Chronic low dose UV exposure and p53 mutation: tilting the odds in early epidermal preneoplasia?
This review addresses how mutation of the TP53 gene (p53) and ultraviolet light alter the behavior of normal progenitor cells in early epidermal preneoplasia. Cancer is thought to evolve from single mutant cells, which expand into clones and ultimately into tumors. While the mutations in malignant lesions have been studied intensively, less is known about the earliest stages of preneoplasia, and how environmental factors may contribute to drive expansion of mutant cell clones. Here we review the evidence that ultraviolet radiation not only creates new mutations but drives the exponential growth of the numerous p53 mutant clones found in chronically exposed epidermis. Published data is reconciled with a new paradigm of epidermal homeostasis which gives insights into the behavior of mutant cells. We also consider the reasons why so few mutant cells progress into tumors and discuss the implications of these findings for cancer prevention.


Determining global mean-first-passage time of random walks on Vicsek fractals using eigenvalues of Laplacian matrices.
The family of Vicsek fractals is one of the most important and frequently studied regular fractal classes, and it is of considerable interest to understand the dynamical processes on this treelike fractal family. In this paper, we investigate discrete random walks on the Vicsek fractals, with the aim to obtain the exact solutions to the global mean-first-passage time (GMFPT), defined as the average of first-passage time (FPT) between two nodes over the whole family of fractals. Based on the known connections between FPTs, effective resistance, and the eigenvalues of graph Laplacian, we determine implicitly the GMFPT of the Vicsek fractals, which is corroborated by numerical results. The obtained closed-form solution shows that the GMFPT approximately grows as a power-law function with system size (number of all nodes), with the exponent lies between 1 and 2. We then provide both the upper bound and lower bound for GMFPT of general trees, and show that the leading behavior of the upper bound is the square of system size and the dominating scaling of the lower bound varies linearly with system size. We also show that the upper bound can be achieved in linear chains and the lower bound can be reached in star graphs. This study provides a comprehensive understanding of random walks on the Vicsek fractals and general treelike networks.


Meeting report: ninth and tenth workshops of the European Paediatric Network for Haemophilia Management (PedNet).
This meeting report presents an overview of the discussions at the ninth and tenth workshops of the European Paediatric Network for Haemophilia Management (PedNet) that occurred in 2005 and 2006. Among numerous topics, a major theme of these workshops was the formation of inhibitors to replacement factor.


Inhibition of DNA repair in cells treated with a combination of alkylating agents.
Aphidicolin (AP) or hydroxyurea (HU) inhibited DNA repair and enhanced cytotoxicity in human ovarian carcinoma cells A2780 treated with L-phenylalanine mustard (L-PAM) combined with cisplatin or thioTEPA, and in the cells treated with cisplatin combined with thioTEPA. In cultures treated with L-PAM or cisplatin alone post-treatment with AP or HU had no effect on DNA repair and produced only additive cytotoxicity. Post-treatment with AP + HU inhibited DNA repair and enhanced cell killing in cultures treated with L-PAM alone. The inhibitor of protein synthesis cycloheximide protected cells from the cytotoxicity of AP + HU but had no effect on synergistic cell killing produced by DNA repair inhibition. In cisplatin-resistant cells A2780/CP post-treatment with AP + HU enhanced the cytotoxicity of L-PAM, but not of cisplatin. However, in resistant cells treated with cisplatin combined with L-PAM or thioTEPA DNA repair inhibitors decreased IC90 of cisplatin. Treatment of cells with two alkylating agents enhanced the sensitivity to DNA repair inhibitors and eliminated low sensitivity to inhibitors of repair associated with drug resistance.


Total occlusion of the common carotid artery with patent internal carotid artery. Identification with color flow Doppler imaging.
With common carotid artery occlusion there is usually no flow in the distal vessels. However, flow to the ipsilateral internal common carotid artery may be maintained by collateral vessels. Nine of 1100 patients referred for carotid duplex sonography were found to have occluded common carotid arteries. Five of these patients had collateral circulation with reconstitution of flow via the external carotid artery. The color Doppler sonograms of three representative patients are presented. There was antegrade flow in the internal carotid artery with retrograde flow in the external carotid artery.


Leaf Polyphenolic Profile as a Determinant of Croatian Native Grapevine Varieties' Susceptibility to Plasmopara viticola.
Since grapevine is highly susceptible to various pathogens, enormous amounts of pesticides are applied each season to achieve profitable production. One of the most destructive grapevine diseases is downy mildew, and their interaction has been in the spotlight for more than a decade. When it comes to a metabolome level, phenolic compounds are relevant to investigate due to their involvement in the plant immune system and known antifungal properties. Croatian grapevine germplasm is highly heterogeneous due to its long history of cultivation in diversified geographical regions. Since it has been found that native varieties react differently to the infection of Plasmopara viticola, the intention of this study is to define if the chemical background of the leaves, i.e., polyphenolic composition, is responsible for these dissimilarities. Therefore, the leaves of 17 genotypes, among which 14 were native and 3 were controls, were analyzed using high-performance liquid chromatography (HPLC) in four terms: before inoculation and 24, 48, and 96 h post inoculation (hpi). During this early phase, significant differences were found neither between the terms nor between the non-inoculated and inoculated samples, except for resveratrol-3-O-glucoside. By applying principal component analysis (PCA) using initial leaf polyphenolic composition, varieties of V. vinifera were clearly separated into three different groups corresponding to their International Organization of Vine and Wine (OIV) classes of susceptibility to P. viticola. Results obtained in this research suggest that the initial constitutive polyphenolic composition of the cultivar leaves has a crucial influence on their susceptibility to P. viticola, and this finding can be used to improve the success of grapevine breeding programs toward downy mildew resistance.


Rethinking the linear regression model for spatial ecological data.
The linear regression model, with its numerous extensions including multivariate ordination, is fundamental to quantitative research in many disciplines. However, spatial or temporal structure in the data may invalidate the regression assumption of independent residuals. Spatial structure at any spatial scale can be modeled flexibly based on a set of uncorrelated component patterns (e.g., Moran's eigenvector maps, MEM) that is derived from the spatial relationships between sampling locations as defined in a spatial weight matrix. Spatial filtering thus addresses spatial autocorrelation in the residuals by adding such component patterns (spatial eigenvectors) as predictors to the regression model. However, space is not an ecologically meaningful predictor, and commonly used tests for selecting significant component patterns do not take into account the specific nature of these variables. This paper proposes "spatial component regression" (SCR) as a new way of integrating the linear regression model with Moran's eigenvector maps. In its unconditioned form, SCR decomposes the relationship between response and predictors by component patterns, whereas conditioned SCR provides an alternative method of spatial filtering, taking into account the statistical properties of component patterns in the design of statistical hypothesis tests. Application to the well-known multivariate mite data set illustrates how SCR may be used to condition for significant residual spatial structure and to identify additional predictors associated with residual spatial structure. Finally, I argue that all variance is spatially structured, hence spatial independence is best characterized by a lack of excess variance at any spatial scale, i.e., spatial white noise.


Induction of class I MHC-restricted, peptide-specific cytolytic T lymphocytes by peptide priming in vivo.
The present study investigated the possibility that protein Ag fragments in the form of peptides could serve as the priming Ag in the generation of a MHC class I-restricted immune response. Trypsin-digested chicken ovalbumin (OVA-TD) fragments were used as the model Ag. The results demonstrate the peptides within OVA-TD, when injected into C57BL/6 mice, could prime T cells which lysed H-2b Ia-EL4 target cells in an OVA-TD-specific manner. In contrast to priming with OVA-TD, immunization of mice with intact OVA did not lead to generation of CTL against OVA-TD or OVA. Furthermore, target cells sensitized with intact OVA failed to be recognized by OVA-peptide-specific CTL indicating that the target cells serving as APC were unable to generate the relevant peptide determinants recognized by the T cells. These results support the idea that the processing pathway within APC for class I-restricted T cells may differ from that used for class II-restricted T cells. Using OVA-TD-specific CTL clones (phenotypically Thy 1+, CD8+, CD4-, Pgp-1+) isolated from primed animals to screen OVA-TD fractions separated by HPLC, two T cell peptide determinants were identified corresponding to OVA sequences 111-122 and 370-381. Both determinants were recognized by CTL clones in the context of the H-2Db molecule.


Evaluation of the Anticancer Activities of the Plant Alkaloids Sanguinarine and Chelerythrine in Human Breast Adenocarcinoma Cells.
Breast cancer is associated with a high mortality rate around the world due to its aggressiveness and high resistance to conventional therapies. Sanguinarine (SAN) and Chelerythrine (CHE) are plant alkaloids extracted from Sanguinaria canadensis and Macleaya cordata, which have been studied for their bioactivities. To determine the anticancer activities of Sanguinarine (SAN) and Chelerythrine (CHE) plant alkaloids. The MTT assay, the alkaline comet assay and cell cycle analyses by flow cytometry were performed. It was observed that SAN was cytotoxic to human breast adenocarcinoma cells (MCF-7) at concentrations of 7.5 µM (24 and 48 hours), effectively reducing cell viability from the concentration of 10 µM for 24 hours and 7.5 µM for 48 hours, by the MTT test. CHE, in turn, was cytotoxic at concentrations of 10 and 20 µM (48 hours), but did not compromise the cellular viability. The comet assay indicated that SAN was genotoxic to the MCF-7 cells, with a significant increment of damage at 10 µM, while none of the tested concentrations of CHE showed a genotoxic effect. The flow cytometry analysis indicated that no cell cycle arrest was caused by both alkaloids, but SAN 10 µM induced a sub-G1 cell population. The results of cytotoxicity, genotoxicity and cell cycle monitoring that are presented in this paper have suggested that SAN has more of a chemotherapeutic activity, as well as having the potential for the development of new therapies for breast cancer, when compared to CHE.


[Indications and outcomes of surgical treatment of gastro-duodenal ulcer in child and adolescent. About 45 cases].
The goal of this study was to determine the indications and assess the results of surgery in the treatment of gastro-duodenal ulcers in children and adolescents. This is a retrospective study of 45 patients operated for duodenal ulcer in Sahloul Teaching Hospital (Susa, Tunisia) over period of 14 years (1988 - 2001). The study is about 41 boys and 4 girls aged between 8 and 18 years (mean age: 15 1/2 years). Surgery was undertaker in cases of bleeding ulcer (9 cases), perforation (26 cases), stenosis (7 cases), resistance to medical treatment (3 cases). The after-effects were mild in 40 cases with an average hospital stay of 6 days. Later after-effects comprised ulcerous relapse (2 cases), stricture of the pyloroplasty (2 cases), an diarrhea follwing vagotomy combined with pyloroplasty in one case. Indications of surgical treatment of gastro-duodenal ulcers in children and adolescents are, nowadays, nearly limited to complicated forms of the illness. Outcomes of surgical treatment are globally satisfactory.


Micropenis: adult follow-up and comparison of size against new norms.
In eight cases of micropenis, the follow-up period was from childhood through adulthood (age range 22 to 31). Topical treatment of the penis with testosterone propionate in childhood increased its size relative to the rest of the body before adolescence. In adolescence and adulthood, the penis with a prior history of treatment with testosterone (N = 5) had no size advantage over the untreated one (N = 3). Topical testosterone postponed the age of developing a coping strategy, but not the necessity of developing one. New data (N = 65) for the stretched length of the adult penis give a M +/- SD of 16.69 +/- 1.90 cm, or 6.57 +/- .75 inches.


[Convulsions in the fifth day of life: a new syndrome?].
Among a series of 98 newborns who experienced neonatal seizures, 20 of them were individualized for they illustrated a "new syndrome": "the seizures of the fifth day of life". These patients were born at term, their maternal and natal history was unremarkable. Seizures always began around the fifth day and most often constituted a real electro-clinical état de mal. EEG reveals alternating sharpened theta waves, a pattern which seems to be characteristic. Some 6 days later, children recovered completely. Further evolution appeared to be always favorable. Although etiological enquiry remained negative, many facts suggested a viral etiology. This syndrome is probably frequent as it was also observed in other neonatal units.


Keratin filaments of mouse epithelial cells are rapidly affected by epidermal growth factor.
The effects of epidermal growth factor (EGF) on the cytokeratin filaments of cultured murine epithelial cells were studied by the indirect immunofluorescence technique with affinity-purified antibodies. Mouse epithelial cells (MMC-E), grown on glass cover slips, and viewed by immunofluorescence microscopy, showed keratin-specific fluorescence as typical bright perinuclear aggregates corresponding to dense paracrystalline granules seen in electron microscopy. Within minutes after an exposure to EGF, the keratin granules in the MMC-E cells decreased. After 10 min of incubation, the cells had spread fibrillar keratin. Such an effect could not be found after a similar exposure to insulin, dexamethasone, dibutyryl cyclic AMP, or antimitotic drugs. EGF, therefore, has a relatively direct effect on the cytoskeletal organization of cultured epithelial cells. These rapid effects on the keratin filaments may explain the simultaneous EGF-induced ultrastructural surface changes of the cells. EGF may thus function as a regulatory factor in the migration of epithelial cells and in the mobility of their cell membranes. The epithelial cell line, MMC-E, should prove a useful model for studies on the action of EGF on nontransformed epithelial cells in vitro.


Medicare Part D: practical practice information for healthcare providers.
To provide an overview of Medicare Part D and useful practice information for healthcare providers to help guide Medicare beneficiaries when choosing a Part D plan. Documents written by the Centers for Medicare & Medicaid Services, Kaiser Family Foundation, and United States Department of Health & Human Services. Although Medicare Part D can provide assistance with prescription drug costs to Medicare beneficiaries, the transition to Medicare Part D in 2006 will be challenging for both beneficiaries and healthcare providers. It is important that both Medicare beneficiaries and healthcare providers understand the complex drug benefit to facilitate the transition to Medicare Part D. It is likely that Medicare Part D formularies will require adjustments to many Medicare beneficiaries' medication regimens. Additionally, it is possible that there will be an increase in the number of prior authorizations and other requirements such as step therapy requests.


How Alligator Immune Peptides Kill Gram-Negative Bacteria: A Lipid-Scrambling, Squeezing, and Extracting Mechanism Revealed by Theoretical Simulations.
Alligator sinensis cathelicidins (As-CATHs) are antimicrobial peptides extracted from alligators that enable alligators to cope with diseases caused by bacterial infections. This study assessed the damaging effects of sequence-truncated and residue-substituted variants of As-CATH4, AS4-1, AS4-5, and AS4-9 (with decreasing charges but increasing hydrophobicity) on the membranes of Gram-negative bacteria at the molecular level by using coarse-grained molecular dynamics simulations. The simulations predicted that all the variants disrupt the structures of the inner membrane of Gram-negative bacteria, with AS4-9 having the highest antibacterial activity that is able to squeeze the membrane and extract lipids from the membrane. However, none of them can disrupt the structure of asymmetric outer membrane of Gram-negative bacteria, which is composed of lipopolysaccharides in the outer leaflet and phospholipids in the inner leaflet. Nonetheless, the adsorption of AS4-9 induces lipid scrambling in the membrane by lowering the free energy of a phospholipid flipping from the inner leaflet up to the outer leaflet. Upon binding onto the lipid-scrambled outer membrane, AS4-9s are predicted to squeeze and extract phospholipids from the membrane, AS4-5s have a weak pull-out effect, and AS4-1s mainly stay free in water without any lipid-extracting function. These findings provide inspiration for the development of potent therapeutic agents targeting bacteria.


The role of APOE on lipid homeostasis and inflammation in normal brains.
The role of APOE in the risk of Alzheimer's disease (AD) has largely focused on its effects on AD pathological processes. However, there are increasing data that APOE genotype affects processes in normal brains. Studies of young cognitively normal humans show effects of APOE genotype on brain structure and activity. Studies of normal APOE knock-in mice show effects of APOE genotype on brain structure, neuronal markers, and behavior. APOE interactions with molecules important for lipid efflux and lipid endocytosis underlie effects of APOE genotype on neuroinflammation and lipoprotein composition. These effects provide important targets for new therapies for reduction of the risk of AD before any signs of pathogenesis.


Surveying.
Several systems for the survey and design for removable partial dentures are based on empiricism and misinformation. Presented here is a systematic approach to the basic requirements for precribing a prosthesis that will be received favorably by the patient.


Association between A/C1166 gene polymorphism of the angiotensin II type 1 receptor and biventricular functions in patients with acute myocardial infarction.
Although there have been several association studies of angiotensin II type 1 receptor (AT1R, A/C1166) gene polymorphism in clinical endpoints such as myocardial infarction (MI), hypertension, aortic stiffness, and left ventricular mass, the relationship between AT1R polymorphism and biventricular function in acute anterior MI has not been studied before. The study group comprised 132 consecutive patients who were admitted to the coronary care unit with their first acute anterior MI. Systolic and diastolic diameters, volumes, inflow properties, ejection fraction and myocardial performance index of both ventricles were measured. AT1R polymorphism was determined using polymerase chain reaction amplification. Based on A/C1166 polymorphism of AT1R, the patients were classified into 3 groups: group 1, A/A (n=91) genotype, group 2 A/C (n=28), and group 3 C/C (n=13) genotype. When the left ventricular and right ventricular echocardiographic functions were compared, all parameters of the 3 groups were found to be similar. No difference was detected in either the genotype distribution or allele frequencies between the patients and the controls for AT1R. The results suggest that A/C1166 polymorphism of AT1R did not influence the risk of either acute MI or biventricular function after anterior MI.


Does Whom Patients Sit Next to during Hemodialysis Affect Whether They Request a Living Donation?
The seating arrangement of in-center hemodialysis is conducive to patients forming a relationship and a social network. We examined how seating in the in-center hemodialysis clinic affected patients forming relationships, whether patients formed relationships with others who have similar transplant behaviors (homophily), and whether these relationships influenced patients (social contagion) to request a living donation from family and friends outside of the clinic. In this 30-month, prospective cohort study, we observed the relationships of 46 patients on hemodialysis in a hemodialysis clinic. Repeated participant surveys assessed in-center transplant discussions and living-donor requests. A separable temporal exponential random graph model estimated how seating, demographics, in-center transplant discussions, and living-donor requests affected relationship formation via sociality and homophily. We examined whether donation requests spread via social contagion using a susceptibility-infected model. For every seat apart, the odds of participants forming a relationship decreased (OR, 0.74; 95% CI, 0.61 to 0.90; P=0.002). Those who requested a living donation tended to form relationships more than those who did not (sociality, OR, 1.6; 95% CI, 1.02 to 2.6; P=0.04). Participants who discussed transplantation in the center were more likely to form a relationship with another participant who discussed transplantation than with someone who did not discuss transplantation (homophily, OR, 1.9; 95% CI, 1.03 to 3.5; P=0.04). Five of the 36 susceptible participants made a request after forming a relationship with another patient. Participants formed relationships with those they sat next to and had similar transplant behaviors. The observed increase in in-center transplant discussions and living-donation requests by the members of the hemodialysis-clinic social network was not because of social contagion. Instead, participants who requested a living donation were more social, formed more relationships within the clinic, and discussed transplantation with each other as a function of health-behavior homophily.


Combined Genetic Biomarkers Confer Susceptibility to Risk of Urothelial Bladder Carcinoma in a Saudi Population.
We evaluated the associations between seven single nucleotide polymorphisms and susceptibility to urothelial bladder carcinoma (UBC) in a Saudi population. Genomic DNA was taken from buccal cells of 52 patients with UBC and 104 controls for genotyping of GSTT1, GSTM1, rs4646903, rs1048943, TP53 rs1042522, rs1801133, and rs1801394 using PCR and TaqMan® assays. The rs1801133 and rs1801394 variants showed strong associations with UBC (OR = 2.3, P = 0.0002; OR = 2.6, P = 0.0001, resp.). Homozygosity of Pro72 conferred a significant double risk in cases compared with controls (30.8% versus 15.4%), but the homozygote Arg/Arg had no effect on risk. Genotypic combinations of GSTM1/GSTT1, rs4646903/rs1048943, and rs1801133/rs1801394 exhibited significant linkage with the disease (χ2 = 10.3, P = 0.006; χ2 = 13.9, P = 0.003; and χ2 = 20.4, P = 0.0004, resp.). The GSTM1 and rs1042522Arg and rs1801394G variant alleles were more frequent in current smokers with UBC (52.4%, 52.5%, and 64.3%, resp.) than were the corresponding wild-types. Despite some variants having only a slight effect on UBC risk, the interaction effect of combined genetic biomarkers-or even the presence of one copy of a variant allele-is potentially much greater. Perhaps more studies regarding next-generation genetic sequencing and its utility can add to the risk of UBC.


Huprine X Attenuates The Neurotoxicity Induced by Kainic Acid, Especially Brain Inflammation.
Huprine X (HX) is a synthetic anticholinesterasic compound that exerts a potent inhibitory action on acetylcholinesterase (AChE) activity, an agonist effect on cholinergic receptors, neuroprotective activity in different neurotoxicity models in vivo and in vitro and cognition enhancing effects in non-transgenic (C57BL/6) and transgenic (3xTg-AD, APPswe) mice. In this study, we assessed the ability of HX (0.8 mg/kg, 21 days) to prevent the damage induced by kainic acid (KA; 28 mg/kg) regarding apoptosis, glia reactivity and neurogenesis in mouse brain. KA administration significantly modified the levels of pAkt1, Bcl2, pGSK3β, p25/p35, increased the glial cell markers and reduced the neurogenesis process. We also observed that pre-treatment with HX significantly reduced the p25/p35 ratio and increased synaptophysin levels, which suggests a protective effect against apoptosis and an improvement of neuroplasticity. The increase in GFAP (88%) and Iba-1 (72%) induced by KA was totally prevented by HX pre-treatment, underlying a relevant anti-inflammatory action of the anticholinesterasic drug. Our findings highlight the potential of HX, in particular, and of AChEIs, in general, to treat a number of diseases that course with both cognitive deficits and chronic inflammatory processes.


Facial Mucosal Level Change Following Maxillary Anterior Single Immediate Tooth Replacement in Extraction Sockets With Facial Bone Wall Defects: A 4- to 15-Year Retrospective Study.
An intact extraction socket has been considered a prerequisite for an immediate implant placement and provisionalization (IIPP) procedure. Recent studies, however, have shown successful outcomes when IIPP was performed in sockets with a facial bone wall defect. This retrospective study evaluated the facial implant mucosal stability following IIPP in extraction sockets with a facial bone wall defect in the esthetic zone. The study included 16 cases in 16 patients who received maxillary anterior single IIPP with contour bone graft (C-BG) and contour connective tissue graft (C-CTG) in compromised extraction sockets (V- or U-shaped defect). After a mean follow-up of 6 years, the implant success rate was 100% (16/16). Minimal and non-statistically significant changes were noted in the facial implant mucosal and marginal bone level. Statistically significant changes were observed in facial implant mucosal thickness gain (2.5 mm [1.8 mm to 3.5 mm]) and midfacial bone sounding reduction (6 mm). Within the confines of this study, IIPP with simultaneous C-BG and C-CTG in fresh extraction sockets exhibiting a V- or U-shaped facial bone wall defect can lead to long-term successful outcomes in terms of mucosal stability, contour bone gain, and marginal bone level stability.


Altered Vascular Permeability in Migraine-associated Brain Regions: Evaluation with Dynamic Contrast-enhanced MRI.
Background Recent studies showed the possible association between inflammation-induced blood-brain barrier (BBB) structural changes followed by greater permeability of the BBB and chronic pain. Thus, measurement of BBB breakdown would be a valuable aid in the diagnosis in migraine. Dynamic contrast material-enhanced (DCE) MRI can determine perfusion and permeability properties related to the BBB. Purpose To evaluate the relationship between permeability of the BBB in migraine-associated brain regions by using DCE MRI. Materials and Methods In this prospective study, from September 2016 to December 2017, 56 study participants underwent DCE MRI after gadobutrol administration and were classified into migraine (n = 35) and healthy control (n = 21) groups. Automatic volumetric segmentation was performed on the pre-contrast-enhanced T1-weighted images by using FreeSurfer, and migraine-associated brain region masks were extracted by using the software NordicICE. The corresponding maps for pharmacokinetic parameters Ktrans (the volume transfer constant) and Vp (the fractional plasma volume) were coregistered with the region-of-interest masks, and their mean values of corresponding total volume of interest were calculated. For comparison analyses, the Mann-Whitney tests were used. Receiver operating characteristic curve analysis and Spearman rank correlation tests were used to identify correlations between clinical characteristics and the aforementioned perfusion parameters. Results Mean age was younger in the migraine group (mean ± standard deviation, 57 years ± 12) than in the healthy control group (mean, 71 years ± 8) (P < .001). In the migraine group, the mean value of Vp in the left amygdala (median, 0.27 mL/100 g) was lower than that in the healthy control group (median, 0.39 mL/100 g) (P = .04). The mean value of Vp in the left amygdala was correlated with the intensity of headache attack in participants with migraine (correlation coefficient, -0.34; P = .04). Conclusion Lower fractional plasma volume in the left amygdala was observed in participants with migraine than in healthy participants. © RSNA, 2019 Online supplemental material is available for this article. See also the editorial by Carroll and Ginat in this issue.


Is heart failure misdiagnosed in hospitalized patients with preserved ejection fraction? From the European Society of Cardiology - Heart Failure Association EURObservational Research Programme Heart Failure Long-Term Registry.
In hospitalized patients with a clinical diagnosis of acute heart failure (HF) with preserved ejection fraction (HFpEF), the aims of this study were (i) to assess the proportion meeting the 2016 European Society of Cardiology (ESC) HFpEF criteria and (ii) to compare patients with restrictive/pseudonormal mitral inflow pattern (MIP) vs. patients with MIP other than restrictive/pseudonormal. We included hospitalized participants of the ESC-Heart Failure Association (HFA) EURObservational Research Programme (EORP) HF Long-Term Registry who had echocardiogram with ejection fraction (EF) ≥ 50% during index hospitalization. As no data on e', E/e' and left ventricular (LV) mass index were gathered in the registry, the 2016 ESC HFpEF definition was modified as follows: elevated B-type natriuretic peptide (BNP) (≥100 pg/mL for acute HF) and/or N-terminal pro-BNP (≥300 pg/mL) and at least one of the echocardiographic criteria: (i) presence of LV hypertrophy (yes/no), (ii) left atrial volume index (LAVI) of >34 mL/m2 ), or (iii) restrictive/pseudonormal MIP. Next, all patients were divided into four groups: (i) patients with restrictive/pseudonormal MIP on echocardiography [i.e. with presumably elevated left atrial (LA) pressure], (ii) patients with MIP other than restrictive/pseudonormal (i.e. with presumably normal LA pressure), (iii) atrial fibrillation (AF) group, and (iv) 'grey area' (no consistent description of MIP despite no report of AF). Of 6365 hospitalized patients, 1848 (29%) had EF ≥ 50%. Natriuretic peptides were assessed in 28%, LV hypertrophy in 92%, LAVI in 13%, and MIP in 67%. The 2016 ESC HFpEF criteria could be assessed in 27% of the 1848 patients and, if assessed, were met in 52%. Of the 1848 patients, 19% had restrictive/pseudonormal MIP, 43% had MIP other than restrictive/pseudonormal, 18% had AF and 20% were grey area. There were no differences in long-term all-cause or cardiovascular mortality, or all-cause hospitalizations or HF rehospitalizations between the four groups. Despite fewer non-cardiac comorbidities reported at baseline, patients with MIP other than restrictive/pseudonormal (i.e. with presumably normal LA pressure) had more non-cardiovascular (14.0 vs. 6.7 per 100 patient-years, P < 0.001) and cardiovascular non-HF (13.2 vs. 8.0 per 100 patient-years, P = 0.016) hospitalizations in long-term follow-up than patients with restrictive/pseudonormal MIP. Acute HFpEF diagnosis could be assessed (based on the 2016 ESC criteria) in only a quarter of patients and confirmed in half of these. When assessed, only one in three patients had restrictive/pseudonormal MIP suggestive of elevated LA pressure. Patients with MIP other than restrictive/pseudonormal (suggestive of normal LA pressure) could have been misdiagnosed with acute HFpEF or had echocardiography performed after normalization of LA pressure. They were more often hospitalized for non-HF reasons during follow-up. Symptoms suggestive of acute HFpEF may in some patients represent non-HF comorbidities.


His-FLAG Tag as a Fusion Partner of Glycosylated Human Interferon-Gamma and Its Mutant: Gain or Loss?
In order to obtain glycosylated human interferon-gamma (hIFNγ) and its highly prone to aggregation mutant K88Q, a secretory expression in insect cells was employed. To facilitate recombinant proteins purification, detection, and stability the baculovirus expression vectors were constructed to bear N-terminal His6-FLAG tag. Although the obtained proteins were glycosylated, we found that their biological activity was 100 times lower than expected. Our attempts to recover the biological properties of both proteins by tag removal failed due to enterokinase resistance of the tag. Surprisingly, the tag was easily cleaved when the proteins were expressed in E. coli cells and the tag-free proteins showed fully restored activity. To shed light on this phenomenon we performed molecular dynamics simulations. The latter showed that the tags interact with the receptor binding domains and the flexible C-termini of the fusion proteins thus suppressing their complex formation with the hIFNγ receptor. We hypothesize that in the case of glycosylated proteins the tag/C-terminal interaction positions the FLAG peptide in close proximity to the glycans thus sterically impeding the enterokinase access to its recognition site.


Work related etiology of amyotrophic lateral sclerosis (ALS): a meta-analysis.
The aim of this meta-analysis was to evaluate the association between ALS and occupational exposure to physical (ELF-EMF) and chemicals (solvents, heavy metals and pesticides) agents. We considered articles published from 1980 up to April 2013; in total, 750 publications were evaluated. The studies had to satisfy the following criteria: 1) cohort or case-control studies; 2) the presence of individual exposures; 3) clinical diagnosis of sporadic ALS or sporadic ALS on the death certificate. We followed the evaluation of quality in two steps. The first step classified studies according to a rating system based on a mix of criteria developed by scientific organizations, especially developed for studies of risk factors for ALS. The ratings obtained range from I (highest) to V (lowest). The data on risk factors derived from studies with Armon ratings of I, II, and III can reach levels of evidence A (established risk factor), B (likely risk factor), or C (possible risk factor). The second step evaluated the exposure and a score from 1 to 4 was assigned to each item; an exposure with a score of 3 or 4 was considered sufficient. Different analyses were performed on ALS and exposure to metals, solvents, pesticides and electromagnetic fields. In our study the heterogeneity was assessed both by χ2-based Q-tests and through the index of inconsistency I² while the measure RR/OR and CI of 95% to estimate the relationship between ALS and the various considered risk factors was employed. The association between exposure to pesticides and ALS as a whole is weak and not significant. With regard to the results of individual studies the following critical synthesis can be reported: 1) the selected studies showed a low level of association between ALS and electromagnetic fields; 2) as regards the solvents, the association with ALS in some studies is combined with a slightly increased risk, particularly in women, and in others a slight but significant linear association is observed; 3) for the metals, in some cases there was a stronger association in women than in men; for individual metals, there was an association especially with chromium and lead; 4) lastly, with regard to the products of agricultural pesticides in general, there was an association with ALS in men but not in women, with a dose-response relationship. The lack of statistically significant association between occupational exposure and ALS is mainly due to the methodological diversity of the studies and the lack of prospective studies at the workplace.


Whenis category learning holistic?
Ward and Scott (1987) recently provided evidence consistent with the idea that category learning can occur analytically whether that learning takes place under intentional or incidental conditions and whether the learner is an adult or a young child. Kemler Nelson (1988) raised concerns about Ward and Scott's conclusions as well as about the logic of some of their arguments. Kemler Nelson also attempted to strengthen the argument that incidental learning conditions induce a less strategic approach to tasks, which necessarily results in a holistic mode of processing. The present paper answers Kemler Nelson's concerns. It also presents arguments in favor of the idea that incidental learning is neither necessarily holistic nor necessarily analytic. It is argued that tasks, whether intentional or incidental, encourage the participant to process particular types of information. If the task encourages or demands the processing of separate features, then that type of information will be stored whether or not the participant was explicitly asked to learn the category membership of presented items. There are varieties of both intentional and incidental category learning, and what the learner does with the presented material is more important than his/her intent to learn. Furthermore, it is argued that the apparently discrepant results discussed by Kemler Nelson and Ward and Scott are all interpretable as specific cases within a more general episodic trace model of processing.


The effects of speed of injection on induction with propofol. A comparison with etomidate.
One hundred and eighty female patients received either propofol 2.5 mg/kg or etomidate 0.3 mg/kg injected over 20, 40 or 80 seconds for induction of anaesthesia after premedication with temazepam 20 mg. The mean induction times for both etomidate and propofol were significantly reduced with increasing speed of injection. The mean induction times for etomidate were significantly less than propofol at the slower rates of injection. At each speed of injection, the decrease in systolic, mean and diastolic arterial blood pressures with etomidate were less than with propofol. The decrease in systolic blood pressure was not significantly affected by injection speed for either drug. Apnoea occurred significantly more frequently with propofol than with etomidate at each speed of injection and the incidence of apnoea greater than 60 seconds with propofol was significantly higher when injected over 20 seconds than 80 seconds. The incidence of pain on injection was unaffected by injection speed for either drug. The incidence of myoclonus and (or) hypertonus was significantly higher following etomidate.


[Fractures of the lower leg treated with the Ilizarov method].
We had 32 patients with leg's fractures treated by Ilizarov method. These of fractures were multifragmentar, unstabily and open fractures with Decolman of soft tissue. Four cases were without damage of skin. 28 patients were with damage of skin. 21 patients had plastic-surgical treatment. Fractures were treated bz Ilizarov method with four of two rings. Treatment were finished in all cases during of period of 6 months to 10 months. Age of these patients were between 30 to 85 years.


Experimental and theoretical study of reactivity trends for methanol on Co/Pt(111) and Ni/Pt(111) bimetallic surfaces.
Methanol was used as a probe molecule to examine the reforming activity of oxygenates on NiPt(111) and CoPt(111) bimetallic surfaces, utilizing density functional theory (DFT) modeling, temperature-programmed desorption, and high-resolution electron energy loss spectroscopy (HREELS). DFT results revealed a correlation between the methanol and methoxy binding energies and the surface d-band center of various NiPt(111) and CoPt(111) bimetallic surfaces. Consistent with DFT predictions, increased production of H2 and CO from methanol was observed on a Ni surface monolayer on Pt(111), designated as Ni-Pt-Pt(111), as compared to the subsurface monolayer Pt-Ni-Pt(111) surface. HREELS was used to verify the presence and subsequent decomposition of methoxy intermediates on NiPt(111) and CoPt(111) bimetallic surfaces. On Ni-Pt-Pt(111) the methoxy species decomposed to a formaldehyde intermediate below 300 K; this species reacted at approximately 300 K to form CO and H2. On Co-Pt-Pt(111), methoxy was stable up to approximately 350 K and decomposed to form CO and H2. Overall, trends in methanol reactivity on NiPt(111) bimetallic surfaces were similar to those previously determined for ethanol and ethylene glycol.


Replication and fine-mapping of genetic predictors of lipid traits in African-Americans.
Circulating lipid concentrations are among the strongest modifiable risk factors for coronary artery disease (CAD). Most genetic studies have focused on Caucasian populations with little information available for populations of African ancestry. Using a cohort of ~2800 African-Americans (AAs) from a biobank at Vanderbilt University (BioVU), we sought to trans-ethnically replicate genetic variants reported by the Global Lipids Genetics Consortium to be associated with lipid traits in Caucasians, followed by fine-mapping those loci using all available variants on the MetaboChip. In AAs, we replicated one of 56 SNPs for total cholesterol (TC) (rs6511720 in LDLR, P=2.15 × 10-8), one of 63 SNPs for high-density lipoprotein cholesterol (HDL-C) (rs3764261 in CETP, P=1.13 × 10-5), two of 46 SNPs for low-density lipoprotein cholesterol (LDL-C) (rs629301 in CELSR2/SORT1, P=1.11 × 10-5 and rs6511720 in LDLR, P=2.47 × 10-5) and one of 34 SNPs for TG (rs645040 in MSL2L1, P=4.29 × 10-4). Using all available variants on MetaboChip for fine mapping, we identified additional variants associated with TC (APOE), HDL-C (LPL and CETP) and LDL-C (APOE). Furthermore, we identified two loci significantly associated with non-HDL-C: APOE/APOC1/TOMM40 and PCSK9. In conclusion, the genetic architecture of lipid traits in AAs differs substantially from that in Caucasians and it remains poorly characterized.


In vitro activity of heather [Calluna vulgaris (L.) Hull] extracts on selected urinary tract pathogens.
Calluna vulgaris L. Hull (Ericaceae) has been used for treatment of urinary tract infections in traditional medicine. In this study we analyzed in vitro antibacterial activity of the plant extracts on different strains of Escherichia coli, Enterococcus faecalis and Proteus vulgaris, as well as the concentrations of total phenols and flavonoids in the extracts. Minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) were determined. The concentrations of total phenols were examined by using Folin-Ciocalteu reagent and ranged between 67.55 to 142.46 mg GAE/g. The concentrations of flavonoids in extracts were determined using spectrophotometric method with aluminum chloride and the values ranged from 42.11 to 63.68 mg RUE/g. The aqueous extract of C. vulgaris showed a significant antibacterial activity. The values of MIC were in the range from 2.5 mg/ml to 20 mg/ml for this extract. Proteus vulgaris strains were found to be the most sensitive. The results obtained suggest that all tested extracts of C. vulgaris inhibit the growth of human pathogens, especially the aqueous extract.


A proposed set of new guidelines for routine blood tests during isotretinoin therapy for acne vulgaris.
Isotretinoin has been proven to be an effective treatment for acne vulgaris. The enclosed package insert with isotretinoin suggests weekly/biweekly laboratory testing (hepatic functions and lipid analysis) but fails to recommend the needed action levels for abnormalities. We provide a statistical analysis of a retrospective study of 141 individuals' course of therapy on isotretinoin and their laboratory blood analysis results. Very few statistically significant elevations in liver enzymes or lipid profiles occurred. More importantly, in only 1 case did these elevations warrant the discontinuation of therapy. The data presented here support the conclusion that limited blood testing should be performed for most patients and that more complete blood testing be done only for those patients with a significant response in liver enzymes, cholesterol or triglycerides. A set of guidelines is proposed for the practicing physician to interpret blood test results.


Why Semmelweis's doctrine was rejected: evidence from the first publication of his results by Friedrich Wieger, and an editorial commenting on the results.
We present English translations of two French documents to show that the main reason for the rejection of Semmelweis's theory of the cause of childbed (puerperal) fever was because his proof relied on the post hoc ergo propter hoc fallacy, and not because Joseph Skoda referred only to cadaveric particles as the cause in his lecture to the Academy of Science on Semmelweis's discovery. Friedrich Wieger (1821-1890), an obstetrician from Strasbourg, published an accurate account of Semmelweis's theory six months before Skoda's lecture, and reported a case in which the causative agent originated from a source other than cadavers. Wieger also presented data showing that chlorine hand disinfection reduced the annual maternal mortality rate from childbed fever (MMR) from more than 7 per cent for the years 1840-1846 to 1.27 per cent in 1848, the first full year in which chlorine hand disinfection was practised. But an editorial in the Gazette médicale de Paris rejected the data as proof of the effectiveness of chlorine hand disinfection, stating that the fact that the MMR fell after chlorine hand disinfection was implemented did not mean that this innovation had caused the MMR to fall. This previously unrecognized objection to Semmelweis's proof was also the reason why Semmelweis's chief rejected Semmelweis's evidence.


Notions of quality and standards for qualitative research reporting.
The utility of qualitative research findings in the health sciences has been the subject of considerable debate, particularly with the advent of qualitative systematic reviews in recent years. There has been a significant investment in the production of guidance to improve the reporting of quantitative research; however, comparatively little time has been spent on developing the same for qualitative research reporting. This paper sets out to examine the possibility of developing a framework for refereed journals to utilize when guiding authors on how to report the results of qualitative studies in the hope that this will improve the quality of reports and subsequently their inclusion in qualitative syntheses and guidelines to inform practice at the point of care.


Three-Dimensional Computer-Aided Detection of Microcalcification Clusters in Digital Breast Tomosynthesis.
We propose computer-aided detection (CADe) algorithm for microcalcification (MC) clusters in reconstructed digital breast tomosynthesis (DBT) images. The algorithm consists of prescreening, MC detection, clustering, and false-positive (FP) reduction steps. The DBT images containing the MC-like objects were enhanced by a multiscale Hessian-based three-dimensional (3D) objectness response function and a connected-component segmentation method was applied to extract the cluster seed objects as potential clustering centers of MCs. Secondly, a signal-to-noise ratio (SNR) enhanced image was also generated to detect the individual MC candidates and prescreen the MC-like objects. Each cluster seed candidate was prescreened by counting neighboring individual MC candidates nearby the cluster seed object according to several microcalcification clustering criteria. As a second step, we introduced bounding boxes for the accepted seed candidate, clustered all the overlapping cubes, and examined. After the FP reduction step, the average number of FPs per case was estimated to be 2.47 per DBT volume with a sensitivity of 83.3%.


Proteomics INTegrator (PINT): An Online Tool To Store, Query, and Visualize Large Proteomics Experiment Results.
The characterization of complex biological systems based on high-throughput protein quantification through mass spectrometry commonly involves differential expression analysis between replicate samples originating from different experimental conditions. Here we present Proteomics INTegrator (PINT), a new user-friendly Web-based platform-independent system to store, visualize, and query proteomics experiment results. PINT provides an extremely flexible query interface that allows advanced Boolean algebra-based data filtering of many different proteomics features such as confidence values, abundance levels or ratios, data set overlaps, sample characteristics, as well as UniProtKB annotations, which are transparently incorporated into the system. In addition, PINT allows developers to incorporate data visualization and analysis tools, such as PSEA-Quant and Reactome pathway analysis, for data set enrichment analysis. PINT serves as a centralized hub for large-scale proteomics data and as a platform for data analysis, facilitating the interpretation of proteomics results and expediting biologically relevant conclusions.


Circulating tumour DNA in the evolving treatment landscape of locally advanced rectal cancer: where does it fit in?
The management of locally advanced rectal cancer (LARC) requires multimodality treatment, typically with neoadjuvant chemoradiotherapy (CRT) followed by total mesorectal excision. However, the treatment landscape is rapidly evolving with total neoadjuvant therapy and non-operative management for selected patients emerging as other novel treatment approaches. With so many treatment options, there is a need for biomarkers to direct a more personalised treatment strategy for patients with LARC. In this review, we summarise the available data regarding the use of circulating tumour DNA (ctDNA) in patients with LARC, as both a marker of treatment response to neoadjuvant therapy and as a marker of minimal residual disease (MRD) after patients have completed definitive local treatment. To date, the ability of ctDNA status to predict for pathologic complete response at any timepoint during multimodality treatment has been variably reported. The most consistent finding across available studies is the ability of ctDNA to detect MRD after CRT and surgery, the presence of which confers a significantly poor prognosis, with increased risk of cancer recurrence and worse overall survival. It is yet to be determined if providing additional therapies to patients with MRD improves outcomes. The available studies assessing the potential utility of ctDNA in LARC are limited by significant heterogeneity in the choice of ctDNA assay, timepoint at which ctDNA was collected, treatment that patients received and length of follow-up, leading to uncertainties about how to implement it into daily clinical practice. As the treatment landscape evolves, larger randomised trials assessing the role of ctDNA in LARC are needed.


Increased risk in esophageal obstruction with slow-release medications.
Although medication-induced (pill) esophagitis has been recognized for a long time, little data are available on the risk of recently introduced slow-release medications. These formulations may have an obstructive capability (undissolved medication blocking an obstructed lumen) or may cause tissue irritation (continuous leakage from a slowly disintegrating pill). We observed a patient with esophageal carcinoma who developed complete obstruction when three Procardia XL (nifedipine) extended-release tablets blocked the narrowed lumen. An intact Procardia XL tablet and a washed shell as a control were implanted subcutaneously in a rat. The intact pill produced a large inflammatory mass: in contrast, no inflammatory response was noted at the control site implanted with a washed shell. In vitro testing of seven different slow-release medications revealed a wide difference in their solubility at a neutral pH and in gastric juice of pH 1.8 (simulation of esophageal or gastric environment). Theolair-SR (anhydrous theophylline, sustained-release) tablets had the highest obstructive, but no irritating potential. Cardizem SR (diltiazem hydrochloride) sustained-release capsules dissolved promptly without obstructive potential. Adalat CC (nifedipine) extended-release tablets also dissolved early at both pH values. Cardizem CD (diltiazem hydrochloride) extended-release capsules and Calan SR (verapamil hydrochloride) sustained-release oral caplets disintegrated into granules that had a low obstructive potential, but their prolonged presence increased the risk of tissue irritation. Ecotrin (enteric-coated aspirin) tablets had a high obstructive and no irritating potential in the first 24 hours, after which they disintegrated and directly contacted the tissue. Procardia XL extended-release tablets had an insoluble shell that continued to leak a tissue-irritating content even after 48 hours, generating a prolonged obstructive and irritating condition. In conclusion, slow-release medications greatly increase the risk of esophageal injury. Their obstructive and tissue-irritating potentials differ widely. Slow-release formulations should be contraindicated in patients who have obstructive esophageal and gastric disorders.


Large osteochondral fractures of the lateral femoral condyle in the adolescent: outcome of bioabsorbable pin fixation.
Large osteochondral fractures of the lateral femoral condyle of the knee in adolescent patients can be diagnostically and therapeutically challenging. Historically, management has involved removal of the fragment, leaving a large area of bone devoid of articular cartilage on the weight-bearing surface of the lateral femoral condyle. This study assessed open reduction and internal fixation of the osteochondral fragments with use of multiple polyglycolic acid rods. Eight patients, between twelve and fifteen years old, with a large (>4 cm(2)) osteochondral fracture of the lateral femoral condyle were treated with open reduction and internal fixation with use of multiple polyglycolic acid rods. Each patient was evaluated at more than five years (a mean of nine years) after the index procedure with a clinical assessment, during which the knee was scored according to the International Knee Documentation Committee and Cincinnati knee rating systems, plain radiographs were made, and magnetic resonance imaging scans were acquired. The majority of patients scored well on both knee rating systems, with no poor results. Five of the eight patients had normal findings on knee radiographs, and three had radiographs that showed minor changes. Magnetic resonance imaging scans of all patients demonstrated intact articular cartilage in the lateral compartment with no area of full-thickness articular cartilage loss. No evidence of articular cartilage thinning was seen in two knees; a small area of <2 cm(2) of cartilage thinning, in four; a moderate area of 2.7 cm(2) of cartilage thinning, in one; and a large area of 11.2 cm(2) of abnormal cartilage signal, in one knee. Osteochondral fracture of the lateral femoral condyle is an injury to which adolescents with ligamentous laxity of the knee are prone. Our results show that internal fixation of these osteochondral fragments with bioabsorbable implants is possible and is a worthwhile option.


Functional domains of the CD11a adhesion molecule in lymphokine activated killer (LAK)-mediated cytolysis.
To study the functional role of the CD11a cell surface molecule in antigen nonspecific cytolysis, a homogenous population of human lymphokine activated killer (LAK) cells were obtained after more than two months of culture in recombinant interleukin-2 (IL-2). Dual parameter immunofluorescence analysis demonstrated that LAK cells from long-term cultures were predominantly CD3+ and CD8+ cells. Monoclonal antibodies (MAb) to six function-associated cell surface molecules were used to inhibit the LAK-target cell interaction. MAb inhibition indicated that the CD11a was involved in the LAK-target cell interaction. None of the other function-associated MAb inhibited killing. A panel of MAb to both the alpha and beta subunits of the CD11a molecule confirmed the anti-CD11a inhibition and demonstrated a hierarchy of functional epitopes. The dominant utilization of CD11a did not appear to depend on IL-2 induction of CD11a surface expression. CD11a surface expression on CD3+ cells did not increase after incubation with IL-2 or other mediators. These findings indicate that CD11a is an important regulatory molecule in LAK-target cell interactions and may play a role in the ability of LAK cells to effectively interact with potential target cells.


Increasing Prevalence of Allergic Rhinitis in China.
Allergic rhinitis (AR) is a critical public health, medical and economic problem in China. AR is also an important risk factor which will cause many diseases or disorders, especially in children. The trend of AR incidence is still on the rise in recent years and has had a significant effect on the general public. This significant increase is alarming, which highlights an urgent need for better understanding of the prevalence status and characteristics, sensitization patterns, and the associated risk factors of AR in order to improve treatment and develop effective prevention strategies.


Pancreatic infiltration but not diabetes occurs in the relative absence of MHC class II-restricted CD4 T cells: studies using NOD/CIITA-deficient mice.
The NOD (nonobese diabetic) mouse is a good animal model for human IDDM. MHC class II-restricted CD4 T cells are necessary for the onset of diabetes in NOD mice. Here, we demonstrate that NOD mice lacking the CIITA (class II transactivator) molecule, and hence deficient in MHC class II expression and peripheral CD4 T cells, show significant pancreatic infiltration but do not develop diabetes. CD4 T cell deficiency, then, does not prevent initial pancreatic infiltration, but does stop progression to insulitis. Adoptive transfer studies show that the paucity of CD4 T cells in NOD-CIITA knockout mice is responsible for the absence of diabetes, since the CD8 T cell and B cell compartments are functional. An autoaggressive CD8+ T cell clone can, however, transfer diabetes in CIITA knockout recipient mice without CD4 T cell help, albeit with some delay compared with that in CIITA-sufficient recipients. This highlights the fact that a high number of in vitro activated autoaggressive CD8 T cells can over-ride the requirement for CD4 T cell help for the onset of diabetes.


[Intrahepatic cholangiocarcinoma on a hydatidic cyst].
Cholangiocarcinomas are malignant tumors arising from the bile ducts. One of the factors associated with the development of malignancy is parasitic infections by helminths trematodes that cause liver fluke infections. This association is very common in south-east Asia, but association with liver hydatidosis has not been reported in the scientific literature. We report a case in which these two diseases were associated and required non-radical surgical treatment, since radiological findings were not suspicious for these entities.


VTA CRF neurons mediate the aversive effects of nicotine withdrawal and promote intake escalation.
Dopaminergic neurons in the ventral tegmental area (VTA) are well known for mediating the positive reinforcing effects of drugs of abuse. Here we identify in rodents and humans a population of VTA dopaminergic neurons expressing corticotropin-releasing factor (CRF). We provide further evidence in rodents that chronic nicotine exposure upregulates Crh mRNA (encoding CRF) in dopaminergic neurons of the posterior VTA, activates local CRF1 receptors and blocks nicotine-induced activation of transient GABAergic input to dopaminergic neurons. Local downregulation of Crh mRNA and specific pharmacological blockade of CRF1 receptors in the VTA reversed the effect of nicotine on GABAergic input to dopaminergic neurons, prevented the aversive effects of nicotine withdrawal and limited the escalation of nicotine intake. These results link the brain reward and stress systems in the same brain region to signaling of the negative motivational effects of nicotine withdrawal.


The importance of wellness among users of complementary and alternative medicine: findings from the 2007 National Health Interview Survey.
This study developed and tested a sociobehavioral wellness model of complementary and alternative medicine (CAM) to differentiate predisposing factors, enabling resources, need, and personal health practices according to use for wellness, for combined wellness and treatment, or for treatment alone. Data were from the 2007 National Health Interview Survey (NHIS), a cross-sectional, nationally representative sample of 23,393 adult Americans. This analysis included people who used at least one CAM modality in the past 12 months (n = 7003 adult users). Prevalence estimates and multinomial logistic regression results were weighted and adjusted for complex sample design. Overall, 86 % of CAM users reported reason for use as wellness (51 %) or wellness combined with treatment (35 %). White women had the lowest (48 %) and Asian men (66 %) had the highest wellness use. Compared to treatment only users, wellness users were significantly more likely to be older, more educated, in better health, and engaged in multiple healthy behaviors. There was support that those with health conditions were using methods for both treatment and to maintain health. The findings underscore the central role of CAM in health self-management and wellness lifestyle. At a time of national health care reform highlighting the importance of health and wellness and employers turning to wellness programs to improve worker performance and well-being, these findings suggest a central role of CAM in those public health endeavors.


The Ty1 integrase protein can exploit the classical nuclear protein import machinery for entry into the nucleus.
Like its retroviral relatives, the long terminal repeat retrotransposon Ty1 in the yeast Saccharomyces cerevisiae must traverse a permanently intact nuclear membrane for successful transposition and replication. For retrotransposition to occur, at least a subset of Ty1 proteins, including the Ty1 integrase, must enter the nucleus. Nuclear localization of integrase is dependent upon a C-terminal nuclear targeting sequence. However, the nuclear import machinery that recognizes this nuclear targeting signal has not been defined. We investigated the mechanism by which Ty1 integrase gains access to nuclear DNA as a model for how other retroelements, including retroviruses like HIV, may utilize cellular nuclear transport machinery to import their essential nuclear proteins. We show that Ty1 retrotransposition is significantly impaired in yeast mutants that alter the classical nuclear protein import pathway, including the Ran-GTPase, and the dimeric import receptor, importin-alpha/beta. Although Ty1 proteins are made and processed in these mutant cells, our studies reveal that an integrase reporter is not properly targeted to the nucleus in cells carrying mutations in the classical nuclear import machinery. Furthermore, we demonstrate that integrase coimmunoprecipitates with the importin-alpha transport receptor and directly binds to importin-alpha. Taken together, these data suggest Ty1 integrase can employ the classical nuclear protein transport machinery to enter the nucleus.


The role of cultural transmission in human demographic change: an age-structured model.
Human populations vary demographically with population sizes ranging from small groups of hunter-gatherers with less than fifty individuals to vast cities containing many millions. Here we investigate how the cultural transmission of traits affecting survival, fertility, or both can influence the birth rate, age structure, and asymptotic growth rate of a population. We show that the strong spread of such a trait can lead to a demographic transition, similar to that experienced in Europe in the late 19th and early 20th centuries, without using ecological or economic optimizing models. We also show that the spread of a cultural trait that increases fertility, but not survival, can cause demographic change similar to the 'Neolithic demographic transition': a period of increased population growth that is thought to have accompanied the transition from hunter-gatherer to agricultural lifestyles. We investigate the roles of vertical, oblique, and horizontal learning of such a trait in this transition and find that compared to vertical learning alone, horizontal and oblique learning can accelerate the trait's spread, lead to faster population growth, and increase its equilibrium frequency.


Somatosensory evoked potential monitoring following severe closed head injury.
This paper describes the results of somatosensory evoked potential (SSEP) monitoring in 65 patients with severe head injury. Intracranial pressure (ICP) monitoring data were available for 63 patients, and arterial-jugular oxygen content (AVDO2) data for 52 patients. Eighty-nine percent of patients with no SSEP activity beyond 50 msec post-stimulus in either hemisphere died or were vegetative survivors (3 month Glasgow Outcome Score). All 17 patients with a good or moderate outcome had long latency cortical activity (i.e. > or = 70 msec post-stimulus) in both hemispheres. Among patients with absent activity in 1 hemisphere, 53% died and 47% were severely disabled (chi 2 = 40, p = 0.0000). In the latter group, age was a significant factor among patients who died or were severely disabled (p < 0.02). Forty-four of 65 patients had either clear-cut deterioration or improvement in SSEPs over the course of monitoring. There were no significant differences in peak ICP between patients with improving or deteriorating SSEPs. In contrast, those with deteriorating SSEPs had a significant drop in AVDO2, compared with patients with improving SSEPs (p < 0.01). Long-term continuous monitoring of SSEPs shows that following severe injury, neurologic function may undergo significant change in approximately two-thirds of patients. Furthermore, ICP does not appear to play a prominent role in neurologic deterioration. AVDO2 measurements indicate that deterioration is more likely associated with perturbation of cerebral oxidative metabolism. SSEP monitoring following severe head injury has proven prognostic value, and is recommended for patients who must be pharmacologically paralyzed for ICP or ventilator management.


Selective iodine imaging using lanthanum K fluorescence.
Time-dependent subtraction techniques have tremendously improved the visualization of iodinated vessels. These techniques suffer from motion artifacts, however, since the mask image is acquired several seconds prior to the contrast image. A K-edge subtraction technique for selectively imaging iodine using the characteristic x rays from a lanthanum secondary target is presented. The K alpha lines of lanthanum closely straddle the K edge of iodine. A prepatient iodine filter will alter the ratio of K alpha 1 to K alpha 2 intensities; by subtracting two images made with different K alpha 1/K alpha 2 ratios, iodinated structures can be isolated. Since the method requires no mask image, motion artifacts are reduced. Preliminary images acquired with an image intensifier/photodiode array detector system are shown. Theoretical performance of this method is compared to other iodine-selective imaging techniques on the basis of exposure and dose. The feasibility of using lanthanum K fluorescence for rapid clinical iodine-selective imaging is discussed.


Multiple imputation for cure rate quantile regression with censored data.
The main challenge in the context of cure rate analysis is that one never knows whether censored subjects are cured or uncured, or whether they are susceptible or insusceptible to the event of interest. Considering the susceptible indicator as missing data, we propose a multiple imputation approach to cure rate quantile regression for censored data with a survival fraction. We develop an iterative algorithm to estimate the conditionally uncured probability for each subject. By utilizing this estimated probability and Bernoulli sample imputation, we can classify each subject as cured or uncured, and then employ the locally weighted method to estimate the quantile regression coefficients with only the uncured subjects. Repeating the imputation procedure multiple times and taking an average over the resultant estimators, we obtain consistent estimators for the quantile regression coefficients. Our approach relaxes the usual global linearity assumption, so that we can apply quantile regression to any particular quantile of interest. We establish asymptotic properties for the proposed estimators, including both consistency and asymptotic normality. We conduct simulation studies to assess the finite-sample performance of the proposed multiple imputation method and apply it to a lung cancer study as an illustration.


Health and social care costs of managing amyotrophic lateral sclerosis (ALS): an Irish perspective.
The aim of this study was to quantify the health and social care costs associated with managing amyotrophic lateral sclerosis (ALS) in Ireland. Resource use of a representative group of deceased ALS patients attending a multidisciplinary ALS clinic was identified from a retrospective chart review and telephone interview with the main caregiver. Unit cost estimates were applied to each resource to identify the cost per patient. Cost drivers were identified using multivariate linear regression. Results showed that from time of diagnosis to death, the cost per month was €1795, 21% of which was attributable to costs associated with the multidisciplinary clinic, 72% to community based care and 7% to aids and appliances. Higher monthly cost was associated with shorter survival and use of gastrostomy and non-invasive ventilation. In conclusion, ALS imposes a significant cost burden on the health services. More work is required to quantify the costs in other sectors, including informal care and productivity losses.


Variability of the adaptive response to low dose radiation in peripheral blood lymphocytes of twins and unrelated donors.
To assess the genetic control of the induction of the adaptive response after low-dose ionizing radiation, the frequencies of chromosome aberrations were evaluated in four pairs of monozygotic twins, two pairs of dizygotic twins, and in nine unrelated individuals. Stimulated cells were exposed to adaptive dose of 5 cGy gamma rays at 24 h and challenge dose of 150 cGy gamma rays at 42 h. Cells were fixed at 48 h and chromatid and isochromatid breaks were evaluated. The adaptive response was found in two pairs of monozygotic twins, but not in the two other pairs. Individual differences in adaptive response between the members of monozygotic twins were very small. In contrast, the variability in the adaptive response between the members of dizygotic twins was much greater and was similar to that observed in the unrelated donors. The results confirmed that heterogeneity in the adaptive response after exposure to low-dose gamma rays was controlled genetically to a considerable extent.


A rationale for stabilization of oxygen-labile enzymes: application to a clostridial hydrogenase.
A general procedure for stabilization of O2-labile enzymes exploiting "salting out" of oxygen from the microenvironment in the molecular layers immediately adjacent to charged surfaces of polyionic solid adsorbents has been developed. Empirical verification of this rationale is provided. The half-life of air inactivation of the O2-labile hydrogenase (EC 184.108.40.206) from Clostridium pasteurianum is increased 20- to 25-fold simply by adsorption (noncovalent binding) in dilute Tris.HCl buffer on common anion exchange supports such as DEAE-cellulose or Dowex 1-X2. Predicted increases in degree of stabilization by using more densely charged adsorbents (such as polyethyleneimine-cellulose), as well as bulkier solvent counter-anions, are found; half-lives for air inactivation for the bound hydrogenase can be increased to 3000-fold longer than that of the free enzyme. Most of the total catalytic activity, assayed as H2 evolution from dithionite mediated by methyl viologen or ferredoxin, is retained, whereas the expected suppression of H2 uptake in the reverse reaction is observed.


Biophenols pharmacology against the amyloidogenic activity in Alzheimer's disease.
Alzheimer's disease characterized by misfolding, aggregation, and accumulation of amyloid fibrils in an insoluble form in the brain, is often known as amyloidosis. The process of aggregation follows a mechanism of seeded polymerization. For decades, a great number of failures in Alzheimer's disease (AD) drug development, with both small molecules and immunotherapies failing to establish a drug/placebo difference or having an unacceptable toxicity have led to the therapeutic research interest towards a group of anti-amyloidogenic compounds originated from plants called biophenols. A number of in vitro and in vivo studies have demonstrated that the plant biophenols bind with amyloid beta (Aβ) toxic oligomers and reducing the fibril formation and toxicity. The exact mechanism of biophenols action against Aβ toxicity is unknown, while studies have suggested the amyloid-binding affinity of biophenols affecting Aβ on various levels, e.g. by direct inhibiting fibril formation or steering oligomer formation into unstructured, inhibiting Aβ aggregation, and promoting nontoxic pathways. Furthermore, biophenols involved in the inhibition of Aβ progression (e.g., oxidative stress and neuroinflammation) and effecting the amyloid precursor protein processing through the direct or indirect inhibition of β-secretase (BACE-1), γ-secretase and/or activation of α-secretase. This critical review account for the biophenols as magic bullet targeting against Aβ, and simulation the results on how biophenols interact with the Aβ monomers and oligomers, highly desirable knowledge for predicting new efficient nutraceutical drugs.


The impact of arterial flow complexity on flow diverter outcomes in aneurysms.
The flow diverter is becoming a standard device for treating cerebral aneurysms. The aim of this in vitro study was to evaluate the impact of flow complexity on the effectiveness of flow diverter stents in a cerebral aneurysm model. The flow pattern of a carotid artery was decomposed into harmonics to generate four flow patterns with different pulsatility indexes ranging from 0.72 to 1.44. The effect of flow diverters on the aneurysm was investigated by injecting red dye or erythrocytes as markers. The recorded images were postprocessed to evaluate the maximum filling of the aneurysm cavity and the washout time. There were significant differences in the cut-off flows between the markers, linked to the flow complexity. Increasing the pulsatility index altered the performance of the flow diverter. The red dye was more sensitive to changes in flow than the red blood cell markers. The flow cut-off depended on the diverter design and the diverter deployment step was crucial for reproducibility of the results. These results strongly suggest that flow complexity should be considered when selecting a flow diverter.


Comparison of immunofluorescence, enzyme immunoassay, and Western blot (immunoblot) methods for detection of antibody to human T-cell leukemia virus type I.
A total of 3,349 serum samples were screened by the immunofluorescence (IF) method for antibody to human T-cell leukemia virus type I (HTLV-I). Only 9 of 2,409 specimens from selected individuals, blood bank donors, patients with encephalitis-meningitis, and human immunodeficiency virus antibody-positive homosexual or bisexual men were reactive by IF. In addition, 940 serum samples from intravenous drug abusers were tested by IF and also by an HTLV-I enzyme immunoassay (EIA) method. Of these, 222 (24%) were positive for both HTLV-I and HTLV-II antigens by IF, and 191 of these 222 were also reactive in the HTLV-I EIA. Of the 31 IF-positive, EIA-negative serum samples, 20 exhibited optical density readings greater than or equal to 70% of the positive cutoff in the EIA, and 29 samples reacted with 1 or more bands in the Western blot (immunoblot) test. An additional 10 specimens that were EIA negative reacted only with HTLV-I by IF. Differences in staining morphology and in reactions on HTLV-I and HTLV-II antigens before and after absorption of the serum specimens with HTLV-I and HTLV-II-infected cell pellets revealed six distinct serological patterns by IF. These results indicate that infections by HTLV-I or by another closely related retrovirus(es) occur in California. Further studies utilizing statistically valid sampling methods are needed to estimate true prevalence rates among various groups. IF and Western blot tests should supplement the EIA method to maximize sensitivity and specificity of test procedures.


Immunological function of vitamin D during human pregnancy.
The well-established classic role of vitamin D is implicated in the regulation of the balance between calcium and phosphorus. Furthermore, vitamin D is also involved in many non-classic physiological processes, mainly including the regulation of cell proliferation, differentiation, apoptosis and immune function, participation in the inflammatory response and maintenance of genome stability function. During pregnancy, vitamin D receptor and its metabolic enzymes are expressed at the placenta and decidua, indicating the potential role in the mechanism of immunomodulation at the maternal-fetal interface. The insufficiency or deficiency of vitamin D may affect the mother directly and is related to specific pregnancy outcomes, such as preeclampsia, gestational diabetes, and recurrent miscarriage. This article reviews the effects of vitamin D on immune regulation during pregnancy.


[Levels of homovanillic acid and 5-hydroxyindoleacetic acid in the cerebrospinal fluid in patients with focal cerebral ischemia].
The investigated group comprised 35 patients where clinical examination revealed focal cerebral ischaemia in the area of the a. cerebri media. In the group of elderly patients above 60 years, as compared with controls, the homovanillic acid (HVA) and 5-hydroxyindolacetic acid (5-HIAA) concentration in cerebrospinal fluid was elevated. In the group of patients under 60 years no changes in the concentration of these metabolites were found. In older patients the increased level of metabolites in cerebrospinal fluid persisted also after three days following the attack, while in younger patients the elevated HVA and 5-HIAA levels were found only in specimens collected up to three days.


[Late manifestation of vitamin K deficiency in breast fed infants].
Two breast fed infants had late manifestations of Vitamin K deficiency. No underlying disease was found in the first case. The second patient was found to have alpha 1-Antitrypsin deficiency (Pi type ZZ). The latter patient initially responded well to a single dose of vitamin K administered orally (3 mg). However, three weeks later, he was admitted to our hospital with severe intracranial hemorrhage due to severe vitamin K deficiency. Vitamin K requirements in infants and clinical characteristics of vitamin K deficiency in infants older than 1 week are discussed.


Integrating multi-omics analyses of Nonomuraea dietziae to reveal the role of soybean oil in [(4'-OH)MeLeu]4-CsA overproduction.
Nonomuraea dietziae is a promising microorganism to mediate the region-specific monooxygenation reaction of cyclosporine A (CsA). The main product [(4'-OH)MeLeu]4-CsA possesses high anti-HIV/HCV and hair growth-stimulating activities while avoiding the immunosuppressive effect of CsA. However, the low conversion efficiency restricts the clinical application. In this study, the production of [(4'-OH)MeLeu]4-CsA was greatly improved by 55.6% from 182.8 to 284.4 mg/L when supplementing soybean oil into the production medium, which represented the highest production of [(4'-OH)MeLeu]4-CsA so far. To investigate the effect of soybean oil on CsA conversion, some other plant oils (corn oil and peanut oil) and the major hydrolysates of soybean oil were fed into the production medium, respectively. The results demonstrated that the plant oils, rather than the hydrolysates, could significantly improve the [(4'-OH)MeLeu]4-CsA production, suggesting that soybean oil might not play its role in the lipid metabolic pathway. To further unveil the mechanism of [(4'-OH)MeLeu]4-CsA overproduction under the soybean oil condition, a proteomic analysis based on the two-dimensional gel electrophoresis coupled with MALDI TOF/TOF mass spectrometry was implemented. The results showed that central carbon metabolism, genetic information processing and energy metabolism were significantly up-regulated under the soybean oil condition. Moreover, the gas chromatography-mass spectrometry-based metabolomic analysis indicated that soybean oil had a great effect on amino acid metabolism and tricarboxylic acid cycle. In addition, the transcription levels of cytochrome P450 hydroxylase (CYP) genes for CsA conversion were determined by RT-qPCR and the results showed that most of the CYP genes were up-regulated under the soybean oil condition. These findings indicate that soybean oil could strengthen the primary metabolism and the CYP system to enhance the mycelium growth and the monooxygenation reaction, respectively, and it will be a guidance for the further metabolic engineering of this strain.


Posttraining epinephrine treatment reduces the need for extensive training.
We studied whether posttraining epinephrine accelerates the process of acquisition, and whether this effect leads to an enduring high level of performance on a long-term memory test (20 days). Rats were submitted to daily massed (30 trials) two-way active avoidance conditioning sessions followed by systemic epinephrine (0.01 mg/kg) or vehicle, until achieving a learning criterion (80% avoidances in one single session, maximum 14 sessions). By the sixth session, 78% of the animals with posttraining epinephrine attained the learning criterion compared to only the 23% of the rats in the vehicle group. Considering the whole acquisition phase, all the epinephrine treated animals, but only 66.67% in the vehicle group, reached the criterion. On the retention test, both groups maintained the level of performance reached at the end of the acquisition phase. We conclude that epinephrine accelerates the process of acquisition by enhancing memory consolidation, and that this effect might be especially useful in high demanding learning tasks, or for animals with low learning capacities.


Violence toward emergency physicians: A prospective-descriptive study.
The highest rate of workplace violence occurs in the health sector, although most cases remain unreported. Emergency services face the majority of these incidents for many reasons, such as the patient profile, long waiting time, and overcrowding. We aimed to determine the characteristics and causes of violence toward emergency physicians. The acts of violence toward emergency physicians over a one-year period were prospectively recorded. After a violent incident took place, a third party separately interviewed the physician exposed to the violent behavior and the perpetrator who displayed this behavior. We examined the perpetrator's reasons for violence, their demographic characteristics, and the medical complaints of patients involved in such events to determine the characteristics and causes of violence. Of the violent acts investigated, 85.1% were verbal, and most were directed toward male doctors by the young male relatives of the patients. More than half of the violent acts occurred within the 15 minutes of presentation to emergency service (60.5%) and at off-hours (69.4%). Concerning the health insurance, 20.4% of the cases were covered by the free green card system, and a small number of the perpetrators of violence lived in rural areas (38.2%). The most common reason for violent behavior was the patients' or their relatives' dissatisfaction with the examination or treatment method (38.2%). Appropriate communication should be established with the patients, and they should be adequately informed about the treatments and interventions to be performed in order to prevent possible acts of violence.


Self-Phosphorization of MOF-Armored Microbes for Advanced Energy Storage.
Utilization of microbes as the carbon source and structural template to fabricate porous carbon has incentivized great interests owing to their diverse micromorphology and intricate intracellular structure, apart from the obvious benefit of "turning waste into wealth." Challenges remain to preserve the biological structure through the harsh and laborious post-synthetic treatments, and tailor the functionality as desired. Herein, Escherichia coli is directly coated with metal-organic frameworks (MOFs) through in situ assembly to fabricate N, P co-doped porous carbon capsules expressing self-phosphorized metal phosphides. While the MOF coating serves as an armoring layer for facilitating the morphology inheritance from the bio-templates and provides metal sources for generating extra porosity and electrochemically active sites, the P-rich phospholipids and N-rich proteins from the plasma membrane enable carbon matrix doping and further yield metal phosphides. These unique structural and compositional features endow the carbon capsules with great capabilities in suppressing polysulfide shuttling and catalyzing reversible oxygen conversion, ultimately leading to the superb performance of lithium-sulfur batteries and zinc-air batteries. Combining the bio-templating strategy with hierarchical MOF assembly, this work opens a new avenue for the fabrication of highly porous and functional carbon for advanced energy applications.


Structural comparison of allogeneic and syngeneic T cell receptor-peptide-major histocompatibility complex complexes: a buried alloreactive mutation subtly alters peptide presentation substantially increasing V(beta) Interactions.
The crystal structures of the 2C/H-2K(bm3)-dEV8 allogeneic complex at 2.4 A and H-2K(bm3)-dEV8 at 2.15 A, when compared with their syngeneic counterparts, elucidate structural changes that induce an alloresponse. The Asp77Ser mutation that imbues H-2K(bm3)-dEV8 with its alloreactive properties is located beneath the peptide and does not directly contact the T cell receptor (TCR). However, the buried mutation induces local rearrangement of the peptide itself to preserve hydrogen bonding interactions between the peptide and the alpha(1) 77 residue. The COOH terminus of the peptide main chain is tugged toward the alpha(1)-helix such that its presentation to the TCR is altered. These changes increase the stability of the allogeneic peptide-major histocompatibility complex (pMHC) complex and increase complementarity in the TCR-pMHC interface, placing greater emphasis on recognition of the pMHC by the TCR beta-chain, evinced by an increase in shape complementarity, buried surface area, and number of TCR-pMHC contacting residues. A nearly fourfold increase in the number of beta-chain-pMHC contacts is accompanied by a concomitant 64% increase in beta-chain-pMHC shape complementarity. Thus, the allogeneic mutation causes the same peptide to be presented differently, temporally and spatially, by the allogeneic and syngeneic MHCs.


Effects of guar meal by-product with and without beta-mannanase Hemicell on broiler performance.
Guar gum production yields a high protein guar meal that can be subdivided into germ and hull fractions. Feeding high concentrations of guar meal reduces body weight and feed efficiency in chickens due to the presence of a residual guar gum. Two experiments determined the upper feeding levels of guar meal and the hull and germ fractions in broiler chickens. An industrial source beta-mannanase (Hemicell) also was fed in combination with guar meals. Experiment 1 utilized a 3 x 4 factorial design to feed broiler chickens diets containing guar germ, guar hull, or guar meal at 4 levels (2.5, 5.0, 7.5, and 10.0%) compared with a negative control diet. Results indicated that any of the 3 guar meals could be fed at a 2.5% dietary inclusion rate without adversely affecting broiler chicken growth to 6 wk of age. In experiment 2, a 4 x 2 factorial design consisting of the 3 by-products meals at 5% inclusion and soybean meal control with and without enzyme tested whether Hemicell could increase inclusion rates without decreasing broiler growth or feed consumption to 6 wk of age. Addition of Hemicell to feed had no effect on measures of growth in chickens fed the control diet. Hemicell significantly improved feed:gain ratio of diets containing 5% of each fraction of guar meal versus the untreated diets. Feed:gain ratio for the Hemicell-treated 5% germ fraction diet was improved to control diet levels. Results indicated that the upper feeding level of guar meal and germ and hull fraction of guar meal is 2.5%, and addition of beta-mannanase (Hemicell) increases the upper feeding level for the germ fraction to 5%.


Comparative evaluation of antimicrobial activity of two root canal sealers: MTA Fillapex and AH 26.
Even after a complete root canal therapy, reinfection may occur as a result of incomplete seal and activation of residual bacteria. Thus, antimicrobial activity is an important characteristic of root canal sealers. MTA Fillapex is a newly developed MTA-based sealer. It has been subjected to various studies evaluating its physical and chemical properties. In this study, we aimed to compare the antimicrobial activity of this sealer to the commonly known widely accepted sealer, AH26. MTA Fillapex and AH 26 were exposed the bacterial suspension of Enterococcus faecalis, Escherichia coli, Streptococcus mutans, and Candida albicans after setting. After incubation and complete evaporation, BHI was added to microtubes. 24 hours later, the liquid content was placed in agar diffusion plate and bacterial count was performed. ANOVA followed by Tukey test, and t-Test were performed to analyze the data. With regard to all four bacterial groups, the bacterial count was significantly lower in MTAFillapex group comparing to AH 26 group. Newly developed MTA Fillapex sealer, has better antimicrobial properties in comparison to the widely accepted AH26 sealer.


Effect of the use of prediagnosis hormones on breast cancer prognosis: MCC-Spain study.
To extend knowledge about the long-term use of hormones in hormone therapy or oral contraception as prognostic factors in breast cancer. The MCC-Spain project is a cohort of 1,685 women with incident breast cancer recruited in Spain. Recruitment was carried out between 2007 and 2010, and the follow-up finished in December 2017. The impact of hormone therapy or oral contraception on breast cancer prognosis was analyzed considering year of birth and menopausal status (1,095 women [65%] were postmenopausal). Hazard ratios (HRs) were estimated using Cox regression models. Death by any cause was considered as the event, and hormone therapy or oral contraception were analyzed as regressors. Oral contraception use for less than 5 years shows an HR of 1.10 (95% CI, 0.75 to 1.62), whereas use for 5 or more years shows an HR of 1.46 (95% CI, 0.95 to 2.25), with a P trend of 0.01, showing a dose-dependent response. Regarding hormone therapy and restricting the analysis to postmenopausal women born between1940 and 1959, where most hormone therapy (consumption) is concentrated, the results did not show any trend. Concerning oral contraception use, our results demonstrate that their use is related to poor prognosis in breast cancer. However, research in this field is limited and controversial, indicating the need for more research in this area. Regarding hormone therapy consumption, our results indicate no association with better prognosis, which contradicts what has previously been published.


Redox Catalysis Facilitates Lignin Depolymerization.
Lignin is a recalcitrant and underexploited natural feedstock for aromatic commodity chemicals, and its degradation generally requires the use of high temperatures and harsh reaction conditions. Herein we present an ambient temperature one-pot process for the controlled oxidation and depolymerization of this potent resource. Harnessing the potential of electrocatalytic oxidation in conjugation with our photocatalytic cleavage methodology, we have developed an operationally simple procedure for selective fragmentation of β-O-4 bonds with excellent mass recovery, which provides a unique opportunity to expand the existing lignin usage from energy source to commodity chemicals and synthetic building block source.


Classification of large-scale fundus image data sets: a cloud-computing framework.
Large medical image data sets with high dimensionality require substantial amount of computation time for data creation and data processing. This paper presents a novel generalized method that finds optimal image-based feature sets that reduce computational time complexity while maximizing overall classification accuracy for detection of diabetic retinopathy (DR). First, region-based and pixel-based features are extracted from fundus images for classification of DR lesions and vessel-like structures. Next, feature ranking strategies are used to distinguish the optimal classification feature sets. DR lesion and vessel classification accuracies are computed using the boosted decision tree and decision forest classifiers in the Microsoft Azure Machine Learning Studio platform, respectively. For images from the DIARETDB1 data set, 40 of its highest-ranked features are used to classify four DR lesion types with an average classification accuracy of 90.1% in 792 seconds. Also, for classification of red lesion regions and hemorrhages from microaneurysms, accuracies of 85% and 72% are observed, respectively. For images from STARE data set, 40 high-ranked features can classify minor blood vessels with an accuracy of 83.5% in 326 seconds. Such cloud-based fundus image analysis systems can significantly enhance the borderline classification performances in automated screening systems.


Emerging infectious bronchitis virus (IBV) in Egypt: Evidence for an evolutionary advantage of a new S1 variant with a unique gene 3ab constellation.
Infectious bronchitis virus (IBV), a gamma-coronavirus, causes infectious bronchitis (IB), a major respiratory disease of chicken. Its high mutation rate in conjunction with recombination of the RNA genome constantly creates IBV variants that are difficult to control by currently available vaccines. In this study, we addressed the question whether small-scale holdings might harbor IBV variants that serve as a reservoir for newly emerging variants. Egyptian IBV isolate EGY/NR725/2016 (NR725/16) from a small-scale broiler farm was assigned to genotype I, clade 23 (S1:GI-23), based on partial S1 gene sequences and corroborated by full genome sequencing. Analysis of the S1 gene established three subclades for historical IBV strains (S1:GI-23.1, S1:GI-23.2.1 and S1:GI-23.2.2) and confirmed NR725/16 as being part of a separate fourth subclade (S1:GI-23.3). Samples from the years 2018 and 2019 revealed that the new subclade prevails in Egypt, carrying fixed mutations within the hypervariable regions (HVR) 1-3 of the S1 protein that affect two neutralization sensitive epitopes at sites 294F, 297S and 306Y (48.2) and 329R (62.1). In addition, recombination was recognized in isolate NR 725/16, with intra-subtype mixing for the entire genes 3ab and E and inter-subtype mixing for the entire gene 6b with a close match to QX like viruses of genotype GI-19. Further analysis of gene 3ab detected the homologous gene pool to NR725/16 in samples from 2013 (3ab:C) and closely related 3ab genotypes in IBV Egyptian isolates from 2016, 2018 and 2019. These data prove a flourishing exchange between poultry holdings with a common gene pool. The continued circulation of viruses harboring genes S1:GI-23.3 and 3ab:C indicates an evolutionary advantage of this combination possibly by combining antigenic escape with modulated pathogenicity to facilitate IBV spread in the vaccinated poultry population in Egypt.


The Society of Toxicologic Pathology: Advances and Adventures in the First 50 Years.
The Society of Toxicologic Pathology (STP, https://www.toxpath.org/) was founded in North America in 1971 as a nonprofit scientific and educational association to promote the professional practice of pathology as applied to pharmaceutical and environmental safety assessment. In the ensuing 50 years, the STP has become a principal global leader in the field. Society membership has expanded to include toxicologic pathologists and allied scientists (eg, toxicologists, regulatory reviewers) from many nations. In addition to serving membership needs for professional development and networking, major STP outreach activities include production of articles and presentations designed to optimize toxicologic pathology procedures ("best practice" recommendations), communicate core principles of pathology evaluation and interpretation ("points to consider" and "opinion" pieces), and participation in international efforts to harmonize diagnostic nomenclature. The STP has evolved into an essential resource for academic, government, and industrial organizations that employ and educate toxicologic pathologists as well as use toxicologic pathology data across a range of applications from assessing product safety (therapies, foods, etc) to monitoring and maintaining environmental and occupational health. This article recapitulates the important milestones and accomplishments of the STP during its first 50 years.