Candidate Attractant Pheromones of Two Potentially Invasive Asian Cerambycid Species in the Genus Xylotrechus.
Research during the 1980s showed that male Xylotrechus pyrrhoderus Bates (Coleoptera: Cerambycidae), a vineyard pest, produce (2S,3S)-2,3-octanediol and (S)-2-hydroxyoctan-3-one as possible pheromone components, but to our knowledge, field tests were not carried out. We confirmed that at least female X. pyrrhoderus were attracted by a 1:1 blend of these two compounds in field trials in Japan. Furthermore, more than 200 males and females of the congener Xylotrechus rufilius Bates were attracted by racemic 2-hydroxyoctan-3-one, and inhibited by syn-2,3-octanediol. Adult X. rufilius recently were intercepted in a shipment from China entering Baltimore, Maryland, raising concerns that this polyphagous species could establish in North America. Our results suggest that traps baited with 2-hydroxyoctan-3-one would be a valuable tool to assess whether X. rufilius has indeed become established, and to monitor for future introductions of X. rufilius.


Risk factors for acute stress disorder in children with burns.
The purpose of this study was to (1) estimate the prevalence of acute stress disorder (ASD) in a sample of burned children, and (2) determine risk factors for ASD in these children. Seventy-two children were assessed for acute stress disorder approximately 10 days after being hospitalized for a burn. Variables hypothesized to predict ASD symptoms (i.e., size of the burn, prior behavioral symptoms, body image, parents' symptoms, heart rate) were also assessed. Based on a diagnosis derived from the ASD module of the Diagnostic Interview for Children and Adolescents (DICA), 31% of children met criteria for ASD. Path analyses revealed that the variables of heart rate, body image, and parents' acute stress symptoms were directly related to the development of ASD symptoms and accounted for 41% of its variance. These variables also mediated the relationship between the size of the burn and ASD symptoms. ASD is found in almost one third of children hospitalized for a burn. A high resting heart rate, lowered body image, and parent's acute stress symptoms were found to be significant risk factors for ASD symptoms.


High-throughput sequencing and analysis of microbial communities in the mangrove swamps along the coast of Beibu Gulf in Guangxi, China.
Mangrove swamp is one of the world's richest and most productive marine ecosystems. This ecosystem also has a great ecological importance, but is highly susceptible to anthropogenic disturbances. The balance of mangrove ecosystem depends largely on the microbial communities in mangrove sediments. Thus, understanding how the mangrove microbial communities respond to spatial differences is essential for more accurate assessment of mangrove ecosystem health. To this end, we performed the first medium-distance (150 km) research on the biogeographic distribution of mangrove microbial communities. The hypervariable regions of 16S rRNA gene was sequenced by Illumina to compare the microbial communities in mangrove sediments collected from six locations (i.e. Zhenzhu harbor, Yuzhouping, Maowei Sea, Qinzhou harbor, Beihai city and Shankou) along the coastline of Beibu Gulf in Guangxi province, China. Collectively, Proteobacteria, Bacteroidetes, Chloroflexi, Actinobacteria, Parvarchaeota, Acidobacteria and Cyanobacteria were the predominant phyla in the mangrove sediments of this area. At genus level, the heat map of microbial communities reflected similarities between study sites and was in agreement with their biogeographic characteristics. Interestingly, the genera Desulfococcus, Arcobacter, Nitrosopumilus and Sulfurimonas showed differences in abundance between study sites. Furthermore, the principal component analysis (PCA) and unweighted UniFrac cluster tree of beta diversity were used to study the biogeographic diversity of the microbial communities. Relatively broader variation of microbial communities was found in Beihai city and Qinzhou harbour, suggesting that environmental condition and historical events may play an important role in shaping the bacterial communities as well. This is the first report on medium-distance range distribution of bacteria in the mangrove swamp ecosystem. Our data is valuable for monitoring and evaluation of the impact of human activity on mangrove habitats from the perspective of microbiome.


Properties of microfiltration membranes: the effects of adsorption and shear on the recovery of an enzyme.
An experimental study of the interaction of the enzyme yeast alcohol dehydrogenase (YADH) with microfiltration membranes has been carried out. Most measurements were made with capillary pore inorganic membranes (Anopore) with some comparative measurements being made with polymeric membranes of low protein affinity (Durapore). It has been shown that the prolonged exposure of the enzyme to the inorganic membrane under low-shear conditions (slow recycle) resulted in a loss of enzyme activity. Under filtration conditions, the membrane permeation rate decreased continuously with time. This decrease could be quantified using the standard blocking filtration law, which describes a decrease in pore volume due to deposition of enzyme on the walls of the pore. No significant loss in activity of permeating enzyme occurred under solution conditions where the enzyme was stable. However, a significant loss of such activity occurred under solution conditions where the enzyme was slightly unstable. The experiments indicate that the likely mechanism for activity loss is a membrane/enzyme interaction resulting from a shear induced deformation of the enzyme structure. Two conclusions of practical importance are drawn from the work.


Success with lifestyle monotherapy in youth with new-onset type 2 diabetes.
Evidence is lacking to support the efficacy of lifestyle modification as first-line therapy in the clinical management of type 2 diabetes mellitus (T2DM) in adolescents. A retrospective chart review of youth diagnosed with T2DM between 1999 and 2008 was conducted. The authors describe the percentage of youth presenting with glycosylated hemoglobin (HbA1c) of <9% who achieved/maintained target glycemic control (HbA1c ≤7.0%) with lifestyle monotherapy during the year following diagnosis. Among the 275 youth with T2DM, 38% (n=104) presented with an HbA1c <9% and were prescribed lifestyle monotherapy at diagnosis. Of the 80 youth who had sufficient follow-up data over 12 months, 54% successfully maintained target glycemic control solely with lifestyle management. The mean HbA1c score at diagnosis was lower in youth who where successful on lifestlye monotherapy compared with those who were not successful. A significant proportion of youth newly diagnosed with T2DM presenting with an HbA1c <9% effectively achieved/maintained target glycemic control with lifestyle recommendations alone for 12 months. Evidence is lacking to support the efficacy of lifestyle modification as first-line therapy in the clinical management of type 2 diabetes mellitus (T2DM) in adolescents. A retrospective chart review of youth diagnosed with T2DM between 1999 and 2008 was conducted. The authors describe the percentage of youth presenting with glycosylated hemoglobin (HbA1c) of <9% who achieved/maintained target glycemic control (HbA1c ≤7.0%) with lifestyle monotherapy during the year following diagnosis. Among the 275 youth with T2DM, 38% (n=104) presented with an HbA1c <9% and were prescribed lifestyle monotherapy at diagnosis. Of the 80 youth who had sufficient follow-up data over 12 months, 54% successfully maintained target glycemic control solely with lifestyle management. The mean HbA1c score at diagnosis was lower in youth who where successful on lifestlye monotherapy compared with those who were not successful. A significant proportion of youth newly diagnosed with T2DM presenting with an HbA1c <9% effectively achieved/maintained target glycemic control with lifestyle recommendations alone for 12 months.


Hemoglobin predicts long-term survival in dialysis patients: a 15-year single-center longitudinal study and a correlation trend between prealbumin and hemoglobin.
Dialysis patients have much higher mortality rates than the general population. Anemia is a common complication of uremia and a major contributor to morbidity and mortality in dialysis patients. The benefits of anemia correction using recombinant human erythropoietin (rHuEPO) are well established. Optimum hemoglobin level for dialysis patients remain controversial. We have investigated the association of enrollment hemoglobin with long-term survival in hemodialysis (HD) and peritoneal dialysis (PD) patients. We enrolled 529 HD and 326 PD patients from 1987 and followed them to April 2003. Demographics, enrollment, and clinical and laboratory data were recorded. The Kaplan-Meier method was used to compute observed survival, and the multivariate Cox regression analysis was used to identify the independent predictors of mortality risk. Mean ages of HD and PD patients were 60 +/- 16 (SD) and 54 +/- 16 (SD) years, respectively. Forty-seven percent of HD patients and 41% of PD patients were diabetic. Mean enrollment hemoglobin levels of HD and PD patients were 9.44 +/- 1.9 and 9.61 +/- 1.77 g/dL respectively. Cumulative 15 year observed survivals of HD (P = 0.05) and PD (P = 0.032) patients with hemoglobin levels greater or equal to 12 g/dL were higher than those with hemoglobin levels less than 12 g/dL. Hemoglobin <12 g/dL was a better predictor of mortality in nondiabetics than diabetics, particularly in HD patients. Both in HD and PD diabetic patients, hemoglobin was not a significant predictor of mortality. By Cox regression analysis, after adjusting for age, race, gender, and months on dialysis at enrollment, the relative risk of mortality of patients with hemoglobin <12 g/dL was 2.13-fold (P = 0.008) higher for HD and 1.85-fold (P = 0.06) higher for PD compared to those with hemoglobin >/=12 g/dL (P = 0.035). A logistic regression analysis revealed a strong inverse relationship between the hemoglobin level and the odds risk of death in HD (OR = 0.83, P = 0.008) and in PD (OR = 0.85, P = 0.02) patients. Enrollment hemoglobin is a predictor of long-term survival in HD and PD patients. Patients with hemoglobin levels that are higher than current treatment recommendations (>12 g/dL) may benefit from long-term survival. Survival of dialysis patients may be improved by better management of malnutrition and anemia.


Two patients with localised hyperhidrosis of the hand based on functional and structural abnormalities of sweat glands.
A 14-year-old girl and a 30-year-old woman presented with localised hyperhidrosis on the dorsal hand and wrist, respectively, provoked by different stimuli such as physical activity and minor trauma to the skin. The skin was seemingly normal in both patients where an iodine-starch test revealed a well-demarcated area of hyperhidrosis. Following histopathological examination, the diagnosis was unilateral localised hyperhidrosis in both cases; one with normal histology and one with a nevus sudoriferous. Both patients were successfully treated with botulinum toxin type A. The 30-year-old woman additionally used low-dose propantheline bromide periodically and experienced long-term remission on this therapy. Hyperhidrosis may embarrass and interfere with patients' school and careers, and it is therefore important to tailor an effective individual treatment.


Improved reduction efficiency, cycling performance, and removal rate of hexavalent chromium by adding water-soluble salts.
Recently, the reaction speed and cycle performance of hexavalent chromium reduction over microsized zero-valent iron (ZVI) with an Fe0 core and iron oxide (FeOx) shell structure have been improved by activating the Fe0-core electrons through electromagnetic coupling between Fe0-core electrons and charges (hexavalent chromium in solution, double-charge layers of the ZVI/solution interface). Herein, the abovementioned electromagnetic coupling was greatly increased by adding salt (CH3COONa, NaCl, NaNO3, and Na2SO4) in the hexavalent chromium solution to increase the charge response. Adding salt greatly improved the reaction speed and cycle performance of hexavalent chromium reduction. It took 8 min to reduce hexavalent chromium with CH3COONa to below the discharge standard of wastewater in the first cycle and 20 min after reducing for 20 cycles. The best apparent rate of constant value (0.416 (min)-1) is nearly four times larger than those without salts. X-ray diffraction and X-ray photoelectron spectroscopy revealed the production of amorphous iron oxide shell with salt. The salt improves the hexavalent chromium reduction speed and cycle performance and impedes the Fe0-core-electron transfer via the produced Fe2O3, resulting in existence of an optimized salt dosage. This work aims to provide an effective route for enhancing the removal efficiency and cycle performance of heavy-metal-ion reduction via Fe0. And this work also proposes a novel viewpoint that adding salt in waste water would increase the electromagnetic coupling between the charges in solution and Fe0-core electrons which could finally activate the redox reaction.


Multiple Fano resonances in monolayer hexagonal non-close-packed metallic shells.
In this study, we first numerically investigate the appearance and properties of multiple Fano resonances in two-dimensional hexagonal non-close-packed arrays of symmetric metallic shells. The coexistence of broad sphere-like plasmon modes formed from the near-field interaction between the individual sphere plasmons and substantially narrower void plasmon modes supported by the inner surface of the individual shell resonant over the same range of energies can produce such Fano resonances. In particular, void and sphere-like plasmon modes of different angular momentum could directly interact without the need of symmetry breaking in the structure. A cost-effective colloidal crystal templating method is utilized to prepare the arrays of the metallic shells with small openings. The effect of the symmetry breaking on the Fano resonances in metallic cup arrays is experimentally and numerically investigated. Further tunability on the Fano resonances is gained by changing the size of the inner dielectric core, hence changing the moment of the void plasmon modes and consequently the resonance frequency. By adopting the polymer dielectric core with gain materials, our study may offer realizable experimental opportunities towards subwavelength low threshold plasmonic lasing.


[Disturbances of wakefulness, sleep and respiratory function in Steinert's disease].
36 night sleep recordings were carried out on 15 patients suffering from myotonia dystrophica. 9 of these patients complained of diurnal hypersomnia. 10 patients had a disturbance of night sleep with a reduction of REM sleep sometimes associated with interruption of the recording with an increase in the light stages of sleep or alternatively with an increase of REM sleep with a reduction in the latency period of the first paradoxical sleep or with narcoleptic elements. 13 patients had abnormally early abolition of chin EMG activity, almost on falling asleep. 11 cases had pathological apnoeic episodes during sleep and in 9 of the 10 patients who underwent respiratory function studies there was a restrictive airways defect. In addition 9 had frank hypoxia without hypercapnia and 4 a right to left shunt. 3 clinically unaffected patients but with affected relatives were also investigated, 2 were found to have sleep disturbances 1 of which was associated with early abolition of tone.


[The educational offer of masters in middle manager for the health professions].
In Italy recent legislation has been introduced regarding middle and top management roles in the health professions. Although universities have begun educational courses and health organizational models for coordination and management roles, unfortunately, there is still a lack of homogeneous and coordinated planning for putting the principles of legislation into practice correctly. Investigation of these words in the main national searching motors: Masters, coordination, health professions. Statistic elaboration with the calculation of average and standard deviation. Graphs with histograms and maps. S.W.O.T. analysis. General and specific data, averages and standard deviations, concerning the principal Masters activated in the academic year 2005/2006, in terms of participants, territorial distribution, profits and expenses , as well as the general number of the students in each classroom. Comparative considerations were made between the data concerning the activation of Masters' courses and Specialist Degrees in the Health Professions and the question of how to develop a correct synergy between the managerial health professionals (Specialist Degree) and middle management professionals (Master). The S.W.O.T. analysis underlines the important innovations in development of an organizational culture within the National Health Service, the great variability in the distribution of Masters' Schools throughout Italy, the need to apply rational and organizational models that combine effectiveness and efficiency without disorientating the professionals and managers holding organizational roles.


The Use of Hypothermia Therapy in Traumatic Ischemic / Reperfusional Brain Injury: Review of the Literatures.
Therapeutic mild hypothermia has been used widely in brain injury. It has evaluated in numerous clinical trials, and there is strong evidence for the use of hypothermia in treating patients with several types of ischemic / reperfusional (I/R) injuries, examples being cardiac arrest and neonatal hypoxic-ischemic encephalopathy.In spite of many basic research projects demonstrating effectiveness, therapeutic hypothermia has not been proven effective for the heterogeneous group of traumatic brain injury patients in multicenter clinical trials. In the latest clinical trial, however, researchers were able to demonstrate the significant beneficial effects of hypothermia in one specific group; patients with mass evacuated lesions. This suggested that mild therapeutic hypothermia might be effective for I/R related traumatic brain injury.In this article we have reviewed much of the previous literature concerning the mechanisms of I/R injury to the protective effects of mild therapeutic hypothermia.


Neurocognitive impairments in individuals at ultra-high risk for psychosis: Who will really convert?
Impairments in neurocognitive function are considered as core features of schizophrenia. Individuals at ultra-high risk (UHR) for psychosis, the 'putative' prodrome of schizophrenia, generally show levels of impairments intermediate between schizophrenia patients and healthy controls. We investigated the neurocognitive performance of individuals at UHR for psychosis, comparing them with patients with first-episode schizophrenia (FES) and healthy controls (HC), and explored the predictivity of baseline neurocognitive function in the UHR group for transition to overt psychosis. Individuals at UHR for psychosis (n = 60), patients with FES (n = 39), and HC subjects (n = 94) participated in the present study. All participants performed a comprehensive neurocognitive battery, consisting of tests for five separate neurocognitive domains (executive function, attention/working memory, processing speed, verbal memory, and spatial memory). UHR subjects were assessed for transition every month during 24 months of follow-up. Neurocognitive performance in the UHR group was largely at intermediate levels. Attention/working memory and verbal memory were significantly different from both the FES and HC groups. In the UHR group, processing speed was decreased to the level of the FES group, while executive function and spatial memory were relatively preserved. In the Cox regression model, spatial memory significantly predicted the transition to overt psychosis in the UHR group. The present study showed that neurocognitive impairments were evident in UHR individuals prior to the onset of overt psychosis. Our findings generally support the neurodevelopmental model of schizophrenia and suggest that there could be different developmental trajectories between converters and non-converters.


On how a myosin tryptophan may be perturbed.
A well-known indication that a nucleotide has bound to myosin is the enhancement of the fluorescence of a specific tryptophan in the "subfragment 1" segment of the protein. Empirically the effect has been enormously useful in myosin enzymology. But beyond an early suggestion that it arises from a purine-tryptophan charge-transfer complex, the mechanism of the effect has not been considered. Here we consider the alternative that it arises from an ionizable group (either another residue or the phosphate of the nucleotide) whose proximity to the tryptophan is altered by substrate binding. We study this possibility by studying the interaction of an ionizable residue and tryptophan when both are incorporated in a diketopiperazine structure. The geometry of the situation is inferred from molecular mechanics simulations. Unexpectedly, the best explanation seems to be that the field of the imposed charge, acting across space, affects events in the excited state of the indole.


The role of EZH2 in ocular diseases: a narrative review.
EZH2, acting as a catalytic subunit of PRC2 to catalyze lysine 27 in histone H3, induces the suppression of gene expression. EZH2 can regulate cell proliferation and differentiation of retinal progenitors, which are required for physiological retinal development. Meanwhile, an abnormal level of EZH2 has been observed in ocular tumors and other pathological tissues. This review summarizes the current knowledge on EZH2 in retinal development and ocular diseases, including inherited retinal diseases, ocular tumors, corneal injury, cataract, glaucoma, diabetic retinopathy and age-related retinal degeneration. We highlight the potential of targeting EZH2 as a precision therapeutic target in ocular diseases.


A model of electrical impedance tomography implemented in nerve-cuff for neural-prosthetics control.
In neural interfaces for peripheral nerve a trade-off exists between the level of invasiveness and the selectivity of neural recordings. In this study, we implement electrical impedance tomography (EIT) in a nerve cuff with the aim to investigate the achievable level of selectivity. Established modelling approaches in neural-EIT are expanded on to be used, for the first time, on myelinated fibres which are abundant in mammalian peripheral nerves and transmit motor commands. The model is then used to evaluate the viability of using EIT with a nerve cuff to record neural activity in peripheral nerves. Fibre impedance models indicate activity in unmyelinated fibres can be screened out from activity in myelinated fibres using operating frequencies above 100 Hz. At 1 kHz the transverse impedance magnitude, which is perpendicular to the fibre length axis, of inactive intra-fascicle tissue and the fraction change during neural activity are estimated to be 1142 Ω cm and -8.8 × 10-4, respectively. At 1 kHz and 10 mm spacing between the impedance measurement electrode pair, the longitudinal impedance magnitude, which is parallel to the fibre length axis, and the fraction change during neural activity are estimated to be 328 Ω cm and -0.30, respectively. We show that a novel EIT drive and measurement electrode pattern which utilises longitudinal current and longitudinal differential boundary voltage measurements could distinguish activity in different fascicles, as well as simultaneous activity in multiple fascicles, of a three-fascicle mammalian nerve using simulated data. The results of this study provide an estimate of the transient change in impedance of intra-fascicle tissue during neural activity in mammalian nerve, and present a viable EIT electrode pattern, both of which are critical steps towards implementing EIT in a nerve cuff for a recording neural interface.


Effectiveness of rituximab for the otolaryngologic manifestations of granulomatosis with polyangiitis (Wegener's).
Ear, nose, and throat (ENT) involvement is the most prevalent manifestation of granulomatosis with polyangiitis (Wegener's) (GPA) and correlates with permanent damage and decreased quality of life. Although prior studies have evaluated the efficacy of rituximab (RTX) for granulomatous features of GPA, none have evaluated its efficacy solely for ENT manifestations. We compared the effectiveness of RTX to other therapies for the ENT manifestations of GPA in a large, well-characterized cohort. We performed a retrospective analysis of 975 visits from 99 GPA patients seen at a tertiary care ENT practice between 2003 and 2013. At each visit, subjects had a complete ENT examination, with ENT activity assessed by a single expert otolaryngologist. ENT disease activity during the observational period in subjects receiving RTX was compared to subjects receiving all other therapy. In total, 48 subjects had never received RTX and 51 received RTX at least once. There was no active ENT disease during 92.4% of the observational period (days) for subjects receiving RTX, compared with 53.7% of the observational period for subjects not receiving RTX (odds ratio 11.0 [95% confidence interval 5.5–22.0], P < 0.0001). Subjects receiving RTX, compared with those receiving methotrexate, azathioprine, cyclophosphamide, or trimethoprim-sulfamethoxazole, were significantly more likely to have no active ENT disease (P < 0.0001 for each comparison). RTX is an effective treatment for ENT manifestations of GPA. Subjects treated with RTX were significantly less likely to have active ENT disease compared with those not receiving RTX. Patients being treated with RTX were 11 times less likely to have active ENT disease than patients being treated with other therapies.


[Videothorascopic lung biopsy--diagnostic yield of one biopsy sample].
The authors evaluate in a retrospective study the diagnostic yield of videothorascopic (VTS) biopsy of the lungs and evaluate the representativeness of one wedge-shaped bioptic specimen of the lungs collected by an endoscopic device according to HRCT, and the macroscopic finding on operation. Based on the indication of a pneumologist in 1993-1999 210 patients were subjected to VTS pulmonary biopsy when all non-invasive diagnostic methods had been exhausted. The bioptic specimens gave diagnostic yields in 202 cases (96.2%), the most frequent histological finding included idiopathic pulmonary fibrosis and sarcoidosis. From the results ensues that collection of one sufficiently large and aimed bioptic specimen leads to a correct diagnosis in a high percentage of cases.


Nitric Oxide Enhances Cytotoxicity of Lead by Modulating the Generation of Reactive Oxygen Species and Is Involved in the Regulation of Pb2+ and Ca2+ Fluxes in Tobacco BY-2 Cells.
Lead is a heavy metal known to be toxic to both animals and plants. Nitric oxide (NO) was reported to participate in plant responses to different heavy metal stresses. In this study, we analyzed the function of exogenous and endogenous NO in Pb-induced toxicity in tobacco BY-2 cells, focusing on the role of NO in the generation of reactive oxygen species (ROS) as well as Pb2+ and Ca2+ fluxes using non-invasive micro-test technology (NMT). Pb treatment induced BY-2 cell death and rapid NO and ROS generation, while NO burst occurred earlier than ROS accumulation. The elimination of NO by 2-4-carboxyphenyl-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (cPTIO) resulted in a decrease of ROS, and the supplementation of NO by sodium nitroprusside (SNP) caused an increased accumulation of ROS. Furthermore, the addition of exogenous NO stimulated Pb2+ influx, thus promoting Pb uptake in cells and aggravating Pb-induced toxicity in cells, whereas the removal of endogenous NO produced the opposite effect. Moreover, we also found that both exogenous and endogenous NO enhanced Pb-induced Ca2+ effluxes and calcium homeostasis disorder. These results suggest that exogenous and endogenous NO played a critical regulatory role in BY-2 cell death induced by Pb stress by promoting Pb2+ influx and accumulation and disturbing calcium homeostasis.


[Czech Ophthalmologic Society's data collecting system for the monitoring and evaluating of the exsudative age-related macular degeneration treatment--the nation-wide project "AMADEUS"].
The Czech Ophthalmologic Society (member of the Czech Medical Society of Jan Evangelista Purkyne) in collaboration with the Institute of Biostatistics and Analysis of the Masaryk University in Brno established a nation-wide information system for the follow-up of the epidemiology and treatment of the exsudative age-related macular degeneration (ARMD). The project named AMADEUS is a multi-centric, non-invasive, observation prospective study with the aim to improve the patients' treatment and to unify the criteria for the follow-up of the ARMD in the real clinical practice in the Czech Republic. The basic instrument of the whole project is a clinical register collecting parametric data from 9 specialized centers. Especially the project monitors the photodynamic therapy with Verteporfyrine (Visudyne) and treatment by anti-VEGF agents, or Pegaptanib (Macugen) and Ranibizumab (Lucentis). The project's protocol is trying to collect representative data about ARMD diagnosis and treatment; during regularly controls, the efficacy and safety of the treatment are followed-up.The data collecting does not influence the treatment strategy or the availability of chosen treatment for the patient. Since October 2008 until the end of the year 2009, the registry collected complex information about more than 1402 newly treated ARMD patients; out of them, in 582 cases the one-year follow-up period was regularly terminated. The available data shows well-considered indication of drugs indications by the doctors; the treated patients fulfill the indications criteria set by the scientific society. According to the data from the registry, in some treating centers the application schedule is not followed-up in some drugs (especially Pegaptanib); there is the possibility to improve the treatment. All the clinical centers participating in the AMADEUS registry will continue in the data collecting, which after a longer period of time will facilitate further treatment optimization and eliminating of the established imperfections. Further information about the project may be found at the web site: www.amadeus.registry.cz.


Hybrid y stenting with the waffle-cone. A technical note.
Endovascular treatment of wide-neck bifurcation aneurysms is challenging and often requires adjunctive techniques and devices. We report our experience with the hybrid Y stenting with the waffle-cone technique, combining Y stent-assisted coiling and waffle-cone stenting techniques. This approach has been described only in a single case report using a combination of open and closed cell stents. We describe four cases treated by hybrid Y stenting with the waffle-cone procedure with a variation from the originally reported technique, consisting in deploying two closed cell stents. All patients were successfully treated without complications. We propose hybrid Y stenting with the waffle-cone for the treatment of wide-neck bifurcation aneurysms as a bailout technique after failure of Y stent-assisted coiling.


Multiplex PCR identification of eight clinically relevant Candida species.
Invasive fungal infections, specifically candidemia, constitute major public health problems with high mortality rates. Therefore, in the last few years, the development of novel diagnostic methods has been considered a critical issue. Herein we describe a multiplex PCR strategy allowing the identification of 8 clinically relevant yeasts of the Candida genus, namely C. albicans, C. glabrata, C. parapsilosis, C. tropicalis, C. krusei, C. guilliermondii, C. lusitaniae and C. dubliniensis. This method is based on the amplification of two fragments from the ITS1 and ITS2 regions by the combination of 2 yeast-specific and 8 species-specific primers in a single PCR reaction. Results from the identification of 231 clinical isolates are presented pointing to the high specificity of this procedure. Furthermore, several Candida isolates were identified directly from clinical specimens which also attests to the method's direct laboratory application. The results from the multiplex reactions with other microorganisms that usually co-infect patients also confirmed its high specificity in the identification of Candida species. Moreover, this method is simple and presents a sensitivity of approximately 2 cells per ml within 5 hours. Furthermore, it allows discrimination of individual Candida species within polyfungal samples. This novel method may therefore provide a clinical diagnostic procedure with direct applicability.


Genetic alterations in juvenile cervical clear cell adenocarcinoma unrelated to human papillomavirus.
Clear cell adenocarcinoma of the cervix (CCAC) is a special type of HPV-independent cervical cancer. It has a low incidence rate, can be difficult to diagnose early, has a poor prognosis. Its peak incidence is in adolescence, which poses a great threat to women's health. Therefore, it is very important to explore the pathogenesis of cervical clear cell adenocarcinoma to guide subsequent treatment and prevention. This study analyzed 3 juvenile patients with CCAC diagnosed at the First Affiliated Hospital of Zhengzhou University. Using next-generation sequencing methods, we analyzed the pathogenesis of the patients and their close relatives by analyzing the genetic alterations of patients. CMTM5 was identified as the only shared mutated gene. Using published literature and comparative analyses of related disease-causing genes, 6 of the 19 genes (ALKBH7, MYCBP, MZF1, RNF207, RRS1, and TUSC2) were screened as genes with mutations in patients and had higher mutation rates in reproductive cancers. Pathway analysis showed that downregulated genes in non-HPV cervical cancer were mainly related to the immune system response, suggesting that non-HPV cervical cancer differs from HPV-infected cervical cancer in that the immune response is weaker, which is consistent with the weak correlation with viral infection.


The costal cartilages in health and disease.
The costal margin, although imaged in many routine radiologic examinations, has been ignored in the radiology literature. Calcification of the costal cartilages follows gender-related patterns and is generally not evident radiographically until after the age of 30 years. Diffuse enlargement of the costochondral junctions may alert the astute observer to the presence of systemic diseases such as acromegaly and rickets. Focal masses have a subtle appearance on plain radiographs and may be better imaged with computed tomography (CT) or magnetic resonance imaging. Chondrosarcoma of the costal margin typically appears as an expansile mass with coarse calcifications and an associated soft-tissue mass. Radiographic and CT features of costochondritis include chondral enlargement or destruction, low-attenuation cartilage at CT, associated soft-tissue swelling, and localized peripheral cartilage calcification. There appears to be an association between heavy premature costal cartilage calcification and certain systemic conditions, such as malignancy, autoimmune disorders, chronic renal failure, and thyroid disease, particularly Graves disease.


Graduate students' knowledge and utilization of campus sexual violence and sexual harassment resources.
Graduate students are uniquely vulnerable to sexual violence and harassment (SVSH) and largely marginalized in campus-based prevention and response efforts. Objective: This study is a preliminary investigation of graduate students' experiences with on-campus SVSH training and knowledge and utilization of SVSH resources. Methods: We conducted 21 in-depth interviews and 8 focus group discussions with 43 graduate students on three public university campuses in California. Results: Graduate students had limited knowledge of SVSH services, and mandatory SVSH training curricula was perceived to center around "responsible employee" duties rather than information about how to prevent or seek help for SVSH themselves. Graduate students had mixed experiences seeking SVSH-related assistance. Conclusions: Graduate students should be prioritized in SVSH prevention and education efforts beyond required responsible employee training. Graduate students are invaluable to the everyday success of universities; accounting for their vulnerabilities in SVSH prevention and response is vital for campus communities everywhere.


Antifungal activity of eupolauridine and its action on DNA topoisomerases.
The azafluoranthene alkaloid eupolauridine has previously been shown to have in vitro antifungal activity and selective inhibition of fungal topoisomerase I. The present study was undertaken to examine further its selectivity and mode of action. Eupolauridine completely inhibits the DNA relaxation activity of purified fungal topoisomerase I at 50 microg/ml, but it does not stabilize the cleavage complex of either human or fungal topoisomerase I. Cleavage complex stabilization is the mode of action of topoisomerase I targeting drugs of the camptothecin family. Also, unlike camptothecin, eupolauridine does not cause significant cytotoxicity in mammalian cells. To determine if the inhibition of topoisomerase I is the principal mode of antifungal action of eupolauridine, Saccharomyces cerevisiae strains with alterations in topoisomerase genes were used in clonogenic assays. The antifungal activity of eupolauridine was not diminished in the absence of topoisomerase I; rather, the cells lacking the enzyme were more sensitive to the drug. Cell-killing activity of eupolauridine was also more pronounced in cells that overexpressed topoisomerase II. In vitro assays with the purified yeast enzyme confirmed that eupolauridine stabilized topoisomerase II covalent complexes. These results indicate that a major target for fungal cell killing by eupolauridine is DNA topoisomerase II rather than topoisomerase I, but does not exclude the possibility that the drug also acts against other targets.


NrdR Transcription Regulation: Global Proteome Analysis and Its Role in Escherichia coli Viability and Virulence.
Bacterial ribonucleotide reductases (RNRs) play an important role in the synthesis of dNTPs and their expression is regulated by the transcription factors, NrdR and Fur. Recent transcriptomic studies using deletion mutants have indicated a role for NrdR in bacterial chemotaxis and in the maintenance of topoisomerase levels. However, NrdR deletion alone has no effect on bacterial growth or virulence in infected flies or in human blood cells. Furthermore, transcriptomic studies are limited to the deletion strain alone, and so are inadequate for drawing biological implications when the NrdR repressor is active or abundant. Therefore, further examination is warranted of changes in the cellular proteome in response to both NrdR overexpression, as well as deletion, to better understand its functional relevance as a bacterial transcription repressor. Here, we profile bacterial fate under conditions of overexpression and deletion of NrdR in E. coli. Biochemical assays show auxiliary zinc enhances the DNA binding activity of NrdR. We also demonstrate at the physiological level that increased nrdR expression causes a significant reduction in bacterial growth and fitness even at normal temperatures, and causes lethality at elevated temperatures. Corroborating these direct effects, global proteome analysis following NrdR overexpression showed a significant decrease in global protein expression. In parallel, studies on complementary expression of downregulated essential genes polA, eno and thiL showed partial rescue of the fitness defect caused by NrdR overexpression. Deletion of downregulated non-essential genes ygfK and trxA upon NrdR overexpression resulted in diminished bacterial growth and fitness suggesting an additional role for NrdR in regulating other genes. Moreover, in comparison with NrdR deletion, E. coli cells overexpressing NrdR showed significantly diminished adherence to human epithelial cells, reflecting decreased bacterial virulence. These results suggest that elevated expression of NrdR could be a suitable means to retard bacterial growth and virulence, as its elevated expression reduces bacterial fitness and impairs host cell adhesion.


An investigation of doubt in obsessive-compulsive disorder.
Clinicians have long considered doubt to be a fundamental characteristic of obsessive-compulsive disorder (OCD). However, the clinical relevance of doubt in OCD has not been addressed. Participants included 1182 adults with OCD who had participated in family and genetic studies of OCD. We used a clinical measure of the severity of doubt, categorized as none, mild, moderate, severe, or extreme. We evaluated the relationship between doubt and OCD clinical features, Axis I disorders, personality and personality disorder dimensions, impairment, and treatment response. The severity of doubt was inversely related to the age at onset of OCD symptoms. Doubt was strongly related to the number of checking symptoms and, to a lesser extent, to the numbers of contamination/cleaning and hoarding symptoms. Doubt also was related to the lifetime prevalence of recurrent major depression and generalized anxiety disorder; to the numbers of avoidant, dependent, and obsessive-compulsive personality disorder traits; and to neuroticism and introversion. Moreover, doubt was strongly associated with global impairment and poor response to cognitive behavioral treatment (CBT), even adjusting for OCD severity and other correlates of doubt. Doubt is associated with important clinical features of OCD, including impairment and cognitive-behavioral treatment response.


Ascorbic acid improves mitochondrial function in liver of arsenic-treated rat.
Arsenic is an ubiquitous and well-documented carcinogenic metalloid. The most common source of arsenic is drinking water. The mechanism of arsenic toxicity in a cell has historically been centered around its inhibitory effects on cellular respiration and mitochondrial injury. Ascorbic acid, a low molecular weight, water-soluble antioxidant, improves the reduced glutathione (GSH) status by recycling oxidized glutathione. Ascorbic acid can improve mitochondrial function by improving the thiol status; thereby preventing reactive oxygen species- mediated damage to liver as well as kidney. Ascorbic acid has been shown to protect membrane and other cellular compartments by regenerating vitamin E. Therefore, ascorbic acid seems to be a suitable protective factor against arsenic toxicity. Present reports describe the effect of ascorbic acid on oxidative phosphorylation, adenosine triphosphatase (ATPase), succinic dehydrogenase, caspase-3 and apoptosis in the liver of rats treated with arsenic trioxide (As(III)). Ultrastructural changes in the mitochondria have also been reported. We show that cotreatments with ascorbic acid and As(III) improve mitochondrial structure and function. We attribute these improvements mainly to antioxidative role of ascorbic acid. Apoptosis was restricted due to caspase-3 inhibition. Ascorbic acid could protect DNA from the attack of reactive oxygen species generated by As(III). Consequently its events led to improved ADP:O ratio, normalized ATPase activity and restored the activity of succinic dehydrogenase. Overall, results support the protective role of ascorbic acid against As( III)-induced liver injury.


Transforming growth factor-beta 1 (TGF-beta1) expression in ovine lentivirus-induced lymphoid interstitial pneumonia.
The aim of this study was to detect the localization of TGF-beta1 protein expression in normal sheep lungs and lungs with interstitial pneumonia associated with infection with maedi-visna virus (MVV). Immunohistochemical localization of TGF-beta1 was determined in 24 lungs of adult sheep naturally infected with MVV and six control lungs of seronegative sheep. The lungs of infected animals showed different lesional degrees: grade 0, no lesions; grade I, mild; grade II, moderate; grade III, severe. In normal lungs, TGF-beta1 was primarily expressed in airway epithelium, bronchial cartilage and glands, endothelial cells and smooth muscle of blood vessels, alveolar macrophages and type II pneumocytes. No staining was observed in alveolar interstitium. In MVV-infected sheep an increased number of positive alveolar and interstitial macrophages and staining of alveolar interstitium was observed in grade I, grade II and some grade III lesions. In grade III lesions an inverse relationship was found between TGF-beta1 staining and smooth muscle hyperplasia. Small lymphoid aggregates, in general, showed strong reactivity, whereas larger ones showed weak reactivity, mainly associated with follicular areas. No significant differences in the staining intensity of airways and blood vessels were observed between control and MVV lungs. The increased expression of TGF-beta1 in early maedi lesions and its down-regulation in more advanced disease suggest the operation of a temporal regulatory mechanism whereby early expression may lead to the smooth muscle hyperplasia which develops during the disease. The striking inverse relationship between TGF-beta1 expression and follicle organization is intriguing and warrants further investigation.


Defining Physiological Predictors of Peripartum Maternal Bacteremia.
This study aims to examine physiological and laboratory parameters associated with peripartum maternal bacteremia. This case-control study matched 115 cases (women with fever and bacteremia during the peripartum period) to 285 controls (defined as the next two febrile women with negative blood cultures at the same institution) from two academic medical centers from 2009 to 2013. Conditional logistic regression models were used to evaluate the association of physiological and laboratory parameters with maternal bacteremia at the time of initial and maximum fever. At the time of initial fever, temperature > 103°F (adjusted odds ratio [aOR]: 5.58, 95% confidence interval [CI]: 2.05-15.19) and respiratory rate (RR) > 20 respirations per minute (aOR: 5.27, 95% CI: 2.32-11.96) were associated with bacteremia. At the time of maximum fever, temperature (> 102°F, aOR: 3.37, 95% CI: 1.61-7.06; > 103°F, aOR: 7.96, 95% CI: 3.56-17.82), heart rate > 110 beats per minute (aOR: 2.20, 95% CI: 1.21-3.99), and RR > 20 (aOR: 3.65, 95% CI: 1.65-8.08) were associated with bacteremia. Bandemia > 10% (aOR: 2.44, 95% CI: 1.07-5.54) was associated with bacteremia. Physiological and laboratory parameters associated with maternal bacteremia differed from those reported with sepsis in the adult critical care population. Further studies of objective markers are needed to improve detection and treatment of peripartum bacteremia.


Molecular surface comparison: application to drug design.
An interactive system for the display and manipulation of molecular surface properties is presented. The property at the molecular surface is mapped onto the sphere by gnomonic projection. This representation allows direct comparison of the surface properties of pairs of molecules. The system allows the user to explore the similarities between a pair of molecules in an interactive manner, and provides extensive visual (color-coded field and field difference maps) and numerical (rms difference value) aids to complement the user's chemical intuition. Examples of the use of the system to study beta-lactam compounds and phosphodiesterase inhibitors are presented.


Clustering of tuberculosis among senegalese immigrants in Italy.
To study clustered Mycobacterium tuberculosis isolates as an indicator of recent TB transmission in a small urban setting in Italy, and to determine associated risk factors. M. tuberculosis strains isolated between 1991 and 1997 were characterised by IS6110 restriction fragment length polymorphism (RFLP) analysis. One hundred and ninety-five isolates were available for RFLP analysis, which revealed 163 different patterns. Available cases were represented by 137 Italians (70%), 32 Senegalese (17%), and 26 other foreign-born cases (13%). A unique fingerprint pattern was found in 143 cases (73.3%), while 52 strains (26.7%) were grouped into 20 clusters. Nineteen cases (10%) were resident in the same quarter of Brescia with a high density of Senegalese immigrants (Area A). An increased probability of yielding clustered M. tuberculosis strains was associated with residence in Area A (OR 3.87, 95%CI 1.42-10.56; P = 0.02) and being Senegalese (OR = 5.96, 95%CI 1.48-23.97; P = 0.005). In the logistic regression analysis, being Senegalese was independently associated with yielding a clustered M. tuberculosis strain. Our results demonstrate a clustering of TB cases among Senegalese immigrants and suggest that RFLP analysis may be used to identify geographical areas where efforts can be targeted to interrupt TB transmission.


From genetics to epigenetics.
In the post human-genome area, the challenge is to derive details of heritable variation in relation to how human variation reflects adaptation to the different environments. Heterozygote advantage represents a superior genetic adaptation presumably explaining the presence of the allele at frequencies above those to be expected from a simple replacement of a homozygous lethal allele by mutation alone (Saugstad 1977a, 1975b, 1972). Mean birthweight of unaffected offspring of parents heterozygous for the phenylketonuria (PKU) allele averaged significantly above mean weight of all Norwegian births, rendering unaffected offspring more viable at birth and thus improving the chance for survival of the allele. A successful adaptation requires natural selection acting on that part of the body that makes a difference in survival. Skin colour variation is such a successful adaptation, for the North as opposed to the dark skins of the equator. Human Evolution in Africa and subsequent adaptations have enabled human survival all over the world with highly different light intensity (Jablonski & Chaplin 2000). That continuous variables, height, pubertal age and brain development, are multifactorially inherited and affected by epigenetic factors, was nicely demonstrated in the increase in height in Norway 1860-1960 with at the same time a reduction in pubertal age by 4yrs which may have affected the final stage in brain development. This created an increased need for brain food, N-3, to secure optimal brain function. Body growth is not brain growth. Given that the consumption of brain food (N-3) has declined to 20% only of the level 100yrs ago, what disorders are to be expected with an N-3 dietary deficit: in pregnancy, infancy and later in life? In this paper I discuss the significance of prepubertal selective pruning of excitatory synapses compared to delayed pruning and suggest relationships with brain disorders.


Caged Molecular Glues as Photoactivatable Tags for Nuclear Translocation of Guests in Living Cells.
We developed dendritic caged molecular glues (CagedGlue-R) as tags for nucleus-targeted drug delivery, whose multiple guanidinium ion (Gu+) pendants are protected by an anionic photocleavable unit (butyrate-substituted nitroveratryloxycarbonyl; BANVOC). Negatively charged CagedGlue-R hardly binds to anionic biomolecules because of their electrostatic repulsion. However, upon exposure of CagedGlue-R to UV light or near-infrared (NIR) light, the BANVOC groups of CagedGlue-R are rapidly detached to yield an uncaged molecular glue (UncagedGlue-R) that carries multiple Gu+ pendants. Because Gu+ forms a salt bridge with PO4-, UncagedGlue-R tightly adheres to anionic biomolecules such as DNA and phospholipids in cell membranes by a multivalent salt-bridge formation. When tagged with CagedGlue-R, guests can be taken up into living cells via endocytosis and hide in endosomes. However, when the CagedGlue-R tag is photochemically uncaged to form UncagedGlue-R, the guests escape from the endosome and migrate into the cytoplasm followed by the cell nucleus. We demonstrated that quantum dots (QDs) tagged with CagedGlue-R can be delivered efficiently to cell nuclei eventually by irradiation with light.


Effect of liposome-encapsulated alpha- or beta-interferon on breast cancer cell lines.
Experimental evidence and clinical studies have indicated that interferons (IFN) inhibit proliferation in a wide panel of neoplasms, including breast cancer. However, the antitumor activity of IFN requires the continuous presence of high concentrations of the drug and is associated with side effects. To explore the potential of liposomes as an IFN delivery system, we compared the effect of free or liposome-encapsulated alpha-IFN and beta-IFN on the growth of two breast cancer cell lines (MCF7 and MDA-MB231). Cells were cultured in the presence of IFN at different concentrations (500, 1000, 2000 IU/ml) or in the presence of multilamellar liposomes (phosphatidylcholine-phosphatidylserine at a molar ratio of 7:3) containing saline buffer, alpha-IFN or beta-IFN. Additional control groups consisted of cells cultured with alpha-IFN or beta-IFN plus empty liposomes. Empty liposomes were not cytotoxic and did not interfere with IFN activity. In both cell lines liposomes encapsulating alpha-IFN (at the highest lipid:drug ratio) inhibited cell growth in a manner similar to that of free alpha-IFN, whereas liposomes encapsulating beta-IFN showed slightly, lower inhibition than free beta-IFN, this was more evident in MCF7 cells. The present results indicate that liposomes encapsulating alpha-IFN or beta-IFN were effective on the growth of both breast cancer cell lines, which are characterized by a different estrogen responsiveness, and that they might be a useful carrier system for the delivery of high doses of IFN.


Continuous cognitive dynamics of the evaluation of trustworthiness in williams syndrome.
The decision to approach or avoid an unfamiliar person is based in part on one's evaluation of facial expressions. Individuals with Williams syndrome (WS) are characterized in part by an excessive desire to approach people, but they display deficits in identifying facial emotional expressions. Likert-scale ratings are generally used to examine approachability ratings in WS, but these measures only capture an individual's final approach/avoid decision. The present study expands on previous research by utilizing mouse-tracking methodology to visually display the nature of approachability decisions via the motor movement of a computer mouse. We recorded mouse movement trajectories while participants chose to approach or avoid computer-generated faces that varied in terms of trustworthiness. We recruited 30 individuals with WS and 30 chronological age-matched controls (mean age = 20 years). Each participant performed 80 trials (20 trials each of four face types: mildly and extremely trustworthy; mildly and extremely untrustworthy). We found that individuals with WS were significantly more likely than controls to choose to approach untrustworthy faces. In addition, WS participants considered approaching untrustworthy faces significantly more than controls, as evidenced by their larger maximum deviation, before eventually choosing to avoid the face. Both the WS and control participants were able to discriminate between mild and extreme degrees of trustworthiness and were more likely to make correct approachability decisions as they grew older. These findings increase our understanding of the cognitive processing that underlies approachability decisions in individuals with WS.


Multisystem Disease, Including Eosinophilia and Progressive Hyper-Creatine-Kinase-emia over 10 Years, Suggests Mitochondrial Disorder.
Eosinophilia has not been reported as a manifestation of a mitochondrial disorder (MID). Here, we report a patient with clinical features suggesting a MID and permanent eosinophilia, multisystem disease, and progressive hyper-creatine-kinase (CK)-emia for at least 10 years. Methods applied included a clinical exam, blood chemical investigations, electrophysiological investigations, imaging, and invasive cardiological investigations. The patient was repeatedly followed up over several years. He required replacement cardiac surgery. In a 57-year-old male, eosinophilia was first detected at the age of 44 years and has remained almost constantly present until today. In addition to eosinophilia, he developed progressive hyper-CK-emia at the age of 47 years. His history was further positive for hepatopathy, hyperlipidemia, hypothyroidism, renal insufficiency, spontaneous Achilles tendon rupture, double vision, exercise intolerance, muscle aching, mild hypoacusis, sensory neuropathy, seizures, and mitral insufficiency/stenosis requiring valve replacement therapy, oral anticoagulation, and pacemaker implantation. Based on the multisystem nature of his abnormalities and permanent hyper-CK-emia, a MID was suspected. Eosinophilia can be associated with a MID with myopathy, possibly as a reaction to myofiber necrosis. If eosinophilia is associated with progressive hyper-CK-emia and multisystem disease, a MID should be suspected.


What Can the Organization of the Brain's Default Mode Network Tell us About Self-Knowledge?
Understanding ourselves has been a fundamental topic for psychologists and philosophers alike. In this paper we review the evidence linking specific brain structures to self-reflection. The brain regions most associated with self-reflection are the posterior cingulate and medial prefrontal (mPFC) cortices, together known as the cortical midline structures (CMSs). We review evidence arguing that self-reflection is special in memory, while noting that these brain regions are often engaged when we think about others in our social worlds. Based on the CMSs' patterns of connectivity and activity, we speculate about three possible interpretations of their role in supporting self-reflection that are somewhat overlapping, and not intended to be mutually exclusive. First, self may be a powerful, but ordinary case for a cognitive system specialized for thinking about people. Second, mPFC may serve as a processing "hub," binding together information from all sensory modalities with internally generated information. Third, mPFC may serve as a cortical director of thought, helping to guide moment-by-moment conscious processing. Suggestions are made for future research avenues aimed at testing such possibilities.


Myostatin: A Skeletal Muscle Chalone.
Myostatin (GDF-8) was discovered 25 years ago as a new transforming growth factor-β family member that acts as a master regulator of skeletal muscle mass. Myostatin is made by skeletal myofibers, circulates in the blood, and acts back on myofibers to limit growth. Myostatin appears to have all of the salient properties of a chalone, which is a term proposed over a half century ago to describe hypothetical circulating, tissue-specific growth inhibitors that control tissue size. The elucidation of the molecular, cellular, and physiological mechanisms underlying myostatin activity suggests that myostatin functions as a negative feedback regulator of muscle mass and raises the question as to whether this type of chalone mechanism is unique to skeletal muscle or whether it also operates in other tissues.


Production of monoclonal mouse IgE antibodies with DNP specificity by hybrid cell lines.
IgE anti-DNP antibody-secreting hybridomas were obtained by polyethylene glycol fusion of murine myeloma cells with spleen cells from mice, primed with DNP-KLH and challenged with DNP-Nippostrongylus brasiliensis extract. The in vivo and in vitro continuously growing hybridomas are producing high amounts of monoclonal IgE anti-DNP antibodies, which are heat-labile, hapten-specific and have rat mast cell sensitizing capacity.


Culturomics and Circular Agronomy: Two Sides of the Same Coin for the Design of a Tailored Biofertilizer for the Semi-Halophyte Mesembryanthemum crystallinum.
According to the EU, the global consumption of biomass, fossil fuels, metals, and minerals is expected to double by 2050, while waste will increase by 70%. In this context, the Circular Economy Action Plan (CEAP) intends to integrate development and sustainability. In this regard, tailored biofertilizers based on plant growth-promoting bacteria (PGPB) can improve plant yield with fewer inputs. In our project, an autochthonous halophyte of the Andalusian marshes, namely Mesembryanthemum crystallinum, was selected for its interest as a source of pharmaceuticals and nutraceuticals. The aim of this work was to use a culturomics approach for the isolation of specific PGPB and endophytes able to promote plant growth and, eventually, modulate the metabolome of the plant. For this purpose, a specific culture medium based on M. crystallinum biomass, called Mesem Agar (MA), was elaborated. Bacteria of three compartments (rhizosphere soil, root endophytes, and shoot endophytes) were isolated on standard tryptone soy agar (TSA) and MA in order to obtain two independent collections. A higher number of bacteria were isolated on TSA than in MA (47 vs. 37). All the bacteria were identified, and although some of them were isolated in both media (Pseudomonas, Bacillus, Priestia, Rosellomorea, etc.), either medium allowed the isolation of specific members of the M. crystallinum microbiome such as Leclercia, Curtobacterium, Pantoea, Lysinibacillus, Mesobacillus, Glutamicibacter, etc. Plant growth-promoting properties and extracellular degrading activities of all the strains were determined, and distinct patterns were found in both media. The three best bacteria of each collection were selected in order to produce two different consortia, whose effects on seed germination, root colonization, plant growth and physiology, and metabolomics were analyzed. Additionally, the results of the plant metabolome revealed a differential accumulation of several primary and secondary metabolites with pharmaceutical properties. Overall, the results demonstrated the feasibility of using "low cost media" based on plant biomass to carry out a culturomics approach in order to isolate the most suitable bacteria for biofertilizers. In this way, a circular model is established in which bacteria help plants to grow, and, in turn, a medium based on plant wastes supports bacterial growth at low prices, which is the reason why this approach can be considered within the model of "circular agronomy".


Adaptive kinetic Monte Carlo for first-principles accelerated dynamics.
The adaptive kinetic Monte Carlo method uses minimum-mode following saddle point searches and harmonic transition state theory to model rare-event, state-to-state dynamics in chemical and material systems. The dynamical events can be complex, involve many atoms, and are not constrained to a grid-relaxing many of the limitations of regular kinetic Monte Carlo. By focusing on low energy processes and asserting a minimum probability of finding any saddle, a confidence level is used to describe the completeness of the calculated event table for each state visited. This confidence level provides a dynamic criterion to decide when sufficient saddle point searches have been completed. The method has been made efficient enough to work with forces and energies from density functional theory calculations. Finding saddle points in parallel reduces the simulation time when many computers are available. Even more important is the recycling of calculated reaction mechanisms from previous states along the dynamics. For systems with localized reactions, the work required to update the event table from state to state does not increase with system size. When the reaction barriers are high with respect to the thermal energy, first-principles simulations over long time scales are possible.


Investigations on milk flow and milk yield from teats with milk flow disorders.
The objective of this study was to investigate peak milk flow, average milk flow, and milk yield in teats with milk flow disorders. A total of 100 hard milking teats were studied in 97 cows. Teats with milk flow disorders were examined endoscopically. Quarter milk flow and quarter milk yield were examined with four Lactocorders attached to a quarter milking machine. Peak milk flow, average milk flow, and milk yield were measured in all teats of the udder before treatment of the affected teat, as well as 1 and 6 mo later. Teats with milk flow disorders were compared to all other teats of the same udder. Before treatment, peak milk flow from affected teats was 20%, average milk flow 14%, and milk yield 53% of the control teats, adjusted for other significant explanatory variables. Milk flow and milk yield increased after surgical treatment of the affected teats. Six months after treatment peak milk flow was 79%, average milk flow 76%, milk yield was 71% compared with control teats. We conclude from these findings that teat endoscopy and measuring quarter milk flow and milk yield with Lactocorders are useful tools for examining teats with milk flow disorders.


Hepatitis C virus differentially modulates activation of forkhead transcription factors and insulin-induced metabolic gene expression.
Chronic hepatitis C virus (HCV) infection is often associated with insulin resistance and hepatic steatosis. Insulin regulates gene expression of key enzymes in glucose and lipid metabolism by modulating the activity of specific Forkhead box transcriptional regulators (FoxO1 and FoxA2) via the phosphatidylinositol 3-kinase (PI3K)-Akt signaling pathway in the liver. In this study, we observed that HCV infection of human hepatocytes impaired insulin-induced FoxO1 translocation from the nucleus to the cytoplasm and significantly reduced accumulation of FoxA2 in the nucleus. Phosphorylation of FoxO1 at Ser(256), a downstream target for Akt, was inhibited in hepatocytes infected with HCV or expressing the core protein or full-length (FL) genome of HCV. Further, an interaction between FoxO1 and 14-3-3 protein, important for FoxO1 translocation, was inhibited in HCV core-expressing cells. Hepatocytes infected with HCV, expressing the core protein alone or polyprotein displayed an increased level of glucose-6-phosphatase (G6P) mRNA. On the other hand, microsomal triglycerol transfer protein (MTP) activity and apolipoprotein B (ApoB) secretion were significantly reduced in hepatocytes expressing HCV proteins. Together, these observations suggest that HCV infection or ectopic expression of the core protein either alone or together with other viral proteins from an FL gene construct differentially modulates FoxO1 and FoxA2 activation and affects insulin-induced metabolic gene regulation in human hepatocytes.


The effect of a single-session attention modification program on response to a public-speaking challenge in socially anxious individuals.
Research suggests that individuals with social anxiety show an attention bias for threat-relevant information However, few studies have directly manipulated attention to examine its effect on anxiety. In the current article, the authors tested the hypothesis that an attention modification program would be effective in reducing anxiety response and improving performance on a public-speaking challenge. Socially anxious participants completed a probe detection task by identifying letters (E or F) replacing one member of a pair of faces (neutral or disgust). The authors trained attention by including a contingency between the location of the neutral face and the probe in one group (Attention Modification Program; AMP). Participants in the AMP group showed significantly less attention bias to threat after training and lower levels of anxiety in response to a public-speaking challenge than did the participants in the Attention Control Condition (ACC) group. Moreover, blind raters judged the speeches of those in the AMP group as better than those in the ACC group. These results are consistent with the hypothesis that attention plays a causal role in the maintenance of social anxiety.


Simulation Modelling in Healthcare: An Umbrella Review of Systematic Literature Reviews.
Numerous studies examine simulation modelling in healthcare. These studies present a bewildering array of simulation techniques and applications, making it challenging to characterise the literature. The aim of this paper is to provide an overview of the level of activity of simulation modelling in healthcare and the key themes. We performed an umbrella review of systematic literature reviews of simulation modelling in healthcare. Searches were conducted of academic databases (JSTOR, Scopus, PubMed, IEEE, SAGE, ACM, Wiley Online Library, ScienceDirect) and grey literature sources, enhanced by citation searches. The articles were included if they performed a systematic review of simulation modelling techniques in healthcare. After quality assessment of all included articles, data were extracted on numbers of studies included in each review, types of applications, techniques used for simulation modelling, data sources and simulation software. The search strategy yielded a total of 117 potential articles. Following sifting, 37 heterogeneous reviews were included. Most reviews achieved moderate quality rating on a modified AMSTAR (A Measurement Tool used to Assess systematic Reviews) checklist. All the review articles described the types of applications used for simulation modelling; 15 reviews described techniques used for simulation modelling; three reviews described data sources used for simulation modelling; and six reviews described software used for simulation modelling. The remaining reviews either did not report or did not provide enough detail for the data to be extracted. Simulation modelling techniques have been used for a wide range of applications in healthcare, with a variety of software tools and data sources. The number of reviews published in recent years suggest an increased interest in simulation modelling in healthcare.


T-cell immunotherapy for human MK-1-expressing tumors using a fusion protein of the superantigen SEA and anti-MK-1 scFv antibody.
The bacterial superantigen staphylococcal enterotoxin A (SEA) is an extremely potent activator of T lymphocytes when presented on major histocompatibility complex (MHC) class II molecules. To develop a tumor-specific superantigen for cancer therapy, we constructed a recombinant fusion protein of SEA and the single-chain variable fragment (scFv) of the FU-MK-1 antibody, which recognizes a glycoprotein antigen (termed MK-1 antigen) present on most carcinomas. We employed recombinant DNA techniques to fuse recombinant mutant SEA to an scFv antibody derived from FU-MK-1 and the resulting fusion protein (SEA/FUscFv) was produced by a bacterial expression system, purified with a metal-affinity column, and characterized for its MK-1-binding specificity and its antitumor activity. The SEA/FUscFv fusion protein retained the reactivity with MK-1-expressing tumor cells, introduced a specific cytotoxicity of lymphokine-activated killer T-cells to the tumor cells, and consequently suppressed the tumor growth in a SCID mouse xenograft model. This genetically engineered SEA/FUscFv fusion protein may serve as a potentially useful immunotherapeutic reagent for human MK-1-expressing tumors.


Single-dose captopril scintigraphy in the neonate with renovascular hypertension: prediction of renal failure, a side effect of captopril therapy.
Baseline and single-dose captopril scintigraphy with 1 mCi of 99mTc-diethylenetriamine-pentaacetic acid (or 99mTc-glucoheptonate) was performed in 5 neonates with renovascular hypertension. Unilateral renal artery thrombosis and/or renal infarction was associated with severe impairment or lack of function on both studies (3 patients). Renal ischemia due to aortic thrombus manifested itself as lack of function only following captopril (2 patients). This approach predicted renal failure as a side effect of captopril therapy in 2 patients, 1 with unilateral (contralateral kidney infarcted) and the other with bilateral renal ischemia from aortic thrombus. Single-dose captopril scintigraphy may be a useful tool to predict tolerance to captopril therapy.


Intensity-modulated radiotherapy for a rendu-osler-weber disease patient with recurrent severe epistaxis: a case report.
We present a case of a Rendu-Osler-Weber disease patient with recurrent life threatening epistaxis demanding multiple blood transfusions despite of repetitive endoscopic laser and electrocoagulations, endovascular embolisation, septodermoplasty, and long-term intranasal dressings. As alternative treatment modalities repeatedly failed and the patient became almost permanently dependent on nasal dressing, we performed a highly conformal intensity-modulated radiotherapy of the nasal cavity; a total dose of 50 Gy in 2 Gy single fractions was applied. The therapy was very well tolerated, no acute toxicities occurred. Two weeks after the last radiation dose had been applied, the nasal dressing could be removed without problems. Endoscopical control revealed an almost avascular white mucosa without any trace of bleeding spots; previously existing hemangiomas and crusts had disappeared. After a 1-year-follow up, the patient had no significant recurrent epistaxis.


Predictive value of SUVmax in visceral pleural invasive lung adenocarcinoma with different diameters.
This study aimed to investigate predictive visceral pleural invasion (VPI) occurrence value of the maximum standardized uptake value (SUVmax) in patients with lung adenocarcinoma (LA). A total of 388 LA patients were divided into D1ab, D1c, D1, D2, D2a, D2b, D3, and all patient groups based on their tumor diameter (D). Patients were also classified into negative VPI (VPI-n) and positive VPI (VPI-p) groups according to VPI presence. SUVmax of patients was measured with 18F-fluorodeoxyglucose (FDG) by PET/computed tomography (18F-PET/CT). Receiver operating characteristic (ROC) analysis and the area under curve (AUC) of SUVmax were applied to determine optimal cut-off value for predicting VPI occurrence. There were significant differences in SUVmax between VPI-n and VPI-p groups ( P < 0.05) at the same tumor diameter. SUVmax cut-off value and sensitivity (Se,%) of VPI occurrence in each group were following: D1ab was 3.79 [AUC = 0.764, P < 0.001], Se86.11%; D1c was 5.47 (AUC = 0.706, P < 0.001), Se 93.75%; D1 was 5.49 (AUC = 0.731, P < 0.001), Se 79.76%; D2 was 7.36 (AUC = 0.726, P < 0.001), Se81.67%. All patient group was 7.26 (AUC = 0.735, P < 0.001), Se74.19%. In LA patients with the same diameter, SUVmax of the VPI-p group was significantly higher than that of the VPI-n group. The cut-off value of SUVmax for predicting VPI of T1 stage, T1 substages, and T2 stage LA could be determined through ROC curve. SUVmax measurement by PET/CT scan in stratified tumor size is helpful for predicting VPI occurrences of the physician.


DPI-3290 [(+)-3-((alpha-R)-alpha-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-(3-fluorophenyl)-N-methylbenzamide]. I. A mixed opioid agonist with potent antinociceptive activity.
Compound (+)-3-((alpha-R)-alpha-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-(3-fluorophenyl)-N-methylbenzamide (DPI-3290), is one of a series of novel centrally acting agents with potent antinociceptive activity that binds specifically and with high affinity to opioid receptors. In saturation equilibrium binding studies performed at 25 degrees C using membranes from rat brain or guinea pig cerebellum, the Ki values measured for DPI-3290 at delta-, mu-, and kappa-opioid receptors were 0.18 +/- 0.02, 0.46 +/- 0.05, and 0.62 +/- 0.09 nM, respectively. In vas deferens isolated from laboratory mice, DPI-3290 decreased electrically induced tension development in a concentration-dependent manner with corresponding IC50 values of 1.0 +/- 0.3, 6.2 +/- 2.0, and 25.0 +/- 3.3 nM at delta-, mu-, and kappa-receptors, respectively. The activity of DPI-3290 in isolated vas deferens tissue was approximately 20,000, 175.8, and 1500 times more efficacious than morphine, and 492, 2.5, and 35 times more efficacious than fentanyl at delta-, mu-, and kappa-receptors, respectively. In ileal strips isolated from guinea pigs, DPI-3290 inhibited tension development with a corresponding IC50 value of 3.4 +/- 1.6 nM at mu-opioid receptors and 6.7 +/- 1.6 nM at kappa-opioid receptors. Intravenous administration of 0.05 +/- 0.007 mg/kg DPI-3290 produced a 50% antinociceptive response in rats. The antinociceptive properties of DPI-3290 were blocked by naloxone (0.5 mg/kg s.c.). Compared with morphine, this study demonstrated that DPI-3290 is more potent and elicited a similar magnitude of antinociceptive activity in the rat, actions mediated by its mixed opioid receptor agonist activity. The marked antinociceptive activity of DPI-3290 will likely provide a means for relieving severe pain in patients that require analgesic treatment.


Automatic Detection of Driver Fatigue Using Driving Operation Information for Transportation Safety.
Fatigued driving is a major cause of road accidents. For this reason, the method in this paper is based on the steering wheel angles (SWA) and yaw angles (YA) information under real driving conditions to detect drivers' fatigue levels. It analyzes the operation features of SWA and YA under different fatigue statuses, then calculates the approximate entropy (ApEn) features of a short sliding window on time series. Using the nonlinear feature construction theory of dynamic time series, with the fatigue features as input, designs a "2-6-6-3" multi-level back propagation (BP) Neural Networks classifier to realize the fatigue detection. An approximately 15-h experiment is carried out on a real road, and the data retrieved are segmented and labeled with three fatigue levels after expert evaluation, namely "awake", "drowsy" and "very drowsy". The average accuracy of 88.02% in fatigue identification was achieved in the experiment, endorsing the value of the proposed method for engineering applications.


Thrombectomy for Anterior Circulation Stroke in a Witnessed Late Time Window Versus Early Time Window.
Thrombectomy is the standard treatment for anterior circulation stroke due to large vessel occlusions in a late time window (6 to 24 hours) for patients selected based on perfusion imaging. Most patients treated in late time window studies presented as unwitnessed or wake-up strokes. Whether patients presenting with unwitnessed stroke have an actual time window greater than 6 hours is unclear. The aim of this study was to assess the outcomes of thrombectomy in the treatment of patients presenting with anterior circulation large vessel stroke in an actual late time window of more than 6 hours. This single-center registry of thrombectomy in the treatment of stroke caused by anterior circulation large vessel occlusions (LVOs) included 430 patients treated between 2011 and 2019. Patients were divided into 2 groups: an early time window (≤ 6 hours) group and a late time window group (> 6 hours). Outcomes of the early and the late time window groups, respectively, were recanalization of 86.8% vs 82.7% (P = .29), symptomatic intracranial hemorrhage of 8.2% vs 5.7% (P = .40), good clinical outcome of 45.4% vs 41.3% (P = .46), and mortality of 20.2% vs 25% (P = .30) at 3 months. Thrombectomy for anterior circulation large vessel occlusions after 6 hours of symptoms onset seems to be as safe and effective as the standard thrombectomy within 6 hours from symptoms onset, even without perfusion analysis. Randomized trials are needed to confirm these findings.


Neurotransmitter receptor agonists regulate growth hormone gene expression in cultured ovine pituitary cells.
The regulation of growth hormone (GH) secretion and GH mRNA content by the dopaminergic agonist, bromocriptine (BRO); the beta-adrenergic agonist; isoproterenol (ISO); the alpha 1-adrenergic agonist, methoxamine (MET); the alpha 2-adrenergic agonist, clonidine (CLON); the serotonergic agonist, quipazine (QUIP); somatostatin (SS) and GH-releasing hormone (GHRH) were studied using cultured ovine anterior pituitary cells. Clonidine and BRO (10(-6) M) inhibited basal and GHRH (10(-10) M)-stimulated GH release. Bromocriptine enhanced GH mRNA content and potentiated the GHRH (10(-8) M)-stimulated content of GH mRNA, while CLON had no effect on GH mRNA. Quipazine had little effect on GH secretion and no effect on GH mRNA content. Methoxamine and ISO (10(-6) M) increased basal secretion of GH and both enhanced GHRH-stimulated GH secretion. Both MET and ISO increased GH mRNA content of cultured ovine pituitary cells. Somatostatin (10(-7) M) inhibited GHRH-stimulated GH secretion and GH mRNA accumulation. These results support the hypothesis that neurotransmitters may regulate or interact to further modulate pituitary hormone release. Moreover, the data indicate that neurotransmitters may not only regulate secretion but also regulate GH mRNA content and thus affect hormone synthesis.


[A CASE OF URETEROARTERIAL FISTULA REQUIRING SURGICAL TREATMENT AFTER ENDOVASCULAR STENT PLACEMENT].
A 36-year-old woman was operated on at the age of 29 years for cervical cancer, and bilateral ureteral stents were inserted during radical hysterectomy. Subsequently, total pelvic irradiation and para-aortic lymph node irradiation were administered as postoperative radiation therapy. Four years following the surgery, the patient visited previous hospital for ureteral stent replacement; however, following this visit, there was no further contact with her. Seven years after the surgery, the patient presented with gross hematuria. Removal of right ureteral stent led to the observation of severe bleeding. The patient was, thus, transferred to our hospital because of suspected right ureteroarterial fistula. Angiography and intravascular ultrasonography showed a pseudoaneurysm at the distal end of the right common iliac artery. Thus, an endovascular stent graft was placed in the right common iliac artery, which led to resolution of the gross hematuria. One month after discharge, the patient developed right pyelonephritis and hydronephrosis; thus, she underwent right nephrostomy. Six months after undergoing right nephrostomy, the patient developed a fever of 39°C and started bleeding from the site of the right nephrostomy. A computerized tomography scan revealed a pseudoaneurysm in the right common iliac artery, and the endovascular stent graft was seen sliding into the artery. Thus, endovascular stent graft removal, pseudoaneurysm resection, and femoral-femoral artery bypass surgeries were performed. Thereafter, the patient showed no recurrence of infection or hematuria and no evidence of blood flow disorder to the lower extremities. In recent years, endovascular treatment for ureteroarterial fistulas is considered as the first-line treatment modality. However, in cases with infection, there is a possibility of vascular wall weakening, resulting in the formation of pseudoaneurysms, and sliding of the endovascular stent graft.


Motor neurone disease in the tropics: findings from Sudan.
In this clinical study the presentation, electromyography and nerve conduction studies were described in different types of motor neurone disease in 28 Sudanese patients seen at El Shaab and Khartoum Teaching Hospitals. The three major clinical subtypes encountered were amyotrophic lateral sclerosis (n = 19), progressive bulbar palsy (n = 7) and progressive muscular atrophy (n = 2). Family history of the disease was found in four patients and those mainly presented with bulbar symptoms. Sudanese patients were found to have an earlier age of onset and a better prognosis of the disease than their caucasian counterparts.


Trametinib suppresses chemotherapy-induced cold and mechanical allodynia via inhibition of extracellular-regulated protein kinase 1/2 activation.
Chemotherapy-induced neuropathy is a common, dose-dependent adverse effect of some anti-cancer drugs and leads to discontinuation of chemotherapy and detrimental dose reductions, thereby affecting the quality of life of cancer patients. Currently, no treatment can effectively prevent or treat chemotherapy-induced neuropathy. Therefore, understanding its underlying molecular mechanisms may help to identify novel therapies for treating it. Some disease-induced neuropathy involve the activation of mitogen-activated protein kinases (MAPKs), such as extracellular-regulated protein kinase 1/2 (ERK1/2). In the present study, we investigated whether ERK1/2 inhibition can prevent chemotherapy-induced neuropathy. We found that trametinib, an MEK inhibitor, suppressed oxaliplatin-, paclitaxel-, vincristine-, and bortezomib-induced cold and mechanical allodynia in mice. In addition, treatment with oxaliplatin, paclitaxel, vincristine, or bortezomib enhanced ERK1/2 and c-Jun N-terminal kinase (JNK) phosphorylation in the spinal cord lumbar segments 4-6, and when combined with trametinib, can prevent chemotherapy-induced neuropathy via the suppression of ERK1/2 activation, but does not affect JNK activation. In conclusion, we demonstrated that the disruption of this pathway by MEK inhibitors suppresses oxaliplatin-, paclitaxel-, vincristine-, and bortezomib-induced neuropathy. This suggests that inhibition of the MEK/ERK pathway could prevent chemotherapy-induced neuropathy and MEK inhibitors could be used in combination with anti-tumor drugs during pharmacotherapy.


Catheter pericardiocentesis for delayed tamponade after cardiac valve operation.
Late tamponade is a rare cause of morbidity and mortality after cardiac valve operation. We describe our recent experience with this entity. This is a single institution, procedure-matched, retrospective review of patients undergoing pericardiocentesis more than 7 days after cardiac operation, during a 7-year period. Pericardiocentesis for delayed tamponade was performed in 43 of 9,612 patients. Although isolated valve operation accounted for 17% of all patients overall, 76% of patients undergoing pericardiocentesis (33 of 43) had undergone isolated valve operation. The average age in this group was 58 years, compared to an average of 68 years in all patients. Patients presented with tamponade an average of 18 days after operation. Positive predictors included elevated prothrombin time on presentation. Of the patient cohort 75% presented with dyspnea, 61% with inability to diurese, and 61% with hypotension. Echocardiography detected effusions in all patients, but specific echocardiographic signs of tamponade were present in only 30%. Of the patients, 97% were successfully treated by pericardiocentesis. All were safely restarted on warfarin. One patient required pericardial window. Delayed cardiac tamponade is more common after isolated valve operation, as opposed to coronary artery bypass grafting and valve/coronary artery bypass grafting. It tends to occur in the third postoperative week in younger patients who are aggressively anticoagulated. Pericardiocentesis with catheter placement is highly effective, and patients can be reanticoagulated safely. This series underestimates the incidence of late tamponade, as some patients may present to outside facilities. The diagnosis is aided by a high degree of suspicion.


Relationship between vitamin B12 and sensory and motor peripheral nerve function in older adults.
To examine whether deficient B12 status or low serum B12 levels are associated with worse sensory and motor peripheral nerve function in older adults. Cross-sectional. Health, Aging and Body Composition Study. Two thousand two hundred and eighty-seven adults aged 72 to 83 (mean 76.5 ± 2.9; 51.4% female; 38.3% black). Low serum B12 was defined as serum B12 less than 260 pmol/L, and deficient B12 status was defined as B12 less than 260 pmol/L, methylmalonic acid (MMA) greater than 271 nmol/L, and MMA greater than 2-methylcitrate. Peripheral nerve function was assessed according to peroneal nerve conduction amplitude and velocity (NCV) (motor), 1.4 g/10 g monofilament detection, average vibration threshold detection, and peripheral neuropathy symptoms (numbness, aching or burning pain, or both) (sensory). B12-deficient status was found in 7.0% of participants, and an additional 10.1% had low serum B12 levels. B12 deficient status was associated with greater insensitivity to light (1.4 g) touch (odds ratio = 1.50, 95% confidence interval = 1.06-2.13) and worse NCV (42.3 vs 43.5 m/s) (β = -1.16, P = .01) after multivariable adjustment for demographics, lifestyle factors, and health conditions. Associations were consistent for the alternative definition using low serum B12 only. No significant associations were found for deficient B12 status or the alternative low serum B12 definition and vibration detection, nerve conduction amplitude, or peripheral neuropathy symptoms. Poor B12 (deficient B12 status and low serum B12) is associated with worse sensory and motor peripheral nerve function. Nerve function impairments may lead to physical function declines and disability in older adults, suggesting that prevention and treatment of low B12 levels may be important to evaluate.


Pharmacokinetics of ceftazidime in normal and impaired renal function.
The concentration of ceftazidime in serum and urine was measured after 2 g i.v. in 10 healthy volunteers and 19 patients with various degrees of renal insufficiency. Elimination observed in normal volunteers can best be described by a two-compartment model. In renal insufficiency elimination of ceftazidime is markedly diminished, resulting in a larger area under the serum level curve (area under the curve; AUC). AUC and glomerular filtration rate (as well as AUC and plasma creatinine) can be brought into a mathematical relation. From these relations a dose reduction factor (DRF) can be derived. By means of this factor a dose can be calculated for each degree of renal impairment which causes the same AUC that would be anticipated in a subject with normal renal function. Dose recommendations in tabular form are presented. The urinary recovery decreases with impaired renal function; nevertheless therapeutical urine levels are observed down to dialysed patients.


Depression and anxiety among mothers who bring their children to a pediatric mental health clinic.
Maternal psychiatric illness is a potent risk factor for child psychiatric disorders, but little is known about rates of psychiatric diagnoses among mothers who bring their children to pediatric mental health clinics. This study investigated rates of psychiatric disorders among mothers of children presenting for psychiatric evaluation and examined the relationship between maternal diagnosis and child psychopathology. Interviewers conducted structured diagnostic interviews with nonpsychotic, school-age children and their mothers (N=222) and collected self-report measures of symptoms, functioning, and social support. One-hundred-thirty-five participating mothers (61 percent) met DSM-IV criteria for a current axis I disorder, most commonly depression (35 percent) and anxiety (42 percent). Children of mothers with a diagnosis met criteria for significantly more diagnoses on the Schedule for Affective Disorders and Schizophrenia for School Age Children, Present and Lifetime version and had significantly higher scores on measures of internalizing and externalizing symptoms than children of mothers without a diagnosis. Two-thirds of mothers with a diagnosis were not receiving psychiatric treatment. More than half the mothers who brought their children for psychiatric treatment were themselves suffering from a psychiatric disorder. Maternal psychiatric illness was, in turn, associated with greater occurrence of psychopathology among offspring, underscoring the importance of developing interventions that address the needs of both children with psychiatric disorders and their at-risk mothers.


The Impact of Hyperglycemia on VEGF Secretion in Retinal Endothelial Cells.
Diabetic retinopathy is a serious sight-threatening complication which is manifested by excessive angiogenesis in diabetic patients. We hypothesize that cultured Rhesus monkey retinal endothelial cells (RhRECs) respond to high glucose with a change in cell proliferation and vascular endothelial growth factor (VEGF) secretion. In our study, 20 000 cells per well were treated without glucose or with 5.5 mM, 18.5 mM and 30 mM glucose for 24 hours. Viable cells were counted using trypan blue dye exclusion method. VEGF concentrations were measured in cell media by ELISA method. The number of viable cells incubated with 5.5 mM glucose increased significantly by 53.7% after 24 hours. In comparison, the number of viable cells decreased by 2.8% at 18.5 mM of glucose and by 20.4% at 30 mM of glucose after 24 hours of incubation. In contrast to this effect of glucose on the number of viable cells, a significant increase in VEGF levels (pg/mL) in the cell media with a glucose concentration of 0 mM compared to 5.5 mM of glucose was found. VEGF secretion in cell medium with 18.5 and 30 mM of glucose increased non-significantly in comparison with euglycemic levels. Our results show that viability of retinal endothelial cells and VEGF release are highly responsive to changes in glucose concentration. Such glucose-induced changes in retinal endothelial cells may negatively impact the integrity of the microvasculature in the diabetic retina leading to angiogenesis and microaneursym.


Dynamic changes in c-Fos and NF-κB gene expression and Ca, Fe, Cu, Zn and Mg content due to brain injury in irradiated rats.
This study aims to investigate the dynamic changes of c-Fos and NF-κB expression, and to evaluate the Ca, Fe, Cu, Zn and Mg content of hippocampal tissues in rat brains injured by 20 Gy of electron beam irradiation. A single dose of 5 MeV is administered to the whole brains of rats to establish animal model of radiation-induced brain injury (RBI). Hematoxylin and eosin staining is performed to observe the pathological changes in brain microvascular endothelial cells. Quantitative reverse transcription-PCR and western blotting assays are utilized to test c-Fos and NF-κB gene expression levels in brain tissue. Inductively coupled plasma-atomic emission spectrometry is leveraged to detect the Ca, Fe, Cu, Zn and Mg contents of the hippocampi. The c-Fos and NF-κB gene expression levels in protective group are lower than those in the irradiated group after MgSO4 treatment. In the irradiated group, Ca content at several time points and Fe content on days 1, 3 and 7 are higher than those in the blank group. Additionally, in the irradiated group, Cu and Zn contents on days 1, 7, 14 and 60 are less than those in the blank group. In RBI model, adding Mg2+ may relieve RBI. The protective mechanisms of Mg2+ in the hippocampi from a variety of brain activity indicators including the c-Fos and NF-κB genes.


Energy absorption is reduced with oleic acid supplements in human short bowel syndrome.
Oleic acid premeal supplements have been described as a method to trigger the ileal brake and thus lengthen transit time and the opportunity for nutrient absorption. The aims of this study were to determine whether oleic acid supplements would lengthen transit time and improve absorption of nutrients in study participants with short bowel syndrome as well as affect diarrhea or patient weight. A double-blind, controlled, random-order crossover trial was conducted in 8 study participants with longstanding and severe short bowel syndrome, employing blue food color appearance, breath hydrogen testing, and radio-opaque markers as measures of transit time. Absorption of energy, protein, fat, and fluid was conducted by classic nutrient balance methods. Diarrhea was estimated by daily stool weight and number of bowel actions. Although 8 patients were enrolled, only 7 completed the study. Transit time was not significantly different between oleic acid and placebo treatment, although peptide YY levels trended higher with the oleic acid treatment. Energy absorption was reduced 14% by oleic acid, significantly more than the 3% reduction by placebo. Fat, protein, and fluid absorption was not changed significantly. Neither diarrhea nor patient body weight was changed by oleic acid. Energy absorption is reduced by oleic acid supplements in severe short bowel syndrome. The study may have lacked power to determine whether oleic acid affects diarrhea or body weight.


Structure-Activity Relationship of PEGylated Polylysine Peptides as Scavenger Receptor Inhibitors for Non-Viral Gene Delivery.
PEGylated polylysine peptides of the general structure PEG30 kDa-Cys-Trp-LysN (N = 10 to 30) were used to form fully condensed plasmid DNA (pGL3) polyplexes at a ratio of 1 nmol of peptide per μg of DNA (ranging from N:P 3:1 to 10:1 depending on Lys repeat). Co-administration of 5 to 80 nmols of excess PEG-peptide with fully formed polyplexes inhibited the liver uptake of (125)I-pGL3-polyplexes. The percent inhibition was dependent on the PEG-peptide dose and was saturable, consistent with inhibition of scavenger receptors. The scavenger receptor inhibition potency of PEG-peptides was dependent on the length of the Lys repeat, which increased 10-fold when comparing PEG30 kDa-Cys-Trp-Lys10 (IC50 of 20.2 μM) with PEG30 kDa-Cys-Trp-Lys25 (IC50 of 2.1 μM). We hypothesize that PEG-peptides inhibit scavenger receptors by spontaneously forming small 40 to 60 nm albumin nanoparticles that bind to and saturate the receptor. Scavenger receptor inhibition delayed the metabolism of pGL3-polyplexes, resulting in efficient gene expression in liver hepatocytes following delayed hydrodynamic dosing. PEG-peptides represent a new class of scavenger inhibitors that will likely have broad utility in blocking unwanted liver uptake and metabolism of a variety of nanoparticles.


Copper regulates cyclic-AMP-dependent lipolysis.
Cell signaling relies extensively on dynamic pools of redox-inactive metal ions such as sodium, potassium, calcium and zinc, but their redox-active transition metal counterparts such as copper and iron have been studied primarily as static enzyme cofactors. Here we report that copper is an endogenous regulator of lipolysis, the breakdown of fat, which is an essential process in maintaining body weight and energy stores. Using a mouse model of genetic copper misregulation, in combination with pharmacological alterations in copper status and imaging studies in a 3T3-L1 white adipocyte model, we found that copper regulates lipolysis at the level of the second messenger, cyclic AMP (cAMP), by altering the activity of the cAMP-degrading phosphodiesterase PDE3B. Biochemical studies of the copper-PDE3B interaction establish copper-dependent inhibition of enzyme activity and identify a key conserved cysteine residue in a PDE3-specific loop that is essential for the observed copper-dependent lipolytic phenotype.