Fructose-1,6-bisphosphatase Inhibits ERK Activation and Bypasses Gemcitabine Resistance in Pancreatic Cancer by Blocking IQGAP1-MAPK Interaction.
Dysregulation of the MAPK pathway correlates with progression of pancreatic ductal adenocarcinoma (PDAC) progression. IQ motif containing GTPase-activating protein 1 (IQGAP1) is a MAPK scaffold that directly regulates the activation of RAF, MEK, and ERK. Fructose-1,6-bisphosphatase (FBP1), a key enzyme in gluconeogenesis, is transcriptionally downregulated in various cancers, including PDAC. Here, we demonstrate that FBP1 acts as a negative modulator of the IQGAP1-MAPK signaling axis in PDAC cells. FBP1 binding to the WW domain of IQGAP1 impeded IQGAP1-dependent ERK1/2 phosphorylation (pERK1/2) in a manner independent of FBP1 enzymatic activity. Conversely, decreased FBP1 expression induced pERK1/2 levels in PDAC cell lines and correlated with increased pERK1/2 levels in patient specimens. Treatment with gemcitabine caused undesirable activation of ERK1/2 in PDAC cells, but cotreatment with the FBP1-derived small peptide inhibitor FBP1 E4 overcame gemcitabine-induced ERK activation, thereby increasing the anticancer efficacy of gemcitabine in PDAC. These findings identify a primary mechanism of resistance of PDAC to standard therapy and suggest that the FBP1-IQGAP1-ERK1/2 signaling axis can be targeted for effective treatment of PDAC. Cancer Res; 77(16); 4328-41. ©2017 AACR.


[Roux-en-Y gastrectomy. A 12 years' experience].
A review of 161 patients who underwent Roux-en-Y biliary diversion and truncal vagotomy from 1978 to 1989 is performed under the double perspective: clinical and functional (using radionuclide semi-solid and liquid gastric emptying (GE) studies). In 46 patients this solution was adopted to treat different kinds of post-gastrectomy syndromes and in 115 to solve the esophageal-duodeno-gastric peptic disease. Some technical details are considered very important to prevent the nominated post Roux-en-Y Syndrome in relationship with the gastroparesis and gastric retention. The overall operative mortality was 2.5%. Five patients were reoperated: two, to complete vagotomy; 2, to solve gastric retention and one with sub-occlusion due to jejunal stricture. Forty one patients with 7.4 +/- 1.3 years after surgery were graded Visick I or II in 82.9% of the cases and 17.1% Visick III or IV. Gastric emptying studies demonstrated that the problems of gastric fullness detected in the immediate post operative period are quite similar to those observed after other kinds of sub-total gastrectomies. After 6 months, the gastric emptying change to a more rapid pattern in the large majority of patients. In the late post operative period is quite common to have no agreement between gastroparesis complains and the objective measurements of the GE, in symptomatic patients. Roux-en-Y gastrectomy solve the problems of post gastrectomy syndromes in 80% of the cases and in our experience, is a method that can be used with advantage to treat the ulcerative peptic disease resistant to the medical treatment in patients with less than 50 years.


High-spatial-resolution whole-body MR angiography with high-acceleration parallel acquisition and 32-channel 3.0-T unit: initial experience.
The purpose of this HIPAA-compliant study was to prospectively evaluate the technical feasibility of a multistation high-spatial-resolution whole-body magnetic resonance (MR) angiography protocol in which high-acceleration parallel imaging (with acceleration factors of three and four) is performed with a 32-channel 3.0-T MR system. After institutional review board approval and written informed consent were obtained, 10 healthy volunteers (four men and six women aged 23-68 years) and four patients (two men and two women aged 56-79 years) suspected of having peripheral vascular disease underwent multistation whole-body contrast material-enhanced MR angiography. Use of multiarray surface coil technology and highly accelerated generalized autocalibrating partially parallel acquisition enabled the acquisition of isotropic high-spatial-resolution three-dimensional data sets for multiple stations. Two radiologists independently evaluated arterial image quality and presence of arterial stenoses. All examinations yielded good or excellent image quality. Interobserver agreement was excellent (kappa = 0.92; 95% confidence interval: 0.86, 0.96). Multistation whole-body MR angiography with high-acceleration parallel acquisition is feasible at 3.0 T. Further clinical studies combined with ongoing optimization of radiofrequency systems and coils seem warranted to advance the potential of this technology.


Trypsin immobilization on three monolithic disks for on-line protein digestion.
The preparation and characterization of three trypsin-based monolithic immobilized enzyme reactors (IMERs) developed to perform rapid on-line protein digestion and peptide mass fingerprinting (PMF) are described. Trypsin (EC 188.8.131.52) was covalently immobilized on epoxy, carbonyldiimidazole (CDI) and ethylenediamine (EDA) Convective Interaction Media (CIM) monolithic disks. The amount of immobilized enzyme, determined by spectrophotometric measurements at 280nm, was comprised between 0.9 and 1.5mg per disk. Apparent kinetic parameters Km* and Vmax*, as well as apparent immobilized trypsin BAEE-units, were estimated in flow-through conditions using N-alpha-benzoyl-L-arginine ethyl ester (BAEE) as a low molecular mass substrate. The on-line digestion of five proteins (cytochrome c, myoglobin, alpha1-acid glycoprotein, ovalbumin and albumin) was evaluated by inserting the IMERs into a liquid chromatography system coupled to an electrospray ionization ion-trap mass spectrometer (LC-ESI-MS/MS) through a switching valve. Results were compared to the in-solution digestion in terms of obtained scores, number of matched queries and sequence coverages. The most efficient IMER was obtained by immobilizing trypsin on a CIM EDA disk previously derivatized with glutaraldehyde, as a spacer moiety. The proteins were recognized by the database with satisfactory sequence coverage using a digestion time of only 5min. The repeatability of the digestion (R.S.D. of 5.4% on consecutive injections of myoglobin 12microM) and the long-term stability of this IMER were satisfactory since no loss of activity was observed after 250 injections.


Prenatal and Postnatal Attachment Among Turkish Mothers Diagnosed with a Mental Health Disorder.
The presence of a mental disorder in the mother is one of the key factors affecting attachment. The present study aimed to evaluate prenatal and postnatal attachment among mothers diagnosed with a mental health disorder by comparing them to a healthy group. The patient group included women who received follow-up care in a psychiatric clinic (74 pregnant and 75 postpartum), and the healthy group consisted of women who attended a follow-up polyclinic (118 pregnant and 82 postpartum). Data were collected using questionnaire forms, including the Prenatal Attachment Inventory and the Maternal Attachment Scale. Mothers diagnosed with a mental health disorder were determined to have lower attachment scores than the healthy group, both during the prenatal and postnatal periods. The literature suggests that mothers diagnosed with a mental health disorder showed low maternal attachment scores during pregnancy and/or the postnatal period. Psychiatric nurses should be involved in initiatives that may increase the prenatal and maternal attachment.


Hydatid disease of the breast.
Cystic hydatid disease is caused by the parasite Echinococcus granulosus. Humans are the accidental intermediate hosts of this organism. Hydatid disease is endemic in countries in which raising sheep and cattle constitutes an important means of livelihood. The most commonly affected organs are the liver and lungs. Involvement of the kidney, bone, brain and other organs is rare. Breast involvement in this disease is also very rare. A case of isolated hydatid cyst of the breast is presented, along with a review of the literature and a discussion on the pertinent clinical and radiological aspects of the disease.


Secretome analysis of ionizing radiation-induced senescent cancer cells reveals that secreted RKIP plays a critical role in neighboring cell migration.
Cellular senescence is a physiological program of irreversible growth arrest that is considered to play an important role in tumor suppression. Recent studies demonstrated that senescent cells secrete multiple growth regulatory proteins that could alter the behavior of neighboring cells. In this study, we investigated the effect of secretory proteins from ionizing radiation (IR) induced senescent tumor cells on normal and tumor cells. Conditioned medium (CM) from IR-induced senescent MCF7 cells significantly increased cell proliferation, invasion, migration, and wound healing activity in MCF7 cells and HUVECs. Comparative proteomics analysis revealed 24 differentially secreted protein spots including Raf kinase inhibitor protein (RKIP), α-Enolase, AKAP9, and MARK4, and the findings were confirmed by Western blot analysis of IR-induced senescent cancer cells. We found that RKIP was secreted via the classical pathway, and the transfection of small interfering RNA against RKIP suppressed CM-induced migration in MCF7 cells. Treatment with recombinant human RKIP increased the migratory activity of MCF7 cells. Taken together, our results demonstrate that the senescence-associated secretory protein RKIP could be the principal target to prevent the potential effects of the secretome from IR-induced senescent tumor cells on neighboring cell migration.


Second- and third-trimester placental hemodynamics and the risks of pregnancy complications: the Generation R Study.
Characteristics of the uterine and umbilical artery blood flow patterns are indirect measures of uteroplacental circulation. We examined whether uterine and umbilical artery resistance indices are influenced by maternal demographic and lifestyle characteristics, track from the second trimester to the third, and are associated with the risk of pregnancy complications. This analysis was embedded among 7,660 pregnant women in the Generation R Study (Rotterdam, the Netherlands, 2001-2005). Placental resistance indices were assessed in the second and third trimesters. Information about pregnancy outcomes was obtained from medical records. Maternal characteristics affected second- and third-trimester placental resistance indices. Correlation coefficients for correlation between the second and third trimesters were 0.50 and 0.32 for uterine artery resistance index and umbilical artery pulsatility index, respectively. Higher placental resistance indices in the second and third trimesters and persistence in the highest tertile of uterine artery resistance index from the second trimester to the third were associated with the risks of preeclampsia, preterm birth, and small size for gestational age at birth (all P's < 0.05). Our study shows that placental resistance indices are influenced by maternal demographic and lifestyle characteristics and track moderately from the second trimester to the third. Increased placental resistance indices in the second and third trimesters are associated with increased risks of adverse pregnancy outcomes.


Transtracheal mediastinal lymphography for visualization of metastatic lymph nodes in carcinoma of the esophagus.
Mediastinal lymphography was carried out preoperatively upon 15 patients with carcinoma of the thoracic part of the esophagus. The tracheal bifurcation was punctured, and contrast medium was slowly injected. Mediastinal lymphograms were taken within 24 hours and, again, three and seven days after this injection. The paratracheal lymph nodes were demonstrated in almost all of the patients, and a filling defect was observed in three patients, leading to possible metastatic involvement. In seven patients, the right pulmonary hilar lymph nodes were demonstrated, and no node was considered to be metastatic. In three, paraesophageal lymph nodes were preoperatively diagnosed as metastatic. All seven lymph nodes in which metastasis was suspected were confirmed to be metastatic at pathologic examination. The smallest node correctly assessed as metastatic was 6 by 6 millimeters.


Physical Activity and Survival in Women With Advanced Breast Cancer.
Several empirical investigations have attempted to characterize the effect of physical activity on cancer mortality, but these investigations have rarely focused on patients with advanced breast cancer. The current study examined the hypothesis that greater physical activity is associated with longer survival among women with advanced breast cancer. We conducted a secondary data analysis of a prospective study of 103 patients with stage IV (n = 100) or locally recurrent (n = 3) breast cancer involved in a group psychotherapy trial. Physical activity was assessed at baseline using the Seven-Day Physical Activity Recall questionnaire, and patients were followed until April 1, 2016, at which time 93 of 103 had died. Greater physical activity level at baseline was significantly associated with longer subsequent survival time in a Cox proportional hazards model (hazard ratio [HR], 0.90; 95% confidence interval [CI], 0.84-0.97; P < .01). Engaging in 1 additional hour per day of moderate activity reduced the hazard of subsequent mortality by 23% (HR, 0.77; 95% CI, 0.65-0.92; P < .01). These results remained significant even after controlling for demographic, medical, cancer, depression, and cortisol variables (HR, 0.91; 95% CI, 0.84-0.99; P < .05). Women with advanced breast cancer who engaged in physical activity for 1 or more hours per day at baseline had an increased likelihood of survival compared with those who exercised less than 1 hour per day. Nurses should consider recommending moderate physical activity for women with advanced breast cancer. Randomized trials of physical activity interventions for this population are needed.


'Because I've been extremely careful': HIV seroconversion, responsibility, citizenship and the neo-liberal drug-using subject.
In this article we examine how injection drug users who do not attribute their HIV infection to engaging in HIV risk behaviours take up and critique discourses of individual responsibility and citizenship relating to HIV risk and HIV prevention. We draw on data from a study in Vancouver, Canada (2006 - 2009) in which we interviewed individuals living with HIV who had a history of injection drug use. In this paper we focus on 6 cases studies of participants who did not attribute their HIV infection to engaging in HIV risk behaviours. We found that in striving to present themselves as responsible HIV citizens who did not engage in HIV risk behaviours, these participants drew on individually-focused HIV prevention discourses. By identifying themselves in these ways, they were able to present themselves as 'deserving' HIV citizens and avoid the blame associated with being HIV positive. However, in rejecting the view that they and their risk behaviours were to blame for their HIV infection and by developing an explanation that drew on broader social, structural and historical factors, these individuals were developing a tentative critique of the importance of individual responsibility in HIV transmission as opposed to dangers of infection from the socio-economic environment. By framing the risk of infection in environmental rather than individual risk-behaviour terms these individuals redistributed responsibility to reflect the social-structural realities of their lives. In this article we reflect on the implications of these findings for public health measures such as risk prevention messages. We note that it is important that such messages are not restricted to individual risk prevention but also include a focus of broader shared responsibilities of HIV.


Epstein-Barr virus Latent Membrane Protein LMP1 reduces p53 protein levels independent of the PI3K-Akt pathway.
Nasopharyngeal carcinoma (NPC) is an epithelial malignancy, which commonly occurs in Southern China, Taiwan, North Africa and Southeast Asia. Nasopharyngeal carcinoma is strongly associated with Epstein-Barr virus infection. The p53 tumour suppressor protein is rarely mutated in NPC suggesting that the inactivation of p53 pathway in NPC could be due to the presence of EBV proteins. The aim of this work was to determine the effects of EBV proteins namely LMP1 and LMP2A on the expression levels of p53 protein. In this work we found that LMP1, but not LMP2A, decreased p53 protein levels. Overexpression of LMP1 resulted in increased ubiquitination of p53 suggesting that the decreased p53 protein levels by LMP1 was due to increased degradation of the protein. The reduction of p53 protein levels was independent of the PI3K-Akt pathway. LMP1, but not LMP2A, reduced p53 protein levels through the increase in the polyubiquitination of p53 protein and was independent of the PI3K-Akt pathway.


Modulation of Brain Activity with Noninvasive Transcranial Direct Current Stimulation (tDCS): Clinical Applications and Safety Concerns.
Transcranial direct current stimulation (tDCS) is a widely-used tool to induce neuroplasticity and modulate cortical function by applying weak direct current over the scalp. In this review, we first introduce the underlying mechanism of action, the brief history from discovery to clinical scientific research, electrode positioning and montages, and parameter setup of tDCS. Then, we review tDCS application in clinical samples including people with drug addiction, major depression disorder, Alzheimer's disease, as well as in children. This review covers the typical characteristics and the underlying neural mechanisms of tDCS treatment in such studies. This is followed by a discussion of safety, especially when the current intensity is increased or the stimulation duration is prolonged. Given such concerns, we provide detailed suggestions regarding safety procedures for tDCS operation. Lastly, future research directions are discussed. They include foci on the development of multi-tech combination with tDCS such as with TMS and fMRI; long-term behavioral and morphological changes; possible applications in other research domains, and more animal research to deepen the understanding of the biological and physiological mechanisms of tDCS stimulation.


Comparison of isoenzyme profiles of Toxoplasma gondii tachyzoites produced under different culture conditions.
The isoenzyme profiles for ten enzymes of tachyzoites either grown in vivo in TG 180 mouse sarcoma cells or cultivated in vitro in human fibroblast cell culture were compared in eight cloned strains by means of isoelectric focusing in polyacrylamide gels. Fibroblast-cultivated tachyzoites of all strains tested showed an extra band in the LDH isoenzyme pattern that was not seen in tachyzoites from TG 180 mouse sarcoma cells. The isoenzyme patterns of four enzymes [aspartate aminotransferase (ASAT), glutathione reductase (GSR), glucose phosphate isomerase (GPI) and amylase] used to differentiate the strains did not change under the two different culture conditions. Nevertheless, the shift observed in the LDH isoenzyme pattern underlines the fact that isoenzyme analysis of Toxoplasma strains could be carried out with tachyzoites produced under the same culture conditions.


Sucrose preference test: A systematic review of protocols for the assessment of anhedonia in rodents.
Anhedonia is described as a decreased ability to experience rewarding and enjoyable activities, a core symptom of major depressive disorder. The sucrose preference test (SPT) is a widely used and reliable behavioural test to assess anhedonia in rodents, based on a two-bottle choice paradigm. To date, different protocols are in use, inducing variability between researchers and hampering comparisons between studies. We performed a systematic review of the SPT protocols used in 2021 to identify the parameters in which they differ and their potential impact. We searched a total of four databases (PubMed, Scopus, Web of Science and Science Direct), from 1st January 2021 to 31st December 2021, and screened a total of 1066 articles. After screening by title and abstract, a total of 415 articles were included in this review. We extracted and analysed the different procedures used, the type of sweet solution and the habituation, deprivation, and testing protocols. The overall quality of the studies was considered very good, however, SPT protocols were extremely variable between studies with a total of 65 different habituation protocols and 104 combinations of food/water deprivation and preference testing duration. As the SPT is one of the most used tests to assess anhedonia in rodents, this work raises awareness of the great variability in SPT protocols being currently used. Furthermore, we call for standardization in the protocol used, and overall improvement of data reporting of methodologies and results, to increase the consistency between studies and allow a better comparison of results between different labs.


Reliable transgene-independent method for determining Sleeping Beauty transposon copy numbers.
The transposon-based gene delivery technique is emerging as a method of choice for gene therapy. The Sleeping Beauty (SB) system has become one of the most favored methods, because of its efficiency and its random integration profile. Copy-number determination of the delivered transgene is a crucial task, but a universal method for measuring this is lacking. In this paper, we show that a real-time quantitative PCR-based, transgene-independent (qPCR-TI) method is able to determine SB transposon copy numbers regardless of the genetic cargo. We designed a specific PCR assay to amplify the left inverted repeat-direct repeat region of SB, and used it together with the single-copy control gene RPPH1 and a reference genomic DNA of known copy number. The qPCR-TI method allowed rapid and accurate determination of SB transposon copy numbers in various cell types, including human embryonic stem cells. We also found that this sensitive, rapid, highly reproducible and non-radioactive method is just as accurate and reliable as the widely used blotting techniques or the transposon display method. Because the assay is specific for the inverted repeat region of the transposon, it could be used in any system where the SB transposon is the genetic vehicle. We have developed a transgene-independent method to determine copy numbers of transgenes delivered by the SB transposon system. The technique is based on a quantitative real-time PCR detection method, offering a sensitive, non-radioactive, rapid and accurate approach, which has a potential to be used for gene therapy.


The chronic effect of amorphous silica nanoparticles and benzo[a]pyrene co-exposure at low dose in human bronchial epithelial BEAS-2B cells.
As the main components of fine particulate matter (PM2.5), silica nanoparticles (SiNPs) and benzo[a]pyrene (B[a]P) have attracted increasing attention recently. However, co-exposure to SiNPs and B[a]P causes pulmonary injury by aggravating toxicity via an unknown mechanism. This study aimed at investigating the toxicity caused due to long-term co-exposure to SiNPs and B[a]P on pulmonary systems at low dose using human bronchial epithelial (BEAS-2B) cells. The characterizations of SiNPs and B[a]P were done by transmission electron microscopy (TEM) and zeta potential granulometry. Cytotoxicity is evaluated using cell counting kit-8 (CCK-8) assay and lactate dehydrogenase (LDH) activity; oxidative stress, cell cycle and apoptosis were assessed by flow cytometry, and inflammatory factors were detected using a Luminex xMAP system. Results show an obvious inhibition of cell proliferation and a marked increase in the LDH expression in the BEAS-2B cells after long-term co-exposure. Furthermore, long-term co-exposure is the most potent in generating intracellular ROS, thus causing inflammation. Cellular apoptotic rate is enhanced in the co-exposed group at low dose. Moreover, the long-term co-exposure induces significant cell cycle arrest, increasing the proportion of cells at the G2/M phase, while decreasing those at the G0/G1 phase. This study is the first attempt to reveal the severe synergistic and additive toxic effects induced by SiNPs and B[a]P co-exposure for long-term in BEAS-2B cells even at low dose.


A Novel, Rapid, and Low-Volume Assay for Therapeutic Drug Monitoring of Posaconazole and Other Long-Chain Azole-Class Antifungal Drugs.
Clinicians need a better way to accurately monitor the concentration of antimicrobials in patient samples. In this report, we describe a novel, low-sample-volume method to monitor the azole-class antifungal drug posaconazole, as well as certain other long-chain azole-class antifungal drugs in human serum samples. Posaconazole represents an important target for therapeutic drug monitoring (TDM) due to its widespread use in treating invasive fungal infections and well-recognized variability of pharmacokinetics. The current "gold standard" requires trough and peak monitoring through high-pressure liquid chromatography (HPLC) or liquid chromatography-tandem mass spectroscopy (LC-MS/MS). Other methods include bioassays that use highly susceptible strains of fungi in culture plates or 96-well formats to monitor concentrations. Currently, no method exists that is both highly accurate in detecting free drug concentrations and is also rapid. Herein, we describe a new method using reduced graphene oxide (rGO) and a fluorescently labeled aptamer, which can accurately assess clinically relevant concentrations of posaconazole and other long-chain azole-class drugs in little more than 1 h in a total volume of 100 µl.IMPORTANCE This work describes an effective assay for TDM of long-chain azole-class antifungal drugs that can be used in diluted human serum samples. This assay will provide a quick, cost-effective method for monitoring concentrations of drugs such as posaconazole that exhibit well-documented pharmacokinetic variability. Our rGO-aptamer assay has the potential to improve health care for those struggling to treat fungal infections in rural or resource-limited setting.


[Enhancement of alphavirus reproduction in cell cultures at an alkaline pH].
Replication of different alphaviruses, among them Semliki Forest, Sindbis, and Venezuelan equine encephalomyelitis viruses, was studied in chick embryo fibroblasts and hamster BHK cells at different pH in a range of 6.8 to 7.9. Incubation of the infected cell cultures in a mild alkaline medium (pH 7.5-7.9) resulted in a marked activation of both one-cycle and multi-cycle reproduction of the alphaviruses under study as compared with that in the neutral medium (pH 6.8-7.2). At an alkaline pH, the rate of amplification and level of synthesis of viral proteins in the infected cells increased markedly, while virus adsorption on cell receptors decreased by 30-50%. It is recommended to use nutrient media with mild alkaline pH for stabilization of alphaviruses reproduction in cell cultures.


Topographical projection of cholinergic neurons in the basal forebrain to the cingulate cortex in the rat.
The cholinergic innervation of the rat's posterior cingulate cortex (Brodmann's area 29) was studied using acetylcholinesterase (AChE) histochemistry. Electrolytic lesion of the ipsilateral medial septum and diagonal band region (MS-DB) reduced the diffuse AChE staining in layers I, II, III and V of the cingulate cortex. Kainic acid lesion of the ipsilateral globus pallidus and substantia innominata area (GP-SI) abolished the dense band of AChE stain in layer IV, with small reductions of AChE stain in other layers. The results indicate that the medial cholinergic pathway from MS-DB terminates diffusely in layers I, II, III and V while the lateral cholinergic pathway from the GP-SI predominantly ends in layer IV of the posterior cingulate cortex.


Perforating BB gun injuries of the globe.
To determine the visual and anatomic outcomes of eyes with perforating BB gun injuries. The authors reviewed the surgical management and final visual outcome of seven patients with BB gun-related perforating injuries of the globe seen by them between 1980 and 1995. Six patients underwent surgery, and one patient refused intervention and was lost to follow-up. Scleral buckles, lensectomies, and vitrectomies were performed in these six cases. Five patients had a final visual acuity of 5/200 or better, with four patients achieving 20/200 or better and two of them having 20/70 or better. A posterior perforation involving the macula or an area temporal to the macula was associated with poor visual outcome. The visual acuity and the relative afferent pupillary defect at presentation or after the initial repair did not correlate with the final visual outcome. In addition, the presence of subretinal blood did not necessarily portend a poor prognosis in these young patients. At least some eyes with perforating injuries can retain good visual acuity with aggressive surgical management using modern vitrectomy techniques. Visual acuity should not necessarily be used as the only exclusion criterion for intervention or enucleation.


Aflatoxin genotoxicity is associated with a defective DNA damage response bypassing p53 activation.
Hepatocellular carcinoma (HCC) is a leading cause of cancer deaths. Aflatoxins, which may play a causative role in 5-28% of HCCs worldwide, are activated in liver cells and induce principally G→T mutations, including the TP53 codon 249(G→T) hotspot mutation. The DNA damage checkpoint response acts as an antitumour mechanism against genotoxic agents, but its role in aflatoxin-induced DNA damage is unknown. We studied the DNA damage checkpoint response of human cells to aflatoxin B1 (AFB1). The treatment of HepG2 hepatoma cells with mutation-inducing doses (3-5 μmol/l) of AFB1 induced DNA adducts, 8-hydroxyguanine lesions and DNA strand breaks that lasted several days. Persistent phospho-H2AX and 53BP1 foci were also detected, but cell growth was not affected. AFB1-exposed HepG2 cells formed phospho-H2AX and 53BP1 foci, but failed to phosphorylate both Chk1 and Chk2. Huh7 hepatoma and HCT116 colorectal cancer cell lines also exhibited a similarly incomplete checkpoint response. p53 phosphorylation also failed, and AFB1-exposed cells did not show p53-dependent G1 arrest or a sustained G2/M arrest. These observations contrasted sharply with the fully functional DNA damage response of cells to Adriamycin. Cotreatment of cells with AFB1 did not inhibit p53 and p21(Cip1) accumulation induced by Adriamycin. Thus, the deficient checkpoint response to AFB1 was not due to an inhibitory effect, but could be explained by an inefficient activation. Genotoxic doses of AFB1 induce an incomplete and inefficient checkpoint response in human cells. This defective response may contribute to the mutagenic and carcinogenic potencies of aflatoxins.


DA1 dopamine receptors in renal cortical collecting duct.
Renal dopamine DA1 receptors are linked to the regulation of sodium transport. We have previously reported the presence of DA1 receptors in the proximal convoluted tubule (PCT) but not in the distal convoluted tubule. However, the DA1 receptor in the collecting duct, the final determinant of electrolyte transport, has not been studied. DA1 receptors were studied in the microdissected cortical collecting duct (CCD) of rats by autoradiography with use of the selective DA1 radioligand 125I-Sch 23982 and by measurement of adenylate cyclase (AC) activity. Specific binding of 125I-Sch 23982 to CCD was saturable with radioligand concentration. The dissociation constant (Kd) was 0.46 +/- 0.08 nM (n = 5), and the maximum receptor density (Bmax) was 1.41 +/- 0.43 fmol/mg protein (n = 5). The DA1 antagonist Sch 23390 was more effective than the DA1 agonist fenoldopam in competing for specific 125I-Sch 23982 binding. Fenoldopam stimulated AC activity in CCD in a concentration-dependent (10(-9)-10(-6) M) manner. The ability of fenoldopam to stimulate AC activity was similar in CCD and PCT even though DA1 receptor density was 1,000 times greater in the CCD than in the PCT. In additional studies, fenoldopam stimulation of AC activity did not influence vasopressin-stimulated AC activity. We conclude that the DA1 receptor in rat CCD is tightly coupled to AC stimulation and that there is no interaction between DA1 agonist-stimulated and vasopressin-stimulated AC activity in the CCD.


Identification and experimental validation of Stearoyl-CoA desaturase is a new drug therapeutic target for osteosarcoma.
Osteosarcoma (OS) is the most common malignant bone tumor. Fatty acid reprogramming plays an essential role in OS progression. However, new fatty acid related therapeutic targets of OS have not been completely elucidated. Therefore, we firstly identified 113 differentially expressed fatty acid metabolism genes using bioinformatic analysis, 19 of which were found to be associated with OS prognosis. Then, 7 hub genes were screened out and yielded a strong prediction accuracy (AUC value = 0.88, at 3 years) for predicting the survival status of OS patients. Furthermore, we confirmed that SCD was highly expressed in OS cells and patients. And Knock-down of SCD impaired proliferation and migration of OS cells. Moreover, SCD was transcriptionally activated by c-Myc to promote proliferation and migration of OS cells. Finally, SCD inhibitor could significantly induce OS ferroptosis in vitro and in vivo. In conclusion, we identified that SCD was a reliable risk factor for OS patients. And SCD was activated by c-Myc. The inhibitor of SCD could significantly impaired OS growth and induce OS ferroptosis, which indicated that SCD was a potential drug target for OS treatment.


High-density-lipoprotein subfraction 3 interaction with glycosylphosphatidylinositol-anchored proteins.
To elucidate further the binding of high-density-lipoprotein subfraction 3 (HDL3) to cells, the involvement of glycosylphosphatidylinositol-anchored proteins (GPI-proteins) was studied. Treatment of cultured cells, such as fibroblasts or SK-MES-1 cells, with a phosphatidylinositol-specific phospholipase C (PI-PLC) significantly decreases specific HDL3 binding. Moreover, PI-PLC treatment of cultured cells or cellular plasma membrane fractions results in releasing proteins. These proteins have a soluble form and can also bind HDL3, as revealed by ligand blotting experiments with HDL3. In order to obtain enriched GPI-proteins, we used a detergent-free purification method to prepare a caveolar membrane fraction. In the caveolar fraction, we obtained, by ligand blotting experiments, the enrichment of two HDL3-binding proteins with molecular masses of 120 and 80 kDa. These proteins were also revealed in a plasma membrane preparation with two other proteins, with molecular masses of 150 and 104 kDa, and were sensitive to PI-PLC treatment. Electron microscopy also showed the binding of Au-labelled HDL3 inside the caveolar membrane invaginations. In SK-MES-1 cells, HDL3 are internalized into a particular structure, resulting in the accumulation and concentration of such specific membrane domains. To sum up, a demonstration has been made of the implication of GPI-proteins as well as caveolae in the binding of HDL3 to cells.


The whole-body withdrawal response of Lymnaea stagnalis. I. Identification of central motoneurones and muscles.
Two muscle systems mediated the whole-body withdrawal response of Lymnaea stagnalis: the columellar muscle (CM) and the dorsal longitudinal muscle (DLM). The CM was innervated by the columellar nerves and contracted longitudinally to shorten the ventral head-foot complex and to pull the shell forward and down over the body. The DLM was innervated by the superior and inferior cervical nerves and the left and right parietal nerves. During whole-body withdrawal, the DLM contracted synchronously with the CM and shortened the dorsal head-foot longitudinally. The CM and the DLM were innervated by a network of motoneurones. The somata of these cells were located in seven ganglia of the central nervous system (CNS), but were especially concentrated in the bilaterally symmetrical A clusters of the cerebral ganglia. The CM was innervated by cells in the cerebral and pedal ganglia and the DLM by cells in the cerebral, pedal, pleural and left parietal ganglia. Individual motoneurones innervated large, but discrete, areas of muscle, which often overlapped with those innervated by other motoneurones. Motoneuronal action potentials evoked one-for-one non-facilitating excitatory junction potentials within muscle fibres. No all-or-nothing action potentials were recorded in the CM or DLM, and they did not appear to be innervated by inhibitory motoneurones. The whole network of motoneurones was electrotonically coupled, with most cells on one side of the CNS strongly coupled to each other but weakly coupled to cells on the contralateral side of the CNS. This electrotonic coupling between motoneurones is probably important in producing synchronous contraction of the CM and DLM when the animal retracts its head-foot complex during whole-body withdrawal.


Measurement of field distributions in ultrasonic cleaning baths: implications for cleaning efficiency.
The information available on ultrasound field distributions in cleaning baths is limited. Two techniques capable of providing this information have been investigated. The first employs a thermistor probe coated with ultrasound absorbing material and uses the rate of temperature rise when the ultrasound is switched on as a measure of local energy density. A motorized scanning frame has been used to map field distributions in three dimensions using the technique. The second technique, the Sarvazyan (dye/paper) method, uses Astralux paper placed in a bath containing an aqueous solution of methylene blue dye. More dye is transferred to the paper in areas where the ultrasound field is most intense. Pockets of gas are trapped in pores in the paper which provide additional nuclei for initiation of cavitation events and these produce small areas of intense staining about 1 mm in diameter, which are related to cavitational activity. The techniques reveal non-uniformities both in the field distribution and in the pattern of cavitational activity in ultrasound cleaning baths. Methods for assessing ultrasound field distributions are required in order to ensure that energy densities are sufficient to initiate cleaning action throughout ultrasonic cleaning baths.


Research progress of photoperiod regulated genes on flowering time in rice.
Rice flowering regulation is an extremely complex process, which is controlled by genetic factors and external environment. Photoperiodic regulatory pathway is pivotal to control flowering in rice, in which florigen genes Hd3a and RTF1 are at the core and they are regulated by upstream Hd1-dependent, Ehd1-dependent, as well as both Hd1- and Ehd1-independent pathways. The three pathways bring a variety of light signal information together to Hd3a and RTF1 for further integration, and then transmit the signals in the form of florigen to the downstream flowering related genes. In this review, we summarize the research progress of photoperiod regulated genes on flowering time in rice, including the photoreceptors and circadian rhythm genes, the florigens, its upstream, downstream and interacting genes. We hope to provide a reference for in-depth study of rice flowering regulation.


Effect of agrin on the distribution of acetylcholine receptors and sodium channels on adult skeletal muscle fibers in culture.
We used the loose patch voltage clamp technique and rhodamine-conjugated alpha-bungarotoxin to study the regulation of Na channel (NaCh) and acetylcholine receptor (AChR) distribution on dissociated adult skeletal muscle fibers in culture. The aggregate of AChRs and NaChs normally found in the postsynaptic membrane of these cells gradually fragmented and dispersed from the synaptic region after several days in culture. This dispersal was the result of the collagenase treatment used to dissociate the cells, suggesting that a factor associated with the extracellular matrix was responsible for maintaining the high concentration of AchRs and NaChs at the neuromuscular junction. We tested whether the basal lamina protein agrin, which has been shown to induce the aggregation of AChRs on embryonic myotubes, could similarly influence the distribution of NaChs. By following identified fibers, we found that agrin accelerated both the fragmentation of the endplate AChR cluster into smaller patches as well as the appearance of new AChR clusters away from the endplate. AChR patches which were fragments of the original endplate retained a high density of NaChs, but no new NaCh hotspots were found elsewhere on the fiber, including sites of newly formed AChR clusters. The results are consistent with the hypothesis that extracellular signals regulate the distribution of AChRs and NaChs on skeletal muscle fibers. While agrin probably serves this function for the AChR, it does not appear to play a role in the regulation of the NaCh distribution.


Epidemiology of retinal detachment.
A survey of rhegmatogenous retinal detachment during 1976 was conducted on the population of Iowa. The annual incidences (per 100,000 populations) of four types of detachment were determined: nontraumatic phakic (6.1), traumatic phakic (1.0), nontraumatic aphakic (4.9), and traumatic aphakic (0.4). The incidences of nontraumatic phakic detachment for men and women were similar, although there was a preponderance of women that reflected their greater representation in the general population. The proportions of men were significantly higher in traumatic detachments compared with nontraumatic detachments. Men tended to be younger than women for all types of detachment; however, only in nontraumatic aphakic detachment was there a significant difference between mean ages. There was an insignificant preponderance of right eye involvement in all four detachment groups.


[The risk factors in operative treatment of an acute and chronic surgical diseases].
According to retrospective analysis of the surgical treatment of patients in presence of cardial risk factors it was established the absence of alternative for surgical intervention while choosing the treatment tactic in 80% of observations, in 16%--the necessity for relaparotomy performance. The direct cause of death in this patients was cardial insufficiency and coronary blood circulation insufficiency, and complications of principal abdominal surgical disease. To improve the results of treatment of this severely ill patients it is expedient to conduct one-stage and the staged surgical and cardiosurgical intervention.


Continuous subcutaneous insulin infusion. A new way to lower risk of severe hypoglycemia, improve metabolic control, and enhance coping in adolescents with type 1 diabetes.
Recommendations from the Diabetes Control and Complications Trial (DCCT) indicate that adolescents with type 1 diabetes should be treated with intensive therapy involving multiple daily injections (MDI) of insulin or insulin pump therapy (continuous subcutaneous insulin infusion [CSII] to help obtain better metabolic control and prevent later complications. Interest has thus focused on insulin pump therapy to help adolescents meet this challenge. The purpose of this study was to examine responses to CSII and MDI in a large group of adolescents with established type 1 diabetes during a 12-month period and to determine whether either treatment regimen more favorably affected clinical and psychosocial outcomes. One-third of 75 youths aged 12-20 years who were candidates for intensive therapy chose CSII as their mode of treatment. Patients received intensive treatment and education as described by the DCCT investigators. Psychosocial data (e.g., quality of life, depression, self-efficacy, and coping) were collected at baseline and at 6-month intervals, and clinical data (e.g., HbA1c levels, adverse events) were collected every 4-6 weeks. Although both MDI- and CSII-treated adolescents initially exhibited improved metabolic control, this level of control was more difficult to sustain for 12 months in the MDI group (at 6 months HbA1c = 8.1, at 12 months HbA1c = 8.3), whereas average HbA1c levels in the CSII group continued to decrease during the 12 months of treatment (at 6 months HbA1c = 7.7, at 12 months HbA1c = 7.5). Despite lower HbA1c levels in CSII-versus MDI-treated patients, the rate of severe hypoglycemic events was reduced by almost 50% in the CSII group (P = 0.01). Self-reported questionnaires demonstrated that there was improvement in self-efficacy, depression, and quality of life in both MDI- and CSII-treated patients. Finally, adolescents using CSII found coping with diabetes to be less difficult than adolescents using MDI did. CSII is an alternative means to lower HbA1c levels and reduce the risk of hypoglycemia without adversely affecting psychosocial outcomes in adolescents with type 1 diabetes.


Cancer dormancy. VII. A regulatory role for CD8+ T cells and IFN-gamma in establishing and maintaining the tumor-dormant state.
Dormant tumor cells resistant to ablative cancer therapy represent a significant clinical obstacle due to later relapse. Experimentally, the murine B cell lymphoma (BCL1) is used as a model of tumor dormancy in mice vaccinated with the BCL1 Ig. Here, we used this model to explore the cellular mechanisms underlying dormancy. Our previous studies have demonstrated that T cell-mediated immunity is an important component in the regulation of tumor dormancy because Id-immune T cells adoptively transferred into passively immunized SCID mice challenged with BCL1 cells significantly increased the incidence and duration of the dormant state. We have extended these observations and demonstrate that CD8+, but not CD4+, T cells are required for the maintenance of dormancy in BCL1 Ig-immunized BALB/c mice. In parallel studies, the transfer of Id-immune CD8+ cells, but not Id-immune CD4+ cells, conferred significant protection to SCID mice passively immunized with nonprotective levels of polyclonal anti-Id and then challenged with BCL1 cells. Furthermore, the ability of CD8+ T cells to induce a state of dormancy in passively immunized SCID mice was completely abrogated by treatment with neutralizing alpha-IFN-gamma mAbs in vivo. In vitro studies demonstrated that IFN-gamma alone or in combination with reagents to cross-link the surface Ig induced both cell cycle arrest and apoptosis in a BCL1 cell line. Collectively, these data demonstrate a role for CD8+ T cells via endogenous production of IFN-gamma in collaboration with humoral immunity to both induce and maintain a state of tumor dormancy.


The UK accelerated immunisation programme and sudden unexpected death in infancy: case-control study.
To investigate whether the accelerated immunisation programme in the United Kingdom is associated, after adjustment for potential confounding, with the sudden infant death syndrome. Population based case-control study, February 1993 to March 1996. Parental interviews were conducted for each death and for four controls matched for age, locality, and time of sleep. Immunisation status was taken from records held by the parents. Five regions in England with a combined population of over 17 million. Immunisation details were available for 93% (303/325) of infants whose deaths were attributed to the sudden infant death syndrome (SIDS); 90% (65/72) of infants with explained sudden deaths; and 95% (1515/1588) of controls. After all potential confounding factors were controlled for, immunisation uptake was strongly associated with a lower risk of SIDS (odds ratio 0.45 (95% confidence interval 0.24 to 0.85)). This difference became non-significant (0.67 (0.31 to 1.43)) after further adjustment for other factors specific to the infant's sleeping environment. Similar proportions of SIDS deaths and reference sleeps (corresponding to the time of day during which the index baby had died) among the controls occurred within 48 hours of the last vaccination (5% (7/149) v 5% (41/822)) and within two weeks (21% (31/149) v 27% (224/822)). No longer term temporal association with immunisation was found (P=0.78). Of the SIDS infants who died within two weeks of vaccination, 16% (5/31) had signs and symptoms of illness that suggested that medical contact was required, compared with 26% (16/61) of the non-immunised SIDS infants of similar age. The findings for the infants who died suddenly and unexpectedly but of explained causes mirrored those for SIDS infants. Immunisation does not lead to sudden unexpected death in infancy, and the direction of the relation is towards protection rather than risk.


Alterations in gait parameters with peripheral artery disease: The importance of pre-frailty as a confounding variable.
Although poor walking is the most common symptom of peripheral artery disease (PAD), reported results are inconsistent when comparing gait parameters between PAD patients and healthy controls. This inconsistency may be due to frailty, which is highly prevalent among PAD patients. To address this hypothesis, 41 participants, 17 PAD (74±8 years) and 24 aged-matched controls (76±7 years), were recruited. Gait was objectively assessed using validated wearable sensors. Analysis of covariate (ANCOVA) tests were used to compare gait parameters between PAD and non-PAD groups, considering age, gender, and body mass index as covariates, while stratified based on frailty status. According to the Fried frailty index, 47% of PAD and 50% of control participants were non-frail and the rest were classified as pre-frail. Within non-frail participants, gait speed, body sway during walking, stride length, gait cycle time, double-support, knee range of motion, speed variability, mid-swing speed, and gait initiation were significantly different between PAD and control groups (effect size d = 0.75±0.43). In the pre-frail group, however, most of the gait differences were diminished except for gait initiation and gait variability. Results suggest that gait initiation is the most sensitive parameter for detecting gait impairment in PAD participants when compared to controls, regardless of frailty status (d = 1.30-1.41; p<0.050). The observed interaction effect between frailty and PAD on gait parameters confirms the importance of assessing functionality in addition to age to provide more consistency in detecting motor performance impairments due to PAD.


[Applying robust management approaches to transit to value-based healthcare].
Health systems require continuous improvement. Along with that, despite the pace of the society development, they face a number of global problems, which can be solved by the transition to value-based healthcare through robust management. The purpose of the study is to analyze the relationship between sustainable healthcare management and life expectancy in the regions of the Russian Federation, with a special focus on the impact of robust management factors on this indicator. The study used theoretical methods: observation, measurement, comparison, analysis, modeling, synthesis, study and generalization, as well as practical ones: modeling using Pandas, Numpy, Scipy, Geopandas, Sklearn, Matplotlib and Seaborn packages for the Python programming language. The study resulted in the construction of a tree-like model of the relationship of indicators, which made it possible to obtain a multi-level list with the mutual influence of factors and thresholds. By examining the dynamics in the relationship between health management strategies and life expectancy across regions, we sought to identify key control factors that can be used to improve health outcomes across the country and assess which ones have more and less impact. The result of the analysis was the determination of the threshold values of indicators, the change in which leads to a significant change in life expectancy.


Managing juvenile Huntington's disease.
Huntington's disease (HD) is a well-recognized progressive neurodegenerative disorder that follows an autosomal dominant pattern of inheritance. Onset is insidious and can occur at almost any age, but most commonly the diagnosis is made between the ages of 35 and 55 years. Onset ≤20 years of age is classified as juvenile HD (JHD). This age-based definition is arbitrary but remains convenient. There is overlap between the clinical pathological and genetic features seen in JHD and more traditional adult-onset HD. Nonetheless, the frequent predominance of bradykinesia and dystonia early in the course of the illness, more frequent occurrence of epilepsy and myoclonus, more widespread pathology, and larger genetic lesion means that the distinction is still relevant. In addition, the relative rarity of JHD means that the clinician managing the patient is often doing so for the first time. Management is, at best, symptomatic and supportive with few or no evidence-based guidelines. In this article, the authors will review what is known of the condition and present some suggestions based on their experience.


Improved results with diabetic below-knee amputations.
This study of 100 consecutive below-knee amputations in 98 diabetic patients was undertaken to review our results and to compare them with a similar report of 20 years ago. Ninety-three limbs were ischemic, and 79% of the patients had significant infection. This finding was similar to that in our previous study group. Twenty-one percent of the patients had previous arterial reconstruction, 11% had had a toe or metatarsal amputation, and 17% required a guillotine (open) amputation to control sepsis. The below- to above-knee amputation ratio was 2.3/1. The selection of level was made on clinical grounds. None of the 100 amputations required revision to above-knee amputation. The mortality rate was 3% and the wound complication rate was 18%. Eighty-three percent of the patients were ambulatory at the time of discharge, which occurred at an average of 35 days. There has been a significant improvement in the number of successful below-knee amputations performed since our previous study. We attribute these results to aggressive surgical control of infection and to close follow-up with early recognition and treatment of healing problems.


Treatment with Fenofibrate plus a low dose of Benznidazole attenuates cardiac dysfunction in experimental Chagas disease.
Trypanosoma cruzi induces serious cardiac alterations during the chronic infection. Intense inflammatory response observed from the beginning of infection, is critical for the control of parasite proliferation and evolution of Chagas disease. Peroxisome proliferator-activated receptors (PPAR)-α, are known to modulate inflammation. In this study we investigated whether a PPAR-α agonist, Fenofibrate, improves cardiac function and inflammatory parameters in a murine model of T. cruzi infection. BALB/c mice were sequentially infected with two T. cruzi strains of different genetic background. Benznidazole, commonly used as trypanocidal drug, cleared parasites but did not preclude cardiac pathology, resembling what is found in human chronic chagasic cardiomyopathy. Fenofibrate treatment restored to normal values the ejection and shortening fractions, left ventricular end-diastolic, left ventricular end-systolic diameter, and isovolumic relaxation time. Moreover, it reduced cardiac inflammation and fibrosis, decreased the expression of pro-inflammatory (IL-6, TNF-α and NOS2) and heart remodeling mediators (MMP-9 and CTGF), and reduced serum creatine kinase activity. The fact that Fenofibrate partially inhibited NOS2 expression and NO release in the presence of a PPAR-α non-competitive inhibitor, suggested it also acted through PPAR-α-independent pathways. Since IκBα cytosolic degradation was inhibited by Fenofibrate, it can be concluded that the NFκB pathway has a role in its effects. Thus, we demonstrate that Fenofibrate acts through PPAR-α-dependent and -independent pathways. Our study shows that combined treatment with Fenofibrate plus Benznidazole is able both to reverse the cardiac dysfunction associated with the ongoing inflammatory response and fibrosis and to attain parasite clearance in an experimental model of Chagas disease.


Radioligand-dependent differences in the molecular properties of the mouse and rat hepatic aryl hydrocarbon receptor complexes.
A comparison of the molecular properties of the male Long-Evans rat and male C57BL/6 mouse hepatic cytosolic aryl hydrocarbon (Ah) receptor complex was determined using 2,3,7,8-[3H]tetrachlorodibenzo-p-dioxin (TCDD) and 2,3,7,8-[3H]tetrachlorodibenzofuran (TCDF) as radioligands. In low salt buffer, the sedimentation coefficients, Stokes radii, relative molecular masses, frictional ratios, axial ratios and gel permeation chromatographic properties of the rat receptor complexes were ligand independent. In contrast, there were several ligand-dependent differences in the mouse Ah receptor complexes formed after incubation in low salt buffer and these include: sucrose density gradient analysis of the 2,3,7,8-[3H]TCDF receptor complex gave a 9.5 S specifically bound peak and a 2.6 S nonspecifically bound peak whereas the corresponding 2,3,7,8-[3H]TCDD receptor complex gave a single 9.6 S specifically bound peak; sucrose density gradient analysis of the two major peaks eluted from a Sephacryl S-300 column chromatographic separation of the 2,3,7,8-[3H]TCDF receptor complex gave two specifically bound peaks at 9.2 and 5.1 S. The molecular properties of the rat hepatic cytosolic receptor complexes incubated in high salt (0.4 M KCl) buffer were ligand independent with one exception, namely the significant difference in the sedimentation coefficient of the specifically bound disaggregated 2,3,7,8-[3H]TCDD receptor complex (6.8 S) and the corresponding 2,3,7,8-[3H]TCDF receptor complex (5.0 S). The major ligand-dependent differences in the mouse receptor complexes incubated in high salt (0.4 M KCl) were associated with the sedimentation coefficients of the complexes derived after direct incubation and after gel permeation chromatography. For example, both ligands gave two specifically bound complexes after chromatography on Sephacryl S-300 column and centrifugation of these fractions gave both the approximately 9 and approximately 5 S peaks; this suggested that there was some equilibration between the aggregated and disaggregated receptor complexes. The behavior of the 2,3,7,8-[3H]TCDF mouse receptor complex was similar after incubation in low or high salt buffer except that sucrose density gradient analysis of the gel permeation chromatographic fractions gave an additional specifically bound peak which sedimented at 7.2 S. These studies demonstrate that the molecular properties of the Ah receptor were dependent on the source of the cytosolic receptor preparation, the ionic strength of the incubation media, and the structure of the radioligand.


Patients' Perspectives on the Quality and Safety of Intravenous Infusions: A Qualitative Study.
The administration of medication or fluids via the intravenous route is a common intervention for many hospital inpatients. However, little research has explored the safety and quality of intravenous therapy from the patient's perspective, despite the role of the patient in patient safety receiving increased attention in recent years. To explore patients' perspectives on the perceived quality and safety of intravenous infusions and identify implications for practice. Qualitative semistructured interviews were conducted with 35 hospital patients receiving intravenous infusions in critical care, oncology day care, general medicine, and general surgery areas within 4 National Health Service hospitals in England. Data were analyzed thematically. Four underlying and interlinked themes were identified: knowledge about intravenous infusions, challenges associated with receiving intravenous infusions, the role of health-care professionals, and patients' attitudes toward receiving infusions. Patients were generally satisfied with receiving infusions; however, factors that contributed to decreased feelings of quality and safety were identified, suggesting areas for intervention. Issues to do with infusion pump alarms, reduced mobility, cannulation, and personal preferences for information, if given more attention, may improve patients' experiences of receiving intravenous infusions.


[Salmonella infection from turtles].
Small turtles are asymptomatic carriers of Salmonella. Infants are particularly at risk of clinical infection. We describe an eight months old boy who became sick with Salmonella. The family had two turtles. Salmonella Abony was found in faeces from the child and in samples from both turtles. Commercial distribution of reptiles is prohibited in Norway. However, illegal import from other countries where no such ban exist is common. There are an estimated 10,000 pet reptiles in the Oslo region, most of them are turtles. More than 90% of turtles may be carriers of Salmonella. Many owners of turtles are not aware of the risk of salmonellosis from their pets.


Electrocoagulation of bleeding in the upper part of the gastrointestinal tract: a preliminary experimental clinical report.
Electrocoagulation of gastric or esophageal bleeding sites was evaluated in dogs using a flexible suction coagulator electrode passed through the endoscope using an electrocautery unit (Cameron-Miller model 80-7910). Acute and chronic coagulation studies in 25 dogs showed that electrocoagulation of both the esophageal and gastric mucosa was safe at an electrocautery unit setting of 5 for three to five seconds. This level of coagulation was successful in stopping bleeding created from actively bleeding esophageal and gastric mucosal defects by taking multiple large biopsy specimens. Based on these data, six patients with active bleeding gastric lesions have undergone mucosal coagulation. This successfully stopped the bleeding initially in all six patients; two patients rebled and required operative intervention within 48 hours. Further clinical evaluation is being implemented to determine its clinical role in the treatment of bleeding in the upper part of the gastrointestinal tract.


Current Pediatric Tertiary Care Admission Practices Following Adenotonsillectomy.
Pediatric adenotonsillectomy is a frequently performed procedure. Few studies have examined perioperative practice patterns for children undergoing adenotonsillectomy. To assess current group practice patterns associated with the perioperative care of children undergoing adenotonsillectomy for sleep-disordered breathing at tertiary care children's hospitals following the release of the 2011 American Academy of Otolaryngology-Head and Neck Surgery (AAO-HNS) clinical practice guidelines. A cross-sectional survey was distributed to the chiefs of 72 pediatric otolaryngology divisions at tertiary care children's hospitals in the United States and Canada from March 25 to April 16, 2014. Internet-based survey responses from the chiefs of pediatric otolaryngology at tertiary care children's hospitals in the United States and Canada, who responded regarding group, rather than individual, practices. Of the 72 surveys sent, 48 responses (67%) were received. Twenty-one respondents (44%) reported that their group has no official admission policy for children with sleep-disordered breathing. Seventy-three percent (29 of 40) reported using some measure of obesity as a criterion for postoperative admission. The AAO-HNS polysomnography criteria for severe obstructive sleep apnea were used by 40% of respondents (16 of 40) as admission criteria, whereas 15% (6 of 40) used the American Academy of Pediatrics criteria for severe obstructive sleep apnea. Seventy-three percent (29 of 40) reported requiring a child to be asleep while breathing room air without oxygen desaturation before discharge to home. An established minimum time for observation was reported by 43 of the respondents (90%). Institution size or volume of adenotonsillectomies performed did not affect the results. Many tertiary care children's hospitals in the United States do not have an official admission policy to guide adenotonsillectomy care. Even for institutions that do have an official admission policy, the policies are not universally aligned with the AAO-HNS clinical practice guidelines. These survey results demonstrate an opportunity to improve quality and safety regarding admission policy practice patterns after pediatric adenotonsillectomy.


Computed tomography colonography (virtual colonoscopy): update on technique, applications, and future developments.
Computed topography colonography (CTC) was first described in 1994 as a rapid, non-invasive imaging method to investigate the colon and rectum. Since the advent of CTC, it has been regarded as a potential alternative technique to conventional colonoscopy for detection of colorectal polyps and cancers. Patients undergo standard bowel preparation 24 to 48 hours before the procedure, using either a standard barium enema preparation or balanced polyethylene glycol (PEG) solution. This rapid examination, without the use of sedation or intervention, is well-tolerated by patients. The potential for limited bowel preparation can reduce discomfort associated with traditional purging techniques significantly, and result in an improved perception of the screening study. CTC is performed using a single or multislice CT scanner, with acquisition of volumetric data from the entire colon. Multislice technology enables fast scanning with high resolution. To minimize the radiation dose, efforts have been made to adapt the tube current to the minimum accepted dose while not diminishing study performance. Acquired CT data are transferred onto a dedicated workstation equipped with navigator software, which permits the radiologist to obtain multiplanar reformations as well as construct an endoluminal model of the air-distended colon. Currently, the most widely accepted application for CTC is following incomplete colonoscopy. Other indications that await further clinical validation include colorectal screening. The collective experience of published studies shows CTC to be an accurate tool for detection of clinically significant colorectal polyps. Specificity and sensitivity of CTC are excellent for polyps larger than 10 mm.


Mycoplasma synoviae surface protein MSPB as a recombinant antigen in an indirect ELISA.
Mycoplasma synoviae is a poultry pathogen causing respiratory disease and synovitis. A number of serological assays have been developed for diagnosis of M. synoviae infection; however, they lack sensitivity and/or are prone to false-positive reactions. Using a combination of PCR and expression cloning, four overlapping regions (regions 1-4) of the surface antigen MSPB of M. synoviae WVU-1853 were expressed in a bacterial expression system. Immunostaining of the resultant polypeptides with chicken sera raised against different M. synoviae strains, or Mycoplasma gallisepticum S6, suggested that region 4 contained a highly antigenic and species-specific domain (amino acids 212-317) [corrected] of MSPB. A fusion protein of region 4 was expressed in the pMAL expression system and purified from cold-osmotic-shock fluids of Escherichia coli cells for use in an indirect ELISA. The potential of the purified antigen for detection of M. synoviae antibodies was assessed with sera obtained from chickens experimentally infected with different strains of M. synoviae or M. gallisepticum, or from uninoculated chickens. All the sera from M. synoviae-inoculated chickens provided higher absorbance values than those from M. gallisepticum-inoculated or uninoculated chickens. Chickens inoculated with M. synoviae 86079/7NS had detectable increases of serum anti-MSPB immunoglobulins at day 7 after inoculation. These studies have identified the most antigenic region of one of the major species-specific surface proteins of M. synoviae, and shown the potential of this protein as a serodiagnostic reagent.


[Topical trends of improving the sanitary-and-epidemiological protection of different territories from bringing extra dangerous viral infections into them and from disseminating such infections].
The state-of-art related with the sanitary-and-epidemiological protection of different territories from bringing into them extra dangerous viral infections and from disseminating such infections (which is a topical issue now addressed by WHO, CIS and the Russian Federation) is elucidated in the paper. Possible trends of perfecting the sanitary-and-epidemiological protection of territories in Russia are under discussion. A differential list of extra dangerous viral infections is defined within the framework of the sanitary-and-epidemiological protection of territories.


A Korean family with a dominantly inherited beta-thalassemia due to Hb Durham-N.C./Brescia.
We describe the molecular and the hematological characteristics of a Korean family with a dominantly inherited beta-thalassemia. Carriers were characterized by moderate anemia, hypochromia, microcytosis, elevated Hb A2 and Hb F levels, and splenomegaly. DNA analysis revealed a CTG (Leu) to CCG (Pro) substitution at codon 114 of the beta-globin gene, that leads to a highly unstable hemoglobin variant, Hb Durham-N.C./Brescia, and this was linked to the beta haplotype V, [+----+-], and framework 2. RNA analysis showed that the proband had comparable levels of mutant and normal beta-mRNA. Translation of the mutant mRNA would give rise to non-functional hyperunstable beta-globin chains, and their degradation would, by placing an additional burden on the proteolytic process of the red blood cell precursors, result in a more severe phenotype.


Microvascular reconstruction after intra-arterial chemotherapy with concomitant radiation.
While the success of microvascular reconstruction is well established, even in the setting of prior radiotherapy, the outcomes in the setting of prior chemoradiation are less well documented. We present our experience with microvascular reconstruction in a unique cohort of patients previously treated with concomitant hyperfractionated radiation and intra-arterial chemotherapy (HYPERRADPLAT). Despite the observation in prior studies of minimal vessel damage in this setting, the hypothesis of this study is that in the late setting of most salvage surgical therapy, either for recurrence or osteoradionecrosis, a different, progressive level of vessel injury may be encountered. Case series with chart review. Tertiary referral academic medical center practice. Eighty-four patients received primary treatment for advanced head and neck squamous cell carcinoma with HYPERRADPLAT. Of these, 8 patients (10%) underwent free tissue transfer reconstruction and a total of 11 free flaps. Wound breakdown, fistula, or both occurred postoperatively in 50% (4/8) of these patients. No complications of the venous anastomoses occurred. Fifty percent (4/8) of patients required return to surgery for arterial failure due to thrombosis of the anastomosis. Two cases of these flaps could not be salvaged. Microvascular reconstruction following HYPERRADPLAT appears to result in a high number of arterial related complications. This experience implies an important delayed treatment effect of HYPERRADPLAT occurs upon recipient arteries. The manner in which this effect may occur in recipient arteries in the setting of more conventional chemoradiation requires further study.


Neurodevelopmental outcomes in children with large temporal arachnoid cysts.
OBJECTIVE Management of children with large temporal arachnoid cysts (TACs) remains controversial, with limited data available on their neurodevelopmental outcome. The aim of this study was to examine neurodevelopmental outcomes in children with large TACs. METHODS In this medical center-based cohort study, 25 patients (19 males) who were diagnosed in childhood with large TACs (9 patients [36%] with a Galassi type II and 16 patients [64%] with a Galassi type III TAC) were examined. The mean ± SD age at assessment was 11.1 ± 5.6 years (range 2.7-22 years). Twelve patients (48%) had right-sided, 12 (48%) had left-sided, and 1 (4%) had bilateral cysts. Nine patients (36%) underwent surgery for the cyst. The siblings of 21 patients (84%) served as control participants. Neurodevelopmental function was assessed using the Adaptive Behavior Assessment System (ABAS), Vanderbilt Behavioral Rating Scale (VBRS), and Developmental Coordination Disorder Questionnaire (DCDQ), and quality of life was measured using the treatment-oriented screening questionnaire (TOSQ). The results of all instruments except for TOSQ were compared with those of the sibling control participants. RESULTS The mean ± SD ABAS score of the patients was 93.3 ± 20.09 compared with 98.3 ± 18.04 of the sibling control participants (p = 0.251). Regarding the incidence of poor outcome (ABAS score < 80), there was a trend for more patients with TAC to have poor outcome than the sibling controls (p = 0.058). Patients who underwent surgery scored significantly worse with regard to the VBRS total score compared with those who did not (p = 0.020), but not on ABAS, DCD, or TOSQ. The mean score of the cognitive and psychological items on TOSQ was lower than that for the physical items (p < 0.001). CONCLUSIONS Children with a large TAC performed similarly to their sibling control participants in neurodevelopmental function. However, a subgroup of those with cysts did have an increased risk for poor outcomes in general function. Neurodevelopmental assessment should be part of the management of all patients with TAC.


Consuming now or later? The interactive effect of timing and attribute alignability.
Decisions are often temporally separated from their outcomes. Using theories of structural alignment and temporal construal, we examined how temporal distance and the associated shift in decision processes moderate susceptibility to context effects. Specifically, in two experiments (one hypothetical, one with real outcomes), we demonstrated that people attend more to nonalignable differences when the outcome of the decision is in the distant future than when it is in the near future. This shift in decision processes was found in preference and choice data, as well as coded written protocols. We further show that this temporal shift cannot be explained by differential involvement with the decision or by the feasibility and desirability of the attributes. Our findings establish temporal distance as an important moderator of structural alignment effects and also extend the implications of temporal construal theory beyond the nature of the attributes to the structural relationships among attributes.


Stable green phosphorescence organic light-emitting diodes with low efficiency roll-off using a novel bipolar thermally activated delayed fluorescence material as host.
A novel bipolar hosting material, 11-(3-(4,6-diphenyl-1,3,5-triazin-2-yl)phenyl)-12,12-dimethyl-11,12-dihydroindeno[2,1-a]carbazole (DPDDC), was designed, synthesized, and characterized for green phosphorescent organic light-emitting diodes (PhOLEDs). The DPDDC exhibits excellent hole and electron transport properties, superior thermal stability, a high glass-transition temperature and a small singlet-triplet energy gap for efficient reverse intersystem crossing from triplet to singlet, reducing the triplet density of the host for PhOLEDs. The electrophosphorescence properties of the devices using DPDDC as the host and three green phosphorescent iridium(iii) complexes, bis(2-(4-tolyl)pyridinato-N,C2')iridium(iii) acetylacetonate, bis(2-phenylpyridine)iridium(iii) acetylacetonate, and bis(4-methyl-2,5-diphenylpyridine)iridium(iii) acetylacetonate [(mdppy)2Iracac] as the emitter were investigated. The green PhOLED with 5 wt% (mdppy)2Iracac presents an excellent performance, including a high power efficiency of 92.3 lm W-1, high external quantum efficiency of 23.6%, current efficiency roll-off as low as 5.5% at 5000 cd m-2 and a twentyfold lifetime improvement (time to 90% of the 5000 cd m-2 initial luminance) over the reference electrophosphorescent device.


Immunoglobulin G4-associated cholangitis mimicking cholangiocarcinoma in a young boy.
Autoimmune pancreatitis is a rare form of chronic pancreatitis, which commonly mimics pancreatic carcinoma. Immunoglobulin G4-associated cholangitis (IAC) is a rare type of autoimmune pancreatitis associated with bile duct involvement, which can present with or without pancreatic involvement. Usually, the bile duct involvement is in the form of multiple intra-and extra-hepatic strictures mimicking primary sclerosing cholangitis. Rarely, there can be an isolated stricture which mimics cholangiocarcinoma. Differentiating these from cholangiocarcinoma, though extremely difficult, is of critical importance since it can be treated without surgical intervention. Most cases with rare presentation mimicking cholangiocarcinoma have been reported in elderly patients. We present one such rare presentation of autoimmune pancreatitis in a young 13-year-old patient in whom hepaticojejunostomy was done for a hilar stricture, which later turned out to be related to IAC. To our knowledge this is the first reported case of its kind from India.


Maternal Social Disadvantage and Newborn Telomere Length in Archived Dried Blood Spots from the Michigan Neonatal Biobank.
Telomeres are the protective caps at the ends of eukaryotic chromosomes. Short telomere length is associated with morbidity and mortality among adults and may mark the biological impact of social experiences. Using archived dried blood spots from the Michigan Neonatal Biobank, this study examined markers of maternal social disadvantage (educational attainment, receipt of public assistance, marital status, and race/ethnicity) from linked birth certificates as predictors of telomere length at birth in a sample of 192 singleton neonates born to non-Hispanic black, non-Hispanic white, and Latina mothers aged 20-35 years. Consistent with two recent studies in newborns, but counter to the idea that maternal social disadvantage is associated with shorter offspring telomere length, we found that infants born to black mothers had longer telomeres than those born to white mothers (b = 0.12, SE = 0.06, p = .05). However, black/white differences in newborn telomere length varied by receipt of public assistance. Among newborns whose mothers received WIC and/or Medicaid, there were no significant black/white differences in telomere length (b = 0.09, SE = 0.08, p = .25). In contrast, among those whose mothers did not receive public assistance-just 6 out of 69 infants born to black mothers versus 41 out of 69 infants born to white mothers-we found that babies born to black mothers had longer telomere length than babies born to white mothers (b = 0.37, SE = 0.16, p = .03). The interaction between black race/ethnicity and receipt of public assistance did not reach the conventional threshold for statistical significance (b = -0.22, SE = 0.15, p = .13), suggesting that this finding may be due to chance. No other markers of maternal social disadvantage were related to infant telomere length. Although replication of these results in a larger sample with more infants born to black mothers with relatively high socioeconomic status is needed, this study offers preliminary support for the hypothesis that race/ethnic differences in newborn telomere length depend on social context.


Identifying Barriers to Idiopathic Pulmonary Fibrosis Treatment: A Survey of Patient and Physician Views.
Antifibrotics are recommended for the treatment of individuals with idiopathic pulmonary fibrosis (IPF), but treatment use remains at ∼60%. To investigate the views of individuals with IPF and pulmonologists on the diagnosis and management of IPF to understand treatment patterns. Interviews and/or online surveys were completed by patients and pulmonologists from Canada, France, Germany, Italy, Spain, and the UK. Responses from physicians were analyzed by time between diagnosis and treatment initiation in the majority of patients with IPF (group A, > 4 months; group B, ≤4 months). Statistical comparisons between physicians were undertaken using z tests, with p < 0.05 considered statistically significant. The physicians in group A saw fewer patients, were less comfortable discussing the IPF prognosis with patients, and had less belief in the benefits of antifibrotic treatments than the physicians in group B. These physicians' attitudes contrasted with those of the patients, who wanted more information about the IPF prognosis and pharmacological treatment options at diagnosis and were more concerned about preventing disease progression than avoiding medication side effects. Differences between countries were found regarding physicians' comfort in discussing the prognosis at diagnosis and access to care. Several barriers to antifibrotic treatment, principally reflecting the differing views and values of patients and physicians, were identified in this study, suggesting a need for better patient-physician communication about pharmacological therapy for IPF.


Management accounting for advanced technological environments.
Management accounting systems designed decades ago no longer provide timely, relevant information for companies in today's highly competitive environment. New operational control and performance measurement systems are recognizing the importance of direct measurement of quality, manufacturing lead times, flexibility, and customer responsiveness, as well as more accurate measures of the actual costs of consumed resources. Activity-based cost systems can assign the costs of indirect and support resources to the specific products and activities that benefit from these resources. Both operational control and activity-based systems represent new opportunities for improved managerial information in complex, technologically advanced environments.


Clinical Features of Chronic Hepatitis B in Treatment-naive Asian Patients With Positive HBeAg and Coexisting Precore and/or Basal Core Promoter Mutations.
Precore or/and basal core promoter (PC/BCP) mutations are frequently detected in hepatitis B e antigen (HBeAg)-negative patients, but little is known about their clinical significance in HBeAg-positive patients. To characterize and report the clinical features of treatment-naive chronic hepatitis B patients who are HBeAg positive and harbor PC and/or BCP mutations. Consecutive treatment-naive patients with chronic hepatitis B between 2004 and 2014 were enrolled. Clinical characteristics were compared based on the stratification of HBeAg status and the presence of PC/BCP mutations. In addition, subset analysis in HBeAg-positive cohort was performed to compare clinical features of patients with and without PC/BCP mutations RESULTS:: Of the 267 patients enrolled from 3 centers, 177 were HBeAg positive and 90 HBeAg negative. When compared with HBeAg-negative patients, HBeAg-positive patients were significantly younger in mean age (37.93 vs. 44.40; P<0.001), had higher levels of median ALT (51 vs. 30.5 U/mL; P<0.001), higher levels of mean HBV DNA (7.50±1.48 vs. 5.10±1.44 log10 copies/mL; P<0.001), and lower frequency of detectable PC/BCP mutations (60.45% vs. 93.33%; P<0.001), but had significantly higher frequency of BCP when mutations were detected (37.85% vs. 22.22%; P=0.013). Among HBeAg-positive patients, when compared with patients with wild type, those with PC/BCP mutations were significantly older (30.63 vs. 42.71; P<0.001), had higher median ALT levels (29.5 vs. 73 U/mL; P<0.001), but there was no significant association with mean HBV DNA levels (7.96 vs. 7.20 log10 copies/mL; P=0.865) or HBV genotype (P=1.000). In the multivariate analysis, only age and ALT were independently associated with PC/BCP mutations in HBeAg-positive patients, but there was no association with HBV genotype or DNA. PC/BCP mutants were frequent (up to 60%) in treatment-naive HBeAg-positive patients and were associated with distinct clinical characteristics when compared with patients with wild type or HBeAg negative. Future large studies are needed to substantiate the long-term clinical outcomes when PC/BCP mutations are detected in HBeAg-positive patients as it may impact the natural history or treatment response in such patients.


Comparison of outcomes and side effects for neoadjuvant chemotherapy with weekly cisplatin and paclitaxel followed by chemoradiation vs. chemoradiation alone in stage IIB-IVA cervical cancer: study protocol for a randomized controlled trial.
Currently, the standard treatment for locally advanced cervical cancer is concurrent chemoradiation (CCRT). The effect of neoadjuvant chemotherapy in advanced cervical cancer is controversial. Studies have shown that the addition of a weekly regimen of neoadjuvant chemotherapy (NACT) followed by CCRT may be superior to a thrice-weekly regimen of NACT and CCRT. Among patients who had not received prior cisplatin, a cisplatin and paclitaxel (TP) regimen resulted in longer overall survival than other regimens. This study aims to investigate the feasibility, safety, and efficacy of NACT with weekly TP followed by CCRT. This is a prospective, randomized, open-labeled, multicentered phase III study. Based on a 65% of 2-year disease-free survival (DFS) rate in the CCRT group and 80% of that in NACT followed by CCRT group, and on prerequisite conditions including an 8% loss to follow-up, a two-sided 5% of type I error probability, and an 80% of power, a total of 300 cases were required for enrollment. Patients with IIB-IVA cervical cancer will be randomly allocated in a 1:1 ratio to one of two intervention arms. In the study arm, patients will receive dose-dense cisplatin (40 mg/m2) and paclitaxel (60 mg/m2) weekly for 4 cycles followed by CCRT (45 Gy in 5 weeks concurrent with cisplatin 40 mg/m2 weekly) plus image-guided adaptive brachytherapy (IGBRT). In the control arm, patients will undergo CCRT treatment. The primary endpoint of the study is 2-year disease-free survival (DFS); the secondary endpoints are 5-year overall survival (OS) and disease-free survival (DFS), the response rate 3 months after treatment completion, grade III/IV adverse effects, and quality of life, and potential biomarkers for predicting treatment response will also be studied. The data gathered from the study will be used to determine whether NACT with weekly TP followed by CCRT may become an optimized treatment for locally advanced cervical cancer. Chinese Clinical Trial Registry ChiCTR1900025327. Registered on 24 August 2019. medresman.org.cn ChiCTR1900025326.


Radiotherapy and tamoxifen in women with completely excised ductal carcinoma in situ of the breast in the UK, Australia, and New Zealand: randomised controlled trial.
As a consequence of mammographic breast screening programmes, ductal carcinoma in situ is diagnosed with increasing frequency. Mastectomy for localised ductal carcinoma in situ is thought to be an over-treatment by many physicians, but there is much controversy as to whether complete local excision alone is sufficient. We aimed to assess the effectiveness of adjuvant radiotherapy and tamoxifen. We used a 2x2 factorial design in a randomised controlled trial. Between May, 1990, and August, 1998, 1701 patients recruited from screening programmes were randomised to both treatments in combination or singly, or to none, or to either one (eg, radiotherapy) with an elective decision to give or to withhold the other (ie, in this case tamoxifen). Patients had complete surgical excision of the lesion confirmed by specimen radiography and histology. Patients have been followed up at least once a year. Median follow-up was 52.6 (range 2.4-118.3) months. Our primary endpoint was the incidence of ipsilateral invasive disease. Ipsilateral invasive disease was not reduced by tamoxifen but recurrence of overall ductal carcinoma in situ was decreased (hazard ratio 0.68 [0.49-0.96]; p=0.03). Radiotherapy reduced the incidence of ipsilateral invasive disease (0.45 [0.24-0.85]; p=0.01) and ipsilateral ductal carcinoma in situ (0.36 [0.19-0.66]; p=0.0004), but there was no effect on the occurrence of contralateral disease. There was no evidence of interaction between radiotherapy and tamoxifen. Radiotherapy can be recommended for patients with ductal carcinoma in situ treated by complete local excision; however, there is little evidence for the use of tamoxifen in these women.


Pulsed oral irrigation in the management of inflammatory periodontal diseases.
While subgingival scaling and root planing are effective at removing plaque, the use of periodic subgingival irrigation with a antimicrobial solution could be a useful adjunct. This paper initially discusses the management of inflammatory periodontal diseases in general, covering current mechanical therapy and chemical antimicrobials, before describing pulsed oral irrigation in more detail.


Meta-analyses of Dehalococcoides mccartyi strain 195 transcriptomic profiles identify a respiration rate-related gene expression transition point and interoperon recruitment of a key oxidoreductase subunit.
A cDNA-microarray was designed and used to monitor the transcriptomic profile of Dehalococcoides mccartyi strain 195 (in a mixed community) respiring various chlorinated organics, including chloroethenes and 2,3-dichlorophenol. The cultures were continuously fed in order to establish steady-state respiration rates and substrate levels. The organization of array data into a clustered heat map revealed two major experimental partitions. This partitioning in the data set was further explored through principal component analysis. The first two principal components separated the experiments into those with slow (1.6±0.6 μM Cl-/h)- and fast (22.9±9.6 μM Cl-/h)-respiring cultures. Additionally, the transcripts with the highest loadings in these principal components were identified, suggesting that those transcripts were responsible for the partitioning of the experiments. By analyzing the transcriptomes (n=53) across experiments, relationships among transcripts were identified, and hypotheses about the relationships between electron transport chain members were proposed. One hypothesis, that the hydrogenases Hup and Hym and the formate dehydrogenase-like oxidoreductase (DET0186-DET0187) form a complex (as displayed by their tight clustering in the heat map analysis), was explored using a nondenaturing protein separation technique combined with proteomic sequencing. Although these proteins did not migrate as a single complex, DET0112 (an FdhB-like protein encoded in the Hup operon) was found to comigrate with DET0187 rather than with the catalytic Hup subunit DET0110. On closer inspection of the genome annotations of all Dehalococcoides strains, the DET0185-to-DET0187 operon was found to lack a key subunit, an FdhB-like protein. Therefore, on the basis of the transcriptomic, genomic, and proteomic evidence, the place of the missing subunit in the DET0185-to-DET0187 operon is likely filled by recruiting a subunit expressed from the Hup operon (DET0112).


Digitizing Tablet and Fahn-Tolosa-Marín Ratings of Archimedes Spirals have Comparable Minimum Detectable Change in Essential Tremor.
Drawing Archimedes spirals is a popular and valid method of assessing action tremor in the upper limbs. We performed the first blinded comparison of Fahn-Tolosa-Marín (FTM) ratings and tablet measures of essential tremor to determine if a digitizing tablet is better than 0-4 ratings in detecting changes in essential tremor that exceed random variability in tremor amplitude. The large and small spirals of FTM were drawn with each hand on two consecutive days by 14 men and four women (age 60±8.7 years [mean±SD]) with mild to severe essential tremor. The drawings were simultaneously digitized with a digitizing tablet. Tremor in each digitized drawing was computed with spectral analysis in an independent laboratory, blinded to the clinical ratings. The mean peak-to-peak tremor displacement (cm) in the four spirals and mean FTM ratings were compared statistically. Test-retest intraclass correlations (ICCs) (two-way random single measures, absolute agreement) were excellent for the FTM ratings (ICC 0.90, 95% CI 0.76-0.96) and tablet (ICC 0.97, 95% CI 0.91-0.99). Log10 tremor amplitude (T) and FTM were strongly correlated (logT=αFTM + β, α≈0.6, β≈-1.27, r=0.94). The minimum detectable change for the tablet and FTM were 51% and 67% of the initial assessment. Digitizing tablets are much more precise than clinical ratings, but this advantage is mitigated by the natural variability in tremor. Nevertheless, the digitizing tablet is a robust method of quantifying tremor that can be used in lieu of or in combination with clinical ratings.


Effectiveness of a 24/7 Dad® Curriculum in Improving Father Involvement: Profiles of Engagement.
Father involvement is a key component in maintaining healthy families and communities. This study presents quantitative results of the first five years of a comprehensive fatherhood training program offered by REACHUP, Inc. in Florida, United States. The program utilized the 24/7 Dad ® curriculum for the fatherhood training program. Key program outcome was differences in pre and post-test scores on self-awareness, fathering skills, parenting skills, relationship skills, and self-care. Demographic and pretest-posttest data collected between 2013 and 2017 were analyzed using chi-square test for categorical variables, McNemar's test for differences in proportions pre- and post-intervention, paired sample t-test to compare means in pretest and posttest scores and analysis of variance (ANOVA) to test the difference between means across years and demographic characteristics. Attendance in the program increased yearly, nearly doubling from 55 participants in 2013 to 97 in 2017. The mean pretest score was 8.90 (±4.04) and the mean posttest score was 16.42 (±4.54) out of 22 total points, representing a highly significant positive effect of the program on self-awareness, fathering skills, parenting skills, relationship skills and self-care which will enable men to establish long-lasting positive relationships with their children. There were significant differences by demographic characteristics. Younger participants tended to score lower on the pretest but made the most knowledge gains following the training as indicated by the difference in pre- and posttest scores (<0.001). Increasing yearly attendance indicates the notion of male involvement is gaining momentum. An important lesson learned over the five-year period is that not all males who participated in the program were biological fathers of infants, young children or adolescents. Many participants were grandfathers, uncles and family friends, indicating that the benefits of a male involvement program can extend beyond the boundaries of biological fatherhood.


Genome resequencing and bioinformatic analysis of SNP containing candidate genes in the autoimmune vitiligo Smyth line chicken model.
The Smyth line (SL) chicken is the only animal model for autoimmune vitiligo that spontaneously displays all clinical and biological manifestations of the human disorder. To understand the genetic components underlying the susceptibility to develop SL vitiligo (SLV), whole genome resequencing analysis was performed in SLV chickens compared with non-vitiliginous parental Brown line (BL) chickens, which maintain a very low incidence rate of vitiligo. Illumina sequencing technology and reference based assembly on Red Jungle Fowl genome sequences were used. Results of genome resequencing of pooled DNA of each 10 BL and SL chickens reached 5.1x and 7.0x coverage, respectively. The total number of SNPs was 4.8 and 5.5 million in BL and SL genome, respectively. Through a series of filtering processes, a total of ~1 million unique SNPs were found in the SL alone. Eventually of the 156 reliable marker SNPs, which can induce non-synonymous-, frameshift-, nonsense-, and no-start mutations in amino acid sequences in proteins, 139 genes were chosen for further analysis. Of these, 14 randomly chosen SNPs were examined for SNP verification by PCR and Sanger sequencing to detect SNP positions in 20 BL and 70 SL chickens. The results of the analysis of the 14 SNPs clearly showed differential frequencies of nucleotide bases in the SNP positions between BL and SL chickens. Bioinformatic analysis showed that the 156 most reliable marker SNPs included genes involved in dermatological diseases/conditions such as ADAMTS13, ASPM, ATP6V0A2, BRCA2, COL12A1, GRM5, LRP2, OBSCN, PLAU, RNF168, STAB2, and XIRP1. Intermolecular gene network analysis revealed that candidate genes identified in SLV play a role in networks centered on protein kinases (MAPK, ERK1/2, PKC, PRKDC), phosphatase (PPP1CA), ubiquitinylation (UBC) and amyloid production (APP). Various potential genetic markers showing amino acid changes and potential roles in vitiligo development were identified in the SLV chicken through genome resequencing. The genetic markers and bioinformatic interpretations of amino acid mutations found in SLV chickens may provide insight into the genetic component responsible for the onset and the progression of autoimmune vitiligo and serve as valuable markers to develop diagnostic tools to detect vitiligo susceptibility.


Gene reporter assay to validate microRNA targets in Drosophila S2 cells.
Bioinformatics programs have helped tremendously in identifying the targets of microRNAs, which are small noncoding RNAs that regulate gene expression posttranscriptionally. However, the partial complementarity between miRNAs and their targets hinders the accuracy of target prediction, necessitating the use of experimental validation procedures. Here, we describe a gene reporter assay typically used in our lab to validate putative miRNA-mRNA interactions in Drosophila S2 cells.