Association between pediatric asthma and adult polycystic ovarian syndrome (PCOS): a cross-sectional analysis of the UAE healthy future Study (UAEHFS).
Asthma and polycystic ovarian syndrome (PCOS) are linked in several possible ways. To date, there has been no study evaluating whether pediatric asthma is an independent risk factor for adult PCOS. Our study aimed to examine the association between pediatric asthma (diagnosed at 0-19 years) and adult PCOS (diagnosed at ≥20 years). We further assessed whether the aforementioned association differed in two phenotypes of adult PCOS which were diagnosed at 20-25 years (young adult PCOS), and at >25 years (older adult PCOS). We also evaluated whether the age of asthma diagnosis (0-10 vs 11-19 years) modified the association between pediatric asthma and adult PCOS. This is a retrospective cross-sectional analysis using the United Arab Emirates Healthy Future Study (UAEHFS) collected from February 2016 to April 2022 involving 1334 Emirati females aged 18-49 years. We fitted a Poisson regression model to estimate the risk ratio (RR) and its 95% confidence interval (95% CI) to assess the association between pediatric asthma and adult PCOS adjusting for age, urbanicity at birth, and parental smoking at birth. After adjusting for confounding factors and comparing to non-asthmatic counterparts, we found that females with pediatric asthma had a statistically significant association with adult PCOS diagnosed at ≥20 years (RR=1.56, 95% CI: 1.02-2.41), with a stronger magnitude of the association found in the older adult PCOS phenotype diagnosed at >25 years (RR=2.06, 95% CI: 1.16-3.65). Further, we also found females reported thinner childhood body size had a two-fold to three-fold increased risk of adult PCOS diagnosed at ≥20 years in main analysis and stratified analyses by age of asthma and PCOS diagnoses (RR=2.06, 95% CI: 1.08-3.93 in main analysis; RR=2.74, 95% CI: 1.22-6.15 among those diagnosed with PCOS > 25 years; and RR=3.50, 95% CI: 1.38-8.43 among those diagnosed with asthma at 11-19 years). Pediatric asthma was found to be an independent risk factor for adult PCOS. More targeted surveillance for those at risk of adult PCOS among pediatric asthmatics may prevent or delay PCOS in this at-risk group. Future studies with robust longitudinal designs aimed to elucidate the exact mechanism between pediatric asthma and PCOS are warranted.


Recent benthic foraminiferal assemblages and their relationship to environmental variables on the shoreface and inner shelf off Valencia (western Mediterranean).
The environmental variables that determine the distributions of benthic foraminiferal assemblages on the shoreface and inner shelf of the north of Valencia province (Western Mediterranean) are identified. The possible influence of variables such as water depth, distance from shore, hydrodynamics, substrate type, carbonate content, organic matter content and human activity is evaluated. Multivariate cluster-Q-type analysis and redundancy analysis (RDA) are used to identify the environmental variables that have the greatest influence on the assemblage distribution. The spatial distribution of the assemblages is closely associated with water depth and substrate. The diversity and abundance of foraminifera shells increase with depth and their conservation improves. The most common species in the study area are Ammonia beccarii, Rosalina globularis, Buccella granulata, Planorbulina mediterranensis, and Lobatula lobatula. The presence of wastewater in the study area has not polluted the foraminiferal assemblages (absence of anomalous shells). The direction of the discharge plume is a potential source of nutrients for deep water.


Hypertension and vascular disease in India and migrant Indian populations in the world.
The association of hypertension, diabetes mellitus and abnormal lipoprotein patterns suggests that this combination has a lethal effect with regard to vascular disease. It is therefore necessary to do something about the known lifestyle factors such as cigarette smoking, obesity and possibly a low fibre diet. The high incidence of ischaemic heart disease among emigrant Indians in South Africa and Trinidad, and the low incidence in blacks of South Africa and the West Indies, suggests that there may be different thresholds for susceptibility to disease in various ethnic groups, beyond which the risk factors begin to operate.


Total mortality risk in relation to use of less-common dietary supplements.
Dietary supplement use is common in older US adults; however, data on health risks and benefits are lacking for a number of supplements. We evaluated whether 10-y average intakes of 13 vitamin and mineral supplements and glucosamine, chondroitin, saw palmetto, Ginko biloba, garlic, fish-oil, and fiber supplements were associated with total mortality. We conducted a prospective cohort study of Washington State residents aged 50-76 y during 2000-2002. Participants (n = 77,719) were followed for mortality for an average of 5 y. A total of 3577 deaths occurred during 387,801 person-years of follow-up. None of the vitamin or mineral 10-y average intakes were associated with total mortality. Among the nonvitamin-nonmineral supplements, only glucosamine and chondroitin were associated with total mortality. The hazard ratio (HR) when persons with a high intake of supplements (> or =4 d/wk for > or =3 y) were compared with nonusers was 0.83 (95% CI: 0.72, 0.97; P for trend = 0.009) for glucosamine and 0.83 (95% CI: 0.69, 1.00; P for trend = 0.011) for chondroitin. There was also a suggestion of a decreased risk of total mortality associated with a high intake of fish-oil supplements (HR: 0.83; 95% CI: 0.70, 1.00), but the test for trend was not statistically significant. For most of the supplements we examined, there was no association with total mortality. Use of glucosamine and use of chondroitin were each associated with decreased total mortality.


Variation in seizure risk increase from antiseizure medication withdrawal among patients with well-controlled epilepsy: a pooled analysis.
Guidelines suggest considering antiseizure medication (ASM) discontinuation in seizure-free patients with epilepsy. Past work has poorly explored how discontinuation effects vary between patients. We evaluated 1) What factors modify the influence of discontinuation on seizure risk; and 2) The range of seizure risk increase due to discontinuation across low- versus high-risk patients. We pooled three datasets including seizure-free patients who did and did not discontinue ASMs. We conducted time-to-first-seizure analyses. First, we evaluated what individual patient factors modified the relative effect of ASM discontinuation on seizure risk via interaction terms. Then, we assessed the distribution of two-year risk increase as predicted by our adjusted logistic regressions. We included 1,626 patients, of whom 678 (42%) planned to discontinue all ASMs. The mean predicted two-year seizure risk was 43% (95% confidence interval [CI] 39%-46%) for discontinuation versus 21% (95% CI 19%-24%) for continuation. The mean two-year absolute seizure risk increase was 21% (95% CI 18%-26%). No individual interaction term was significant after correcting for multiple comparisons. The median (interquartile range [IQR]) risk increase across patients was 19% (IQR 14%-24%; range 7%-37%). Results were unchanged when restricting analyses to only the two RCTs. No single patient factor significantly modified the influence of discontinuation on seizure risk, though we captured how absolute risk increases change for patients that are at low- versus high-risk. Patients should likely continue ASMs if even a 7% two-year increase in the chance of any more seizures would be too much and should likely discontinue ASMs if even a 37% risk increase would be too little. In between these extremes, individualized risk calculation and a careful understanding of patient preferences are critical. Future work will further develop a two-armed individualized seizure risk calculator and contextualize seizure risk thresholds below which to consider discontinuation.


A Novel Therapeutic Strategy for Pancreatic Cancer: Targeting Cell Surface Glycan Using rBC2LC-N Lectin-Drug Conjugate (LDC).
Various cancers, including pancreatic ductal adenocarcinoma (PDAC), remain intractable even with costly tumor-targeting antibody drugs. Because the outermost coatings of cancer cells are composed of cell-specific glycan layers (glycocalyx), lectins, proteins with glycan-binding potential, were evaluated for possible use as drug carriers in PDAC treatment. A human PDAC cell line with well-to-moderately differentiated properties (Capan-1) was subjected to lectin microarray analysis to identify specific lectin-glycan pairs. The selected lectin was fused with a bacterial exotoxin for the construction of a lectin-drug conjugate (LDC), and its safety and antitumor effects were evaluated. A specific affinity between a recombinant bacterial C-type lectin (rBC2LC-N) and Capan-1 was identified, and its positivity was confirmed in 69 human samples. In contrast to the belief that all lectins mediate harmful hemagglutination, rBC2LC-N did not cause hemagglutination with human erythrocytes and was safely administered to mice. The 50% inhibitory concentration of LDC to Capan-1 (1.04 pg/mL = 0.0195 pmol/L) was 1/1,000 lower than that reported for conventional immunotoxins. The intraperitoneal administration of LDC reduced the tumor weight from 390 to 130.8 mg (P < 0.01) in an orthotopic model and reduced the number of nodules from 48 to 3 (P < 0.001) and improved survival from 62 to 105 days in a peritoneal dissemination model (P < 0.0001). In addition, the effect of LDC was reproduced in nodules from patient-derived PDAC xenografts through intravenous injection. Herein, we show the concept of utilizing lectins as drug carriers to target glycans on the cancer cell surface, highlighting new insights into cancer treatments. Mol Cancer Ther; 17(1); 183-95. ©2017 AACR.


[Embryonal mortality in swine: conditions for a low incidence].
Embryonic mortality is an important cause of reproductive losses in the pig. The embryonic mortality rate, 30 per cent on average, will be reduced under optimal management conditions if (1) all sows are inseminated between 10 and 25 hours before ovulation; (2) semen of boars of proven fertility is used; and (3) variation in embryonic development is small. The uterine capacity of sows should also improved to enable the lower mortality rate to be expressed in larger litters.


Histogenesis of clear cell sarcoma of tendons and aponeuroses. An electron-microscopic, biochemical, enzyme histochemical, and immunohistochemical study.
For the purpose of clarifying the histogenesis of clear cell sarcoma of tendons and aponeuroses (CCS) as well as the problem of whether or not CCS is a heterogeneous group of neoplasms, studies based on various methods were performed. Analysis of glycosaminoglycans gave the same results for amelanotic CCS and synovial sarcoma, and the DOPA reaction gave the same negative results for amelanotic CCS and synovial sarcoma. However, the DOPA reaction was also negative in an amelanotic recurrent tumor of a melanotic CCS, and electron-microscopic studies revealed a close resemblance between amelanotic CCS and melanotic CCS. Further, enzyme histochemical studies showed definite differences between synovial sarcoma and amelanotic CCS but gave identical results for amelanotic and melanotic CCS. Immunohistochemical studies revealed the presence of S-100 protein in all CCS cases, both amelanotic and melanotic. These results indicate that CCS is not a heterogeneous group of neoplasms, and that both amelanotic and melanotic CCS are of neural crest origin.


Uneven-aged silviculture can enhance within stand heterogeneity and beetle diversity.
Uneven-aged silviculture may better maintain species assemblages associated with old-growth forests than clear felling in part due to habitat heterogeneity created by maintaining standing retention strips adjacent to harvest trails. Retention strips and harvest trails created at the time of tree removal will likely have different microclimate and may harbor different assemblages. In some cases, the resultant stand heterogeneity associated with uneven-aged silviculture may be similar to natural small-scale disturbances. For beetles, increased light and temperature as well as potential access to young vegetation and deadwood substrates present in harvset trails may harbor beetle assemblages similar to those found in natural gaps. We sampled saproxylic beetles using flight intercept traps placed in harvest corridors and retention strips in 9 replicated uneven-aged spruce stands in central Sweden. We compared abundance, species richness and composition between harvest corridors and retention strips using generalized linear models, rarefaction, permutational multivariate analysis of variance and indicator species analysis. Canopy openness doubled, mean temperature and variability in daily temperature increased and humidity decreased on harvest trails. Beetle richness and abundance were greater in harvests trails than in retention strips and the beetle species composition differed significantly between habitats. Twenty-five species were associated with harvest trails, including three old-growth specialists such as Agathidium discoideum (Erichson), currently red-listed. We observed only one species, Xylechinus pilosus (Ratzeburg) that strongly favored retention strips. Harvest trails foster both open habitat species and old-growth species while retention strips harbored forest interior specialists. The combination of closed canopy, stratified forest in the retention strips and gap-like conditions on the harvest trails thus increases overall species richness and maintains more diverse assemblages at the stand level than would otherwise be seen in less heterogeneous stand types. This suggests that uneven-aged silviculture may provide added conservation benefits for both open habitat and old-growth specialists than silvicultural approaches that reduce stand heterogeneity.


Medroxyprogesterone acetate and dihydrotestosterone induce coronary hyperreactivity in intact male rhesus monkeys.
Coronary hyperreactivity (CH), characterized by persistent severe vasoconstrictions in response to vasoconstrictor challenge, is oppositely influenced by progesterone (P) and medroxyprogesterone acetate (MPA) treatment in surgically menopausal primates. In this study we tested whether multiweek MPA or dihydrotestosterone (DHT) exposure induced CH in intact male rhesus monkeys. Coronary angiographic experiments with intracoronary serotonin and the thromboxane A(2) analog U46619 stimulated brief vasoconstriction (for 1-3 min) in large epicardial coronaries in untreated male monkeys. In contrast, MPA- and DHT-treated monkeys displayed long-duration constrictions (>5 min), with significantly greater reductions in the minimal diameters of epicardial coronaries. Immunocytochemistry demonstrated androgen receptors (AR) and P receptors in aorta and coronary arteries, and immunocytochemistry and Western blotting showed AR and P receptors in rhesus coronary vascular muscle cells. In vivo, MPA or DHT increased thromboxane prostanoid (TP) receptor expression in the aorta. In vitro, MPA or DHT increased, whereas P did not change, TP receptor expression in primary coronary vascular muscle cell. This MPA- or DHT-mediated increase in TP receptor expression was attenuated by the AR antagonist flutamide. MPA or DHT induction of CH in intact adult male primates, hypothesized to occur via androgenic up-regulation of vascular muscle TP receptor expression, could predispose to CH-mediated myocardial ischemia.


Percutaneous device embolization of an aneurysmal pulmonary artery in an infant weighing <3 kilograms.
Pulmonary artery aneurysm (PAA) and pulmonary artery pseudoaneurysm (PAP) are rare diagnoses in the pediatric population and carry a high risk of mortality if rupture occurs. There is currently no standard therapeutic approach to PAAs and PAPs. Reports of surgical intervention describe high mortality. We present a case of an infant with a PAP that was successfully treated with a percutaneous device closure. Our approach included deployment of a 6-mm Amplatzer Vascular Plug 2 (Abbott, St. Paul, MN) in the right lower pulmonary artery segmental branch just proximal to the origin of the pseudoaneurysm. Subsequent imaging 1-month post-procedure demonstrated a >50% reduction in the size of the PAP when compared to original imaging studies and near-complete resolution 14 months following the intervention. Percutaneous device placement to occlude the vessel supplying peripheral PAAs and PAPs may be a reasonable alternative to open surgical resection when treating patients with this rare, but potentially life-threatening vascular anomaly. To our knowledge, this is the first case describing a successful device closure of a PAP in an infant weighing <3 kg.


Intracerebral electrical stimulation of the right anterior fusiform gyrus impairs human face identity recognition.
Brain regions located between the right fusiform face area (FFA) in the middle fusiform gyrus and the temporal pole may play a critical role in human face identity recognition but their investigation is limited by a large signal drop-out in functional magnetic resonance imaging (fMRI). Here we report an original case who is suddenly unable to recognize the identity of faces when electrically stimulated on a focal location inside this intermediate region of the right anterior fusiform gyrus. The reliable transient identity recognition deficit occurs without any change of percept, even during nonverbal face tasks (i.e., pointing out the famous face picture among three options; matching pictures of unfamiliar or familiar faces for their identities), and without difficulty at recognizing visual objects or famous written names. The effective contact is associated with the largest frequency-tagged electrophysiological signals of face-selectivity and of familiar and unfamiliar face identity recognition. This extensive multimodal investigation points to the right anterior fusiform gyrus as a critical hub of the human cortical face network, between posterior ventral occipito-temporal face-selective regions directly connected to low-level visual cortex, the medial temporal lobe involved in generic memory encoding, and ventral anterior temporal lobe regions holding semantic associations to people's identity.


The vanadium nitrogenase of Azotobacter chroococcum. Purification and properties of the Fe protein.
1. Nitrogenase activity of a strain of Azotobacter chroococcum lacking the structural genes of Monitrogenase (nifHDK) was associated with a V + Fe-containing protein and an Fe-containing protein [Robson, Eady, Richardson, Miller, Hawkins & Postgate (1986) Nature (London) 322, 388-390; Eady, Robson, Richardson, Miller & Hawkins (1987) Biochem. J. 244, 197-207]. 2. The Fe protein was purified to homogeneity by the criterion of Coomassie Blue staining after electrophoresis in 10% or 17% (w/v) polyacrylamide gels in the presence of SDS. One type of subunit, of Mr 32,000 +/- 2000, was found. 3. The native protein had an Mr of 62,500 +/- 2500 and contained approximately 4 Fe atoms and 4 acid-labile sulphide groups per molecule. The amino acid composition was similar to those of other purified Fe proteins, and, characteristically, tryptophan was absent. The specific activities (nmol of protein/min per mg of protein) when assayed under optimum conditions with the VFe protein from this strain were 1211 for H2 evolution under Ar, 337 for NH3 from N2 formation and 349 for C2H2 reduction. Activity of the Fe protein was O2-labile with a t1/2 of 36 s in air. At low temperatures the dithionite-reduced protein exhibited e.p.r. signals consistent with the presence of both S = 1/2 and S = 3/2 spin states. These signals were similar to those given by other nitrogenase Fe proteins, as were the changes in their line shape that occurred in the presence of MgATP or MgADP. The absorbance spectra showed that an increase in absorption occurred in the visible range on reversible oxidation of the dithionite-reduced protein. The oxidized-minus-reduced epsilon 420 was 6000 M-1.cm-1.


Impact of Lung Biopsy on Lung Function in Idiopathic Pulmonary Fibrosis.
Video-assisted surgical lung biopsy (SLB) is performed in 10-30% of cases to establish the diagnosis of idiopathic pulmonary fibrosis (IPF). The aim of the study was to analyze the impact of SLB on lung function in patients eventually diagnosed with IPF. This is an observational, retrospective, monocentric study of all consecutive patients eventually diagnosed with IPF in multidisciplinary discussion who underwent SLB over 10 years in a specialized center. The primary end point was the variation in forced vital capacity (FVC) before and after the SLB. The secondary end points were the variations in forced expiratory volume in one second (FEV1), total lung capacity (TLC), carbon monoxide diffusion capacity (DLCO), and morbidity and mortality associated with the SLB. In 118 patients who underwent SLB and were diagnosed with IPF, a relative decrease in FVC of 4.8% (p < 0.001) was found between measurements performed before and after the procedure. The mean FVC decrease was 156 ± 386 mL in an average period of 185 days, representing an annualized decline of 363 ± 764 mL/year. A significant decrease was also observed after SLB in FEV1, TLC, and DLCO. Complications within 30 days of SLB occurred in 14.4% of patients. Two patients (1.7%) died within 30 days, where one of them had poor lung function. Survival at 1 year was significantly poorer in patients with FVC <50% at baseline. In this uncontrolled study in patients ultimately diagnosed with IPF, SLB was followed by a significant decline in FVC, which appears to be numerically greater than the average decline in the absence of treatment in the literature. Summary at a Glance: This study evaluated the change in lung function in 118 consecutive patients diagnosed with idiopathic pulmonary fibrosis by surgical lung biopsy. Forced vital capacity decreased by 156 ± 386 mL in a mean of 185 days between the last measurement before and first measurement after biopsy, representing an annualized decline of 363 ± 764 mL/year.


Risk factors for loss of pulmonary function after wedge resection for peripheral ground-glass opacity dominant lung cancer.
This study aimed to identify the risk factors for pulmonary functional deterioration after wedge resection for early-stage lung cancer with ground-glass opacity, which remain unclear, particularly in low-risk patients. We analysed 237 patients who underwent wedge resection for peripheral early-stage lung cancer in JCOG0804/WJOG4507L, a phase III, single-arm confirmatory trial. The changes in forced expiratory volume in 1 s were calculated pre- and postoperatively, and a cutoff value of -10%, the previously reported reduction rate after lobectomy, was used to divide the patients into 2 groups: the severely reduced group (≤-10%) and normal group (>-10%). These groups were compared to identify predictors for severe reduction. Thirty-seven (16%) patients experienced severe reduction. Lesions with a total tumour size ≥1 cm were significantly more frequent in the severely reduced group than in the normal group (89.2% vs 71.5%; P = 0.024). A total tumour size of ≥1 cm [odds ratio (OR), 3.287; 95% confidence interval (CI), 1.114-9.699: P = 0.031] and pleural indentation (OR, 2.474; 95% CI, 1.039-5.890: P = 0.041) were significant predictive factors in the univariable analysis. In the multivariable analysis, pleural indentation (OR, 2.667; 95% CI, 1.082-6.574; P = 0.033) was an independent predictive factor, whereas smoking status and total tumour size were marginally significant. Of the low-risk patients who underwent pulmonary wedge resection for early-stage lung cancer, 16% experienced severe reduction in pulmonary function. Pleural indentation may be a risk factor for severely reduced pulmonary function in pulmonary wedge resection.


Polysome morphology: evidence for endocrine control during chick embryogenesis.
Surgical removal of the pituitary gland had little apparent effect on the distribution or morphology of skin and feather polysomes in chicken embryos incubated for 12 days. However, polysome patterns obtained from 15-day-old hypophysectomized embryos differed markedly from those of their controls. In addition, a tetrad-shaped polysome, characteristic of the 158S peak of the 12-day-old embryo but not of the 15-day-old control, is still retained in the operated embryo at 15 days. Therefore, it appears that after day 12 of embryogenesis the structure of the four-ribosome polysome from skin and feathers is contingent on a functional hypophysis.


Dietary nitrate improves sprint performance and cognitive function during prolonged intermittent exercise.
It is possible that dietary nitrate (NO3 (-)) supplementation may improve both physical and cognitive performance via its influence on blood flow and cellular energetics. To investigate the effects of dietary NO3 (-) supplementation on exercise performance and cognitive function during a prolonged intermittent sprint test (IST) protocol, which was designed to reflect typical work patterns during team sports. In a double-blind randomised crossover study, 16 male team-sport players received NO3 (-)-rich (BR; 140 mL day(-1); 12.8 mmol of NO3 (-)), and NO3 (-)-depleted (PL; 140 mL day(-1); 0.08 mmol NO3 (-)) beetroot juice for 7 days. On day 7 of supplementation, subjects completed the IST (two 40-min "halves" of repeated 2-min blocks consisting of a 6-s "all-out" sprint, 100-s active recovery and 20 s of rest), on a cycle ergometer during which cognitive tasks were simultaneously performed. Total work done during the sprints of the IST was greater in BR (123 ± 19 kJ) compared to PL (119 ± 17 kJ; P < 0.05). Reaction time of response to the cognitive tasks in the second half of the IST was improved in BR compared to PL (BR first half: 820 ± 96 vs. second half: 817 ± 86 ms; PL first half: 824 ± 114 vs. second half: 847 ± 118 ms; P < 0.05). There was no difference in response accuracy. These findings suggest that dietary NO3 (-) enhances repeated sprint performance and may attenuate the decline in cognitive function (and specifically reaction time) that may occur during prolonged intermittent exercise.


Haemostatic function in myocardial infarction.
Coagulation factor VIII, von Willebrand factor, antithrombin, fibrinogen, plasminogen activator capacity, and inhibitors of fibrinolysis, including a recently discovered fast inhibitor of tissue plasminogen activator, were measured three to six months after myocardial infarction in 116 male and 32 female patients aged less than 45 and in 136 age and sex matched random controls. Plasma concentrations of fibrinogen and the fast inhibitor of tissue plasminogen activator were raised in male patients (with or without correction for orosomucoid levels, blood group distribution, tobacco and alcohol consumption, and weight/height index) and plasminogen activator capacity was reduced. In female patients the concentrations of factor VIII, von Willebrand factor, the fast inhibitor of tissue plasminogen activator, alpha 2-antiplasmin, and C1 inhibitor were significantly increased. The increase in factor VIII concentrations depended strongly on a persisting inflammatory response. Multivariate analysis indicated that a combination of fibrinogen and tissue plasminogen activator inhibitor concentrations gave the best independent discrimination between male patients and controls. For female patients the best combination was von Willebrand factor and tissue plasminogen activator inhibitor. Male patients with multiple vessel atheromatosis at coronary angiography had higher fibrinogen concentrations than those with atheromatosis of a single vessel. Atheromatosis was defined as sharp-edged, plaque-like, or irregular indentations, often multiple, into the vessel lumen without features suggesting fibromuscular hyperplasia.


Mold infections in lung transplant recipients.
Fungal infections continue to produce morbidity and mortality in lung transplant recipients despite the widespread use of antifungal prophylaxis. There has been a decline in Candida infections but Aspergillus species predominate. Other mold pathogens including Fusarium, Scedosporium, and Zygomycetes also cause infections in lung transplant recipients. Furthermore, the widespread use of antifungal prophylaxis has prompted a delay in onset of Aspergillus infection in lung transplant recipients. Pulmonary parenchymal disease has become the most common manifestation of invasive aspergillosis. Among the risk factors pre- or posttransplant Aspergillus colonization is the most important risk factor reported in several retrospective studies. Recently posttransplant colonization has been implicated in the development of bronchiolitis obliterans syndrome. Other factors that have been reported include preceding cytomegalovirus infections, hypogammaglobulinemia, and single-lung transplantation. The risk factors for other mold infections such as Scedosporium, Fusarium, and Zygomycetes are not well studied. The best antimold prophylaxis strategy and choice of drug remains to be elucidated. Most lung transplant centers use either voriconazole or inhaled amphotericin preparations. However, data have emerged regarding the increased risk of squamous cell cancer in lung transplant recipients on voriconazole prophylaxis. Advances in the diagnosis and treatment of invasive aspergillosis have resulted in a significant decrease in mortality.


[Fibrin removal from mouse immune ascitic fluids to arbovirus using beta-propiolactone].
A modification of acid precipitation of fibrin in immune ascitic fluids (IAF) employing beta-propiolactone has been developed. The procedure removes fibrin completely without affecting the titres of specific antibody. This modification is not inferior to previously described methods for fibrin removal from IAF and has a number of advantages. In addition to removing fibrin from IAF, beta-propiolactone prevents possible virus contamination of IAF and sterilizes the preparation additionally.


[The results of primary radiotherapy in vaginal carcinoma].
Cancer of the vagina is the least frequent primary malignant tumor of the female genital tract except carcinoma of the fallopian tube. Radiation therapy is the preferred treatment in most cases. Between 1965 and 1991, 39 patients (median age 66 years) with primary carcinoma of the vagina were treated with radiation therapy at our clinic. The mean observation period was 37 months. Classification according to the FIGO yielded a stage I in 43%, stage II in 24%, stage III in 22% and stage IV in 11%. Histological differentiation resulted in 35 squamous cell carcinomas and 4 adenocarcinomas. In 69%, the tumor was found on the posterior or lateral wall of the vagina, in 43% it arose from the upper third of the vagina. Standard therapy consisted of combined brachy- and teletherapy. Most of the brachytherapy applications were performed with a radium source. Median survival was 37 months, calculated according to the Kaplan-Meier method. The 5-year actuarial survival rate for all stages was 41% (stage 1: 62%, stage II: 44%, stage III: 25%). Sixty-eight percent of all patients achieved a complete remission, 19% a partial response. Significant prognostic factors were stage of disease and histological grading. Our results demonstrate the value of radiation therapy for the treatment of primary carcinoma of the vagina. Combined treatment with both external beam radiation and brachytherapy should be preferred.


A conceptual framework for organismal biology: linking theories, models, and data.
Implicit or subconscious theory is especially common in the biological sciences. Yet, theory plays a variety of roles in scientific inquiry. First and foremost, it determines what does and does not count as a valid or interesting question or line of inquiry. Second, theory determines the background assumptions within which inquiries are pursued. Third, theory provides linkages among disciplines. For these reasons, it is important and useful to develop explicit theories for biology. A general theory of organisms is developed, which includes 10 fundamental principles that apply to all organisms, and 6 that apply to multicellular organisms only. The value of a general theory comes from its utility to help guide the development of more specific theories and models. That process is demonstrated by examining two domains: ecoimmunology and development. For the former, a constitutive theory of ecoimmunology is presented, and used to develop a specific model that explains energetic trade-offs that may result from an immunological response of a host to a pathogen. For the latter, some of the issues involved in trying to devise a constitutive theory that covers all of development are explored, and a more narrow theory of phenotypic novelty is presented. By its very nature, little of a theory of organisms will be new. Rather, the theory presented here is a formal expression of nearly two centuries of conceptual advances and practice in research. Any theory is dynamic and subject to debate and change. Such debate will occur as part of the present, initial formulation, as the ideas presented here are refined. The very process of debating the form of the theory acts to clarify thinking. The overarching goal is to stimulate debate about the role of theory in the study of organisms, and thereby advance our understanding of them.


Evaluation of the regular practice of breast cancer screening in a health area.
Breast cancer screening has proved to be efficacious only in clinical trials or structured programs. However, little is known of its effectiveness as a regular practice. This study is an assessment of breast cancer screening in regular practice in a Spanish area of 350,000 inhabitants through analysis of existing sources of information. It is evident that this screening is insufficient, inefficient, very variable, nonspecific, and probably ineffective, although there is insufficient information to prove it. The immediate implementation of a well-structured and accredited screening program is essential to overcome the current limitations.


Multicenter analysis of the use of transjugular intrahepatic portosystemic shunt for management of MPN-associated portal hypertension.
BCR-ABL1-negative myeloproliferative neoplasms (MPNs) are clonal stem cell disorders defined by proliferation of one or more myeloid lineages, and carry an increased risk of vascular events and progression to myelofibrosis and leukemia. Portal hypertension (pHTN) occurs in 7-18% of MPN patients via both thrombotic and nonthrombotic mechanisms and portends a poor prognosis. Transjugular intrahepatic portosystemic shunt (TIPS) has been used in the management of MPN-associated pHTN; however, data on long-term outcomes of TIPS in this setting is limited and the optimal management of medically refractory MPN-associated pHTN is not known. In order to assess the efficacy and long-term outcomes of TIPS in MPN-associated pHTN, we performed a retrospective analysis of 29 MPN patients who underwent TIPS at three academic medical centers between 1997 and 2016. The majority of patients experienced complete clinical resolution of pHTN and its clinical sequelae following TIPS. One, two, three, and four-year overall survival post-TIPS was 96.4%, 92.3%, 84.6%, and 71.4%, respectively. However, despite therapeutic anticoagulation, in-stent thrombosis occurred in 31.0% of patients after TIPS, necessitating additional interventions. In conclusion, TIPS can be an effective intervention for MPN-associated pHTN regardless of etiology. However, TIPS thrombosis is a frequent complication in the MPN population and indefinite anticoagulation post-TIPS should be considered.


A study of practical parameters and their relative importance as perceived by various stakeholders in clinical trials.
A contract research organization (CRO) is a company which conducts a Good Clinical Practice (GCP) in clinical trial. There are literally hundreds of CROs worldwide employing a workforce of nearly 100,000 professionals. The project proposes the study of practical parameters and their relative importance as perceived by the various stakeholders in clinical trials. The survey was conducted in Bangalore and New Delhi. Primary market data was obtained by primary market research which included 80 clinical trial stakeholders by having a preliminary communication with them, followed by administering a questionnaire along with prior permission. There were 15 Sponsors/ CROs, 27 Investigators /Monitors and 38 Ethics committee members involved in the study. It was shown from the study that a clinical investigator involved in a clinical trial is responsible for ensuring that an investigation is conducted according to the signed investigator statement, the investigational plan, and applicable regulations; for protecting the rights, safety, and welfare of the subjects under the investigator's care; and for the control of drugs under investigation. It was also shown from the study that the sponsors of a clinical trial carry the ultimate responsibility for the initiation, management and financing of the clinical trial. The study has identified a specific training need at the level of the individual stakeholder to perform a particular job function and to identify the actual practical parameters in the Indian context important for the conduction of clinical trials (GCP) with respect to the different stakeholders, to determine the relative importance of these parameters as perceived by various stakeholders involved in clinical trials, and to identify the relative contributions of different stakeholders to the success/ satisfactory conduct of a clinical trial.


15-LOX-1: a novel molecular target of nonsteroidal anti-inflammatory drug-induced apoptosis in colorectal cancer cells.
Nonsteroidal anti-inflammatory drugs (NSAIDs) appear to act via induction of apoptosis-programmed cell death-as potential colorectal cancer chemopreventive agents. NSAIDs can alter the production of different metabolites of polyunsaturated fatty acids (linoleic and arachidonic acids) through effects on lipoxygenases (LOXs) and cyclooxygenases. 15-LOX-1 is the main enzyme for metabolizing colonic linoleic acid to 13-S-hydroxyoctadecadienoic acid (13-S-HODE), which induces apoptosis. In human colorectal cancers, the expression of this enzyme is reduced. NSAIDs can increase 15-LOX enzymatic activity in normal leukocytes, but their effects on 15-LOX in neoplastic cells have been unknown. We tested the hypothesis that NSAIDs induce apoptosis in colorectal cancer cells by increasing the protein expression and enzymatic activity of 15-LOX-1. We assessed 15-LOX-1 protein expression and enzymatic activity, 13-S-HODE levels, and 15-LOX-1 inhibition in association with cellular growth inhibition and apoptosis induced by NSAIDs (primarily sulindac and NS-398) in two colorectal cancer cell lines (RKO and HT-29). All P values are two-sided. Sulindac and NS-398 progressively increased 15-LOX-1 protein expression in RKO cells (at 24, 48, and 72 hours) in association with subsequent growth inhibition and apoptosis. Increased 13-S-HODE levels and the formation of 15-hydroxyeicosatetraenoic acid on incubation of the cells with the substrate arachidonic acid confirmed the enzymatic activity of 15-LOX-1. Inhibition of 15-LOX-1 in RKO cells by treatment with caffeic acid blocked NS-398-induced 13-S-HODE production, cellular growth inhibition, and apoptosis (P =. 007, P<.0001, and P<.0001, respectively); growth inhibition and apoptosis were restored by adding exogenous 13-S-HODE (P<.0001 for each) but not its parent compound, linoleic acid (P = 1.0 for each). Similar results occurred with other NSAIDs and in HT-29 cells. These data identify 15-LOX-1 as a novel molecular target of NSAIDs for inducing apoptosis in colorectal carcinogenesis.


How to Implement Game-Based Learning in a Smart Classroom? A Model Based on a Systematic Literature Review and Delphi Method.
Game-based learning (GBL) can allow learners to acquire and construct knowledge in a fun and focused learning atmosphere. A systematic literature review of 42 papers from 2010 to 2020 in this study showed that the current difficulties in implementing GBL in classrooms could be classified into the following categories: infrastructure, resources, theoretical guidance, teacher's capabilities and acceptance of GBL. In order to solve the above problems, the study constructs a technology enhanced GBL model, from the four parts of learning objective, learning process, learning evaluation, and smart classroom. In addition, this study adopted the Delphi method, inviting a total of 29 scholars, experts, teachers and school managers to explore how to implement GBL in smart classrooms. Finally, the technology enhanced GBL model was validated and the utilization approaches were provided at the conclusion part.


Neonatal uterine prolapse - a case report.
Uterine prolapse is commonly seen in the geriatric age group. Congenital vaginouterine prolapse is a rare condition occurring in neonates and is usually associated with spinal cord malformations in about 85% of cases. Several modalities of treatment have been described for neonatal uterine prolapse. Conservative treatment in the form of simple digital reposition, use of pessary or other self-retaining device is usually sufficient to treat this condition, which is self-limiting and regressive. Here we report our first case of neonatal uterine prolapse, managed successfully with simple digital reposition.


Stability of occlusal outcome during long-term retention: the time-dependent variation of the American Board of Orthodontics index.
The aim of this retrospective cohort study was to assess long-term occlusal changes at debond and a median of 8 years afterwards (in retention) with the American Board of Orthodontics (ABO) objective grading system and identify risk factors. Fifty patients (median age: 14.3 years at debond; 60% female) treated with fixed appliances (25 with and 25 without premolar extractions) were included. The occlusal outcome was assessed with the ABO tool and analyzed statistically at 5%. Extraction treatment was associated with better occlusal outcome than non-extraction treatment (34.2 versus 40.9 points; P = 0.009). In retention, ABO scores improved by 7.4 points, while patients with worse debond finishing improved more afterwards (P = 0.001). Alignment/rotations deteriorated in 58% of the cases and occlusal relationships in 38% of the cases. Marginal ridges improved more for extraction than non-extraction patients (28% versus 0%; P = 0.001). Occlusal relationships improved more for cases that 'passed' the ABO requirements at debond than failed cases (64% versus 28%; P = 0.02). Furthermore, patients with worse debond ABO scores were more likely to deteriorate at alignment/rotations in retention. Finally, the proportion of cases passing the ABO requirements improved considerably between debond (28%) and in retention (54%) as half (47%) of the cases that had failed the ABO requirements at debond passed them in retention. Considerable long-term occlusal changes are seen post-debond, which mostly favour improved settling. Extraction treatment and higher finishing quality at debond significantly influenced the chance for improvement. However, setting a cut-off score to denote treatment excellence showed considerable instability through time.


Polyethylene glycol modification of adenovirus reduces platelet activation, endothelial cell activation, and thrombocytopenia.
Thrombocytopenia is one of the complications for in vivo administration of adenovirus serotype 5 (Ad5) vectors after intravenous injection. In this paper, we investigated the mechanism of Ad5-induced thrombocytopenia and how these effects are attenuated by polyethylene glycol (PEG) modification of Ad5 (Ad-PEG). After intravenous injection, accelerated platelet loss was observed in Ad-injected mice but not in their Ad-PEG-injected counterparts. This platelet loss induced by Ad5 corresponded with increases in coagulation D-dimer levels, splenomegaly, and, later, production of megakaryocytes in the bone marrow. In contrast, these responses were blunted or ablated after injection of Ad-PEG. Ad5 activated both platelets and endothelial cells directly in vitro as evidenced by induction of P-selectin and the formation of von Willebrand factor-platelet strings and in vivo as evidenced by the induction of E-selectin messenger RNA. PEGylation blunted these observed activations. These data suggest that Ad5 may induce thrombocytopenia by direct activation of endothelial cells in addition to its direct effects on platelets. This link provides an important clue for the understanding of the mechanisms of thrombocytopenia associated with Ad5. Given that PEGylation blunted interactions of Ad with platelets and endothelial cells, reduced D-dimer formation, reduced thrombocytopenia, and reduced splenomegaly, these data suggest that this simple vector modification may have utility to improve the safety of Ad vectors for human gene therapy.


SCUBE1: a promising biomarker in renal cell cancer.
To investigate the efficacy of signal peptide-CUB-EGF domain-containing protein 1 (SCUBE-1) as a novel biomarker of renal tumors. 48 individuals were included in the study. The patient group (Group-1) consisted of 23 subjects diagnosed with renal tumor, and the control group (Group-2) of 25 healthy individuals. Patients diagnosed with renal tumor received surgical treatment consisting of radical or partial nephrectomy. Blood specimens were collected following overnight fasting. Signal peptide-CUB-EGF domain-containing protein 1 (SCUBE-1), soluble urokinase plasminogen activator receptor (suPAR) and carbonic anhydrase IX (CA IX) levels were measured from plasma samples. Patients in groups 1 and 2 were compared in terms of these biochemical parameters. The 23-member renal tumor group was made up of 17 (73.91%) male and 6 (26.08%) female patients with a mean age of 58.5±15.7 years (range 25 to 80). The 24-member healthy control group was made up of 16 (64%) male and 9 (36%) female subjects with a mean age of 52.4±9.12 years (range 40 to 67). Analysis revealed significant elevation in SCUBE-1 levels in the renal tumor group (p=0.005). No significant differences were detected between the groups with regard to CA IX or suPAR measurements (p=0.062 vs. p=0.176). SCUBE-1 appears to represent a promising biomarker in the diagnosis and follow-up of patients with renal tumor.


TGF beta in murine morphogenetic processes: the early embryo and cardiogenesis.
The tissue distribution of TGF beta-1 RNA was examined within whole mouse embryos from implantation to 10.5 days gestational age and, in the developing heart, up to 8 days postpartum. The earliest high level expression of TGF beta-1 RNA is at 7.0 days postcoitum (p.c.) in the cardiac mesoderm. At 8.0 days gestational age, cardiac TGF beta-1 RNA expression is limited to endocardial cells. By 9.5 days p.c., this expression pattern becomes regionalized to those cells that overlie cardiac cushion tissue. High TGF beta-1 RNA levels continue to persist in endothelial cells of the heart valves until approximately one week postpartum. The TGF beta-1 RNA distribution was compared with the extracellular distributions of polypeptides for TGF beta and J1/tenascin. As previously reported, endothelial expression of TGF beta-1 RNA is correlated with mesenchymal expression of TGF beta polypeptide, suggesting a paracrine mode of action for this growth factor in cardiac development. Minor discrepancies in the distributions of TGF beta-1 RNA and the extracellular form of the TGF beta polypeptide suggest that translational or post-translational control of protein levels occurs and/or the possibility that the antibody used may also recognise other members of the TGF beta polypeptide family. A correlation between endothelial TGF beta-1 expression and distribution of J1/tenascin in the mesenchyme gives further support to the proposition that the biological effects of TGF beta-1 may, in part, be mediated by J1/tenascin.


Study on the structure and strength characteristics of loess under the action of sodium sulfate.
In recent years, with the increasing frequency of human engineering activities, the phenomenon of sodium sulfate erosion has been widely observed in the Loess Plateau. This not only leads to difficulties in land reclamation but also affects human health, posing a significant risk to the investment environment in the Northwest region of China. In this study, three types of loess were treated with sodium sulfate to prepare remolded soil samples with salt content levels of 0%, 0.5%, 1.0%, 1.5%, 2.0%, and 2.5%. Observations and tests were conducted at multiple scales. The results indicate significant differences in the structural characteristics of the three types of loess under the influence of sodium sulfate. The higher the salt content in the loess, the greater the degree of structural damage. Subsequently, macroscopic mechanical properties were determined through direct shear tests, and it was found that as the salt content in the loess increased, the strength decreased. The resulting macroscopic mechanical properties showed a strong correlation with the microstructural characteristics. This study provides valuable insights for soil and water conservation and geological disaster prevention in the Loess Plateau region.


The rules of gene expression in plants: organ identity and gene body methylation are key factors for regulation of gene expression in Arabidopsis thaliana.
Microarray technology is a widely used approach for monitoring genome-wide gene expression. For Arabidopsis, there are over 1,800 microarray hybridizations representing many different experimental conditions on Affymetrix ATH1 gene chips alone. This huge amount of data offers a unique opportunity to infer the principles that govern the regulation of gene expression in plants. We used bioinformatics methods to analyze publicly available data obtained using the ATH1 chip from Affymetrix. A total of 1887 ATH1 hybridizations were normalized and filtered to eliminate low-quality hybridizations. We classified and compared control and treatment hybridizations and determined differential gene expression. The largest differences in gene expression were observed when comparing samples obtained from different organs. On average, ten-fold more genes were differentially expressed between organs as compared to any other experimental variable. We defined "gene responsiveness" as the number of comparisons in which a gene changed its expression significantly. We defined genes with the highest and lowest responsiveness levels as hypervariable and housekeeping genes, respectively. Remarkably, housekeeping genes were best distinguished from hypervariable genes by differences in methylation status in their transcribed regions. Moreover, methylation in the transcribed region was inversely correlated (R2 = 0.8) with gene responsiveness on a genome-wide scale. We provide an example of this negative relationship using genes encoding TCA cycle enzymes, by contrasting their regulatory responsiveness to nitrate and methylation status in their transcribed regions. Our results indicate that the Arabidopsis transcriptome is largely established during development and is comparatively stable when faced with external perturbations. We suggest a novel functional role for DNA methylation in the transcribed region as a key determinant capable of restraining the capacity of a gene to respond to internal/external cues. Our findings suggest a prominent role for epigenetic mechanisms in the regulation of gene expression in plants.


[Spontaneous polyploidy in laboratory mice. Embryological and cytogenetic analysis].
The developmental patterns of mice with spontaneous genomic aberrations at the pre- and post-implantation embryonic stages have been studied. The frequency of spontaneous triploidy varies in different strains from 1.7 to 5.8%. Digeny is the principal cytogenetical mechanism for triploidy. The triploid embryos of all the strains under study are characterized by the total delay of development already at the blastocyst stage. The most of triploids die at the stages of neurula and beginning of active organogenesis. A few triploids are resorbed during placentation. In the CBA mice, the triploidization results in the characteristic syndrome: disproportionally reduced amniotic vesicle, hypertrophied allantoic rudiment, reduction of neural plate, absence of head folds, notochord and mesenchyme. The spontaneous tetraploidy in mice occurs very rarely and is accompanied by severe developmental defects already at the preimplantation stages.


CircRNA ZNF609 Knockdown Suppresses Cell Growth via Modulating miR-188/ELF2 Axis in Nasopharyngeal Carcinoma.
Circular RNAs (circRNAs) and microRNAs (miRNAs) have been reported to act as the important regulators in nasopharyngeal carcinoma (NPC). CircRNA ZNF609 (circ-ANF609) and miR-188 have been, respectively, reported to play a pro-cancer and anti-cancer role in NPC. The purpose of this study is to reveal the functional relation of circ-ZNF609 and miR-188 in NPC development. The transcription level and protein level of genes were detected by quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot assay, respectively. Cell proliferation was analyzed using 3-(4, 5-dimethyl-2-thiazolyl)-2, 5-diphenyl-2-H-tetrazolium bromide (MTT) assay. Furthermore, flow cytometry analysis was used to assess cell cycle transition and cell apoptosis rate. Besides, the interaction between miR-188 and circ-ZNF609 or E74-like factor 2 (ELF2) was predicted by starbase or microT-CDS, and then confirmed by the dual luciferase reporter assay and RIP assay. Circ-ZNF609 and ELF2 levels were increased and miR-188 level was decreased in NPC. Circ-ZNF609 knockdown significantly inhibited cell proliferation and cell cycle transition, as well as accelerated apoptosis in NPC cells. Interestingly, circ-ZNF609 directly bound to miR-188. Circ-ZNF609 regulated NPC cell growth through modulating miR-188 expression. In addition, miR-188 suppressed NPC cell growth via directly targeting ELF2. Finally, we confirmed that circ-ZNF609 mediated miR-188 level to modulate ELF2 expression. Our findings demonstrated that circ-ZNF609 depletion-repressed proliferation and cell cycle transition, and induced apoptosis of NPC cells via modulation of miR-188/ELF2 axis, providing potential targets for the therapy of NPC.


Variability in growth responses of non-O157 EHEC isolates in leafy vegetables, sprouted seeds and soil extracts occurs at the isolate level.
Foods of plant origin are recognised as a major source of foodborne pathogens, in particular for Shigatoxigenic Escherichia coli (STEC). Most work for STEC and plant-based fresh produce has focused on the most prevalent outbreak serogroup, O157. However, non-O157 STEC is an emerging hazard, and as such it is important to characterise aspects within this group that reflect their ability to colonise alternative hosts and habitats relevant to horticultural production. Growth kinetics were quantified for a diverse set of clinical enterohaemorrhagic E. coli isolates in extracts made from different tissues of spinach, lettuce or sprouted seeds, or from soil, to represent association with ready-to-eat fresh produce production. For leafy vegetables, spinach apoplast supported the fastest rates of growth and lettuce root extracts generated the slowest growth rates. Growth rates were similar for the majority of isolates in fenugreek or alfalfa sprouted seed extracts. Monosaccharides were the major driver of bacterial growth. No correlations were found for growth rates between different serotypes or for Shigatoxin gene carriage. Thus, growth rates varied in a plant-dependent and isolate-dependent manner, for all plant or soil extracts tested, indicative of isolate-specific differences in metabolic flexibility. These findings are relevant for risk assessment of non-O157 STEC.


Routine intraoperative ureteric stenting for kidney transplant recipients.
Major urological complications (MUCs) after kidney transplantation contribute to patient morbidity and compromise graft function. The majority arise from the vesicoureteric anastomosis and present early after transplantation. Ureteric stents have been successfully used to treat such complications. A number of centres have adopted a policy of universal prophylactic stenting, at the time of graft implantation, to reduce the incidence of urine leaks and ureteric stenosis. Stents are associated with specific complications and some centres advocate a policy of only stenting selected anastomoses. To examine the benefits and harms of routine ureteric stenting to prevent urological complications in kidney transplant recipients. We searched the Cochrane Renal Group's Specialised Register (up to 8 January 2013) through contact with the Trials' Search Co-ordinator using search terms relevant to this review. All RCTs and quasi-RCTs were included in our meta-analysis. Four reviewers assessed the studies for quality against four criteria (allocation concealment, blinding, intention-to-treat and completeness of follow-up). The primary outcome was the incidence of MUCs. Further outcomes of interest were graft and patient survival and the incidence of adverse events (urinary tract infection (UTI), haematuria, irritative symptoms, pain and stent migration). Statistical analyses were performed using the random effects model and the results expressed as relative risk (RR) with 95% confidence intervals (CI). Seven RCTs (1154 patients) of low or moderate quality were identified. The incidence of MUCs was significantly reduced (RR 0.24, 95% CI 0.07 to 0.77, P = 0.02, NNT 13) by universal prophylactic stenting. This was dependent on whether the same surgeon performed, or was in attendance, during the operations. Two patients lost their grafts to infective urinary tract complications in the stented group. UTIs, in general, were more common in stented patients (RR 1.49, 95% CI 1.04 to 2.15) unless the patients were prescribed cotrimoxazole 480 mg/d: in which case the incidence was equivalent (RR 0.97, 95% CI 0.71 to 1.33). Stents appeared generally well tolerated, although studies using longer stents (≥ 20 cm) for longer periods (> 6 weeks) had more problems with encrustation and migration. Routine prophylactic stenting reduces the incidence of MUCs. Studies comparing selective stenting and universal prophylactic stenting, whilst difficult to design and analyse, would address the unresolved quality of life and economic issues.


Community-Acquired Acute Kidney Injury: A Nationwide Survey in China.
This study aimed to describe the burden of community-acquired acute kidney injury (AKI) in China based on a nationwide survey about AKI. Cross-sectional and retrospective study. A national sample of 2,223,230 hospitalized adult patients from 44 academic/local hospitals in Mainland China was used. AKI was defined according to the 2012 KDIGO AKI creatinine criteria or an increase or decrease in serum creatinine level of 50% during the hospital stay. Community-acquired AKI was identified when a patient had AKI that could be defined at hospital admission. The rate, cause, recognition, and treatment of community-acquired AKI were stratified according to hospital type, latitude, and economic development of the regions in which the patients were admitted. All-cause in-hospital mortality and recovery of kidney function at hospital discharge. 4,136 patients with community-acquired AKI were identified during the 2 single-month snapshots (January 2013 and July 2013). Of these, 2,020 (48.8%) had cases related to decreased kidney perfusion; 1,111 (26.9%), to intrinsic kidney disease; and 499 (12.1%), to urinary tract obstruction. In the north versus the south, more patients were exposed to nephrotoxins or had urinary tract obstructions. 536 (13.0%) patients with community-acquired AKI had indications for renal replacement therapy (RRT), but only 347 (64.7%) of them received RRT. Rates of timely diagnosis and appropriate use of RRT were higher in regions with higher per capita gross domestic product. All-cause in-hospital mortality was 7.3% (295 of 4,068). Delayed AKI recognition and being located in northern China were independent risk factors for in-hospital mortality, and referral to nephrology providers was an independent protective factor. Possible misclassification of AKI and community-acquired AKI due to nonstandard definitions and missing data for serum creatinine. The features of community-acquired AKI varied substantially in different regions of China and were closely linked to the environment, economy, and medical resources.


Sensory receptor repertoire in cyprid antennules of the barnacle Balanus improvisus.
Barnacle settlement involves sensing of a variety of exogenous cues. A pair of antennules is the main sensory organ that the cyprid larva uses to explore the surface. Antennules are equipped with a number of setae that have both chemo- and mechanosensing function. The current study explores the repertoire of sensory receptors in Balanus improvisus cyprid antennules with the goal to better understand sensory systems involved in the settling behavior of this species. We carried out transcriptome sequencing of dissected B. improvisus cyprid antennules. The generated transcriptome assembly was used to search for sensory receptors using HMM models. Among potential chemosensory genes, we identified the ionotropic receptors IR25a, IR8a and IR93a, and several divergent IR candidates to be expressed in the cyprid antennules. We found one gustatory-like receptor but no odorant receptors, chemosensory or odorant-binding proteins. Apart from chemosensory receptors, we also identified 13 potential mechanosensory genes represented by several transient receptor potential channels (TRP) subfamilies. Furthermore, we analyzed changes in expression profiles of IRs and TRPs during the B. improvisus settling process. Several of the sensory genes were differentially expressed during the course of larval settlement. This study gives expanded knowledge about the sensory systems present in barnacles, a taxonomic group for which only limited information about receptors is currently available. It furthermore serves as a starting point for more in depth studies of how sensory signaling affects settling behavior in barnacles with implications for preventing biofouling.


Impact of early biliary complications on long-term outcomes in adult-to-adult living donor liver transplant recipients.
An adult-to-adult living donor liver transplant (LDLT) has emerged as a possible option to help alleviate the organ shortage. The aim of this study was to analyze our experience with biliary complications in LDLT recipients and to identify their risk factors for biliary complications. This paper aimed to describe therapeutic interventions and to evaluate the impact of biliary complications on long-term patient and graft survival rates. We evaluated biliary complications in a cohort of 120 LDLT recipients at a single institution and studied the impact on long-term graft and patient survival. Of the 120 recipients, 26 (21.7%) developed biliary complications. Endoscopy was the initial choice of treatment for recipients with biliary complications. The median time for resolution of bile leaks was 37 days; for resolution of strictures, 82 days. A decreased risk of biliary complications was associated with an interrupted duct-to-duct (versus continuous choledocho-choledochostomy) (hazard ratio [HR]=0.22, P=0.002) and a Roux-en-Y hepaticojejunostomy (HR=0.13, P<0.001). In multivariate analysis of factors associated with graft failure and patient mortality, biliary complications were unrelated to long term (3 and 5 years) graft failure or patient mortality. In our study LDLT recipients had a 21.7% incidence of biliary complications, however, with successful endoscopic techniques, long-term patient and graft survival rates were not negatively affected.


Knowledge of Iraqi primary health care physicians about breastfeeding.
A questionnaire survey was conducted on 50 primary health care physicians in Ramadi city, Iraq, in 2001 to assess their knowledge and identify misperceptions about breastfeeding. Basic knowledge about the main processes of breastfeeding was good (when to start feeding, frequency of feeding, relactation, importance of psychological factors), but there were deficiencies in their ability to deal with some practical problems related to breastfeeding. Only 64% would advise continuation of breastfeeding when a lactating mother discovers that she is pregnant, 38% of them thought a mother's ability to breastfeed was related to breast size and only 66% knew when to start feeding after caesarean section. Steps for improving the knowledge and training are addressed.


Regulation of the epithelial to mesenchymal transition and metastasis by Raf kinase inhibitory protein-dependent Notch1 activity.
Raf kinase inhibitory protein (RKIP), an endogenous inhibitor of the extracellular signal-regulated kinase (ERK) pathway, has been implicated as a suppressor of metastasis and a prognostic marker in cancers. However, how RKIP acts as a suppressor during metastasis is not fully understood. Here, we show that RKIP activity in cervical and stomach cancer is inversely correlated with endogenous levels of the Notch1 intracellular domain (NICD), which stimulates the epithelial to mesenchymal transition (EMT) and metastasis. The levels of RKIP were significantly decreased in tumor tissues compared to normal tissues, whereas NICD levels were increased. Overexpression of RKIP in several cell lines resulted in a dramatic decrease of NICD and subsequent inhibition of several mesenchymal markers, such as vimentin, N-cadherin, and Snail. In contrast, knockdown of RKIP exhibited opposite results both in vitro and in vivo using mouse models. Nevertheless, knockdown of Notch1 in cancer cells had no effect on the expression of RKIP, suggesting that RKIP is likely an upstream regulator of the Notch1 pathway. We also found that RKIP directly interacts with Notch1 but has no influence on the intracellular level of the γ-secretase complex that is necessary for Notch1 activation. These data suggest that RKIP plays a distinct role in activation of Notch1 during EMT and metastasis, providing a new target for cancer treatment.


[The pharmacokinetics of the marker preparations antipyrine and sulfadimezine in children suffering from bronchial asthma].
The pharmacokinetics of marker drugs antipyrine (phenazone) and sulfadimezine (sulfadimidine) was studied in 50 children with bronchial asthma and preasthmatic diseases and 6 healthy children. A decrease of antipyrine elimination rate in the patients depending on the severity, duration and phase of the disease was revealed. The specific character of xenobiotic detoxication in sick children confirms the dissociation of the functioning of the enzymatic systems of microsomal oxidation and acetylation. The necessity of the pharmacological control in bronchial asthma in children is discussed.


Plasma Omega-3 Fatty Acids and Risk for Incident Dementia in the UK Biobank Study: A Closer Look.
Dietary omega-3 fatty acids are promising nutrients in dementia. Several prospective cohort studies have examined the relationships between circulating omega-3 (an objective biomarker of dietary intake) and incident dementia, the largest to date being a report from the UK Biobank (n = 102,722). Given the recent release of new metabolomics data from baseline samples from the UK Biobank, we re-examined the association in a much larger sample (n = 267,312) and also focused on associations with total omega-3, docosahexaenoic acid (DHA), and non-DHA omega-3. Using Cox regression models, we observed that the total omega-3 status was inversely related to the risk of Alzheimer's (Q5 vs. Q1, hazard ratio [95% confidence interval] = 0.87 [0.76; 1.00]) and all-cause dementia (Q5 vs. Q1, 0.79 [0.72; 0.87]). The strongest associations were observed for total omega-3 (and non-DHA omega-3) and all-cause dementia. In prespecified strata, we found stronger associations in men, and in those aged ≥60 years at baseline (vs. those aged 50-59). Thus, in the largest study to date on this topic, we confirmed the favorable relationships between DHA and risk for dementia, and we also found evidence that non-DHA omega-3 may be beneficial. Finally, we have better defined the populations most likely to benefit from omega-3-based interventions.


HLA-DR is aberrantly expressed at feto-maternal interface in pre-eclampsia.
In normal pregnancy, villous cytotrophoblast and syncytiotrophoblast do not express HLA Class I and Class II molecules, while invasive extravillous trophoblast only express class I HLA-C and the atypical class Ib antigens, HLA-G, -E and -F. Inadequate maternal tolerance of invasive trophoblast has been proposed as a possible immunologic trigger of poor trophoblast invasion and subsequent occurrence of pre-eclampsia. This study aimed to investigate possible aberrant expression of class II HLA-DR on placentae and syncytiotrophoblast-derived extracellular vesicles (STEVs), obtained by dual placental perfusion, from pre-eclampsia (n = 23) and normal pregnant (n = 14) women. Here we demonstrate that HLA-DR can be detected in syncytiotrophoblast from a significant proportion of pre-eclampsia but not control placentae. HLA-DR was also observed, by flow cytometry, on STEVs and associated with placental alkaline phosphatase to validate their placental origin. HLA-DR positive syncytiotrophoblast was detected in placental biopsies from pre-eclampsia but not normal control cases, using immunohistochemistry. The HLA may be fetal or maternal origin. In the latter case a possible mechanism of acquisition is trogocytosis.


Correlation of granulocyte intracellular activities of cyclic nucleotide phosphodiesterases with leukocyte count in patients with chronic myelogenous leukaemia.
The activity of adenosine cyclic 3':5'-monophosphate phosphodiesterase in granulocytes of patients with CML essentially depends on the granulocyte donor's WBC count. The ratio of cAMP-PDE/cGMP-PDE activities in CML granulocytes strongly correlates with CML host WBC count. The regression analysis of cyclic nucleotide phosphodiesterase activities and counts of individual constituents of the white blood cell population present in the blood of CML patients showed the primary relationship between the natural logarithm of total WBC count and the cAMP-PDE/cGMP-PDE activity. The results suggest that the properties of CML granulocytes depend on the accumulation of these cells in the CML host.


Fracture strength of teeth with coronal destruction after core build-up restoration with bulk fill materials.
This study aimed to evaluate the fracture strength and failure modes of different core techniques in teeth with simulated coronal destruction. Forty teeth were endodontically prepared and the specimens were divided into four experimental groups (n = 10) according to the core composition: Filtek One Bulk Fill-FOBF, Filtek Z350 XT-FZ350 (standard group), Filtek Bulk Fill Flow-FBFF, and LuxaCore Z-LCZ. CAD/CAM Monolithic zirconia crowns were obtained and cemented with RelyX U200. After storage in distilled water at 37°C for 48 h, the specimens were subjected to thermal cycling and to compressive strength mechanical tests. Statistical analyses (α = 0.05) were performed by non-parametric Kruskal-Wallis, Dunn post hoc, and Fisher's exact tests. No significant differences (p > 0.05) were observed among FOBF, FZ350, and FBFF (mean ranks = 20.30, 12.20, and 23.20, respectively). LCZ (mean rank = 26.30) produced results similar to those of FOBF and FBFF (p > 0.05) and higher than those of FZ350 (p = 0.042). The most frequent type of failure was irreparable, regardless of the experimental condition. The lowest percentages of reparable fractures were produced by FOBF group (10%). The use of bulk fill materials, including the "core-and-post" LCZ dual-cure resin composite, did not impair the fracture strength of endodontically treated teeth with coronal destruction. Resin composite bulk fill materials that can be used as a core-and-post cementation in an only stage are interesting, since they enable clinicians to work with one only material, and avoid several materials interfaces, technical sensitivity, and longer chair-time due to multistep procedures.


Towards a handheld probe based on optical coherence tomography for minimally invasive spine surgeries.
Minimally invasive surgical (MIS) techniques for the correction of scoliosis are under development. The installation of fusionless implants targeting the vertebral growth plate requires precise identification of spinal micro-structures. During ex vivo studies, we demonstrate that optical coherence tomography (OCT) allows visualization of spinal tissues including the growth plate, the intervertebral disc and the vertebral body. This study aims at designing a handheld probe using OCT and assessing its potential for use in MIS. An OCT handheld probe was built which satisfies criteria for resolution, penetration and field of view required for spinal MIS techniques. Ex vivo images of rat tail and porcine vertebrae enabled differentiating musculoskeletal tissues of the spine (growth plate, intervertebral disc and vertebral body). Pending in vivo studies on porcine models, we evaluated the probe on a human finger and demonstrated its ability to image human tissues at video rate (25 fps) with proper imaging depth and resolution. These preliminary results showed the potential of the OCT probe for dynamic and precise imaging of spinal tissues.


Quantitative measurements of proton motive force and motility in Bacillus subtilis.
The protein motive force of metabolizing Bacillus subtilis cells was only slightly affected by changes in the external pH between 5 and 8, although the electrical component and the chemical component of the proton motive force contributed differently at different external pH. The electrical component of the proton motive force was very small at pH 5, and the chemical component was almost negligible at pH 7.5. At external pH values between 6 and 7.7, swimming speed of the cells stayed constant. Thus, either the electrical component or the chemical component of the proton motive force could drive the flagellar motor. When the proton motive force of valinomycin-treated cells was quantitatively decreased by increasing the external K+ concentration, the swimming speed of the cells changed in a unique way: the swimming speed was not affected until about--100 mV, then decreased linearly with further decrease in the proton motive force, and was almost zero at about--30 mV. The rotation rate of a flagellum, measured by a tethered cell, showed essentially the same characteristics. Thus, there are a threshold proton motive force and a saturating proton motive force for the rotation of the B. subtilis flagellar motor.


Isolation and characterization of a human collagen alpha 1(I)-like gene from a cosmid library.
We have isolated a human collagen alpha 1(I)-like gene from a cosmid library. The clone which contains 37kb of human DNA has been shown to contain this gene by DNA sequencing, hybrid arrest and hybrid selection assays and Northern blot hybridizations. The collagen gene sequence extends through most of the cloned DNA and must, therefore, be at least 35kb in length.


Unexpected and widespread connections between bacterial glycogen and trehalose metabolism.
Glycogen, a large α-glucan, is a ubiquitous energy storage molecule among bacteria, and its biosynthesis by the classical GlgC-GlgA pathway and its degradation have long been well understood - or so we thought. A second pathway of α-glucan synthesis, the four-step GlgE pathway, was recently discovered in mycobacteria. It requires trehalose as a precursor, and has been genetically validated as a novel anti-tuberculosis drug target. The ability to convert glycogen into trehalose was already known, so the GlgE pathway provides a complementary way of cycling these two metabolites. As well as containing cytosolic storage glycogen, mycobacteria possess an outer capsule containing a glycogen-like α-glucan that is implicated in immune system evasion, so the GlgE pathway might be linked to capsular α-glucan biosynthesis. Another pathway (the Rv3032 pathway) for α-glucan biosynthesis in mycobacteria generates a methylglucose lipopolysaccharide thought to be associated with fatty acid metabolism. A comparative genomic analysis was carried out to evaluate the occurrence and role of the classical pathway, the new GlgE pathway and the Rv3032 pathway across bacteria occupying very different ecological niches. The GlgE pathway is represented in 14 % of sequenced genomes from diverse bacteria (about half as common as the classical pathway), while the Rv3032 pathway is restricted with few exceptions to mycobacteria, and the GlgB branching enzyme, usually presumed to be associated with the classical pathway, correlates more strongly with the new GlgE pathway. The microbiological implications of recent discoveries in the light of the comparative genomic analysis are discussed.


Roles of Chromatin Remodelling and Molecular Heterogeneity in Therapy Resistance in Glioblastoma.
Cancer stem cells (CSCs) represent a therapy-resistant reservoir in glioblastoma (GBM). It is now becoming clear that epigenetic and chromatin remodelling programs link the stemlike behaviour of CSCs to their treatment resistance. New evidence indicates that the epigenome of GBM cells is shaped by intrinsic and extrinsic factors, including their genetic makeup, their interactions and communication with other neoplastic and non-neoplastic cells, including immune cells, and their metabolic niche. In this review, we explore how all these factors contribute to epigenomic heterogeneity in a tumour and the selection of therapy-resistant cells. Lastly, we discuss current and emerging experimental platforms aimed at precisely understanding the epigenetic mechanisms of therapy resistance that ultimately lead to tumour relapse. Given the growing arsenal of drugs that target epigenetic enzymes, our review addresses promising preclinical and clinical applications of epidrugs to treat GBM, and possible mechanisms of resistance that need to be overcome.


Development and application of the human intestinal tract chip, a phylogenetic microarray: analysis of universally conserved phylotypes in the abundant microbiota of young and elderly adults.
In this paper we present the in silico assessment of the diversity of variable regions of the small subunit ribosomal RNA (SSU rRNA) gene based on an ecosystem-specific curated database, describe a probe design procedure based on two hypervariable regions with minimal redundancy and test the potential of such probe design strategy for the design of a flexible microarray platform. This resulted in the development and application of a phylogenetic microarray for studying the human gastrointestinal microbiota--referred as the human intestinal tract chip (HITChip). Over 4800 dedicated tiling oligonucleotide probes were designed based on two hypervariable regions of the SSU rRNA gene of 1140 unique microbial phylotypes (< 98% identity) following analysis of over 16,000 human intestinal SSU rRNA sequences. These HITChip probes were hybridized to a diverse set of human intestinal samples and SSU rRNA clones to validate its fingerprinting and quantification potential. Excellent reproducibility (median Pearson's correlation of 0.99) was obtained following hybridization with T7 polymerase transcripts generated in vitro from SSU rRNA gene amplicons. A linear dose-response was observed with artificial mixtures of 40 different representative amplicons with relative abundances as low as 0.1% of total microbiota. Analysis of three consecutively collected faecal samples from ten individuals (five young and five elderly adults) revealed temporal dynamics and confirmed that the adult intestinal microbiota is an individual-specific and relatively stable ecosystem. Further analysis of the stable part allowed for the identification of a universal microbiota core at the approximate genus level (90% sequence similarity). This core consists of members of Actinobacteria, Bacteroidetes and Firmicutes. Used as a phylogenetic fingerprinting tool with the possibility for relative quantification, the HITChip has the potential to bridge the gaps in our knowledge in the quantitative and qualitative description of the human gastrointestinal microbiota composition.


[The clinical efficacy of the calcium antagonist amlodipine in patients with ischemic heart disease and arterial hypertension].
Overall, eighteen male patients with ischemic heart disease (IHD) and functional class II and III angina concurrent with stage II hypertensive disease were studied for clinical effectiveness of amlodipine (Norvasc), a new calcium antagonist, versus nifedipine and placebo. It has been ascertained that amlodipine (10 mg/day) had a significant antianginal and anti-ischemic effect and antihypertensive activity throughout 24 hours as well whereas nifedipine was effective for 6 to 8 hours. Amlodipine did not affect the well-being of the examined patients.


Zinc finger and BTB domain-containing protein 3 is essential for the growth of cancer cells.
ZBTB3 belongs to the Zinc finger and BTB/POZ domain containing transcription factor family; however, its biological role has rarely been studied. We demonstrate for the first time, to our knowledge, that ZBTB3 is an essential factor for cancer cell growth via the regulation of the ROS detoxification pathway. Suppression of ZBTB3 using two different short hairpin RNAs in human melanoma, lung carcinoma, and breast carcinoma results in diminished cell growth. In addition, we found that suppression of ZBTB3 activates a caspase cascade, including caspase-9, -3, and PARP leading to cellular apoptosis, resulting from failed ROS detoxification. We identified that ZBTB3 plays an important role in the gene expression of ROS detoxification enzymes. Our results reveal that ZBTB3 may play a critical role in cancer cell growth via the ROS detoxification system. Therefore, therapeutic strategies that target ZBTB3 could be used in selective cancer treatments.


Hemophagocytic syndrome in patients with unexplained cytopenia: report of 15 cases.
To investigate the frequency of hemophagocytic syndrome in a series of patients with otherwise unexplained cytopenia. In this cross-sectional, single-centre study, bone marrow specimens (n=288) were obtained from the patients with unexplained cytopenia. The diagnosis of hemophagocytic syndrome was made according to universally accepted criteria. Characteristics of the patients, as well as the clinical and laboratory findings were reported. Fifteen cases (5.2%) fulfilled the hemophagocytic syndrome criteria, including 8 males (53.3%) and 7 females (46.7%) with a mean age of 39.7±20.7 (range: 14-72) years at the time of diagnosis. The main clinical and laboratory findings were cytopenia (100%), fever (73.3%), hyperferritinemia (66.7%), elevated erythrocyte sedimentation rate (60%), hypertriglyceridemia (60%), organomegaly (53.3%), elevated liver enzymes (53.3%), lymphadenopathy (26.7%), neurological symptoms (20%), and skin rash (13.3%). Two patients (13.3%) died before a diagnosis was made. Our findings indicate that the hemophagocytic syndrome is not a rare pathologic condition in patients with otherwise unexplained cytopenia. Without treatment, the mortality rate may be high.


New antibody and immunoassay pretreatment strategy to screen polychlorinated biphenyls in Korean transformer oil.
Development and modifications are described that expand the application of an immunoassay from the detection of Kanechlors (Japanese technical PCBs mixtures) to the detection of Aroclors (U. S. technical PCB mixtures, used in Korea) in contaminated Korean transformer oil. The first necessary modification was the development of a new antibody with a reactivity profile favorable for Aroclors. The second modification was the addition of a second column to the solid-phase extraction method to reduce assay interference caused by the Korean oil matrix. The matrix interference is suspected to be caused by the presence of synthetic oils (or similar materials) present as contaminants. The modified assay was validated by comparison to high-resolution gas chromatography/high-resolution mass spectrometry analysis, and was shown to be tolerant of up to 10% of several common synthetic insulating oils. Finally the screening performance of the modified assay was evaluated using 500 used transformer oil samples of Korean origin, and was shown to have good performance in terms of false positive and false negative rates. This report provides evidence for the first establishment of immunoassay screening for Aroclor based PCB contamination in Korean transformer oil.


[Clinical implications of epigenetic changes].
Inherited and acquired changes in DNA can influence the coding for gene products (proteins). When the function of a protein is disturbed, this may lead to disease. DNA in chromatin can be condensed or be arranged in an open structure. The activity of genes is significantly affected by the accessibility to DNA by transcription factors and other proteins involved in the transcription of genes. The accessibility of DNA is regulated by epigenetic processes, including methylation of cytosine. In these circumstances the nucleic sequence of the DNA does not change. Nevertheless, disturbances of these processes can also culminate in disease. Epigenetic changes to DNA are reversible. This offers opportunities for treatment and recovery in conditions that are a result of disturbed epigenetic processes.


Calibration of a Dust Scattering Instrument Using Tomographic Techniques and Its Application to a Dust Sensor Instrument.
The characterization of suspended dust near the Martian surface is extremely relevant to understand the climate of Mars. In this frame, a Dust Sensor instrument, an infrared device designed to obtain the effective parameters of Martian dust using the scattering properties of the dust particles, was developed. The purpose of this article is to present a novel methodology to calculate, from experimental data, an instrumental function of the Dust Sensor that allows solving the direct problem and providing the signal that this instrument would provide given a distribution of particles. The experimental method is based on recording the signal measured when a Lambertian reflector is gradually introduced into the interaction volume at different distances from the detector and source and applying tomography techniques (inverse Radon transform) to obtain the image of a section of the interaction volume. This method provides a complete mapping of the interaction volume experimentally, which determines the Wf function. The method was applied to solve a specific case study. Among the advantages of this method, it should be noted that it avoids assumptions and idealizations of the dimensions of the volume of interaction and reduces the time required to carry out simulations.


Prevalence of methicillin-resistant Staphylococcus aureus among veterinarians: an international study.
Pig farmers and veterinarians in contact with livestock in The Netherlands have a higher risk of methicillin-resistant Staphylococcus aureus (MRSA) carriage than the general population. The objective of this study was to investigate whether this is also true for other professionals in contact with pigs in an international setting. A convenience sample of 272 participants at an international conference on pig health in Denmark was screened for MRSA carriage using combined nose/throat swabs and were asked to complete a questionnaire concerning animal contacts, exposure to known MRSA risk-factors, and the protective measures taken when entering pig farms. In total, 34 (12.5%) participants from nine countries carried MRSA. Thirty-one of these isolates were non-typeable by pulsed-field gel electrophoresis following SmaI digestion of chromosomal DNA. All of the non-typeable isolates belonged to spa types (t011, t034, t108, t571, t567 and t899) that correspond to multilocus sequence type 398. All of the above-mentioned spa types, with the exception of t899, have been isolated previously from either Dutch pigs, pig farmers and/or veterinarians. Protective measures, e.g., masks, gowns and gloves, did not protect against MRSA acquisition. Transmission of MRSA from pigs to staff tending to these animals appears to be an international problem, creating a new reservoir for community-acquired MRSA (CA-MRSA) in humans in Europe, and possibly worldwide. The rise of a new zoonotic source of MRSA could have a severe impact on the epidemiology of CA-MRSA, and may have consequences for the control of MRSA, especially in those countries that maintain a low prevalence by means of search-and-destroy policies.


Nonalcoholic steatohepatitis recurrence after liver transplant.
Nonalcoholic steatohepatitis (NASH) is the fastest growing indication for liver transplant (LT)worldwide and is deemed to be the foremost indication in the near future. Recurrence of NASH can occur post LT and has been observed to be a common phenomenon. Baseline metabolic co-morbidities and worsening of metabolic profile post LT are the principal drivers of NASH recurrence. Liver biopsy remains the gold standard for establishing the diagnosis. However, noninvasive methods including transient elastography (TE) and magnetic resonance imaging (MRI) seem to be promising. The implications of recurrent NASH on post LT outcomes, graft steatosis, progression to fibrosis, overall survival, and cardiovascular associations warrant careful evaluation. Control of metabolic parameters and weight gain along with tailored immunosuppression remain the cornerstone of management. Extrapolation of the ever-increasing armamentarium of NASH pharmacotherapy specifically in this population of recurrent NAFLD remains a challenge for the future.


Determination of fenpyroximate in apples by supercritical fluid extraction and packed capillary liquid chromatography with UV detection.
A method using off-line supercritical fluid extraction (SFE) and micro liquid chromatography (microLC) with UV detection at 260 nm, was developed for selective determination of fenpyroximate in apple samples. The packed capillary liquid chromatography method utilises 20 microl injection volumes with on-column focusing. A 350x0.32 mm capillary column packed with Kromasil 100-C18 of 5 microm particle size was used with a mobile phase of acetonitrile-10 mM ammonium acetate (85:15, v/v) at a flow of 5 microl/min. A two-step SFE procedure was used to extract fenpyroximate selectively in 2 g apple samples, with Hydromatrix (HMX) added as a water absorbent at a 1:1 (w:w) ratio. Fenpyroximate was extracted at 200 bar and 90 degrees C for 15 min using carbon dioxide at a flow of 2 ml/min, and solvent trapping collection in 10 ml acetonitrile. The volume of the acetonitrile extract was reduced by evaporation and water was added to a final composition of acetonitrile-water (40:60, v/v). The resulting 2.0 ml solution was filtered using a 0.45 microm poly(vinylidene difluoride) syringe filter before microLC analysis. Validation of the method was accomplished with apple samples spiked with fenpyroximate, covering the range of 0.1 to 1.0 microg/kg. The within-day and between-day repeatabilities were in the range 4-18% relative standard deviation. Accuracy, measured as recovery, was found to be approximately 60%. Apple samples from a field treated with fenpyroximate were analysed. None of the samples contained fenpyroximate above the quantification level.


Efferocytosis-induced lactate enables the proliferation of pro-resolving macrophages to mediate tissue repair.
The clearance of apoptotic cells by macrophages (efferocytosis) prevents necrosis and inflammation and activates pro-resolving pathways, including continual efferocytosis. A key resolution process in vivo is efferocytosis-induced macrophage proliferation (EIMP), in which apoptotic cell-derived nucleotides trigger Myc-mediated proliferation of pro-resolving macrophages. Here we show that EIMP requires a second input that is integrated with cellular metabolism, notably efferocytosis-induced lactate production. Lactate signalling via GPR132 promotes Myc protein stabilization and subsequent macrophage proliferation. This mechanism is validated in vivo using a mouse model of dexamethasone-induced thymocyte apoptosis, which elevates apoptotic cell burden and requires efferocytosis to prevent inflammation and necrosis. Thus, EIMP, a key process in tissue resolution, requires inputs from two independent processes: a signalling pathway induced by apoptotic cell-derived nucleotides and a cellular metabolism pathway involving lactate production. These findings illustrate how seemingly distinct pathways in efferocytosing macrophages are integrated to carry out a key process in tissue resolution.


Improving outcomes in single chamber leadless pacemakers: strategies for minimizing vascular complications.
Leadless pacemaker therapy is associated with a significant reduction in lead-related complication rate compared to conventional transvenous single chamber pacemaker therapy. However, a significant complication rate of 1.2% was observed in vascular access due to the use of large delivery femoral sheath (27Fr). The aim of this study was to evaluate the effectiveness of real-time ultrasound guidance and Z suture technique in reducing total and major vascular complications in leadless pacemaker therapy. In this study, we performed a retrospective and prospective analysis of all adverse events associated with leadless pacemaker (Micra) implantation by two operators at a single tertiary center from December 2016 to December 2018. To mitigate the risk of vascular complications, all patients underwent real-time ultrasound-guided venipuncture for vascular access, as well as the application of a Z-suture technique for hemostasis at the end of the procedure. Data were collected on implant indications, implant procedure details, complications, and follow-up information. In this study, 45 patients with an age range of 24 to 94 years (mean 76 ± 14 years) were recruited, with 21 (46.6%) being female. The pacing indications for the patients included atrial fibrillation (24, 53.3%), vascular (7, 15.5%), infection (9, 20%), cognitive/frailty (3, 6.6%), and occupational (2, 4.4%). The implant procedures were performed under general anesthesia in 6 (13.3%) of the cases, and under local anesthesia and sedation in 39 (86.6%) of the cases. A single deployment was achieved in 43 (95.5%) of the patients, while 2 deployments were required in 2 (4.4%) of the patients. Notably, no vascular or major complications were reported in our cohort of patients. The results of this observational study indicate that incorporating real-time ultrasound guidance during venipuncture and the use of a Z-suture technique significantly reduce the occurrence of both total and major vascular complications associated with the implantation of leadless pacemaker. However, more robust and larger studies are required in order to confirm these results and implications for clinical practice.


Sequence changes in the ton box region of BtuB affect its transport activities and interaction with TonB protein.
Uptake of cobalamins by the transporter protein BtuB in the outer membrane of Escherichia coli requires the proton motive force and the transperiplasmic protein TonB. The Ton box sequence near the amino terminus of BtuB is conserved among all TonB-dependent transporters and is the only known site of mutations that confer a transport-defective phenotype which can be suppressed by certain substitutions at residue 160 in TonB. The crystallographic structures of the TonB-dependent transporter FhuA revealed that the region near the Ton box, which itself was not resolved, is exposed to the periplasmic space and undergoes an extensive shift in position upon binding of substrate. Site-directed disulfide bonding in intact cells has been used to show that the Ton box of BtuB and residues around position 160 of TonB approach each other in a highly oriented and specific manner to form BtuB-TonB heterodimers that are stimulated by the presence of transport substrate. Here, replacement of Ton box residues with proline or cysteine revealed that residue side chain recognition is not important for function, although replacement with proline at four of the seven Ton box positions impaired cobalamin transport. The defect in cobalamin utilization resulting from the L8P substitution was suppressed by cysteine substitutions in adjacent residues in BtuB or in TonB. This suppression did not restore active transport of cobalamins but may allow each transporter to function at most once. The uncoupled proline substitutions in BtuB markedly affected the pattern of disulfide bonding to TonB, both increasing the extent of cross-linking and shifting the pairs of residues that can be joined. Cross-linking of BtuB and TonB in the presence of the BtuB V10P substitution became independent of the presence of substrate, indicating an additional distortion of the exposure of the Ton box in the periplasmic space. TonB action thus requires a specific orientation for functional contact with the Ton box, and changes in the conformation of this region block transport by preventing substrate release and repeated transport cycles.