), with a wide range of severity reported; notably, 8/38 (22%) had average intellect. Behavioral and sleep dysregulation were prominent, in 29/38 (76%) and 20/38 (53%), respectively. Autistic features were present in 22/38 (58%), of whom 12 had a formal diagnosis of autism spectrum disorder. We had additional data from 5 genotype-positive mothers, all with average intellect and 3 with epilepsy, and from 1 genotype-positive father. Our series represents a robust cohort with carefully curated PCDH19 variants. We observed seizures as a core feature with a range of seizure types and severity. Whereas the majority of individuals had ID, we highlight the possibility of average intellect in the setting of PCDH19-related epilepsy. We also note the high prevalence and severity of neurobehavioral phenotypes associated with likely pathogenic variants in PCDH19. Sleep dysregulation was also a major area of concern. Our data emphasize the importance of appropriate referrals for formal neuropsychological evaluations as well as the need for formal prospective studies to characterize the PCDH19-related neurodevelopmental syndrome in children and their genotype-positive parents.


Validation of the knowledge evaluation questionnaire of the cardiopulmonary resuscitation training program in high school students.
There is an urgent need for generalized training in cardiopulmonary resuscitation (CPR) techniques, starting with secondary education. Validated instruments for assessing the efficacy of such interventions are not yet available. This study aimed to validate an evaluation questionnaire of a CPR training program for high school students, to analyze the levels of readability, difficulty, reliability, and content validity, as well as the fit the purpose for which they were designed, the trait they are intended to measure. An instrumental study was conducted in 2 phases. In the first phase, an inter-judge validation was carried out with 11 experts in CPR accredited instructors of basic and advanced CPR by the American Heart Association. In the second phase, the psychometric properties were evaluated from the perspective of Item Response Theory. During May of the 2017/18 and 2018/19 academic years, 259 4th-year secondary school students from a high school in the southeastern area of the island of Gran Canaria (mean age: 15.78 years; 50.60% male) were surveyed anonymously using the questionnaire to be validated. The questionnaire was easily readable (74.12 Flesch-Szigriszt Index); the difficulty level (Easy/Very Easy) in the context of this secondary school level of education and the ability level of the respondents overlapped sufficiently and there was no gender bias. The questionnaire was able to discriminate between respondents of slightly more than 7 levels of expertise, from low knowledge of CPR to high knowledge of CPR (Separation Index 7.53). The model fit was excellent (infit = 1/outfit = 1.01). The content validity index was adequate. The separation index and reliability exceeded what was considered adequate for guaranteed use. The level of difficulty of the items and the level of ability of the respondents is in line with the educational level of the students. The questionnaire did not produce a gender bias in response probability. The questionnaire is easily understandable and can discriminate between different levels of ability without differential gender bias, and its reliability is outstanding, as it exceeds the minimum criteria.


Horizontal Plasmonic Ruler Based on the Scattering Far-Field Pattern.
A novel method is proposed to detect the horizontal shift of a specific nanoblock relative to a reference nanoblock using surface plasmon modes at nanometer resolution. To accomplish this task, two orthogonal localized surface plasmon resonances were excited within the air gap region between the silver nanoblocks at the respective wavelengths, 890 nm, and 1100 nm. This technique utilized the scattering far-field intensities of the two block nanostructures at the two specific wavelengths at two specific directional spots. The ratio of the scattering intensities at the two spots changed according to the horizontal shift of the block that moved. Correspondingly, this ratio can be used to provide the precise location of the block. This method can be applied to many fields, including label-free bio-sensing, bio-analysis and alignment during nano-fabrication, owing to the high resolution and simplicity of the process.


On the nature of burnout-insomnia relationships: a prospective study of employed adults.
This prospective study was designed to test the hypothesis that burnout and insomnia predict each other's incidence and intensification across time. Burnout is conceptualized as representing individuals' unique affective response to their exposure to chronic stressors. Apparently healthy respondents (1356) completed questionnaires during periodic health examinations undergone at two time points T(1) and T(2), about 18 months apart. Burnout was assessed by the Shirom-Melamed Burnout Measure, while insomnia was assessed by the Brief Athens Insomnia Scale. Depressive symptomatology, neuroticism, body mass index, age, gender, follow-up duration, and T(1) levels of the criterion were controlled. Burnout and insomnia were found to be only moderately associated at T(1). However, logistic regression results indicated that burnout significantly predicted the development of new cases of insomnia at 18-month follow-up [odds ratio (OR)=1.93; 95% confidence interval (95% CI)=1.45-2.58], even after adjusting for depression and other potent confounders. Likewise, insomnia significantly predicted the onset of new cases of burnout at 18-month follow-up (OR=1.64; 95% CI=1.30-2.08). Hierarchical regression results indicted that T(1) burnout significantly predicted an increase in T(2) insomnia (beta=.05, P<.05), and that T(1) insomnia significantly predicted an increase in T(2) burnout (beta=.07, P<.05). The results indicate that burnout and insomnia recursively predict each other's development and intensification over time, thus suggesting that either might be a risk factor for the other across time. Possible mechanisms of link between burnout and insomnia, as well as the clinical implications of the findings, were suggested.


Molecular cloning and characterization of rat estrogen receptor cDNA.
A cDNA clone of rat uterus estrogen receptor (ER) has been isolated and sequenced. This clone contains a complete open reading frame encoding 600 amino acid residues which is 5 and 11 amino acids larger than the corresponding molecules of human and chicken, respectively. The molecular weight of this protein is calculated to be 67,029. When this clone was ligated to the pSV2 vector and transfected into COS7 cells, a protein was produced that had the same affinity to estrogen as rat uterus ER. This sequence shows 88% homology with human ER; 528 amino acids are identical and 14 amino acids are conservative substitutions. The comparison of rat, human and chicken ER sequences indicate the presence of three highly conserved regions suggesting that these regions play important roles in ER function. The putative DNA-binding domain is completely identical in rat, human and chicken. The C-terminal half region which is thought to be the estrogen binding domain is also highly conserved and is rich in hydrophobic amino acid residues. Southern blot analysis of genomic DNA with ER cDNA as a probe has shown that related sequences are present in the genome.


Episodic case management in home care.
Home care clinicians are being given increasing responsibility for managing a patient's care from admission to discharge and beyond. Under PPS, case management oversight using model(s) unique to an agency's case mix is critical to the financial and quality outcomes of the entire organization. This article provides the latest thinking on case management and how agencies and clinicians can manage cases successfully.


Addressing cluster-constant covariates in mixed effects models via likelihood-based boosting techniques.
Boosting techniques from the field of statistical learning have grown to be a popular tool for estimating and selecting predictor effects in various regression models and can roughly be separated in two general approaches, namely gradient boosting and likelihood-based boosting. An extensive framework has been proposed in order to fit generalized mixed models based on boosting, however for the case of cluster-constant covariates likelihood-based boosting approaches tend to mischoose variables in the selection step leading to wrong estimates. We propose an improved boosting algorithm for linear mixed models, where the random effects are properly weighted, disentangled from the fixed effects updating scheme and corrected for correlations with cluster-constant covariates in order to improve quality of estimates and in addition reduce the computational effort. The method outperforms current state-of-the-art approaches from boosting and maximum likelihood inference which is shown via simulations and various data examples.


Proteomics discovery of radioresistant cancer biomarkers for radiotherapy.
Radiotherapy (RT) is one of the most important strategies in cancer treatment. Radioresistance is a major challenge to RT and results in locoregional recurrence and metastasis. Thus, there is a great interest in investigating biomarkers to distinguish radiosensitive from radioresistant (RR) cancer patients. The development of proteomic techniques has sparked new searches for novel proteins for cancer biomarker discovery. Modern proteomic techniques allow for a high-throughput analysis of samples with the visualization and quantification of thousands of potential protein and peptide markers. The discovery of RR biomarkers can provide a clue for predicting RT response and discover therapeutic targets for developing personalised medicine of individual patients. In the past decade, emerging advanced proteomic technologies have been performed to identify radiation-related biomarkers in human cancers. This review discusses the mass spectrometry (MS)-based proteomic techniques in RR cancer biomarker discovery, summarises RR biomarkers identified in cancers from proteomics-based findings and explores potential values of RR biomarkers for future clinical trials.


Balloon Uterine Tamponade Device After Peripartum Hysterectomy for Morbidly Adherent Placenta.
Perioperative hemorrhage is a common complication of peripartum hysterectomy for morbidly adherent placenta. We present an application of a balloon uterine tamponade device in the setting of a cesarean delivery and subsequent supracervical hysterectomy for abnormal placentation. A 33-year-old gravid woman, 6 para 3022, at 33 2/7 weeks of gestation was admitted in preterm labor, with placenta previa and suspected morbidly adherent placenta, for a planned cesarean delivery and hysterectomy. After supracervical hysterectomy, colloid resuscitation and packing failed to provide hemostasis. A transcervical balloon uterine tamponade device subsequently was placed intraperitoneally and left on tension owing to the need for further tamponade. Use of a balloon uterine tamponade device intraperitoneally posthysterectomy was associated with hemorrhage control. This application may facilitate timely management and streamlining of obstetric resources for postpartum hemorrhage.


Angiotensin-converting enzyme inhibitors-induced angioedema of the small bowel mimicking postoperative complication.
Angioedema of the small bowel (ASB) is an extremely rare side effect of the angiotensin-converting enzyme inhibitors (ACEI). We present a case of ACEI-induced ASB mimicking postoperative complication. The diagnosis of ACEI-induced ASB should be considered in patients using these drugs and presenting sudden gastrointestinal symptoms and thickening of small bowel not attributable to other diseases.


MEDICAL PRACTICE IN CHILDREN PRESENTING FEVER WITH PETECHIAL RASH TO AN EMERGENCY DEPARTMENT.
The association of fever and petechiae in children is one of the most alarming findings for a paediatrician. To quickly distinguish between benign and life-threatening conditions is challenging in many cases. We aimed to evaluate the clinical practice of children presenting with fever and petechiae as initial symptoms. 41 patients (age 3 months-11 years) presenting with fever and petechiae were identified in an Emergency Paediatric Assessment Unit over a period of 9 months. General data, symptoms and signs were assessed for each patient. The work-up consisted in: complete blood count, inflammatory tests, coagulation tests, Monospot test, nasopharyngeal rapid tests, blood culture, and cerebrospinal fluid culture where appropriate. Most children were <5 years of age (70.7%). Female to male ratio was 1:2.4. The most common clinical diagnoses were: viral respiratory illness (48.8%, 20/41) and upper respiratory tract infection (17.1%, 7/41). Meningococcal disease was found in one case. CRP>6 mg/l was poorly correlated with serious illness. The following variables were strongly associated with serious illness: ill appearance, shivering, lethargy, back rigidity, ESR>50 mm/h and prolonged capillary refill time. 59% (24/41) of children were treated with antibiotics, however, at discharge 42%(10/24) of them, did not have a work-up suggestive for a bacterial illness. Screening for low prevalence but high morbidity conditions, as the meningococcal disease, with an extensive work-up is time and resource consuming and may lead to unmotivated antibiotic use. Larger studies are needed to change the emergency practice for management of fever and rash.


Distribution of Neuroendocrine Cells in the Transition Zone of the Prostate.
Objectives. To evaluate the distribution of neuroendocrine (NE) cells which may influence the development of benign prostatic hyperplasia (BPH) in the transition zone (TZ). Methods. We reviewed specimens from 80 patients who underwent radical prostatectomy in our institution and evaluated the density of NE cells in the TZ. They were histologically classified into 3 groups: those with no adenomatous nodule in the TZ (group A), those with small nodules with normal epithelium and stroma around them in the TZ (group B), and those with large nodules occupying the TZ (group C). In the patients of group B, intra-adenoma (adenomatous nodules) and extra-adenoma (normal tissue) NE cells in the TZ were separately counted. Results. There were 22, 23, and 35 patients in groups A, B, and C, respectively. The median density of NE cells in the TZ of group B patients, 2.80/mm2, was significantly higher than that of NE cells in group A, 1.43/mm2, and group C, 0.61/mm2 (p < 0.001). In group B, the median density of extra-adenoma NE cells was significantly higher than that of intra-adenoma. Conclusions. Many NE cells exist around small adenoma in the TZ. NE cells may influence the initial growth of BPH in a paracrine fashion. Trial Registration. This study approved by our institutional review board was retrospectively registered (#272-14).


Immunostimulatory Properties of Lipid Modified CpG Oligonucleotides.
Innate immune responses recognizing pathogen associated molecular patterns play important roles in adaptive immunity. As such, ligands which mimic the conserved products of microbial and activate innate immunity are widely used as adjuvants for vaccines. Synthetic single strand oligodeoxynucleotides (ODNs) containing unmethylated cytosine-guanine (CpG) motifs which bind Toll-like receptor 9 (TLR9) are powerful molecular adjuvants, potentiating both humoral and cellular responses. However, CpG ODN's in vitro potency has not been translated to in vivo settings primarily due to issues associated with delivery and toxicity. A major challenge in clinical application of CpG ODN is the efficient delivery to lymph nodes, the anatomic sites where all the immune responses are initiated. Targeting CpG to the key antigen presenting cells (APC) is essential for its application as a vaccine adjuvant, as it not only enhances CpG's efficacy, but also greatly reduces the systemic toxicity. We recently discovered an "albumin-hitchhiking" approach by which CpG ODNs were conjugated to a lipophilic lipid tail and follow subcutaneous injection, accumulated in lymph nodes by binding and transporting with endogenous albumin. This molecular approach targets CpG to antigen presenting cells in the draining lymph nodes via an endogenous albumin-mediated mechanism and simultaneously improves both the efficacy and safety of CpG as a vaccine adjuvant. Since CpG ODNs can be divided into structurally distinct classes, and each class of CpG ODN activates different types of immune cells and triggers different types of immunostimulatory activities, it is important to thoroughly evaluate the efficacy of this "albumin-hitchhiking" strategy in each class of CpG. Here we compare the immunostimulatory activities of three classes of lipid conjugated CpG ODNs in vitro and in vivo. Three representative sequences of lipid modified CpG ODNs were synthesized and their stimulatory effects as a vaccine adjuvant were evaluated. Our results showed that in vitro, lipid modified class A CpG exhibited enhanced stimulatory activities toward TLR transfected reporter cells or bone-marrow derived dendritic cells, whereas lipid-modification of class B or C CpG reduces the activation of TLR9 by 2-3 fold, as compared with unmodified class B and class C CpG, respectively. However, in vivo coadministration of ovalbumin (OVA) protein antigen mixed with lipid-conjugated class B or C CpG ODNs, but not class A CpGs induced dramatically increased OVA-specific humoral and cytotoxic CD8+ T cells responses compared with OVA mixed with unmodified CpGs. Further, lipid-modification greatly reduces the toxicity associated with CpG by minimizing the systemic dissemination. Taken together, these results demonstrated that amphiphilic modification of three classes of CpG motifs differentially affected and modulated the immunostimulatory activities in vitro and in vivo. Our study highlights the importance of in vivo lymph node targeting of CpG ODNs in fulfilling their use as vaccine adjuvants, providing implications for the rational design of molecular adjuvant for subunit vaccines.


Selective membrane wrapping on differently sized nanoparticles regulated by clathrin assembly: A computational model.
Nanoparticles (NPs) enter cells via multiple pathways, all of which are NP size dependent. Previous studies indicated that the clathrin-mediated endocytosis has different selectivity for the NP size, but the regulatory mechanism remains unclear and difficult to study at the molecular scale in vivo. By means of computer simulation, here we design membrane wrapping on differently sized NPs with mimic clathrin assembly at the opposite membrane side. With relatively large NPs readily wrapped by a pure membrane as manifested, clathrin modulates the process and tunes the size selectivity. Although finite curvature can be generated by cage-like clathrin assembly to facilitate membrane wrapping on relatively small NPs, the clathrin assemblage has a certain range of size, which is mismatched with larger NPs. Besides, the local membrane patch is rigidified by clathrin to increase the barrier of membrane wrapping on larger NPs. Competition of these items determines whether membrane wrapping on NPs is promoted or suppressed, and can be tuned by the NP-membrane adhesion strength, clathrin concentration, and inter-NP distance. Our results highlight the significance of complex environment in altering the nature of NP interaction with cell membranes, and are expected to help design NPs for biomedical applications requiring precise control of NP uptake or cell membrane attachment.


Control of regulatory T cells and airway tolerance by lung macrophages and dendritic cells.
Airway tolerance, a state of immunological surveillance, suppresses the development of lung inflammatory disorders that are driven by various pathological effector cells of the immune system. Tolerance in the lung to inhaled antigens is primarily mediated by regulatory T cells (Treg cells) that can inhibit effector T cells via a myriad of mechanisms. Accumulating evidence suggests that regulatory antigen-presenting cells are critical for generating Treg cells and/or maintaining the suppressive environment in the lung. This review focuses on the control of airway tolerance by Treg cells and the role of regulatory lung tissue and alveolar macrophages, and lung and lymph node dendritic cells, in contributing to airway tolerance that is associated with suppression of allergic asthmatic disease.


Clinical trials in pediatric cancer: parental perspectives on informed consent.
To better understand parental perceptions of the informed consent process in pediatric oncology clinical trials, 20 parents of newly diagnosed children at two pediatric cancer centers described their perceptions in a semi-structured interview. They recalled well the diagnosis, the general treatment plan, and the statistics of survival and/or cure, but the research nature of the clinical trials, particularly randomization, was not well understood. However, despite the need to assimilate a great deal of information, time pressure to make decisions, and reportedly high levels of distress during the discussions, parents expressed general satisfaction with the informed consent discussions with their pediatric oncology providers. However, half to two thirds of parents felt there had been inadequate discussion of alternatives to the proposed treatment and of the research nature of the protocol. While further study of the informed consent process should be conducted in larger, representative samples, the findings from this pilot study suggest that a goal of future informed consent interventions should be to improve parents' understanding of the research aspects of treatment. It is critical to parents' ability to provide informed consent that they feel satisfied that they know alternatives to proposed treatment and that they understand the randomization of treatments, which is the gold standard of clinical trials in pediatric oncology.


Subnano Pt Particles from a First-Principles Stochastic Surface Walking Global Search.
Subnano transition metal particles have wide applications in chemistry. For the complexity of their potential energy surface, it has long been a great challenge for both theory and experiment to determine the structure of subnano clusters and thus predict their physiochemical properties. Here we explore the structure configurations for 35 subnano PtN (N = 12-46) clusters using a first-principles Stochastic Surface Walking (SSW) global search. For each cluster, thousands of structure candidates are collected from a parallel SSW search. This leads to the finding of 20 new global minima in 35 clusters, which reflects the essence of a first-principles global search for revealing the structure of subnano transition metal clusters. PtN subnano clusters with N being 14, 18, 22, 27, 36, and 44 have higher stability than their neighboring size clusters and are characterized as magic number clusters. These PtN subnano clusters exhibit metallic characteristics with a diminishing HOMO-LUMO gap, much poorer binding energy (by 1-1.7 eV), and a much higher Fermi level (by 1-1.5 eV) than bulk metal, implying their high chemical activity. By analyzing their structures, we observe the presence of a rigid core and a soft shell for PtN clusters and find that the core-shell 3-D architecture evolves as early as N > 22. For these core-shell clusters, a good core-shell lattice match is the key to achieve the high stability.


Immunogenicity of the P-8 amastigote antigen in the experimental model of canine visceral leishmaniasis.
The P-8 proteoglycolipid complex (P-8 PGLC), an amastigote antigen of Leishmania pifanoi, has been demonstrated to induce protection in mouse models, as well as to induce Tc1/Th1-like cellular responses in American cutaneous leishmaniasis patients. Because the immunization with P-8 PGLC in the murine model does not appear to be genetically restricted, we have studied the reactivity of the P-8 PGLC in Leishmania infantum infected dogs. In this study, it is shown that PBMC from experimentally infected dogs (asymptomatic, oligosymptomatic) significantly proliferated in response to soluble leishmanial antigen (SLA) or the P-8 PGLC. Further, quantification of the gene expression induced by the stimulation with P-8 in asymptomatically infected dogs showed an up-regulation of IFN-gamma and TNF-alpha, which were three to 4-fold higher than that induced by soluble Leishmania antigen (SLA). While no measurable induction of IL-10 was observed, low levels of IL-4 mRNA were observed in response to both P-8 and SLA antigens. Thus, our studies establish that P-8 is recognized by infected canines and elicits a potentially curative/protective Th1-like immune response. The identification of Leishmania antigens that elicit appropriate immune responses across different host species (humans, canine) and disease manifestations (cutaneous or visceral) could be an advantage in generating a general vaccine for leishmaniasis.


Separation of haemoglobin HbE and HbA by the fully automated, high-pressure liquid chromatography Tosoh HLC-723 G7 analyzer.
High-pressure liquid chromatography instruments specifically devised for separating haemoglobin (Hb) fractions have been increasingly employed by the hospital laboratories over the recent years since they allow easy and fast screening for several Hb variants. Although such instruments may be proposed as sensitive, specific and reliable alternatives to the classic electrophoretic techniques, a major drawback of this screening strategy is the almost identical retention time of several Hb variants. In particular, at least 18 Hb variants have been reported in the same retention window as HbA(2), including HbE, the second most common beta-chain variant in humans after sickle cell trait. Recently, we evaluated the performance characteristics of an improved buffer formulation originally conceived for Hb variants separation procedures on the fully automated high-pressure liquid chromatography instrument Tosoh G7. At variance with other fully automated high-pressure liquid chromatography analyzers, the elution pattern on the G7 in subjects heterozygous for HbE is characterized by the presence of four suggestive peaks (HbF, HbA, HbA(2) and HbE), confirming the effective separation of HbE from HbA(2). Because of its potential value in the diagnosis of the thalassaemia syndromes, the effective separation of HbA(2) from HbE can provide clinical laboratories with a valuable information for the diagnostic reasoning.


Sea-urchin-like Au nanocluster with surface-enhanced raman scattering in detecting epidermal growth factor receptor (EGFR) mutation status of malignant pleural effusion.
Somatic mutations in the epidermal growth factor receptor (EGFR) gene are common in patients with lung adenocarcinomas and are associated with sensitivity to the small-molecule tyrosine kinase inhibitors (TKIs). For 10%-50% of the patients who experienced malignant pleural effusion (MPE), pathological diagnosis might rely exclusively on finding lung cancer cells in the MPE. Current methods based on polymerase chain reaction were utilized to test EGFR mutation status of MPE samples, but the accuracy of the test data was very low, resulting in many patients losing the chance of TKIs treatment. Herein, we synthesized the sea-urchin-like Au nanocluster (AuNC) with an average diameter of 92.4 nm, composed of 15-nm nanopricks. By introducing abundant sharp nanopricks, the enhancement factor of AuNC reached at 1.97 × 10(7). After capped with crystal violet (CV), polyethylene glycol, and EGFR mutation specific antibody, the AuNC-EGFR had excellent surface-enhanced Raman scattering (SERS) activity and EGFR mutation targeted recognition capability in lung cancer cells. Characteristic SERS signal at 1617 cm(-1) of CV was linear correlation with the number of H1650 cells, demonstrating the minimum detection limit as 25 cells in a 1-mL suspension. The gold mass in single H1650 cells exposed to AuNC-E746_750 for 2 h ranged from 208.6 pg to 231.4 pg, which approximately corresponded to 56-62 AuNCs per cell. Furthermore, SERS was preclinically utilized to test EGFR mutation status in MPE samples from 35 patients with lung adenocarcinoma. Principal component analysis (PCA) and the support vector machine (SVM) algorithm were constructed for EGFR mutation diagnostic analysis, yielding an overall accuracy of 90.7%. SERS measurement based on sea-urchin-like AuNC was an efficient method for EGFR mutation detection in MPE, and it might show great potential in applications such as predicting gene typing of clinical lung cancer in the near future.


Organic effects of associating paclitaxel with a lipid-based nanoparticle system on a nonhuman primate, Cebus apella.
Lipid-based nanoparticle systems have been used as vehicles for chemotherapeutic agents in experimental cancer treatments. Those systems have generally been credited with attenuating the severe toxicity of chemotherapeutic agents. This study aimed to investigate the effects of associating paclitaxel (PTX) with a lipid-based nanoparticle system on a nonhuman primate, Cebus apella, documenting the toxicity as measured by serum biochemistry, which is a detailed analysis of blood and tissue. Eighteen C. apella were studied: three animals were treated with cholesterol-rich nanoemulsion (LDE) only, without PTX, administered intravenously every 3 weeks, during six treatment cycles; six animals were treated with PTX associated with LDE at the same administration scheme, three with lower (175 mg/m2) and three with higher (250 mg/m2) PTX doses; and six animals were treated with commercial PTX, three with the lower and three with the higher doses. In the LDE-PTX group, no clinical toxicity appeared, and the weight-food consumption curve was similar to that of the controls. Two animals treated with commercial PTX presented weight loss, nausea and vomiting, diarrhea, skin flaking, 70% loss of body hair, and decreased physical activity. The use of LDE as a carrier at both lower and higher doses reduced the toxicity of the drug in this species, which is closely related to human subjects. This was observed not only by clinical, biochemical, and hematological profiles but also by the histopathological analysis. The results of this study support the assumption that lipid-based nanoparticle systems used as drug carriers can serve as valuable tools to decrease the toxicity and increase the safety of chemotherapeutic agents.


Factors associated with pneumococcal vaccination in elderly people: a cross-sectional study among elderly club members in Miyakonojo City, Japan.
Pneumonia is the third leading cause of death in Japan. All elderly people aged 65 years or older are recommended to receive a pneumococcal vaccine. A subsidy for part of the cost of routine pneumococcal vaccination in this age group was introduced in 2014. Factors related to vaccination behavior among elderly adults have not been well reported. The purpose of this study was to investigate factors associated with vaccine uptake among elderly people in Japan. We conducted a cross-sectional study, using a self-administered questionnaire among elderly club members aged 65 years or older in one city of Japan in April 2017. The participants were selected from among all elderly club members in the study area. Variables extracted from the questionnaire were analyzed using logistic regression analysis. A total of 208 elderly club members participated in the study. The mean age (± SD) was 77.2 (± 5.3) years. The pneumococcal vaccination rate was 53.2%. Logistic regression analysis revealed three variables that had a significant association with pneumococcal vaccination: a recommendation for vaccination from medical personnel (aOR 8.42, 95% CI 3.59-19.72, p < 0.001), receiving influenza vaccination in any of the previous three seasons (aOR 3.94, 95% CI 1.70-9.13, p = 0.001), and perception of the severity of pneumonia (aOR 1.23, 95% CI 1.03-1.48, p = 0.026). Although the pneumococcal vaccination rate in this study was increased compared with previous reports, almost half of study participants had not yet received vaccination. Our findings could be helpful for developing vaccination strategies to increase the vaccine coverage in the elderly population.


Neurocognitive deficits related to poor decision making in people behind bars.
Using a novel quantitative model of repeated choice behavior, we investigated the cognitive processes of criminal offenders incarcerated for various crimes. Eighty-one criminals, including violent offenders, drug and sex offenders, drivers operating a vehicle while impaired, and 18 matched controls were tested. The results were also contrasted with those obtained from neurological patients with focal brain lesions in the orbitofrontal cortex and from drug abusers. Participants performed the computerized version of the Iowa gambling task (Bechara, Damasio, Damasio, & Anderson, 1994), and the results were decomposed into specific component processes, using the expectancy valence model (Busemeyer & Stout, 2002). The findings indicated that whereas all the criminal groups tended to select disadvantageously, the cognitive profiles exhibited by different groups were considerably different. Certain subpopulations--most significantly, drug and sex offenders--overweighted potential gains as compared with losses, similar to chronic cocaine abusers. In contrast, assault/murder criminals tended to make less consistent choices and to focus on immediate outcomes and, in these respects, weremore similar to patients with orbitofrontal damage. The present cognitive model provides a novel way for building a bridge between cognitive neuroscience and complex human behaviors.


Atypical synophthalmos with arhinencephaly unilateralis.
This article describes a rare case of a 4-month-old infant with atypical synophthalmos with ipsilateral arhinencephaly unilateralis, ethmoid sinus, and lacrimal apparatus and brain abnormalities--diagnosed on the basis of the clinical picture and imaging findings.


Identification of gastric cancer types based on hyperspectral imaging technology.
Gastric cancer is becoming the second biggest cause of death from cancer. Treatment and prognosis of different types of gastric cancer vary greatly. However, the routine pathological examination is limited to the tissue level and is easily affected by subjective factors. In our study, we examined gastric mucosal samples from 50 normal tissue and 90 cancer tissues. Hyperspectral imaging technology was used to obtain spectral information. A two-classification model for normal tissue and cancer tissue identification and a four-classification model for cancer type identification are constructed based on the improved deep residual network (IDRN). The accuracy of the two-classification model and four-classification model are 0.947 and 0.965. Hyperspectral imaging technology was used to extract molecular information to realize real-time diagnosis and accurate typing. The results show that hyperspectral imaging technique has good effect on diagnosis and type differentiation of gastric cancer, which is expected to be used in auxiliary diagnosis and treatment.


Vancomycin-induced DRESS syndrome in a female patient.
DRESS syndrome (drug rash with eosinophilia and systemic symptoms) is a hypersensitivity reaction with skin rashes, eosinophilia, fever, lymph node enlargement and internal organ involvement. A 60-year-old diabetic woman was hospitalized at the University Hospitals of Geneva for mid-leg amputation due to peripheral arterial occlusive disease. No drug allergy was reported. Because of a wound infection by methicillin-resistant Staphylococcus aureus, treatment with vancomycin (2 g/day) in continuous perfusion was initiated. Approximately 2 weeks later, she developed a toxidermia with fever, a progressive maculopapular skin rash, eosinophilia and acute renal insufficiency. The skin biopsy revealed a necrosis with lymphocytic and eosinophilic infiltrations, supporting the suspicion of DRESS syndrome. A cure was achieved by the withdrawal of vancomycin and the administration of methylprednisolone (1 g/day), antihistaminics and topical mometasone, without the introduction of other antibiotics. Vancomycin can be a cause of DRESS syndrome. A high index of suspicion is warranted in order not to miss this potentially lethal disease.


Dietary intake of spices and herbs in habitual northeast thai diets.
Spices and herbs are rich in polyphenols and widely used in habitual diets in the tropical regions. To elucidate their effects on human health, intake of the portion of spices and herbs from habitual diets should be determined. Consumption patterns were determined from 24-hour records or recalls of 181 men and 370 women in Khonkaen and Ubon Ratchathani provinces, representing upper and lower northeast Thailand. There was a slight variation in dishes, but twelve spices/herbs were commonly used in the two areas. The amounts of spices/ herbs in the four most common dishes (Somtum, Jaew, Pon and Kang-Nor-Mai) were estimated by weighing ingredients before and after cooking. The average amount of spices/herbs consumed was 4.9, 26.1, 14 and 11 g/meal, contributing 36.6, 43.1, 20.6 and 29.8 mg polyphenols/meal for Somtum, Jaew, Pon and Kang- Nor-Mai, respectively. Chili was common in all recipes, with an average amount of 8.3-27.5 mg polyphenols/meal. In conclusion, habitual northeast Thai diets contain several spices/herbs and a substantial amount of polyphenols was commonly consumed.


A dual-omics approach for profiling plant responses to biostimulant applications under controlled and field conditions.
A comprehensive approach using phenomics and global transcriptomics for dissecting plant response to biostimulants is illustrated with tomato (Solanum lycopersicum cv. Micro-Tom and Rio Grande) plants cultivated in the laboratory, greenhouse, and open field conditions. Biostimulant treatment based on an Ascophyllum nodosum extract (ANE) was applied as a foliar spray with two doses (1 or 2 l ha-1) at three different phenological stages (BBCH51, BBCH61, and BBCH65) during the flowering phase. Both ANE doses resulted in greater net photosynthesis rate, stomatal conductance, and fruit yield across all culture conditions. A global transcriptomic analysis of leaves from plants grown in the climate chamber, revealed a greater number of differentially expressed genes (DEGs) with the low ANE dose compared to the greater one. The second and third applications induced broader transcriptome changes compared to the first one, indicating a cumulative treatment effect. The functional enrichment analysis of DEGs highlighted pathways related to stimulus-response and photosynthesis, consistent with the morpho-physiological observations. This study is the first comprehensive dual-omics approach for profiling plant responses to biostimulants across three different culture conditions.


Routine intraoperative cholangiography during cholecystectomy is a cost-effective approach when analysing the cost of iatrogenic bile duct injuries.
The total cost of bile duct injuries (BDIs) in an unselected national cohort of patients undergoing cholecystectomy are unknown. The aim was to evaluate costs associated with treatment of cholecystectomy-related BDIs and to calculate cost effectiveness of routine vs. on-demand intraoperative cholangiography (IOC). Data from Swedish patients suffering a BDI during a 5 year period were analysed. Questionnaires to investigate loss-of-production and health status (EQ-5D) were distributed to patients who suffered a BDI during cholecystectomy and who underwent uneventful cholecystectomy (matched control group). Costs per quality-adjusted-life-year (QALY) gained by intraoperative diagnosis were estimated for two strategies: routine versus on-demand IOC during cholecystectomy. Intraoperative diagnosis, immediate intraoperative repair, and minor BDI were all associated with reduced direct treatment costs compared to postoperative diagnosis, delayed repair, and major BDI (all p < 0.001). No difference was noted in loss-of-production for minor versus major BDIs or between different treatment strategies. The cost per QALY gained with routine intraoperative cholangiography (ICER-incremental cost-effectiveness ratio) to achieve intraoperative diagnosis was €50,000. Intraoperative detection and immediate intraoperative repair is the superior strategy with less than half the cost and superior functional patient outcomes than postoperative diagnosis and delayed repair. The cost per QALY gained (ICER) using routine IOC was considered reasonable.


Characterization of hyaluronic acid and synovial fluid in stagnation point elongational flow.
Hyaluronic acid (HA) is an important biomacromolecule, which fulfils a number of vital physiological functions (especially in the joint synovial fluid) and also has consumer and pharmaceutical applications. HA solution properties have already been quite thoroughly characterized in response to steady shear flows but are less well understood in highly deforming extensional flows. In this study, flow-induced birefringence measurements are made as a function of the strain rate in planar elongational flow at the stagnation point of a cross-slot device using HA solutions of a range of molecular weights (0.9×10(6) g mol(-1)≤Mw≤4.8×10(6) g mol(-1)) and at dilute concentrations. The results provide macromolecular relaxation times, molecular weight distributions and the extensional viscosities and Trouton ratios of the fluids. The HA relaxation time is found to vary as τ∼Mw1.8, which is consistent with a partially solvated, expanded coil. An intrinsic Trouton ratio is defined, which varies as [Tr]∼Mw2. The measurement of birefringence with strain rate is shown to be highly sensitive to the molecular weight distribution and can resolve subtle changes due to macromolecular degradation and the presence of fracture products. Mechanical degradation experiments in the cross-slots indicate midchain scission of HA macromolecules, strongly suggesting near full extension of the high-molecular weight fraction in the stagnation point extensional flow field. Taken together the results suggest a possible method for analysis of the HA in synovial fluid, and this concept is tested using synovial fluid obtained from porcine tarsal joint.


Synthesis and Biological Evaluation of (S)-Amino-2-methyl-4-[(76)Br]bromo-3-(E)-butenoic Acid (BrVAIB) for Brain Tumor Imaging.
The novel compound, (S)-amino-2-methyl-4-[(76)Br]bromo-3-(E)-butenoic acid (BrVAIB, [(76)Br]5), was characterized against the known system A tracer, IVAIB ([(123)I]8). [(76)Br]5 was prepared in a 51% ± 19% radiochemical yield with high radiochemical purity (≥98%). The biological properties of [(76)Br]5 were compared with those of [(123)I]8. Results showed that [(76)Br]5 undergoes mixed amino acid transport by system A and system L transport, while [(123)I]8 had less uptake by system L. [(76)Br]5 demonstrated higher uptake than [(123)I]8 in DBT tumors 1 h after injection (3.7 ± 0.4% ID/g vs 1.5 ± 0.3% ID/g) and also showed higher uptake vs [(123)I]8 in normal brain. Small animal PET studies with [(76)Br]5 demonstrated good tumor visualization of intracranial DBTs up to 24 h with clearance from normal tissues. These results indicate that [(76)Br]5 is a promising PET tracer for brain tumor imaging and lead compound for a mixed system A and system L transport substrate.


Apoptosis induced in mouse hepatitis virus-infected cells by a virus-specific CD8+ cytotoxic T-lymphocyte clone.
Morphological changes of mouse hepatitis virus-infected J774.1 cells cocultured with cloned mouse hepatitis virus-specific CD8+ cytotoxic T lymphocytes were examined by electron microscopy. Condensation and margination of chromatin, cellular shrinkage with severe vacuolar degeneration, and blebbing were observed. In addition, fragmentation of cellular DNA was observed, and a decrease in virus titer was accompanied by those changes. These findings show that the cloned cytotoxic T lymphocytes induce in the target cell an internal degradation program termed apoptosis, which results in virus clearance.


A quantile regression model for failure-time data with time-dependent covariates.
Since survival data occur over time, often important covariates that we wish to consider also change over time. Such covariates are referred as time-dependent covariates. Quantile regression offers flexible modeling of survival data by allowing the covariates to vary with quantiles. This article provides a novel quantile regression model accommodating time-dependent covariates, for analyzing survival data subject to right censoring. Our simple estimation technique assumes the existence of instrumental variables. In addition, we present a doubly-robust estimator in the sense of Robins and Rotnitzky (1992, Recovery of information and adjustment for dependent censoring using surrogate markers. In: Jewell, N. P., Dietz, K. and Farewell, V. T. (editors), AIDS Epidemiology. Boston: Birkhaäuser, pp. 297-331.). The asymptotic properties of the estimators are rigorously studied. Finite-sample properties are demonstrated by a simulation study. The utility of the proposed methodology is demonstrated using the Stanford heart transplant dataset.


Surrogate decision making: reconciling ethical theory and clinical practice.
The care of adult patients without decision-making abilities is a routine part of medical practice. Decisions for these patients are typically made by surrogates according to a process governed by a hierarchy of 3 distinct decision-making standards: patients' known wishes, substituted judgments, and best interests. Although this framework offers some guidance, it does not readily incorporate many important considerations of patients and families and does not account for the ways in which many patients and surrogates prefer to make decisions. In this article, the authors review the research on surrogate decision making, compare it with normative standards, and offer ways in which the 2 can be reconciled for the patient's benefit.


Identification of the skin basement-membrane autoantigen in epidermolysis bullosa acquisita.
Epidermolysis bullosa acquisita is an acquired chronic blistering disease of the skin, in which separation of the skin occurs in the basement-membrane zone between the epidermis and the dermis. There is evidence that blistering is initiated by an immune process. Using serum samples from nine patients as a source of antibodies, we have identified a major protein of the basement membrane of human skin that serves as the antigen (or target) for autoantibodies in this disorder. This previously unrecognized protein, which consists of two components of 290,000 and 145,000 daltons, is distinct from other known components of the basement membrane. These studies provide evidence that epidermolysis bullosa acquisita is a specific disease that is different from other primary bullous diseases, such as bullous pemphigoid and pemphigus vulgaris, and suggest that the basement-membrane component that has been identified may have a role in normal epidermal-dermal adherence.


Microscopic modes and free energies of 3-phosphoinositide-dependent kinase-1 (PDK1) binding with celecoxib and other inhibitors.
Celecoxib, also known as Celebrex (approved by FDA in 1998) and remembered as the fastest-selling drug in history, was used as a cyclooxygenase-2 (COX-2) selective inhibitor having both anti-inflammatory and anticancer activities. Most recent studies have revealed that the apoptotic activity of celecoxib (and its derivatives) is actually independent of the COX-2 inhibitory activity and that celecoxib also inhibits the kinase activity of 3-phosphoinositide-dependent protein kinase-1 (PDK1), suggesting that the well-known anticancer activity of celecoxib is not due to the inhibition of COX-2, but possibly is due to the inhibition of PDK1. It is highly desirable to develop new celecoxib derivatives as PDK1-specifc inhibitors to avoid the side effects of COX-2 inhibitors. To understand how PDK1 binds with celecoxib and its derivatives, we have performed extensive molecular docking and combined molecular dynamics (MD) simulations and molecular mechanics/Poisson-Boltzmann surface area (MM-PBSA) binding free energy calculations on eight representative PDK1 inhibitors, leading to the finding of a new, more favorable binding mode which is remarkably different from the previously proposed binding mode. Based on the determined most stable binding structures, the calculated binding free energies are all in good agreement with the corresponding experimental data, and the biological activity data available for celecoxib and its derivatives can be better interpreted. The obtained new insights, concerning both the binding mode and computational protocol, will be valuable not only for future rational design of novel, more potent PDK1-specific inhibitors as promising anticancer therapeutics, but also for rational design of drugs targeting other proteins.