STAT3 expression is a prognostic marker in upper urinary tract urothelial carcinoma.
Signal transducer and activator of transcription 3 (STAT3) plays a prominent role in the growth and invasion of several types of solid tumors. In this study, to assess the expression status and prognostic significance of the STAT3 pathway in upper urinary tract urothelial carcinoma (UTUC), we immunohistochemically stained for STAT3 and STAT3 pathway proteins, sphingosine-1-phosphate receptor 1 (S1PR1) and interleukin-6 (IL-6), in a tissue microarray containing 99 UTUC specimens. There were no significant associations between STAT3, S1PR1, or IL-6 expression pattern and tumor grade or pT stage. However, the patients with high STAT3 tumor had a significantly higher risk of both disease progression (p = 0.009) and cancer-specific mortality (p = 0.009), but not with tumors expressing S1PR1 or IL-6. High STAT3 expression in the nucleus was also associated with a significantly higher risk of both disease progression (p = 0.003) and cancer-specific mortality (p = 0.034). Multivariate analysis revealed that high STAT3 expression in the nucleus was significantly associated with cancer-specific survival after adjustment for pathological stage, lymph node involvement, lymphovascular invasion, and tumor grade (HR = 2.136, 95% CI = 1.009-4.767, p = 0.047). Our findings indicated that STAT3 could be a cancer-promoting factor and potentially a significant prognostic factor in UTUC.


Rosai-Dorfman Disease-Utility of 18F-FDG PET/CT for Initial Evaluation and Follow-up.
The role of imaging in the management of Rosai-Dorfman disease (RDD), a rare non-Langerhans cell histiocytosis, is not clearly defined. We present an analysis of FDG PET/CT findings obtained for initial disease characterization, follow-up evaluation, and treatment planning for this disease. From an institutional pathology database (2001-2018), we identified RDD patients who underwent FDG PET/CT scans either as part of clinical care or when done as part of clinical trials. For all scans, sites of abnormal FDG uptake were assessed, and SUVmax was measured. Comparison of PET/CT findings was made with anatomic (CT/MRI-based) imaging, where available. Instances of changing treatment based on PET/CT were recorded. We reviewed 109 FDG PET/CT scans in 27 patients with RDD. Five of 27 patients had only nodal/cutaneous disease, whereas 22 patients had extranodal disease, most commonly in bone (n = 9) and central nervous system (n = 7). PET/CT identified sites of active disease in 24 of 27 patients. All identified bone and extraskeletal lesions, except for a brain lesion in 1 patient, were FDG-avid. In 6 of 20 patients (30%) with available prior CT or MRI, PET/CT demonstrated additional RDD lesions (bones: n = 5, pleura: n = 1) that were not apparent on anatomic imaging; 3 of these lesions were outside the CT field of view, and 3 were not recognized on CT. Overall, 13 of 109 PET/CT scans led to a change in management, affecting 41% (11/27) of patients. FDG PET/CT was valuable in defining disease extent and optimizing treatment strategy in patients with RDD.


Selection of a multidrug resistance plasmid by sublethal levels of antibiotics and heavy metals.
How sublethal levels of antibiotics and heavy metals select for clinically important multidrug resistance plasmids is largely unknown. Carriage of plasmids generally confers substantial fitness costs, implying that for the plasmid-carrying bacteria to be maintained in the population, the plasmid cost needs to be balanced by a selective pressure conferred by, for example, antibiotics or heavy metals. We studied the effects of low levels of antibiotics and heavy metals on the selective maintenance of a 220-kbp extended-spectrum β-lactamase (ESBL) plasmid identified in a hospital outbreak of Klebsiella pneumoniae and Escherichia coli. The concentrations of antibiotics and heavy metals required to maintain plasmid-carrying bacteria, the minimal selective concentrations (MSCs), were in all cases below (almost up to 140-fold) the MIC of the plasmid-free susceptible bacteria. This finding indicates that the very low antibiotic and heavy metal levels found in polluted environments and in treated humans and animals might be sufficiently high to maintain multiresistance plasmids. When resistance genes were moved from the plasmid to the chromosome, the MSC decreased, showing that MSC for a specific resistance conditionally depends on genetic context. This finding suggests that a cost-free resistance could be maintained in a population by an infinitesimally low concentration of antibiotic. By studying the effect of combinations of several compounds, it was observed that for certain combinations of drugs each new compound added lowered the minimal selective concentration of the others. This combination effect could be a significant factor in the selection of multidrug resistance plasmids/bacterial clones in complex multidrug environments. Importance: Antibiotic resistance is in many pathogenic bacteria caused by genes that are carried on large conjugative plasmids. These plasmids typically contain multiple antibiotic resistance genes as well as genes that confer resistance to biocides and heavy metals. In this report, we show that very low concentrations of single antibiotics and heavy metals or combinations of compounds can select for a large plasmid that carries resistance to aminoglycosides, β-lactams, tetracycline, macrolides, trimethoprim, sulfonamide, silver, copper, and arsenic. Our findings suggest that the low levels of antibiotics and heavy metals present in polluted external environments and in treated animals and humans could allow for selection and enrichment of bacteria with multiresistance plasmids and thereby contribute to the emergence, maintenance, and transmission of antibiotic-resistant disease-causing bacteria.


Melioidosis of the head and neck.
Melioidosis is a potentially deadly infection that can affect any organ system. Reports of melioidosis of the ENT/head and neck region are relatively uncommon. Four cases are presented: (i) parotid abscess evolving into necrotising fasciitis, (ii) acute sinusitis and parapharyngeal cellulitis resulting in upper airway obstruction, (iii) acute suppurative lymphadenitis (iv) and chronic suppurative otitis media causing meningoencephalitis. Three of the four cases are believed to be unique, as a literature review of melioidosis in ENT/head and neck is also presented. Some practical issues of management are also discussed. Not suspecting melioidosis does not change contemporary empirical broadspectrum antibiotic therapy. The value of suspicion or on confirmation of diagnosis lies in anticipating and planning for rapid change.


Segregation of sublattice domains in nitrogen-doped graphene.
Atomic-level details of dopant distributions can significantly influence the material properties. Using scanning tunneling microscopy, we investigate the distribution of substitutional dopants in nitrogen-doped graphene with regard to sublattice occupancy within the honeycomb structure. Samples prepared by chemical vapor deposition (CVD) using pyridine on copper exhibit well-segregated domains of nitrogen dopants in the same sublattice, extending beyond 100 nm. On the other hand, samples prepared by postsynthesis doping of pristine graphene exhibit a random distribution between sublattices. On the basis of theoretical calculations, we attribute the formation of sublattice domains to the preferential attachment of nitrogen to the edge sites of graphene during the CVD growth process. The breaking of sublattice symmetry in doped graphene can have important implications in its electronic applications, such as the opening of a tunable band gap in the material.


Modulation of force development by Na+, K+, Na+ K+ pump and KATP channel during muscular activity.
Extracellular K+ concentration increases during exercise and especially during fatigue development. It has been proposed that K+ is an important factor in the etiology of skeletal muscle fatigue because it suppresses membrane excitability and eventually force development. Based on the effect of K+, it has then been proposed the Na+ K+ pump reduces increases in extracellular K+ concentration while the ATP-sensitive K+ channel (KATP channel) allows for rapid increases in extracellular K+ to suppress force development when ATP levels start to fall or when the levels of metabolic end-products become high. However, recent studies have now demonstrated that an increase in extracellular K+ concentration can be advantageous to muscle during exercise because it not only stimulates vasodilation and the exercise pressor reflex, but it also potentiates force development when the Na+ concentration gradient is maintained. A new hypothesis is therefore proposed in which the Na+ K+ pump is important in maintaining the Na+ concentration gradient (and not the K+ concentration gradient as previously suggested), while the activation of KATP channels is important to increase the K+ efflux and extracellular concentration. This situation then optimizes the development of force during exercise. Another hypothesis is proposed in which more KATP channels are activated while the activity of the Na+ K+ pump is reduced when ATP levels start to decrease to allow for an accumulation of intracellular Na+ and further increases in extracellular K+ concentration. These concentration changes then reduce membrane excitability and force development (i.e., fatigue) to protect muscle against large ATP depletion and function impairment.


Treatment response in relation to subthreshold bipolarity in patients with major depressive disorder receiving antidepressant monotherapy: a post hoc data analysis (KOMDD study).
The aim of this observational study was to determine whether subthreshold bipolarity affects treatment response and remission in patients with major depressive disorder receiving antidepressant (AD) monotherapy over a 6-month follow-up period. Seventy-eight patients with major depressive disorder were stratified into two subgroups according to the presence of subthreshold bipolarity, identified using the Korean version of the Mood Disorder Questionnaire (K-MDQ), which classifies patients as positive for a screening of bipolarity based on the cutoff for the total K-MDQ score (ie, 7 points). They received AD monotherapy such as escitalopram, sertraline, paroxetine, or tianeptine for 6 months. The Beck Depression Inventory (BDI), Hamilton Depression Rating Scale (HAMD), Hamilton Anxiety Scale, and Beck Scale for Suicide Ideation were applied at baseline, 1 week, 3 weeks, 2 months, 3 months, and 6 months. The mean HAMD, BDI, and Beck Scale for Suicide Ideation scores were higher in the bipolarity group than in the nonbipolarity group at 3 weeks. The mean BDI score was also higher in the bipolarity group than in the nonbipolarity group at 6 months. Evaluation of the ratio of improvement for each scale revealed different patterns of percentage changes between the two groups over the 6-month follow-up period. Furthermore, the response and remission rates (as assessed using BDI and HAMD scores) were higher in the nonbipolarity group than in the bipolarity group, with the exception of HAMD scores at the 3-week follow-up time point. The findings of this study showed that depressed patients with bipolarity had a worse response to AD monotherapy than did those without bipolarity.


Role of chondroitin sulfate-hyaluronan interactions in the viscoelastic properties of extracellular matrices and fluids.
The purpose of this study was to investigate the role of chondroitin sulfate-hyaluronan interactions in the viscoelastic properties of tissues and fluids, using capillary and cone-on-plate viscometers. Chondroitin sulfate markedly increased the viscosity of hyaluronan solutions at a wide range of hyaluronan mass (50-1900 kDa) under physiological conditions of pH, temperature, ionic strength and glycosaminoglycan concentration (0.5-40 mg/ml), although the viscosity of the chondroitin sulfate solutions themselves was very low. In the assay using a cone-on-plate viscometer, chondroitin sulfate increased the viscosity of hyaluronan solutions at various shear rates. At low shear rates, the viscosity of a chondroitin sulfate (5 mg/ml)-hyaluronan (0.5 mg/ml) mixture was about 40% of that of an aggrecan (5 mg/ml)-hyaluronan (0.5 mg/ml) mixture, and at 2.8-fold higher concentrations, chondroitin sulfate elicited the same effect on the viscosity of hyaluronan solutions (5 mg/ml) as an aggrecan monomer. In the presence of oscillatory motion, the addition of aggrecan increased the elasticity (storage) modulus G' and the viscosity (loss) modulus G" of hyaluronan solutions and markedly decreased the loss tangent G"/G' at frequencies corresponding to normal joint movements. In contrast, chondroitin sulfate had only a marginal effect on the loss tangent G"/G', although it increased G' and G". These findings demonstrated that chondroitin sulfate, as well as aggrecan, increases the viscosity of hyaluronan solutions, although chondroitin sulfate has less effect on the elasticity of hyaluronan solutions than that of aggrecan, and suggest that chondroitin sulfate may play an important physiological role in determining the viscoelastic properties of extracellular matrices and fluids.


Alzheimer disease: quantitative analysis of I-123-iodoamphetamine SPECT brain imaging.
To enable a more quantitative diagnosis of senile dementia of the Alzheimer type (SDAT), the authors developed and tested a semiautomated method to define regions of interest (ROIs) to be used in quantitating results from single photon emission computed tomography (SPECT) of regional cerebral blood flow performed with N-isopropyl iodine-123-iodoamphetamine. SPECT/IMP imaging was performed in ten patients with probable SDAT and seven healthy subjects. Multiple ROIs were manually and semiautomatically generated, and uptake was quantitated for each ROI. Mean cortical activity was estimated as the average of the mean activity in 24 semiautomatically generated ROIs; mean cerebellar activity was determined from the mean activity in separate ROIs. A ratio of parietal to cerebellar activity less than 0.60 and a ratio of parietal to mean cortical activity less than 0.90 allowed correct categorization of nine of ten and eight of ten patients, respectively, with SDAT and all control subjects. The degree of diminished mental status observed in patients with SDAT correlated with both global and regional changes in IMP uptake.


Mechanism of platelet inhibition by nitric oxide: in vivo phosphorylation of thromboxane receptor by cyclic GMP-dependent protein kinase.
Nitric oxide (NO) is a potent vasodilator and inhibitor of platelet activation. NO stimulates production of cGMP and activates cGMP-dependent protein kinase (G kinase), which by an unknown mechanism leads to inhibition of Galphaq-phospholipase C-inositol 1, 4,5-triphosphate signaling and intracellular calcium mobilization for several important agonists, including thromboxane A2 (TXA2). To explore the mechanism of platelet inhibition by NO, activation of platelet TXA2 receptors in the presence of cGMP was studied. The nonhydrolyzable analog 8-bromo-cyclic GMP (8-Br-cGMP) potently inhibited activation of the TXA2-specific GTPase in platelet membranes in a concentration-dependent fashion, suggesting that G kinase catalyzes the phosphorylation of some proximal component of the receptor-G protein signaling pathway. Nanomolar concentrations of G kinase were found to catalyze the phosphorylation of platelet TXA2 receptors in vitro, but not Galphaq copurifying with the TXA2 receptors in these experiments. Using immunoaffinity methods, in vivo phosphorylation of TXA2 receptors by cyclic GMP was demonstrated from 32P-labeled cells treated with 8-Br-cGMP. Peptide mapping studies of in vivo phosphorylated TXA2 receptors demonstrated cGMP mediates phosphorylation of the carboxyl terminus of the TXA2 receptor. G kinase also catalyzed the phosphorylation of peptides corresponding to the cytoplasmic tails of both alpha and beta forms of the receptor but not control peptide or a peptide corresponding to the third intracytoplasmic loop of the TXA2 receptor. These data identify TXA2 receptors as cGMP-dependent protein kinase substrates and support a novel mechanism for the inhibition of cell function by NO in which activation of G kinase inhibits signaling by G protein-coupled receptors by catalyzing their phosphorylation.


[Sprains and dislocations of the wrist joint and carpal bones].
In case of persistent swelling and painful limitation of mobility, "distorsion" can be accepted as the definitive diagnosis, only if osseous and ligamentous injuries of the wrist and carpus have been ruled out with sufficient certainty. According to current knowledge multiform injuries of the carpus originate from a three dimensional impact of forces, which besides the well-known hyperextension and ulnar deviation of the wrist include intercarpal supination as a rotatory component. Depending on the effective forces and due to the biomechanical strength of the restraining ligaments (which changes in relation to carpal declination), a progressive perilunar instability develops around the lunate bone, extending from the radial to the ulnar side of the radiocarpal joint.


Effects of dietary starch source on electrophysiological intestinal epithelial properties and intestinal glucose uptake in growing goats.
In ruminants, the potential benefit of by-pass starch to improve energy supply is under discussion. As efficient intestinal starch digestion and monosaccharide absorption are important prerequisites for an energetic benefit compared to ruminal fermentation, this study was conducted to characterise potential adaptations of intestinal tissues to different dietary starch sources qualitatively. The Ussing chamber technique was used to determine electrophysiological parameters of jejunal tissues and glucose flux rates. Kinetics of sodium-dependent glucose uptake into isolated brush-border membrane vesicles (BBMV) were calculated, and the expression level of sodium-dependent glucose transporter 1 (SGLT1) was determined. Samples were collected from goats that were assigned to three dietary treatments differing in starch content (hay/concentrate) and starch source (wheat/corn). Additionally, ingesta samples were analysed for starch and glucose contents. Jejunal tissues from hay-fed animals showed higher tissue conductances (G t) and numerically higher short-circuit currents (I sc). Unidirectional glucose flux rates were higher for hay-fed animals, whereas net flux rates were unaffected. The maximal glucose transport capacity into BBMV was increased for concentrate-fed animals, but the affinity and SGLT1 expression were not affected. Our results may indicate an adaptation of glucose uptake via SGLT1 to variations in dietary starch but it could not be excluded that intestinal uptake capacity was saturated under the given conditions or that the measured capacity was sufficient for absorption of available glucose.


IRDC-Net: An Inception Network with a Residual Module and Dilated Convolution for Sign Language Recognition Based on Surface Electromyography.
Deaf and hearing-impaired people always face communication barriers. Non-invasive surface electromyography (sEMG) sensor-based sign language recognition (SLR) technology can help them to better integrate into social life. Since the traditional tandem convolutional neural network (CNN) structure used in most CNN-based studies inadequately captures the features of the input data, we propose a novel inception architecture with a residual module and dilated convolution (IRDC-net) to enlarge the receptive fields and enrich the feature maps, applying it to SLR tasks for the first time. This work first transformed the time domain signal into a time-frequency domain using discrete Fourier transformation. Second, an IRDC-net was constructed to recognize ten Chinese sign language signs. Third, the tandem CNN networks VGG-net and ResNet-18 were compared with our proposed parallel structure network, IRDC-net. Finally, the public dataset Ninapro DB1 was utilized to verify the generalization performance of the IRDC-net. The results showed that after transforming the time domain sEMG signal into the time-frequency domain, the classification accuracy (acc) increased from 84.29% to 91.70% when using the IRDC-net on our sign language dataset. Furthermore, for the time-frequency information of the public dataset Ninapro DB1, the classification accuracy reached 89.82%; this value is higher than that achieved in other recent studies. As such, our findings contribute to research into SLR tasks and to improving deaf and hearing-impaired people's daily lives.


Recurrent Metastatic Breast Cancer in Internal Mammary Lymph Nodes along the Translocated Left Internal Mammary Artery Bypass Graft.
Internal mammary lymph node (IMLN) is the second most common site for nodal metastases in breast cancer. The authors present a case of a 58-year-old woman with a history of coronary artery bypass graft surgery 1 year prior who presented with a neck mass. Imaging showed an enlarged IMLN along the course of the translocated left internal mammary artery (LIMA) bypass graft on the surface of the heart, and the patient was later proven to have recurrent breast cancer. To the authors' knowledge, this is the first case report in the literature of a breast cancer recurrence in an IMLN along the postoperative translocated LIMA bypass graft. Keywords: Adults, CT, PET/CT, Breast, Thorax, Lymphatic, Metastases © RSNA, 2021.


High-dose intravenous immunoglobulins: a promising therapeutic approach for idiopathic systemic capillary leak syndrome.
The systemic capillary leak syndrome (SCLS), also known as Clarkson's disease, is a life-threatening disorder of unknown cause. It is characterised by recurrent acute episodes of hypotension, weight gain and generalised oedema with haemoconcentration and hypoproteinaemia caused by paroxysmal capillary hyperpermeability with a shift of plasma fluid from the intravascular to the interstitial space. We report the case of a 40-year-old woman with chronic SCLS treated with high-dose intravenous immunoglobulins, after a prophylactic therapy with theophylline and terbutaline was poorly tolerated and failed to decrease the frequency and severity of the attacks sufficiently.


Generating explanations and tutorial problems from Bayesian networks.
We present a system that generates explanations and tutorial problems from the probabilistic information contained in Bayesian belief networks. BANTER is a tool for high-level interaction with any Bayesian network whose nodes can be classified as hypotheses, observations, and diagnostic procedures. Users need no knowledge of Bayesian networks, only familiarity with the particular domain and an elementary understanding of probability. Users can query the knowledge base, identify optimal diagnostic procedures, and request explanations. We describe BANTER's algorithms and illustrate its application to an existing medical model.


Severe sepsis during pregnancy.
Severe sepsis is a major cause of mortality among critically ill patients. Early recognition accompanied by early initiation of broad-spectrum antibiotics with source control and fluid resuscitation improves outcomes. Hemodynamic resuscitation starts with fluid therapy followed by vasopressors if necessary. Cases refractory to first-line vasopressors (norepinephrine) will require second-line vasopressors (epinephrine or vasopressin) and low-dose steroid therapy. Resuscitation goals should include optimization of central venous oxygenation and serum lactate.


Stroke and atrial fibrillation: to anticoagulate or not.
After reviewing these published studies, I think one can conclude that in the patient population with chronic and/or paroxysmal atrial fibrillation, warfarin is beneficial and the benefits outweigh the risks. However, it is important to point out that patients at high risk for embolic disease, for example, dilated cardiomyopathy patients, were rarely included in these trials. The five trials mentioned above do not address this patient population. Current opinion is that these individuals should receive anticoagulation despite the lack of objective evidence that anticoagulation is beneficial if the risk of bleeding is not excessive. The five trials also do not address the population of patients categorized as having "lone atrial fibrillation," that is, atrial fibrillation occurring in patients with no structural heart disease. The general consensus in the low embolic risk patient, (i.e., the patient < 60 years of age who has lone atrial fibrillation) is that the risk of anticoagulation is greater than the benefit. My final thought on the subject concerns the risk of pulmonary emboli in this patient population. My guess is that this group of patients is at high risk for small pulmonary emboli, which in many instances may be subclinical--for example, clots too small to result in persistent tachypnea or tachycardia. As far as I can tell, there are no randomized trials on the prevention of pulmonary emboli in patients with chronic or paroxysmal atrial fibrillation using anticoagulation or aspirin. I guess the systemic emboli trial data are sufficient to indicate a protective effect on the lungs as well as on the brain.(ABSTRACT TRUNCATED AT 250 WORDS)


FaStaNMF: a Fast and Stable Non-negative Matrix Factorization for Gene Expression.
Gene expression analysis of samples with mixed cell types only provides limited insight to the characteristics of specific tissues. In silico deconvolution can be applied to extract cell type specific expression, thus avoiding prohibitively expensive techniques such as cell sorting or single-cell sequencing. Non-negative matrix factorization (NMF) is a deconvolution method shown to be useful for gene expression data, in part due to its constraint of non-negativity. Unlike other methods, NMF provides the capability to deconvolve without prior knowledge of the components of the model. However, NMF is not guaranteed to provide a globally unique solution. In this work, we present FaStaNMF, a method that balances achieving global stability of the NMF results, which is essential for inter-experiment and inter-lab reproducibility, with accuracy and speed. Results: FaStaNMF was applied to four datasets with known ground truth, created based on publicly available data or by using our simulation infrastructure, RNAGinesis. We assessed FaStaNMF on three criteria - speed, accuracy, and stability, and it favorably compared to the standard approach of achieving reproduceable results with NMF. We expect that FaStaNMF can be applied successfully to a wide array of biological data, such as different tumor/immune and other disease microenvironments.


Expression of Histidine Decarboxylase and Its Roles in Inflammation.
Histamine is a well-known mediator of inflammation that is released from mast cells and basophils. To date, many studies using histamine receptor antagonists have shown that histamine acts through four types of receptors: H1, H2, H3, and H4. Thus, histamine plays more roles in various diseases than had been predicted. However, our knowledge about histamine-producing cells and the molecular mechanisms underlying histamine production at inflammatory sites is still incomplete. The histamine producing enzyme, histidine decarboxylase (HDC), is commonly induced at inflammatory sites during the late and chronic phases of both allergic and non-allergic inflammation. Thus, histamine levels in tissues are maintained at effective concentrations for hours, enabling the regulation of various functions through the production of cytokines/chemokines/growth factors. Understanding the regulation of histamine production will allow the development of a new strategy of using histamine antagonists to treat inflammatory diseases.


Effect of Dietary Ramie Powder (Boehmeria nivea) at Various Levels on Growth Performance, Carcass and Meat Qualities, Biochemical Indices, and Antioxidative Capacity of Linwu Ducks.
Current experiment was designed to check the effect of dietary supplementation of ramie powder on the growth performance, carcass and meat qualities and antioxidative capacity of Linwu ducks. A total of 312 ducks at 21-day-age were equally divided into 4 groups, fed with control diet, control diet supplemented of 3, 6, or 12% ramie powder, respectively. The results showed that dietary supplementation of 6 and 12% ramie powder increased the final weight and daily body weight gain (P < 0.05), and dietary supplementation of 6% ramie improved the cooking loss of the leg meat 45-mins-postmortem compared with the control group (P < 0.05). Moreover, dietary supplementation of 6% ramie powder promoted the antioxidative capacity of the ducks by increasing the serum activities of superoxide dismutase and glutathione (P < 0.05), as well as the mRNA expressions of glutathione peroxidase 1 in the breast meat and superoxide dismutase 1 in the leg meat (P < 0.05). This experiment demonstrated that dietary supplementation of ramie powder showed beneficial efficacy on the growth performance of Linwu ducks. It corroborated the potential of dietary ramie being used as poultry feed ingredient and suggested that 6% was the proper supplementation rate of ramie powder in Linwu ducks' feed.


Inter-hospital extracorporeal life support.
A 60-year-old man with history of hypertension and unspecified left ventricular dysfunction had chest pain at home at 9 am. At 1 pm he was transported to a peripheal hospital and treated for acute myocardial infarction. At 4.30 pm, despite pharmacological and intra aortic balloon pump support , the extreme hemodynamic instability and the echocardiographic signs forced the doctors in charge to contact the "extracorporeal membrane oxygenation team" of our Intensive Care Unit. The team, that in our hospital is composed of an intensivist, a cardiac surgeon, a perfusionist and a nurse, reached the hospital at 5.15 pm and performed a percutaneous cannulation of right femoral artery and left femoral vein connecting the patient to the extracorporeal membrane oxygenation circuit. At 6.30 pm the patient on extracorporeal membrane oxygenation was transferred by ambulance to the Cardiac Surgery Intensive Care Unit of San Gerardo Hospital in Monza. On day 20 he was transferred back to the original hospital without neurological deficits, with normal renal function and normal blood gas analysis.


Substituent effects in nitro derivatives of carbazoles investigated by comparison of low-temperature crystallographic studies with density functional theory (DFT) calculations.
The crystal structure of 9H-carbazole, C12H9N, (I), has been redetermined at low temperature for use as a reference structure in a comparative study with the structures of 1-nitro-9H-carbazole, C12H8N2O2, (II), and 9-nitrocarbazole, C12H8N2O2, (III). The molecule of (I) has crystallographically imposed mirror symmetry (Z' = 0.5). All three solid-state structures are slightly nonplanar, the dihedral angles between the planes of the arene and pyrrole rings ranging from 0.40 (7)° in (III) to 1.82 (18)° in (II). Nevertheless, a density functional theory (DFT) study predicts completely planar conformations for the isolated molecules. To estimate the influence of nitro-group substitution on aromaticity, the HOMA (harmonic oscillator model of aromaticity) descriptor of π-electron delocalization has been calculated in each case. The HOMA indices for the isolated and solid-state molecules are relatively consistent and decrease in value for aromatic rings that are substituted with a π-electron-withdrawing nitro group. Substitution of the arene ring influences the π-electron delocalization in the ring only weakly, showing strong resistance to a perturbation of its geometry, contrary to what is observed for nitro substitution of the five-membered heterocyclic pyrrole ring. In (II), the molecules are arranged in near-planar dimers connected to each other by strong N-H···O hydrogen bonds that stack parallel to the crystallographic b axis. A similar stacking arrangement is observed in (III), although here the stacked structure is formed by stand-alone molecules.


Combined effect of foot arch structure and an orthotic device on stress fractures.
In a prospective study, quantitative measures of the structure of the longitudinal arch of the foot were established and related to the incidence of stress fractures in the bones of the lower limbs of military recruits. In addition, the role of a semirigid orthotic device (Langer military stress orthotic) in preventing stress fractures was evaluated as a function of the structure of the longitudinal arch. Femoral and tibial stress fractures were found to be more prevalent in the presence of feet with high arches, whereas the incidence of metatarsal fractures was higher in feet with low arches. The use of an orthotic device reduced the incidence of femoral stress fractures only in the presence of feet with high arches and the incidence of metatarsal fractures only among feet with low arches. The findings suggest that the normal foot with a low arch acts as a better shock absorber than the normal foot with a high arch, and that an orthotic device may improve the shock absorbing capacity of the arch.


Dual field-of-view step-zoom metalens.
A conventional optical zoom system is bulky, expensive, and complicated for real-time adjustment. Recent progress in metasurface research has provided a new solution to achieve innovative compact optical systems. In this Letter, we propose a highly integrated step-zoom lens with dual field of view (FOV) based on double-sided metasurfaces. With silicon nanobrick arrays of spatially varying orientations sitting on both sides of a transparent substrate, this ultrathin step-zoom metalens can be designed to focus an incident circular polarized beam with handedness-dependent FOVs without varying the focal plane, which is important for practical applications. The proposed dual FOV step-zoom metalens, with advantages such as ultracompactness, flexibility, and replicability, can find applications in fields that require ultracompact zoom imaging and beam focusing.


Access to Methotrexate Monitoring in Latin America: A Multicountry Survey of Supportive Care Capacity.
High-dose methotrexate (HDMTX) is used to treat a broad spectrum of cancers. Methotrexate (MTX) monitoring and adequate supportive care are critical for safe drug administration; however, MTX level timing is not always possible in low- and middle-income countries. The aim of this study was to evaluate HDMTX supportive care capacity and MTX monitoring practices in Latin America (LATAM) to identify gaps and opportunities for improvement. A multicenter survey was conducted among LATAM pediatric oncologists. Twenty healthcare providers from 20 institutions answered the online questionnaire. HDMTX was used to treat acute lymphoblastic leukemia (ALL; 100%), non-Hodgkin lymphoma (84.2%), diffuse large B-cell lymphoma (47.4%), osteosarcoma (78.9%), and medulloblastoma (31.6%). Delays in starting HDMTX infusion were related to bed shortages (47.4%) and MTX shortages (21.1%). MTX monitoring was performed at an in-hospital laboratory in 52%, at an external/nearby laboratory in 31.6%, and was not available in 10.5%. Median interval between sampling and obtaining MTX levels was ≤ 2 h in 45% and ≥ 6 h in 30%, related to laboratory location. Sites without access to MTX monitoring reduced the MTX dose for patients with high-risk ALL or did not include MTX in the treatment of patients with osteosarcoma. Respondents reported that implementation of point-of-care testing of MTX levels is feasible. In LATAM, highly variable supportive care capacity may affect the safe administration of MTX doses. Improving accessibility of MTX monitoring and the speed of obtaining results should be prioritized to allow delivery of full doses of MTX required by the current protocols.


Locus coeruleus.
The locus coeruleus (LC) contains norepinephrine (NE)-synthesizing neurons that send diffuse projections throughout the central nervous system. The LC-NE system has a major role in arousal, attention and stress responses. In the brain, NE may also contribute to long-term synaptic plasticity, pain modulation, motor control, energy homeostasis and control of local blood flow. The LC is severely affected in neurodegenerative disorders including Parkinson disease (PD). Involvement of the noradrenergic neurons of the LC precedes that of dopaminergic neurons of the substantia nigra pars compacta and has been increasingly recognized as a potential major contributor to cognitive manifestations in early PD, particularly impaired attention. Abnormal noradrenergic signaling may also potentially contribute to motor manifestations of the disease.This makes the LC-NE system a major contributor to the pathobiology and potential target for therapy of PD.


[Mechanisms of action and clinical importance of C3-nephritic-factor (author's transl)].
The C3-nephritic-factor is an autoantibody specific against C3-convertases. This IgG-immunoglobulin is particularly found in patients suffering from membranoproliferative glomerulonephritis and causes a complement-activation under elimination of physiological regulator mechanisms. The clinical importance of this factor is discussed.


In vitro growth and maturation of caprine oocytes.
This study was conducted to culture in vitro caprine pre-antral follicles for determining the competence of growth and maturation of oocytes and establishing a suitable culture system for oocyte maturation from pre-antral follicles. Two different culture methods (microdrop and agar gel clot) were employed to culture caprine pre-antral follicles. The pre-antral follicles were isolated from prepubertal goat ovaries by treatment with collagenase and DNase. The isolated pre-antral follicles were cultured in basic culture medium for 9 days (for growth). And oocytes were cultured in maturation culture medium for another 2 days for maturation. The result demonstrated that the growth rate of oocytes cultured in microdrops was significantly (p < 0.05) higher than that in agar gel clots, whereas the viability of oocytes in microdrops was considerably (p < 0.05) lower than that in agar gel clots. The oocytes grew over 150 microm in diameter, and two of 151 oocytes cultured in microdrops yielded morphologically abnormal first polar bodies. However, the size of oocytes cultured in agar gel approached to 120 microm in diameter and no polar body was produced.


D-serine in glia and neurons derives from 3-phosphoglycerate dehydrogenase.
d-Serine is an endogenous ligand for NMDARs generated from l-serine by the enzyme serine racemase (Srr). Both neuronal and glial localizations have been reported for d-serine and Srr. 3-Phosphoglycerate dehydrogenase is an exclusively astrocytic enzyme that catalyzes the first committed step of l-serine biosynthesis. Using transgenic mice expressing enhanced green fluorescent protein under the Srr promoter and mice with targeted deletion of Srr or 3-Phosphoglycerate dehydrogenase, we demonstrate predominantly neuronal sources of d-serine dependent on astrocytic supply of l-serine. These findings clarify the cellular basis for the regulation of NMDAR neurotransmission by d-serine.


[Pharmacokinetics, biological availability and residues of sulfadoxine and trimethoprim when used jointly on calves].
In calves (cross-breds--Bulgarian Brown Cattle breed and Black Spot Cattle bred) weighing about 189 kg pharmacokinetics of sulphadoxine (SD) and trimethoprim (TMP) was studied. The two substances were administered in combination (5 + 1) as a dosage form Tridoxin (Pharmachim, Bulgaria; 24% injectable solution) (TD) at a dose 15 mg/kg m. The results show that after intramuscular administration TD is absorbed relatively rapidly. SD and TMP have systemic availability 94.1 +/- 18.1% and 52.5 +/- 6.2% and produce blood levels, after a single dose of TD, higher than potentiated minimum inhibitory concentrations for 24-48 h and 5(4-8) h, respectively. Upon intravenous administration the two-compartmental model is applicable for the distribution and elimination of SD and TMP (for TMP in part of the animals one-compartmental model is applicable). The two substances are distributed relatively widely in organs and tissues. The biological half-life of TD--t1/2 beta for SD is 14.36 +/- 1.40 h and for TMP--2.40 +/- 0.31 (for one-compartmental model--1.92 +/- 0.26) h, Vd--429.9 +/- 16.9 ml/kg and for TMP in part of the animals one-compartmental model is applicable). The two substances are distributed relatively widely in organs and tissues. The biological half-life of TD--t1/2 beta for SD is 14.36 +/- 1.40 h and for TMP--2.40 +/- 0.31 (for one-compartmental model--1.92 +/- 0.26) h, Vd--429.9 +/- 16.9 ml/kg and for TMP in part of the animals one-compartmental model is applicable). The two substances are distributed relatively widely in organs and tissues. The biological half-life of TD--t1/2 beta for SD is 14.36 +/- 1.40 h and for TMP--2.40 +/- 0.31 (for one-compartmental model--1.92 +/- 0.26) h, Vd--429.9 +/- 16.9 ml/kg and 655.8 +/- 77.6 (for one-compartmental model--671.7 +/- 40.0) ml/kg, ClB--0.35 +/- 0.02 ml/kg/min and 2.87 +/- 0.35 (for one-compartmental model--4.15 +/- 0.80) ml/kg/min, respectively. After intramuscular injection at the dose used a suitable withdrawal time for meat and internal organs is 5 days and for milk--2 days.


Kinetics and mechanisms of the ozone/bromite and ozone/chlorite reactions.
Ozone reactions with XO(2)(-) (X = Cl or Br) are studied by stopped-flow spectroscopy under pseudo-first-order conditions with excess XO(2)(-). The O(3)/XO(2)(-) reactions are first-order in [O(3)] and [XO(2)(-)], with rate constants k(1)(Cl) = 8.2(4) x 10(6) M(-1) s(-1) and k(1)(Br) = 8.9(3) x 10(4) M(-1) s(-1) at 25.0 degrees C and mu = 1.0 M. The proposed rate-determining step is an electron transfer from XO(2)(-) to O(3) to form XO(2) and O(3)(-). Subsequent rapid reactions of O(3)(-) with general acids produce O(2) and OH. The OH radical reacts rapidly with XO(2)(-) to form a second XO(2) and OH(-). In the O(3)/ClO(2)(-) reaction, ClO(2) and ClO(3)(-) are the final products due to competition between the OH/ClO(2)(-) reaction to form ClO(2) and the OH/ClO(2) reaction to form ClO(3)(-). Unlike ClO(2), BrO(2) is not a stable product due to its rapid disproportionation to form BrO(2)(-) and BrO(3)(-). However, kinetic spectra show that small but observable concentrations of BrO(2) form within the dead time of the stopped-flow instrument. Bromine dioxide is a transitory intermediate, and its observed rate of decay is equal to half the rate of the O(3)/BrO(2)(-) reaction. Ion chromatographic analysis shows that O(3) and BrO(2)(-) react in a 1/1 ratio to form BrO(3)(-) as the final product. Variation of k(1)(X) values with temperature gives Delta H(++)(Cl) = 29(2) kJ mol(-1), DeltaS(++)(Cl) = -14.6(7) J mol(-1) K(-1), Delta H(++)(Br) = 54.9(8) kJ mol(-1), and Delta S(++)(Br) = 34(3) J mol(-1) K(-1). The positive Delta S(++)(Br) value is attributed to the loss of coordinated H(2)O from BrO(2)(-) upon formation of an [O(3)BrO(2)(-)](++) activated complex.


Formation of protein/surfactant adsorption layer as studied by dilational surface rheology.
The review discusses the mechanism of formation of protein/surfactant adsorption layers at the liquid - gas interface. The complexes of globular proteins usually preserve their compact structure a low surfactant concentrations. Therefore a simple kinetic model of the adsorption of charged compact nanoparticles is discussed first and compared with experimental data. The increase of surfactant concentrations results in various conformational transitions in the surface layer. One can obtain information on the changes of the adsorption layer structure using the dilational surface rheology. The kinetic dependencies of the dynamic surface elasticity are strongly different for the adsorption of unfolded macromolecules and compact globules, and have local maxima in the former case corresponding to different steps of the adsorption. These distinctions allow tracing the changes of the tertiary structure of protein/surfactant complexes in the surface layer. The adsorption from mixed solutions of ionic surfactants with β-casein, β-lactoglobulin, bovine serum albumin and myoglobin is discussed with some details.


[Treatment of fracture of neck of femur in the aged with hollow compression screw].
To summarize the clinical results of hollow compression screw in treatment of fracture of neck of femur in the aged. From November 1993 to October, 1998, 52 aged patients with several types of fracture of neck of femur were treated; among them, there were 25 males and 27 females aged from 60 to 83 years (70 years on average). There were 48 cases of fresh fracture and 4 cases of old fracture. Forty-two cases were performed closed reduction internal fixation, 10 cases with open reduction internal fixation. All the patients could sit by themselves 4 to 6 days after operation, and could walk with a crutch 10 to 15 days after operation. The mobility of hip joint was nearly normal 4 weeks after operation. All the patients were followed 26 to 84 months, 48.5 months on average. Bone union was achieved in 50 cases, nonunion in 2 cases. The average healing time was 4.7 months. There were no other complications, such as ankylosis and muscular atrophy, but ischemic necrosis in 3 cases. This method has following advantages, convenient manipulation, less injury, stable fixation, and the short-term recovery, which avoid some common complications. It is a reliable method worthy of popularizing.


PROTEOMICS ANALYSIS OF OVEREXPRESSED PLASMA PROTEINS IN RESPONSE TO COLD ACCLIMATION IN Ostrinia furnacalis.
Many insects in temperate regions overwinter in diapause. In these insects, one of the metabolic adaptations to cold stress is the synthesis of responsive proteins. Using proteomic analysis, an investigation aimed to a better understanding of the molecular adaptation mechanisms to cold stress was carried out in Ostrinia furnacalis larva. Proteins were extracted from the larval hemolymph collected from both control and overwintering larva. By polyethylene glycol precipitation, approximately 560 protein spots were separated and visualized on two-dimensional (2D) gels after silver staining. Eighteen protein spots were found to be upregulated in overwinter larval plasma in different patterns. As an initial work, 13 of these proteins were identified using MALDI TOF/TOF MS. The differentially overexpressed proteins include heat shock 70 kDa cognate protein, small heat shock protein (sHSP), putative aliphatic nitrilase, arginine kinase, phosphoglyceromutase, triosephosphateisomerase, and glutathione transferase. Alterations in the levels of these proteins were further confirmed by qPCR. This study is the first analysis of differentially expressed plasma proteins in O. furnacalis diapause larvae under extremely low temperature conditions and gives new insights into the acclimation mechanisms responsive to cold stress. Our results also support the idea that energy metabolism, alanine and proline metabolism, and antioxidative reaction act in the cold acclimation of O. furnacalis diapause larvae.


An ancient role for collier/Olf/Ebf (COE)-type transcription factors in axial motor neuron development.
Mammalian motor circuits display remarkable cellular diversity with hundreds of motor neuron (MN) subtypes innervating hundreds of different muscles. Extensive research on limb muscle-innervating MNs has begun to elucidate the genetic programs that control animal locomotion. In striking contrast, the molecular mechanisms underlying the development of axial muscle-innervating MNs, which control breathing and spinal alignment, are poorly studied. Our previous studies indicated that the function of the Collier/Olf/Ebf (COE) family of transcription factors (TFs) in axial MN development may be conserved from nematodes to simple chordates. Here, we examine the expression pattern of all four mouse COE family members (mEbf1-mEbf4) in spinal MNs and employ genetic approaches in both nematodes and mice to investigate their function in axial MN development. We report that mEbf1 and mEbf2 are expressed in distinct MN clusters (termed "columns") that innervate different axial muscles. Mouse Ebf1 is expressed in MNs of the hypaxial motor column (HMC), which is necessary for breathing, while mEbf2 is expressed in MNs of the medial motor column (MMC) that control spinal alignment. Our characterization of Ebf2 knock-out mice uncovered a requirement for Ebf2 in the differentiation program of a subset of MMC MNs and revealed for the first time molecular diversity within MMC neurons. Intriguingly, transgenic expression of mEbf1 or mEbf2 can rescue axial MN differentiation and locomotory defects in nematodes (Caenorhabditis elegans) lacking unc-3, the sole C. elegans ortholog of the COE family, suggesting functional conservation among mEbf1, mEbf2 and nematode UNC-3. These findings support the hypothesis that genetic programs controlling axial MN development are deeply conserved across species, and further advance our understanding of such programs by revealing an essential role for Ebf2 in mouse axial MNs. Because human mutations in COE orthologs lead to neurodevelopmental disorders characterized by motor developmental delay, our findings may advance our understanding of these human conditions.


[Whole body MRI--diagnostic strategy of the future?].
Whole body magnetic resonance imaging (MRI) opens new opportunities in diagnostic radiology as systemic disease entities can be examined with high sensitivity. This can lead to a change of paradigm, so that not only organ-related but rather disease-specific MRI examination protocols can be applied which focus on the underlying pathophysiology of the disease. Whole body MRI has already been successfully used for several oncological and non-oncological indications. In addition, whole body MRI has broadened the discussion regarding its use for secondary prevention. Compared to computed tomography, MRI does not use radiation. Although whole body MRI is still in an early stage, the enormous medical and economical potential can be envisioned.


Influence of sodium tripolyphosphate coupled with (-)-epigallocatechin on the in vitro digestibility and emulsion gel properties of myofibrillar protein under oxidative stress.
The objective of this study was to investigate the effect of (-)-epigallocatechin (EGC; at 0, 10, and 100 μmol g-1 protein) coupled with sodium tripolyphosphate (STP) on the in vitro digestibility and emulsion gel properties of myofibrillar protein (MP) under oxidative stress. The addition of both EGC and STP inhibited protein carbonyl formation but promoted the loss of thiol and free amine groups. Combined with the results of tryptophan fluorescence, surface hydrophobicity, electrophoresis, and solubility, the presence of STP enhanced the covalent reactions between the quinone of EGC and the thiols and free amines of MP. The combination of EGC at 10 μmol g-1 and STP increased the protein digestion rate in the gastric tract and contributed to an improved emulsion gel structure with higher gel elasticity, strength, water-holding capacity, and oxidative stability. This improvement could be attributed to the moderation of MP-EGC cross-linking, which was homogeneously formed among the adsorbed and/or unadsorbed proteins. Thus, oil droplets adhered better to the gel matrix. However, EGC at 100 μmol g-1 coupled with STP led to the formation of excessive non-disulfide covalent bonds, which aggravated the aggregation of MP. This ultimately reduced the protein digestibility and the nutritional value, caused the coalescence of oil droplets as well as the collapse of the gel structure, and thus, an overall decrease in the gel properties and oxidative stability. These results indicated that the enhanced oxidative stability and gelling capacity of MP without nutrition deterioration can be attained through tripolyphosphate coupled with lower doses of EGC.


The emerging role of advanced nursing practice in acute pain management throughout Canada.
The purpose of this study was to describe the role qualifications and responsibilities related to advanced nursing practice in acute pain management across Canada. The Canadian Nurses Association national framework on advanced nursing practice was used as a guide to identify role components for nurses within this specialty. A self-administered questionnaire of fixed choice and open-ended questions was mailed to nurses in acute pain management throughout Canada. Respondents identified their primary role responsibilities as clinical, educational, and administrative. Role challenges included lack of administrative/colleague support, complexity of pain problems, role definition, and acceptance. Key areas of positive outcomes involved the patient as well as interdisciplinary and nursing teams. Nurses described the ability to provide continuity of care, patient and staff education, and leadership in pain management as important and rewarding. The role of advanced nursing practice in acute pain management throughout Canada is evolving. The affect of this role promises to enhance the quality of pain management for healthcare professionals and their patients.


Are archaebacteria merely derived 'prokaryotes'?
The archaebacteria are a group of prokaryotes which seem as distinct from the true bacteria (eubacteria) as they are from eukaryotes. The evidence on which this conclusion rests is of two types: genotypic (quantitative)--that is, comparative sequence studies, and phenotypic (qualitative)--that is, differences in various organismal characteristics. The differences between archaebacteria and true bacteria are so great, both quantitatively and qualitatively, that the two bacterial groups should be considered as representing separate primary lines of descent, each tracing directly back to the universal ancestor. Furthermore, this ancestor itself seems not to be a prokaryote; rather it was a far simpler type of organism, one properly called a progenote. If this is true, the discovery of archaebacteria marks a major advance in the biologist's attempts to understand the basis for the evolution of the cell.


Opposing roles of EGF in IFN-alpha-induced epithelial barrier destabilization and tissue repair.
Balance between damaging influences and repair mechanisms determines the degree of tissue deterioration by inflammatory and other injury processes. Destabilization of the proximal tubular barrier has been previously shown to be induced by IFN-alpha, a cytokine crucial for linking innate and adaptive immune responses. EGF was implicated in rescue mechanisms from renal injury. To study the interplay between the two processes, we determined if EGF can prevent IFN-alpha-induced barrier permeabilization. EGF did not counteract but even exacerbated the IFN-alpha-induced decrease of transepithelial electrical resistance in LLC-PK1 monolayers. For this effect Erk1/2 activation was necessary, linking barrier regulation to EGF-induced cell cycle progression. In contrast to its damage-intensifying effect, EGF also facilitated the regeneration of epithelial barrier function after the termination of IFN-alpha treatment. This effect was not mediated by Erk1/2 activation or cell proliferation since U0126, an Erk1/2 inhibitor, did not prevent but ameliorated recovery. However, EGF accelerated the downregulation of caspase-3 in recovering cells. Similarly, a pan-caspase inhibitor was able to block caspase activity and, concomitantly, promote restoration of barrier function. Thus, barrier repair might be linked to an EGF-mediated antiapoptotic mechanism. EGF appears to sensitize epithelial cells to the detrimental effects of IFN-alpha but also helps to restore barrier function in the healing phase. The observed dual effect of EGF might be explained by the different impact of proproliferative and antiapoptotic signaling pathways during and after cytokine treatment. The timing of epithelial exposure to damaging agents and repair factors was identified as a crucial parameter determining tissue fate.


Phase I study of biweekly paclitaxel and carboplatin for frail patients with advanced non-small cell lung cancer.
The aim of this phase I study was to determine the maximum tolerated dose (MTD) and to evaluate the toxicity of the biweekly paclitaxel and carboplatin combination chemotherapy in frail patients with advanced non-small cell lung cancer (NSCLC). Seventeen unresectable and previously untreated NSCLC patients participated in this study. Frail patients (>80 years old with PS 0-1 and adequate organ functions, or <80 years old with PS 2 or <80 with PS 0-1 and one inadequate organ function of bone marrow, liver, or kidney) of NSCLC were enrolled in this study. Both paclitaxel and carboplatin were administered on day 1 and repeated biweekly. The starting dose of paclitaxel 120 mg/m2 and carboplatin was AUC 3 /d on day 1 every 2 weeks for 4 to 8 cycles. Seventeen frail patients received a total of 1 to 10 cycles. The major hematologic toxicity was neutropenia. Nonhematologic toxicities, including numbness and constipation, were generally mild and reversible. The MTD of paclitaxel were determined as 140 mg/m2. The recommended phase II study dose of paclitaxel was determined as 120 mg/m2 with area under the curve 3 biweekly for 1 day. An objective response was observed in 8 of 17 patients (47%) with frail patients. The combination chemotherapy of biweekly paclitaxel and carboplatin appears to be tolerable and sufficiently effective in frail patients with NSCLC. A phase II trial is underway.


Occupational stress and health care use.
This study investigated the relationship between health care use and (a) stressful work events; (b) strain; (c) social support; (d) type of job and industry; and (e) the individual characteristics of control, commitment, and length of time in position. A sample of 260 individuals (95 men, 165 women) from two different industries was used. Correlational analyses suggested that health care claims and costs were positively related to stressful work events and strain and negatively related to employees' length of time in position. Industry type also played a role in predicting the health care variables. Multivariate analyses suggested that environmental, stressor, and strain variables accounted for up to 16% of the variance in health care costs and 21.5% of the variance in number of health care claims.


Biliverdin Protects the Isolated Rat Lungs from Ischemia-reperfusion Injury via Antioxidative, Anti-inflammatory and Anti-apoptotic Effects.
Biliverdin (BV) has a protective role against ischemia-reperfusion injury (IRI). However, the protective role and potential mechanisms of BV on lung IRI (LIRI) remain to be elucidated. Thus, we aimed to investigate the protective role and potential mechanisms of BV on LIRI. Lungs were isolated from Sprague-Dawley rats to establish an ex vivo LIRI model. After an initial 15 min stabilization period, the isolated lungs were subjected to ischemia for 60 min, followed by 90 min of reperfusion with or without BV treatment. Lungs in the I/R group exhibited significant decrease in tidal volume (1.44 ± 0.23 ml/min in I/R group vs. 2.41 ± 0.31 ml/min in sham group; P< 0.001), lung compliance (0.27 ± 0.06 ml/cmH2O in I/R group vs. 0.44 ± 0.09 ml/cmH2O in sham group; P< 0.001; 1 cmH2O=0.098 kPa), and oxygen partial pressure (PaO2) levels (64.12 ± 12 mmHg in I/R group vs. 114 ± 8.0 mmHg in sham group; P< 0.001; 1 mmHg = 0.133 kPa). In contrast, these parameters in the BV group (2.27 ± 0.37 ml/min of tidal volume, 0.41 ± 0.10 ml/cmH2O of compliance, and 98.7 ± 9.7 mmHg of PaO2) were significantly higher compared with the I/R group (P = 0.004, P< 0.001, and P< 0.001, respectively). Compared to the I/R group, the contents of superoxide dismutase were significantly higher (47.07 ± 7.91 U/mg protein vs. 33.84 ± 10.15 U/mg protein; P = 0.005) while the wet/dry weight ratio (P < 0.01), methane dicarboxylic aldehyde (1.92 ± 0.25 nmol/mg protein vs. 2.67 ± 0.46 nmol/mg protein; P< 0.001), and adenosine triphosphate contents (297.05 ± 47.45 nmol/mg protein vs. 208.09 ± 29.11 nmol/mg protein; P = 0.005) were markedly lower in BV-treated lungs. Histological analysis revealed that BV alleviated LIRI. Furthermore, the expression of inflammatory cytokines (interleukin-1β, interleukin-6, and tumor necrosis factor-β) was downregulated and the expression of cyclooxygenase-2, inducible nitric oxide synthase, and Jun N-terminal kinase was significantly reduced in BV group (all P< 0.01 compared to I/R group). Finally, the apoptosis index in the BV group was significantly decreased (P < 0.01 compared to I/R group). BV protects lung IRI through its antioxidative, anti-inflammatory, and anti-apoptotic effects.


Aneurysms of the Intracranial Segment of the Ophthalmic Artery Trunk: Case Report and Systematic Literature Review.
Aneurysms arising from the ophthalmic artery trunk (OAT) are very rare, particularly in the artery's intracranial course. The onset of a subarachnoid hemorrhage (SAH) from a ruptured OAT aneurysm in this segment is extremely rare. We present a case and discuss the anatomy, clinical significance, and therapeutic options for an aneurysm at this site. We also retrospectively analyzed the record of a patient with a ruptured aneurysm of the intracranial segment of the OAT and conducted a comprehensive and systematic review of the PubMed and Scopus databases for literature on this pathology. Only one case report of SAH from an aneurysm of the intracranial segment of the OAT was published in the literature. Only in our case was the intracranial OAT segment aneurysm discovered in the acute phase of SAH. Conventional angiography with three-dimensional acquisition may help detect aneurysms at this level. Detailed knowledge of the anatomy of the OAT is of paramount importance for both surgical and endovascular approaches. Surgical treatment is complex because of difficulties in accessing the orbital region and the risk of optic nerve and vascular injuries. Endovascular treatment, when feasible, could be a good alternative to reduce the risk of loss of vision related to surgical manipulation.


Transcriptional regulation of IFN-λ genes in hepatitis C virus-infected hepatocytes via IRF-3·IRF-7·NF-κB complex.
Hepatitis C virus (HCV) infection in hepatocytes stimulates innate antiviral responses including the production of type III interferons (IFN-λ), including IL-28A, IL-28B, and IL-29. However, the molecular mechanism(s) regulating the expression of IFN-λ genes in HCV-infected hepatocytes remains undefined. In this study, we examined regulatory elements involved in the induction of IFN-λ genes following HCV infection in hepatocytes and further determined the binding of specific transcription factor(s) to promoter regions of IFN-λ genes. Our studies reveal that the regulatory portion for IL-28A, IL-28B, and IL-29 genes is localized to a 1-kb region in their respective promoters. Notably, interferon regulatory factor (IRF)-3 and -7 are the key transcriptional factors for the induction of IL-28A and IL-28B genes, whereas NF-κB is an additional requirement for the induction of the IL-29 gene. Ligation of Toll-like receptors (TLR) 3, 7, 8, and 9, which also activate IRFs and NF-κB, resulted in more robust production of IFN-λ than that observed with HCV infection, verifying the importance of TLR pathways in IFN-λ production. Furthermore, the addition of IFN-λ to HCV-infected hepatocytes decreased viral replication and produced a concurrent reduction in microRNA-122 (miR-122). The decrease in viral replication was enhanced by the co-administration of IFN-λ and miR-122 inhibitor (miRIDIAN), suggesting that such combinatorial therapies may be beneficial for the treatment of chronic HCV infection.


Clinical Experience of the Klippel-Trenaunay Syndrome.
The Klippel-Trenaunay syndrome (KTS) is characterized by three clinical features, namely cutaneous capillary malformations, venous malformations, and soft tissue and/or bony hypertrophy of the extremities. The varied manifestations are attributed to the unpredictable clinical nature and prognosis of the syndrome. To elucidate the clinical characteristics of this disease, we reviewed a relatively large number of KTS patients who presented to our vascular anomalies center. We conducted a retrospective study with 19 patients who were diagnosed with KTS and treated in our vascular anomalies clinic between 2003 and 2014, and examined their demographic characteristics, their clinical features, and the treatments administered. The sex distribution was balanced, with 9 (47%) males and 10 (53%) females. The mean follow-up period was 4.1 years (range, 7 months-9 years). Most of the patients received conservative treatments such as medication or physiotherapy. Compression therapies such as wearing of elastic garments/bandages were also administered, and surgical interventions were considered only when the patients became excessively symptomatic. Other treatments included laser therapy and sclerotherapy, and all the treatments were adjusted according to each case, tailored to the conditions of the individual patients. KTS is an extremely rare, multifactorial disorder that induces widely varied symptoms. Because of this unique feature, plastic surgeons, when not careful, tend to attach a one-sided importance to typical symptoms such as limb hypertrophy or capillary malformation and thus overlook other symptoms and clinical features. KTS can be suspected in all infants who show capillary malformations or limb hypertrophy and require a multi-disciplinary approach for comprehensive management.


Changes in peripapillary and subfoveal choroidal thickness in patients with central retinal vein occlusion.
We sought to evaluate changes of mean peripapillary choroidal thickness (PCT) and subfoveal choroidal thickness (SFCT) over 12 months in patients with unilateral central retinal vein occlusion (CRVO). Our retrospective, observational study included 19 patients with treatment-naïve, unilateral CRVO who completed at least 12 months of follow-up period. Mean PCT and mean SFCT in CRVO-affected eyes and unaffected contralateral eyes were measured at each follow-up visit, and then compared. Differences between baseline and 12 months (ΔSFCT and ΔPCT) and percentage changes (ΔSFCT or ΔPCT/baseline×100%) were determined. We also investigated the predictive factors for visual outcome in the CRVO-affected eyes. In the CRVO-affected eyes, mean PCT was 146.7±41.9 μm at baseline, and 106.5±24.2 μm at 12 months (P < 0.001). Mean PCT of the contralateral eyes was 129.8±42.6 μm at baseline and 124.6±39.7 μm at 12 months (P = 0.089). Mean SFCT of CRVO-affected eyes was 225.8±77.9 μm at baseline, and 199.4±66.6 μm at 12 months (P = 0.009). Mean SFCT of the contralateral eyes was 218.4±83.0 μm at baseline, and 208.4±78.1 μm at 12 months (P = 0.089). Δ PCT was -41.6±25.3 μm in the CRVO-affected eyes, and -5.2±5.8 μm in the contralateral eyes (P<0.001). % PCT was -24.9±14.0% in the CRVO-affected eyes, and -4.0±0.4% in the contralateral eyes (P = 0.001). Δ SFCT was -26.4±24.6 μm in the CRVO-affected eyes, and -9.5±16.7μm in the contralateral eyes (P = 0.016). % SFCT was -10.4±9.8% in the CRVO-affected eyes, and -3.4±6.4% in the contralateral eyes (P = 0.015). Among the various factors, BCVA at baseline (β = 0.797, P = 0.001) and % SFCT (β = 0.712, P = 0.001) were significantly associated with visual outcome at 12 months in the CRVO-affected eyes. Both peripapillary and subfoveal choroidal thickness reduced significantly over 12 months in the CRVO-affected eyes, but not in the contralateral eyes. In addition, the absolute reduction amount and reduction ratio of PCT and SFCT were significantly greater in the CRVO-affected eyes than the contralateral eyes.


Machine learning in the diagnosis of asthma phenotypes during coronavirus disease 2019 pandemic.
During the coronavirus disease 2019 (COVID-19) pandemic, it has become a pressing need to be able to diagnose aspirin hypersensitivity in patients with asthma without the need to use oral aspirin challenge (OAC) testing. OAC is time consuming and is associated with the risk of severe hypersensitive reactions. In this study, we sought to investigate whether machine learning (ML) based on some clinical and laboratory procedures performed during the pandemic might be used for discriminating between patients with aspirin hypersensitivity and those with aspirin-tolerant asthma. We used a prospective database of 135 patients with non-steroidal anti-inflammatory drug (NSAID)-exacerbated respiratory disease (NERD) and 81 NSAID-tolerant (NTA) patients with asthma who underwent OAC. Clinical characteristics, inflammatory phenotypes based on sputum cells, as well as eicosanoid levels in induced sputum supernatant and urine were extracted for the purpose of applying ML techniques. The overall best ML model, neural network (NN), trained on a set of best features, achieved a sensitivity of 95% and a specificity of 76% for diagnosing NERD. The 3 promising models (i.e., multiple logistic regression, support vector machine, and NN) trained on a set of easy-to-obtain features including only clinical characteristics and laboratory data achieved a sensitivity of 97% and a specificity of 67%. ML techniques are becoming a promising tool for discriminating between patients with NERD and NTA. The models are easy to use, safe, and achieve very good results, which is particularly important during the COVID-19 pandemic.


Strong coupling theory of heavy fermion criticality II.
We present a theory of the scaling behavior of the thermodynamic, transport and dynamical properties of a three-dimensional metal governed by d-dimensional fluctuations at a quantum critical point, where the electron quasiparticle effective mass diverges. We determine how the critical bosonic order parameter fluctuations are affected by the effective mass divergence. The coupled system of fermions and bosons is found to be governed by two stable fixed points: the conventional weak-coupling fixed point and a new strong-coupling fixed point, provided the boson-boson interaction is irrelevant. The latter fixed point supports hyperscaling, characterized by fractional exponents. The theory is applied to the antiferromagnetic critical point in certain heavy fermion compounds, in which the strong-coupling regime is reached.


[Effects of polyphenols on activity of glycosyl hydrolases in the cecum of rats fed obesity inducing diets].
The results of experimental studies indicate that the preventive and therapeutic effects of polyphenols in obesity are accompanied by a significant decrease in the severity of dysbiosis caused by the predominance of fats and simple carbohydrates in the diet, especially fructose, and the restoration of the functional state of the microbiota. The aim of the work was to study the effect of quercetin and resveratrol - polyphenols, widely represented in the daily human diet, on the activity of bacterial glycosidases in rats receiving diets high in fructose or fat and fructose. Material and methods. Using spectrophotometric analysis, the activity of β-galactosidase (Gal), β-glucosidase (Glu) and β-glucuronidase (Gluс) was studied in the content of the cecum of Wistar rats receiving a semi-synthetic diet and a 20% solution of fructose instead of drinking water (hfr diet) or a semi-synthetic diet with a high (30%) fat content and a 20% solution of fructose instead of drinking water (hf/hfr diet). Results and discussion. Feeding rats with the hfr diet for 20 weeks led to the suppression of Gal activity by 35, Glu by 46 and Gluс by 31%. With the inclusion of quercetin in the hfr diet at a dose of 34 mg/kg b.w. enzyme activity was restored to the control values and exceeded the level of activity in rats fed hfr ration without quercetin by 60, 100 and 47%, respectively, for Gal, Glu, and Gluс. Feeding rats with the hf/hfr diet for 10 weeks did not have a significant impact on the activity of bacterial enzymes. The inclusion of resveratrol in the hf/hfr diet at a dose of 10 mg/kg b.w. resulted in a decrease in Glu activity by 58 and Gluс by 28%, and an increase in resveratrol dose to 100 mg/kg b.w. caused further suppression of Gal activity by 30, Glu by 76 and Gluc by 64% comparative to the activity in rats on the hf/hfr diet without resveratrol. Conclusion. The obtained data suggest that quercetin restores reduced by hfr diet activity of glycosyl hydrolases of the cecum microflora of rats, most likely due to an increase in the representation of the types of enzyme activity carriers. The suppressive effect of resveratrol on the activity of glycosyl hydrolases of the cecum microflora of rats fed a hf/hfr diet may be the result of its direct action on enzymes and is not associated with the effect on the composition of the intestinal microbiota.


Introduction: the plurality of modeling.
Philosophers of science have recently focused on the scientific activity of modeling phenomena, and explicated several of its properties, as well as the activities embedded into it. A first approach to modeling has been elaborated in terms of representing a target system: yet other epistemic functions, such as producing data or detecting phenomena, are at least as relevant. Additional useful distinctions have emerged, such as the one between phenomenological and mechanistic models. In biological sciences, besides mathematical models, models now come in three forms: in vivo, in vitro and in silico. Each has been investigated separately, and many specific problems they raised have been laid out. Another relevant distinction is disciplinary: do models differ in significant ways according to the discipline involved-medicine or biology, evolutionary biology or earth science? Focusing on either this threefold distinction or the disciplinary boundaries reveals that they might not be sufficient from a philosophical perspective. On the contrary, focusing on the interaction between these various kinds of models, some interesting forms of explanation come to the fore, as is exemplified by the papers included in this issue. On the other hand, a focus on the use of models, rather than on their content, shows that the distinction between biological and medical models is theoretically sound.


The influence of human settlement on the distribution and diversity of iron-oxidizing bacteria belonging to the Gallionellaceae in tropical streams.
Among the neutrophilic iron-oxidizing bacteria (FeOB), Gallionella is one of the most abundant genera in freshwater environments. By applying qPCR and DGGE based on 16S rRNA gene-directed primers targeting Gallionellaceae, we delineated the composition and abundance of the Gallionellaceae-related FeOB community in streams differentially affected by metal mining, and explored the relationships between these community characteristics and environmental variables. The sampling design included streams historically impacted by mining activity and a non-impacted stream. The sediment and water samples harbored a distinct community represented by Gallionella, Sideroxydans, and Thiobacillus species. Sequences affiliated with Gallionella were exclusively observed in sediments impacted by mining activities, suggesting an adaptation of this genus to these environments. In contrast, Sideroxydans-related sequences were found in all sediments including the mining impacted locations. The highest and lowest relative frequencies of Gallionellaceae-related FeOB were associated with the lowest and highest concentrations of Fe, respectively. The data enclosed here clearly show distinct species-specific ecological niches, with Gallionella species dominating in sediments impacted by anthropogenic activities over Sideroxydans species.


Use of an exotic host plant shifts immunity, chemical defense, and viral burden in wild populations of a specialist insect herbivore.
Defense against natural enemies constitutes an important driver of herbivore host range evolution in the wild. Populations of the Baltimore checkerspot butterfly, Euphydryas phaeton (Nymphalidae), have recently incorporated an exotic plant, Plantago lanceolata (Plantaginaceae), into their dietary range. To understand the tritrophic consequences of utilizing this exotic host plant, we examined immune performance, chemical defense, and interactions with a natural entomopathogen (Junonia coenia densovirus, Parvoviridae) across wild populations of this specialist herbivore. We measured three immune parameters, sequestration of defensive iridoid glycosides (IGs), and viral infection load in field-collected caterpillars using either P. lanceolata or a native plant, Chelone glabra (Plantaginaceae). We found that larvae using the exotic plant exhibited reduced immunocompetence, compositional differences in IG sequestration, and higher in situ viral burdens compared to those using the native plant. On both host plants, high IG sequestration was associated with reduced hemocyte concentration in the larval hemolymph, providing the first evidence of incompatibility between sequestered chemical defenses and the immune response (i.e., the "vulnerable host" hypothesis) from a field-based study. However, despite this negative relationship between IG sequestration and cellular immunity, caterpillars with greater sequestration harbored lower viral loads. While survival of virus-infected individuals decreased with increasing viral burden, it ultimately did not differ between the exotic and native plants. These results provide evidence that: (1) phytochemical sequestration may contribute to defense against pathogens even when immunity is compromised and (2) herbivore persistence on exotic plant species may be facilitated by sequestration and its role in defense against natural enemies.


Fibrinogen Levels Are Associated with Lymph Node Involvement and Overall Survival in Gastric Cancer Patients.
Combination of perioperative chemotherapy with gastrectomy with D2 lymphadenectomy improves long-term survival in patients with gastric cancer. The aim of this study was to investigate the predictive value of preoperative levels of CRP, albumin, fibrinogen, neutrophil-to-lymphocyte ratio and routinely used tumor markers (CEA, CA 19-9, CA 72-4) for lymph node involvement. This retrospective study was conducted in 136 patients who underwent surgery between 2007 and 2015. Bivariable and multivariable analyses were performed in order to identify important characteristics associated with the risk of lymph node involvement. Kaplan-Meier survival curves and log-rank tests were used to compare overall survival. Lymph node involvement was significantly affected by preoperative fibrinogen (p=0.008) and albumin (p=0.023). Poor clinical condition, T and N staging and fibrinogen level above 3.5 g/l were significantly associated with worse overall survival. Preoperative fibrinogen and albumin levels are significantly associated with lymphoid metastases in patients with gastric cancer.


Automatic detection of basal cell carcinoma by hyperspectral imaging.
The purpose of this study was to test the ability of hyperspectral imaging (HSI) combined with unsupervised anomaly detectors to automatically differentiate basal cell carcinoma (BCC) from normal skin. Hyperspectral images of the face of a female patient with a BCC of the lower lip were acquired using a visible/near-infrared HSI system and two anomaly detection algorithms (Reed-Xiaoli and Reed-Xiaoli/Uniform Target hybrid anomaly detectors) were used to detect pathological tissue from normal skin. The results revealed that the receiver operating characteristic curve of the Reed-Xiaoli/Uniform Target hybrid detector was higher than that of the Reed-Xiaoli detector in the range of false positive rates between 0 and 0.8. The area under curve values were good (0.7074 and 0.8607, respectively) with Reed-Xiaoli/Uniform Target hybrid detector performing better. In conclusion, HSI combined with either of two anomaly detectors can play a promising role in the automated screening of BCC.


Expression of the trefoil peptides pS2 and human spasmolytic polypeptide (hSP) in Barrett's metaplasia and the native oesophageal epithelium: delineation of epithelial phenotype.
The distribution of the two trefoil peptides pS2 and human spasmolytic polypeptide (hSP) and their mRNAs was investigated in 90 selected oesophageal biopsies, 23 of which contained epithelium with wholly gastric cardiac-type morphology, 52 specialized (intestinal)-type metaplasia, and 15 non-metaplastic oesophageal epithelium. No fundic-type epithelium was represented. The cardiac-type epithelium resembled true gastric antral epithelium, with hSP and pS2 mRNA localization to the superficial/foveolar compartment and hSP mRNA alone in deeper glands. The pattern of peptide distribution was broadly in line with the mRNA, but hSP peptide was generally not demonstrable in the surface epithelium. pS2 immunostaining was diffusely cytoplasmic, whereas in specialized-type mucosa it was aggregated and cytoplasmic. hSP mRNA was demonstrable in surface epithelium of incomplete- but not complete-type intestinal (specialized) metaplasia. Deep glands with morphological features of pyloric glands/ulcer-associated cell lineage (UACL) typically contained only hSP peptide and its mRNA. In three biopsies containing specialized epithelium, small foci morphologically identical to true small intestinal surface epithelium were seen in which only pS2 mRNA and peptide were found and then only in rare goblet cells. Neither squamous epithelium nor oesophageal glands contained demonstrable pS2/hSP mRNA or peptide. The function of these proteins in the metaplastic mucosa of Barrett's oesophagus is unknown but they may reflect an epithelium responding to repeated insult. Their localization facilitates definition of the disparate epithelium types seen in this portion of the gut, with both native gastric and intestinal epithelia, and may help to pinpoint high-risk epithelium in Barrett's oesophagus, a potentially preneoplastic condition.


Antigen-induced airway obstruction and the influence of vagus blockade.
Respiratory hypersensitivity to Ascaris antigens is carried out on 9 dogs. The participation of vagus reflex on this respiratory distress is studied in 4 of these dogs. The dogs were exposed initially to Ascaris aerosol, then to egg albumin and NaCl aerosol for control, and once more to Ascaris aerosol after bilateral vagi blockade and lavage, respectively. The principal parameters studied were deltaPoes (mm Hg)/100 ml TV as a measurement of flow resistance in the airways, and respiratory rates (Poes=changes of oesphagus pressure; TV=tidal volume). All the animals presented a significant respiratory distress with Ascaris aerosol, which could be clearly avoided with the central bilateral blockade of nervus vagus.


Ginsenoside Rh4 inhibits inflammation-related hepatocellular carcinoma progression by targeting HDAC4/IL-6/STAT3 signaling.
This study aimed to investigate the effects of Ginsenoside Rh4 (Rh4) on inflammation-related hepatocellular carcinoma (HCC) progression and the underlying mechanism. HCC cells (HUH7 and LM3) were induced by lipopolysaccharide (LPS) to establish an inflammatory environment in the absence or presence of Rh4. CCK-8, wound healing and transwell assays were employed to analyze the viability, migration and invasion of HCC cells. Ki67 expression was detected by immunofluorescence method. Besides, the levels of glucose and lactic acid were tested by kits. The expression of proteins related to migration, glycolysis and histone deacetylase 4 (HDAC4)/IL-6/STAT3 signaling was measured with western blot. The transplantation tumor model of HCC in mice was established to observe the impacts of Rh4 on the tumor growth. Results indicated that Rh4 restricted the viability and Ki67 expression in HCC cells exposed to LPS. The elevated migration and invasion of HCC cells triggered by LPS were reduced by Rh4. Additionally, Rh4 treatment remarkably decreased the contents of glucose and lactic acid and downregulated LDHA and GLUT1 expression. The database predicated that Rh4 could target HDAC4, and our results revealed that Rh4 downregulated HDAC4, IL-6 and p-STAT3 expression. Furthermore, the enforced HDAC4 expression alleviated the effects of Rh4 on the proliferation, migration, invasion and glycolysis of HCC cells stimulated by LPS. Taken together, Rh4 could suppress inflammation-related HCC progression by targeting HDAC4/IL-6/STAT3 signaling. These findings clarify a new anti-cancer mechanism of Rh4 on HCC and provide a promising agent to limit HCC development.


Patient and Microbial Genomic Factors Associated with Carbapenem-Resistant Klebsiella pneumoniae Extraintestinal Colonization and Infection.
Carbapenem-resistant Klebsiella pneumoniae (CRKP) is a critical-priority antibiotic resistance threat that has emerged over the past several decades, spread across the globe, and accumulated resistance to last-line antibiotic agents. While CRKP infections are associated with high mortality, only a subset of patients acquiring CRKP extraintestinal colonization will develop clinical infection. Here, we sought to ascertain the relative importance of patient characteristics and CRKP genetic background in determining patient risk of infection. Machine learning models classifying colonization versus infection were built using whole-genome sequences and clinical metadata from a comprehensive set of 331 CRKP extraintestinal isolates collected across 21 long-term acute-care hospitals over the course of a year. Model performance was evaluated based on area under the receiver operating characteristic curve (AUROC) on held-out test data. We found that patient and genomic features were predictive of clinical CRKP infection to similar extents (AUROC interquartile ranges [IQRs]: patient = 0.59 to 0.68, genomic = 0.55 to 0.61, combined = 0.62 to 0.68). Patient predictors of infection included the presence of indwelling devices, kidney disease, and length of stay. Genomic predictors of infection included presence of the ICEKp10 mobile genetic element carrying the yersiniabactin iron acquisition system and disruption of an O-antigen biosynthetic gene in a sublineage of the epidemic ST258 clone. Altered O-antigen biosynthesis increased association with the respiratory tract, and subsequent ICEKp10 acquisition was associated with increased virulence. These results highlight the potential of integrated models including both patient and microbial features to provide a more holistic understanding of patient clinical trajectories and ongoing within-lineage pathogen adaptation.IMPORTANCE Multidrug-resistant organisms, such as carbapenem-resistant Klebsiella pneumoniae (CRKP), colonize alarmingly large fractions of patients in regions of endemicity, but only a subset of patients develop life-threatening infections. While patient characteristics influence risk for infection, the relative contribution of microbial genetic background to patient risk remains unclear. We used machine learning to determine whether patient and/or microbial characteristics can discriminate between CRKP extraintestinal colonization and infection across multiple health care facilities and found that both patient and microbial factors were predictive. Examination of informative microbial genetic features revealed variation within the ST258 epidemic lineage that was associated with respiratory tract colonization and increased rates of infection. These findings indicate that circulating genetic variation within a highly prevalent epidemic lineage of CRKP influences patient clinical trajectories. In addition, this work supports the need for future studies examining the microbial genetic determinants of clinical outcomes in human populations, as well as epidemiologic and experimental follow-ups of identified features to discern generalizability and biological mechanisms.


Leptin receptor mutation results in defective neutrophil recruitment to the colon during Entamoeba histolytica infection.
Amebiasis is an enteric infection caused by Entamoeba histolytica, with symptoms ranging in severity from asymptomatic colonization to dysentery. Humans with the Q223R leptin receptor mutation have increased susceptibility to amebiasis, but the mechanism has been unclear. Using a mouse model expressing the mutation, we tested the impact of the Q223R mutation on the innate immune response to E. histolytica infection. The 223R mutation resulted in delayed clearance of amebae from the cecum, as had been previously observed. We found that neutrophil influx to the site of the infection was reduced 12 h after infection in 223R mice. Depletion of neutrophils with anti-Ly6G monoclonal antibody increased susceptibility of wild-type mice to infection, supporting the importance of neutrophils in innate defense. Leptin expression was increased in the cecum by E. histolytica infection, suggesting that leptin could serve as a homing signal for neutrophils to the gut. Interestingly, neutrophils from mice with the 223R mutation had diminished chemotaxis toward leptin. This impaired chemotaxis likely explained the reduced gut infiltration of neutrophils. The newly recognized effect of the leptin receptor Q223R mutation on neutrophil chemotaxis and the impact of this mutation on multiple infectious diseases suggest a broader impact of this mutation on susceptibility to disease. The Q223R leptin receptor mutation results in increased susceptibility of children and adults to E. histolytica, one of the leading causes of diarrhea morbidity and mortality in children of the developing world. Here we show that the mutation results in reduced neutrophil infiltration to the site of infection. This decreased infiltration is likely due to the mutation's impact on neutrophil chemotaxis toward leptin, an inflammatory agent upregulated in the cecum after infection. The significance of this work thus extends beyond understanding E. histolytica susceptibility by also providing insight into the potential impact of leptin on neutrophil function in other states of altered leptin signaling, which include both malnutrition and obesity.


The effects of cosmic particle radiation on pocket mice aboard Apollo XVII: appendix II. Evaluation of oral, dental, and skeletal tissues.
A sparse neutrophilic leukocytic infiltrate was found in the gingival sulcus, both in the flight and the control animals, while no changes were observed in the palate. Mitoses in gingival and palatal tissues were in approximately equal numbers in all animal groups. The tongues of flight mice and controls contained areas characterized by vascular dilatation, separation of muscle bundles, and regressive and degenerative changes in muscle fibers. Mucous glands in the posterior part of the tongue of flight and control animals exhibited acinar distension. Also examined were the vertebral column; femur, knee joint, tibia and fibula of the right hindlimb; and the tracheal cartilages. No evidence of cosmic ray particle effects was found in any of these tissues.


MATERNAL INHERITANCE AND ITS EFFECT ON ADAPTIVE EVOLUTION: A QUANTITATIVE GENETIC ANALYSIS OF MATERNAL EFFECTS IN A NATURAL PLANT POPULATION.
A mother can influence a trait in her offspring both by the genes she transmits (Mendelian inheritance) and by maternal attributes that directly affect that trait in her offspring (maternal inheritance). Maternal inheritance can alter the direction, rate, and duration of adaptive evolution from standard Mendelian models and its impact on adaptive evolution is virtually unexplored in natural populations. In a hierarchical quantitative genetic analysis to determine the magnitude and structure of maternal inheritance in the winter annual plant, Collinsia verna, I consider three potential models of inheritance. These range from a standard Mendelian model estimating only direct (i.e., Mendelian) additive and environmental variance components to a maternal inheritance model estimating six additive and environmental variance components: direct additive (σAo2) and environmental (σEo2) variances; maternal additive (σAm2) and environmental (σEm2) variances; and the direct-maternal additive (σApAm) and environmental (σEm2) covariances. The structure of maternal inheritance differs among the 10 traits considered at four stages in the life cycle. Early in the life cycle, seed weight and embryo weight display substantial σAm2, a negative σAoAm, and a positive σEoEm. Subsequently, cotyledon diameter displays σAo2 and σAm2 of roughly the same magnitude and negative σAoAm. For fall rosettes, leaf number and length are best described by a Mendelian model. In the spring, leaf length displays maternal inheritance with significant σAo2 and σAm2 and a negative σAoAm. All maternally inherited traits show significant negative σAoAm. Predicted response to selection under maternal inheritance depends on σAo2 and σAm2 as well as σAoAm. Negative σAoAm results in predicted responses in the opposite direction to selection for seed weight and embryo weight and predicted responses near zero for all subsequent maternally inherited traits. Maternal inheritance persists through the life cycle of this annual plant for a number of size-related traits and will alter the direction and rate of evolutionary response in this population.


Elective appendicovesicostomy in association with Monfort abdominoplasty in the treatment of prune belly syndrome.
To evaluate the role of elective appendicovesicostomy in association with Monfort abdominoplasty to avoid urinary tract infection (UTI) and renal damage in the post-operative follow-up of patients with prune belly syndrome. We followed 4 patients operated in our institution (UNIFESP) (Monfort, orchidopexy and Mitrofanoff) and compared them to 2 patients treated similarly, but without an appendicovesicostomy, in a second institution (UFBA). We evaluated postoperative clinical complications, UTI and preservation of renal parenchyma. Patients were followed as outpatients with urinalysis, ultrasonography (US) and occasionally with renal scintigraphy. Mean follow-up was 23.5 months. Immediate post-operative course was uneventful. We observed that only one patient with the Mitrofanoff channel persisted with UTI, while the 2 patients used as controls persisted with recurrent pyelonephritis (> 2 UTI year). Our data suggest that no morbidity was added by the appendicovesicostomy to immediate postoperative surgical recovery and that this procedure may have a beneficial effect in reducing postoperative UTI events and their consequences by reducing the postvoid residuals in the early abdominoplasty follow-up. However, we recognize that the series is small and only a longer follow-up with a larger number of patients will allow us to confirm our suppositions. We could not make any statistically significant assumptions regarding differences in renal preservation due to the same limitations.


Oxytocin ameliorates cisplatin-induced nephrotoxicity in Wistar rats.
The clinical use of cisplatin (CP) is highly limited because of its renal toxicity and the production of reactive oxygen species (ROS) that intensify the cytotoxic effects. Oxytocin (OT) was previously shown to have antioxidant activity. Experimental study on male Wistar albino rats performed in the Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia. Forty-eight male Wistar albino rats were classified into four equal groups: a control group, OT only-treated group which received OT twice (500 micro g/kg intraperitoneally (ip) 30 minutes and just before saline administration), a CP-induced nephrotoxicity group that received a single dose of CP (7.5 mg/kg ip) and treated with saline, and CP+OT group treated with the same previous doses. Seventy-two hours after CP administration, the rats were sacrificed and blood was withdrawn for determination of urea, creatinine, albumin and lactate dehydrogenase (LDH). The kidneys were extracted for histopathological examination and determination of the tissue levels of reduced glutathione (GSH), thiobarbituric acid reactive substances (TBARS) and nitric oxide end product nitrite (NO(2)). Glutathione S-transferase (GST), catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPx) and myeloperoxidase (MPO) activities were assessed. CP-induced renal injury was evidenced histopathologically and manifested by a significant increase in serum LDH activity as well as urea and creatinine levels. Moreover, renal injury was associated with decreased renal tissue activities of CAT, SOD, GPx and GST as well as GSH level. On the other hand, renal tissue content of TBARS and NO(2) as well as the activity of MPO were increased. Alterations in these biochemical and histopathological indices due to CP were attenuated by OT. OT protected rats from CP-induced nephrotoxicity. Such protection is attributed, at least in part, to its antioxidant activity.


Neurogenesis from Sox2 expressing cells in the adult cerebellar cortex.
We identified a rare undifferentiated cell population that is intermingled with the Bergmann glia of the adult murine cerebellar cortex, expresses the stem cell markers Sox2 and Nestin, and lacks markers of glial or neuronal differentiation. Interestingly, such Sox2+ S100- cells of the adult cerebellum expanded after adequate physiological stimuli in mice (exercise), and Sox2+ precursors acquired positivity for the neuronal marker NeuN over time and integrated into cellular networks. In human patients, SOX2+ S100- cells similarly increased in number after relevant pathological insults (infarcts), suggesting a similar expansion of cells that lack terminal glial differentiation.


[Pharmacology and mechanism of action of opiates administered by the subarachnoid route].
The sites of action of spinally administered opiates are specific receptors (mu kappa delta) located in the spinal dorsal horn. Pharmacokinetics of spinally administered opiates are determined by their lipophilic property. Morphine has a weak octanol-water partition coefficient and remains in the CSF during a long period following the cephalic movements of lumbar CSF to the supraspinal structures. More lipophilic opiates are rapidly eliminated from the CSF. Nevertheless, significant pethidine concentrations are documented in the ventricular CSF, due to vascular absorption of the drug. Pharmacokinetics features of different opiates determine the duration of analgesia and the risk of respiratory depression after spinal injection.