The wheat Em promoter drives reporter gene expression in embryo and aleurone tissue of transgenic barley and rice.
The early methionine (Em) proteins are members of the late embryogenesis abundant (LEA) group of proteins that have been considered to be embryo specific. The ability of a 646-bp wheat Em promoter to control green fluorescent protein (gfp) expression was investigated in transgenic barley and rice. Seeds of transgenic plants expressed gfp in the developing embryo but also in the aleurone layer. The 646-bp Em promoter also directed strong gfp expression in cells comprising the junction between the endosperm transfer cells and cells of the aleurone layer. Em-gfp expression in transgenic barley showed differences in spatial and temporal control when compared with that observed in transgenic rice. Em-gfp expression was also detected in mature aleurone cells of transgenic barley and rice with and without abscisic acid (ABA) treatment. Reverse transcriptase-polymerase chain reaction (RT-PCR) results indicated the presence of Em and Em-homologous transcript in embryo, aleurone and endosperm tissues of wheat and of barley and rice, respectively. These results suggest that Em proteins may be expressed in both the embryo and aleurone during seed development, possibly providing protection against desiccation in these two tissues that survive seed drying. They may also have a similar role in these tissues during germination. The Em promoter from wheat may be useful in the expression of novel genes in cereal grains, as an embryo- and aleurone-specific promoter complementing other available endosperm- and pericarp-specific promoters to collectively increase the expression of transgenes in seeds.


[Pathophysiology and management of perioperative hypothermia].
The paper is a review of pathophysiology and management of perioperative hypothermia. The advanced methods of rewarming, such as passive and active: external and core used in clinic allow for efficient management ant prophylactics of hypothermia. Thermotherapy with use of infrared ceiling heaters CTS and mobile MTC as well as Infutherm system applying by authors are desirable and even indispensable in contemporary equipment of surgery clinics, cardiovascular surgery clinics and burn centers. The ideal rewarming method should be safe and enable fast, reliable and predictable warming or rewarming. The clinical parameter to determine the efficacy of rewarming is the change of core temperature. There is no doubt that active warming with forced-air warmers (Warm Touch 5700 and Bair Hugger 500) or radiative heaters (IR-A:Hydrosun 500, IR-C radiation: CTC X, MTC) is more effective than use of standard, passive insulation hospital blankets or convectional heaters. Actually the forced-air warmers are counted to be more useful in cardiovascular surgery hypothermia management, because of fast rate core temperature rise and faster rise in mean skin temperature compared to the control group. CTC X and MTC Aragona radiative heaters are useful in burn management being the most effective when the distance of heater from the patient body is less than 80 cm. The observation of 60 consecutive extensive burns leads to conclusion that long-lasting dressings in burn patients when the whole body is not covered and protected, can be performed safely only in conditions excluding heat losses and core temperature drop. While the cold intravenous fluids may significantly contribute to the temperature drop depending on the volume infused, the use of fluids warming systems as well as external heat application is absolutely indicated to improve the heat balance of the patient body.


The effects of the insecticide acephate on the growth and nutrient uptake of an aquatic bacterium.
The effects of high (1000 ppm) and low (1 ppm) concentrations of acephate on the rate of growth and nutrient uptake by an aquatic bacterium (identified as Chromobacterium lividum ) were investigated. This insecticide increased doubling time, decreased maximum cellular yield, and reduced cell size when C. lividum was grown in the presence of high acephate concentrations. Total [14C]glucose and 14C-labeled amino acids uptake rates were reduced by the high acephate concentration. The high acephate concentration did not affect active uptake of [14C]cycloleucine, a nonmetabolized amino acid analogue. Low concentration of acephate had little apparent influence upon these metabolic processes.


MTHFR c.1793G>A polymorphism is associated with congenital cardiac disease in a Chinese population.
To investigate whether genetic variants in methylenetetrahydrofolate reductase (MTHFR) and methylenetetrahydrofolate dehydrogenase (MTHFD) genes are associated with risk of congenital cardiac disease. Accumulative evidence suggests that hyperhomocysteinaemia is associated with risk of congenital cardiac disease. Inherited polymorphisms in key folate metabolic pathway genes, MTHFR and MTHFD, may influence the efficiency of folate metabolism and plasma level of homocysteine. A two-stage case-control study of congenital cardiac disease was conducted by genotyping MTHFR c.1793G>A and four other variants - MTHFR c.677C>T, c.1298A>C, and MTHFD c.1958G>A, c.401C>T - in a Chinese population consisting of 1033 congenital cardiac disease patients and 1067 non-congenital cardiac disease patients. The variant genotypes of MTHFR c.1793GA/AA were associated with a significantly decreased risk of congenital cardiac disease in two stages combined, with an adjusted odds ratio of 0.67 and a 95% confidence interval of 0.54-0.84 (p = 0.0004). In comparison with wild-type homozygote c.1793GG, the effect was significant in isolated perimembranous ventricular septal defect patients with an adjusted odds ratio of 0.60 and a 95% confidence interval of 0.43-0.83 (p = 0.0003). These findings indicate that MTHFR c.1793G>A may have a role in susceptibility to sporadic congenital cardiac disease.


Successful control of a school based measles outbreak by immunization.
In an outbreak of measles in North Wales centred on a secondary school in 1991, 74 cases occurred over a period of 51 days. Before the outbreak started, 27% pupils did not have a history of measles or immunization and were considered susceptible. Active case finding and identification and vaccination of susceptible contacts commenced after the fourth generation of cases and further reduced the pool of susceptible schoolchildren from 17%, at the onset of the vaccination campaign, to 8%. A fifth generation of cases did not occur. Delays in diagnosis (mean 2.8 days) and notification (mean 6.1 days) hampered control. There was no evidence of primary vaccine failure (observed vaccine efficacy 97%). Sixty-nine (93%) cases were considered preventable. Reasons for the apparent success of the intervention are discussed.


Impulse noise and neurosensory hearing loss. Relationship to small arms fire.
The problems of noise are not limited to the simple annoyance of an individual. Noise can produce a permanent hearing handicap. Many everyday activities and hobbies are associated with hazardous exposure to noise. The hunter and the sport shooter are potential subjects of severe and unresolvable hearing loss.Noise-induced hearing loss develops insidiously. The means of prevention are far more simple than is correction of the loss. Wearing ear protectors, plugs or earmuffs, is advisable during exposure to hazardous noise.


Synchronization properties of network motifs: influence of coupling delay and symmetry.
We investigate the effect of coupling delays on the synchronization properties of several network motifs. In particular, we analyze the synchronization patterns of unidirectionally coupled rings, bidirectionally coupled rings, and open chains of Kuramoto oscillators. Our approach includes an analytical and semianalytical study of the existence and stability of different in-phase and out-of-phase periodic solutions, complemented by numerical simulations. The delay is found to act differently on networks possessing different symmetries. While for the unidirectionally coupled ring the coupling delay is mainly observed to induce multistability, its effect on bidirectionally coupled rings is to enhance the most symmetric solution. We also study the influence of feedback and conclude that it also promotes the in-phase solution of the coupled oscillators. We finally discuss the relation between our theoretical results on delay-coupled Kuramoto oscillators and the synchronization properties of networks consisting of real-world delay-coupled oscillators, such as semiconductor laser arrays and neuronal circuits.


Free Carriers versus Excitons in CH3NH3PbI3 Perovskite Thin Films at Low Temperatures: Charge Transfer from the Orthorhombic Phase to the Tetragonal Phase.
We have investigated the dynamic optical properties of CH3NH3PbI3 (MAPbI3) perovskite thin films at low temperatures using time-resolved photoluminescence, optical transient absorption (TA), and THz TA spectroscopy. Optical spectroscopic results indicate that the high-temperature tetragonal phase still remains in the MAPbI3 thin films at low temperatures in addition to the major orthorhombic phase. The fast charge transfer from the orthorhombic phase to the tetragonal phase is likely to suppress the formation of excitons in the orthorhombic phase. Consequently, the near-band-edge optical responses of the photocarriers in both the tetragonal and orthorhombic phases of the MAPbI3 thin films are more accurately described by a free-carrier model, rather than an excitonic model even at low temperatures.


[Inhibitory effects of silymarin on hepatic fibrosis induced by dimethylnitrosamine: experiment with rats].
To investigate the antifibrotic effects of silymarin on hepatic fibrosis. Sixty-one male Wistar rats were randomly divided into three groups: control group (15 rats); DMN model group (23 rats), injected intraperitoneally with dimethylnitrosamine (DMN) 10 mg/kg twice per week for 8 weeks to induce hepatic fibrosis; and silymarin group (23 rats), injected intraperitoneally with DMN and given silymarin 50 mg/kg by gastric gavage daily for 8 weeks. Eight weeks late all rats were sacrificed. Blood samples were collected to measure the alanine transaminase (ALT), aspirate aminotransferase (AST), albumin, and total bilirubin (TBIL). The hydroxyproline (Hyp) content in the liver tissue was measured. The histopathological changes as well as the fibrosis stages and score were examined by microscopy. The levels of ALT, AST, and TBIL of the silymarin groups were 59 U/L +/- 19 U/L, 159 U/L +/- 39 U/L, and mean rank 24 respectively, all significantly lower than those of the DMN model group (128 U/L +/- 25 U/L, 246 U/L +/- 61 U/L, and mean rank 37 respectively, P < 0.01, P = 0.001, and P = 0.003). Compared with DMN rats, the level of Hyp of the silymarin was lower by 42.6%, the hepatic score of the silymarin was 6.2 +/- 2.4, significantly than that of the DMN model group (12.8 +/- 4.4, P = 0.001), and more cases in the silymarin group were at the lower stages. Silymarin markedly inhibits and reverse the progression of hepatic fibrosis induced by dimethylnitrosamine.


Participation of Leukotrienes in the Immune Modulation of Oral Tolerance.
Oral tolerance (OT) is characterized as a peripheral immune tolerance form, in which, mature lymphocytes in lymphoid tissues associated with mucosa, become non-functional or hypo responsive due to prior oral administration of antigen. OT is an important immunological phenomenon due to its therapeutic potential in inflammatory processes and others diseases. Here we evaluated leukotriene role in the induction of OT, as well as, the production of cytokines IL-5 and IFN-γ in leukotriene deficient animals (knock-out). Our results suggested that even in the presence of OT and leukotrienes absence, cytokine IFN-γ remains being secreted, which gives us an indication of immune system specificity and also that IFN-γ participates in various immune processes.


Distinct antimicrobial resistance patterns and antimicrobial resistance-harboring genes according to genomic species of Acinetobacter isolates.
Using 58 isolates of Acinetobacter species recovered from a university hospital between August 2004 and March 2005, we performed genomic identification by amplified rRNA gene restriction analysis (ARDRA) and investigated the existence of metallo-beta-lactamase (MBL) producers and extended-spectrum beta-lactamase (ESBL) producers. Genomic species identification of Acinetobacter strains using ARDRA showed that 40 strains were genomic species 2 (Acinetobacter baumannii), 9 were 13 sensu Tjernberg and Ursing (13TU), 5 were Acinetobacter phenon 6/ct 13TU, and 4 were Acinetobacter genospecies 3. Among 58 strains, 13 isolates were MBL producers carrying bla(IMP-1) or bla(VIM-2) and 13 isolates were ESBL producers carrying bla(PER-1). Notably, the MBL producers were mostly 13TU, Acinetobacter phenon 6/ct 13TU, and Acinetobacter genospecies 3, which showed susceptibility to ciprofloxacin and ampicillin-sulbactam. However, 12 of 13 strains carrying bla(PER-1) were A. baumannii, showing multidrug resistance. The data revealed that the antimicrobial resistance patterns and resistance-harboring genes of Acinetobacter species are remarkably distinct according to the genomic species of Acinetobacter isolates.


Comparison of clinical features, molecular alterations, and prognosis in morphological subgroups of lung invasive mucinous adenocarcinoma.
We performed this analysis to distinguish the differences in two subtypes of lung invasive mucinous adenocarcinoma (IMA) with different kinds of morphological performances, in clinicopathological and molecular features, as well as prognosis. On the basis of morphological performance, we divided lung IMAs into two subgroups, mucus-in-cell adenocarcinoma (MICA) and mucus-out-of-cell adenocarcinoma (MOCA). We investigated differences in clinicopathological characteristics, recurrence-free survival (RFS), overall survival (OS), and a spectrum of well-identified driver-gene mutations, including EGFR, KRAS, HER2, BRAF, ALK, ROS1, and RET, between the two subgroups. Of 1,699 lung adenocarcinomas, 148 were identified as IMAs (97 MICAs and 51 MOCAs). The MICA patient group had significantly better RFS than did the MOCA group (39.4 months versus 33.0 months, respectively, log rank P=0.020) and significantly better OS (54.2 months versus 45.1 months, log rank P=0.034). There were no differences in RFS and OS between those with IMAs and those with mucus-negative adenocarcinomas. The frequency of the EGFR gene mutation was significantly higher in MOCAs than in MICAs (P<0.001). In contrast, the KRAS gene had a significantly higher mutational frequency in MICAs (P=0.01). MOCAs also had a significantly higher incidence of lymph-node metastasis (P<0.05). To our knowledge, this study represents the first comparison of clinical features, molecular alterations, and prognosis in morphological subgroups of lung IMAs. Clinical and pathological features in conjunction with molecular data indicate that IMA should be divided into different subgroups.


Multi-Granularity Graph Convolution Network for Major Depressive Disorder Recognition.
Major depressive disorder (MDD) is the most common psychological disease. To improve the recognition accuracy of MDD, more and more machine learning methods have been proposed to mining EEG features, i.e. typical brain functional patterns and recognition methods that are closely related to depression using resting EEG signals. Most existing methods typically utilize threshold methods to filter weak connections in the brain functional connectivity network (BFCN) and construct quantitative statistical features of brain function to measure the BFCN. However, these thresholds may excessively remove weak connections with functional relevance, which is not conducive to discovering potential hidden patterns in weak connections. In addition, statistical features cannot describe the topological structure features and information network propagation patterns of the brain's different functional regions. To solve these problems, we propose a novel MDD recognition method based on a multi-granularity graph convolution network (MGGCN). On the one hand, this method applies multiple sets of different thresholds to build a multi-granularity functional neural network, which can remove noise while fully retaining valuable weak connections. On the other hand, this method utilizes graph neural network to learn the topological structure features and brain saliency patterns of changes between brain functional regions on the multi-granularity functional neural network. Experimental results on the benchmark datasets validate the superior performance and time complexity of MGGCN. The analysis shows that as the granularity increases, the connectivity defects in the right frontal(RF) and right temporal (RT) regions, left temporal(LT) and left posterior(LP) regions increase. The brain functional connections in these regions can serve as potential biomarkers for MDD recognition.


Sequential effects of follicle-stimulating hormone and luteinizing hormone on mouse cumulus expansion in vitro.
LH and FSH play critical roles in the development and function of the cumulus oophorus of the mammalian follicle, but the significance of cumulus LH receptors and the nature of the functional interaction between LH and FSH in relation to the process of cumulus expansion are not well understood. Controversy may arise from contradictory results of cumulus LH receptor assays, possibly as a consequence of relative sensitivities of the assays utilized, limited availability of tissue of specific developmental stages, or limitations on the access of radiolabeled ligands to cumulus LH receptors in the intact follicle. It has also been difficult to understand the basis for the apparent difference in gonadotropin requirements for cumulus expansion in vitro and in vivo; FSH seems to be required for expansion in vitro and LH initiates expansion in vivo. In this study, we show that expansion of mouse cumulus-oocyte complexes (COCs) in vitro occurs to a degree comparable to that seen in vivo when COCs are challenged with highly purified FSH (hpFSH) and highly purified LH (hpLH) together or when treatment with hpFSH precedes treatment with LH. Saturation radioreceptor assays revealed that FSH up-regulates cumulus cell LH receptors in the absence of LH and that LH may stimulate expansion upon binding to these acutely formed receptors. A model of cumulus expansion describing effects of both FSH and LH in vivo is proposed.


[Endometrium proteins].
Research in animal and human reproduction attends with proteins of the endometrium increasingly. Especially in the time of the blastocyst implantation and during survival of the fetal allograft the protein pattern of the endometrium could be important. In the development of the blastocyst of rabbits uteroglobin rendered as a sensitive marker for the biological activity of progesterone. In animal models the desynchronisation of the uteroglobin secretion demonstrated the inhibition of the implantation. In human an alpha 2-globulin was found represented an analogon regarding to rabbits uteroglobin possibly. In the female genital host defense mechanisms of the mucosal barriere especially local produced immunoglobins are important. During pregnancy decidual suppressor factors the maternal tolerance of the fetus.


Isolation of cDNAs from a mouse astroglial cell line by a subtracted cDNA library.
Astrocytes belong to the glial cell population and represent a major subclass of the CNS. Although different subtypes of astrocytes have been described according to their morphological characteristics, biochemical markers of each subtype of astrocytes are not yet available. We have thus undertaken to compare gene expression pattern of different astroglial subtypes. In this study we have taken advantage of two astroglial cell clones derived from 8 day postnatal mouse cerebellar explants and which might be the in vitro equivalents of the velate protoplasmic (D19) and of the Golgi-Bergmann (C8S) astrocytes (Alliot and Pessac, Brain Res., 306: 283-291, 1984). We have constructed a subtracted cDNA library derived from cytoplasmic poly(A)+ RNAs of the D19 cell line. This library was enriched 12-fold for D19 specific sequences by subtractive hybridization with an excess of cytoplasmic poly(A)+ RNAs purified from the C8S astroglial clone. This subtracted library was differentially screened with cDNA probes derived from D19 and C8S cell lines; both probes were subtracted with C8S poly(A)+ RNAs. Eight cDNA clones corresponding to transcripts overexpressed in D19 were selected. Three cDNAs encode for smooth muscle actin, one for fibronectin and one for polyadenylate binding protein. The three other gene products have not been previously reported. The in vivo distribution pattern of these sequences in various mouse adult tissues shows that all these transcripts are expressed in the cerebellum and/or in the brain.


Evaluation of [68Ga]Ga-PSMA PET/CT for therapy response assessment of [177Lu]Lu-PSMA radioligand therapy in metastasized castration refractory prostate cancer and correlation with survival.
The aim of this retrospective study was to evaluate the use of [68Ga]Ga-PSMA PET/CT in therapy response assessment (TRA) of mCRPC patients treated with [177Lu]Lu-PSMA-617 and its correlation with overall survival (OS). Thirty-nine patients were included in the study. Patient-/lesion-based early and late response assessment (ERA/LRA) was defined as PET2 (after two therapy cycles) vs. PET1 (before the first cycle) (n = 29) and end of treatment PET vs. PET1 (n = 17), respectively. PET-based response (PET parameters; modified (m) PERCIST/EORTC), biochemical response (ΔPSA; category-based) and category-based clinical response (CRA) was tested for correlation/agreement. PET-based TRA was correlated with OS. A significant correlation/agreement was shown between PET parameters and CRA as well as biochemical response in LRA of all lesions and between mPERCIST-based and category-based PSA response assessment in LRA (bone lesion-based, P = 0.045, κ = 0.184). At ERA, OS was significantly higher in CR/PR/SD compared to progressive disease applying mPERCIST/EORTC criteria (P = 0.0024). In [177Lu]Lu-PSMA-617-treated mCRPC patients OS of the group of CR/PR/SD was significantly higher compared to the progressive disease group (mPERCIST/EORTC) in ERA. Therefore, [68Ga]Ga-PSMA PET might serve as a complementary diagnostic tool for TRA offering prognostic value regarding OS.


Cystic fibrosis newborn screening: a pilot study to maximize carrier screening.
Newborn screening for cystic fibrosis (CF) is expanding because early diagnosis has been shown to result in improved nutrition and growth. Most newborns identified by a mutation panel have a single detected mutation and require sweat testing to exclude an additional undetected mutation. The resulting identification of CF carrier newborns, although not the primary purpose of screening, has three potential benefits, (1) the detection of trait-trait couples, (2) presymptomatic testing of these couples' previously born children who may have undetected CF, and (3) a carrier parent alerting his/her extended family members to the chance of also being a CF carrier. Reaping each benefit requires genetic counseling of parents and their accepting carrier testing. The purpose of this study was to utilize the sweat testing visit to educate parents about the value of carrier testing for themselves and their blood relatives. We compared special care (genetic counseling after explaining the sweat test result and offering of parental DNA testing, all on the sweat test visit) versus standard care (sweat test result reported by phone to the parents the next day by the newborn's physician, ideally with the recommendation to arrange genetic counseling and parental carrier testing). In the first year of New York State CF screening, 64 newborns with one detected mutation were reported in the nine-county region that includes Rochester. Of these, parents of 39 agreed to participate in the study and to be randomized to special or standard care. Sixty-one parents completed both the initial and 1-year follow-up questionnaires (30 couples and one mother). Of the 61 parents, 23 had carrier testing after the birth of the baby. The frequency of such parental testing was significantly higher in the special care group (17/34 or 50%) than in the standard care group (6/27 or 22%) (p < 0.05). This is the first evidence from a randomized trial that genetic counseling and offering carrier testing to parents on the sweat test visit increases identification of carrier parents. Such identification detects trait-trait parents and facilitates carrier testing among relatives.


The assessment and management of cancer treatment-related diarrhea.
Cancer treatment-induced diarrhea affects a high percentage of patients with cancer that receive chemotherapy or radiation treatment. Widely used criteria for measuring treatment-induced diarrhea, such as the National Cancer Institute Common Toxicity Criteria, do not account for important characteristics of treatment-induced diarrhea. These characteristics include the assessment of the duration of the diarrhea, coexisting symptoms, abdominal cramping, or the presence of nocturnal diarrhea. Until recently, there were no universally accepted guidelines for the management of diarrhea. An expert panel developed guidelines with recommendations regarding assessment of the patient and treatment. These guidelines stress the importance of a thorough assessment of the patient, and treatment based upon severity of symptoms. By employing these guidelines, the aggressive management of diarrhea may impact the overall morbidity of this symptom. Education regarding the importance of diarrhea is essential. Patients who are informed will better understand their role in managing this side effect and when to contact their health care provider with emergent symptoms. Early recognition and management of diarrhea will be essential to improve control of diarrhea, and in turn will positively impact patients' quality of life.


Physiologic versus pathologic hypertrophy: endurance exercise and chronic pressure overload.
Endurance exercise requires that the heart maintain a highly elevated cardiac output for an extended period of time, working against a slightly elevated afterload. Endurance athletes manifest a large ventricular volume, characterized on echocardiogram by an increased end-diastolic internal diameter and wall thickness. This article describes the structural, functional, and biochemical alterations in the heart as a result of the physiologic stress of exercise, along with the signaling mechanisms for these changes. The article also compares exercise-induced hypertrophy and hypertrophy from chronic pressure overload.


[Effect of neuroglobin on oxygen-glucose deprivation and reoxygenation induced autophagy in a human neuroblastoma cell line].
Objective: To investigate the effect of neuroglobin on oxygen-glucose deprivation and reoxygenation (OGD/R) induced autophagy in a human neuroblastoma cell line (SH-SY5Y). Methods: SH-SY5Y cells were transfected with plasmids (or vector) to establish a stable cell line of NGB overexpression (OE). After treated with OGD/R, cells were collected for the analyses of mRNA (Atg5, Atg7, BECN1 and FUNDC1) and protein levels of LC3. Furthermore, mitochondrial and cytosolic fractions were isolated for protein levels of PINK1 and Parkin. Results: Treatment of OGD/R significantly increased the levels of mRNA of Atg5, Atg7, BECN1 and FUNDC1 (peak levels were 4.90±0.71, 6.72±0.75, 2.71±0.39 and 3.96±0.78 fold, all P<0.05). The protein level of Parkin increased in mitochondria and decreased in cytoplasm after the treatment. Compared with the vector group, Ngb OE group showed a significant higher level of FUNDC1 mRNA (3.96±0.78 versus 6.86±0.63 fold, P<0.05), while Atg5, Atg7 and BECN1 mRNA levels showed no significant difference. Moreover, the mitochondrial or cytosolic protein levels of PINK1 or Parkin showed no significant difference between Ngb OE and vector group. Conclusions: Overexpression of Ngb can not affect autophagy or mitohpagy in OGD/R treated SH-SY5Y cells. Overexpression of Ngb can increase the mRNA level of FUNDC1 and the mechanism needs further study.


Testosterone replacement in elderly men.
Testosterone deficiency is common in aging men and is associated not only with decreased libido and sexual functioning but also with the aging process and quality of life. This article reviews the findings associated with hypoandrogenism and outlines the treatments that are available for men with documented testosterone deficiency.


Evaluation of intracardiac shunts.
This article will review the qualitative and quantitative methods of radionuclide evaluation of intracardiac shunts. Radionuclide angiocardiography of the cardiopulmonary system has proven adequate, with few exceptions, for qualitative detection of left-to-right and right-to-left intracardiac shunts. Numerous authors have reported on the detection of intracardiac shunts using qualitative methods such as rapid sequential visualization of nuclide angiocardiography using the scintillation camera with Polaroid, 35mm or 70mm film. Recent development of videotape storage systems and computers offers a quantitative technique of permanently recording the nuclide angiocardiogram and thus the capability for replay and analysis of the study. Quantitative analysis of the nuclide angiogram in the form of heart chamber dilution curves or pulmonary dilution curves permits 1) determination of the presence or absence of left-to-right, right-to-left, or bi-directional intracardiac shunts, including shunts which might go undetected using the qualitative techniques, 2) shunt location at the atrial or ventricular level, 3) determination of the functional status of a corrective left-to-right shunt, and 4) shunt quantitation. By quantitative analysis of the isotope dilution curves, it is possible to calculate the size of left-to-right or right-to-left intracardiac shunts (Qp/Qs ratio) to within 10% of the values obtained at cardiac catheterization.


Oxygen adsorption on the Al₉Co₂(001) surface: first-principles and STM study.
Atomic oxygen adsorption on a pure aluminum terminated Al9Co2(001) surface is studied by first-principle calculations coupled with STM measurements. Relative adsorption energies of oxygen atoms have been calculated on different surface sites along with the associated STM images. The local electronic structure of the most favourable adsorption site is described. The preferential adsorption site is identified as a 'bridge' type site between the cluster entities exposed at the (001) surface termination. The Al-O bonding between the adsorbate and the substrate presents a covalent character, with s-p hybridization occurring between the states of the adsorbed oxygen atom and the aluminum atoms of the surface. The simulated STM image of the preferential adsorption site is in agreement with experimental observations. This work shows that oxygen adsorption generates important atomic relaxations of the topmost surface layer and that sub-surface cobalt atoms strongly influence the values of the adsorption energies. The calculated Al-O distances are in agreement with those reported in Al2O and Al2O3 oxides and for oxygen adsorption on Al(111).


Secondary malignancies after bone marrow transplantation in adults.
The records of 557 consecutive adult recipients of allogeneic-related and -unrelated and syngeneic bone marrow transplants (BMTs) were reviewed to determine the incidence of secondary cancers. Four hundred fifty-six patients were transplanted for acute lymphocytic leukemia (ALL; n = 79), acute myelogenous leukemia (AML; n = 182), and chronic myelogenous leukemia (CML; n = 195); 42 patients were transplanted for aplastic anemia (AA) and 59 for a variety of other hematologic and nonhematologic disorders, malignant and nonmalignant. Conditioning regimens included high-dose chemotherapy with or without total-body irradiation (TBI). Statistical analyses determined the cumulative incidence of developing a secondary cancer and elucidated the associated risk factors. Complete records (1 to 24 years of follow-up) on all patients were available. Nine patients developed 10 secondary cancers for a cumulative actuarial risk of 12% (95% confidence interval [CI], 4.3 to 23.0) 11 years after transplant. The age-adjusted incidence of secondary cancer was 4.2 times higher than that of primary cancer in the general population. Eight of the 10 were epithelial in origin and three were cutaneous. TBI and acute graft-versus-host disease (GVHD) with a severity > or = grade II were associated with the development of any secondary cancer. On the other hand, chronic GVHD was a risk factor only for the development of secondary skin neoplasms. Adult recipients of BMT face a significant risk of developing a secondary malignancy. Their risk is similar to that of other patients with hematologic malignancies who are treated with chemoradiotherapy only. Epithelial tumors, rather than the more commonly reported Epstein-Barr virus (EBV)-associated lymphomas, were most common. The fact that we did not routinely use T-cell-depleted marrow grafts nor anti-T-cell immunoglobulin for the treatment of acute GVHD may explain this variance.


Thrombopoietin serum levels do not correlate with thrombocytopenia in hepatic schistosomiasis.
In severe forms of cirrhosis reduced liver synthesis of thrombopoietin (Tpo) can contribute to thrombocytopenia. In the hepatosplenic form of schistosomiasis, portal hypertension is the most evident clinical complication, although a deficiency of protein synthesis may be detected early. Our aim was to determine, for the first time in schistosomiasis, Tpo serum concentrations in patients with chronic forms of the disease. Twenty-four patients with the pure form of schistosomiasis were studied; 13 had the hepatosplenic form (HE, with portal hypertension) and 11 had the hepatointestinal form (HI, without portal hypertension). Patients were HBsAg, anti-HBc and anti-HCV negative, and reported alcohol ingestion below 160 g/week. The Tpo serum concentration, determined in 10 healthy volunteers, varied from undetectable (< 15 pg/mL) to 489 pg/mL (median 208 pg/mL). The HE and HI groups differed (p = 0.004) in regard to the prothrombin index, thrombocytemia and gamma-glutamyltransferase but not in regard to Tpo (p = 0.622). No significant correlation was found between Tpo and the other parameters (p > 0.05). The results suggest that Tpo serum concentration does not mirror and/or has no significant participation in the mechanisms responsible for the thrombocytopenia observed in schistosomiasis patients with splenomegaly and portal hypertension.


Transfer RNA Modification: Presence, Synthesis, and Function.
Transfer RNA (tRNA) from all organisms on this planet contains modified nucleosides, which are derivatives of the four major nucleosides. tRNA from Escherichia coli/Salmonella enterica serovar Typhimurium contains 33 different modified nucleosides, which are all, except one (Queuosine [Q]), synthesized on an oligonucleotide precursor, which by specific enzymes later matures into tRNA. The structural genes for these enzymes are found in mono- and polycistronic operons, the latter of which have a complex transcription and translation pattern. The synthesis of the tRNA-modifying enzymes is not regulated similarly, and it is not coordinated to that of their substrate, the tRNA. The synthesis of some of them (e.g., several methylated derivatives) is catalyzed by one enzyme, which is position and base specific, whereas synthesis of some has a very complex biosynthetic pathway involving several enzymes (e.g., 2-thiouridines, N 6-cyclicthreonyladenosine [ct6A], and Q). Several of the modified nucleosides are essential for viability (e.g., lysidin, ct6A, 1-methylguanosine), whereas the deficiency of others induces severe growth defects. However, some have no or only a small effect on growth at laboratory conditions. Modified nucleosides that are present in the anticodon loop or stem have a fundamental influence on the efficiency of charging the tRNA, reading cognate codons, and preventing missense and frameshift errors. Those that are present in the body of the tRNA primarily have a stabilizing effect on the tRNA. Thus, the ubiquitous presence of these modified nucleosides plays a pivotal role in the function of the tRNA by their influence on the stability and activity of the tRNA.


Associations between vitamin D receptor polymorphisms and susceptibility to Behcet's disease: A meta-analysis.
The vitamin D receptor (VDR) gene polymorphisms have been reported to be related to the development of Behcet's disease (BD). However, the results have been inconsistent among diverse populations. Therefore, this comprehensive meta-analysis has been designed to assess a more accurate association between VDR polymorphisms and BD susceptibility. An electronic literature search was conducted to identify eligible studies. Pooled odds ratios (OR) with corresponding 95% confidence interval (CI) were calculated in different genetic models to assess this association. A total of six separate comparisons comprised of 468 cases and 516 controls were included in the meta-analysis model. The meta-result demonstrated that A allele of ApaI (A vs. a: 1.54 95% CI = 1.04-2.26, P = 0.029), and F allele of FokI (F vs. f: OR = 0.58, 95% CI = 0.45-0.76, P = 0.007) polymorphisms were associated with the risk of BD in total and African populations, respectively. This significant association was also found in recessive and homozygotes models. Subgroup analysis indicated that FokI variant among Africans and ApaI variant among Caucasian were significantly associated with the risk of BD. No relationship was found between Bsmi and TaqI polymorphisms and BD risk. This meta-analysis demonstrated the association between FokI and ApaI polymorphisms in VDR gene with the risk of BD, providing insights into the potential role of vitamin D receptor in the pathogenesis of BD.


Visualization and Inhibition of Mitochondria-Nuclear Translocation of Apoptosis Inducing Factor by a Graphene Oxide-DNA Nanosensor.
High concentrations of oxidized low density lipoprotein (oxLDL) induce aberrant apoptosis of vascular smooth muscle cells (VSMCs) in atherosclerotic plaques. This apoptosis cannot be blocked completely by the inhibition of caspase, and it eventually potentiates plaque disruption and risk for cardiovascular disease. Given the important role of apoptosis inducing factor (AIF) in caspase-independent apoptosis, here we develop an AIF-targeting nanosensor by the assembly of graphene oxide (GO) nanosheets and dye-labeled DNA hybrid structures. This nanosensor selectively localizes in the cytosol of VSMCs, where it exhibits a "turn-off" fluorescence signal. Under oxLDL stimuli, the release of AIF from mitochondria into cytosol liberates the DNA hybrid structures from the surface of GO and results in a "turn-on" fluorescence signal. This nanosensor is shown to possess rapid response, high sensitivity, and selectivity for AIF that enables real-time imaging of AIF translocation in VSMCs. Using this novel nanosensor, a better assessment of the apoptotic level of VSMCs and a more accurate evaluation of the extent of atherosclerotic lesions can be obtained. More importantly, the abundant binding between DNA hybrid structures and AIF inhibits the translocation of AIF into the nucleus and subsequent apoptosis in VSMCs. This inhibition may help stabilize plaque and reduce the risk of heart attack and stroke.


Korea Superconducting Tokamak Advanced Research vacuum and gas puffing system.
A piezoelectric valve, which has a flow rate of about 463 mbar l/s, has been installed to fuel the Korea Superconducting Tokamak Advanced Research (KSTAR) tokamak. The valve flow rate is in situ calibrated by analyzing the pressure rise curve while fueling the vessel at a constant rate. The calibration method and results are presented. In addition to the flow rate, other vacuum system parameters, such as the pumping speed and the vessel volume, were experimentally obtained. Based on these measurements, a KSTAR vacuum system simulator was developed to calculate the valve drive signal to obtain a programmed pressure trace. An arbitrarily shaped pressure trace was successfully controlled in KSTAR with this hardware and software system.


Whence the energy term of the rate constant?
Insights into the causes of energy barriers to reactions are obtained from our E* model for hydrogen abstractions. Results of the model are in good agreement with all eight experimentally studied symmetrical reactions of the type X-H + (*)X --> X(*) + H-X. The E* energy is broken down into three components: energy needed to overcome triplet repulsion between the terminal Xs, energy needed to bring the H-X bonds to their transition state distances, and energy gain by the resonance stabilization of delocalization of the odd electron over three atoms. The strength of the X-H bond is a minor factor. The conclusion that triplet repulsion is a major factor is supported by the London equation and by results of recent high level theoretical calculations. The E* model requires inputs of bond dissociation energies, bond lengths, and infrared stretching frequencies of X-H and X-X. Some reported failures of E* are shown to have been caused by use of input values subsequently found to be incorrect.


Trends in self-reported visual impairment in the United States: 1984 to 2010.
To explore trends in the prevalence of self-reported visual impairment in the noninstitutionalized adult US population during the 27-year period from 1984 to 2010. Data obtained from the National Health Interview Survey (NHIS) and the Survey of Income and Program Participation (SIPP) were used to analyze trends in the prevalence of self-reported visual impairment in the United States. Representative, population-based samples of between 45 000 and 92 000 adults (NHIS) and between 37 000 and 71 000 adults (SIPP) during each year of data collection. Survey results were age-adjusted to a standard (2010) population. Sampling weights were used throughout the analysis using strata and primary sampling unit variables provided in the public use datasets to appropriately take into account the complex design of the surveys. The statistical significance of trends was estimated by computing the difference in chi-squares of a fit to a linear trendline and a fit without a trend. The trends and percent change in the prevalence of visual impairment from 1984 to 1996 and from 1997 to 2010 for NHIS and 1984 to 2010 for SIPP. On the basis of NHIS data, the prevalence of activity-limiting visual impairment among persons aged ≥65 years declined by 51.7% (P < 0.001), from 3.5% in 1984 to 1.7% in 1996, and by 45.8% (P < 0.001), from 3.1% in 1997 to 1.7% in 2010. On the basis of SIPP data, the prevalence of functional visual impairment in the same age category declined by 58.3% (P < 0.001), from 23.3% in 1984 to 9.7% in 2010, whereas the prevalence of severe functional impairment declined by 47.1% (P < 0.001), from 5.1% to 2.7%. There was a marked reduction in the prevalence of self-reported visual impairment in the noninstitutionalized adult US population during the period from 1984 to 2010.


Draft Genome Sequence of Acetobacter tropicalis Type Strain NBRC16470, a Producer of Optically Pure d-Glyceric Acid.
Here we report the 3.7-Mb draft genome sequence of Acetobacter tropicalis NBRC16470(T), which can produce optically pure d-glyceric acid (d-GA; 99% enantiomeric excess) from raw glycerol feedstock derived from biodiesel fuel production processes.


Mitral valve prolapse. Recent concepts and observations.
The conditions associated with prolapse of the posterior leaflet of the mitral valve are multiple. The mechanisms of mitral valve prolapse as well as the pathogenesis of pain and ectopic impulse formation are reviewed. Propranolol appears to be the drug of choice for the symptomatic treatment of patients with this syndrome since it decreases myocardial oxygen demand and wall tension thus reducing or abolishing the discrepancy between myocardial oxygen demand and supply within the mitral apparatus. It has also been reported to modify the auscultatory findings associated with this condition. The frequency of this mitral valve abnormality in patients with obstructive coronary artery disease is reviewed. It appears that prolapse of the posterior leaflet scallops in patients with significant obstructive coronary artery disease represents an intermediate stage before mitral insufficiency occurs. This group of patients with papillary muscle dysfunction includes those with prolapsed leaflets without mitral insufficiency, those with systolic murmurs and compensated heart failure and others with progressive cardiac decompensation and severe mitral regurgitation.


Quality of Life of Following Mild Traumatic Brain Injury in Youth Soccer Players Title Page.
Pediatric mild traumatic brain injuries (mTBI) represent an evolving field of interest in youth athletics. While most players recover within 4 weeks, some have symptoms that last longer. Little is known about youth health-related quality of life (HRQoL) following mTBI. To characterize youth HRQoL following soccer-related mTBI and to identify predictors of individual differences in HRQoL recovery. Prospective cohort study. Youth Soccer. Soccer players, ages 8-17 years, who sustained mTBI (n=23), orthopedic injuries (OI, n=24), or remained uninjured (n=23) during a single season. HRQoL was assessed via the Pediatric Quality of Life Version 4.0 and post-concussive symptomatology via the Health and Behavior Index. Serial assessments occurred at 24-48 hours, 7 days, 30 days and 90 days post-injury via telephone interview. Seven days post-injury, the mTBI and OI groups had poorer Total HRQoL (F[2,67] =11.35, p<0.001) than uninjured controls. At 7 days, the mTBI group had the poorest Psychosocial HRQoL, while OI had the poorest Physical HRQoL. Differences between the mTBI group and uninjured controls resolved by 30 days. Within the mTBI group, players with significant post-concussive symptoms at 7 days had poorer Total (F[1,21]=23.071, p<=0.001; F[1,21]=5.798, p=0.028), Psychosocial (F[1,21]=16.488, p=<0.001; F[1,21]=5.050, p=0.039), and Physical HRQoL (F[1,21]=21.671, p=<0.001; F[1,21]=5.119, p=0.038) at 7 and 30 days than players with minimal symptoms, and these differences resolved by 90 days. As a groups, youth soccer players who sustained mTBI had transient impairments in HRQoL that resolved by 30 days. A subset of players with significant post-concussive symptoms at 7 days post-injury have poorer HRQoL for at least 30 days post-injury than those whose post-concussive symptoms had resolved within a week of injury. This suggests ongoing recovery in this subset at 30 days and potential utility of HRQoL as a measure of recovery.


Investigation of CNT growth by substrate temperature control using thermal CVD method.
Influence of metal catalyst (Fe) surface condition was investigated for the growth of carbon nanotubes (CNTs). Surface condition of 5 nm thick Fe coated on Si substrate was changed by varying substrate temperature during the CNTs synthesis in a thermal CVD method. Acetylene and argon were used as precursor and carrier gas, respectively, for the synthesis of CNTs. After the growth, the CNTs were removed from the substrate and the post-growth condition of the substrate surface was studied by scanning electron microscopy (SEM), X-ray photoelectron spectroscopy (XPS), and atomic force microscopy (AFM). Unlike the case of untreated Fe-coated Si substrate, XPS analysis shows Si peaks from the thermal treated substrate/samples, which indicates the formation of Fe nanoparticles. AFM results indicate that 750 degrees C is optimum temperature for the nanoparticle formation. Moreover, SEM results show that 700 degrees C is optimum temperature for the CNTs synthesis. The results of this study clarify that the optimum temperature for nanoparticle formation and CNT synthesis are different.


Thermal effects in guest-host systems: [Zn2 (bdc)(S-lac)(dmf)]•PhEtOH: A DSC and NMR study.
Differential scanning calorimetry and nuclear magnetic resonance were used to investigate thermal effects in the guest-host systems where homochiral metal-organic sorbent [Zn2 (bdc)(S-lac)(dmf)] is considered as a host while 1-phenylethanol enantiomers and their racemic mixture serve as guest molecules. A maximum energy gain from the guest-host interaction was observed in the system with the racemic mixture. The effect of host-guest recognition was revealed for the case of the host and guest having a similar type of chirality in the presence of antipode guest molecules.


[Retained cholelithiasis--a risk factor after endoscopic papillotomy?].
Endoscopic papillotomy (EPT) today is in well defined indications an accepted procedure for the therapy of common bile duct stones. In patients with stone gallbladder in situ and bile duct stones it has been recommended to remove the gallbladder after papillotomy in order to prevent late complications. The present study shows that the gallbladder in situ is not necessarily a significant risk factor. On an average of 34,9 months (16-84) after EPT of 223 patients with a follow up, 83,7% were free of symptoms or significantly improved. Cholecystectomy was performed in 43 patients (18,9%): in 24 (11,6%) within an interval , in 13 (6,3%) as an emergency operation following a complication of EPT and in 2 (1%) months later because of recurrent cholecystitis. In patients over 70 years of age with increased risk for surgery therefore a gallbladder with stones after EPT must not absolutely be removed. A wait and see attitude may be justified.


External anal sphincter electromyography in multiple system atrophy: implications for diagnosis, clinical correlations, and novel insights into prognosis.
Multiple system atrophy is a sporadic, progressive, adult-onset, neurodegenerative disorder characterized by autonomic dysfunction symptoms, parkinsonian features, and cerebellar signs in various combinations. An early diagnosis of multiple system atrophy is of utmost importance for the proper prevention and management of its potentially fatal complications leading to the poor prognosis of these patients. The current diagnostic criteria incorporate several clinical red flags and magnetic resonance imaging markers supporting diagnosis of multiple system atrophy. Nonetheless, especially in the early disease stage, it can be challenging to differentiate multiple system atrophy from mimic disorders, in particular Parkinson's disease. Electromyography of the external anal sphincter represents a useful neurophysiological tool for differential diagnosis since it can provide indirect evidence of Onuf's nucleus degeneration, which is a pathological hallmark of multiple system atrophy. However, the diagnostic value of external anal sphincter electromyography has been a matter of debate for three decades due to controversial reports in the literature. In this review, after a brief overview of the electrophysiological methodology, we first aimed to critically analyze the available knowledge on the diagnostic role of external anal sphincter electromyography. We discussed the conflicting evidence on the clinical correlations of neurogenic abnormalities found at external anal sphincter electromyography. Finally, we reported recent prognostic findings of a novel classification of electromyography patterns of the external anal sphincter that could pave the way toward the implementation of this neurophysiological technique for survival prediction in patients with multiple system atrophy.


Coordination modes in the formation of the ternary Am(III), Cm(III), and Eu(III) complexes with EDTA and NTA: TRLFS, 13C NMR, EXAFS, and thermodynamics of the complexation.
The formation and the structure of the ternary complexes of trivalent Am, Cm, and Eu with mixtures of EDTA+NTA (ethylenediamine tetraacetate and nitrilotriacetate) have been studied by time-resolved laser fluorescence spectroscopy, 13C NMR, extended X-ray absorption fine structure, and two-phase metal ion equilibrium distribution at 6.60 m (NaClO4) and a hydrogen ion concentration value (pcH) between 3.60 and 11.50. In the ternary complexes, EDTA binds via four carboxylates and two nitrogens, while the binding of the NTA varies with the hydrogen ion concentration, pcH, and the concentration ratios of the metal ion and the ligand. When the concentration ratios of the metal to ligand is low (1:1:1-1:1:2), two ternary complexes, M(EDTA)(NTAH)(3-) and M(EDTA)(NTA)(4-), are formed at pcH ca. 9.00 in which NTA binds via three carboxylates, via two carboxylates and one nitrogen, or via two carboxylates and a H2O. At higher ratios (1:1:20 and 1:10:10) and pcH's of ca. 9.00 and 11.50, one ternary complex, M(EDTA)(NTA)(4-), is formed in which NTA binds via three carboxylates and not via nitrogen. The two-phase equilibrium distribution studies at tracer concentrations of Am, Cm, and Eu have also confirmed the formation of the ternary complex M(EDTA)(NTA)(4-) at temperatures between 0 and 60 degrees C. The stability constants (log beta111) for these metal ions increase with increasing temperature. The endothermic enthalpy and positive entropy indicated a significant effect of cation dehydration in the formation of the ternary complexes at high ionic strength.


Gene Replacement Therapy: A Primer for the Health-system Pharmacist.
Comprehensive review of gene replacement therapy with guidance and expert opinion on handling and administration for pharmacists. There are currently ∼2600 gene therapy clinical trials worldwide and 4 Food and Drug Administration (FDA)-approved gene therapy products available in the United States. Gene therapy and its handling are different from other drugs; however, there is a lack of guidance from the National Institutes of Health (NIH), FDA, Centers for Disease Control and Prevention (CDC), World Health Organization (WHO), and professional associations regarding their pharmaceutical application. Although the NIH stratifies the backbone biologicals of viral vectors in gene therapies into risk groups, incomplete information regarding minimization of exposure and reduction of risk exists. In the absence of defined guidance, individual institutions develop their own policies and procedures, which often differ and are often outdated. This review provides expert opinion on the role of pharmacists in institutional preparedness, as well as gene therapy handling and administration. A suggested infrastructural model for gene replacement therapy handling is described, including requisite equipment acquisition and standard operating procedure development. Personnel, patient, and caregiver education and training are discussed. Pharmacists have a key role in the proper handling and general management of gene replacement therapies, identifying risk level, establishing infrastructure, and developing adequate policies and protocols, particularly in the absence of consensus guidelines for the handling and transport of gene replacement therapies.


Associations of ChREBP and Global DNA Methylation with Genetic and Environmental Factors in Chinese Healthy Adults.
Age, gender, diet, gene and lifestyle have been reported to affect metabolic status and disease susceptibility through epigenetic pathway. But it remains indistinct that which factors account for certain epigenetic modifications. Our aim was to identify the influencing factors on inter-individual DNA methylation variations of carbohydrate response element binding protein (ChREBP) and global genome in peripheral blood leucocytes (PBLs). ChREBP DNA methylation was determined by bisulfite sequencing, and genomic 5mdC contents were quantified by capillary hydrophilic-interaction liquid chromatography/ in-source fragmentation/ tandem mass spectrometry system in about 300 healthy individuals. Eleven single nucleotide polymorphisms (SNPs) spanning ChREBP and DNA methyltransferase 1 (DNMT1) were genotyped by high resolution melting or PCR-restriction fragment length polymorphism. DNMT1 mRNA expression was analyzed by quantitative PCR. We found ChREBP DNA methylation levels were statistically associated with age (Beta (B) = 0.028, p = 0.006) and serum total cholesterol concentrations (TC) (B = 0.815, p = 0.010), independent of sex, concentrations of triglyceride, high density lipoprotein cholesterol, low density lipoprotein cholesterol (LDL-C), fasting blood glucose and systolic blood pressure, diastolic blood pressure, PBLs counts and classifications. The DNMT1 haplotypes were related to ChREBP (odds ratio (OR) = 0.668, p = 0.029) and global (OR = 0.450, p = 0.015) DNA methylation as well as LDL-C, but not DNMT1 expression. However, only the relation to LDL-C was robust to correction for multiple testing (ORFDR = 1.593, pFDR = 0.013). These results indicated that the age and TC were independent influential factors of ChREBP methylation and DNMT1 variants could probably influence LDL-C to further modify ChREBP DNA methylation. Certainly, sequential comprehensive analysis of the interactions between genetic variants and blood lipid levels on ChREBP and global DNA methylation was required.


Lung Metastases in Patients with Well-Differentiated Gastroenteropancreatic Neuroendocrine Neoplasms: An Appraisal of the Validity of Thoracic Imaging Surveillance.
To evaluate the impact of lung metastases (LM) on overall survival (OS) in well-differentiated (WD) stage IV gastroenteropancreatic neuroendocrine neoplasms (GEP-NEN) patients along with developing surveillance strategies for thoracic imaging. Thirty-four patients with LM, from 3 centres, were identified (22 small intestine/12 pancreatic; 17 grade 1/15 grade 2/2 of unknown grade). For comparison, we used 106 stage IV WD, grade 1 and 2 GEP-NEN patients with metastatic disease confined in the abdomen. LM prevalence was 4.9% (34/692). Eleven patients (32%) presented with synchronous LM whereas 23 (68%) developed metachronous LM at a median of 25 months (range 1-150 months). Patients with metachronous LM had already established liver and/or para-aortic lymph node metastases. Eighteen of 23 patients (78%) with metachronous LM exhibited concomitant progression in the abdomen. Median OS of WD GEP-NEN patients with LM was shorter than for those with stage IV disease without extra-abdominal metastases (56 [95% CI 40.6-71.6] vs. 122.7 [95% CI 70.7-174.8] months; log-rank p = 0.001). Among patients with progressive stage IV disease, the subset of patients with LM exhibited shorter OS (log-rank p = 0.005). LM were also confirmed as an independent prognostic factor for survival in multivariable analysis (HR 0.18; 95% CI 0.07-0.45; p < 0.0001). LM, although relatively rare in patients with WD stage IV GEP-NENs, may impact patients' outcome. The development of metachronous LM is associated with concomitant disease progression in established abdominal metastases in most patients. These patient-related parameters could be utilized for a stratified surveillance approach, mainly reserving thoracic imaging for GEP-NEN patients with progressive disease in the abdomen.


Destructive, granulating lesion in the temporal bone after elevated plasma homocysteine.
This is a presentation of a seemingly new otolaryngologic disease. This study was conducted at a tertiary referral center. A 38-year-old healthy man developed left-sided sudden deafness with vertigo and temporary left facial palsy. A granulating and destructive lesion in the left temporal bone was discovered; repeated histologic examination only showed simple granulation tissue. After 6 months, a part of the bony cochlea was extruded. With approximately 8 months' delay and after the patient had had postoperative lung embolism, plasma homocysteine was found to be significantly elevated, a condition known as an independent risk factor for thromboembolic lesions. In the acquired form, it is most often caused by nutritional deficiency of vitamin B cofactors. Accordingly, the patient was treated with folic acid, which rapidly normalized plasma homocysteine. Subsequently, the granulation tissue in the temporal bone gradually disappeared, clinically and radiologically, and the lesion healed, obviously without cochlea function. Thromboembolic lesion in the left temporal bone, probably in the thin end artery a. labyrintina, i.e., an avascular osteonecrosis. During the latest years, an association between avascular osteonecrosis (most often in the hip) and conditions with increased risk of thrombosis such as hyperhomocystinemia has been established but, to the best of our knowledge, it is never with a lesion in the temporal bone.


Validation of a simplified method to determine left atrial volume by computed tomography in patients with atrial fibrillation.
The success of catheter ablation of atrial fibrillation (AF) is highly dependent on a preprocedural assessment of the size and shape of the left atrium. The most precise method to determine left atrial (LA) volume using computed tomography requires manually tracing the LA area of each cross-sectional image. This is a labor-intensive and time-consuming technique. The purpose of this study was to compare LA volume derived using the "gold-standard" multiple-slice technique with LA volume estimated using 3 orthogonal LA dimensions in patients with AF. The patient population was composed of 100 patients referred for catheter ablation of AF (87 men, mean age 57 +/- 12 years). AF was paroxysmal in 49 patients and persistent in 51. Each patient underwent computed tomography before catheter ablation, and LA volume was measured using the 2 methods. The mean LA volume measured using the multiple-slice technique was 136 +/- 46 ml. According to the simpler estimation approach, the mean LA volume was 112 +/- 41 ml. A close correlation was noted between atrial volumes determined using the 2 methods (r = 0.91, p <0.001). There was a mean underestimation of LA volume by the estimation technique of 17 +/- 13%. In conclusion, the results of this study reveal that LA volume determined using an estimation approach correlates closely with true LA volume as determined using the gold-standard multiple-slice approach. This estimation approach underestimates true LA volume by approximately 20%.


Early experience with robotically assisted laparoscopic donor nephrectomy.
The da Vinci robotic system became available at our institution in late August 2000. We decided to use this system to perform robotically assisted laparoscopic donor nephrectomies. A prospective study was conducted of 10 consecutive patients who underwent robotically assisted laparoscopic donor nephrectomy between January and May 2001. The mean operative time was 166 minutes. The mean hospital stay was 1.8 days. The need for parenteral pain medication was limited to the first postoperative day. All kidneys were transplanted successfully; no rejections occurred. This early experience suggests that the results of robotically assisted laparoscopic donor nephrectomy are similar to those of laparoscopic donor nephrectomy. We believe that robotic surgery, which enables regaining of the hand-eye coordination and three-dimensional view lost in laparoscopic surgery, allows us to perform the donor nephrectomy with greater precision, confidence, and comfort.


Acute Kidney Injury Induced by Immune Checkpoint Inhibitors in Lung Cancer Patients.
Immune checkpoint inhibitors (ICIs) are novel immunotherapy drugs that have significantly improved the outcomes of a variety of cancers including lung cancer. However, ICIs could induce immune-related adverse effects (irAEs) characterized by clinical manifestations that resemble autoimmune disorders. The main type of IrAEs in the kidneys is acute kidney injury (AKI). In this review, we describe the types of ICIs targeting lung cancer, especially those approved by the U.S. Food and Drug Administration for clinical trials in lung cancer patients. Next, we summarize current understandings of the mechanisms involved in ICIs-induced AKI. Finally, we highlight further directions to address ICIs-associated AKI for the benefits of lung cancer patients in the clinic.


Repeated inhalation of adrenomedullin ameliorates pulmonary hypertension and survival in monocrotaline rats.
Adrenomedullin (AM) is a potent vasodilator peptide. We investigated whether inhalation of aerosolized AM ameliorates monocrotaline (MCT)-induced pulmonary hypertension in rats. Male Wistar rats given MCT (MCT rats) were assigned to receive repeated inhalation of AM (n = 8) or 0.9% saline (n = 8). AM (5 mug/kg) or saline was inhaled as an aerosol using an ultrasonic nebulizer for 30 min four times a day. After 3 wk of inhalation therapy, mean pulmonary arterial pressure and total pulmonary resistance were markedly lower in rats treated with AM than in those given saline [mean pulmonary arterial pressure: 22 +/- 2 vs. 35 +/- 1 mmHg (-37%); total pulmonary resistance: 0.048 +/- 0.004 vs. 0.104 +/- 0.006 mmHg.ml(-1).min(-1).kg(-1) (-54%), both P < 0.01]. Neither systemic arterial pressure nor heart rate was altered. Inhalation of AM significantly attenuated the increase in medial wall thickness of peripheral pulmonary arteries in MCT rats. Kaplan-Meier survival curves demonstrated that MCT rats treated with aerosolized AM had a significantly higher survival rate than those given saline (70% vs. 10% 6-wk survival, log-rank test, P < 0.01). In conclusion, repeated inhalation of AM inhibited MCT-induced pulmonary hypertension without systemic hypotension and thereby improved survival in MCT rats.


Health-Related Research Projects in Fiji and Papua New Guinea: A Cross-Sectional Analysis of Fiji and Papua New Guinea Health Research Portals.
Evidence-based medicine and evidence-based public health rely on the best available evidence generated in a specific area for it to be implemented in healthcare practice. This study assesses the range of research studies conducted in Fiji and Papua New Guinea (PNG) islands by reviewing the types of studies now registered with the respective health research registry portals. We assessed all studies registered on the Fiji Health Research Portal (FHRP) and Papua New Guinea Health Research Portal (PNGHRP) since 2014 for the following details: year of registration; study type and participants; field of research; basic statistical analyses; and multicentric or single center study. A total of 99 studies were registered in the FHRP and 6 in PNGHRP during the period under review. Nearly, one fourth of the studies from Fiji and one third from PNG islands are studies evaluating various health policies without involving or collecting data from human subjects. All the registered studies in both the islands were observational (rather than experimental). A total of 58.2% of the registered studies in FHRP and 66.7% in PNGHRP were performed as student projects. A geographic scope of 21.2% of the proposed studies in FHRP and 33.3% in PNGHRP was limited to the respective islands. We conclude from the present analysis that there is a clear need for conducting more high-quality research in both Fiji and PNG in order to meet the health needs of the respective nations. More research focusing on health needs and contributing factors to both communicable and noncommunicable diseases are the need of the hour in both of these south Pacific islands.


Ultrafast nonlinear absorption enhancement of monolayer MoS2 with plasmonic Au nanoantennas.
In this work, we experimentally study the nonlinear absorption enhancement of saturable absorption and two-photon absorption on a hybrid structure comprising a monolayer MoS2 and Au nanoantennas via femtosecond I-scan measurement. Specifically, a 13-fold increment in the linear absorption coefficient is attained at 1.85 eV, along with an 8-fold enhancement of the two-photon absorption coefficient at 1.65 eV, which is attributed to exciton-plasmon coupling resonance and plasmonic hot electron transfer. The exciton-plasmon coupling effect is characterized by stable photoluminescence experiments. Furthermore, the exciton recombination time is extracted from the pump-probe measurement, whose value in the hybrid structure is shortened from 18.5 ps (pure MoS2) to 1.84 ps. Our findings facilitate a new perspective to modulate the nonlinear optical response and to promote the performance of nonlinear photonic devices.


[A Case of Advanced Gastric Cancer with Simultaneous Liver Metastasis for Long-Term Survival with Multimodal Therapy].
We report a case of advanced gastric cancer with simultaneous liver metastasis in which long-term survival has been obtained by multimodal therapy. Case 75-year-old, male. Esophagogastroduodenoscopy revealed advanced type 2 cancer in the greater curvature of the angular incisure. Computed tomography showed a single 20 mm mass was found in liver S2. Histopathological findings indicated that differentiated adenocarcinoma(tub1, HER2 3+). Diagnosis was gastric cancer, cT4aN0M1HEP, Stage Ⅳ. Tumor shrinkage was obtained after 2 courses of capecitabine/cisplatin/trastuzumab. Laparoscopic distal gastrectomy and partial liver resection was performed. Histopathological findings indicated tub1, ypT4aN0M1HEP, ypStage Ⅳ, grade 1a. A single 10 mm recurrence was observed in liver S1/2 13 months after first surgery. After chemotherapy, rehepatic resection was performed. Three years have passed since the last hepatectomy, and the patient is currently undergoing recurrence-free follow-up.


From the office to the pub: the role of smoking-relevant contexts and cue-elicited urge to smoke.
The present study investigates how environmental contexts can affect cue-elicited urge to smoke. A total of 33 smokers were repeatedly presented with a cue predicting smoking and a cue predicting no smoking in one room and the effect of context change in a different room was assessed. Results endorsed earlier findings that a cue predicting smoking availability elicited more urge to smoke than a cue predicting smoking unavailability. Furthermore, this study shows that a context switch from a low smoking-relevant room to a high smoking-relevant room reduces the learned differential urge responding between the two availability cues. These findings are discussed in relation to the role that smoking-relevant contexts play in the generalization of differential urge responding after a context switch. Furthermore, implications for government policies on smoking and clinical issues are discussed.


Impact of Headgroup Asymmetry and Protonation State on the Aggregation Behavior of a New Type of Glycerol Diether Bolalipid.
In the present work, we describe the synthesis and the temperature-dependent aggregation behavior of a new class of asymmetrical glycerol diether bolalipids. These bolalipids are composed of a membrane-spanning alkyl chain with 32 carbon atoms (C32) in the sn-3 position, a methyl-branched C16 alkyl chain in the sn-2 position, and a zwitterionic phosphocholine headgroup in the sn-1 position of a glycerol moiety. The long C32 alkyl chain is terminated either by a second phosphocholine (PC-Gly(2C16Me)C32-PC) or by a phosphodimethylethanolamine headgroup (PC-Gly(2C16Me)C32-Me2PE). The temperature- and pH-dependent aggregation behavior of both lipids was studied using differential scanning calorimetry (DSC), Fourier transform infrared (FTIR) spectroscopy, small-angle X-ray scattering (SAXS), and small-angle neutron scattering (SANS) experiments. The morphology of the formed aggregates in an aqueous suspension was visualized by transmission electron microscopy (TEM). We show that PC-Gly(2C16Me)C32-PC and PC-Gly(2C16Me)C32-Me2PE at pH 5 self-assemble into large lamellar aggregates and large lipid vesicles. Within these structures, the bolalipid molecules are probably assembled in a monolayer with fully interdigitated chains. The lipid molecules seem to be tilted with respect to the layer normal to ensure a dense packing of the alkyl chains. A temperature increase leads to a transition from a lamellar gel phase to the liquid-crystalline phase at about 28-30 °C for both bolalipids. The lamellar aggregates of PC-Gly(2C16Me)C32-Me2PE started to transform into nanofibers when the pH value of the suspension was increased to above 11. At pH 12, these nanofibers were the dominant aggregates.


Polymer-DNA Nanoparticle-Induced CXCR4 Overexpression Improves Stem Cell Engraftment and Tissue Regeneration in a Mouse Hindlimb Ischemia Model.
Peripheral arterial disease affects nearly 202 million individuals worldwide, sometimes leading to non-healing ulcers or limb amputations in severe cases. Genetically modified stem cells offer potential advantages for therapeutically inducing angiogenesis via augmented paracrine release mechanisms and tuned dynamic responses to environmental stimuli at disease sites. Here, we report the application of nanoparticle-induced CXCR4-overexpressing stem cells in a mouse hindlimb ischemia model. We found that CXCR4 overexpression improved stem cell survival, modulated inflammation in situ, and accelerated blood reperfusion. These effects, unexpectedly, led to complete limb salvage and skeletal muscle repair, markedly outperforming the efficacy of the conventional angiogenic factor control, VEGF. Importantly, assessment of CXCR4-overexpressing stem cells in vitro revealed that CXCR4 overexpression induced changes in paracrine signaling of stem cells, promoting a therapeutically desirable pro-angiogenic and anti-inflammatory phenotype. These results suggest that nanoparticle-induced CXCR4 overexpression may promote favorable phenotypic changes and therapeutic efficacy of stem cells in response to the ischemic environment.


A multicentre randomised controlled trial of the McGrath™ Mac videolaryngoscope versus conventional laryngoscopy.
Before completion of this study, there was insufficient evidence demonstrating the superiority of videolaryngoscopy compared with direct laryngoscopy for elective tracheal intubation. We hypothesised that using videolaryngoscopy for routine tracheal intubation would result in higher first-pass tracheal intubation success compared with direct laryngoscopy. In this multicentre randomised trial, 2092 adult patients without predicted difficult airway requiring tracheal intubation for elective surgery were allocated randomly to either videolaryngoscopy with a Macintosh blade (McGrath™) or direct laryngoscopy. First-pass tracheal intubation success was higher with the McGrath (987/1053, 94%), compared with direct laryngoscopy (848/1039, 82%); absolute risk reduction (95%CI) was 12.1% (10.9-13.6%). This resulted in a relative risk (95%CI) of unsuccessful tracheal intubation at first attempt of 0.34 (0.26-0.45; p < 0.001) for McGrath compared with direct laryngoscopy. Cormack and Lehane grade ≥ 3 was observed more frequently with direct laryngoscopy (84/1039, 8%) compared with McGrath (8/1053, 0.7%; p < 0.001) No significant difference in tracheal intubation-associated adverse events was observed between groups. This study demonstrates that using McGrath videolaryngoscopy compared with direct laryngoscopy improves first-pass tracheal intubation success in patients having elective surgery. Practitioners may consider using this device as first choice for tracheal intubation.


Safety assessment in Child A cirrhotic patients treated with Ombitasvir/Paritaprevir/Ritonavir and Dasabuvir with Ribavirin.
In our country, the national program for hepatitis C virus treatment with ombitasvir/paritaprevir/ritonavir and dasabuvir was approved for patients with stage four of liver fibrosis and stage three associated with specific comorbidities. Our aim was to analyze the characteristics associated with the presence of adverse events in patients receiving this antiviral regimen, with ribavirin in cirrhotic patients. We prospectively studied a cohort of adults with hepatitis C virus infection with Child A cirrhosis, treated for 12 weeks with ombitasvir/paritaprevir/ritonavir/dasabuvir and ribavirin, which have been followed in an infectious diseases tertiary-care hospital. We included 137 adult patients diagnosed with compensated cirrhosis, hepatitis C virus genotype 1b infected, 82 (60%) previously treated. We recorded 201 adverse events in 98 (71.5%) patients, with a median number of events per patient of one. The intensity of adverse events was classified as mild, moderate and severe in 50%, 36% and 14% of cases, respectively. Forty-five (22%) episodes required medical intervention. The most frequently reported adverse events were pruritus 34(35%), asthenia 22(22%) and insomnia 15(15%). The presence of severe adverse events was associated with the presence of comorbidities (p = 0.01, OR : 9.5, 95% CI : 1.2-74.3) and with the presence of associated medication (p = 0.02, OR : 3.9, 95% CI : 1.08-14.2). At the end of current treatment, 136 (99.2%) patients had undetectable viral load. We found a high number of adverse events, but most of them were mild or moderate and only one quarter of them required medical intervention. Only severe adverse events were associated with comorbidities and associated medication.


[Genital herpes].
In developed countries, genital herpes is, together with papillomavirus infections, among the most common sexually transmitted diseases. HSV is a dormant virus causing lifelong infection and recurring with or without clinical symptoms. Exposure to lesions and to asymptomatic viral shedding result in transmission. Thus, in most cases, finding the exact path of viral transmission is impossible. The diagnosis is often clinical: classic lesion presentation and typical localised recurrences. The confirmation of the diagnosis is obtained by virus isolation, the most sensitive method is PCR but viral culture techniques are the most widely used. Today, the nucleoside analog antivirals (aciclovir, valacicovir, famciclovir, penciclovir), are the only efficient and well tolerated treatments for genital herpes. The virus resistance to these molecules in immunocompetent patients is very low and has not increased since their introduction. Thus, for these patients, treatment failure is generally due to low bioavailability which is resolved by increasing doses. Ideally a vaccine against herpes should be prophylactic (preventing primary infection) and therapeutic (preventing recurrences). None is available today despite intensive research for the past two decades.


On-Field Methodological Approach to Monitor the Menstrual Cycle and Hormonal Phases in Elite Female Athletes.
Currently, there are no guidelines for implementing the monitoring of menstrual status, including the natural menstrual cycle (NC) or oral contraception (OC), in a sport setting. We aimed to provide a feasible, on-field methodological approach for monitoring NC and OC in female athletes. We developed a smartphone app with daily questionnaires to monitor both NC and OC phases in 19 elite female soccer players (23.7 [4.4] y) over 7 months. Adherence and compliance were evaluated. The NC and OC phases were based on calendar data to establish an individual menstrual profile for each athlete. The initial questionnaire revealed that the vast majority of female players (80%) were interested in monitoring their menstrual status. The online monitoring yielded high athlete adherence (87.0% [14.2%]) with a slight decrease over the winter break and at the end of the championship, which necessitated adaptations to promote compliance. Monitoring identified the specific menstrual pattern of each athlete and highlighted large interindividual variability. This study assesses, for the first time, the interest of female players in monitoring their menstrual status. It provides a new methodological approach, as well as guidelines for optimizing on-field monitoring. It also anticipates some obstacles sport staff may encounter when trying to implement such follow-up. It is essential to better understand the menstrual profile of athletes and determine its potential impacts on well-being and performance.


Ten Tanzanian transplants: problems and perspectives.
A strategy of live related donor kidney transplantation coupled to the briefest possible preparatory period of haemodialysis was adopted as the most cost effective treatment for a selected group of 9 Tanzanian patients who received a total of 10 grafts. Patient and donor selection and preparation were carried out at Muhimbuli Medical Centre, Dar es Salaam, and the transplant procedure and first few months of follow-up were done at St. Thomas' Hospital, London. There was a high incidence of complications which drew attention to particular risk factors in the group treated. The high cost of treating these individuals emphasizes the need for research into chronic communicable and non-communicable diseases in Africa and highlights the dilemma of appropriate use of resources in serving the world's medical needs.


Photocontrolled SiRNA Delivery and Biomarker-Triggered Luminogens of Aggregation-Induced Emission by Up-Conversion NaYF4:Yb3+Tm3+@SiO2 Nanoparticles for Inducing and Monitoring Stem-Cell Differentiation.
Controlling the differentiation of stem cells and monitoring cell differentiation has attracted much research interest since the discovery of stem cells. In this regard, a novel near-infrared (NIR) light-activated nanoplatform is obtained by encapsulating the photoactivatable caged compound (DMNPE/siRNA) and combining a MMP13 cleaved imaging peptide-tetrapheny-lethene (TPE) unit conjugated with the mesoporous silica-coated up-conversion nanoparticles (UCNPs) for the remote control of cell differentiation and, simultaneously, for the real-time monitoring of differentiation. Upon NIR light illumination, the photoactivated caged compound is activated, and the siRNA is released from UCNPs, allowing controlled differentiation of stem cells by light. More importantly, MMP13 enzyme triggered by osteogenic differentiation would effectively cleave the TPE probe peptide, thereby allowing the real-time monitoring of differentiation in living stem cells by aggregation-induced emission (AIE).


Health service organisations and professionals: an information systems model for transforming the nexus between accreditation and practice.
This paper presents a qualitative research approach used to generate data and theoretical insights for information systems design in a highly regulated health service organisation. Ethnographical and sociological analytic techniques were used for sensemaking in the domain, and then identifying key structures affecting the conduct of the health service. A key aspect was taking a futures perspective of possibilities for evolution of these structures. From this, a continuum model representing the nexus between accreditation and practice was developed, varying the degree of integration of information systems for organisation and individual-level accreditation. The paper uses the model to discuss the implications of possibilities for design in organisations where accreditation requirements have implications for work practice and information systems design.


Mechanisms regulating intracellular pH are activated during growth of the mouse oocyte coincident with acquisition of meiotic competence.
Oocytes grow within ovarian follicles, and only gain the ability to complete meiosis when they are nearly fully grown. We have found that both of the major types of intracellular pH regulatory mechanisms in the mammal-the Na+/H+ and HCO3-/Cl- exchangers-were essentially inactive in mouse oocytes over most of the course of their growth. However, as oocytes approached full size, Na+/H+ and HCO3-/Cl- exchangers became simultaneously active, and, at the same time, the intracellular pH of isolated oocytes increased sharply by about 0.25 pH unit. This activation of intracellular pH regulatory mechanisms and increase in pH occurred coincident with the acquisition of meiotic competence. The activation of pH regulatory mechanisms during oocyte growth represents a previously unknown milestone in the development of the capacity of the oocyte to function independently upon ovulation.


Proliferation zones in the axolotl brain and regeneration of the telencephalon.
Although the brains of lower vertebrates are known to exhibit somewhat limited regeneration after incisional or stab wounds, the Urodele brain exhibits extensive regeneration after massive tissue removal. Discovering whether and how neural progenitor cells that reside in the ventricular zones of Urodeles proliferate to mediate tissue repair in response to injury may produce novel leads for regenerative strategies. Here we show that endogenous neural progenitor cells resident to the ventricular zone of Urodeles spontaneously proliferate, producing progeny that migrate throughout the telencephalon before terminally differentiating into neurons. These progenitor cells appear to be responsible for telencephalon regeneration after tissue removal and their activity may be up-regulated by injury through an olfactory cue. There is extensive proliferation of endogenous neural progenitor cells throughout the ventricular zone of the adult axolotl brain. The highest levels are observed in the telencephalon, especially the dorsolateral aspect, and cerebellum. Lower levels are observed in the mesencephalon and rhombencephalon. New cells produced in the ventricular zone migrate laterally, dorsally and ventrally into the surrounding neuronal layer. After migrating from the ventricular zone, the new cells primarily express markers of neuronal differentiative fates. Large-scale telencephalic tissue removal stimulates progenitor cell proliferation in the ventricular zone of the damaged region, followed by proliferation in the tissue that surrounds the healing edges of the wound until the telencephalon has completed regeneration. The proliferative stimulus appears to reside in the olfactory system, because telencephalic regeneration does not occur in the brains of olfactory bulbectomized animals in which the damaged neural tissue simply heals over. There is a continual generation of neuronal cells from neural progenitor cells located within the ventricular zone of the axolotl brain. Variable rates of proliferation were detected across brain regions. These neural progenitor cells appear to mediate telencephalic tissue regeneration through an injury-induced olfactory cue. Identification of this cue is our future goal.


Prognostic Role of Neutrophil-to-Lymphocyte Ratio in Patients with Human Papillomavirus-Positive Oropharyngeal Cancer.
Objective To investigate the prognostic impact of the neutrophil-to-lymphocyte ratio (NLR) for human papillomavirus-positive oropharyngeal cancer (HPV+ OPC). Study Design Retrospective institutional database analysis. Setting Tertiary referral medical center. Material and Methods In total, 104 patients with HPV+ OPC were enrolled. From the blood laboratory data checked within 4 weeks before initiation of primary treatment, NLR was calculated. The association between clinicopathological characteristics and NLR was analyzed, and the prognostic role was evaluated based on overall survival (OS) and disease-free survival (DFS). Results According to the cutoff value (2.42) for NLR, the patients were classified into the low NLR group (n = 61) or the high NLR group (n = 43). High NLR was associated with a higher rate of advanced T classification ( P = .007) and diabetes mellitus ( P = .01). The proportion of surgery-based treatment was lower in the high NLR group (20.9% vs 42.6%, P = .02). The high NLR group showed a lower 5-year OS rate (85.3% vs 96.3%, P = .09) and a lower 5-year DFS rate (68.1% vs 94.7%, P = .01) than those in the low NLR group. Multivariate analysis showed that advanced N classification was a significant predictor for worse 5-year OS (hazard ratio [HR], 17.40; 95% confidence interval [CI], 2.36-128.29) and that both advanced N classification (HR, 7.78; 95% CI, 2.33-25.93) and high NLR (HR, 4.16; 95% CI, 1.24-13.95) were important prognosticators for worse 5-year DFS. Conclusion Elevated pretreatment NLR was associated with poor DFS in patients with HPV+ OPC.


Cell entry of arginine-rich peptides is independent of endocytosis.
Arginine-rich peptides are a subclass of cell-penetrating peptides that are taken up by living cells and can be detected freely diffusing inside the cytoplasm and nucleoplasm. This phenomenon has been attributed to either an endocytic mode of uptake and a subsequent release from vesicles or to direct membrane penetration (transduction). To distinguish between both possibilities, we have blocked endocytic pathways suggested to be involved in uptake of cell-penetrating peptides. We have then monitored by confocal microscopy the uptake and distribution of the cell-penetrating transactivator of transcription (TAT) peptide into living mammalian cells over time. To prevent side effects of chemical inhibitors, we used genetically engineered cells as well as different temperature. We found that a knockdown of clathrin-mediated endocytosis and a knock-out of caveolin-mediated endocytosis did not affect the ability of TAT to enter cells. In addition, the TAT peptide showed the same intracellular distribution throughout the cytoplasm and nucleus as in control cells. Even incubation of cells at 4 degrees C did not abrogate TAT uptake nor change its intracellular distribution. We therefore conclude that this distribution results from TAT peptide that directly penetrated (transduced) the plasma membrane. The formation of nonselective pores is unlikely, because simultaneously added fluorophores were not taken up together with the TAT peptide. In summary, although the frequency and kinetics of TAT transduction varied between cell types, it was independent of endocytosis.


The Colibactin Genotoxin Generates DNA Interstrand Cross-Links in Infected Cells.
Colibactins are hybrid polyketide-nonribosomal peptides produced by Escherichia coli, Klebsiella pneumoniae, and other Enterobacteriaceae harboring the pks genomic island. These genotoxic metabolites are produced by pks-encoded peptide-polyketide synthases as inactive prodrugs called precolibactins, which are then converted to colibactins by deacylation for DNA-damaging effects. Colibactins are bona fide virulence factors and are suspected of promoting colorectal carcinogenesis when produced by intestinal E. coli Natural active colibactins have not been isolated, and how they induce DNA damage in the eukaryotic host cell is poorly characterized. Here, we show that DNA strands are cross-linked covalently when exposed to enterobacteria producing colibactins. DNA cross-linking is abrogated in a clbP mutant unable to deacetylate precolibactins or by adding the colibactin self-resistance protein ClbS, confirming the involvement of the mature forms of colibactins. A similar DNA-damaging mechanism is observed in cellulo, where interstrand cross-links are detected in the genomic DNA of cultured human cells exposed to colibactin-producing bacteria. The intoxicated cells exhibit replication stress, activation of ataxia-telangiectasia and Rad3-related kinase (ATR), and recruitment of the DNA cross-link repair Fanconi anemia protein D2 (FANCD2) protein. In contrast, inhibition of ATR or knockdown of FANCD2 reduces the survival of cells exposed to colibactin-producing bacteria. These findings demonstrate that DNA interstrand cross-linking is the critical mechanism of colibactin-induced DNA damage in infected cells.IMPORTANCE Colorectal cancer is the third-most-common cause of cancer death. In addition to known risk factors such as high-fat diets and alcohol consumption, genotoxic intestinal Escherichia coli bacteria producing colibactin are proposed to play a role in colon cancer development. Here, by using transient infections with genotoxic E. coli, we showed that colibactins directly generate DNA cross-links in cellulo Such lesions are converted into double-strand breaks during the repair response. DNA cross-links, akin to those induced by metabolites of alcohol and high-fat diets and by widely used anticancer drugs, are both severely mutagenic and profoundly cytotoxic lesions. This finding of a direct induction of DNA cross-links by a bacterium should facilitate delineating the role of E. coli in colon cancer and engineering new anticancer agents.


Fibrous dysplasia of bone associated with primary hyperparathyroidism.
Fibrous dysplasia of bone and primary hyperparathyroidism (PHPT) may occur in patients with McCune-Albright Syndrome. A small number of cases with both diagnoses that are not associated with the above-mentioned genetic disorder have been published in the literature. It is uncertain if these disorders are linked in some way. In the present study, we aimed to further explore a potential relationship between PHPT and fibrous dysplasia of bone. We conducted a retrospective review of all cases seen at Mayo Clinic, Rochester, Minnesota, between 1976 and 2011 that were diagnosed with both PHPT and fibrous dysplasia of bone. We identified 10 patients who were diagnosed with both PHPT and fibrous dysplasia of bone. Fibrous dysplasia was polyostotic in 7 (70%) cases. It affected the lower extremities in 6 (60%) patients, the skull or facial bones in 4 (40%), and was localized to one rib in 1 patient (10%). In 4 patients, fibrous dysplasia was diagnosed first, between 9 to 50 years before being diagnosed with PHPT. Two cases of fibrous dysplasia were recognized between 2 and 5 years after the diagnosis of PHPT. The remaining 4 patients were diagnosed with both conditions at approximately the same time. It remains unclear if the association between fibrous dysplasia of bone and PHPT is more than coincidental, although the possibility of a rare familial genetic syndrome is not completely excluded.


Clinical Applications of the Standard Error of Measurement for Occupational and Phsical Therapists.
Standardized pediatric testing is a common tool used to gather information is the assessment process for occupational and physical therapists. A description of the application of the standard error of measurement (SEM) for interpretation of children's scores from standardized norm- referenced tests is given. Three case examples are presented to demonstrate the use of the SEM and its impact on children's test scores when therapist are making critical clinical decisions. Recommendations for therapist related to interpreting standardized testing, reporting test scores, and measuring intervention progress are included.


Neutrophil serine proteases and their endogenous inhibitors in coronary artery ectasia patients.
Proteolytic enzymes possibly contribute to coronary artery ectasia (CAE). This study aimed to determine whether neutrophils, neutrophil serine proteases (NSPs), and their endogenous inhibitors participated in the pathological process of CAE. The study consisted of 30 patients with CAE, 30 patients with coronary artery disease (CAD), and 29 subjects with normal coronary arteries (Control). The following circulating items were measured: the main NSPs, including human neutrophil elastase (HNE), cathepsin G (CG), and proteinase 3 (PR3); soluble elastin (sElastin), which was a degradation product of elastin fibres; NSP inhibitors such as α1-protease inhibitor (α1-PI), α2-macroglobulin (α2-MG), secretory leucoprotease inhibitor (SLPI), and elafin; as well as two neutrophil activation markers (myeloperoxidase and lactoferrin) and three classic neutrophil activators [tumor necrosis factor-α (TNF-α), interleukin-8 (IL-8), and bacterial endotoxin]. The levels of HNE, CG, and sElastin were elevated in the CAE group. The levels of α1-PI and α2-MG were also significantly increased in the CAE group. The levels of myeloperoxidase and lactoferrin were higher in the CAE group. The levels of TNF-α, IL-8, and endotoxin were unchanged in the CAE group compared with those in the CAD group. Neutrophils may participate in the process of vessel extracellular matrix destruction and coronary ectasia by releasing NSPs in a non-classical manner.


Intra- and interspecific genetic diversity of New Zealand hairworms (Nematomorpha).
Hairworms (Nematomorpha) are a little-known group of parasites, and despite having been represented in the taxonomic literature for over a century, the implementation of molecular genetics in studies of hairworm ecology and evolution lags behind that of other parasitic taxa. In this study, we characterize the genetic diversity of the New Zealand nematomorph fauna and test for genetic structure within the most widespread species found. We provide new mitochondrial and nuclear ribosomal sequence data for three previously described species from New Zealand: Gordius paranensis, Parachordodes diblastus and Euchordodes nigromaculatus. We also present genetic data on a previously reported but undescribed Gordius sp., as well as data from specimens of a new Gordionus sp., a genus new for New Zealand. Phylogenetic analyses of CO1 and nuclear rDNA regions correspond with morphological classification based on scanning electron microscopy, and demonstrate paraphyly of the genus Gordionus and the potential for cryptic species within G. paranensis. Population-level analyses of E. nigromaculatus showed no genetic differentiation among sampling locations across the study area, in contrast to previously observed patterns in known and likely definitive hosts. Taken together, this raises the possibility that factors such as definitive host specificity, intermediate host movement, and passive dispersal of eggs and larvae may influence host-parasite population co-structure in hairworms.