Psychological and social problems in HIV infection: interviews with general practitioners in London.
To assess current practice and opinions of general practitioners in London about managing psychological and social problems relating to HIV infection. A stratified random sample of general practitioners, including those with a range of experience of people with HIV infection, were interviewed by medically trained interviewers. Doctor's surgeries. 270 General practitioners working within the area covered by London postcodes. Two thirds of doctors had treated at least one patient with HIV infection and described their work with these patients. General practitioners were counselling and educating many of their patients about AIDS and associated risk behaviours and were aware of the need for careful attention to confidentiality. Doctors with no experience of patients with HIV infection were often older, in singlehanded practice, less inclined to deal with drug abusers or to counsel their patients on risk behaviours, and more in favour of insurance companies' policies towards people with HIV infection. General practitioners in London are quickly becoming involved in the care of patients with HIV infection and their relatives and friends. Many are counselling patients and testing for antibodies themselves and regard this as an integral part of their work. A considerable workload in primary care comprised patients who obsessively fear contracting HIV infection.


Glycans in the roles of parasitological diagnosis and host-parasite interplay.
The investigation of the glycan repertoire of several organisms has revealed a wide variation in terms of structures and abundance of glycan moieties. Among the parasites, it is possible to observe different sets of glycoconjugates across taxa and developmental stages within a species. The presence of distinct glycoconjugates throughout the life cycle of a parasite could relate to the ability of that organism to adapt and survive in different hosts and environments. Carbohydrates on the surface, and in excretory-secretory products of parasites, play essential roles in host-parasite interactions. Carbohydrate portions of complex molecules of parasites stimulate and modulate host immune responses, mainly through interactions with specific receptors on the surface of dendritic cells, leading to the generation of a pattern of response that may benefit parasite survival. Available data reviewed here also show the frequent aspect of parasite immunomodulation of mammalian responses through specific glycan interactions, which ultimately makes these molecules promising in the fields of diagnostics and vaccinology.


Transduction of proteins into leishmania tarentolae by formation of non-covalent complexes with cell-penetrating peptides.
Cell-penetrating peptides (CPPs) are used to transport peptides, proteins, different types of ribonucleic acids (or mimics of these molecules), and DNA into live cells, both plant and mammalian. Leishmania belongs to the class of protozoa having, in comparison to mammalian cells, a different lipid composition of the membrane, proteoglycans on the surface, and signal pathways. We investigated the uptake of two different and easily detectable proteins into the non-pathogenic strain Leishmania tarentolae. From the large number of CPPs available, six and a histone were chosen specifically for their ability to form non-covalent complexes. For Leishmania we used the enzyme β-galactosidase and fluorescent labeled bovine serum albumin as cargoes. The results are compared to similar internalization studies using mammalian cells [Mussbach et al., ]. Leishmania cells can degrade CPPs by a secreted and membrane-bound chymotrypsin-like protease. Both cargo proteins were internalized with sufficient efficiency and achieved intramolecular concentrations similar to mammalian cells. The transport efficiencies of the CPPs differed from each other, and showed a different rank order for both cargoes. The intracellular distribution of fluorescent-labeled bovine serum albumin showed highest concentrations in the nucleus and kinetoplast. Leishmania are susceptible to high concentrations of some CPPs, although comparably dissimilar to mammalian cells. MPG-peptides are more cytotoxic in Leishmania than in mammalian cells, acting as antimicrobial peptides. Our results contribute to a better understanding of molecular interactions in Leishmania cells and possibly to new treatments of leishmaniasis.


Immune complex effects on murine macrophages. II. Immune complex effects on activated macrophages cytotoxicity, membrane IL 1, and antigen presentation.
We investigated the effects of immune complexes on macrophage functions in vitro. Immune complexes inhibit lymphokine induction of both I-Ak expression and cytotoxic activity by fetal calf serum elicited macrophages during long-term (7 days) culture. In addition, induction of antigen presentation was significantly inhibited by immune complexes. Expression of membrane interleukin 1 (IL-1) (a membrane-bound bound form of the T cell mitogen required for antigen presentation by fixed cells) was minimally inhibited by immune complexes. Therefore, inhibition of antigen presentation was primarily due to effects on Ia expression rather than membrane IL 1 expression. The inhibitory effect of immune complexes was not found during short-term culture (4 to 48 hr) when activated macrophages (bearing high levels of Ia) from mice infected with Listeria monocytogenes were examined. Immune complexes maintained or even increased levels of both I-Ak and cytotoxicity in activated macrophages. The implications of these findings for immune complex modulation of the immune response are discussed.


Reinforcement learning for context aware segmentation.
The ability to learn from user behavior during image segmentation to replicate the innate human ability to adapt shape delineation to contextually specific local information is an important area of study in image understanding. Current approaches to image segmentation usually incorporate specific designs, either relying on generic image features or specific prior knowledge, which usually prevent their application in different contextual settings. In this paper, a general segmentation framework based on reinforcement learning is proposed. It demonstrates how user-specific behavior can be assimilated in-situ for effective model adaptation and learning. It incorporates a two-layer reinforcement learning algorithm that constructs the model from accumulated experience during user interaction. As the algorithm learns 'pervasively' whilst the user performs manual segmentation, no additional steps are required for the training process, allowing the method to adapt and improve its accuracy as experience is acquired. Detailed validation of the method on in-vivo magnetic resonance (MR) data demonstrates the practical value of the technique in significantly reducing the level of user interaction required, whilst maintaining the overall segmentation accuracy.


A comparison of survival rates for hip fracture patients with or without subsequent osteoporotic vertebral compression fractures.
Little is known about the effect of a subsequent osteoporotic vertebral compression fracture on the survival rate of patients with a previous hip fracture. In this study, we aimed to compare the survival rates of hip fracture patients with and without subsequent osteoporotic vertebral compression fractures and determine the risk factors associated with subsequent fracture. During 2000-2008, 933 initial hip fracture patients were reviewed and divided into two groups: subsequent fracture group (160 patients) and single hip fracture group (i.e., no subsequent fracture; 773 patients). All information pertaining to their most recent fracture event(s), including mortality causes/rates, were recorded. Differences in mortality rates and hazard ratios (HRs) between the two groups were also analyzed. The 1-year and 1-to-5-year mortality rates were 1.3% and 1.9%, respectively, in the subsequent fracture group, and 4.7% and 1.4%, respectively, in the single hip fracture group, with no significant differences observed. Interestingly, the HR for mortality was significantly higher in the single hip fracture group than in the subsequent fracture group (p < 0.05). The significant risk factors for subsequent fractures were identified as knee osteoarthritis, neurological disease, and an initial hip fracture with intertrochanteric involvement. Our findings indicate that the occurrence of a vertebral compression fracture after an initial hip fracture does not greatly impact patient survival. Conversely, patients presenting with a single hip fracture have a significantly higher mortality-HR, indicating that single hip fracture patients without subsequent fracture should be provided with the same standard of care as patients with subsequent fractures.


Purulent otitis media in children and adults.
This study was designed to compare tympanic membrane (TM) and middle ear (ME) pathologies of temporal bones from children and adults with purulent otitis media (POM). Thirty-four temporal bones were used from 22 subjects ages 2 days to 76 years with histopathologic evidence of POM. There were 55 age-matched controls. Histopathologic findings of the TM and ME in children and adults with POM were compared. Clinical histories and the presence of complications were recorded. The incidence of POM was more common in male children than in females. There was a significant increase in the thickness of the posterosuperior and posteroinferior quadrants in children with POM compared to non-OM children. In adults with POM, there was a significant decrease in the thickness of the posteroinferior and anteroinferior quadrants compared to non-OM adults. Children with POM showed a significant increase in the anterioinferior and posteroinferior quadrants and the umbo compared to adults with POM. Pathology of the TM and ME occurred in adults and children, but severity was greater in children. Residual mesenchyme was frequently observed in temporal bones of children. Serious complications such as labyrinthtis and meningitis were observed more frequently in children. All cases with meningitis had labyrinthitis, previous histories of otitis media and had been treated with antibiotics. Although POM occurs in both children and adults, pathologic changes of the middle ear are more severe, and complications (labyrinthitis and meningitis) occur more often in children. Our findings suggest the need to monitor children carefully under the age of 2 years who have POM.


Three-dimensional reconstruction of a peroxisomal reticulum in regenerating rat liver: evidence of interconnections between heterogeneous segments.
The three-dimensional (3-D) form and the interrelationship of peroxisomes (Po) in the model of regenerating rat liver after partial hepatectomy were studied by computer-assisted 3-D reconstruction of serial ultrathin sections. Po were labeled cytochemically for either catalase, which stains them all uniformly, or for D-amino acid oxidase (DAA-OX), which gives a heterogeneous reaction with lightly and darkly stained PO. In regenerating rat liver, Po exhibit marked pleomorphism with some budding forms and dumbbell-shaped ones. The 3-D reconstruction revealed many single spherical Po measuring 0.15-0.8 micron in diameter. In addition, two to five Po were found interconnected with each other via narrow 30-50-nm hourglass-shaped bridges forming a reticulum. Such aggregates of Po measured 1.5-2.5 microns across. Whereas all segments of this reticulum stained homogeneously for catalase, they exhibited a marked difference in the intensity of the DAA-OX reaction. These observations are consistent with the view of peroxisomal proliferation by budding or fragmentation from preexisting ones. Under such conditions of rapid growth as in regenerating liver, Po may be interconnected forming a reticulum. The interconnections between Po with differing DAA-OX activities suggest that they originate from the same parent organelle.


[Tooth transplantation: an extra dimension in orthodontics].
In the first part of the presentation, the content of orthodontics has been briefly explained by means of some clinical cases. The main part of the presentation consisted of discussing patient treatment by means of autogenous tooth transplantation with special emphasis on its indications and contra-indications. When a tooth transplantation is carried out properly, a success percentage of 90%, even forty years after treatment, can be expected. This high percentage has been reported in a recent study. The success of tooth transplantation is mainly due to the timing of the transplantation and the non-traumatic handling during surgery. According to the literature, the ideal moment for tooth transplantation is when half to three quarters of the root has been formed. One of the indications for tooth transplantation is the transplantation of a tooth in the cleft of a cleft palate patient. Two cleft palate patients have been presented in which tooth transplantation was carried out after bone grafting in the alveolar cleft. Finally some findings of a recent study, carried out at our department, dealing with cryopreservation of teeth before transplantation, has been presented. According to the findings of this study, cryopreservation, after removal of the pulp tissue does not inhibit the normal ingrowth of new pulp tissue after transplantation.


[Associative connections of the visual area of the neuronally-isolated cat cortex].
The associative pathways of the visual zone (fields 17 and 18) of the neuronal-isolated cortex of the cat were studied by the methods of Nauta-Gygax and Fink-Heimer. The cortex was isolated by the method proposed by M. M. Khananashvili (1961) by means of transection of projectional systems of the fibres connecting the cortex with subcortical structures in the site of their maximum concentration-in the internal capsule. Fields 17 and 18 were shown to have short associative pathways running both within the limits of the fields proper and to fields 17, 7 and to Clara-Bishop region disposed in the depth of the suprasylvian fissure. The site of termination of the associative libres was all layers of the cortex in some degree. It is assumed that the cytoarchitectonical fields in the neuronal-isolated cortex during conditioning interacts by means of intracortical fibres shown in the present investigation.


Ca antagonists do not alter aldosterone secretion during established Na depletion.
Conscious sheep whose sole adrenal gland had been transplanted to the neck to allow access to the adrenal vasculature were used to study the effect of calcium antagonists on aldosterone secretion. All animals were sodium depleted by uncompensated loss of parotid saliva. The drugs EDTA, verapamil, methoxyverapamil, nisoldipine, lanthanum, propylmethylenedioxyindene, and ryanodine were infused on separate occasions in three or four increasing dose levels. All infusions were made to produce known concentrations directly into the adrenal arterial blood supply. None of these infusions had any significant effect on aldosterone secretion rate, cortisol secretion rate, and little or no effect on plasma [Na], [K], or blood pressure. At high infusion rates some agents (verapamil, methoxyverapamil) caused tachycardia. In contrast, angiotensin II stimulation of aldosterone secretion is inhibited by both verapamil and nisoldipine. The data demonstrate that the sustained elevation of aldosterone secretion caused by sodium depletion is not dependent on a sustained alteration in transmembrane calcium flux. Furthermore, if circulating angiotensin II is the primary stimulus to aldosterone during sodium depletion, its mechanism of action appears to switch to one which is not dependent on calcium alone.


Speciation of echinostomes: evidence for the existence of two sympatric sibling species in the complex Echinoparyphium recurvatum (von Linstow 1873) (Digenea: Echinostomatidae).
Evidence for the existence of 2 first intermediate host-specific sibling species of the 45 collar-spined echinostome Echinoparyphium recurvatum is presented. Experimental studies on their life-cycles were carried out under controlled laboratory conditions. The two entities were found to be morphologically indistinguishable in all major respects, yet they exhibited distinct biological characteristics. One of the sibling species utilizes the freshwater lymnaeid pulmonate snail Lymnaea peregra as first intermediate host, and the adults occur in the anterior small intestine of the wildfowl experimental definitive host Anas platyrhynchos. The other utilizes the freshwater mesogastropod prosobranch snail Valvata piscinalis as first intermediate host, and the adults occur in the posterior small intestine and rectum of A. platyrhynchos. The existence of the two sibling species in sympatry may be explained by the fact that the life-cycles of the two forms represent two distinct cycles of transmission serving to reduce excessive competition between them.


The welfare consequences and efficacy of training pet dogs with remote electronic training collars in comparison to reward based training.
This study investigated the welfare consequences of training dogs in the field with manually operated electronic devices (e-collars). Following a preliminary study on 9 dogs, 63 pet dogs referred for recall related problems were assigned to one of three Groups: Treatment Group A were trained by industry approved trainers using e-collars; Control Group B trained by the same trainers but without use of e-collars; and Group C trained by members of the Association of Pet Dog Trainers, UK again without e-collar stimulation (n = 21 for each Group). Dogs received two 15 minute training sessions per day for 4-5 days. Training sessions were recorded on video for behavioural analysis. Saliva and urine were collected to assay for cortisol over the training period. During preliminary studies there were negative changes in dogs' behaviour on application of electric stimuli, and elevated cortisol post-stimulation. These dogs had generally experienced high intensity stimuli without pre-warning cues during training. In contrast, in the subsequent larger, controlled study, trainers used lower settings with a pre-warning function and behavioural responses were less marked. Nevertheless, Group A dogs spent significantly more time tense, yawned more often and engaged in less environmental interaction than Group C dogs. There was no difference in urinary corticosteroids between Groups. Salivary cortisol in Group A dogs was not significantly different from that in Group B or Group C, though Group C dogs showed higher measures than Group B throughout sampling. Following training 92% of owners reported improvements in their dog's referred behaviour, and there was no significant difference in reported efficacy across Groups. Owners of dogs trained using e-collars were less confident of applying the training approach demonstrated. These findings suggest that there is no consistent benefit to be gained from e-collar training but greater welfare concerns compared with positive reward based training.


Synthesis of lysine-containing sulphonium salts and their properties as proteinase inhibitors.
Some sulphonium salts derived from lysine were synthesized with the general structure R-Lys-CH2S+-(alkyl)2. They were examined as inhibitors of the cysteine proteinase clostripain, which has a preference for cleaving peptide bonds at the carboxy group of basic amino acids, and of a number of trypsin-related serine proteinases. Clostripain was irreversibly inactivated by all reagents examined, but in the case of the serine proteinases, depending on the reagent structure, irreversible and reversible inhibitions were observed. These were kinetically characterized.


Identification, mapping and linkage analysis of randomly amplified DNA polymorphisms in Tetrahymena thermophila.
Using the random amplified polymorphic DNA (RAPD) technique and exploiting the unique genetics of Tetrahymena thermophila, we have identified and characterized 40 DNA polymorphisms occurring between two inbred strains (B and C3) of this ciliated protozoan. These RAPD markers permit the PCR amplification of a DNA species using template DNA from SB1969 (B strain) but fail to do so using DNA from C3-368-5 (C3 strain). Polymorphisms were mapped to chromosomes using a panel of monosomic strains constructed by crossing B strain-derived nullisomic strains to inbred strain C3. They map to all five chromosomes and appear to be evenly distributed throughout the genome. Chromosomal groups were then analyzed for linkage using meiotic segregants; four linkage groups were identified in chromosomes 1R 2L, 3 and 5. The RAPD method appears useful for the construction of a genetic map of the Tetrahymena genome based on DNA polymorphisms.


Highwire regulates guidance of sister axons in the Drosophila mushroom body.
Axons often form synaptic contacts with multiple targets by extending branches along different paths. PHR (Pam/Highwire/RPM-1) family ubiquitin ligases are important regulators of axon development, with roles in axon outgrowth, target selection, and synapse formation. Here we report the function of Highwire, the Drosophila member of the PHR family, in promoting the segregation of sister axons during mushroom body (MB) formation. Loss of highwire results in abnormal development of the axonal lobes in the MB, leading to thinned and shortened lobes. The highwire defect is attributable to guidance errors after axon branching, in which sister axons that should target different lobes instead extend together into the same lobe. The highwire mutant MB displays elevation in the level of the MAPKKK Wallenda/DLK (dual leucine zipper kinase), a previously identified substrate of Highwire, and genetic suppression studies show that Wallenda/DLK is required for the highwire MB phenotype. The highwire lobe defect is limited to α/β lobe axons, but transgenic expression of highwire in the pioneering α'/β' neurons rescues the phenotype. Mosaic analysis further shows that α/β axons of highwire mutant clones develop normally, demonstrating a non-cell-autonomous role of Highwire for axon guidance. Genetic interaction studies suggest that Highwire and Plexin A signals may interact to regulate normal morphogenesis of α/β axons.


Tracking Ultrafast Change of Multiterahertz Broadband Response Functions in a Photoexcited Dirac Semimetal Cd3As2 Thin Film.
The electromagnetic response of Dirac semimetals in the infrared and terahertz frequency ranges is attracting growing interest for potential applications in optoelectronics and nonlinear optics. The interplay between the free-carrier response and interband transitions in the gapless, linear dispersion relation plays a key role in enabling novel functionalities. Here we investigate ultrafast dynamics in thin films of a photoexcited Dirac semimetal Cd3As2 by probing the broadband response functions as complex quantities in the multiterahertz region (10-45 THz, 40-180 meV, or 7-30 μm), which covers the crossover between the inter- and intraband response. We resolve dynamics of the photoexcited nonthermal electrons, which merge with originally existing carriers to form a single thermalized electron gas and how it is facilitated by high-density excitation. We also demonstrate that a large reduction of the refractive index by 80% dominates the nonequilibrium infrared response, which can be utilized for designing ultrafast switches in active optoelectronics.


Biological activities of C3 beta c, a novel neutrophil chemoattractant derived from the beta-chain of rat complement C3.
Biological activities of C3 beta c, which is a C-terminal fragment of the beta-chain of rat complement C3, have been studied by in vivo and in vitro experiments. C3 beta c was purified as a novel neutrophil chemoattractant from the exudate of the chronic phase of rat carrageenin-induced inflammation. The purified C3 beta c induced neutrophil chemotaxis in vivo when C3 beta c was injected into the preformed air-pouch on the back of rats. C3 beta c transiently increased the intracellular free Ca2+ concentration of neutrophils and enhanced the adhesion of neutrophils to fibrinogen in vitro, suggesting that C3 beta c has the ability to express an adhesion molecule of rat neutrophils. In addition, C3 beta c at low concentrations (10(-10)-10(-11) M) stimulated rat macrophages to produce cytokine-induced neutrophil chemoattractant-2, a member of the interleukin-8 family. Furthermore, C3 beta c enhanced vascular permeability in vivo, which is suppressed by cyproheptadine, suggesting that C3 beta c may have the characteristics of an anaphylatoxin. Our results suggest that C3 beta c contributes to oedema formation and neutrophil accumulation at inflammatory sites in rats.


[18F]FDG PET immunotherapy radiomics signature (iRADIOMICS) predicts response of non-small-cell lung cancer patients treated with pembrolizumab.
Background Immune checkpoint inhibitors have changed the paradigm of cancer treatment; however, non-invasive biomarkers of response are still needed to identify candidates for non-responders. We aimed to investigate whether immunotherapy [18F]FDG PET radiomics signature (iRADIOMICS) predicts response of metastatic non-small-cell lung cancer (NSCLC) patients to pembrolizumab better than the current clinical standards. Patients and methods Thirty patients receiving pembrolizumab were scanned with [18F]FDG PET/CT at baseline, month 1 and 4. Associations of six robust primary tumour radiomics features with overall survival were analysed with Mann-Whitney U-test (MWU), Cox proportional hazards regression analysis, and ROC curve analysis. iRADIOMICS was constructed using univariate and multivariate logistic models of the most promising feature(s). Its predictive power was compared to PD-L1 tumour proportion score (TPS) and iRECIST using ROC curve analysis. Prediction accuracies were assessed with 5-fold cross validation. Results The most predictive were baseline radiomics features, e.g. Small Run Emphasis (MWU, p = 0.001; hazard ratio = 0.46, p = 0.007; AUC = 0.85 (95% CI 0.69-1.00)). Multivariate iRADIOMICS was found superior to the current standards in terms of predictive power and timewise with the following AUC (95% CI) and accuracy (standard deviation): iRADIOMICS (baseline), 0.90 (0.78-1.00), 78% (18%); PD-L1 TPS (baseline), 0.60 (0.37-0.83), 53% (18%); iRECIST (month 1), 0.79 (0.62-0.95), 76% (16%); iRECIST (month 4), 0.86 (0.72-1.00), 76% (17%). Conclusions Multivariate iRADIOMICS was identified as a promising imaging biomarker, which could improve management of metastatic NSCLC patients treated with pembrolizumab. The predicted non-responders could be offered other treatment options to improve their overall survival.


UPΦ phages, a new group of filamentous phages found in several members of Enterobacteriales.
Filamentous phages establish chronic infections in their bacterial hosts, and new phages are secreted by infected bacteria for multiple generations, typically without causing host death. Often, these viruses integrate in their host's genome by co-opting the host's XerCD recombinase system. In several cases, these viruses also encode genes that increase bacterial virulence in plants and animals. Here, we describe a new filamentous phage, UPϕ901, which we originally found integrated in a clinical isolate of Escherichia coli from urine. UPϕ901 and closely related phages can be found in published genomes of over 200 other bacteria, including strains of Citrobacter koseri, Salmonella enterica, Yersinia enterocolitica, and Klebsiella pneumoniae. Its closest relatives are consistently found in urine or in the blood and feces of patients with urinary tract infections. More distant relatives can be found in isolates from other environments, including sewage, water, soil, and contaminated food. Each of these phages, which we collectively call 'UPϕ viruses', also harbors two or more novel genes of unknown function.


[Radioiodine therapy for benign thyroid diseases (version 5). German Guideline].
The version 5 of the guideline for radioiodine therapy of benign thyroid disorders is an update of the version 4, which was published by the German Society of Nuclear Medicine (Deutsche Gesellschaft für Nuklearmedizin, DGN) in co-ordination with the German Society of Endocrinology (Deutsche Gesellschaft für Endokrinologie, DGE, Sektion Schilddrüse) and the German Society of General- and Visceral-Surgery (Deutsche Gesellschaft für Allgemein- und Viszeralchirurgie, DGAV) in 2007. This guideline was harmonized with the recommendations of the European Association of Nuclear Medicine (EANM). According to the German "Directive on Radiation Protection in Medicine" the physician specialised in nuclear medicine ("Fachkunde in der Therapie mit offenen radioaktiven Stoffen") is responsible for the justfication to treat with radioiodine. Therefore, relevant medical indications for radioiodine therapy and alternative therapeutic options are discussed within the guideline. This procedure guideline is developed in the consensus of a representative expert group. This fulfils the level S1 (first step) within the German classification of Clinical Practice Guidelines.


Evaluation of efficacy of mineral oil, charcoal, and smectite in a rat model of equine cantharidin toxicosis.
The efficacy of orally administered therapeutics for the treatment of cantharidin intoxication has not been evaluated in controlled studies. To develop a model of acute cantharidin intoxication in laboratory rats and to evaluate in this model the relative efficacy of 3 gastrointestinal therapies used to treat equine cantharidin toxicosis. Sixty-four male Sprague-Dawley rats. A blinded, randomized, controlled study was performed on rats surgically implanted with telemetry transmitters for evaluating heart rate, locomotor activity, and body temperature. Orogastric administration of cantharidin was performed within 15 seconds before administration of mineral oil, activated charcoal, or smectite. Negative control groups received therapeutic agents alone. Urine was collected for cantharidin analysis. Rats were sacrificed 24 hours after intoxication, and tissues were collected for histopathologic evaluation. Data analysis included ANOVA procedures and contingency tables. Six of 8 cantharidin-intoxicated rats treated with mineral oil died; bradycardia and hypothermia developed in the animals of this group 0-8 hours after intoxication. Rats treated with mineral oil had higher urine cantharidin concentrations than rats receiving cantharidin alone or with smectite (P = .04). The most severe hypothermia (30.6°C ± 1.0) developed in rats administered mineral oil at 4-8 hours after intoxication, whereas those treated with charcoal (35.2°C ± 0.8) had mean body temperatures higher than all other treatment groups (P = .03). Survival times in the charcoal (P = .16) and smectite (P = .12) treatment groups were not statistically different from negative controls. Mineral oil is often used in the treatment of equine cantharidin toxicosis. Our findings suggest that mineral oil increases cantharidin absorption, worsening morbidity and fatality in rats.


Adhesion molecule CADM1 contributes to gap junctional communication among pancreatic islet α-cells and prevents their excessive secretion of glucagon.
Cell adhesion molecule-1 (CADM1) is a recently identified adhesion molecule of pancreatic islet α-cells that mediates nerve-α-cell interactions via trans-homophilic binding and serves anatomical units for the autonomic control of glucagon secretion. CADM1 also mediates attachment between adjacent α-cells. Since gap junctional intercellular communication (GJIC) among islet cells is essential for islet hormone secretion, we examined whether CADM1 promotes GJIC among α-cells and subsequently participates in glucagon secretion regulation. Dye transfer assays using αTC6 mouse α-cells, which endogenously express CADM1, supported this possibility; efficient cell-to-cell spread of gap junction-permeable dye was detected in clusters of αTC6 cells transfected with nonspecific, but not with CADM1-targeting, siRNA. Immunocytochemical analysis of connexin 36, a major component of the gap junction among αTC6 cells, revealed that it was localized exclusively to the cell membrane in CADM1-non-targeted αTC6 cells, but diffusely to the cytoplasm in CADM1-targeted cells. Next, we incubated CADM1-targeted and non-targeted αTC6 cells in a medium containing 1 mM glucose and 200 mM arginine for 30 min to induce glucagon secretion, and found that the targeted cells secreted three times more glucagon than did the non-targeted. We conducted similar experiments using pancreatic islets that were freshly isolated from wild-type and CADM1-knockout mice, and expressed glucagon secretion as ratios relative to baseline values. The increase in ratio was larger in CADM1-knockout islets than in wild-type islets. These results suggest that CADM1 may serve as a volume limiter of glucagon secretion by sustaining α-cell attachment necessary for efficient GJIC.


Diatomic Hönl-London factor computer program.
A new method is presented for computation of diatomic rotational line strengths, or Hönl-London factors. The traditional approach includes separately calculating line positions and Hönl-London factors and assigning parity labels. The present approach shows that one merely computes the line strength for all possible term differences and discards those differences for which the strength vanishes. Numerical diagonalization of the upper and lower Hamiltonians is used, which directly obtains the line positions, Hönl-London factors, total parities, and e/f parities for both heteronuclear and homonuclear diatomic molecules. The FORTRAN computer program discussed is also applicable for calculating n-photon diatomic spectra.


Effects of vaccination with a Moraxella bovis bacterin on the subsequent development of signs of corneal disease and infection with M bovis in calves under natural environmental conditions.
A vaccination study was conducted for infectious bovine keratoconjunctivitis (IBK) in 440 purebred Hereford cattle (cows and their newborn calves) of the USDA Meat Animal Research Center cattle herd at Clay Center, Ne. The cattle were allotted to 4 groups: 60 calves were vaccinated with an autogenous Moraxella bovis bacterin (group 1); 60 calves that were matched with group 1 calves were designated nonvaccinated matched controls (group 2); 99 calves were peer group nonvaccinated controls (group 3); and 219 cows, the dams of the calves, were nonvaccinated consorts (group 4). The infection rates in cattle groups 1, 2, 3, and 4 during the summer were 96.6, 98.3, 100, and 79.1%, respectively, and the disease rates were 90, 93, 85, and 20%. The infection and the disease rates were significantly (P less than 0.01) different between claves and cows. The disease rate was also significantly different between older and younger cows. A larger percentage of the affected calves and cows had mild or moderate (61%) signs of IBK rather than severe (39%) signs. The rate of body weight gain was reduced in calves with severe signs of IBK. The results seemed to indicate that little would be gained by vaccinating cattle against IBK under the conditions of study.


Combined Effects of Exercise Training and Nutritional Supplementation in Cancer Patients in the Context of the COVID-19: A Perspective Study.
The 2019 coronavirus (COVID-19) epidemic, has caused unprecedented global social and economic impacts and many deaths. Many risk factors have been identified in the progression of COVID-19 to severe and critical stages, and it is shown that the coronavirus appears more severely in people with cancer. Pro-inflammatory status and weakened immune system due to cancer-related treatments can be determinants in the immune system's response to the coronavirus in these patients. Higher physical activity levels are associated with lower hospitalization rates and mortality in COVID-19. Also, regular exercise training can improve immune system responses, modulate inflammatory responses, and improve psychological parameters in cancer patients. The interactive effects of nutritional supplements on immune responses and anti-inflammatory status have been shown in some studies. The purpose of this perspective article was to investigate the interaction between dietary supplementation and regular physical exercise in controlling risk factors associated with coronavirus in cancer patients. In addition to appropriate dietary habits, some nutritional supplements, especially vitamin D, have been shown to improve the immune system's response against COVID-19 and cancer. Using lifestyle strategies such as regular physical activity and intake of functional compounds as supplements can be effective in treatment outcomes, quality of life, and overall survival in cancer patients. We proposed that combining dietary supplements and exercise training in cancer patients can boost immune responses against COVID-19 and probably improve vaccine responses. Angiotensin (ANG)-(1-7) Mas receptor axis can probably activate following exercise training and vitamin D combination. And can prevent pulmonary injury, hematological alterations, and hyperinflammatory state in COVID-19.


Antidiabetic activity of standardized extract of Picrorhiza kurroa in rat model of NIDDM.
The present study was undertaken to investigate the effect of standardized aqueous extract of Picrorhiza kurroa Royle ex Benth. on diabetes. Diabetes mellitus was induced with streptozotocinnicotinamide and rats found diabetic were orally administered standardized aqueous extract of Picrorhiza kurroa (100 and 200 mg/kg, p.o.) or glibenclamide (10 mg/kg, p.o.) or vehicle (0.3% carboxy methyl cellulose suspension) for 14 days. Fasting blood glucose levels and lipid profiles were measured in control as well as diabetic rats after two week treatment. In addition, liver glycogen level of Picrorhiza kurroa extract (PkE) treated diabetic rats were compared to that of control and diabetic control rats. Oral glucose tolerance test was also performed on nondiabetic normal rats. Statistical analyses were performed by one way analysis of variance followed by Tukey-Kramer multiple comparisons test. PkE treatment induced significant reduction (p < 0.001) in elevated fasting blood glucose level in streptozotocinnicotinamide induced type-2 diabetic rats. In oral glucose tolerance test, oral administration of PkE increased the glucose tolerance. PkE treatment also significantly (p < 0.001) reversed the weight loss associated with streptozotocin treatment. These findings provide in vivo evidence that standardized extract of Picrorhiza kurroa possess significant antidiabetic activity in streptozotocin-nicotinamide induced type-2 diabetes mellitus in rats.


Unveiling the complex pattern of intermolecular interactions responsible for the stability of the DNA duplex.
Herein, we provide new insights into the intermolecular interactions responsible for the intrinsic stability of the duplex structure of a large portion of human B-DNA by using advanced quantum mechanical methods. Our results indicate that (i) the effect of non-neighboring bases on the inter-strand interaction is negligibly small, (ii) London dispersion effects are essential for the stability of the duplex structure, (iii) the largest contribution to the stability of the duplex structure is the Watson-Crick base pairing - consistent with previous computational investigations, (iv) the effect of stacking between adjacent bases is relatively small but still essential for the duplex structure stability and (v) there are no cooperativity effects between intra-strand stacking and inter-strand base pairing interactions. These results are consistent with atomic force microscope measurements and provide the first theoretical validation of nearest neighbor approaches for predicting thermodynamic data of arbitrary DNA sequences.


Serum lipids, lipoprotein(a) and apo(a) isoforms in patients with established coronary artery disease and their relation to disease and prognosis after coronary by-pass surgery.
Consecutive patients (n=964) undergoing coronary angiography were studied and compared with a random population sample regarding serum lipids and lipoproteins with focus on lipoprotein(a) (Lp[a]) levels and apo(a) isoforms. The patients were also followed for 5 years after the angiography, and the prognostic value of serum lipoproteins were analyzed. The patients were divided in two groups: Group 1 (n=814) consisted of patients with angina pectoris and at least one coronary artery with 50% stenosis and group 2 (n=150) patients with none of the coronary arteries significantly obstructed ( < 50%). As controls a random population sample was selected (n=197). Blood samples were collected before coronary angiography for determination of serum lipids, Lp(a) and isoforms of apo(a). When group 1 and group 2 patients were compared, group 1 was found to have higher serum cholesterol, triglycerides, apoB and Lp(a) as well as lower HDL and apoAI. When group 1 was compared with the random sample, after correction for age and sex, similar differences were observed, except that the difference in Lp(a) was not significant. The high Lp(a) levels among patients was found to be primarily due to the female patients, where the difference compared to both group 2 and controls was highly significant (P=0.007 and P=0.001, respectively). There was a significant difference in the apo(a) isoform distribution between group 1 patients and control subjects (P=0.0003), with a higher frequency of low molecular weight isoforms among patients. This was also significant for the male subgroup (P=0.001). Lp(a), LDL, total cholesterol, triglycerides. apoB, HDL and apoAI were significantly related to the number of major coronary arteries with > 50% stenosis. Mortality during follow-up was,in a univariate analysis, significantly correlated to several factors related to the degree of heart disease and to LDL (P=0.02) and apoB (P < 0.01). Increased mortality was, however, related to low levels of apoB and LDL. For cardiac mortality no significant correlation to lipoprotein variables were found. In conclusion established lipoprotein risk factors were more frequent among patient with angina pectoris and verified coronary stenosis. Furthermore high Lp(a) levels and a high frequency of low molecular weight isoforms of apo(a) were found in coronary patients. Higher Lp(a) levels were observed both for female and male patients, the differences were, however, significant only for the female patients. None of the lipoprotein variables could predict coronary death during the follow-up period.


Long-term follow-up of children treated for high-grade gliomas: children's oncology group L991 final study report.
High-grade gliomas of the CNS are characterized by poor treatment response and prognosis for long-term survival. The Children's Oncology Group (COG) L991 study investigated the neuropsychological, behavioral, and quality of life (QoL) outcomes after treatment on the Children's Cancer Group (CCG) trial for high-grade gliomas (CCG-945). Fifty-four patients (29 males, 25 females) with a median age of 8.8 years at diagnosis (range, 0.2 to 19.5 years) were enrolled at 25 institutions in North America, representing 81% of available survivors; median length of follow-up was 15.1 years (range, 9.5 to 19.2 years), and median age at study evaluation was 23.6 years (range, 11.3 to 36 years). Standardized tests of neuropsychological functioning and QoL were performed. Descriptive statistics summarized principal findings, and one-way analysis of variance identified potential predictors of outcomes. With an average follow-up time of 15 years, survivors demonstrated intellectual functioning within the low-average range. Executive functioning and verbal memory were between the low-average and borderline ranges. In contrast, visual memory and psychomotor processing speed were between the borderline and impaired ranges, respectively. Approximately 75% of patient reported overall QoL within or above normal limits for both physical and psychosocial domains. Nonhemispheric tumor location (midline or cerebellum), female sex, and younger age at treatment emerged as independent risk factors. These results serve as a benchmark for comparison with future pediatric high-grade glioma studies, in addition to identifying at-risk cohorts that warrant further research and proactive interventions to minimize late effects while striving to ensure survival.


Sun drying of seedless and seeded grapes.
In this study, sun drying behaviour of seedless and seeded grapes was investigated. The drying study showed that the times taken for drying of seedless and seeded grapes of berry size of 1.72 cm and 2.20 cm thicknesses from the initial moisture contents of 78.2% and 79.5% (w.b.) to final moisture content of around 22% (w.b.) were 176 and 228 h in open sun drying, respectively. The drying data were fitted to 12 thin-layer drying models. The performance of these models were compared using the determination of coefficient (R(2)), mean relative percent error (P), reduced chi-square (χ (2)) and root mean square error (RMSE) between the observed and predicted moisture ratios. The results showed that Midilli et al. model was found to satisfactorily describe the sun drying curves of seedless and seeded grapes. The effective moisture diffusivity values were estimated from Fick's diffusion model by 1.02 × 10(-11) and 1.66 × 10(-11) m(2)/s for seeded and seedless grapes.


A photoelicitation exploration on formally homeless people experience with Universal Credit: System error and 'the government don't care'.
This article explores the impact of Universal Credit (UC) on a group of formerly homeless people who were forcibly made to experience a system of full of errors and government that, in their view, did not care. The experience of a marginalised and vulnerable group with complex needs allows one to consider the impacts of welfare reforms on vulnerable people. The research was conducted with formerly homeless contacted via organisations that support people who experienced homelessness in Brighton, Southeast of the UK. Five people (32 years and older) participated. Qualitative data were obtained in photo-elicitation interviews and were thematically analysed. Findings were that they faced a system of error as well as experiencing a sense the government did not care about their situation. The participants expressed their views on how the UC process made them 'struggle' and caused them to have to 'use food banks', and argued that the staff did not know the policy. The system is singled out as the cause of UC claimants' destitution. For the participants, policymakers' negligence, contempt, and detachment were not hard to understand. The article provides implications for practice and research.


Spatial information outflow from the hippocampal circuit: distributed spatial coding and phase precession in the subiculum.
Hippocampal place cells convey spatial information through a combination of spatially selective firing and theta phase precession. The way in which this information influences regions like the subiculum that receive input from the hippocampus remains unclear. The subiculum receives direct inputs from area CA1 of the hippocampus and sends divergent output projections to many other parts of the brain, so we examined the firing patterns of rat subicular neurons. We found a substantial transformation in the subicular code for space from sparse to dense firing rate representations along a proximal-distal anatomical gradient: neurons in the proximal subiculum are more similar to canonical, sparsely firing hippocampal place cells, whereas neurons in the distal subiculum have higher firing rates and more distributed spatial firing patterns. Using information theory, we found that the more distributed spatial representation in the subiculum carries, on average, more information about spatial location and context than the sparse spatial representation in CA1. Remarkably, despite the disparate firing rate properties of subicular neurons, we found that neurons at all proximal-distal locations exhibit robust theta phase precession, with similar spiking oscillation frequencies as neurons in area CA1. Our findings suggest that the subiculum is specialized to compress sparse hippocampal spatial codes into highly informative distributed codes suitable for efficient communication to other brain regions. Moreover, despite this substantial compression, the subiculum maintains finer scale temporal properties that may allow it to participate in oscillatory phase coding and spike timing-dependent plasticity in coordination with other regions of the hippocampal circuit.


Serum soluble epidermal growth factor receptor concentrations decrease in postmenopausal metastatic breast cancer patients treated with letrozole.
Previous studies have implicated estrogen as a regulator of epidermal growth factor receptor (EGFR) expression in breast tumors. We therefore speculated that estrogen might modulate serologic soluble EGFR (sEGFR) concentrations in breast cancer patients. Accordingly, we measured serum sEGFR concentrations in postmenopausal women with metastatic breast cancer (MBC) treated with letrozole, an aromatase inhibitor that blocks estrogen synthesis. Serum specimens were obtained prior to and following 1 and 3 months of letrozole therapy. We report that sEGFR concentrations do not differ between MBC patients prior to letrozole treatment and age- and postmenopause-matched healthy women (P = 0.468). In contrast, however, sEGFR concentrations decreased significantly in 76% of MBC patients after both 1 month (P = 0.006) and 3 months (P = 0.003) of letrozole therapy versus pretreatment concentrations. Within the limitations of this study, we found no evidence for an association between pretreatment sEGFR concentrations or decreased treatment sEGFR concentrations and either progression-free or overall survival. Nonetheless, we conclude that future prospective studies are warranted to determine if baseline and/or longitudinal serum sEGFR concentrations may be useful for predicting disease progression and survival, and/or for monitoring responsiveness to aromatase inhibitors or other endocrine therapies in breast cancer patients.


ErbB-2 signals through Plexin-B1 to promote breast cancer metastasis.
Diagnosis of metastatic breast cancer is associated with a very poor prognosis. New therapeutic targets are urgently needed, but their development is hampered by a lack of understanding of the mechanisms leading to tumor metastasis. Exemplifying this is the fact that the approximately 30% of all breast cancers overexpressing the receptor tyrosine kinase ErbB-2 are characterized by high metastatic potential and poor prognosis, but the signaling events downstream of ErbB-2 that drive cancer cell invasion and metastasis remain incompletely understood. Here we show that overexpression of ErbB-2 in human breast cancer cell lines leads to phosphorylation and activation of the semaphorin receptor Plexin-B1. This was required for ErbB-2-dependent activation of the pro-metastatic small GTPases RhoA and RhoC and promoted invasive behavior of human breast cancer cells. In a mouse model of ErbB-2-overexpressing breast cancer, ablation of the gene encoding Plexin-B1 strongly reduced the occurrence of metastases. Moreover, in human patients with ErbB-2-overexpressing breast cancer, low levels of Plexin-B1 expression correlated with good prognosis. Our data suggest that Plexin-B1 represents a new candidate therapeutic target for treating patients with ErbB-2-positive breast cancer.


Acute myeloid leukemia in the real world: why population-based registries are needed.
Population-based registries may provide data complementary to that from basic science and clinical intervention studies, all of which are essential for establishing recommendations for the management of patients in the real world. The same quality criteria apply for the evidence-based label, and both high representation and good data quality are crucial in registry studies. Registries with high coverage of the target population reduce the impact of selection on outcome and the subsequent problem with extrapolating data to nonstudied populations. Thus, data useful for clinical decision in situations not well covered by clinical studies can be provided. The potential clinical impact of data from population-based studies is exemplified with analyses from the Swedish Acute Leukemia Registry containing more than 3300 acute myeloid leukemia (AML) patients diagnosed between 1997 and 2006 with a median follow-up of 6.2 years on (1) the role of intensive combination chemotherapy for older patients with AML, (2) the impact of allogeneic stem cell transplantation on survival of younger patients with AML, and (3) the continuing problem with early deaths in acute promyelocytic leukemia. We also present the first Web-based dynamic graph showing the complex interaction between age, performance status, the proportion of patients given intensive treatment, early death rate, complete remission rate, use of allogeneic transplants, and overall survival in AML (non-AML).


Analysis of plasma 3-methoxytyramine, normetanephrine and metanephrine by ultraperformance liquid chromatography-tandem mass spectrometry: utility for diagnosis of dopamine-producing metastatic phaeochromocytoma.
Measurements of plasma normetanephrine (NMN) and metanephrine (MN) provide a sensitive test for diagnosis of phaeochromocytomas and paragangliomas (PPGLs), but do not allow detection of dopamine-producing tumours. Here we introduce a novel mass spectrometric based method coupled to ultraperformance liquid chromatography (LC-MS/MS) for measuring NMN, MN and 3-methoxytyramine (MTY), the O-methylated metabolite of dopamine. Specific collision-induced fragment ions assessed by multireaction monitoring transitions were used for identification, with quantification according to signal intensities of analytes relative to stable isotope labelled internal standards. Results for solid-phase extracted samples from 196 subjects analysed by LC-MS/MS were compared with those analysed by liquid chromatography with electrochemical detection (LC-ECD). Concentration ranges in 125 volunteers were compared with those from 63 patients with PPGLs, including 14 with metastatic disease. The LC-MS/MS method showed linearity over four orders of magnitude with analytical sensitivity sufficient to measure to 0.02 nmol/L. Intra- and inter-assay coefficients of variation ranged from 2.8% to 13.5%. NMN and MN were respectively measured 17% and 10% higher and MTY 26% lower by LC-MS/MS than by LC-ECD. Medians and ranges for 3-methoxytramine, NMN and MN were respectively 0.08 (0.03-0.13), 0.35 (0.13-0.95) and 0.15 (0.07-0.33) nmol/L in volunteers. Among patients with PPGLs, plasma methoxytyramine was six-fold higher in patients with than without metastastases (1.09 versus 0.19 nmol/L) and in three patients was the only metabolite increased. The LC-MS/MS method enables accurate, selective and sensitive measurements of catecholamine O-methylated metabolites that should be particularly useful for screening and management of dopamine-producing metastatic PPGLs.


Valine and isoleucine requirement of 20- to 45-kilogram pigs.
Three experiments were conducted to determine the Val and Ile requirements in low-CP, corn-soybean meal (C-SBM) AA-supplemented diets for 20- to 45-kg pigs. All experiments were conducted for 26 to 27 d with purebred or crossbred barrows and gilts, which were blocked by initial BW. Treatments were replicated with 5 or 6 pens of 3 or 4 pigs per pen. At the beginning of Exp. 1 and the end of all experiments, blood samples were obtained from all pigs to determine plasma urea N (PUN) concentrations. All diets were C-SBM with 0.335% supplemental Lys to achieve 0.83% standardized ileal digestible (SID) Lys, which is the Lys requirement of these pigs. In Exp. 1, 0, 0.02, 0.04, 0.06, 0.08, or 0.10% L-Val was supplemented to achieve 0.51, 0.53, 0.55, 0.57, 0.59, or 0.61% dietary SID Val, and Thr, Trp, Met, and Ile were supplemented to maintain Thr:Lys, Trp:Lys, TSAA:Lys, and Ile:Lys ratios of 0.71, 0.20, 0.62, and 0.60, respectively. Also, supplemental Gly and Glu were added to all diets to achieve 1.66% Gly + Ser and 3.28% Glu, which is equal to the Gly + Ser and Glu content of a previously validated positive control diet that contained no supplemental AA. Treatment differences were considered significant at P < 0.10. Valine addition increased ADG, ADFI, and G:F in pigs fed 0.51 to 0.59% SID Val (linear, P < 0.08), but ADG and ADFI were decreased at 0.61% SID Val (quadratic, P ≤ 0.10). On the basis of ADG and G:F, the SID Val requirement is between 0.56 and 0.58% in a C-SBM diet supplemented with AA. In Exp. 2 and 3, 0, 0.02, 0.04, 0.06, or 0.08% L-Ile was supplemented to achieve 0.43, 0.45, 0.47, 0.49, or 0.51% dietary SID Ile, and Thr, Trp, Met, and Ile were supplemented to maintain Thr:Lys, Trp:Lys, TSAA:Lys, and Val:Lys ratios of 0.71, 0.20, 0.62, and 0.74, respectively. Also, supplemental Gly and Glu were added to achieve 1.66% Gly + Ser and 3.28% Glu as in Exp. 1. Data from Exp. 2 and 3 were combined and analyzed as 1 data set. Daily BW gain, ADFI, and G:F were not affected by Ile additions to the diet; however, ADFI was decreased among pigs fed the diet with 0.45% SID Ile (P < 0.10) compared with pigs fed the 0.43% SID Ile diet. Broken-line analysis requirements could not be estimated for the combined data from Exp. 2 or 3. The results of this research indicate that the SID Val requirement is between 0.56 to 0.58% (0.67 to 0.70 SID Val:Lys), and the Ile requirement is adequate at 0.43% SID Ile (0.52 SID Ile:Lys) for 20- to 45-kg pigs.


Chronic nifedipine treatment diminishes cardiac inotropic response to nifedifine: functional upregulation of dihydropyridine receptors.
Chronic treatment with nifedipine induces up-regulation of functional active Ca2+ channels in cardiac muscle membranes. Adult male New Zealand White rabbits (NZW) were treated with nifedipine (20 mg/day) for 25 days. In isovolumic perfused hearts at constant coronary flow and heart rate (HR) the left ventricular developed pressure (LVDP) and its first derivative (dP/dt) were monitored. Basal contractility and contractility at different end-diastolic volumes (EDV) were higher in nifedipine-treated animals, with no changes in diastolic chamber stiffness. Dose response to nifedipine in pretreated animals showed less decrease in contractility than in controls [ED50 = 1.09 +/- 0.09 x 10-7 (control) and 1.55 +/- 0.17 x 10-7 M nifedipine (treated) (p < 0.05)]. Ca2+ channel density was assessed by specific binding at the dihydropyridine receptor with [methyl-3H]PN 200-110. In cardiac membranes, maximal binding capacity (Bmax) was 269 +/- 38 (n = 7, control) and 429 +/- 46 fmol/mg protein (n = 7, treated) (p < 0.05), without significant changes in dissociation constant. In addition, we noted no changes in dihydropyridine (DHP) binding sites in aortic membranes. Our results offer a possible explanation for the lack of decrease in contractility despite the persistent hypotensive effect in hypertensive patients during chronic treatment with nifedipine.


Methylenetetrahydrofolate reductase polymorphism (MTHFR C677T) and bone mineral density in Chinese men and women.
The relationship between MTHFR (C677T) genotypes of the methylenetetrahydrofolate reductase, bone mineral density (BMD), and vertebral fracture was studied in 657 Chinese men and women. No association between MTHFR (C677T) and BMD was found in postmenopausal women (aged 55-59 years, n=178), elderly women (aged 70-79 years, n=247), or elderly men (aged 70-79 years, n=232) at the hip, spine, or total body (P >0.05 by ANCOVA). In all study groups, there was no effect of an interaction between MTHFR (C677T) and daily dietary calcium intake on BMD (P >0.05 for the interaction effects by two-way ANCOVA). No statistically significant association was observed between MTHFR (C677T) genotypes and vertebral fracture. The MTHFR (C677T) genotypes for CC, CT, and TT among elderly women with or without vertebral fracture were 5%, 33%, 62%; 6%, 37%, and 57%, respectively, and those for elderly men with and without vertebral fracture were 9%, 31%, 60%; 5%, 35%, and 60%, respectively. The prevalence of TT in our study group was 5% compared to 8% in the Danish or 18.6% in the Japanese. We found no association between MTHFR (C677T) and BMD of Chinese men or women. It would be interesting to study the interactions with folate, B12, and homocysteine.


Extending coalescent theory to autotetraploids.
We develop coalescent models for autotetraploid species with tetrasomic inheritance. We show that the ancestral genetic process in a large population without recombination may be approximated using Kingman's standard coalescent, with a coalescent effective population size 4N. Numerical results suggest that this approximation is accurate for population sizes on the order of hundreds of individuals. Therefore, existing coalescent simulation programs can be adapted to study population history in autotetraploids simply by interpreting the timescale in units of 4N generations. We also consider the possibility of double reduction, a phenomenon unique to polysomic inheritance, and show that its effects on gene genealogies are similar to partial self-fertilization.


Early orthognathic surgery with postsurgical bone-anchored retention in unilateral cleft lip and palate: A case report.
We present a case report of early Le Fort I osteotomy with maxillary advancement retained postoperatively by Class III elastics anchored on miniplates in a growing patient with complete unilateral cleft lip and palate (UCLP). A 14-year-old boy who underwent orthognathic surgery at the pubertal growth spurt was presented. During surgery, Bollard miniplates were installed in the posterior region of the maxilla and in the anterior region of the mandible. Class III elastics anchored on miniplates were used at night (8-10 h) starting 60 days after surgery. The force of the elastics progressively increased from 100 g to 250 g. The elastics were replaced daily. The positive overjet remained stable over 15 months of postoperative follow-up. Maxillary advancement was adequately retained using Bollard miniplates and the facial profile remained stable until the end of facial growth.


Search for the Lepton-Flavor-Violating Decays B_{s}^{0}→τ^{±}μ^{∓} and B^{0}→τ^{±}μ^{∓}.
Results are reported from a search for the rare decays B_{s}^{0}→τ^{±}μ^{∓} and B^{0}→τ^{±}μ^{∓}, where the τ lepton is reconstructed in the channel τ^{-}→π^{-}π^{+}π^{-}ν_{τ}. These processes are effectively forbidden in the standard model, but they can potentially occur at detectable rates in models of new physics that can induce lepton-flavor-violating decays. The search is based on a data sample corresponding to 3 fb^{-1} of proton-proton collisions recorded by the LHCb experiment in 2011 and 2012. The event yields observed in the signal regions for both processes are consistent with the expected standard model backgrounds. Because of the limited mass resolution arising from the undetected τ neutrino, the B_{s}^{0} and B^{0} signal regions are highly overlapping. Assuming no contribution from B^{0}→τ^{±}μ^{∓}, the upper limit B(B_{s}^{0}→τ^{±}μ^{∓})<4.2×10^{-5} is obtained at 95% confidence level. If no contribution from B_{s}^{0}→τ^{±}μ^{∓} is assumed, a limit of B(B^{0}→τ^{±}μ^{∓})<1.4×10^{-5} is obtained at 95% confidence level. These results represent the first limit on B(B_{s}^{0}→τ^{±}μ^{∓}) and the most stringent limit on B(B^{0}→τ^{±}μ^{∓}).


Diagnostic accuracy and association to disability of clinical test findings associated with patellofemoral pain syndrome.
To investigate the diagnostic accuracy and association to disability of selected functional findings or physical examination tests for patellofemoral pain syndrome (PFPS) in patients with anterior knee pain. A sample of 76 consecutive patients with anterior knee pain was further subdivided into PFPS and other diagnoses. Routine physical examination tests were examined in a prospective, consecutive-subjects design for a cohort of patients with anterior knee pain. Diagnostic accuracy findings, including sensitivity, specificity, positive (PPV) and negative (NPV) predictive value, and positive (LR+) and negative (LR-) likelihood ratios, were calculated for each test. PPV and NPV reflect the percentage of time of positive or a negative test (respectively) accurately captures the diagnosis of the condition. LR+ and LR- reflect alterations in post-test probability when the test is positive or negative (respectively). Lastly, associations to disability (International Knee Documentation Committee (IKDC) subjective form) were calculated for each clinical finding. Diagnostic accuracy analyses of individual functional assessment and situational phenomena suggest that the strongest diagnostic test is pain encountered during resisted muscle contraction of the knee (PPV=82%; LR+=2.2; 95% CI: 0.99-5.2). Clusters of test findings were substantially more diagnostic, with any two of three positive findings of muscle contraction, pain during squatting, and pain during palpation yielding the following values: PPV=89%; LR+=4.0 (95% CI: 1.8-10.3). No individual or clustered test findings were significantly associated with the IKDC score. Combinations of functional assessment tests and situational phenomena are diagnostic for PFPS and may serve to rule in and rule out the presence of PFPS. Single findings are not related to disability scores (IKDC).


A New Greenhouse Method to Assay Soybean Resistance to Brown Stem Rot.
Greenhouse, growth chamber, and field experiments were conducted to develop a method to assess resistance of soybeans to Cadophora gregata (Phialophora gregata), causal agent of brown stem rot (BSR). In the new method, C. gregata is introduced at the base of the stems of 2-week-old soybeans, and the presence of the fungus is assessed in the tips of the stems 5 weeks later. To test the effectiveness of the method, two populations of soybeans and 10 checks were inoculated at the stem base and then assayed for fungal colonization of the stem tips, percentage of symptomatic leaflets, and percent internal stem length discolored. The lines also were planted in naturally infested fields to assess for percent internal stem length discolored, and were tested for the presence/absence of a BSR-resistant molecular marker. Greenhouse, field, and molecular marker data were compared. Linear regression analysis suggested that percentage of plants with colonized stem tips explained 41 to 64% of the variability (P < 0.0001) in percent stem length discolored in the field and 58 to 85% of the variability (P < 0.0001) in molecular marker data for BSR resistance. Percent stem length discolored assessed in the greenhouse had the lowest correlation with percent stem length discolored in the field and with the molecular marker. Of three incubation temperatures tested, 22°C was the most conducive for distinguishing resistant/susceptible soybeans using the colonization method.


Noninvasive loading of the murine tibia: an in vivo model for the study of mechanotransduction.
Transgenic and knockout mice present a unique opportunity to study mechanotransduction pathways in vivo, but the difficulty inherent with applying externally controlled loads to the small mouse skeleton has hampered this approach. We have developed a novel device that enables the noninvasive application of controlled mechanical loads to the murine tibia. Calibration of tissue strains induced by the device indicated that the normal strain environment was repeatable across loading bouts. Two in vivo studies were performed to show the usefulness of the device. Using C57Bl/6J mice, we found that dynamic but not static loading increased cortical bone area. This result is consistent with previous models of bone adaptation, and the lack of adaptation induced by static loading serves as a negative control for the device. In a preliminary study, transgenic mice selectively overexpressing insulin-like growth factor 1 (IGF-1) in osteoblasts underwent a low-magnitude loading regimen. Periosteal bone formation was elevated 5-fold in the IGF-1-overexpressing mice but was not elevated in wild-type littermates, showing the potential for synergism between mechanical loading and selected factors. Based on these data, we anticipate that the murine tibia-loading device will enhance assessment of mechanotransduction pathways in vivo and, as a result, has the potential to facilitate novel gene discovery and optimization of synergies between drug therapies and mechanical loading.


[Diagnostic approach to solitary peripheral pulmonary lesions].
Peripheral localization and lack of symptoms are reasons why it is difficult to establish the diagnosis of peripheral pulmonary lesions commonly of malignant nature. Therefore thoracotomy often represents a diagnostic and therapeutic method at the same time. There is a need to define an adequate and optimal diagnostic approach to these lesions in order to establish their etiology, if possible, at low costs. This retrospective study included 50 patients with peripheral solitary pulmonary lesions (PSPL) who underwent thoracotomy at the Institute of Lung Diseases in Sremska Kamenica. In all patients both bronchoscopy and transthoracic puncture were performed prior to surgery. Having evaluated the diagnostic procedures, their proper sequence has then been applied in the prospective group of another 50 patients admitted to the Institute for similar lesions. In the retrospective group the etiology of PSPL was established by bronchoscopy in 4% and using transthoracic puncture in 58% of patients, with sensitivity, specificity and accuracy of 78.78%, 100% and 85.1%, respectively. In the prospective group, transthoracic puncture (TTP) provided the final diagnosis in 70% of patients, with 86.2% sensitivity, 100% specificity and 90% accuracy. Transthoracic puncture is a method of choice in preoperative diagnostics of solitary peripheral pulmonary lesions, quite like thoracotomy in cases where applied diagnostic procedures were inefficient.


Cytochrome P450 in vitro reaction phenotyping: a re-evaluation of approaches used for P450 isoform identification.
Marker substrates, chemical inhibitors, and inhibitory antibodies are important tools for the identification of cytochrome P450 (P450) isoform responsible for the metabolism of therapeutic agents in vitro. In view of the versatile and nonspecific nature of P450 enzymes, many of the marker substrates and chemical inhibitors used for P450 in vitro reaction phenotyping are isoform selective but not specific. Recently, the use of marker substrate and chemical inhibitors in CYP2D6 in vitro reaction phenotyping was questioned by Granvil et al. (2002). In comparison of a panel of 15 recombinant P450 enzymes, they found that in addition to CYP2D6, CYP1A1 is also capable of catalyzing the formation of 4-hydroxylated metabolite of debrisoquine and that the intrinsic clearance of debrisoquine by CYP2D6-mediated 4-hydroxylation is only about twice that by CYP1A1. In their study, they have also demonstrated that quinidine inhibits both CYP2D6- and CYP1A1-mediated debrisoquine 4-hydroxylation. In view of these important findings, we have reevaluated various approaches used to identify P450 isoform(s) responsible for the metabolism of therapeutic agents. While acknowledging the value of inhibitory antibodies in P450-phenotyping studies, it is our opinion that in well conducted in vitro experiments, isoform-selective chemical inhibitors can also provide valuable and reliable information. Hopefully, future efforts may produce even better P450 isoform-selective marker substrates and inhibitors.


Weight Gain after Interferon-Free Treatment of Chronic Hepatitis C-Results from the German Hepatitis C-Registry (DHC-R).
Chronic hepatitis C can be treated very effectively with direct-acting antivirals (DAA) with only minor side effects compared to an interferon-containing treatment regimen. The significance of metabolic comorbidities after HCV cure is not well defined. This study aims to investigate short- and long-term weight change of patients receiving interferon-free antiviral treatment for chronic hepatitis C. The German Hepatitis C-registry (DHC-R) is a national multicenter real-world cohort. A total of 5111 patients were followed prospectively after DAA treatment for up to 3 years. Weight change compared to baseline was analyzed at end of treatment and at years 1, 2, and 3 after completion of antiviral therapy. Regression analysis was performed to identify baseline predictors for weight change. While there was no relevant mean weight change (-0.2 kg, SD 4.3 kg) at the end of antiviral treatment, weight started to increase during long-term follow-up reaching +1.7 kg (SD 8.0 kg, p < 0.001) compared to baseline at 3 years (follow-up year 3, FU3) after completion of antiviral therapy. 48%, 31%, and 22% of patients had a weight gain greater than 1, 3, and 5 kg at FU3, respectively. During follow-up, a body mass index (BMI) <30 proved to be the only consistent predictor for weight gain. DAA treatment is followed by a substantial weight gain (+3 kg or more) in one-third of the patients during long-term follow-up. Non-obese patients seemed to be most vulnerable to weight gain. The body compartment involved in weight gain as well as the mechanism of weight gain remain to be elucidated.


Thoracoscopy with Concurrent Esophagoscopy for Persistent Right Aortic Arch in 9 Dogs.
To report the diagnosis, treatment, and short-term outcome in dogs with suspected persistent right aortic arch (PRAA) undergoing thoracoscopy with concurrent esophagoscopy. Multi-institutional retrospective case series. Dogs with suspected PRAA (n=9). Medical records were reviewed from 2012 to 2016. Dogs undergoing thoracoscopy for PRAA at 3 referral hospitals were included. Signalment, clinical signs, diagnostic imaging, anesthesia protocol (including the use of one-lung ventilation), surgical approach, complications, and short-term outcome were recorded. Dogs underwent a left-sided intercostal thoracoscopic approach with concurrent intraoperative esophagoscopy. The ligamentum arteriosum (LA) and constricting fibers were divided using a vessel-sealing device using a 3 or 4 port thoracoscopy technique. Visualization and dissection of the LA was aided by transesophageal illumination by esophagoscopy. Thoracoscopy confirmed PRAA in 9 dogs, with an aberrant left subclavian artery (LS) identified in 5 dogs. Major complications occurred in 2 dogs: postoperative hemorrhage from the LS and esophageal perforation, which resulted in euthanasia. Median follow-up was 250 days (range, 56-1,595). Regurgitation resolved in 4 of 8 surviving dogs. One dog had recurrence of regurgitation 1,450 days postoperatively, esophageal compression by the LS was identified, and regurgitation resolved following LS transection. Esophagoscopy aided identification and dissection of the LA in all cases. Due to the potential for the LS to cause clinical esophageal constriction postoperatively, a recommendation for LS transection may be warranted. Vascular clips can also be considered as an alternative for vessel ligation to avoid complications associated with vessel-sealing device use.


Acute aortic occlusion. A 40-year experience.
To review a large experience with acute aortic occlusion (AAO) to better define the cause, clinical presentation, treatment, prognostic variables, and outcome. Retrospective review of 46 consecutive patients with AAO during a 40-year period. A large urban tertiary care referral center in Detroit, Mich. Adult patients with arteriographic and/or operative confirmation of acute occlusion of the abdominal aorta plus signs and symptoms of acute ischemia. Operative and nonoperative treatment of AAO. Mortality, morbidity, and long-term survival. Other variables measured included cause, risk factors, and effects of duration and severity of ischemia and treatment methods on outcome. Two primary causes were identified--embolism (65%) and thrombosis (35%). Heart disease and female gender were risk factors for embolism, while smoking and diabetes were risk factors for thrombosis. Severity of ischemia on presentation correlated better with outcome than duration of ischemia. The hospital mortality rate was 35% and morbidity, 74%, with no difference between the two groups. Recurrent arterial embolism occurred in 43% of patients with embolic AAO. Seventy-two percent of AAO survivors were alive 5 years after therapy. Acute aortic occlusion remains a serious vascular surgical emergency with significant morbidity and mortality, even when recognized promptly and treated appropriately. Nevertheless, survivors have a reasonable long-term outcome. Permanent anticoagulation is suggested in patients with embolic AAO to minimize a high incidence of recurrent arterial embolism.


Ultrasensitive N-photon interferometric autocorrelator.
We demonstrate a novel method to measure Nth-order (N=1,2,3,4) interferometric autocorrelation with high sensitivity and temporal resolution. It is based on the combination of linear absorption and nonlinear detection in a superconducting nanodetector, providing much higher efficiency than methods based on all-optical nonlinearities. Its temporal resolution is only limited by the quasiparticle energy relaxation time, which is directly measured to be in the 20 ps range for the NbN films used in this work. We present a general model of interferometric autocorrelation with these nonlinear detectors and discuss the comparison with other approaches and possible improvements.


Distinguishing benign from malignant pulmonary nodules with helical chest CT in children with malignant solid tumors.
To retrospectively assess whether computed tomographic (CT) findings can indicate the benign or malignant nature of pulmonary nodules in pediatric patients with malignant solid primary tumors. With institutional review board approval, waived parental and patient consent, and HIPAA compliance, the authors determined the incidence of malignancy among 81 pulmonary nodules that were sampled at biopsy within 3 weeks after chest CT (January 1999 to September 2003) in 41 young patients with malignant solid tumors. Three radiologists independently and retrospectively reviewed these scans and the available previously obtained scans, classifying nodules as benign, malignant, or indeterminate on the basis of their number, unilateral versus bilateral distribution, size, margins (indistinct vs distinct), calcification, growth, and associated adenopathy. These classifications were compared with nodule histologic type, and interreviewer agreement was assessed. The median patient age was 14.8 years (mean, 13.7 years; range, 5-21 years). Twenty-four of the 41 patients (58%) had at least one biopsy-proved malignant nodule. Four (10%) patients had both benign and malignant nodules; 17 (42%) had only benign nodules. Reviewer 1 classified 65% (39 of 60) of nodules correctly; reviewer 2, 57% (37 of 65); and reviewer 3, 67% (43 of 64). Interreviewer agreement was slight to moderate (kappa </= 0.43, P </= .03). In contrast to findings in adults, sharply defined nodules in younger individuals were more likely to be malignant (P = .03) and nodule size was not associated with malignancy (P >/= .32). The frequency of benign nodules and the inconsistency of predictions based on CT features suggest the need for better predictors of pulmonary nodules being malignant or benign, so as to reduce unnecessary thoracotomy in pediatric patients with solid malignancy. .


Intimate partner violence and health provider training and screening in the news.
Intimate partner violence is a significant women's health issue. Since the news media can play a role in policy development, it is important to understand how newspapers have portrayed training and screening. The purpose of this study was to describe the frequency and nature of print news coverage of health issues related to partner violence, specifically, provider training and screening by health providers. We conducted a content analysis on articles obtained from major city and state capital daily newspapers from 20 states. News articles and editorials mentioning intimate partner violence and provider training and screening were examined for the years 1994 through 2001 (N = 188). Results showed that print news coverage was limited and received low levels of attention, indicating little potential to influence either policy or individual behavior. However, when the issue was covered, little debate or controversy was present, and a broad discussion of the issue was generally provided. News coverage of training and screening could be improved by increasing dissemination of research results, illustrating the policy implications of these issues, and offering resource information to women experiencing violence.


Effects of CO2 enrichment on benthic primary production and inorganic nitrogen fluxes in two coastal sediments.
Ocean acidification may alter the cycling of nitrogen in coastal sediment and so the sediment-seawater nitrogen flux, an important driver of pelagic productivity. To investigate how this perturbation affects the fluxes of NOX- (nitrite/nitrate), NH4+ and O2, we incubated estuarine sand and subtidal silt in recirculating seawater with a CO2-adjusted pH of 8.1 and 7.9. During a 41-day incubation, the seawater kept at pH 8.1 lost 97% of its NOX- content but the seawater kept at pH 7.9 lost only 18%. Excess CO2 increased benthic photosynthesis. In the silt, this was accompanied by a reversal of the initial NOX- efflux into influx. The estuarine sand sustained its initial NOX- influx but, by the end of the incubation, released more NH4+ at pH 7.9 than at pH 8.1. We hypothesise that these effects share a common cause; excess CO2 increased the growth of benthic microalgae and so nutrient competition with ammonia oxidising bacteria (AOB). In the silt, diatoms likely outcompeted AOB for NH4+ and photosynthesis increased the dark/light fluctuations in the pore water oxygenation inhibiting nitrification and coupled nitrification/denitrification. If this is correct, then excess CO2 may lead to retention of inorganic nitrogen adding to the pressures of increasing coastal eutrophication.


Minimum Bactericidal Concentration of Ciprofloxacin to Pseudomonas aeruginosa Determined Rapidly Based on Pyocyanin Secretion.
Infections due to Pseudomonas aeruginosa (P. aeruginosa) often exhibit broad-spectrum resistance and persistence to common antibiotics. Persistence is especially problematic with immune-compromised subjects who are unable to eliminate the inhibited bacteria. Hence, antibiotics must be used at the appropriate minimum bactericidal concentration (MBC) rather than at minimum inhibitory concentration (MIC) levels. However, MBC determination by conventional methods requires a 24 h culture step in the antibiotic media to confirm inhibition, followed by a 24 h sub-culture step in antibiotic-free media to confirm the lack of bacterial growth. We show that electrochemical detection of pyocyanin (PYO), which is a redox-active bacterial metabolite secreted by P. aeruginosa, can be used to rapidly assess the critical ciprofloxacin level required for bactericidal deactivation of P. aeruginosa within just 2 hours in antibiotic-treated growth media. The detection sensitivity for PYO can be enhanced by using nanoporous gold that is modified with a self-assembled monolayer to lower interference from oxygen reduction, while maintaining a low charge transfer resistance level and preventing electrode fouling within biological sample matrices. In this manner, bactericidal efficacy of ciprofloxacin towards P. aeruginosa at the MBC level and bacterial persistence at the MIC level can be determined rapidly, as validated at later timepoints using bacterial subculture in antibiotic-free media.


Enhanced cytotoxic activity of cetuximab in EGFR-positive lung cancer by conjugating with gold nanoparticles.
Cetuximab (C225) is a unique agent, targeting epidermal growth factor receptor (EGFR)-positive cancer. However, the therapeutic effect of C225 in EGFR high-expressing non-small cell lung cancer (NSCLC) remains poor. Here, we report that conjugation of C225 with gold nanoparticles (AuNPs) enhances the cytotoxicity of C225 in NSCLC both in vitro and in vivo. The NSCLC cell lines A549 (EGFR(high)) and H1299 (EGFR(low)) were employed to investigate different responses to C225, IgG-AuNPs and C225-AuNPs. The antitumor properties of C225-AuNPs were explored in vivo by establishing a tumor xenograft model in nude mice. Overall, the therapeutic effect of C225-AuNPs was more pronounced in EGFR(high) A549 cells compared with EGFR(low) H1299 cells. The cytotoxic effect of C225-AuNPs in A549 cells increased in a dose-dependent manner. C225-AuNPs significantly suppressed A549 cell proliferation and migration capacity and accelerated apoptosis compared with C225, and this effect was probably due to enhanced EGFR endocytosis and the subsequent suppression of downstream signaling pathway. Finally in the tumor xenograft of nude mice, treatment with C225-AuNPs also led to a significant reduction in tumor weight and volume with low toxicity. Our findings suggest that C225-AuNPs conjugate has promising potential for targeted therapy of EGFR positive NSCLC patients.


A randomised controlled trial of an implementation strategy delivered at scale to increase outdoor free play opportunities in early childhood education and care (ECEC) services: a study protocol for the get outside get active (GOGA) trial.
Increased outdoor play time in young children is associated with many health and developmental benefits. This study aims to evaluate the impact of a multi-strategy implementation strategy delivered at scale, to increase opportunities for outdoor free play in Early Childhood Education and Care (ECEC) services. The study will employ a parallel-group randomised controlled trial design. One hundred ECEC services in the Hunter New England region of New South Wales, Australia, will be recruited and randomised to receive either a 6-month implementation strategy or usual care. The trial will seek to increase the implementation of an indoor-outdoor routine (whereby children are allowed to move freely between indoor and outdoor spaces during periods of free play), to increase their opportunity to engage in outdoor free play. Development of the strategy was informed by the Behaviour Change Wheel to address determinants identified in the Theoretical Domains Framework. ECEC services allocated to the control group will receive 'usual' implementation support delivered as part of state-wide obesity prevention programs. The primary trial outcome is the mean minutes/day (calculated across 5 consecutive days) of outdoor free play opportunities provided in ECEC services measured at baseline, 6-months (primary end point) and 18-months post baseline. Analyses will be performed using an intention-to-treat approach with ECEC services as the unit of analysis, using a linear mixed effects regression model to assess between-group differences. A sensitivity analysis will be undertaken, adjusting for service characteristics that appear imbalanced between groups at baseline, and a subgroup analysis examining potential intervention effect among services with the lowest baseline outdoor free play opportunities. Identifying effective strategies to support the implementation of indoor-outdoor routines in the ECEC setting at scale is essential to improve child population health. Australian New Zealand Clinical Trials Registry ( ACTRN12621000987864 ). Prospectively registered 27th July 2021, ANZCTR - Registration.


IFIT5 positively regulates NF-κB signaling through synergizing the recruitment of IκB kinase (IKK) to TGF-β-activated kinase 1 (TAK1).
Precise regulation of NF-κB signaling pathways is essential to effective host immune response. However, the specific molecular mechanism underlying NF-κB activation by different stimuli is not fully understood. Here we demonstrate that IFIT5, one of the interferon induced tetratricopeptide repeat family members, enhances IKK phosphorylation and NF-κB activation through interacting with TAK1 and IKK. Following TNF-α treatment, IFIT5 interacted with TAK1 or IKK complex and synergized the recruitment of IKK to TAK1 in a dose dependent manner. Consistent with these observations, knockdown of IFIT5 decreased the recruitment of IKK to TAK1 and markedly weakened IKK phosphorylation, further reducing the production of NF-κB target genes IL-8 and ICAM-1. Moreover, we found that IFIT5 also promoted SeV-induced IKK phosphorylation and NF-κB activation by regulating the recruitment of IKK to TAK1. Our findings identify a previously unrecognized role of IFIT5 as a positive regulator in IKK phosphorylation and NF-κB activation, highlighting that IFIT5 serves as an important mediator in innate immunity.


Gluconeogenesis using glycerol as a substrate in bloodstream-form Trypanosoma brucei.
Bloodstream form African trypanosomes are thought to rely exclusively upon glycolysis, using glucose as a substrate, for ATP production. Indeed, the pathway has long been considered a potential therapeutic target to tackle the devastating and neglected tropical diseases caused by these parasites. However, plasma membrane glucose and glycerol transporters are both expressed by trypanosomes and these parasites can infiltrate tissues that contain glycerol. Here, we show that bloodstream form trypanosomes can use glycerol for gluconeogenesis and for ATP production, particularly when deprived of glucose following hexose transporter depletion. We demonstrate that Trypanosoma brucei hexose transporters 1 and 2 (THT1 and THT2) are localized to the plasma membrane and that knockdown of THT1 expression leads to a growth defect that is more severe when THT2 is also knocked down. These data are consistent with THT1 and THT2 being the primary routes of glucose supply for the production of ATP by glycolysis. However, supplementation of the growth medium with glycerol substantially rescued the growth defect caused by THT1 and THT2 knockdown. Metabolomic analyses with heavy-isotope labelled glycerol demonstrated that trypanosomes take up glycerol and use it to synthesize intermediates of gluconeogenesis, including fructose 1,6-bisphosphate and hexose 6-phosphates, which feed the pentose phosphate pathway and variant surface glycoprotein biosynthesis. We used Cas9-mediated gene knockout to demonstrate a gluconeogenesis-specific, but fructose-1,6-bisphosphatase (Tb927.9.8720)-independent activity, converting fructose 1,6-bisphosphate into fructose 6-phosphate. In addition, we observed increased flux through the tricarboxylic acid cycle and the succinate shunt. Thus, contrary to prior thinking, gluconeogenesis can operate in bloodstream form T. brucei. This pathway, using glycerol as a physiological substrate, may be required in mammalian host tissues.


Vulnerability Assessment of Buildings due to Land Subsidence using InSAR Data in the Ancient Historical City of Pistoia (Italy).
The launch of the medium resolution Synthetic Aperture Radar (SAR) Sentinel-1 constellation in 2014 has allowed public and private organizations to introduce SAR interferometry (InSAR) products as a valuable option in their monitoring systems. The massive stacks of displacement data resulting from the processing of large C-B and radar images can be used to highlight temporal and spatial deformation anomalies, and their detailed analysis and postprocessing to generate operative products for final users. In this work, the wide-area mapping capability of Sentinel-1 was used in synergy with the COSMO-SkyMed high resolution SAR data to characterize ground subsidence affecting the urban fabric of the city of Pistoia (Tuscany Region, central Italy). Line of sight velocities were decomposed on vertical and E-W components, observing slight horizontal movements towards the center of the subsidence area. Vertical displacements and damage field surveys allowed for the calculation of the probability of damage depending on the displacement velocity by means of fragility curves. Finally, these data were translated to damage probability and potential loss maps. These products are useful for urban planning and geohazard management, focusing on the identification of the most hazardous areas on which to concentrate efforts and resources.


Manipulation of the acute inflammatory response by dietary polyunsaturated fatty acid modulation.
Dietary polyunsaturated fatty acid modulation has been used as an anti-inflammatory strategy in experimental models of disease as well as in clinical trials. To elucidate the mechanisms underlying the anti-inflammatory effects of manipulating dietary polyunsaturated fatty acids, the in vivo effects of essential fatty acid (EFA) deficiency and (n-3) fatty acid supplementation were contrasted using a model of acute inflammation induced by the i.p. injection of zymosan into mice. Both diets led to a substantial decrease in tissue (n-6) fatty acid content. EFA deficiency was also characterized by the accumulation of (n-9) fatty acids, particularly 20:3 (n-9), the fatty acid that uniquely characterizes the deficiency state. Dietary (n-3) fatty acid supplementation led instead to marked increases in (n-3) fatty acids, especially 20:5 (n-3). With respect to the antiinflammatory effects of the two diets, EFA deficiency, but not (n-3) fatty acid supplementation, depleted levels of resident peritoneal macrophages. EFA deficiency was also more effective than (n-3) fatty acid supplementation in inhibiting the influx of polymorphonuclear neutrophils in response to zymosan. The effect of the two diets on the in vivo generation of leukotriene(LT)B also differed markedly. EFA deficiency completely inhibited the synthesis of LTB. Dietary (n-3) fatty acid supplementation, in contrast, reduced the production of LTB4 by only 50%. With (n-3) fatty acid supplementation LTB5 was produced. The more modest effect of (n-3) fatty acid supplementation in decreasing LTB4 generation was not due to blockade of the cyclooxygenase pathway. EFA deficiency, but not (n-3) fatty acid supplementation, was associated with the decreased synthesis of thromboxane. Although dietary fatty acid modulation has been shown to diminish platelet activating factor (PAF) synthesis, studies using the PAF receptor blocker, L659989, established that PAF was not a significant factor in the elicitation of leukocytes in this model of inflammation. In summary, the anti-inflammatory effect of EFA deficiency was more marked that that of dietary (n-3) fatty acid supplementation in acute inflammation. This difference in anti-inflammatory potential appeared to be due to either the greater effect of EFA deficiency in decreasing levels of resident peritoneal macrophages or in suppressing the in vivo generation of LTB4.


Wear Resistance of Cu/Ag Multilayers: A Microscopic Study.
The microscopic wear behavior of copper-silver multilayer samples was studied by performing sliding wear tests using a tribo-indenter. Multilayers with an average composition of Cu90Ag10 and Ag layer thicknesses ranging from 2 to 20 nm were grown by magnetron sputtering. For reference, a homogeneous Cu90Ag10 solid solution film was similarly grown. The thin films were subjected to two-dimensional wear tests by rastering a cono-spherical diamond indenter under loads of 100-400 μN for 1-20 consecutive passes or cycles. The wear volumes were determined by atomic force microscopy. Characterization of the specimens employed nanoindentation, nanoscratch, and transmission electron microscopy (TEM). Wear rates were found to reach steady state after five cycles or less. The hardness values of the as-grown and worn samples both increased with decreasing thickness of the Cu and Ag layers, whereas the steady-state wear rates decreased. Notably, the wear resistance increased faster than the corresponding increase in indentation hardness, indicating a deviation from the Archard's law. An inverse relationship between the wear rate and hardness was, however, recovered when using scratch hardness, suggesting that scratch hardness is a better predictor of wear resistance. Characterization of subsurface wear microstructures by TEM revealed that forced chemical mixing and dissolution of layers occur to a depth of ≈40 to 50 nm, stabilizing a chemically homogeneous solid solution below the wear surface. Comparative wear tests on thicker multilayers revealed that Cu/Ag interfaces reduced the wear rate significantly, thus helping to rationalize the high wear resistance of thin multilayers.


[Effect of cold adaptation on the feeding behavior of genetically obese Zucker rats].
A diurnal hyperphagia is certainly the main factor of adiposity in the genetically obese Zucker fa/fa rat. In a previous experiment it was observed that cold-acclimatization suppressed hyperphagia and stopped the increase in obesity. In this work, the chronology of modification in the feeding pattern is studied during the first month of cold exposure (10 degrees C). The main cold-induced modifications are observed after 2 weeks of cold exposure. Possibly the decrease in metabolic efficiency of food could parallel the cold-induced enhancement of energetic capacity of brown adipose tissue which has been described elsewhere. This tissue could play a role in the obesity of the Zucker rat.