Antiendothelial αvβ3 Antibodies Are a Major Cause of Intracranial Bleeding in Fetal/Neonatal Alloimmune Thrombocytopenia.
Fetal/neonatal alloimmune thrombocytopenia is a severe bleeding disorder, which can result in intracranial hemorrhage (ICH), leading to death or neurological sequelae. In whites, maternal anti-human platelet antigen-1a (HPA-1a) antibodies are responsible for the majority of cases. No predictive factors for ICH are available to guide prophylactic treatment during pregnancy. In this study, we investigated antibodies from mothers with ICH-positive fetal/neonatal alloimmune thrombocytopenia and with ICH-negative fetal/neonatal alloimmune thrombocytopenia to identify serological and functional differences between the groups. In an antigen capture assay, we observed a stronger binding of +ICH antibodies to endothelial cell (EC)-derived αvβ3. By absorption experiments, we subsequently identified anti-HPA-1a antibodies of anti-αvβ3 specificity in the +ICH but not in the -ICH cohort. Only the anti-αvβ3 subtype, but not the anti-β3 subtype, induced EC apoptosis of HPA-1a-positive ECs by caspase-3/7 activation, and mediated by reactive oxygen species. In addition, only the anti-αvβ3 subtype, but not the anti-β3 subtype, interfered with EC adhesion to vitronectin and with EC tube formation. We conclude that the composition of the anti-HPA-1a antibody subtype(s) of the mother may determine whether ICH occurs. Analysis of anti-HPA-1a antibodies of the anti-αvβ3 subtype in maternal serum has potential in the diagnostic prediction of ICH development and may allow for modification of prophylactic treatment in fetal/neonatal alloimmune thrombocytopenia.


[Follow-up management of recently operated capsule and ligament injuries of the knee joint].
The guidelines for the treatment of ligament injuries of the knee joint are subject to continuous changes due to new experiences in the field of functional anatomy and pathophysiology, as well as to the progressive changes in surgical treatment. The authors suggest answers to the questions of immobilisation, appropriate support, mobilisation, etc., questions which as yet have no final and binding solutions. They also discuss the problems of muscle atrophy and the time at which sportive activities of varying strains may be taken up again.


Interactions between Nutrition and the "Ram Effect" in the Control of Ovarian Function in the Merino Ewe.
We tested whether short-term nutritional supplementation (500 g lupin grain per head daily) would affect the response of ewes to the ram effect. Experiment 1 (end of non-breeding season): ewes were supplemented for either Days -6 to -1 relative to ram introduction (n = 24) or for 12 days after ram introduction (Days 11 to 22 of the ram-induced cycle; n = 29). Controls (n = 30) were not supplemented. Across all groups, 94-100% of ewes ovulated. Supplementation before ram introduction did not affect ovulation rate at the ram-induced ovulation but increased it during the ram-induced cycle (Control 1.37; supplemented 1.66; p < 0.05). Experiment 2 (the middle of non-breeding season): the supplement was fed for Days -5 to -1 relative to ram introduction. Again, supplementation did not increase number ovulating (Control 16/29; Supplemented 10/29) but it did increase ovulation rate at the ram-induced ovulation (Control 1.31; Supplemented 1.68; p < 0.05). In neither experiment did supplementation affect the frequency of short cycles. Supplementation before ram introduction did not improve the percentage of ewes ovulating or reduce the frequency of short cycles (so will not improve the synchrony of lambing). However, supplementation after ram introduction can increase prolificacy.


A novel pathogenic frameshift variant in AXIN2 in a man with polyposis and hypodontia.
WNT signaling is pivotal in embryogenesis and tissue homeostasis. Aberrant WNT signaling, due to mutations in components of this pathway, contributes to the development and progression of human cancers, including colorectal cancer. AXIN2, encoded by the AXIN2 gene, is a key negative regulator and target of the canonical WNT signaling pathway. Germline mutations in AXIN2 are associated with absence of permanent teeth (hypo- and oligodontia) and predisposition to gastrointestinal polyps and cancer. The limited number of patients makes an accurate genotype-phenotype analysis currently challenging. We present the case of a 55-year-old male with colorectal polyposis and hypodontia. Genetic testing confirmed a novel frameshift germline mutation in exon 8 of the AXIN2 gene. In addition, we provide an updated overview of germline AXIN2 mutations reported in literature. Although the number of missing teeth is less severe in our patient than in some previously reported cases, our findings provide additional evidence that missing teeth and gastrointestinal neoplasia are associated with rare pathogenic AXIN2 germline mutations.


Comparison of Different Thawing Protocols in Human Cryopreserved Venous Grafts.
The aim of our study was to assess the impact of different thawing protocols on morphological changes arising in cryopreserved human saphenous vein grafts. The study was performed in 12 saphenous vein grafts harvested in brain death donors. Storage in the vapor phase of liquid nitrogen for 3 or 5 years followed. Two thawing protocols were tested: slow thawing in a refrigerator at temperature +4°C for 2 hr and rapid thawing-in a water bath at +37°C. Grafts were processed for scanning electron microscopy. Comparisons of continuous parameters under study between experimental groups were performed using the t-test (age, cold ischemia time, exposure to cryoprotectant, time of storage, total thawing time, mean thawing rate, morphology scoring of thawed HSVG) and the median test (HSVG length). Categorical parameters (sex and blood group) were formally tested using the chi-square test. All samples were evaluated according to morphological changes and scored in terms of morphologically intact endothelium, confluent endothelium with structural inhomogeneity, disruption of the intercellular contacts, separation of the endothelial cells, complete loss of the endothelium, and damage of the subendothelial layers. There is no statistically significant difference between the sample sets at the significance level of 0.05. There was no association with donors' age, sex, and time of storage. Human cryopreserved saphenous vein grafts in our experimental work showed no difference in terms of structural deterioration of the endothelial surface and basal membrane depending on different thawing protocols used.


Development of a dynamic deformable thorax phantom for the quality management of deformable image registration.
The purpose of this study was to develop a novel dynamic deformable thorax phantom for deformable image registration (DIR) quality assurance (QA) and to verify as a tool for commissioning and DIR QA. The phantom consists of a base phantom, an inner phantom, and a motor-derived piston. The base phantom is an acrylic cylinder phantom with a diameter of 180 mm. The inner phantom consists of deformable, 20 mm thick disk-shaped sponges. To evaluate the physical characteristics of the phantom, we evaluated its image quality and deformation. DIR accuracies were evaluated using the three types of commercially DIR software (MIM, RayStation, and Velocity AI) to test the feasibility of this phantom. We used different DIR parameters to test the impact of parameters on DIR accuracy in various phantom settings. To evaluate DIR accuracy, a target registration error (TRE) was calculated using the anatomical landmark points. The three locations (i.e., distal, middle, and proximal positions) had different displacement amounts. This result indicated that the inner phantom was not moved but deformed. In cases with different phantom settings and marker settings, the ranges of the average TRE were 0.63-15.60 mm (MIM). In cases with different DIR parameters settings, the ranges of the average TRE were as follows: 0.73-7.10 mm (MIM), 8.25-8.66 mm (RayStation), and 8.26-8.43 mm (Velocity). These results suggest that our phantom could evaluate the detailed DIR behaviors with TRE. Therefore, this is indicative of the potential usefulness of our phantom in DIR commissioning and QA.


Differential aversive outcome expectancies for high- and low-predation fear-relevant animals.
There is now considerable evidence that phobic responding is associated with a bias towards expecting aversive or traumatic outcomes following encounters with the phobic stimulus (e.g. Behavioural Brain Sci. 18 (1995) 289-325; Phobias: A Handbook of Theory, Research and Treatment. Wiley, Chichester, 1997). In terms of conditioning contingencies, this can be described as a bias towards expecting an aversive unconditioned stimulus (UCS) following a phobic conditioned stimulus (CS). The disease-avoidance model of animal fears (Anxiety Res. 4 (1992a) 314; Matchett and Davey, 1991) suggests that common animal fears may be mediated by at least two kinds of selective associations: (1) a bias towards expecting physically harmful consequences associated with predatory animals, and (2) a bias towards expecting disgust or disease-relevant consequences associated with animals that are fear-relevant (FR) but normally physically harmless. The present study investigated this model of selective associations by comparing the UCS expectations elicited by high-predation FR, low-predation FR and safe (fear-irrelevant) animals. The results indicate that high-predation animals are selectively associated with a pain relevant UCS, whilst low-predation animals are selectively associated with a disgust-relevant UCS. Safe animals were not strongly associated with either class of UCS. These findings provide evidence for a possible associative mechanism by which changes in nonspecific levels of disgust sensitivity may directly affect levels of fear to low-predation FR animals.


Identification of dementia and MCI cases in health information systems: An Italian validation study.
The identification of dementia cases through routinely collected health data represents an easily accessible and inexpensive method to estimate the prevalence of dementia. In Italy, a project aimed at the validation of an algorithm was conducted. The project included cases (patients with dementia or mild cognitive impairment [MCI]) recruited in centers for cognitive disorders and dementias and controls recruited in outpatient units of geriatrics and neurology. The algorithm based on pharmaceutical prescriptions, hospital discharge records, residential long-term care records, and information on exemption from health-care co-payment, was applied to the validation population. The main analysis was conducted on 1110 cases and 1114 controls. The sensitivity, specificity, and positive and negative predictive values in discerning cases of dementia were 74.5%, 96.0%, 94.9%, and 79.1%, respectively, whereas in detecting cases of MCI these values were 29.7%, 97.5%, 92.2%, and 58.1%, respectively. The variables associated with misclassification of cases were also identified. This study provided a validated algorithm, based on administrative data, which can be used to identify cases with dementia and, with lower sensitivity, also early onset dementia but not cases with MCI.


Medical teleconferencing with high-definition video presentation on the 'usual' Internet.
Although medical teleconferences on advanced academic networks have been common (Telemed J E Health 15:112-117, 1; Asian J Endosc Surg 3:185-188, 2; Surg Today 41:1579-1581, 3; Telemedicine development center of Asia. http://www.aqua.med.kyushu-u.ac.jp/eg/index.html . Accessed 6 March 2013, 4), reports regarding 'usual' Internet teleconferences or tele-lectures employing a telecommunication system for business use are very rare. Medical teleconferences and tele-lectures on the Internet were held three times between our institutions and other institutions, using the 'HD Com' made by Panasonic (HD Com. http://panasonic.biz/com/visual/ . Accessed 6 March 2013, 5), which is a high-definition telecommunication system for business tele-meeting. All of our medical telecommunications were successfully completed without any troubles. This system allows for all kinds of presentations using personal computers to be made from each station, so that discussions with high-definition surgical video presentation, which has recently been developed, could be effortlessly established despite the distance between institutions. Unlike telecommunication using advanced academic networks, this system can run without any need for specific engineering support, on the usual Internet. Medical telecommunication employing this system is likely to become common among ordinary hospitals in the near future.


Silica nanoparticles mediated insect pest management.
Silicon is known for mitigating the biotic and abiotic stresses of crop plants. Many studies have proved beneficial effects of bulk silicon against biotic stresses in general and insect pests in particular. However, the beneficial effects of silica nanoparticles in crop plants against insect pests were barely studied and reported. By virtue of its physical and chemical nature, silica nanoparticles offer various advantages over bulk silicon sources for its applications in the field of insect pest management. Silica nanoparticles can act as insecticide for killing target insect pest or it can act as a carrier of insecticide molecule for its sustained release. Silica nanoparticles can improve plant resistance to insect pests and also aid in attracting natural enemies via enhanced volatile compounds emission. Silica nanoparticles are safe to use and eco-friendly in nature in comparison to synthetic pesticides. This review provides insights into the applications of silica nanoparticles in insect pest management along with discussion on its synthesis, side effects and future course of action.


[Effect of consumption of alfalfa extract (Medicago sativa) on induced iron deficiency anemia in mice (Mus musculus)].
To determine the effect of alfalfa extract consumption on induced iron deficiency anemia in mice. Thirty M. musculus albino mice of the BALB/c strain were used for this study. All of them were males, with a mean weight of 23±33.7 g. Three groups of 10 mice each were formed: a) negative control group with sufficient iron (HS), which received 40g/d of balanced feed for seven weeks; b) positive control group with iron deficiency (HD), which received 40g/d of a diet plan for anemia for seven weeks; and c) experimental group with iron deficiency (HD), which received 40g/d of a diet plan for anemia for seven weeks and 20g/d of alfalfa extract (EA) from week five. Hemoglobin levels were measured. At the end of the treatment, a significant difference was observed in hemoglobin levels between the positive (8.41±3.9 g/dL) and experimental (13.4±3.3 g/dL) control groups (T student, p<0.05). There was no significant difference in hemoglobin levels at the end of the induction period between the positive (8.76±3.9 g /dL) and experimental (8.59±3.1 g/dL) groups (T student, p>0.05). Under experimental conditions, alfalfa has an antianemic effect based on the results of hemoglobin levels.


A prospective randomized controlled trial comparing plating augmented with coracoclavicular fixation and hook plate fixation of displaced distal-third clavicle fractures.
Two popular methods used to treat distal-third clavicle fractures are the traditional hook plate and the anatomically contoured locking plate. No consensus exists on whether one method is more effective than the other. Therefore, the aim of this study was to compare the efficacy of a traditional hook plate with that of an anatomically contoured locking plate augmented with coracoclavicular fixation in the treatment of distal-third clavicle fractures. Enrolled patients were randomly assigned to either the hook plate group (n = 13) or the locking plate group (n = 17). Follow-up assessments (clinical and radiologic) were performed at 6 and 12 months postoperatively. In both groups, union was achieved in 91% of cases at 6 months and 100% at 12 months. No differences in Disabilities of the Arm, Shoulder and Hand (DASH) and Constant-Murley shoulder scores were noted between the hook plate and locking plate groups at 12 months. From 6 to 12 months, DASH scores improved in the hook plate group (P = .007) and Constant-Murley shoulder scores tended to improve (P = .075). Surgical time was longer in the locking plate group than in the hook plate group (P < .001). Similar functional outcomes and union rates were achieved in both groups at 12 months postoperatively. However, the improvement in DASH scores in the hook plate group from 6 to 12 months suggests that patients treated with an anatomically contoured locking plate make a quicker recovery than patients treated with a hook plate.


[Behaviour of plasma renin activity during long-term treatment with propranolol (author's transl)].
17 patients (40 +/- 9 years) with essential hypertension were included in the study. A monotherapy of 120, 160 or 240 mg propranolol per day was administered orally according to the antihypertensive effect. Four weeks after treatment, blood pressure and heart rate showed a statistically significant decrease and remained unchanged over a period of six months. Plasma renin activity decreased significantly from 5.7 +/- 6.3 ng/ml/h at the beginning of the study to 1.8 +/- 1.3 ng/ml/h after 4 weeks. 5 months later however plasma renin activity increased again to 5.0 +/- 0.9 ng/ml/h. The difference was statistically significant. From 17 patients 7 (41%) had lower levels of plasma renin activity after 6 months treatment when compared with pretreatment values. In only 3 patients (18%) was plasma renin activity lower after 6 months than after four weeks. We conclude that the increase in plasma renin activity is a reactive mechanism to the reduced blood pressure under long-term conditions. The decrease of plasma renin activity in short-term treatment of essential hypertension is not a mechanism responsible for the antihypertensive effect of propranolol during long-term treatment.


Programming correlated magnetic states with gate-controlled moiré geometry.
The ability to control the underlying lattice geometry of a system may enable transitions between emergent quantum ground states. We report in situ gate switching between honeycomb and triangular lattice geometries of an electron many-body Hamiltonian in rhombohedral (R)-stacked molybdenum ditelluride (MoTe2) moiré bilayers, resulting in switchable magnetic exchange interactions. At zero electric field, we observed a correlated ferromagnetic insulator near one hole per moiré unit cell with a widely tunable Curie temperature up to 14 K. Applying an electric field switched the system into a half-filled triangular lattice with antiferromagnetic interactions; further doping this layer-polarized superlattice tuned the antiferromagnetic exchange interaction back to ferromagnetic. Our work demonstrates R-stacked MoTe2 moirés to be a laboratory for engineering correlated states with nontrivial topology.


Boosting thermoelectric efficiency using time-dependent control.
Thermoelectric efficiency is defined as the ratio of power delivered to the load of a device to the rate of heat flow from the source. Till date, it has been studied in presence of thermodynamic constraints set by the Onsager reciprocal relation and the second law of thermodynamics that severely bottleneck the thermoelectric efficiency. In this study, we propose a pathway to bypass these constraints using a time-dependent control and present a theoretical framework to study dynamic thermoelectric transport in the far from equilibrium regime. The presence of a control yields the sought after substantial efficiency enhancement and importantly a significant amount of power supplied by the control is utilised to convert the wasted-heat energy into useful-electric energy. Our findings are robust against nonlinear interactions and suggest that external time-dependent forcing, which can be incorporated with existing devices, provides a beneficial scheme to boost thermoelectric efficiency.


Associations between histogram analysis parameters derived from morphological sequences and histopathological tissue alterations in myositis and other myopathies: a preliminary study.
Magnetic resonance imaging (MRI) is a cornerstone in diagnosis of myopathies. Recently, imaging techniques, such as histogram analysis are used to obtain novel imaging biomarkers. The present study sought to elucidate possible associations between histopathology derived from muscle biopsies and histogram parameters derived from clinical MRI in myositis and other myopathies. 20 patients with myopathies were included in this retrospective study. MRI was performed using a 1.5T MRI scanner including T2- and T1- weighted images. The histogram parameters of the MRI sequences were obtained of the biopsied muscle. The histopathology analysis included the scoring systems proposed by Tateyama et al., Fanin et al., Allenbach et al. and immunohistochemical stainings for MHC-I, CD68, CD8 and CD4. Entropy derived from T2-weighted images showed strong positive associations with the inflammation scores (r=0.71, p=0.0005 with Allenbach et al score and r=0.68, p=0.001 with Tateyama score). Furthermore, there were strong associations between entropy derived from T2-weighted images with MHC-I staining (r=0.67, p=0.022), with the amount of CD20 cells (r=0.70, p=0.022), with the amount of CD4 positive cells (r=0.78, p=0.0075) and with the amount of CD8 positive cells (r=0.79, p=0.004). Other parameters showed no associations with the investigated histopathology features. Entropy derived from T2-weighted images showed strong associaitions with inflammation scores and with the sole amount of immune cells in myopathies. These results need to be confirmed by clinical studies, whether it is also related to clinical performance or can predict treatment response.


High resolution parametric description of slow wave sleep.
We propose a new framework for quantitative analysis of sleep EEG, compatible with the traditional analysis, based upon adaptive time-frequency approximation of signals. Using a high resolution description of EEG rhythms and transients in terms of their time occurrence and width, frequency and amplitude, we present a detailed detection and parameterization of delta waves, including also the time occupied by each delta wave-a parameter inaccessible directly by previously applied signal processing methods. To validate the proposed parameterization, we construct a simple detector of sleep stages 3 and 4, based explicitly upon the classical criteria related to delta waves. To properly compare its performance to the inter-expert agreements and other expert systems, we sort out and discuss the methodology of reporting concordance in this context. Since the proposed parameterization proves to be compatible with the visual analysis of EEG, we can derive new variables for quantitative analysis of EEG patterns recognized for decades. As examples, we present a continuous description of delta waves and sleep spindles in the overnight sleep, and compare results to the traditional FFT-based estimates.


Use of Aloe Vera and Turmeric Paste as a Supplementary Medicine in Oral Submucosal Fibrosis: A Pilot Study.
Oral submucosal fibrosis is the major health issue affecting 2.5 million Indian population under the age of 40 years. All the available treatments give only symptomatic relief which is short lived.The incidence of Oral submucosal fibrosis still rising alarmingly and there is a dire need to search for an effective and safe remedy because of lack of present therapies to either provide a complete cure or treating the patients at the cost of adverse effects. A total of 140 clinically diagnosed patients with Oral submucosal fibrosis (diagnosed on the basis of reduction in interincisal distance on maximum mouth opening and palpable fibrous bands involving oral mucosa) within the age range of 18-50 years with decreased interincisal opening were selected (time period 1.5 year). These patients were given Inj. Triamcinolone (40 mg) and Inj Hyaluronidase every 21 days. Pt was divided in 2 groups (each containing both males and females) those receiving Triamcinolone ointment alone BD (control) and those receiving Triamcinolone ointment BD along with turmeric & aloe vera paste combination (test). A statistically significant improvement was seen in both burning sensation and mouth opening in both males and females. The result of the study shows that the synergistic action of these herbs results in higher efficacy and highly potent Oral submucosal fibrosis treatment.


Cardioprotective effects of 3-phosphoinositide-dependent protein kinase-1 on hypoxic injury in cultured neonatal rat cardiomyocytes and myocardium in a rat myocardial infarct model.
3-Phosphoinositide-dependent protein kinase-1 (PDK1) is involved in numerous cellular responses. In this study, we investigated the protective effects of PDK1 gene expression against hypoxic conditions in cultured rat CMCs (rCMCs) and in a rat myocardial infarction (MI) model using the lentiviral vector (LeV) system. LeV-PDK1 transfer effectively reduced the apoptotic cell death caused by hypoxic injury as compared to LeV-GFP transfer in rCMCs the expression of survival proteins increased in the LeV-PDK1 group, whereas apoptosis signaling decreased in the rCMCs and in infarcted hearts treated with LeV-PDK1. LeV-PDK1 transfer also reduced apoptosis and infarct size and attenuated myocardial wall thinning and ventricular remodeling in a rat MI model. These findings suggest that PDK1 has a protective role in the injured ischemic myocardium via overexpression of the cell survival pathway in CMCs. Hence PDK1 can be used as a treatment strategy for myocardial salvage inin hypoxic injury.


Disintegration rate measurement of a 152Eu solution.
The procedure followed by the Laboratório de Metrologia Nuclear at the IPEN-CNEN/SP, in São Paulo, for the standardization of 152Eu is described. The disintegration rate of 152Eu has been measured using the 4pi beta-gamma coincidence technique, using a 4pi proportional counter, filled with P-10 gas and operated at 0.1 MPa, coupled to one HPGe detector for the gamma-ray emission. Two discrimination windows were set in the gamma-channel, one related to the beta branch (344 keV) and the other related to the electron capture events (1408.03 keV), in order to determine the counting efficiencies for beta, X-ray and Auger electron events in the proportional counter. The activity of solution was determined by a biparametric extrapolation curve obtained for the two selected gamma-windows.


Simultaneous resistance to two or more broad-spectrum anthelmintics by gastrointestinal nematode parasites of sheep and goats.
The detection, by means of faecal egg count reduction tests and larval cultures, of two cases of multiple anthelmintic resistance in goats and two in sheep, is reported. The former cases appeared to involve resistance to all three broad-spectrum drench groups (benzimidazole, levamisole, ivermectin) by mainly Ostertagia spp., the latter resistance to two of them (benzimidazole, levamisole) by Trichostrongylus spp.


Two Cases of Right Atrial Mural Endocarditis Caused by Staphylococcus Aureus.
Mural endocarditis is a rare clinical entity with an extremely high mortality rate. It is usually predisposed by an underlying structural intracardiac abnormality. We present two cases of mural endocarditis occurring in the right atrium which were complicated by septic pulmonary embolism, one of which was predisposed by a jet lesion secondary to a coronary artery fistula. Both cases were successfully managed conservatively with excellent long-term outcomes.


Assessment of Alcohol-Induced Dose Dumping with a Hydrocodone Bitartrate Extended-Release Tablet Formulated with CIMA(®) Abuse Deterrence Technology.
Greater drug content requirements for extended-release (ER) opioids necessitate greater protection against dose dumping. Hydrocodone ER employs the CIMA(®) Abuse-Deterrence Technology platform, which provides resistance against rapid release of the active moiety when the tablet is manipulated or taken with alcohol. Assess effects of alcohol on hydrocodone ER pharmacokinetics. Open-label, crossover (January 25-April 30, 2010). Single center. Forty healthy adults. Subjects received all four treatments in a randomized manner (separated by a minimum 5-day washout): hydrocodone ER 15 mg with 240 mL water and 240 mL orange juice containing 4, 20, and 40% alcohol in a fasted state. Naltrexone was administered to minimize opioid-related adverse events. Effect of alcohol on pharmacokinetics of hydrocodone ER assessed by comparing systemic exposure [maximum plasma drug concentration (Cmax) and area under the plasma drug concentration-versus-time curve from time 0 to infinity (AUC0-∞)] after administration with alcohol or with water. Geometric means ratios of hydrocodone ER with 4, 20, and 40% alcohol relative to water were 1.05, 1.09, and 1.14, respectively, for Cmax and 1.07, 1.13, and 1.17, respectively, for AUC0-∞. All 90% confidence intervals for these geometric means ratios fell within the limits of 0.8 and 1.25. Increasing alcohol concentrations did not notably affect systemic exposure but were associated with increased adverse events. Hydrocodone ER tablets were resistant to dose dumping when administered with alcohol in healthy subjects based on similar systemic exposures observed across all treatments.


Abundance and biomass of heterotrophic flagellates, and factors controlling their abundance and distribution in sediments of Botany Bay.
The abundance and biomass of heterotrophic flagellates were estimated monthly in sediments of Botany Bay during March 1999-February 2000. The annual abundance and biomass were in the ranges of 0.46-4.70 x 10(5) cells/cm(3) and of 0.30-8.61 micro g C/cm(3), respectively. The majority of heterotrophic flagellates (93-100%) were less than 10 mm in length and few flagellates were larger than 10 mm. Of the total microbial carbon biomass, heterotrophic flagellates made up about 5% (but at times up to 35%). The contribution of heterotrophic flagellates varied from month to month, and among the sites. The abundance of heterotrophic flagellates was negatively correlated with sediment grain size and positively correlated with the abundance of bacteria, algae (autotrophic flagellates and diatoms), and their probable grazers. A best subsets regression analysis showed that bacterial and algal abundance are the most important factors controlling the abundance of heterotrophic flagellates. When the previously reported grazing rates on bacteria were applied, heterotrophic flagellates would consume a maximum of 64% of bacterial standing stock daily in Botany Bay, suggesting that heterotrophic flagellates are important as bacterivores. However, the importance of heterotrophic flagellate grazing probably varies significantly among the sites and from month to month.


In vivo metabolism and clearance of substance P and co-expressed tachykinins in rat striatum.
Neurons expressing the preprotachykinin A gene, which encodes the sequences of substance P, neurokinin A, neuropeptide gamma and neuropeptide K, exemplify peptide co-existence. Furthermore, there is also evidence that substance P fragments have biological activity. However, the relative contribution of each of these peptides to tachykinin signalling is still poorly understood. An important factor which will determine the characteristics of the signal mediated by co-localised peptides is their clearance from the extracellular space. The striatum, in which tachykinins are present and exert neuromodulatory roles, can be used as a model to investigate this aspect. Therefore, in this study we characterised in vivo in the striatum the metabolism and clearance of substance P and of the other three co-expressed peptides. After intrastriatal administration of 1 pmol, tritiated substance P disappeared too rapidly for metabolites to be detected. However, when 10 nmol substance P and 1 pmol tritiated substance P were co-injected, substance P(1-4) and substance P(1-7), which are biologically active, were detected as major metabolites. Under these conditions, the rate of decay of tritiated substance P was 0.2 nmol/min. The effects of the peptidase inhibitors thiorphan, bestatin and captopril suggested that neutral endopeptidase 24.11 and aminopeptidases were involved in primary substance P cleavages, whereas angiotensin-converting enzyme was involved in secondary cleavages. The monitoring of the decay of unlabelled substance P by high-performance liquid chromatography gave a rate of 0.16 nmol/min. Using high-performance liquid chromatography with capillary electrophoresis, the rates of decay of 10 nmol neurokinin A or neuropeptide gamma were five and seven times faster than that of substance P. In contrast, over the time course of the experiment, no significant decay of neuropeptide K was detected. These results show that substance P disappears rapidly from the extracellular space, and supports the formation in vivo of major N-terminal active substance P metabolites. Our study also highlights significant differences in the clearance of co-expressed tachykinins and suggests that certain species may disappear relatively slowly from the extracellular space, and thus may make a significant temporal and spatial contribution to signalling.


Phase II study to assess the efficacy of hypofractionated stereotactic radiotherapy in patients with large cavernous sinus hemangiomas.
Cavernous sinus hemangioma is a rare vascular tumor. The direct microsurgical approach usually results in massive hemorrhage. Although radiosurgery plays an important role in managing cavernous sinus hemangiomas as a treatment alternative to microsurgery, the potential for increased toxicity with single-session treatment of large tumors is a concern. The purpose of this study was to assess the efficacy of hypofractionated stereotactic radiotherapy in patients with large cavernous sinus hemangiomas. Fourteen patients with large (volume >20 cm(3)) cavernous sinus hemangiomas were enrolled in a prospective Phase II study between December 2007 and December 2010. The hypofractionated stereotactic radiotherapy dose was 21 Gy delivered in 3 fractions. After a mean follow-up of 15 months (range, 6-36 months), the magnetic resonance images showed a mean of 77% tumor volume reduction (range, 44-99%). Among the 6 patients with cranial nerve impairments before hypofractionated stereotactic radiotherapy, 1 achieved symptomatic complete resolution and 5 had improvement. No radiotherapy-related complications were observed during follow-up. Our current experience, though preliminary, substantiates the role of hypofractionated stereotactic radiotherapy for large cavernous sinus hemangiomas. Although a longer and more extensive follow-up is needed, hypofractionated stereotactic radiotherapy of 21 Gy delivered in 3 fractions is effective in reducing the tumor volume without causing any new deficits and can be considered as a treatment modality for large cavernous sinus hemangiomas.


Targeting NEK2 impairs oncogenesis and radioresistance via inhibiting the Wnt1/β-catenin signaling pathway in cervical cancer.
NEK2, a serine/threonine kinase involved in mitosis, has been found to function in chromosome instability, tumor progression and metastasis, but its role in cervical cancer radioresistance remains unknown. We detected the protein levels of NEK2 in cervical carcinoma tissues and paired paracarcinoma tissues by immunohistochemistry. The roles of NEK2 in oncogenesis were examined using cell growth and colony formation assays, EdU assay, apoptosis assay as well as in vivo mouse model. γ-H2AX and Rad51 foci formation, neutral comet assay and clonogenic cell survival assay were applied to determine the radiosensitivity of cervical cancer cells. RNA-seq was performed to identify the downstream effector of NEK2. The gene expression levels were measured by Real-time PCR. We report that NEK2 protein level is overexpressed and correlated with the tumor stage and lymph node metastasis in cervical cancer tissues. Furthermore, we provided evidence that depletion of NEK2 impairs oncogenesis and enhances radiosensitivity in cervical cancer. Using RNA sequencing, we identify Wnt1 as a key downstream effector of NEK2. Knockdown of NEK2 downregulates the mRNA and protein levels of Wnt1, thereby inhibiting the activation of the Wnt/β-catenin signaling pathway. More importantly, the observed consequences induced by NEK2 depletion in cervical cancer cells can be partially rescued by Wnt1 overexpression. Our results demonstrate that NEK2 activates the Wnt/β-catenin signaling pathway via Wnt1 to drive oncogenesis and radioresistance in cervical cancer, indicating that NEK2 may be a promising target for the radiosensitization of cervical cancer.


catena-Poly[[bis-(quinolin-8-amine-κ2 N,N')cadmium(II)]-μ-cyanido-κ2 N:C-[dicyanidonickel(II)]-μ-cyanido-κ2 C:N].
In the title compound, [CdNi(C9H8N2)2(CN)4] n , the Cd and Ni atoms both lie on centres of inversion in space group P21/c. The Cd atom is coordinated by two bidentate quinolin-8-amine ligands and by the N atoms of two cyano ligands, while the square planar Ni atom is coordinated by the C atoms of four cyano ligands. These units form a one-dimensional coordination polymer containing an (-NC-Ni-CN-Cd-) n backbone, and the coordination polymer chains are linked into a three-dimensional array by a combination of N-H⋯N and C-H⋯N hydrogen bonds, augmented by a π-π stacking inter-action.


Suprapubic versus transurethral bladder drainage after colposuspension/vaginal repair.
Ninety-two patients with preoperative sterile urine undergoing colposuspension or vaginal repair operation for stress urinary incontinence and/or genital descensus were randomized to either suprapubic or transurethral postoperative catheter drainage. The prevalence of significant bacteriuria on the fifth postoperative day was statistically significantly lower when using suprapubic catheter (20.8%) than with transurethral catheter drainage (45.5%). This applied especially to colposuspension. The rate of postoperatively impaired bladder emptying also tended to be reduced when using suprapubic catheter. At follow-up after one year, postoperative bacteriuria was closely correlated to increased rates of both clinical cystitis and asymptomatic significant bacteriuria. Thus it is recommended to use suprapubic bladder drainage not only after colposuspension but also after vaginal repair in an effort to avoid an increased risk of urinary infections.


Clinical characteristics and treatment outcomes of pigmented tumors in central nervous system: Focusing on melanocytic tumors.
Pigmented tumors are rare neoplasm of central nervous system. Melanocytic tumor, including primary and metastatic lesions, is the most common type. Owing to the rarity, the differential diagnosis of pigmented tumors and clinical management of melanocytic tumor remain challenge. Therefore, focusing on melanocytic tumors, the clinical, radiological, histopathological features and treatment outcomes were presented and analyzed in this study. We identified 22 melanocytic tumors, 2 melanotic medulloblastomas, 2 melanotic ependymomas and 1 melanotic schwannoma. Compared with metastatic melanocytic tumors (MMTs), primary melanocytic tumors (PMTs) were characterized by younger age (36.11 ± 17.96 vs. 51.69 ± 12.58 years, p = 0.0262), lower possibility to be multiple lesions (11.1%vs. 61.5%, p = 0.0306), higher proportion of hypointensity on T2-weighted images (66.7% vs. 15.4%, p = 0.0260) and higher frequency in black appearance (77.8% vs. 23.1%, p = 0.0247). During the follow-up, 4 PMTs and 11 MMTs (71.4%) experienced tumor progression. PMTs had better prognosis than MMTs that progression-free survival (PFS) rate of PMT was 50.0% but decreased to 23.1% for MMTs at 12 months (p = 0.0123). Cox proportional hazards regression revealed that multiplicity of tumor was an independent predictor for PFS. None of patient with multiple tumors was in PFS after 12 months' follow-up whereas PFS rate was 40.5% for single tumor (p = 0.0002). In conclusion, radiological appearances, especially hypointensity on T2-weighted images, might be an indication for PMT. MMTs are more likely to be multiple intraparenchymal masses in elder patients located in supratentorial region. Current treatments included operation, radiotherapy and chemotherapy are not competent to control tumor progression and other therapeutic modalities are urgently needed.


Copolymers of pharmaceutical grade lactic acid and sebacic acid: drug release behavior and biocompatibility.
Pharmaceutical grade D,L-lactic acid, which is rather an economic source in comparison to lactide monomer, was utilized for synthesis of a series of copolymers with sebacic acid. Polymers were characterized by GPC, FTIR, NMR and DSC techniques, and formulated into blank and methotrexate (MTX) loaded microspheres by emulsion-solvent evaporation method. In vitro degradation of blank microspheres was studied by FTIR, GPC and SEM analysis. MTX loaded microspheres showed the encapsulation efficiency of 44-64% and were in the size range of 40-60 microm. These were used to study the release profile of the encapsulated drug. The release was found to be affected by the pH and buffer concentration of the release medium which was in turn revealed by solubility studies of MTX. The overall study demonstrates significance of drug as well as polymer properties on release. Biocompatibility of polymer was evaluated by injecting microspheres subcutaneously into Sprague-Dawley (SD) rat and no local histopathological abnormalities were found.


Cytokine-induced killer cell/dendritic cell-cytokine-induced killer cell immunotherapy for the postoperative treatment of gastric cancer: A systematic review and meta-analysis.
Immunotherapy is emerging as a new treatment strategy for gastric cancer(GC). However, the efficacy and safety of this technique remain unclear. This meta-analysis aimed to assess the effect of cytokine-induced killer cell (CIK)/dendritic cell-cytokine-induced killer cell (DC-CIK) treatment for GC after surgery. Hazard ratio (HR), overall survival (OS) rates, and disease-free survival (DFS) rates were calculated using a Mantel-Haenszel (M-H) fixed-effects model (FEM), and results were displayed using forest plots. Publication bias was assessed by Begg test, and data were presented using funnel plots. Date robustness was assessed by the trim and fill method. Descriptive analysis was performed on T lymphocytes and adverse effects. In total, 9 trials, including 1216 patients, were eligible for inclusion in this meta-analysis. Compared with the control group, the HR for OS was 0.712 (95% confidence interval [CI] 0.594-0.854) and 0.66 (95% CI 0.546-0.797) for overall (DFS). The risk ratio (RR) of the 3 and 5-year OS rate was 1.29 (95% CI 1.15-1.46) and 1.73 (95% CI 1.36-2.19), respectively. The RR for the 3 and 5-year DFS rate 1.40 (95% CI 1.19-1.65) and 2.10 (95% CI1.53-2.87), respectively. The proportion of patients who were CD3+, CD4+, and CD4+/CD8+ increased in the cellular therapy groups. No fatal adverse reactions were noted. Chemotherapy combined with CIK/DC-CIK therapy after surgery resulted in low HR, and significantly increasing OS rates, DFS rates, and T-lymphocyte responses in patients with GC.


Accuracy of anatomical landmark identification using different CBCT- and MSCT-based 3D images: an in vitro study.
The aim of this study was to evaluate the reproducibility of anatomical landmarks and the accuracy of different cone-beam CTs (CBCTs/DVTs) and a multislice spiral CT (MSCT) scanner. A human, fresh-frozen cadaver head was scanned with four CBCTs (Accuitomo 3D, 3D eXam, Pax Reve 3D, Pax Zenith 3D) and one MSCT (SOMATOM Sensation 64) scanner. The three-dimensional (3D) reconstruction of the volume data sets and location of the anthropometric landmarks (n=11), together with linear (n=5) and angular (n=1) measurements were carried out by three examiners using the program VoXim® 6.1. The measurements were taken twice at a 14-day interval. Descriptive analyses were made and the standard deviations were used to compare differences in the accuracy of landmark identification. The descriptive statistics showed distinct differences in the reference points in the three axes of the coordinate system. Because of anatomical and morphological factors, the pogonion and gnathion reference points displayed higher standard deviations when set on the transverse plane (SD(CBCT) Pog: 0.66-1.57 mm; SD(MSCT) Pog: 0.14-1.09 mm; SD(CBCT) Gn: 1.05-1.77 mm; SD(MSCT) Gn: 0.20-0.85 mm), thus showing less accuracy. However, standard deviations on the sagittal and vertical planes were smaller. Genion, anterior nasal spine and infradentale had very low standard deviations on all three planes. The distance (Mfl-Mfr) and angle (Krl-Krr-Ge) revealed significantly smaller standard deviations in the MSCT (SD(CBCT) Krl-Krr-Ge: 0.51-0.75 mm; SD(MSCT) Krl-Krr-Ge: 0.22 mm). The CBCT devices evaluated in this study are suitable for taking exact 3D measurements of anatomical structures and meet all requirements for 3D cephalometric analysis.


Electron microscopic study of the rat liver after its orthotopic and auxiliary syngeneic transplantation.
Results of electron microscopic studies on orthotopic and auxiliary syngeneic liver transplants in rats are presented. Examinations were performed about 50 d after both types of liver transplantation. The results obtained in auxiliary transplants in the form of collagenisation within intracellular and Disse's spaces, focal hepatocyte degeneration, the appearance of numerous myelin structures in the form of membranes, and increase in number of microvilli on the hepatocyte surface together with their elongated shape indicate a disadvantageous influence of the host's liver on the transplant. In orthotopically transplanted livers only proliferation of biliary canaliculi and degeneration of hepatocytes at low grade were observed.


Absent common carotid artery associated with amaurosis fugax: a case report.
A patient with amaurosis fugax and extensive atherosclerosis of the internal carotid artery combined with an absent common carotid artery that required extra-anatomic reconstruction is presented.


Biomarkers of systemic inflammation predict survival with first-line immune checkpoint inhibitors in non-small-cell lung cancer.
Pembrolizumab is an established first-line option for patients with advanced non-small-cell lung cancer (NSCLC) expressing programmed death-ligand 1 ≥50%. Durable responses are seen in a subset of patients; however, many derive little clinical benefit. Biomarkers of the systemic inflammatory response predict survival in NSCLC. We evaluated their prognostic significance in patients receiving first-line pembrolizumab for advanced NSCLC. Patients treated with first-line pembrolizumab for advanced NSCLC with programmed death-ligand 1 expression ≥50% at two regional Scottish cancer centres were identified. Pretreatment inflammatory biomarkers (white cell count, neutrophil count, neutrophil/lymphocyte ratio, platelet/lymphocyte ratio, albumin, prognostic nutritional index) were recorded. The relationship between these and progression-free survival (PFS) and overall survival (OS) were examined. Data were available for 219 patients. On multivariate analysis, albumin and neutrophil count were independently associated with PFS (P < 0.001, P = 0.002, respectively) and OS (both P < 0.001). A simple score combining these biomarkers was explored. The Scottish Inflammatory Prognostic Score (SIPS) assigned 1 point each for albumin <35 g/l and neutrophil count >7.5 × 109/l to give a three-tier categorical score. SIPS predicted PFS [hazard ratio 2.06, 95% confidence interval (CI) 1.68-2.52 (P < 0.001)] and OS [hazard ratio 2.33, 95% CI 1.86-2.92 (P < 0.001)]. It stratified PFS from 2.5 (SIPS2), to 8.7 (SIPS1) to 17.9 months (SIPS0) (P < 0.001) and OS from 5.1 (SIPS2), to 12.4 (SIPS1) to 28.7 months (SIPS0) (P < 0.001). The relative risk of death before 6 months was 2.96 (95% CI 1.98-4.42) in patients with SIPS2 compared with those with SIPS0-1 (P < 0.001). SIPS, a simple score combining albumin and neutrophil count, predicts survival in patients with NSCLC receiving first-line pembrolizumab. Unlike many proposed prognostic scores, SIPS uses only routinely collected pretreatment test results and provides a categorical score. It stratifies survival across clinically meaningful time periods that may assist clinicians and patients with treatment decisions. We advocate validation of the prognostic utility of SIPS in this and other immune checkpoint inhibitor treatment settings.


An EPR and NMR study of supramolecular effects on paramagnetic interaction between a nitroxide incarcerated within a nanocapsule with a nitroxide in bulk aqueous media.
A 15N-labeled nitroxide was incarcerated into an octa acid nanocapsule, which was confirmed by 1H NMR and EPR spectroscopy. Electron paramagnetic interaction between the 15N-labeled incarcerated nitroxide and a 14N-labeled free nitroxide in the external aqueous solution was observed by EPR spectroscopy. The observation of spin-spin interaction, through the walls of the cancer and is reflected in the simultaneous line-broadening of both the 15N-labeled and 14N-labeled nitroxides. The computer-assisted analysis of the EPR data further provides direct information on the motion and the polarity of both the incarcerated paramagnetic nitroxide and the nitroxides in the external bulk aqueous phase. We also show how communication between an incarcerated guest and molecules in the bulk solvent can be enhanced or inhibited by supramolecular factors such as Coulombic attraction or repulsion between a charged guest@host complex (incarcerated 15N nitroxide) and charged molecules in the aqueous phase.


Evidence for an extra-abdominal site of action for the 5-HT3 receptor antagonist BRL24924 in the inhibition of radiation-evoked emesis in the ferret.
Recent studies have implicated 5-HT3(5-HT-M) receptors in the genesis of retching and vomiting evoked by antineoplastic agents. Such receptors have so far only been located peripherally, notably on the vagus. Therefore, the effects of bilateral abdominal vagotomy and antagonism of 5-HT3 receptors have been investigated on retching and vomiting induced by radiation. The gastrokinetic substituted benzamide BRL24924, (Beecham Pharmaceuticals) which has 5-HT3 receptor antagonist properties, was used. Using the ferret, it was shown that whole body x-radiation produced retching and vomiting, which was most severe during the 30 min following irradiation, and continued for at least 90 min. Abdominal vagotomy almost totally abolished the retching and vomiting, occurring during the 30 min immediately after irradiation. The following 60 min period was similar to that of control animals. This would suggest that the emetic events can be divided into a vagally-dependent and independent phase. In a small dose, BRL 24924 mimicked abdominal vagtotomy, in a larger dose, it almost totally abolished the retching and vomiting throughout the entire 90 min period. These results suggest that 5-HT3 receptor antagonists are capable of ameliorating radiation-induced retching and vomiting and that, while an important site of their action could be the abdominal vagi, other areas are probably also involved.


Development of an assay for human growth hormone in urine using commercially available reagents.
An assay for the measurement of human growth hormone in urine (u-HGH) has been developed using commercially available reagents and its analytical variables have been investigated. The procedure is sensitive to 0.50 muU/L urine, has an interassay precision of 6.2-7.5 (CV%) over the standard curve, and shows good parallelism and recovery. Urine samples for the assay can be collected in plain plastic bottles, stored at room temperature for up to 24 h and, after adding preservative, at -20 C before assay for three months. There was a good correlation between the responses of HGH in serum and in urine during clonidine and insulin stimulation tests.


Determination of the retinobenzoic acid derivative Am580 in rat plasma by high-performance liquid chromatography.
A specific liquid chromatographic method for the determination of 4-[[(5,6,7,8,8-tetrahydro-5,5,8,8-tetramethyl-2- naphthalenyl)carbonyl]amino]benzoic acid (Am580) in rat plasma is described. The procedure includes one-step isolation of the compound and the internal standard (naphthol AS) from protein precipitated with acetonitrile, resolution on a reversed-phase column (Supelcosil LC18-DB, 5 microns) with water-acetonitrile-methanol-n-butanol (45:40:14:1, v/v) containing 65 mM ammonium acetate as elution system and UV absorbance detection at 280 nm. The assay was linear over a wide range (25-5000 ng ml-1) and the limit of quantitation was 25 ng ml-1 using 0.2 ml of plasma. It was precise and reproducible enough for pharmacokinetic studies. Application to a preliminary disposition study in the rat indicated that Am580 was characterized by a relatively large apparent volume of distribution (1.1-1.5 1 kg-1) and small clearance (8.8-9.7 ml min-1 kg-1). Its pharmacokinetic behaviour was linear within the dose range considered (2 and 10 mg kg-1, i.p.).


Cause-specific life years lost in individuals with treatment-resistant depression: A Danish nationwide register-based cohort study.
Depression is associated with excess mortality, but it is not known how treatment-resistance influences life expectancy. We estimated cause-specific excess mortality and Life Years Lost (LYL) in patients with treatment-resistant depression (TRD). The population included all individuals born and living in Denmark who redeemed their first prescription for an antidepressant at age 18-69 years between 2005 and 2012, identified in the Danish National Prescription Registry. TRD was defined as at least two additional and different antidepressant trials within two years. Mortality rate ratios (MRRs) were estimated with Cox regression adjusted for age at first prescription, calendar year and comorbidity. Differences in life expectancy were estimated by the Life Years Lost (LYL) method. The cohort included 154,513 first-time pharmacologically treated patients with depression, of whom 8,294 (5.4%) were identified as having TRD. Patients were followed for 1,032,245 person-years during which 9,795 deaths occurred. Men and women with TRD had significantly higher mortality than non-TRD (aMRR: 1.34, 95% CI 1.18-1.52 and aMRR: 1.39, 95% CI 1.19-1.63, respectively). Life expectancy for men and women with TRD was 1.21 (95% CI 0.36-2.44) and 1.24 (95% CI 0.35-2.34) years shorter than in all patients with depression. Suicide accounted for the majority of excess LYL, with 1.10 (95% CI 0.46-1.61) years in men and 0.82 (95% CI 0.44-1.27) years in women with TRD. Using redeemed prescriptions to define TRD may increase the risk of misclassification. Patients not responding adequately to several treatment trials are at increased risk for premature death, particularly suicide.


Mediators of Treatment Effects in a Randomized Clinical Trial of Multisystemic Therapy-Health Care in Adolescents With Poorly Controlled Asthma: Disease Knowledge and Device Use Skills.
Determine whether Multisystemic Therapy-Health Care (MST-HC) improved asthma knowledge and controller device use skills among African-American youth with poorly controlled asthma and whether any improvements mediated changes in illness management. A randomized controlled trial was conducted with 170 adolescents with moderate to severe asthma. Families were randomized to MST-HC or attention control. Data were collected at baseline and 6 and 12 months after intervention completion. In linear mixed models, adolescents in the MST-HC group had increases in asthma knowledge; asthma knowledge was unchanged for attention control. Controller device use skills increased for adolescents in the MST-HC group, while skills declined for attention control. Both knowledge and skills mediated the relationship between intervention condition and changes in illness management. Tailored, home-based interventions that include knowledge and skills building components are one means by which illness management in African-American youth with poorly controlled asthma can be improved.


Competition kinetics using the UV/H2O2 process: a structure reactivity correlation for the rate constants of hydroxyl radicals toward nitroaromatic compounds.
The rate constants for hydroxyl radical reaction toward a set of nitroaromatic substrates kS, have been measured at 25 degrees C using competition experiments in the UV/H2O2 process. For a given pair of substrates S1 and S2, the relative reactivity beta (defined as kS1/kS2) was calculated from the slope of the corresponding double logarithmic plot, i.e., of ln[S1] vs. ln[S2]. This method is more accurate and remained linear for larger conversions in comparison with the plots of ln[S1] and ln[S2] against time. The rate constants measured ranged from 0.33 to 8.6 x 10(9) M(-1)s(-1). A quantitative structure-reactivity relationship was found using the Hammett equation. Assuming sigma values to be additive, a value of -0.60 was obtained for the reaction constant rho. This value agrees with the high reactivity and the electrophilic nature of HO* radical.


Methane production and microbial community structure in single-stage batch and sequential batch systems anaerobically co-digesting food waste and biosolids.
Anaerobic co-digestion of food waste and biosolids was carried out in sequential batch and single-stage batch systems in four treatments. Methane yield, which was used as a functional process parameter, differed between treatments, with the single-stage batch system generating lower volumes than the sequential batch systems. Volatile fatty acid (VFA) concentrations and pH in the leachate also differed between treatments. VFA concentrations were highest and methane generation yields lowest in the single-stage batch system in comparison to the sequential batch systems. The anaerobic microbial community structure of the domains Archaea and Bacteria, determined by denaturing gradient gel electrophoresis, differed between treatments and was correlated to a number of environmental parameters such as pH, VFA concentration and methane generation rate. Methane generation rate was significantly correlated to the community structure of Bacteria but not Archaea. This indicated that the substrates that are produced by acetogens (Bacteria) are important for the growth and community structure of the methanogens (Archaea). Community structure of Archaea changed over time, but this had no observable effect on functional ability based on methane yields. Microbial diversity (H') was shown to be not important in developing a functionally successful anaerobic microbial community.


The potential steroid hormone contribution of farm animals to freshwaters, the United Kingdom as a case study.
The combined farm animal population is considerably larger than the human one in the United Kingdom, implying a possibly important contribution to the environmental load of steroid hormones entering water. To make comparisons on the amount of steroid hormones produced by the different livestock, information was gathered on the structure of the UK farm animal populations and the amount of hormones excreted by animals at each of their life stages. An individual normalised dairy cow excretes two orders of magnitude more, and a normalised pig excretes more than one order of magnitude more steroid oestrogens than a normalised human. In terms of excretion, the combined farm animal population (including sheep and poultry) probably generates around four times more oestrogens than the human population in the UK. The biggest contributor on the animal side is the relatively small dairy cow population. If steroid oestrogens behave like herbicides, in which a worst case loss to surface waters is around 1%, then it could be argued that farm animals are responsible for 15% of all the oestrogens in UK waters. When simulations were made with the MACRO pesticide leaching model, predicted concentrations for field drains failed to exceed 1 ng/L. The rapid biodegradation rates, and high sorption rates taken from the literature and used in the model suggested less than 0.001% of oestrogens would reach the field drains. This survey suggests that direct excretion of steroid hormones by animals into water courses, or discharges from farmyard drains, are likely to be more important sources of contamination rather than via normal agricultural scenarios.


Role of Stat5 in type I interferon-signaling and transcriptional regulation.
Type I interferons are pleiotropic cytokines that transduce signals via activation of multiple downstream signaling cascades, including the Jak-Stat pathway. Although the roles of Stat1 and Stat2 in Type I interferon signaling are well established, the roles that other Stat-family members play in the induction of IFN-responses remain to be defined. In previous studies, we have shown that Stat5 associates with the CrkL adapter and forms a signaling complex that binds DNA. In the present study, we provide evidence that Stat5 is phosphorylated on serines 725/730 in an IFNalpha- and IFNbeta-dependent manner, providing direct evidence that serine phosphorylation of the protein is a component of an interferon signaling cascade. Such serine phosphorylation of Stat5 is Map kinase- and PI 3(')-kinase independent, while the activation of the serine kinase that phosphorylates Stat5 is regulated by upstream tyrosine kinase activity. Using mouse embryonic fibroblasts with targeted disruption of the Stat5a and Stat5b genes, we demonstrate that full activation of Stat5 is required for Type I interferon-dependent gene transcription via GAS elements. Altogether, our data provide evidence that Stat5 plays an important role in IFN-signaling and participates in the induction of Type I IFN-dependent responses. Furthermore, our results strongly suggest that, in addition to phosphorylation on tyrosine residues, phosphorylation on serine residues exhibits regulatory effects on the transcriptional capacity of Stat5.


Barrett's esophagus: incidence and prevalence estimates in a rural Mid-Western population.
Barrett's esophagus (BE) predisposes to adenocarcinoma of the esophagus and survival in esophageal adenocarcinoma is low. We studied patients diagnosed with BE in the Marshfield Epidemiologic Study Area (MESA). Our objectives were to estimate the prevalence of diagnosed BE, estimate the annual incidence of initial diagnosis of BE, and characterize the demographics of patients diagnosed with BE. We retrospectively reviewed medical records of patients diagnosed with BE until December 31, 2002. The esophagogastroduodenoscopy (EGD) reports were reviewed to establish the presence of columnar epithelium. All slides were retrieved and reviewed by a gastrointestinal pathologist to establish the presence of intestinal metaplasia and dysplasia. Chart abstraction was conducted using a standardized form. BE was histologically confirmed in 216 patients. All were white, 165 (76%) were male, and 81% had a hiatal hernia. Median age at diagnosis was 65.5 yr (range 17-94). Long-segment BE (LSBE) was present in 112 (51.9%) patients. The prevalence of histologically confirmed BE in MESA was 261.8 (95% CI 222.5-301.1) per 100,000 people. The incidence of an initial diagnosis of BE between 1996 and 2002 was 32.7 per 100,000 person-years (95% CI 27.1-38.2) and did not change significantly over the study period despite an increase in EGD rates. At the initial diagnosis, 41.7% of the patients were on proton pump inhibitors. Dysplasia was present in 24.5% of patients. The incidence of initial diagnosis of BE in a stable white population did not change significantly over a 7-yr period, despite an increase in EGD rates.


Science teachers' interactions with resources for formative assessment purposes.
Using a case-study approach, we aim to understand how teachers interact with both analogue and digital resources in the science classroom for formative assessment (FA) purposes and their justifications for such interactions. The study was conducted in the context of a European Union project on FA in science and mathematics education. The case involved two Norwegian primary school teachers teaching their grades 5 and 7 students a series of science lessons on the topic "how to prevent microorganisms from spreading." The data set consisted of lesson plans, classroom observations, pre- and post-interviews conducted with teachers, student tasks, post-interviews with students, and student work. We identified eight analogue and digital resources, which were used to employ five FA strategies. The strategies that were most commonly used related to "engineering effective classroom discussions" that elicited evidence of student understanding and "activating students" as autonomous learners and peer instructors. The teachers' rationales for using the selected resources were mainly connected to their effectiveness, practicality, and relevance. Teacher interactions with the selected resources are described, and educational implications are discussed.


Molecular identification of Theileria spp. in ruminants and ticks from southern littoral of Caspian Sea, Iran.
The present study aimed at evaluating the presence of tick-borne apicomplexan parasites including Theileria ovis, Theileria lestoquardi, Theileria annulata, and Theileria orientalis in 92 cattle and 105 sheep from 6 different districts of Guilan and Mazandaran Provinces, in the southern littoral of Caspian Sea. Furthermore, ixodid ticks were collected from the same animals. Stained blood smears were microscopically evaluated for the presence of blood parasites, and a specific PCR was applied for the detection of Theileria species. Besides, ticks were subsequently examined by species-specific PCR. Microscopic examination of blood smears demonstrated no evidence of intraerythrocytic piroplasms. Species-specific diagnostic PCRs demonstrated that 52.17% of sheep blood samples were positive for T. ovis. In addition, 31.03% and 24.13% of cattle blood samples were positive for T. annulata and T. orientalis, respectively. Moreover, 3 species of the ixodid ticks, namely, Rhipicephalus annulatus (58.47%), Ixodes ricinus (29.82%), and Haemaphysalis inermis (11.69%), were identified in Guilan Province, while Hyalomma detritum (73.03%) and Rhipicephalus sanguineus (26.92%) were found in Mazandaran Province. Additionally, by obtaining the data with respect to tick-borne apicomplexan parasites in 122 infected ticks, 35.24%, 22.95%, and 2.45% of tick samples were positive for T. annulata, T. orientalis, and T. ovis, respectively. Species-specific PCR revealed that H. inermis and R. annulatus were positive for T. orientalis. In addition, T. annulata was found in R. annulatus, H. inermis, and H. detritum. Besides, T. ovis was the only species of Theileria found in R. sanguineus. In conclusion, the results revealed that T. annulata infection was prevalent among cattle and ovine theileriosis caused by T. ovis was the only Theileria species found in sheep in the studied areas of the southern littoral of Caspian Sea. R. annulatus, H. inermis, and H. detritum were the main vectors for T. annulata, followed by H. inermis and R. annulatus for T. orientalis, and R. sanguineus for T. ovis.


Iron Pyrite Nanocrystals: A Potential Catalyst for Selective Transfer Hydrogenation of Functionalized Nitroarenes.
We report a solution-based synthetic method to produce shape-tunable iron pyrite (FeS2) nanocrystals using iron oxy-hydroxide (β-FeOOH) as a precursor and their application for selective reduction of functionalized nitroarenes to aniline derivatives with formic acid-triethylamine (HCOOH-Et3N) as a hydrogen donor system.


Myf5-/- :MyoD-/- amyogenic fetuses reveal the importance of early contraction and static loading by striated muscle in mouse skeletogenesis.
The mechanical loading of striated muscle is thought to play an important role in shaping bones and joints. Here, we examine skeletogenesis in late embryogenesis (embryonic day 18.5) in Myf5-/-:MyoD-/- fetuses completely lacking striated muscle. The phenotype includes enlarged and fused cervical vertebrae and postural anomalies, some viscerocranial anomalies, long bone truncation and fusion, absent deltoid tuberosity of the humerus, scapular and clavicular hypoplasia, cleft palate, and cleft sternum. In contrast, neurocranial bone development was essentially normal. While the magnitude of individual effects varied throughout the skeletal system, the results are consistent with skeletal development depending on functional muscles. Novel abnormalities in the amyogenic fetuses relative to less severely paralyzed phenotypes extend our understanding of skeletogenic dependence on embryonic muscle contraction and static loading.


Hemoglobin-mediated nitric oxide signaling.
The rate that hemoglobin reacts with nitric oxide (NO) is limited by how fast NO can diffuse into the heme pocket. The reaction is as fast as any ligand/protein reaction can be and the result, when hemoglobin is in its oxygenated form, is formation of nitrate in what is known as the dioxygenation reaction. As nitrate, at the concentrations made through the dioxygenation reaction, is biologically inert, the only role hemoglobin was once thought to play in NO signaling was to inhibit it. However, there are now several mechanisms that have been discovered by which hemoglobin may preserve, control, and even create NO activity. These mechanisms involve compartmentalization of reacting species and conversion of NO from or into other species such as nitrosothiols or nitrite which could transport NO activity. Despite the tremendous amount of work devoted to this field, major questions concerning precise mechanisms of NO activity preservation as well as if and how Hb creates NO activity remain unanswered.


Effect of pre-exercise phototherapy applied with different cluster probe sizes on elbow flexor muscle fatigue.
Phototherapy has been used for reducing muscle fatigue. In view of the various types of phototherapy cluster probes available in the market, the purpose of this study was to compare the effects of a similar phototherapy dosage with two different cluster probes on elbow flexor muscle fatigue: small cluster probe (SC = 9 diodes; 7.5 cm(2)) vs. large cluster probe (LC = 33 diodes; 30.2 cm(2)). Ten physically active male aged 18-35 years participate in a randomized, crossover, double-blind, placebo-controlled trial, which each participant was submitted to the same testing protocol in four sessions (separated by at least 48 h) with different treatments: LC-phototherapy, SC-phototherapy, LC-placebo, and SC-placebo. The elbow flexion maximal isometric voluntary contraction (MIVC) was performed before and after a fatigue protocol (60 % of MIVC until exhaustion). Electromyography (EMG) of the biceps brachii muscle was collected during all testing procedure. Phototherapy with dose of 60 J per muscle [LC: 33 diodes = 5 lasers (850 nm), 12 LEDs (670 nm), 8 LEDs (880 nm), and 8 LEDs (950 nm); SC: 9 diodes = 5 lasers (850 nm) and 4 LEDs (670 nm)] or placebo applications occurred before fatigue protocol. Two-way ANOVA (treatment and time factors) and one-way ANOVA were used, followed by LSD post hoc. Time to exhaustion was significantly higher in active LC (15 %; p = 0.031) and SC (14 %; p = 0.038) in comparison with their respective placebo treatments, without differences between LC and SC (p > 0.05) or between placebo conditions (p > 0.05). This larger exercise tolerance in phototherapy conditions was not accompanied by a higher decrement in the volunteers' maximal strength capacity (11-15 %; p > 0.05 for all). EMG signals presented no difference between the four condition tested here. In both large and small cluster probes (according parameters tested in this study) led to reduced fatigue in elbow flexor muscles, without difference between them.


Cervical necrotizing fasciitis: management challenges in poor resource environment.
Necrotizing fasciitis of the head and neck is a rare and potentially fatal disease. It is a bacterial infection characterized by spreading along fascia planes and subcutaneous tissue resulting in tissue necrosis and likely death. It is commonly of dental or pharyngeal origin. Factors affecting the success of the treatment are early diagnosis, appropriate antibiotics and surgical debridement. Our study showed eight patients, five males and three females with mean age of 49.25 years (range 20-71 years). Clinical presentations were a rapidly progressing painful neck swelling, fever, dysphagia and trismus. The aetiology varied from idiopathic, pharyngeal/tonsillar infection, trauma and nasal malignancy. There were associated variable comorbidities (diabetes mellitus, HIV infection, hypertension and congestive cardiac failure). All the patients received early and aggressive medical treatment. The earliest time of surgery was 12 h after admission because of the poor financial status of patients. Three cases came in with complications of the disease and were not fit for extensive debridement under general anaesthesia. For them limited and reasonable bed side debridement was done. Mortality was 50 % from multiple organ failure, HIV encephalopathy, aspiration pneumonitis and septicemia. The duration of hospital stay for the patients that died ranged from 1 to 16 days and 4 to 34 days for the survivor. Our study heightens awareness and outlines the management challenges of necrotizing fasciitis of the head and neck in a poor resource setting.


Serotonergic modulation of the limbic system.
The limbic system is composed of cortical as well as subcortical structures, which are intimately interconnected. The resulting macrostructure is responsible for the generation and expression of motivational and affective states. Especially high levels of serotonin are found in limbic forebrain structures. Serotonin projections to these structures, which arise from serotonergic cell body groups in the midbrain, form a dense plexus of axonal processes. In many areas of the limbic system, serotonergic neurotransmission can best be described as paracrine or volume transmission, and thus serotonin is believed to play a neuromodulatory role in the brain. Serotonergic projections to limbic structures, arising primarily from the dorsal and median raphe nuclei, compose two distinct serotonergic systems differing in their topographic organization, electrophysiological characteristics, morphology, as well as sensitivity to neurotoxins and perhaps psychoactive or therapeutic agents. These differences may be extremely important in understanding the role of these two serotonergic systems in normal brain function and in mental illness. Central serotonergic neurons or receptors are targets for a variety of therapeutic agents used in the treatment of disorders of the limbic system.


Cooperative bird differentiates between the calls of different individuals, even when vocalizations were from completely unfamiliar individuals.
Hypotheses proposed to explain the evolution of cooperative behaviour typically require differentiation between either groups of conspecifics (e.g. kin/non-kin) or, more typically, individuals (e.g. reciprocal altruism). Despite this, the mechanisms that facilitate individual or class recognition have rarely been explored in cooperative species. This study examines the individual differentiation abilities of noisy miners (Manorina melanocephala), a species with one of the most complex avian societies known. Miners permanently occupy colonies numbering into hundreds of individuals. Within these colonies, cooperative coalitions form on a fission-fusion basis across numerous contexts, from social foraging through to mobbing predators. Birds often use individually distinctive 'chur' calls to recruit others to a caller's location, facilitating coalition formation. I used the habituation-discrimination paradigm to test the ability of miners to differentiate between the chur calls of two individuals that were both either: (i) familiar, or (ii) unfamiliar to the focal subject. This technique had not, to my knowledge, been used to assess vocalization differentiation in cooperative birds previously, but here demonstrated that miners could correctly use the spectral features of signals to differentiate between the vocalizations of different individuals, regardless of their familiarity. By attending to individual differences in recruitment calls, miners have a communication system that is capable of accommodating even the most complex cooperative hypotheses based upon acoustic information.


Factors influencing hospitalized patients' perception of individualized nursing care: a cross-sectional study.
Individualized care is a cornerstone of patient-centered nursing care. To foster individualized care, influencing factors should be known. The aim of this study was to identify the individual and organizational factors influencing hospitalized patients' perception of individualized care. A cross-sectional study was conducted of 606 patients from 20 wards from five hospitals across Germany. Individualized care and potential influencing factors were assessed via structured questionnaires. To identify influencing factors, we applied a hierarchical linear model with two levels. Self-rated health, length of ward stay, educational level and shared decision-making process about nursing care were perceived to influence individualized care. A higher rating of health and longer ward stay correlated with improved perceptions of individualized nursing care. In addition, an educational level of nine or fewer years and a perceived shared decision-making process about nursing care positively influenced the perception of nursing care as being tailored to individual needs. Several factors influence patients' perception of individualized care. However, only the decision-making process can be actively influenced by nurses. Therefore, nurses should be encouraged to promote shared decision-making regarding patients' nursing care. DRKS00005174 (Date of registration: 2013/08/01).


Outcomes of postchemotherapy retroperitoneal lymph node dissection following high-dose chemotherapy with stem cell transplantation.
Characterizing the role of postchemotherapy retroperitoneal lymph node dissection (PC-RPLND) after high-dose chemotherapy (HDCT) has been limited by small sample sizes. This study reports on survival after HDCT with stem cell support and PC-RPLND as well as histologic findings in the retroperitoneum. The prospectively maintained testicular cancer database of Indiana University was queried for patients receiving HDCT with stem cell transplantation before PC-RPLND. The cause and date of death were obtained through patient chart review and contact with referring physicians. The Kaplan-Meier method was used to evaluate overall survival (OS). The log-rank test was used for tests of significance. A multivariate, backward, stepwise Cox regression model was built to evaluate predictors of overall mortality. A total of 92 patients were included in the study. In the entire cohort, the retroperitoneal (RP) histology findings at the time of PC-RPLND were necrosis (26%), teratoma (34%), and cancer (38%). Sixty-six patients (72%) harbored either a teratoma or active cancer in the RP specimen at PC-RPLND. The median follow-up for the entire cohort was 80.6 months. A total of 28 patients (30%) died during follow-up. The 5-year OS rate of the entire cohort was 70%. The most significant predictor of death was PC-RPLND performed in the desperation setting with elevated markers. Despite these patients being heavily pretreated with multiple cycles of chemotherapy, including HDCT, approximately three-fourths were found to have a teratoma and/or active cancer in the retroperitoneum. This underscores the importance of PC-RPLND for rendering patients free of disease and providing a potential for cure.


Potentiation of coxsackievirus B3 infection in adult mice pretreated with a gold salt.
In mice treated with sodium aurothiomalate (myocrisin), prior to infection with Coxsackievirus B3, 90% of the animals died by the 11th day postinfection (p.i.). A mortality of 10% was noted in mice receiving myocrisin only, and no deaths occurred in animals infected with virus alone. The highest amount of virus was recovered from the pancreas of myocrisin-treated mice on day 3 p.i. This was over 500-fold higher than the virus titer found in the pancreas of mice infected with virus only. Generally the titer of virus present in different organs was higher at every point in drug-treated animals as compared to intact mice infected with the virus. A high and persistent viremia was present in myocrisin-treated mice; in contrast a low viremia followed by virus clearance from the blood was observed in intact mice infected with the virus. The antibody response was studied in intact and myocrisin-treated mice infected with the virus. In both groups, no neutralizing antibodies were detected on days 1, 2, and 3 p.i. On day 7 after infection, the titers of antibodies were 1:16 and 1:12 in intact and myocrisin-treated mice, respectively. Administration of hyperimmune anti-Coxsackievirus B3 serum 6 hours after infection protrected in myocrisin-treated group of mice against lethal disease. The results of these studies suggest that (1) antibodies alone may not be sufficient to limit the spread and persistence of virus in natural infections and (2) in the absence of any apparent histopathological differences the increased multiplication of Coxsackievirus B3 could be the cause of death in myocrisin-treated mice.


Data based model for predicting COVID-19 morbidity and mortality in metropolis.
There is an ongoing need for scientific analysis to help governments and public health authorities make decisions regarding the COVID-19 pandemic. This article presents a methodology based on data mining that can offer support for coping with epidemic diseases. The methodological approach was applied in São Paulo, Rio de Janeiro and Manaus, the cities in Brazil with the most COVID-19 deaths until the first half of 2021. We aimed to predict the evolution of COVID-19 in metropolises and identify air quality and meteorological variables correlated with confirmed cases and deaths. The statistical analyses indicated the most important explanatory environmental variables, while the cluster analyses showed the potential best input variables for the forecasting models. The forecast models were built by two different algorithms and their results have been compared. The relationship between epidemiological and environmental variables was particular to each of the three cities studied. Low solar radiation periods predicted in Manaus can guide managers to likely increase deaths due to COVID-19. In São Paulo, an increase in the mortality rate can be indicated by drought periods. The developed models can predict new cases and deaths by COVID-19 in studied cities. Furthermore, the methodological approach can be applied in other cities and for other epidemic diseases.


Phosphodiesterase 10A (PDE10A) as a novel target to suppress β-catenin and RAS signaling in epithelial ovarian cancer.
A leading theory for ovarian carcinogenesis proposes that inflammation associated with incessant ovulation is a driver of oncogenesis. Consistent with this theory, nonsteroidal anti-inflammatory drugs (NSAIDs) exert promising chemopreventive activity for ovarian cancer. Unfortunately, toxicity is associated with long-term use of NSAIDs due to their cyclooxygenase (COX) inhibitory activity. Previous studies suggest the antineoplastic activity of NSAIDs is COX independent, and rather may be exerted through phosphodiesterase (PDE) inhibition. PDEs represent a unique chemopreventive target for ovarian cancer given that ovulation is regulated by cyclic nucleotide signaling. Here we evaluate PDE10A as a novel therapeutic target for ovarian cancer. Analysis of The Cancer Genome Atlas (TCGA) ovarian tumors revealed PDE10A overexpression was associated with significantly worse overall survival for patients. PDE10A expression also positively correlated with the upregulation of oncogenic and inflammatory signaling pathways. Using small molecule inhibitors, Pf-2545920 and a novel NSAID-derived PDE10A inhibitor, MCI-030, we show that PDE10A inhibition leads to decreased ovarian cancer cell growth and induces cell cycle arrest and apoptosis. We demonstrate these pro-apoptotic properties occur through PKA and PKG signaling by using specific inhibitors to block their activity. PDE10A genetic knockout in ovarian cancer cells through CRISP/Cas9 editing lead to decreased cell proliferation, colony formation, migration and invasion, and in vivo tumor growth. We also demonstrate that PDE10A inhibition leads to decreased Wnt-induced β-catenin nuclear translocation, as well as decreased EGF-mediated activation of RAS/MAPK and AKT pathways in ovarian cancer cells. These findings implicate PDE10A as novel target for ovarian cancer chemoprevention and treatment.


Intracardiac rhabdomyoma--report of a patient and review of literature.
This report describes a rare case of intracardiac rhabdomyoma in an infant, review of the literature, and its management.


Metastasizing chordoma of the lumbar spine.
Chordoma is a dysontogenetic bone tumour that appears in the region of the axial skeleton. Its malignant transformation has been underestimated in the past, since the incidence of metastasis is disputed. This paper describes a chordoma of the fifth lumbar vertebra, which at first was monolocular, but in the course of the disease led to a diffuse metastasis of the spine. Specific histological findings and the differential diagnosis of the chordoma are discussed, as well as previous descriptions in the literature relating to course, diagnosis, and therapy.


A mathematical model with young predation.
We generalize the model of [21] in which the author considered a predator-prey system with predators eating only the young ones (or eggs) of the prey species. The prime assumption of the present paper is that the birth rate (per unit individual per unit time) of predators depends not only on the current prey egg-level but also on all previous prey egg-levels. It is seen that under this assumption an otherwise stable system may be stable as well as unstable leading to the conclusion that young predation with time delay is less stable than without it. Finally for the model of [21] we prove a result which shows that large predation rates help in the co-existence of both predator and prey species.


Association between wildfires and coccidioidomycosis incidence in California, 2000-2018: a synthetic control analysis.
The frequency and severity of wildfires in the Western United States have increased over recent decades, motivating hypotheses that wildfires contribute to the incidence of coccidioidomycosis, an emerging fungal disease in the Western United States with sharp increases in incidence observed since 2000. While coccidioidomycosis outbreaks have occurred among wildland firefighters clearing brush, it remains unknown whether fires are associated with an increased incidence among the general population. We identified 19 wildfires occurring within California's highly endemic San Joaquin Valley between 2003 and 2015. Using geolocated surveillance records, we applied a synthetic control approach to estimate the effect of each wildfire on the incidence of coccidioidomycosis among residents that lived within a hexagonal buffer of 20 km radii surrounding the fire. We did not detect excess cases due to wildfires in the 12 months (pooled estimated percent change in cases: 2.8%; 95% confidence interval [CI] = -29.0, 85.2), 13-24 months (7.9%; 95% CI = -27.3, 113.9), or 25-36 months (17.4%; 95% CI = -25.1, 157.1) following a wildfire. When examined individually, we detected significant increases in incidence following three of the 19 wildfires, all of which had relatively large adjacent populations, high transmission before the fire, and a burn area exceeding 5,000 acres. We find limited evidence that wildfires drive increases in coccidioidomycosis incidence among the general population. Nevertheless, our results raise concerns that large fires in regions with ongoing local transmission of Coccidioides may be associated with increases in incidence, underscoring the need for field studies examining Coccidioides spp. in soils and air pre- and post-wildfires.


Facile preparation of activated carbon supported nano zero-valent iron for Cd(Ⅱ) removal in aqueous environment.
Activated carbon-supported nano-zero-valent iron (nZVI@AC) is considered to be one of the most promising materials for in-situ remediation of pollutants in aqueous environment, while liquid phase reduction (LPR) is one of the most commonly used preparation methods for nZVI@AC. However, the complex operation and the requirement of various agents limit the practical application of the traditional liquid-phase reduction (TLPR). In this study, an improved liquid phase reduction method (ILPR) was proposed, which was characterized by solid-state dosing of reducing agents. Compared with TLPR, ILPR simplified the preparation process, while there was no requirement of polyethylene glycol and ethanol. When the Cd(II) removal efficiency was used as the evaluation index, the preferred parameters of ILPR were as follows: AC/FeSO4·7H2O mass ratio was 15:1; NaBH4 dosage was 8 g; ultrasonic time was 1 h; stirring time was 20 min. Moreover, the Cd(II) removal efficiency of nZVI@AC prepared by ILPR (nZVI@AC-I) was greater than 92.00%, which was superior to that of nZVI@AC prepared by TLPR (nZVI@AC-T). The characterization results showed that the pore parameters, surface functional groups and iron contents of nZVI@AC-I and nZVI@AC-T were basically the same. However, the distribution of iron-containing particles on the surface of nZVI@AC-I was more uniform. Furthermore, the Fe0 in nZVI@AC-I had a smaller particle size and a higher content. Overall, this study provided a promising approach for nZVI@AC preparation.


A novel strategy for enhancing extracellular secretion of recombinant proteins in Escherichia coli.
Secretion of cytoplasmic expressed proteins into culture medium has significant commercial advantages in large-scale production of proteins. Our previous study demonstrated that the membrane permeability of Escherichia coli could be significantly improved when Thermobifida fusca cutinase, without a signal peptide, was expressed in cytoplasm. This study investigated the extracellular production of other recombinant proteins, including both secretory and cytosolic proteins, with co-expression of cutinase. When the secretory enzymes, xylanase and α-amylase, were co-expressed with cutinase, the culture period was shortened by half, and the productivity was 7.9 and 2.0-fold to that of their individual control without co-expression, respectively. When the normally cytosolic proteins, xylose isomerase and trehalose synthase, were co-expressed with cutinase, more than half of the target proteins were "secreted" into the culture medium. Moreover, by using β-galactosidase to detect membrane leakage, the improved secretion of the above model proteins was confirmed not to be due to cell lysis. The study provides a novel strategy for enhancing extracellular secretion of recombinant proteins in E. coli.


Genetic Instability and Disease Prognostication.
Genetic instability is a striking feature of human cancers, with an impact on the genesis, progression and prognosis. The clinical importance of genomic instability and aneuploidy is underscored by its association with poor patient outcome in multiple cancer types, including breast and colon cancer. Interestingly, there is growing evidence that prognostic gene expression signatures simply reflect the degree of genomic instability. Additionally, also the proteome is affected by aneuploidy and has therefore become a powerful tool to screen for new targets for therapy, diagnosis and prognostication. In this context, the chapter presents the impact of genomic instability on disease prognostication occurring in human cancers.


lncRNA EPS15-AS1 affects the biological behavior of liver cancer stem cells by regulating EPS15 expression.
To investigate whether long non-coding RNA (lncRNA) EPS15-antisense RNA (EPS15-AS1) affects the biological behavior of liver cancer stem cells (LCSCs) by targeting EPS15. The expression of EPS15 in liver cancer was analyzed based on TCGA database. The expression of EPS15-AS1 and EPS15 in LCSCs was detected by real-time quantitative PCR (RT-qPCR). MTT method, flow cytometry, and Transwell assay were used to detect the effects of EPS15-AS1 and EPS15 expression on the biological behavior of LCSCs. EPS15 was highly expressed in liver cancer tissues in TCGA, and EPS15 was closely related to the survival and prognosis of liver cancer patients (P<0.05). EPS15 was highly expressed in LCSCs, while lncRNA EPS15-AS1 was lowly expressed in LCSCs (P<0.05). After silencing lncRNA EPS15-AS1, the proliferation, invasion, and EPS15 protein expression of LCSCs were promoted (P<0.05) while apoptosis was suppressed (P<0.05). After overexpression of lncRNA EPS15-AS1, the proliferation, invasion, and EPS15 protein expression of LCSCs were suppressed while the apoptosis ability was promoted. However, simultaneous overexpression of lncRNA EPS15-AS1 and EPS15 attenuated the effect of lncRNA EPS15-AS1 overexpression alone on proliferation and apoptosis of LCSCs. lncRNA EPS15-AS1 overexpression can inhibit proliferation and invasion but promote apoptosis of LCSCs by down-regulating the expression of EPS15.


Plaque characteristics on coronary CT angiography associated with the positive findings of fractional flow reserve and instantaneous wave-free ratio.
Fractional flow reserve (FFR) and instantaneous wave-free ratio (iFR) are useful in determining indications for revascularization of coronary artery disease (CAD). Although the discordance of FFR and iFR was noted in approximately 20%, this cause has not been well established. We investigated patient background and features on coronary CT angiography (CCTA) showing not only FFR- and iFR-positive findings but also discordance between FFR ≤ 0.8 and iFR ≤ 0.89. Subjects were consecutively treated in 83 cases with 105 vessels in which stenosis of 30-90% was detected at one vessel of at least 2 mm or more in the major epicardial vessels and FFR and iFR was performed within subsequent 90 days, among suspected CAD which underwent CCTA. The factors affecting not only FFR- and iFR-positive findings, respectively, but also discordance between FFR and iFR was evaluated using logistic regression analysis on per-patient and per-vessel basis. FFR- and iFR-positive findings were observed in 42 vessels (40.0%) and 34 vessels (32.3%), respectively. Discordance between FFR ≤ 0.8 and iFR ≤ 0.89 was observed in 22 vessels (21.0%) of 21 patients. In multivariate logistic analysis, LAD (OR 3.55; 95%CI 1.20-11.71; p = 0.0217) and lumen volume/myocardial weight (L/M) ratio (OR 0.93; 0.86-0.99, p = 0.0290) were significant predictors for FFR-positive findings. For iFR-positive findings, LAD (OR 3.86; 95%CI 1.12-13.31; p = 0.0236) was only significant predictor. In FFR ≤ 0.8 and iFR > 0.89 group (15 vessels, 14.3%), positive remodeling (PR) (OR 5.03, 95%CI 1.23-20.48, p = 0.0205) was significant predictor. In FFR > 0.8 and iFR ≤ 0.89 group (7 vessels, 6.7%), there were no significant predictors. On CCTA characteristics, a relevant predictor for FFR-positive findings included low L/M ratio. PR was significant predictor in FFR-positive, iFR-negative patients among those with discordance between the FFR and iFR.


Candida albicans virulence and drug-resistance requires the O-acyltransferase Gup1p.
GUP1 gene was primarily identified in Saccharomyces cerevisiae being connected with glycerol uptake defects in association with osmotic stress response. Soon after, Gup1p was implicated in a complex and extensive series of phenotypes involving major cellular processes. These include membrane and wall maintenance, lipid composition, bud-site selection, cytoskeleton orientation, vacuole morphology, secretory/endocytic pathway, GPI anchors remodelling, and lipid-ordered domains assembly, which is compatible with their inclusion in the Membrane Bound O-acyl transferases (MBOAT) family. In mammals, it has been described as a negative regulator of the Sonic hedgehog pathway involved in morphogenesis, differentiation, proliferation, among other processes. We show that Candida albicans Gup1p strongly interferes with the capacity of cells to develop hyphae, to adhere, to invade, and to form a biofilm, all of which are significant virulence factors. Furthermore, the mutant colonies exhibited an aberrant morphology/differentiation pattern. Identically to S. cerevisiae, Cagup1Δ null mutant was more resistant to antifungals like fluconazole, ketoconazole, and clotrimazole, and displayed an abnormal even sterol distribution at the plasma membrane. This work is the first study in the opportunistic yeast Candida albicans, showing a role for the GUP1 gene in virulence as well as in the mechanisms underlying antifungal resistance. Moreover, its impact is even more significant since these results, taken together with all the knowledge about GUP1 gene (from S. cerevisiae and mammals) give consistence to the possibility that Gup1p may be part of a yeast morphogenic pathway parallel to the mammalian Hedgehog.