The Agrobacterium tumefaciens vir gene transcriptional activator virG is transcriptionally induced by acid pH and other stress stimuli.
A set of Agrobacterium tumefaciens operons required for pathogenesis is coordinately induced during plant infection by the VirA and VirG proteins. The intracellular concentration of VirG increases in response to acidic media, and this response was proposed to be regulated at the level of transcription at a promoter (P2) that resembles the Escherichia coli heat shock promoters. To test this hypothesis, we first constructed a virG-lacZ transcriptional fusion. A strain containing this fusion had higher levels of beta-galactosidase activity in acidic media than in media at neutral pH. Second, primer extension analysis of virG indicated that acidic media stimulated the transcription of this promoter. To determine whether P2 is a member of a heat shock-like regulon in A. tumefaciens, five agents that induce E. coli heat shock genes were tested for their abilities to induce a P2-lacZ fusion in A. tumefaciens. P2 was most strongly induced by low pH, was moderately stimulated by CdCl2 or mitomycin C, and was slightly induced by P2 as measured by beta-galactosidase activity and primer extension analysis. Induction by these treatments did not require any Ti plasmid-encoded function or the chromosomally encoded RecA protein. We also pulse-labeled cellular proteins after a shift to low pH and detected several proteins whose synthesis was induced by these conditions. We conclude that P2 is primarily induced by acid pH and secondarily by certain other stimuli, each of which is stressful to cell growth. This stress induction is at least partly independent of the heat shock and SOS responses.


Pattern of preschool behavior problems in New Zealand, using the Behavior Check List.
The main aim of the study was to identify the pattern of behaviour problems in preschool children to enable early recognition and intervention. Three hundred and twenty children, in eight randomly selected preschool centres, aged between 2.5 and 5 years, were included in the study. Parents completed the Behaviour Check List (BCL),a screening measure for preschool behaviour problems. Dependency, temper tantrums, and being difficult to manage were the commonly rated symptoms when moderate-severe problems were examined. Developmental problems decreased with increasing age, while relationship problems and worries that were cognitively mediated worsened. There were no major differences in the patterns between boys and girls. On cross-cultural comparison, parents in New Zealand rated their children lower on the BCL compared to those in the UK. Factor analysis of the BCL yielded seven factors. The two main factors 'predominantly conduct' and 'predominantly emotional' consisted of a mixture of conduct (difficulty in managing, temper tantrums, sibling rivalry) and emotional (unhappy mood, worry, fears) problems. The other five factors were related to developmental problems. These results help clinicians identify the emerging pattern of preschool behaviour problems that change with increasing age and vary with differing cultures. Categorical presentation of preschool behaviour problems support the view that they should be included in a classification system.


Liver and Other Gastrointestinal Cancers Are Frequent in Mexican Americans.
Disease patterns in Mexican American health-disparity populations differ from larger US populations. This study is aimed to determine frequency of gastrointestinal cancers in Mexican Americans. We analyzed self-reported data from the Cameron County Hispanic Cohort where we find high rates of risk factors for cancer: obesity (48.5 %) and diabetes (30.7 %). Participants provided cancer histories about themselves and first- and second-degree relatives. Logistic regression models assessed risk factors. Frequencies of cancer sites were ranked and validated using concurrent age local cancer registry data. Among 9,249 individuals (participants and their relatives), there were 1,184 individuals with reports of cancer. Among cohort participants under 70 years of age, the most significant risk factor for all-cause cancers was diabetes (OR 3.57, 95 % CI 1.32, 9.62). Participants with metabolic syndrome were significantly more likely to report cancer in relatives [1.73 (95 % CI 1.26, 2.37]. Among cancers in fathers, liver cancer was ranked third, stomach fourth, colorectal sixth, and pancreas tenth. In mothers, stomach was third, liver fourth, colorectal seventh, and pancreas eleventh. The unusual prominence of these cancers in Mexican Americans, including liver cancer, was supported by age-adjusted incidence in local registry data. Gastrointestinal system cancers, particularly, liver cancer, in a Mexican American health disparity cohort and their relatives rank higher than in other ethnicities and are associated with high rates of diabetes and metabolic syndrome. Effective prevention of diabetes and low-tech, high-quality screening strategies for gastrointestinal cancers are needed in health disparity communities.


Dynamic Walking of a Legged Robot in Underwater Environments.
In this research, the dynamic walking of a legged robot in underwater environments is proposed. For this goal, the underwater zero moment point (Uzmp) is proposed in order to generate the trajectory of the centre of the mass of the robot. Also, the underwater zero moment point auxiliary (Uzmp aux.) is employed to stabilize the balance of the robot before it undergoes any external perturbations. The concept demonstration of a legged robot with hydraulic actuators is developed. Moreover, the control that was used is described and the hydrodynamic variables of the robot are determined. The results demonstrate the validity of the concepts that are proposed in this article, and the dynamic walking of the legged robot in an underwater environment is successfully demonstrated.


Outcomes in acute ischemic stroke patients without angiographically documented arterial occlusion.
Patients with acute ischemic stroke who undergo emergent cerebral angiography for consideration of intra-arterial treatment and do not have an angiographically demonstrable occlusion pose a management dilemma. The authors reviewed their experience to determine the clinical out comes of patients with ischemic stroke evaluated within 6 hours of symptom onset in whom negative angiograms were obtained. A prospective registry was maintained for all patients (N = 56) who were considered for intra-arterial thrombolysis. Patients without angiographic arterial occlusion were not treated with thrombolytics, and data pertaining to clinical characteristics and neuroimaging findings was collected. Follow-up data were acquired through clinic visits or telephone interviews at 5.5 +/- 5.0 months (mean +/- SD), range 1 to 15 months, after onset of stroke. Of the 56 patients, no arterial occlusion was observed in 17 (30%) patients (mean age 65.8 +/- 13.0 years; 7 were men). The mean (+/- SD) baseline National Institute of Health stroke scale score was 10.2 +/- 7.1. Symptoms were referable to the anterior or posterior circulation in 76% and 18% of the patients, respectively; they could not be localized to either circulation in 6%. Follow-up neuroimaging studies demonstrated cerebral infarction in 12 of 14 patients. Eleven of the 17 had a favorable long-term recovery as assessed by the modified Rankin Scale (score 0 or 1). Five other patients had modified Rankin Scale scores of 3 (n = 1), 4 (n = 2), or 5 (n = 2). One patient died during the follow-up period. With regard to location of ischemic deficits, the highest rate of death or dependency was observed in patients with pontine infarction (three of four patients). Although the outcome following ischemic stroke in patients without angiographically documented occlusion appears to be better than that reported for patients with angiographically documented occlusion, death or disability is observed in at least one third of the patients. There fore, acute ischemic stroke in the absence of angiographic occlusion is not entirely a "benign" entity and can be particularly devastating when the brainstem is involved.


[Biosynthesis of protein and reserve substances by yeasts growing on different substrates with limited sources of mineral nutrition].
The content of protein and reserve compounds was studied in yeast cells growing on glucose, hexadecane and ethanol in a complete medium and in media limited with a source of nitrogen, phosphorus or sulfur. It was shown that the proportion between these components characterises the direction of biosynthetic processes in the cell depending on cultivation conditions. This is strongly shifted towards protein synthesis in the period of exponential growth when constructive processes are active. When the growth is limited with the sources of mineral nutrition, the content of protein drops down abruptly while that of the reserve compounds, lipids and carbohydrates, rises. Glycogen prevails in cells grown on glucose whereas lipids are the major component of cells cultivated on hexadecane. Nitrogen, phosphorus and sulfur deficiency causes quantitative and qualitative changes in the composition of free and bound amino acids in yeast biomass. The degree of these changes depends on the nature of the growth--limiting factor.


Calcium and magnesium concentrations in uterine fluid and blood serum during the estrous cycle in the bovine.
To investigate uterine and serum Ca(++) and Mg(++) variations during the estrous cycle in the bovine, 66 genital tracts and blood samples were collected from Urmia abattoir, Urmia, Iran. The phase of the estrous cycle was determined by examination of the structures present on ovaries and uterine tonicity. Of the collected samples, 17 were pro-estrus, 12 estrus, 14 metestrus and 23 diestrus. The uterine fluid was collected by gentle scraping of the uterine mucosa with a curette. The mean ± SEM concentration of serum Ca(++) in pro-estrus, estrus, metestrus and diestrus was 5.77 ± 0.69, 8.87 ± 1.83, 10.95 ± 1.52, 11.09 ± 1.08 mg dL(-1), and the mean concentration of uterine fluid Ca(++) was 4.40 ± 0.72, 3.15 ± 0.67, 5.89 ± 0.88, 8.63 ± 0.97 mg dL(-1), respectively. The mean concentration of serum Mg(++) in pro-estrus, estrus, metestrus and diestrus was 3.53 ± 0.30, 4.20 ± 0.52, 3.49 ± 0.38, 3.39 ± 0.29 mg dL(-1), and mean concentration of uterine fluid Mg(++) was 5.27 ± 0.42, 4.92 ± 0.60, 5.56 ± 0.30, 5.88 ± 0.36 mg dL(-1), respectively. The serum and uterine fluid Ca(++) in pro-estrus were significantly different from those of the metestrus and diestrus. In all stages of estrous cycle the mean concentration of serum Ca(++) was higher than that in the uterine fluid. The difference between serum and uterine fluid Ca(++) in estrus, metestrus and diestrus was significant. There was no significant difference between serum Mg(++) content nor was it different from uterine fluid Mg(++) content at any stages of estrous cycle. In all stages of estrous cycle the uterine fluid Mg(++) was higher than that of the serum. These results suggest that during the estrous cycle in the cow, Ca(++) is passively secreted in uterine fluids and is mostly dependent on blood serum Ca(++) variations but Mg(++) is secreted independently and does not follow variations in the serum concentrations.


Light scattering from normal and dysplastic cervical cells at different epithelial depths: finite-difference time-domain modeling with a perfectly matched layer boundary condition.
The finite-difference time-domain (FDTD) method provides a flexible approach to studying the scattering that arises from arbitrarily inhomogeneous structures. We implemented a three-dimensional FDTD program code to model light scattering from biological cells. The perfectly matched layer (PML) boundary condition has been used to terminate the FDTD computational grid. We investigated differences in angle-dependent scattering properties of normal and dysplastic cervical cells. Specifically, the scattering patterns and phase functions have been computed for normal and dysplastic cervical cells at three different epithelial depths, namely, basal/parabasal, intermediate, and superficial. Construction of cervical cells within the FDTD computational grid is based on morphological and chromatin texture features obtained from quantitative histopathology. The results show that angle-dependent scattering characteristics are different not only for normal and dysplastic cells but also for cells at different epithelial depths. The calculated scattering cross-sections are significantly greater for dysplastic cells. The scattering cross-sections of cells at different depths indicate that scattering decreases in going from the superficial layer to the intermediate layer, but then increases in the basal/parabasal layer. This trend for epithelial cell scattering has also been observed in confocal images of ex vivo cervical tissue.


Design of applicators for a 27 MHz multielectrode current source interstitial hyperthermia system; impedance matching and effective power.
In interstitial heating one of the main requirements for achieving a certain elevated temperature in a tumour is that the effective power per applicator (Peff), i.e. the power which is actually deposited in the tissue, is sufficiently high. In this paper this requirement is discussed for the applicators of the 27 MHz multielectrode current source (MECS) interstitial hyperthermia (IHT) system. To minimize power reflection, the applicator impedance was matched with the generator impedance by adjusting the length of the coaxial cable in between. Transmission line losses, applicator efficiency and subsequently Peff were computed for several applicator types. The actual Peff per electrode was obtained from calorimetric measurements. Experiments with RC loads, which can be seen as perfect applicators, were performed to investigate the effect of mismatching on Peff. Applicator losses were measured for clinically used applicators, both single- and dual-electrode, utilizing saline phantoms. A simple spherical tumour model, using the effective heat conductivity (keff) to account for heat transport, was used to estimate Peff for a given tumour size, implant size and applicator density. Computations of Peff of various MECS-IHT electrodes were in close agreement with the phantom measurements. Most of the initial generator power was absorbed in the transmission line (60-65%). The efficiency of the applicators was about 65%. For both single- and dual-electrode applicators the effective electrode power was found to be about 1 W. Model calculations show that Peff of 1 W is sufficient to reach a minimum tumour temperature of 43 degrees C in well perfused tumours (keff = 3 W m-1 degree C-1), using a typical implant with 2 cm electrodes and 1.5 cm spacing. Mismatching can considerably affect Peff. Both a reduction to almost zero and a two-fold increase are possible. However, because the matching theory is well understood, mismatching is not a serious problem in clinical practice and can even be used to increase Peff if necessary. We conclude that the applicator design and the impedance matching method chosen in the MECS system allow heating to temperatures in the therapeutic range with implants used in clinical practice.


Immunoproteomically identified GBAA_0345, alkyl hydroperoxide reductase subunit C is a potential target for multivalent anthrax vaccine.
Anthrax is caused by the spore-forming bacterium Bacillus anthracis, which has been used as a weapon for bioterrorism. Although current vaccines are effective, they involve prolonged dose regimens and often cause adverse reactions. High rates of mortality associated with anthrax have made the development of an improved vaccine a top priority. To identify novel vaccine candidates, we applied an immunoproteomics approach. Using sera from convalescent guinea pigs or from human patients with anthrax, we identified 34 immunogenic proteins from the virulent B. anthracis H9401. To evaluate vaccine candidates, six were expressed as recombinant proteins and tested in vivo. Two proteins, rGBAA_0345 (alkyl hydroperoxide reductase subunit C) and rGBAA_3990 (malonyl CoA-acyl carrier protein transacylase), have afforded guinea pigs partial protection from a subsequent virulent-spore challenge. Moreover, combined vaccination with rGBAA_0345 and rPA (protective antigen) exhibited an enhanced ability to protect against anthrax mortality. Finally, we demonstrated that GBAA_0345 localizes to anthrax spores and bacilli. Our results indicate that rGBAA_0345 may be a potential component of a multivalent anthrax vaccine, as it enhances the efficacy of rPA vaccination. This is the first time that sera from patients with anthrax have been used to interrogate the proteome of virulent B. anthracis vegetative cells.


Semi-quantitative assessment of 99Tcm-sestamibi uptake in lung cancer: relationship with clinical response to chemotherapy.
The objectives of this study were to measure semi-quantitatively uptake of 99Tcm-sestamibi (99Tcm-MIBI) by tumour tissue in patients with lung cancer and to investigate its relationship with clinical response to chemotherapy. 99Tcm-MIBI single photon emission tomography was performed at the time of diagnosis in 31 patients with biopsy-proven lung cancer (19 small cell carcinomas, 12 non-small cell carcinomas), all of whom were undergoing chemotherapy. Fifteen patients were also investigated 2 weeks after the first and third cycles of chemotherapy. To quantify 99Tcm-MIBI uptake, a tumour/lung (T/L) ratio was calculated for the tomographic slices. The response to chemotherapy was rated as complete remission, partial remission or no remission using dimensional criteria. The results were expressed as the median and inter-quartile range; non-parametric statistical analyses were used. Forty one neoplastic localizations (31 primary tumours and 10 hilar or mediastinal lymph node masses) were assessed. The median T/L ratio of the primary tumours was 1.85 (range 1.7-2.4). Patients with a different response to chemotherapy had a significantly different median T/L ratio before chemotherapy: complete remission (n = 8), T/L ratio = 2.95 (range 2.20-3.25); partial remission (n = 10), 2.15 (range 1.77-2.40); no remission (n = 13), 1.70 (range 1.47-1.75) (Kruskal-Wallis, P < 0.0001). A T/L ratio of 1.80 gave sensitivity of 83%, specificity of 85% and accuracy of 84% in the prediction of the response to chemotherapy. The patients with small cell carcinomas demonstrated greater 99Tcm-MIBI uptake than those with non-small cell carcinomas: T/L ratio, median 2.30 (range 1.76-3.00) vs 1.70 (range 1.50-1.78) (Mann-Whitney U-test, P = 0.001). No significant difference in 99Tcm-MIBI uptake was observed between the 10 lymph node metastases and the corresponding primary tumours: T/L ratio, median 2.30 (range 1.75-2.50) vs 2.15 (1.77-3.00) (Wilcoxon's paired samples rank test, N.S.). Of the 15 patients who were monitored with scintigraphy during chemotherapy, 10 showed complete or partial remission and a parallel reduction in their T/L ratio. The other five patients showed no response to chemotherapy and their T/L ratio was either unaffected or increased. We conclude that the semi-quantitative assessment of 99Tcm-MIBI uptake may have a significant role to play in the management of lung cancer, providing an effective means of predicting the efficacy of chemotherapy and of selecting subgroups of patients requiring radiotherapy or combined protocols before the start of treatment. 99Tcm-MIBI imaging may also be of use in monitoring clinical response to chemotherapy.


The biology of cancer metastasis.
The formation of a metastasis entails a complex sequence of events with the end result dependent on the interaction of malignant cells with host factors. Intrinsic properties of the metastatic tumor cells, including production of proteolytic enzymes, cell surface properties, adhesiveness, and the ability to grow in a distant organ environment, act in concert to influence the tumor cells' interactions with host cells in forming metastases. Life-threatening metastases are formed only by those tumor cells that have survived all steps in a process that has been shown in many experimental studies to be a highly selective event. The results of studies on the distribution of radiolabelled mouse melanoma cells injected into syngeneic mice support the concept that the fate of tumor cells released into the bloodstream is determined by sequential and selective events, and introduces a third regulatory factor. Cells endowed with metastatic properties, isolated by cloning a heterogeneous tumor or selected from a metastasis, have a higher probability of forming metastases than cells not so endowed, yet this probability is not 100%. Metastasis should thus be considered as a selective, sequential and stochastic process. Interruption of the process at any stage will prevent the formation of metastatic disease. Hence, a better understanding of the metastatic process will provide the basis for rational approaches for the prevention or destruction of this most fatal aspect of cancer.


Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for peritoneal carcinomatosis in a liver graft recipient: a case report.
Cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy is a potentially curative approach for peritoneal carcinomatosis of colonic origin. So far experience concerning the use of this treatment option in transplant recipients is lacking. We herein present the case of a 31-year-old man who had previously been liver transplanted for primary sclerosing cholangitis. Approximately 10 years after transplantation colon carcinoma with co-existing peritoneal carcinomatosis was diagnosed. Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy were conducted. Operative management under tacrolimus medication did not trigger infections, wound healing disorders or graft function impairment. At one year follow-up no tumor recurrence was detected. Recent literature suggests that proctocolectomy for colorectal cancer is considered feasible in liver graft recipients. Virtually all patients suffering from primary sclerosing cholangitis exhibit co-existing ulcerative colitis, rendering this subset of patient at risk for developing colonic malignancies. Furthermore chronic immunosuppression may facilitate malignant growth. The most feared complication in colorectal carcinomas is the occurence of peritoneal carcinomatosis, for which cytoreduction plus hyperthermic intraperitoneal chemotherapy may be a curative option. This, so far unique, case report suggests that even in this patient subset this treatment is feasible and for further cases this dual-approach for the management of PC in transplant recipients should be taken into account.


Influence of growing system on nitrate accumulation in two varieties of lettuce and red radicchio of Treviso.
Green leafy vegetables contribute greatly to the total intake of nitrates from the daily diet. This study evaluates the influence of different cultivation systems on nitrate accumulation in leafy vegetables. Two varieties of lettuce (Lactuca sativa L.) (Lattuga Romana, Foglia di Quercia) and two varieties of red radicchio of Treviso (Cychorium intibus L.) (Early, Late) were selected. Lettuce varieties were both organically and biodynamically grown; red radicchio varieties were conventionally grown both in the field and in spring water. Both lettuce varieties biodynamically grown accumulated 1.3-2 times less nitrate than the respective organically grown plants. The two lettuce varieties showed differences in nitrate accumulating capacity: Foglia di Quercia was almost three times richer in nitrate than Lattuga Romana. The traditional growing systems applied to the red radicchio of Treviso varieties strongly influenced nitrate accumulation in leaves, the Early variety having up to 15 times higher nitrate than the Late variety. Our findings on nitrate levels in both lettuce and red radicchio of Treviso varieties suggest that both genetic factors and cultivation systems strongly affect the nitrate accumulation capacity. This study also highlights how the cultivation strategy can reduce nitrate levels in leafy vegetables, suggesting the possibility of modulating the N supply along the harvesting time.


Towards Placental Surface Vasculature Exploration in Virtual Reality.
We present a case study evaluating the potential for interactively identifying placental surface blood vessels using magnetic resonance imaging (MRI) scans in virtual reality (VR) environments. We visualized the MRI data using direct volume rendering in a high-fidelity CAVE-like VR system, allowing medical professionals to identify relevant placental vessels directly from volume visualizations in the VR system, without prior vessel segmentation. Participants were able to trace most of the observable vascular structure, and consistently identified blood vessels down to diameters of 1 mm, an important requirement in diagnosing vascular diseases. Qualitative feedback from our participants suggests that our VR visualization is easy to understand and allows intuitive data exploration, but complex user interactions remained a challenge. Using these observations, we discuss implications and requirements for spatial tracing user interaction methods in VR environments. We believe that VR MRI visualizations are the next step towards effective surgery planning for prenatal diseases.


Trehalose metabolism genes in Caenorhabditis elegans and filarial nematodes.
The sugar trehalose is claimed to be important in the physiology of nematodes where it may function in sugar transport, energy storage and protection against environmental stresses. In this study we investigated the role of trehalose metabolism in nematodes, using Caenorhabditis elegans as a model, and also identified complementary DNA clones putatively encoding genes involved in trehalose pathways in filarial nematodes. In C. elegans two putative trehalose-6-phosphate synthase (tps) genes encode the enzymes that catalyse trehalose synthesis and five putative trehalase (tre) genes encode enzymes catalysing hydrolysis of the sugar. We showed by RT-PCR or Northern analysis that each of these genes is expressed as mRNA at all stages of the C. elegans life cycle. Database searches and sequencing of expressed sequence tag clones revealed that at least one tps gene and two tre genes are expressed in the filarial nematode Brugia malayi, while one tps gene and at least one tre gene were identified for Onchocerca volvulus. We used the feeding method of RNA interference in C. elegans to knock down temporarily the expression of each of the tps and tre genes. Semiquantitative RT-PCR analysis confirmed that expression of each gene was silenced by RNA interference. We did not observe an obvious phenotype for any of the genes silenced individually but gas-chromatographic analysis showed >90% decline in trehalose levels when both tps genes were targeted simultaneously. This decline in trehalose content did not affect viability or development of the nematodes.


Control of mammary tumor differentiation by SKI-606 (bosutinib).
C-Src is infrequently mutated in human cancers but it mediates oncogenic signals of many activated growth factor receptors and thus remains a key target for cancer therapy. However, the broad function of Src in many cell types and processes requires evaluation of Src-targeted therapeutics within a normal developmental and immune-competent environment. In an effort to understand the appropriate clinical use of Src inhibitors, we tested an Src inhibitor, SKI-606 (bosutinib), in the MMTV-PyVmT transgenic mouse model of breast cancer. Tumor formation in this model is dependent on the presence of Src, but the necessity of Src kinase activity for tumor formation has not been determined. Furthermore, Src inhibitors have not been examined in an autochthonous tumor model that permits assessment of effects on different stages of tumor progression. Here we show that oral administration of SKI-606 inhibited the phosphorylation of Src in mammary tumors and caused a rapid decrease in the Ezh2 Polycomb group histone H3K27 methyltransferase and an increase in epithelial organization. SKI-606 prevented the appearance of palpable tumors in over 50% of the animals and stopped tumor growth in older animals with pre-existing tumors. These antitumor effects were accompanied by decreased cellular proliferation, altered tumor blood vessel organization and dramatically increased differentiation to lactational and epidermal cell fates. SKI-606 controls the development of mammary tumors by inducing differentiation.


Investigation of genetic interaction between simian rotavirus SA11 and reovirus.
Rotavirus and reovirus are physically and genetically very similar. Their genetic interaction would have important implications for understanding both the epidemiology of rotavirus and the biological basis of rotavirus pathogenicity. A permissive line of rhesus macaque kidney cells, MA104, was infected with the simian rotavirus SA11 and various temperature sensitive mutants of reovirus (type 3 groups A, B, C, D, G, type 1 M79, and type 2 122). The mixed cell infections were carried out at permissive temperature in the presence of absence of proteolytic enzymes, and the progeny were plated at a non-permissive temperature in mouse L cells, which are non-permissive to SA11. The progeny clones were labelled with 32P and analyzed by polyacrylamide gel electrophoresis. There was no evidence for genetic reassortment. Under this heavy selection pressure, such reassortment would have been apparent if it occurred with a frequency greater than 10-5 to 10-3.


pitkin(D), a novel gain-of-function enhancer of position-effect variegation, affects chromatin regulation during oogenesis and early embryogenesis in Drosophila.
The vast majority of the >100 modifier genes of position-effect variegation (PEV) in Drosophila have been identified genetically as haplo-insufficient loci. Here, we describe pitkin(Dominant) (ptn(D)), a gain-of-function enhancer mutation of PEV. Its exceptionally strong enhancer effect is evident as elevated spreading of heterochromatin-induced gene silencing along euchromatic regions in variegating rearrangements. The ptn(D) mutation causes ectopic binding of the SU(VAR)3-9 heterochromatin protein at many euchromatic sites and, unlike other modifiers of PEV, it also affects stable position effects. Specifically, it induces silencing of white+ transgenes inserted at a wide variety of euchromatic sites. ptn(D) is associated with dominant female sterility. +/+ embryos produced by ptn(D)/+ females mated with wild-type males die at the end of embryogenesis, whereas the ptn(D)/+ sibling embryos arrest development at cleavage cycle 1-3, due to a combined effect of maternally provided mutant product and an early zygotic lethal effect of ptn(D). This is the earliest zygotic effect of a mutation so far reported in Drosophila. Germ-line mosaics show that ptn+ function is required for normal development in the female germ line. These results, together with effects on PEV and white+ transgenes, are consistent with the hypothesis that the ptn gene plays an important role in chromatin regulation during development of the female germ line and in early embryogenesis.


Quantification of intramyocardial hemorrhage volume using magnetic resonance imaging with three-dimensional T1-weighted sequence in patients with ischemia-reperfusion injury: a semi-automated image processing technique.
Although intramyocardial hemorrhage (IMH) is a poor prognostic factor caused by ischemia reperfusion injury, little evidence is available regarding the association between IMH volume and biomarkers. In the present study, we measured IMH volume using three-dimensional (3D) T1-weighted magnetic resonance imaging (T1-MRI) and investigated its association with biomarkers. Moreover, the accuracy of semi-automatic measurement of IMH volume was validated. We retrospectively enrolled 33 consecutive patients (mean age 67 ± 11 years) who underwent cardiac MRI after reperfusion therapy for acute myocardial infarction. IMH was observed in 4 patients (12.1%). Receiver operating characteristics (ROC) analysis of creatine kinase (CK) and CK-muscle/brain (CK-MB) tests for detecting IMH were performed. IMH volume measured using semi-automatic methods by a 2 standard deviation (SD) threshold was compared to manual measurements using the Spearman's correlation coefficient (ρ) and Bland-Altman analyses. ROC analysis revealed optimal cutoff values of CK: 2460 IU/l and CK-MB: 231 IU/l (area under the curve: 0.95 and 0.91; sensitivity: 86% and 79%; specificity: 100% for both). IMH volume with the 2SD threshold correlated with that of the manual measurement [5.84 g (3.30 to 9.00) g vs. 8.07 g (5.37 to 9.33); ρ: 0.85, p < 0.01; bias (limit of agreement): - 0.01 g (- 0.51 to 0.49); intraclass correlation coefficients 0.84 (0.75 to 0.90)]. Our findings could help identify the risk of IMH after reperfusion therapy with biomarkers. 3D T1-MRI can semi-automatically provide accurate IMH volume without being time-consuming.


Replacing inpatient care by outpatient care in the treatment of deep venous thrombosis--an economic evaluation. TASMAN Study Group.
Two clinical trials in patients with acute deep venous thrombosis have indicated that the outpatient management with fixed-dose, subcutaneous low-molecular-weight heparin is at least as effective and safe as inpatient treatment with unfractionated intravenous heparin with respect to recurrent venous thromboembolism and major bleeding. We performed an economic evaluation alongside one of these trials to assess the cost consequences of the outpatient management strategy. Data were collected through case record forms, complemented by a prospective questionnaire in 78 consecutive patients, interviews with health care providers, and hospital data bases. Our study demonstrated that seventy-five percent of patients allocated to low-molecular-weight heparin received treatment either entirely at home or after a brief hospital stay. Fifteen percent of these patients required professional domiciliary care. Within-centre comparisons of resource utilisation in terms of natural units showed that outpatient management with low-molecular-weight heparin reduced the average number of hospital days in the initial treatment period in nine centres by 59 percent (95% CI: 43 to 71 percent) accompanied by a limited increase in outpatient and professional domiciliary care. The average reduction in hospital days at the end of follow up was 40 percent (95% CI: 25 to 54 percent). A cost-minimisation analysis, focusing on resource utilisation directly related to the treatment of deep venous thrombosis and associated costs in one centre demonstrated a cost reduction of 64 percent (95% CI: 56 to 72 percent) with the outpatient management with low-molecular-weight heparin. These data suggest that outpatient management of patients with proximal venous thrombosis using low-molecular-weight heparin reduces resource utilisation and total treatment cost. Implementation should be preceded by a cautious evaluation of a potential cost shifting and organisational prerequisites.


Species number and endemism: the galapagos archipelago revisited.
Regression analyses to determine plant species number are repeated for the Galápagos Islands with new data. The multiple curvilinear regression gives the best prediction of species number, with island area making the only significant contribution. The proportion of species endemic to the Galápagos is highest in the arid, transition zone and on small islands, and lowest in the littoral and mesic zones. This is explained in terms of zone-specific immigration and extinction rates and the very recent appearance of moist upland climates in the archipelago.


Mechanical modulation of terahertz wave via buckled carbon nanotube sheets.
Manipulation of terahertz (THz) wave plays an important role in THz imaging, communication, and detection. The difficulty in manipulating the THz wave includes single function, untunable, and inconvenient integration. Here, we present a mechanically tunable THz polarizer by using stretchable buckled carbon nanotube sheets on natural rubber substrate (BCNTS/rubber). The transmittance and degree of polarization of THz wave can be modulated by stretching the BCNTS/rubber. The experiments showed that the degree of polarization increased from 17% to 97%, and the modulation depth reached 365% in the range of 0.2-1.2 THz, as the BCNTS/rubber was stretched from 0% to 150% strain. These changes can be also used for high strain sensing up to 150% strain, with a maximum sensitivity of 2.5 M/S. A spatial modulation of THz imaging was also realized by stretching and rotating BCNTS/rubber. The theoretical analysis and numerical modeling further confirm the BCNTS/rubber changes from weak anisotropic to highly anisotropic structure, which play key roles in THz wave modulation. This approach for active THz wave manipulation can be widely used in polarization imaging, wearable material for security, and highly sensitive strain sensing.


A prospective pilot study of the efficacy and safety of Elipse intragastric balloon: A single-center, single-surgeon experience.
Elipse™ is the least invasive IGB for weight loss that needs no sedation or endoscopy. It is a swallowable capsule filled with 550 mL of fluid, which stays in the stomach for 16 weeks and is excreted from the gastrointestinal tract. Kuwait is one of the first countries to start using Elipse™ as a weight loss device. This study aims to evaluate the efficacy and safety of Elipse™ intragastric balloon (IGB). This is a single-center prospective pilot study of 51 Elipse™ insertions at our clinic. The patients were followed for 4 months to monitor their weight and body mass index (BMI) at 1, 2, and 4 months. Total weight loss, % excess weight loss (%EWL), % total body weight loss (%TBWL), and change in BMI and waist circumference (WC) were recorded at the end of the study. A short survey was administered to evaluate symptoms, complications, and overall satisfaction. Fifty-one patients participated, of which five had Elipse™ removed because of intolerance. One case vomited the balloon; one had early deflation. The total weight loss was 8.84 kg, %TBWL 10.44%, %EWL 40.84%, change in BMI 3.42 kg/m2, and the total WC reduction 8.62 cm. Symptoms after insertion were severe, whereas those during excretion were mild and self-limiting. No serious complications were recorded, and the overall satisfaction was above average. Our data proves that Elipse™ is a safe and effective device for weight loss. Nevertheless, some limitations were observed that need to be overcome for better outcomes. Larger studies are needed to support our findings.


Idiopathic Hypersomnia and Kleine-Levin Syndrome: Primary Disorders of Hypersomnolence Beyond Narcolepsy.
Daytime sleepiness is common amongst children and adolescents. Inadequate sleep duration, inappropriate school start times, and the delay in sleep phase of adolescence may all contribute. Nocturnal sleep disruption due to sleep disorders such as obstructive sleep apnea or restless legs syndrome/periodic limb movement disorder may also lead to daytime sleepiness. Profound sleepiness however, when occurring in the setting of adequate sleep duration, is rare amongst children and adolescents and may prompt consideration of a central disorder of hypersomnolence (CDH). Narcolepsy is the archetypal and most studied form of CDH and a detailed review of the presentation, evaluation, treatment of narcolepsy is included separately in this edition of Seminars in Pediatric Neurology. In addition to narcolepsy, 2 other forms of primary CDH exist, idiopathic hypersomnia (IH) and Kleine-Levin syndrome (KLS). Onset of IH and KLS occurs most frequently during the pediatric age range and presentation may include signs of encephalopathy in addition to hypersomnolence. As such, they are of particular relevance to pediatric neurology and associated fields. Unfortunately, when compared to narcolepsy little is known about IH and KLS, at both the physiologic and clinical level. This review will focus on the presentation, evaluation, and management of idiopathic hypersomnia and Kleine-Levin syndrome in the pediatric population.


[Study on several ultrasound markers combined maternal serum biochemical markers to screen fetal chromosomal aneuploidy at 11 to 13(+)6 weeks of gestation].
To evaluate the efficiency of combined screening for chromosomal abnormalities in the first trimester and the ultrasound characteristics of these fetuses. Retrospective study for 5000 singleton pregnancies by combined screening of trisomies 21, 18, 13 and Turner syndrome.Risk algorithms were developed for calculation of patient-specific risks for each of the three trisomies based on maternal age, fetal nuchal translucency, free β human chorionic gonadotropin and serum pregnancy associated plasma protein A at 11 to 13(+6) weeks of pregnant. The value of nuchal translucency (NT) and β-hCG and pregnancy-associated plasma protein A (PAPP-A) level were inputted computer, and calculate the risk value ( ≥ 1: 270) by automatic analysis software. Two hundred and four cases with high risk were performed transabdominal chorionic villus biopsy to detect the fetal chromosomal karyotypes. Meanwhile, other ultrasonic characteristics of fetal were elevated. (1) Five thousand cases of pregnant women were detected, including 4983 normal cases, 62 cases were induced labor for a variety of reasons in the second trimester, including 40 cases with normal karyotype but with congenital heart disease, 17 cases of chromosome abnormalities (9 cases trisomy 21, 2 cases trisomy 18, 1 cases trisomy 13, 4 cases 45X), 2 cases spina bifida, 2 cases digestive tract obstruction, 1 cases giant bladder.One case with low risk of fetal chromosomal abnormalities in combined screening, but high risk of age (maternal age were over 40 years old), it was 21 trisomy syndrome after the prenatal diagnosis.(2) Five cases of nasal bone loss in 9 cases of trisomy 21 (5/9), 5 cases with three tricuspid regurgitation (5/9), 4 cases of venous ductus a wave flow reverse (4/9), 3 cases of fetal nasal bone loss accompanied by tricuspid regurgitation and venous ductus a wave flow reverse (3/9).One case of nasal bone loss in 2 cases of trisomy 18, 2 cases were tricuspid regurgitation and venous ductus a wave flow reverse. Two cases in 4 cases of 45X had venous ductus a wave flow reverse. There were 8 cases (0.16%) nasal bone absence in 4983 cases of normal karyotype fetus, 48 cases (0.96%) of tricuspid regurgitation and 44 cases (0.88%) of venous ductus a wave flow reverse. Thirty-two cases in 40 cases (80%) of fetal congenital heart disease were tricuspid regurgitation, 30 cases of venous ductus a wave flow reverse (75%).Eight cases of nasal bone absence normal karyotype fetus were found the nasal bone at 20 weeks gestation. Combination screening of nuchal translucency with serum markers in the first trimester were high detection rate and low false positive rate; a wave reversion and fetal nasal bone absence accompanied by tricuspid regurgitation can improve the detection rate of abnormal karyotype; abnormalities ultrasound marker may be associated with fetal congenital heart disease at 11-13(+6) weeks of pregnancy.


Characterization of the assembly and processing of infectious laryngotracheitis virus glycoprotein B.
Infectious laryngotracheitis virus (ILTV) is an alpha-herpesvirus that causes severe upper respiratory infections in chickens. Although ten putative ILTV glycoprotein genes have been identified by sequence analysis, no ILTV glycoprotein has been extensively characterized. In order to delineate the synthesis and processing pathway of ILTV glycoprotein B (gB), rabbit polyclonal antibodies were raised against a Cro-gB-beta-galactosidase fusion protein. Through immunoprecipitation analysis of ILTV-infected chicken embryo liver cells it was determined that ILTV gB is initially synthesized as a 110 kDa monomeric precursor protein which rapidly assembles into homodimers composed of 100 kDa subunits. The dimer form of ILTV gB is rapidly cleaved to form two disulphide-linked species of 58 kDa. The apparent reduction in mass (from 110 to 100 kDa) of the mature form of gB during processing in the Golgi apparatus appears to be a common feature of avian herpesvirus gB proteins.


Recovery of consciousness and cognition after general anesthesia in humans.
Understanding how the brain recovers from unconsciousness can inform neurobiological theories of consciousness and guide clinical investigation. To address this question, we conducted a multicenter study of 60 healthy humans, half of whom received general anesthesia for 3 hr and half of whom served as awake controls. We administered a battery of neurocognitive tests and recorded electroencephalography to assess cortical dynamics. We hypothesized that recovery of consciousness and cognition is an extended process, with differential recovery of cognitive functions that would commence with return of responsiveness and end with return of executive function, mediated by prefrontal cortex. We found that, just prior to the recovery of consciousness, frontal-parietal dynamics returned to baseline. Consistent with our hypothesis, cognitive reconstitution after anesthesia evolved over time. Contrary to our hypothesis, executive function returned first. Early engagement of prefrontal cortex in recovery of consciousness and cognition is consistent with global neuronal workspace theory.


Astragaloside IV/lncRNA-TUG1/TRAF5 signaling pathway participates in podocyte apoptosis of diabetic nephropathy rats.
This study aims to figure out the mechanism of astragaloside IV (AS-IV) in the protection of podocyte apoptosis in diabetic nephropathy (DN) rats. Streptozotocin (STZ) was used to induce diabetes in rats, and the diabetic rats were treated with 5 mg/kg/d of AS-IV for 12 weeks. Albuminuria level, relative TUG1 and TRAF5 levels, and TRAF5 and cleaved-caspase-3 protein levels were examined by ELISA, quantitative reverse transcription (qRT)-PCR, and Western blot analyses, respectively. The interaction between TUG1 and TRAF5 was confirmed by RNA pull-down and RNA precipitation. TUNEL assay was used to detect podocyte apoptosis. Compared with control rats, DN rats had higher albuminuria and TRAF5 levels and lower TUG1 level. AS-IV treatment attenuated albuminuria and TRAF5 levels and improved TUG1 level in DN rats. TUG1 was downregulated and TRAF5 was upregulated in high-glucose-treated MPC5 cells, and AS-IV ameliorated the TUG1 level. In addition, TUG1 interacted with TRAF5, and TUG1 overexpression promoted degradation of TRAF5 protein. Besides, AS-IV modulated TRAF5 expression through regulating TUG1. AS-IV decreased podocyte apoptosis via the TUG1/TRAF5 pathway. Finally, in vivo experiment proved that si-TUG1 abrogated the protective effect of AS-IV on DN. AS-IV attenuated podocyte apoptosis and protected diabetic rats from DN via the lncRNA-TUG1/TRAF5 pathway.


Prokaryotic and Fungal Characterization of the Facilities Used to Assemble, Test, and Launch the OSIRIS-REx Spacecraft.
To characterize the ATLO (Assembly, Test, and Launch Operations) environment of the OSIRIS-REx spacecraft, we analyzed 17 aluminum witness foils and two blanks for bacterial, archaeal, fungal, and arthropod DNA. Under NASA's Planetary Protection guidelines, OSIRIS-REx is a Category II outbound, Category V unrestricted sample return mission. As a result, it has no bioburden restrictions. However, the mission does have strict organic contamination requirements to achieve its primary objective of returning pristine carbonaceous asteroid regolith to Earth. Its target, near-Earth asteroid (101955) Bennu, is likely to contain organic compounds that are biologically available. Therefore, it is useful to understand what organisms were present during ATLO as part of the larger contamination knowledge effort-even though it is unlikely that any of the organisms will survive the multi-year deep space journey. Even though these samples of opportunity were not collected or preserved for DNA analysis, we successfully amplified bacterial and archaeal DNA (16S rRNA gene) from 16 of the 17 witness foils containing as few as 7 ± 3 cells per sample. Fungal DNA (ITS1) was detected in 12 of the 17 witness foils. Despite observing arthropods in some of the ATLO facilities, arthropod DNA (COI gene) was not detected. We observed 1,009 bacterial and archaeal sOTUs (sub-operational taxonomic units, 100% unique) and 167 fungal sOTUs across all of our samples (25-84 sOTUs per sample). The most abundant bacterial sOTU belonged to the genus Bacillus. This sOTU was present in blanks and may represent contamination during sample handling or storage. The sample collected from inside the fairing just prior to launch contained several unique bacterial and fungal sOTUs that describe previously uncharacterized potential for contamination during the final phase of ATLO. Additionally, fungal richness (number of sOTUs) negatively correlates with the number of carbon-bearing particles detected on samples. The total number of fungal sequences positively correlates with total amino acid concentration. These results demonstrate that it is possible to use samples of opportunity to characterize the microbiology of low-biomass environments while also revealing the limitations imposed by sample collection and preservation methods not specifically designed with biology in mind.


Semi-pilot scale production of biodiesel from waste frying oil by genetically improved fungal lipases.
This paper addresses the issue of combining the usage of waste frying oil (WFO), as a feedstock, and a lipase produced in solid-state fermentation (SSF), as a biocatalyst, for semi-pilot scale production of biodiesel as fatty acid methyl esters (FAME). Two fungal mutants namely; Rhizopus stolonifer 1aNRC11 mutant F (1F) and Aspergillus tamarii NDA03a mutant G (3G) were used as a cocatalyst. The two mutants were cultivated separately by SSF in a tray bioreactor. The dried fermented solid of 1F and 3G mutants were used in a ratio of 3:1, respectively, for WFO transesterification. Optimization of several semi-pilot process stages including SSF and WFO transesterification reaction conditions resulted in 92.3% conversion of WFO to FAME. This FAME yield was obtained after 48 h using 10% cocatalyst (w/w of WFO), 10% water (w/w of WFO) and 3:1 methanol/ WFO molar ratio at 30 °C and 250 rpm. A preliminary economic evaluation of produced biodiesel price (190 $/Ton) is less than half the price of petroleum diesel in Egypt (401$/Ton) and is about 40.3% the price of biodiesel produced using a pure enzyme, which is a promising result. This strategy makes the biodiesel synthesis process greener, economical and sustainable.


Effect of the substitution of butter by double cross-linked egg yolk granules/sodium alginate emulsion gel on properties of baking dough during frozen storage.
In this study, double cross-linked egg yolk granules (EYGs)/sodium alginate (SA) emulsion gel was constructed and used as butter substitute. The water binding capacity, rheology properties and microstructure of EYGs/SA emulsion gel showed that the network structure tended to be complete when the concentration of SA reached 1% (m/v). SA stabilized the EYGs/SA droplets and enhanced the spatial network structure of emulsion gel. After substitution for butter, the network structure of EYGs/SA emulsion gel with more water bounded and the polyhydroxy structure of SA molecules endowed dough with more water retention capacity. Meanwhile, the destruction of the microstructure of the replaced dough with EYGs/SA emulsion gel was significantly inhibited compared with the un-substituted dough after freezing. The baking ability results showed a satisfactory baking effect after substitution. Overall, this study provides a new avenue in the field of fat replacement and the application of EYGs/SA emulsion gels.


Fatal hemolytic uremic syndrome associated with day care surgery and anaesthesia: a case report.
Thrombotic angiopathies, i.e. haemolytic uremic syndrome and thrombotic thrombocytopenic purpura, are thought to occur in patients with a combination of risk factors (e.g., an infection with shiga-toxin-producing Escherichia coli (E. coli) or low activity of the metalloproteinase Adamts-13) and a pathophysiological trigger (e.g., anti-endothelial antibodies, cytokines or activation of chemokine receptor 4). To our knowledge, this is the first report describing an association between haemolytic uremic syndrome and routine surgery and anaesthesia. We present a case in which a 67-year-old Caucasian female developed fatal haemolytic uremic syndrome in the immediate postoperative period of uncomplicated day care surgery. The patient had suffered gastrointestinal symptoms followed by confusion approximately two weeks before surgery, but had been without any symptoms in the week before surgery. Haemolytic uremic syndrome with cerebral symptoms ranging from initial anxiety to subsequent seizures and coma developed within a few hours after the end of surgery. In addition, acute kidney failure and severe thrombocytopenia occurred about the same time. During intensive care, the patient was found to be positive for enterohaemorrhagic E. coli (EHEC) in faeces. Anaesthesiologists should be notified that haemolytic uremic syndrome is an uncommon differential diagnosis in patients with postoperative seizures and coma. Patients with a recent enterohemmoragic E.Coli infection should be followed postoperatively for signs of haemolytic uremic syndrome.


Adhesion of four Bifidobacterium strains to human intestinal mucus from subjects in different age groups.
The number of bifidobacteria in faeces and intestinal contents has been shown to be reduced with increasing age of the subject. The adhesion of four Bifidobacterium strains was tested to mucus isolated from subjects of different age. All strains bound significantly less to mucus isolated from elderly subjects, compared to mucus from the other age groups. Two of the tested strains also showed decreased adhesion to mucus isolated from 6-month-old and adult subjects compared to the adhesion to mucus from 2-month-old subjects. The results suggest that reduced adhesion may be a factor involved in the decreasing colonisation of elderly subjects by bifidobacteria.


Resolution of myocardial phospholipase C into several forms with distinct properties.
Phospholipase C activity capable of hydrolysing phosphatidylinositol in bovine heart was resolved into four forms (I-IV) by ion-exchange chromatography. Some of these forms could only be detected if the assay was performed at acidic pH (I and IV) or in the presence of deoxycholate (II). Gel-filtration chromatography indicated that the four forms had different molecular weights in the range 40000-120000. I, II and III all had pH optima in the range 4.5-5.5. However, the major form (III) also had substantial activity at pH 7.0 and above. The activities of I, II and III at pH 7.0 were stimulated by deoxycholate; this effect was most marked with I and II, which had very low activity at this pH. All forms of the enzyme were inhibited by EGTA and required 2-5 mM-CaCl2 for maximal activity. When the fractions eluted from the ion-exchange and gel-filtration columns were assayed with polyphosphoinositides as substrates there was a close correspondence to the elution profile obtained with phosphatidylinositol as substrate; there was no evidence for the existence in heart of phospholipase C activities specific for individual phosphoinositides.


Altered Ocular Fibrillin Microfibril Composition in Mice With a Glaucoma-Causing Mutation of Adamts10.
Previously, we identified a G661R mutation of ADAMTS10 (a disintegrin-like and metalloprotease with thrombospondin type 1 motif 10) as being disease causative in a colony of Beagles with inherited primary open-angle glaucoma (POAG). Mutations in ADAMTS10 are known to cause Weill-Marchesani syndrome (WMS), which is also caused by mutations in the fibrillin-1 gene (FBN1), suggesting functional linkage between ADAMTS10 and fibrillin-1, the principal component of microfibrils. Here, we established a mouse line with the G661R mutation of Adamts10 (Adamts10G661R/G661R) to determine if they develop features of WMS and alterations of ocular fibrillin microfibrils. Intraocular pressure (IOP) was measured using a TonoLab rebound tonometer. Central cornea thickness (CCT), anterior chamber depth (ACD) and axial length (AL) of the eye were examined by spectral-domain optical coherence tomography. Sagittal eye sections from mice at postnatal day 10 (P10) and at 3 and 24 months of age were stained with antibodies against fibrillin-1, fibrillin-2, and ADAMTS10. IOP was not elevated in Adamts10G661R/G661R mice. Adamts10G661R/G661R mice had smaller bodies, thicker CCT, and shallower ACD compared to wild-type mice but normal AL. Adamts10G661R/G661R mice displayed persistent fibrillin-2 and enhanced fibrillin-1 immunofluorescence in the lens zonules and in the hyaloid vasculature and its remnants in the vitreous. Adamts10G661R/G661R mice recapitulate the short stature and ocular phenotypes of WMS. The altered fibrillin-1 and fibrillin-2 immunoactivity in Adamts10G661R/G661R mice suggests that the G661R mutation of Adamts10 perturbs regulation of the fibrillin isotype composition of microfibrils in the mouse eye.


Abuse liability of intravenous buprenorphine/naloxone and buprenorphine alone in buprenorphine-maintained intravenous heroin abusers.
Sublingual buprenorphine is an effective maintenance treatment for opioid dependence, yet intravenous buprenorphine misuse occurs. A buprenorphine/naloxone formulation was developed to mitigate this misuse risk. This randomized, double-blind, cross-over study was conducted to assess the intravenous abuse potential of buprenorphine/naloxone compared with buprenorphine in buprenorphine-maintained injection drug users (IDUs). Intravenous heroin users (n = 12) lived in the hospital for 8-9 weeks and were maintained on each of three different sublingual buprenorphine doses (2 mg, 8 mg, 24 mg). Under each maintenance dose, participants completed laboratory sessions during which the reinforcing and subjective effects of intravenous placebo, naloxone, heroin and low and high doses of buprenorphine and buprenorphine/naloxone were examined. Every participant received each test dose under the three buprenorphine maintenance dose conditions. Intravenous buprenorphine/naloxone was self-administered less frequently than buprenorphine or heroin (P < 0.0005). Participants were most likely to self-administer drug intravenously when maintained on the lowest sublingual buprenorphine dose. Subjective ratings of 'drug liking' and 'desire to take the drug again' were lower for buprenorphine/naloxone than for buprenorphine or heroin (P = 0.0001). Participants reported that they would pay significantly less money for buprenorphine/naloxone than for buprenorphine or heroin (P < 0.05). Seven adverse events were reported; most were mild and transient. These data suggest that although the buprenorphine/naloxone combination has intravenous abuse potential, that potential is lower than it is for buprenorphine alone, particularly when participants received higher maintenance doses and lower buprenorphine/naloxone challenge doses. Buprenorphine/naloxone may be a reasonable option for managing the risk for buprenorphine misuse during opioid dependence treatment.


[Enteral detoxication using polymethylsiloxane in the comprehensive treatment of septic forms of acute hematogenous osteomyelitis in newborn babies].
With regard for the role of bacterial and viral toxins and proteases in the pathogenesis of septic forms of acute hematogenous osteomyelitis, the use of enteral detoxication in the pediatric practice has been substantiated. The authors within 1988-1989, in 35 newborns with septic forms of acute hematogenous osteomyelitis used for detoxication the "Enterosgel" preparation. Control of the state of patients was accomplished by means of bacteriologic, biochemical and immunologic methods. A high detoxicative and antiinflammatory activity of the preparation and its harmlessness for the newborns have been proved.


Can D-dimer levels predict the treatment outcome in a patient with tuberculosis?
Tuberculous peritonitis is a leading cause of mortality and morbidity particularly in the developing world. Delay in initiation of treatment distinctively increases mortality. Treatment response to anti-tuberculosis drugs is usually observed by regression of symptoms and clearance of ascites. With initiation of treatment, laboratory values including CA-125 levels generally return to normal levels in 3 months. However, there is still no consensus about treatment response during the follow-up period. Serum D-dimer level is used as an inflammation marker in some cases. A case with Tuberculous peritonitis successfully monitorised by serum D-dimer levels is presented.


Electrical responses of gastric smooth muscles in streptozotocin-induced diabetic rats.
Electrical responses of gastric smooth muscles produced by transmural nerve stimulation, acetylcholine, norepinephrine, or K-free solution were investigated in streptozotocin-induced diabetic rats, using intracellular microelectrode techniques. In muscles from diabetic rats, 1) the resting membrane potential remained unchanged, 2) slow waves disappeared or were markedly reduced in amplitude, 3) the excitatory junction potential was absent, and in most cases only an inhibitory junction potential of reduced amplitude was elicited, 4) the amplitude of the hyperpolarization generated after superfusion with K-free solution was reduced, 5) the sensitivity of the acetylcholine-induced membrane depolarization was increased, and 6) the norepinephrine-induced hyperpolarization was reduced because of functional loss of alpha- and beta-adrenoceptors. Thus diabetes mellitus caused functional impairment of neuromuscular transmission, reduced the maximum activity of the electrogenic pump, increased the sensitivity of muscarinic receptors, reduced the sensitivity of adrenoceptors, and reduced the myogenic activity in gastric smooth muscles. These alterations in the properties of smooth muscle may be involved in the diabetes-induced gastroparesis.


The Scholarly and Pedagogical Benefits of the Legal Laboratory: Lessons from the Consortium for the Advanced Study of Brain Injury at Yale Law School.
In our article, we share the lessons we have learned after creating and running a successful legal laboratory over the past seven years at Yale Law School. Our legal laboratory, which focuses on the intersection of law and severe brain injury, represents a unique pedagogical model for legal academia, and is closely influenced by the biomedical laboratory.


3D reconstruction and analysis of wing deformation in free-flying dragonflies.
Insect wings demonstrate elaborate three-dimensional deformations and kinematics. These deformations are key to understanding many aspects of insect flight including aerodynamics, structural dynamics and control. In this paper, we propose a template-based subdivision surface reconstruction method that is capable of reconstructing the wing deformations and kinematics of free-flying insects based on the output of a high-speed camera system. The reconstruction method makes no rigid wing assumptions and allows for an arbitrary arrangement of marker points on the interior and edges of each wing. The resulting wing surfaces are projected back into image space and compared with expert segmentations to validate reconstruction accuracy. A least squares plane is then proposed as a universal reference to aid in making repeatable measurements of the reconstructed wing deformations. Using an Eastern pondhawk (Erythimus simplicicollis) dragonfly for demonstration, we quantify and visualize the wing twist and camber in both the chord-wise and span-wise directions, and discuss the implications of the results. In particular, a detailed analysis of the subtle deformation in the dragonfly's right hindwing suggests that the muscles near the wing root could be used to induce chord-wise camber in the portion of the wing nearest the specimen's body. We conclude by proposing a novel technique for modeling wing corrugation in the reconstructed flapping wings. In this method, displacement mapping is used to combine wing surface details measured from static wings with the reconstructed flapping wings, while not requiring any additional information be tracked in the high speed camera output.


Cd2+ resistance mechanisms in Methanosarcina acetivorans involve the increase in the coenzyme M content and induction of biofilm synthesis.
To assess what defence mechanisms are triggered by Cd(2+) stress in Methanosarcina acetivorans, cells were cultured at different cadmium concentrations. In the presence of 100 μM CdCl2, the intracellular contents of cysteine, sulfide and coenzyme M increased, respectively, 8, 27 and 7 times versus control. Cells incubated for 24 h in medium with less cysteine and sulfide removed up to 80% of Cd(2+) added, whereas their cysteine and coenzyme M contents increased 160 and 84 times respectively. Cadmium accumulation (5.2 μmol/10-15 mg protein) resulted in an increase in methane synthesis of 4.5 times in cells grown on acetate. Total phosphate also increased under high (0.5 mM) Cd(2+) stress. On the other hand, cells preadapted to 54 μM CdCl2 and further exposed to > 0.63 mM CdCl2 developed the formation of a biofilm with an extracellular matrix constituted by carbohydrates, DNA and proteins. Biofilm cells were able to synthesize methane. The data suggested that increased intracellular contents of thiol molecules and total phosphate, and biofilm formation, are all involved in the cadmium resistance mechanisms in this marine archaeon.


Revision of the genus Pelecinobaccha Shannon, description of Relictanum gen. nov., and redescription of Atylobaccha flukiella (Curran, 1941) (Diptera: Syrphidae).
Recent phylogenetic analyses of Ocyptamus Macquart, 1834 (Diptera, Syrphidae) confirmed the paraphyly of this genus and provided evidence to divide it into several monophyletic subgroups, of which the largest is the clade traditionally treated as the Ocyptamus tristis species group. This group is here redefined, divided into the genera Pelecinobaccha Shannon, 1927 and Relictanum gen. nov., and revised along with the closely related and newly resurrected genus Atylobaccha Hull, 1949. Twenty-four new species (22 in Pelecinobaccha and two in Relictanum) are described and 35 species (27 in Pelecinobaccha, seven in Relictanum and Atylobaccha flukiella Curran, 1941) are redescribed. Pelecinobaccha is divided into four species groups (P. adspersa species group, P. brevipennis species group, P. peruviana species group and P. susio species group). An identification key, illustrations and distribution maps for all species from this study are also presented.


(Very) polar organic compounds in the Danube river basin: a non-target screening workflow and prioritization strategy for extracting highly confident features.
Recently, more and more research has been focused on the analysis of polar organic compounds as they tend to be persistent and mobile in the aquatic environment. The serial coupling of reversed-phase and hydrophilic interaction liquid chromatography allows the separation of analytes of an extended polarity range within a single run. The non-target screening approach was driven by high-resolution mass spectrometry and is able to detect unexpected compounds. It is therefore capable of complementing regular monitoring of surface water. Non-target screening, however, can produce massive data sets. Here, a data processing method is presented focusing on unravelling tentative polar compounds from the full scan data of 51 samples of the Danube river and its tributaries. The feature extraction method was optimized to 34 reference compounds at two concentration levels and was then applied to real samples. Features were matched by accurate mass with anthropogenic substances stored in the compound database STOFF-IDENT located on the FOR-IDENT platform. In order to extract polar candidates, the retention time interval corresponding to the HILIC separation was connected to compounds with a negative log D value. As a result, 67 candidates were detected which were found to be plausible. Finally, features were prioritized based on an identification certainty classification system as well as their frequency of occurrence. Therefore, several feature-candidate compound pairs could be suggested for confirmation via reference materials. The presented non-target screening strategy followed by a database query is transferrable to other sample sets and other data evaluation tools.


The effectiveness of transdiagnostic cognitive behavioural therapy for anxiety disorders: the role of and impact of comorbid depression.
Transdiagnostic Cognitive Behaviour Therapy (tCBT), an intervention designed to be applicable across multiple diagnoses, was introduced to improve limitations in traditional therapy such as cost and access to trained therapists. It has been established as an effective and efficacious treatment for anxiety disorders, though there has been little research focussed on the role of depression. The current study investigated the role of comorbid depression during tCBT for anxiety disorders in primary care settings as an outcome and a moderator of anxiety outcomes. Results of multi-level ANOVAs indicated no significant difference in anxiety outcomes regardless of whether there was a comorbid depression diagnosis in the tCBT condition, and that individuals with a comorbid depression diagnosis experienced significantly greater reduction in anxiety severity than those without. Depression symptom severity decreased to a significantly greater extent in the tCBT condition than in TAU when the outcome measure of Patient Health Questionnaire was utilised as the outcome measure, but this was not mirrored when the Clinician Severity Rating was utilised as the outcome measure. This study provides preliminary support for the effectiveness of Transdiagnostic Cognitive Behaviour therapy for those with both a principal anxiety disorder and comorbid depression in symptom reduction.


Don't let it distract you: how information about the availability of reward affects attentional selection.
Previous research has shown that attentional selection is affected by reward contingencies: previously selected and rewarded stimuli continue to capture attention even if the reward contingencies are no longer in place. In the current study, we investigated whether attentional selection also is affected by stimuli that merely signal the magnitude of reward available on a given trial but, crucially, have never had instrumental value. In a series of experiments, we show that a stimulus signaling high reward availability captures attention even when that stimulus is and was never physically salient or part of the task set, and selecting it is harmful for obtaining reward. Our results suggest that irrelevant reward-signaling stimuli capture attention, because participants have learned about the relationship between the stimulus and reward. Importantly, we only observed learning after initial attentional prioritization of the reward signaling stimulus. We conclude that nonsalient, task-irrelevant but reward-signaling stimuli can affect attentional selection above and beyond top-down or bottom-up attentional control, however, only after such stimuli were initially prioritized for selection.


Of microbes and mange: consistent changes in the skin microbiome of three canid species infected with Sarcoptes scabiei mites.
Sarcoptic mange is a highly contagious skin disease caused by the ectoparasitic mite Sarcoptes scabiei. Although it afflicts over 100 mammal species worldwide, sarcoptic mange remains a disease obscured by variability at the individual, population and species levels. Amid this variability, it is critical to identify consistent drivers of morbidity, particularly at the skin barrier. Using culture-independent next generation sequencing, we characterized the skin microbiome of three species of North American canids: coyotes (Canis latrans), red foxes (Vulpes vulpes) and gray foxes (Urocyon cinereoargenteus). We compared alpha and beta diversity between mange-infected and uninfected canids using the Kruskal-Wallis test and multivariate analysis of variance with permutation. We used analysis of composition of microbes and gneiss balances to perform differential abundance testing between infection groups. We found remarkably consistent signatures of microbial dysbiosis associated with mange infection. Across genera, mange-infected canids exhibited reduced microbial diversity, altered community composition and increased abundance of opportunistic pathogens. The primary bacteria comprising secondary infections were Staphylococcus pseudintermedius, previously associated with canid ear and skin infections, and Corynebacterium spp., previously found among the gut flora of S. scabiei mites and hematophagous arthropods. This evidence suggests that sarcoptic mange infection consistently alters the canid skin microbiome and facilitates secondary bacterial infection, as seen in humans and other mammals infected with S. scabiei mites. These results provide valuable insights into the pathogenesis of mange at the skin barrier of North American canids and can inspire novel treatment strategies. By adopting a "One Health" framework that considers mites, microbes and the potential for interspecies transmission, we can better elucidate the patterns and processes underlying this ubiquitous and enigmatic disease.


Identification of proteins and miRNAs that specifically bind an mRNA in vivo.
Understanding regulation of an mRNA requires knowledge of its regulators. However, methods for reliable de-novo identification of proteins binding to a particular RNA are scarce and were thus far only successfully applied to abundant noncoding RNAs in cell culture. Here, we present vIPR, an RNA-protein crosslink, RNA pulldown, and shotgun proteomics approach to identify proteins bound to selected mRNAs in C. elegans. Applying vIPR to the germline-specific transcript gld-1 led to enrichment of known and novel interactors. By comparing enrichment upon gld-1 and lin-41 pulldown, we demonstrate that vIPR recovers both common and specific RNA-binding proteins, and we validate DAZ-1 as a specific gld-1 regulator. Finally, combining vIPR with small RNA sequencing, we recover known and biologically important transcript-specific miRNA interactions, and we identify miR-84 as a specific interactor of the gld-1 transcript. We envision that vIPR will provide a platform for investigating RNA in vivo regulation in diverse biological systems.


Blood Performance: A New Formula for Fish Growth and Health.
Monitoring fish health in a repeatable and accurate manner can contribute to the profitability and sustainability of aquaculture. Haematological and blood biochemistry parameters have been powerful tools and becoming increasingly common in aquaculture studies. Fish growth is closely related to its health status. A fish with a higher growth rate is more likely to be a healthy one. Any change in the physiological status of the fish, from pollution to nutritional stress, can cause changes in the blood parameters. Various aquaculture studies have measured the following components: red blood cells, white blood cells, haemoglobin, haematocrit, and total protein. However, because these parameters do not always follow the same trend across experimental fish, it is difficult to draw a firm conclusion about which parameter should be considered. Therefore, Blood Performance (BP) as a new formula is introduced, which is a more reliable indicator. This formula is simple and sums up the natural logarithm of the five above-mentioned parameters. More than 90 published peer-reviewed articles that measured these five parameters in the last six years confirmed the reliability and validity of this formula. Regardless of which supplements were added to the diets, the fish with a higher growth rate had higher BP as well. In addition, in 44 studies out of 53 articles, there was a significant positive correlation between specific growth rate and BP. Under different stressful situations, from pollution to thermal stress, the fish under stress had a lower BP than the control. Fish meal and fish oil replacement studies were further evidence for this formula and showed that adding excessive alternative proteins decreased growth along with BP. In conclusion, BP can be a reliable indicator of fish health and growth when it is compared between groups in the same experiment or farm. Although there was a positive correlation between specific growth rate and BP, comparing BP between experiments is not recommended. Standardising the haematological assays can improve the reliability and accuracy of BP across experiments.


[The experience in organizing the medical support of allied convoys during the Great Patriotic War on the northern maritime theater].
The medical support of allied convoys during the Great Patriotic War had a number of features. The Intensity of power of the fighting, the meteorological conditions, the composition of convoy's forces, the kind of enemy's weapon - had a significant impact on the structure of losses in personnel. The main type of medical care on the ships of 2-3rd rank was predoctor care. On the large and small antisubmarine ships and torpedo boats - it was first aid. The factor which has been affecting the amount of assistance - was a one-time inflow of a significant number of victims. Medical-evacuation provision of the convoys was carried out by the ships medical service without the use of amplification and sanitary ships. The most part of the wounded were taken to the coastal fleet hospitals later than 12 hours after the wound. The war experience has shown that in the distant convoys qualified surgical assistance may be provided in case of organizing it in this convoy and in case of using high-speed vehicles.


The Maternal Phenylketonuria International Study: 1984-2002.
The purpose of this report is to review the obstetric medical, psychological, and nutritional aspects and outcome of the women and offspring enrolled in the Maternal Phenylketonuria Study, which was established to assess the efficacy of a phenylalanine (Phe)-restricted diet in preventing the morbidity associated with this disorder. A total of 382 women with hyperphenylalaninemia (HPA) were enrolled in the study and completed 572 pregnancies. Outcome measures were analyzed with chi2, Fisher exact text, analysis of variance, t test, Wilcoxon nonparametric test, and multiple logistic regression. Outcome measures were stratified according to maternal HPA classification and the time when dietary control was achieved. Optimal birth outcomes occurred when maternal blood Phe levels between 120 and 360 micromol/L were achieved by 8 to 10 weeks of gestation and maintained throughout pregnancy (trimester averages of 600 micromol/L). Mothers with mild HPA achieved similar birth outcomes as mothers who were in control preconceptually and those in control by 8 to 10 weeks of pregnancy. Before conception, counseling and early entrance into a prenatal care program is essential in achieving optimal fetal outcome in women with HPA. The achievement of pre- and periconceptional dietary control with a Phe-restricted diet significantly decreased morbidity in the offspring of women with HPA.


A whole-cell and single-channel study of the voltage-dependent outward potassium current in avian hepatocytes.
Voltage-dependent membrane currents were studied in dissociated hepatocytes from chick, using the patch-clamp technique. All cells had voltage-dependent outward K+ currents; in 10% of the cells, a fast, transient, tetrodotoxin-sensitive Na+ current was identified. None of the cells had voltage-dependent inward Ca2+ currents. The K+ current activated at a membrane potential of about -10 mV, had a sigmoidal time course, and did not inactivate in 500 ms. The maximum outward conductance was 6.6 +/- 2.4 nS in 18 cells. The reversal potential, estimated from tail current measurements, shifted by 50 mV per 10-fold increase in the external K+ concentration. The current traces were fitted by n2 kinetics with voltage-dependent time constants. Omitting Ca2+ from the external bath or buffering the internal Ca2+ with EGTA did not alter the outward current, which shows that Ca2+-activated K+ currents were not present. 1-5 mM 4-aminopyridine, 0.5-2 mM BaCl2, and 0.1-1 mM CdCl2 reversibly inhibited the current. The block caused by Ba was voltage dependent. Single-channel currents were recorded in cell-attached and outside-out patches. The mean unitary conductance was 7 pS, and the channels displayed bursting kinetics. Thus, avian hepatocytes have a single type of K+ channel belonging to the delayed rectifier class of K+ channels.


Synthesis of artemiside and its effects in combination with conventional drugs against severe murine malaria.
This research describes the use of novel antimalarial combinations of the new artemisinin derivative artemiside, a 10-alkylamino artemisinin. It is a stable, highly crystalline compound that is economically prepared from dihydroartemisinin in a one-step process. Artemiside activity was more pronounced than that of any antimalarial drug in use, both in Plasmodium falciparum culture and in vivo in a murine malaria model depicting cerebral malaria (CM). In vitro high-throughput testing of artemiside combinations revealed a large number of conventional antimalarial drugs with which it was additive. Following monotherapy in mice, individual drugs reduced parasitemias to nondetectable levels. However, after a period of latency, parasites again were seen and eventually all mice became terminally ill. Treatment with individual drugs did not prevent CM in mice with recrudescent malaria, except for piperaquine at high concentrations. Even when CM was prevented, the mice developed later of severe anemia. In contrast, most of the mice treated with drug combinations survived. A combination of artemiside and mefloquine or piperaquine may confer an optimal result because of the longer half life of both conventional drugs. The use of artemiside combinations revealed a significant safety margin of the effective artemiside doses. Likewise, a combination of 1.3 mg/kg of body weight artemiside and 10 mg/kg piperaquine administered for 3 days from the seventh day postinfection was completely curative. It appears possible to increase drug concentrations in the combination therapy without reaching toxic levels. Using the drug combinations as little as 1 day before the expected death of control animals, we could prevent further parasite development and death due to CM or anemic malaria. Earlier treatment may prevent cognitive dysfunctions which might occur after recovery from CM.


Genomic findings in schizophrenia and their implications.
There has been substantial progress in understanding the genetics of schizophrenia over the past 15 years. This has revealed a highly polygenic condition with the majority of the currently explained heritability coming from common alleles of small effect but with additional contributions from rare copy number and coding variants. Many specific genes and loci have been implicated that provide a firm basis upon which mechanistic research can proceed. These point to disturbances in neuronal, and particularly synaptic, functions that are not confined to a small number of brain regions and circuits. Genetic findings have also revealed the nature of schizophrenia's close relationship to other conditions, particularly bipolar disorder and childhood neurodevelopmental disorders, and provided an explanation for how common risk alleles persist in the population in the face of reduced fecundity. Current genomic approaches only potentially explain around 40% of heritability, but only a small proportion of this is attributable to robustly identified loci. The extreme polygenicity poses challenges for understanding biological mechanisms. The high degree of pleiotropy points to the need for more transdiagnostic research and the shortcomings of current diagnostic criteria as means of delineating biologically distinct strata. It also poses challenges for inferring causality in observational and experimental studies in both humans and model systems. Finally, the Eurocentric bias of genomic studies needs to be rectified to maximise benefits and ensure these are felt across diverse communities. Further advances are likely to come through the application of new and emerging technologies, such as whole-genome and long-read sequencing, to large and diverse samples. Substantive progress in biological understanding will require parallel advances in functional genomics and proteomics applied to the brain across developmental stages. For these efforts to succeed in identifying disease mechanisms and defining novel strata they will need to be combined with sufficiently granular phenotypic data.


Correction: Injectable postoperative enzyme-responsive hydrogels for reversing temozolomide resistance and reducing local recurrence after glioma operation.
Correction for 'Injectable postoperative enzyme-responsive hydrogels for reversing temozolomide resistance and reducing local recurrence after glioma operation' by Zongren Zhao et al., Biomater. Sci., 2020, 8, 5306-5316, DOI: 10.1039/D0BM00338G.


Virological Suppression and Patterns of Resistance Amongst Patients on Antiretroviral Therapy at 4 Nigerian Military Hospitals.
In resource-constrained settings, plasma HIV-1 RNA quantification has not been routinely available for the monitoring of response to antiretroviral therapy. This study evaluated virological suppression rates amongst patients on first-line ART in four Nigerian military hospitals. We conducted a cross-sectional study of 325 randomly selected adult clinic clients (≥18 years old) on first-line ART regimens at four Nigerian military hospitals. Plasma HIV-1 RNA was assayed using a Roche COBAS TaqMan48 with High Pure System. Virological failure was defined as HIV-1 RNA >1000 copies/ml. Specimens with HIV-1 RNA >1000 copies/ml were referred for genotyping. HIV-1 RNA results were obtained in 322 participants. Two hundred and seventy-eight study participants (86.3%) had HIV viral RNA < 1000 copies/ml, including 273 (84.8%) with HIV- 1 RNA <400 copies/ml. HIV drug resistance genotyping results were obtained in 35 of 44 study participants with HIV-1 RNA >1000 copies/ml. Only 14% (5/35) had no resistance mutations. Of the remainder, 10% (3/30) had no nucleoside analogue mutations while 33% (10/30) had only M184V along with non-nucleoside reverse transcriptase inhibitor (NNRTI) mutations (K103N or Y188C). 25% (5/25) of participants failing on Zidovudine had more than two thymidine analogue mutations (TAMs). We observed a high virological suppression rate among the study participants. However, a large proportion of virologically unsuppressed clients had identifiable resistance mutations. The study demonstrates that viral load monitoring is feasible at Nigerian military hospitals and supports the current WHO HIV treatment guidelines which emphasize virological monitoring of patients on ART for early detection of treatment failure.


Are there any benefits from minimizing fasting and optimization of nutrition and fluid management for patients undergoing day surgery?
As a result of advances in anaesthesia and surgery, an increasing number of surgical procedures are currently possible in the ambulatory setting. Nausea/vomiting and sedation/drowsiness are often associated with delayed discharge and readmission. These symptoms are also related to pharmacological treatment as well as dehydration and fasting. The evidence that preoperative fasting and dehydration not only reduces preoperative well being, but may also affect postoperative recovery is currently being reviewed. In association with minor surgical procedures, rehydration with approximately 1 l fluid, and in cases with a moderate degree of surgery, such as laparoscopic surgery, 1-3 l fluid, given perioperatively will improve postoperative well being and recovery. Administration of a carbohydrate-rich beverage not only provides fluid but also counteracts the negative effects of preoperative fasting, which in turn reduces preoperative hunger and improves well being. Postoperatively, this treatment reduces insulin resistance, which may be relevant in surgery with significant postoperative stress response. Two studies on laparoscopic cholecystectomy demonstrate different results regarding effects on postoperative outcome and nausea/vomiting and further evaluation is required. When preoperative dehydration is corrected, postoperative well being and clinical outcome improves. Avoiding preoperative fasting by administration of carbohydrate-rich beverages improves preoperative well being while effects on postoperative recovery in patients undergoing ambulatory surgery need to be further evaluated.


Cutaneous melanoma: fishing with chips.
DNA microarray technology is a versatile platform that allows rapid genetic analysis to take place on a genome-wide scale and has revolutionized the way cancers are studied. This platform has enabled researchers to characterize mechanisms central to tumorigenesis and understand important molecular events in the multi-step tumor progression model of cutaneous melanoma and other cancers. In melanoma, multiple global gene expression profiling studies using various DNA microarray platforms and various experimental designs have been performed. Each study has been able to capture and characterize either the involvement of a novel pathway or a novel cause-effect-relationship. The use of microarrays to define subclasses, to identify differentially regulated genes within a mutational context to analyze epigenetically regulated genes has resulted in an unprecedented understanding of the biology of cutaneous melanoma that may lead to more accurate diagnosis, more comprehensive prognosis, prediction and more effective therapeutic interventions. Related DNA microarray platforms like array-comparative genomic hybridization (CGH) have also been instrumental to identify many non-random chromosomal alterations; however, studies identifying validated targets as a result of CGH are limited. Thus, there exists significant opportunity to discover novel melanoma genes and translate such discoveries into meaningful clinical endpoints. In this review, we focus on various DNA microarray-based studies performed in cutaneous melanoma and summarize our current understanding of the genetics and biology of melanoma progression derived from accumulating genomic information.


Reliability of the Roussel Uclaf Causality Assessment Method for assessing causality in drug-induced liver injury.
The Roussel Uclaf Causality Assessment Method (RUCAM) was developed to quantify the strength of association between a liver injury and the medication implicated as causing the injury. However, its reliability in a research setting has never been fully explored. The aim of this study was to determine test-retest and interrater reliabilities of RUCAM in retrospectively-identified cases of drug induced liver injury. The Drug-Induced Liver Injury Network is enrolling well-defined cases of hepatotoxicity caused by isoniazid, phenytoin, clavulanate/amoxicillin, or valproate occurring since 1994. Each case was adjudicated by three reviewers working independently; after an interval of at least 5 months, cases were readjudicated by the same reviewers. A total of 40 drug-induced liver injury cases were enrolled including individuals treated with isoniazid (nine), phenytoin (five), clavulanate/amoxicillin (15), and valproate (11). Mean +/- standard deviation age at protocol-defined onset was 44.8 +/- 19.5 years; patients were 68% female and 78% Caucasian. Cases were classified as hepatocellular (44%), mixed (28%), or cholestatic (28%). Test-retest differences ranged from -7 to +8 with complete agreement in only 26% of cases. On average, the maximum absolute difference among the three reviewers was 3.1 on the first adjudication and 2.7 on the second, although much of this variability could be attributed to differences between the enrolling investigator and the external reviewers. The test-retest reliability by the same assessors was 0.54 (upper 95% confidence limit = 0.77); the interrater reliability was 0.45 (upper 95% confidence limit = 0.58). Categorizing the RUCAM to a five-category scale improved these reliabilities but only marginally. The mediocre reliability of the RUCAM is problematic for future studies of drug-induced liver injury. Alternative methods, including modifying the RUCAM, developing drug-specific instruments, or causality assessment based on expert opinion, may be more appropriate.


Developmental coordination disorder: is clumsy motor behavior caused by a lesion of the brain at early age?
Children presenting with Developmental Coordination Disorder or clumsiness often exhibit signs of minor neurological dysfunction (MND). The data of the Groningen Perinatal Project, a long-term follow-up project on the relations between prenatal and perinatal adversities and neurological, behavioral, and cognitive development revealed that two basic forms of MND can be distinguished: simple and complex MND. During school age children with simple MND are characterized by the presence of one or two dysfunctional clusters of MND, in adolescence by the presence of choreiform dyskinesia or hypotonia. Probably the major sources of origin of simple MND are genetic constitution and stress during early life. Simple MND might reflect the lower tail of the normal distribution of the quality of non-pathological brain function. In line with this hypothesis is the finding that simple MND is associatedwith only a moderately increased risk for learning- and behavioral problems. Children with complex MND present at school age with at least three dysfunctional clusters of MND, in adolescence with problems in fine manipulation or coordination. Perinatal adversities play an evident etiological role in the development of complex MND, suggesting that it might be attributed to a lesion of the brain at early age. In line with this idea is the finding that complex MND shows a strong correlation with attention and learning problems.


Diversification of Simple Arenes into Complex (Amino)cyclitols.
Highly oxygenated cyclohexanes, including (amino)cyclitols, are featured in natural products possessing a notable range of biological activities. As such, these building blocks are valuable tools for medicinal chemistry. While de novo synthetic strategies have provided access to select compounds, challenges including stereochemical density and complexity have hindered the development of a general approach to (amino)cyclitol structures. This work reports the use of arenophile chemistry to access dearomatized intermediates which are amenable to diverse downstream transformations. Practical guidelines were developed for the synthesis of natural and non-natural (amino)cyclitols from simple arenes through a series of strategic functionalization events.


The impact of technology dependency on device acceptance and quality of life in persons with implantable cardioverter defibrillators.
The impact of implantable cardioverter defibrillator (ICD) technology on the quality of life (QOL) experienced by recipients has been a major focus of recent research. Numerous studies have found psychological distress to be important in determining QOL in persons receiving ICDs, yet the source of psychological distress is not well understood. The aim of this study was to determine the impact of technology dependency on psychological outcomes in ICD recipients. With the use of a cross-sectional design, 161 ICD recipients from 1 device clinic were mailed self-administered questionnaires, including the Dependency on Technology Scale, Brief Illness Perception Questionnaire, Florida Shock Anxiety Scale, Florida Patient Acceptance Survey, and Short Form-12 (SF-12). Hierarchical multiple regressions and analyses of variance were performed. The final sample size was 101 participants. Mean (SD) age was 68 (13) years; 72% of the participants were men, 99% were white, and 30% reported receiving a shock(s). A total of 80% reported positive attitudes toward technology dependency; 14%, neutral; and 6%, negative (Dependency on Technology Scale). Illness perceptions were positive (Brief Illness Perception Questionnaire; mean[SD], 34.5 [12.6]), shock anxiety was elevated (Florida Shock Anxiety Scale; mean [SD], 16.5 [6.7]), and device acceptance was good (Florida Patient Acceptance Survey; mean [SD], 74.9 [17.0]). Physical health QOL was low (SF-12; mean [SD], 38.6 [11.3]) and mental health QOL was moderate (SF-12; mean [SD], 50.6 [10.0]). Attitudes toward technology dependency significantly accounted for the variance seen in device acceptance and mental health QOL beyond age, gender, number of shocks, illness perceptions, and shock anxiety by 5.7% (P = .001) and 3.3% (P = .04), respectively. Significant differences were seen in device acceptance between those with negative and neutral attitudes (P = .001) and those with negative and positive attitudes (P < .001) and in shock anxiety and mental health QOL between those with negative and those with positive attitudes (P < .001). Attitudes toward technology dependency is significantly associated with psychological outcomes and may explain the psychological distress in some ICD recipients. Degree of positivity toward technology dependency influences these outcomes. Research evaluating attitudes toward technology dependency and testing of interventions focusing on these attitudes is warranted.