Estimation of critical behavior from the density of states in classical statistical models.
We present a simple and efficient approximation scheme which greatly facilitates the extension of Wang-Landau sampling (or similar techniques) in large systems for the estimation of critical behavior. The method, presented in an algorithmic approach, is based on a very simple idea, familiar in statistical mechanics from the notion of thermodynamic equivalence of ensembles and the central limit theorem. It is illustrated that we can predict with high accuracy the critical part of the energy space and by using this restricted part we can extend our simulations to larger systems and improve the accuracy of critical parameters. It is proposed that the extensions of the finite-size critical part of the energy space, determining the specific heat, satisfy a scaling law involving the thermal critical exponent. The method is applied successfully for the estimation of the scaling behavior of specific heat of both square and simple cubic Ising lattices. The proposed scaling law is verified by estimating the thermal critical exponent from the finite-size behavior of the critical part of the energy space. The density of states of the zero-field Ising model on these lattices is obtained via a multirange Wang-Landau sampling.


Regulation of nucleus accumbens activity by the hypothalamic neuropeptide melanin-concentrating hormone.
The lateral hypothalamus and the nucleus accumbens shell (AcbSh) are brain regions important for food intake. The AcbSh contains high levels of receptor for melanin-concentrating hormone (MCH), a lateral hypothalamic peptide critical for feeding and metabolism. MCH receptor (MCHR1) activation in the AcbSh increases food intake, while AcbSh MCHR1 blockade reduces feeding. Here biochemical and cellular mechanisms of MCH action in the rodent AcbSh are described. A reduction of phosphorylation of GluR1 at serine 845 (pSer(845)) is shown to occur after both pharmacological and genetic manipulations of MCHR1 activity. These changes depend upon signaling through G(i/o), and result in decreased surface expression of GluR1-containing AMPA receptors (AMPARs). Electrophysiological analysis of medium spiny neurons (MSNs) in the AcbSh revealed decreased amplitude of AMPAR-mediated synaptic events (mEPSCs) with MCH treatment. In addition, MCH suppressed action potential firing MSNs through K(+) channel activation. Finally, in vivo recordings confirmed that MCH reduces neuronal cell firing in the AcbSh in freely moving animals. The ability of MCH to reduce cell firing in the AcbSh is consistent with a general model from other pharmacological and electrophysiological studies whereby reduced AcbSh neuronal firing leads to food intake. The current work integrates the hypothalamus into this model, providing biochemical and cellular mechanisms whereby metabolic and limbic signals converge to regulate food intake.


Photophysical and electrochemical characterisation of the interactions between components in neutral pi-associated
The electrochemical and photophysical properties of a variety of neutral pi-associated [2]catenanes have been explored by using cyclic voltammetry, absorption and luminescence spectrophotometry and the measurement of exited-state lifetimes. Several trends that could be correlated with interactions between the mechanically linked components of the structures were revealed from comparative study of catenane precursors, model compounds and the [2]catenanes themselves. Throughout, emphasis is placed on pair-wise comparisons between systems which differ in a single structural feature. Substitution in a catenane of a pyromellitic diimide unit by a naphthalene diimide yields more readily reduced derivatives, whose absorption spectra reveal charge transfer within the catenane to be a lower energy process of reduced intensity. Conversion of the butadiyne links within the diimide macrocycle of the catenanes to saturated chains results in an increase in both the energy and intensity of their charge-transfer bands; electrochemically these derivatives are all harder to reduce than the parent systems. Replacement of one of the electron-donating components of the catenanes with a less effective aromatic donor bearing a carboxy group also decreases the energy and intensity of the charge-transfer feature and is accompanied by a slightly more ready reduction. A sequence of reduction and translational events is proposed to explain the intriguing electrochemical behaviour of a catenane that contains one pyromellitic and one naphthalene diimide. For some systems the photophysical and electrochemical techniques, whilst exploring distinct physical phenomena, are shown to be in good agreement by comparison of shifts of electrochemical reduction waves with those of charge-transfer absorption features.


Detection of Chlamydia Developmental Forms and Secreted Effectors by Expansion Microscopy.
Expansion microscopy (ExM) is a novel tool to improve the resolution of fluorescence-based microscopy that has not yet been used to visualize intracellular pathogens. Here we show the expansion of the intracellular pathogen Chlamydia trachomatis, enabling to differentiate its two distinct forms, catabolic active reticulate bodies (RB) and infectious elementary bodies (EB), on a conventional confocal microscope. We show that ExM enables the possibility to precisely locate chlamydial effector proteins, such as CPAF or Cdu1, within and outside of the chlamydial inclusion. Thus, we claim that ExM offers the possibility to address a broad range of questions and may be useful for further research on various intracellular pathogens.


Assessing an alternative for "negative variance components": A gentle introduction to Bayesian covariance structure modeling for negative associations among patients with personalized treatments.
The multilevel model (MLM) is the popular approach to describe dependences of hierarchically clustered observations. A main feature is the capability to estimate (cluster-specific) random effect parameters, while their distribution describes the variation across clusters. However, the MLM can only model positive associations among clustered observations, and it is not suitable for small sample sizes. The limitation of the MLM becomes apparent when estimation methods produce negative estimates for random effect variances, which can be seen as an indication that observations are negatively correlated. A gentle introduction to Bayesian covariance structure modeling (BCSM) is given, which makes it possible to model also negatively correlated observations. The BCSM does not model dependences through random (cluster-specific) effects, but through a covariance matrix. We show that this makes the BCSM particularly useful for small data samples. We draw specific attention to detect effects of a personalized intervention. The effect of a personalized treatment can differ across individuals, and this can lead to negative associations among measurements of individuals who are treated by the same therapist. It is shown that the BCSM enables the modeling of negative associations among clustered measurements and aids in the interpretation of negative clustering effects. Through a simulation study and by analysis of a real data example, we discuss the suitability of the BCSM for small data sets and for exploring effects of individualized treatments, specifically when (standard) MLM software produces negative or zero variance estimates. (PsycInfo Database Record (c) 2023 APA, all rights reserved).


Leptin and insulin signaling in dopaminergic neurons: relationship between energy balance and reward system.
The central actions of leptin and insulin are essential for the regulation of energy and glucose homeostasis. In addition to the crucial effects on the hypothalamus, emerging evidence suggests that the leptin and insulin signaling can act on other brain regions to mediate the reward value of nutrients. Recent studies have indicated the midbrain dopaminergic neurons as a potential site for leptin' and insulin's actions on mediating the feeding behaviors and therefore affecting the energy balance. Although molecular details about the integrative roles of leptin and insulin in this subset of neurons remain to be investigated, substantial body of evidence by far imply that the signaling pathways regulated by leptin and insulin may play an essential role in the regulation of energy balance through the control of food-associated reward. This review therefore describes the convergence of energy regulation and reward system, particularly focusing on leptin and insulin signaling in the midbrain dopaminergic neurons.


Intracellular type III secretion by cytoplasmic Shigella flexneri promotes caspase-1-dependent macrophage cell death.
The Gram-negative bacterium Shigella flexneri triggers pro-inflammatory apoptotic cell death in macrophages, which is crucial for the onset of an acute inflammatory diarrhoea termed bacillary dysentery. The Mxi-Spa type III secretion system promotes bacterial uptake and escape into the cytoplasm, where, dependent on the translocator/effector protein IpaB, caspase-1 [interleukin (IL)-1beta-converting enzyme] and its substrate IL-1beta are activated. Here, we show that in the course of a macrophage infection, IpaB is secreted intracellularly for more than 1 h post-infection and progressively accumulates in aggregates on the bacterial surface. Concomitantly, the bacterial pool of IpaB is gradually depleted. The protonophore carbonyl cyanide m-chlorophenylhydrazone (CCCP) dose-dependently inhibited the Mxi-Spa-dependent secretion of IpaB triggered by the dye Congo red in vitro and abolished translocation of IpaB into the host-cell cytoplasm of S. flexneri-infected macrophages. CCCP specifically inhibited S. flexneri-triggered macrophage death in a dose-dependent manner, even if added up to 60 min post-infection. Addition of CCCP 15 min after infection blocked macrophage cell death, the activation of caspase-1 and the maturation of IL-1beta, without affecting uptake or escape of S. flexneri from the phagosome. By contrast, CCCP used at the same concentration had no effect on ATP-induced caspase-1 activation or staurosporine-induced apoptosis. Our results indicate that under the conditions used, CCCP rapidly and specifically blocks bacterial type III secretion, and thus, intracellular type III secretion promotes cytotoxicity of S. flexneri.


Significance of neoadjuvant therapy for borderline resectable pancreatic cancer: a multicenter retrospective study.
Neoadjuvant therapy (NAT) is increasingly used to improve the prognosis of patients with borderline resectable pancreatic cancer (BRPC) albeit with little evidence of its advantage over upfront surgical resection. We analyzed the prognostic impact of NAT on patients with BRPC in a multicenter retrospective study. Medical data of 165 consecutive patients who underwent treatment for BRPC between January 2010 and December 2014 were collected from ten institutions. We defined BRPC according to the National Comprehensive Cancer Network guidelines, and subclassified patients according to venous invasion alone (BR-PV) and arterial invasion (BR-A). The rates of NAT administration and resection were 35% and 79%, respectively. There were no significant differences in resection rates and prognoses between patients in the BR-PV and BR-A subgroups. NAT did not have a significant impact on prognosis according to intention-to-treat analysis. However, in patients who underwent surgical resection, NAT was independently associated with longer overall survival (OS). The median OS of patients who underwent resection after NAT (53.7 months) was significantly longer than that of patients who underwent upfront (17.8 months) or no resection (14.9 months). The rates of superior mesenteric or portal vein invasion, lymphatic invasion, venous invasion, and lymph node metastasis were significantly lower in patients who underwent resection after NAT than in those who underwent upfront resection despite similar baseline clinical profiles. Resection after NAT in patients with BRPC is associated with longer OS and lower rates of both invasion to the surrounding tissues and lymph node metastasis.


Highlights from the Faraday Discussion on New Directions in Porous Crystalline Materials, Edinburgh, UK, June 2017.
A lively discussion on new directions in porous crystalline materials took place in June 2017, with the beautiful city of Edinburgh as a backdrop, in the context of the unique Faraday Discussions format. Here, 5 minute presentations were given on papers which had been submitted in advance of the conference, with copious time allocated for in-depth discussion of the work presented. Prof. Mircea Dincă (MIT), chair of the scientific committee, opened the conference by welcoming the many different nationalities attending, and outlining the format of discussions.


Female rats exhibit greater susceptibility to early alcohol-induced liver injury than males.
It is known that women develop hepatic injury more rapidly and with exposure to less ethanol than men; however, mechanisms remain unclear. The purpose of this study was to determine if an enteral alcohol delivery model could be used to study susceptibility of females to alcohol-induced liver injury. Male and female Wistar rats (age- or weight-matched) were given ethanol (11-12 g.kg-1.day-1) continuously for up to 4 wk via intragastric feeding, and control rats received a high-fat diet without ethanol. There were no significant differences in body weight among the groups studied. Furthermore, mean ethanol concentrations, their cyclic pattern in urine, and rates of ethanol elimination were also not different between the genders under these conditions. Ethanol treatment elevated serum aspartate aminotransferase levels in male rats to 126 +/- 10 IU/l after 4 wk. In females, however, values increased more rapidly and reached significantly higher values at 4 wk (168 +/- 18 IU/l). Steatosis, inflammation, and necrosis assessed histologically also developed more rapidly and were more severe in females than males. Steatosis due to ethanol exposure, which was localized in centrilobular areas in males, was panlobular in the female. Moreover, endotoxin in plasma, intercellular adhesion molecule 1 expression in hepatic sinusoidal-lining cells, and the number of infiltrating inflammatory cells in the liver were 2-2.5-fold greater in females than males. These changes possibly account for increased hepatic injury due to ethanol in the female.


Activity of the new cephalosporin ceftaroline against bacteraemia isolates from patients with community-acquired pneumonia.
The activity of ceftaroline, a novel cephalosporin, was evaluated against 1337 isolates from patients with bacteraemic community-acquired pneumonia (CAP) requiring hospitalisation (including 119 Haemophilus influenzae, 9 Moraxella catarrhalis, 164 Staphylococcus aureus, 1007 Streptococcus pneumoniae and 38 Streptococcus pyogenes). Minimum inhibitory concentrations (MICs) were determined by broth microdilution according to Clinical and Laboratory Standards Institute (CLSI) guidelines, and susceptibility category assessments were made using CLSI or US Food and Drug Administration (FDA) breakpoints. Ceftaroline MICs were < or = 0.008-0.06 mg/L against H. influenzae, 0.25-2mg/L against methicillin-resistant S. aureus (MRSA), 0.06-1mg/L against methicillin-susceptible S. aureus, 0.015-0.5mg/L against M. catarrhalis and < or = 0.008-0.5mg/L against S. pneumoniae, and all S. pyogenes isolates had ceftaroline MICs < or = 0.008mg/L. Ceftaroline was more active than ceftriaxone or cefepime both against MRSA and penicillin-resistant pneumococci. More than 90% of MRSA isolates were resistant to clarithromycin and levofloxacin but were susceptible to linezolid or tigecycline. A high rate of clarithromycin resistance was also observed in the pneumococci. Ceftaroline was very active in vitro against all CAP isolates, including MRSA and penicillin-non-susceptible pneumococci, in contrast to the other beta-lactams tested. These data confirm ceftaroline as a new cephalosporin with enhanced anti-Gram-positive activity and suggest that ceftaroline has the potential to be a useful new agent in the treatment of CAP-associated bacteraemic infections.


Microbiota-driven transcriptional changes in prefrontal cortex override genetic differences in social behavior.
Gene-environment interactions impact the development of neuropsychiatric disorders, but the relative contributions are unclear. Here, we identify gut microbiota as sufficient to induce depressive-like behaviors in genetically distinct mouse strains. Daily gavage of vehicle (dH2O) in nonobese diabetic (NOD) mice induced a social avoidance behavior that was not observed in C57BL/6 mice. This was not observed in NOD animals with depleted microbiota via oral administration of antibiotics. Transfer of intestinal microbiota, including members of the Clostridiales, Lachnospiraceae and Ruminococcaceae, from vehicle-gavaged NOD donors to microbiota-depleted C57BL/6 recipients was sufficient to induce social avoidance and change gene expression and myelination in the prefrontal cortex. Metabolomic analysis identified increased cresol levels in these mice, and exposure of cultured oligodendrocytes to this metabolite prevented myelin gene expression and differentiation. Our results thus demonstrate that the gut microbiota modifies the synthesis of key metabolites affecting gene expression in the prefrontal cortex, thereby modulating social behavior.


Topotactic condensation of layer silicates with ferrierite-type layers forming porous tectosilicates.
Five different hydrous layer silicates (HLSs) containing fer layers (ferrierite-type layers) were obtained by hydrothermal syntheses from mixtures of silicic acid, water and tetraalkylammonium/tetraalkylphosphonium hydroxides. The organic cations had been added as structure directing agents (SDA). A characteristic feature of the structures is the presence of strong to medium strong hydrogen bonds between the terminal silanol/siloxy groups of neighbouring layers. The five-layered silicates differ chemically only with respect to the organic cations. Structurally, they differ with respect to the arrangement of the fer layers relative to each other, which is distinct for every SDA-fer-layer system. RUB-20 (containing tetramethylammonium) and RUB-40 (tetramethylphosphonium) are monoclinic with stacking sequence AAA and shift vectors between successive layers 1a0 + 0b0 + 0.19c0 and 1a0 + 0b0 + 0.24c0, respectively. RUB-36 (diethyldimethylammonium), RUB-38 (methyltriethylammonium) and RUB-48 (trimethylisopropylammonium) are orthorhombic with stacking sequence ABAB and shift vectors 0.5a0 + 0b0± 0.36c0, 0.5a0 + 0b0 + 0.5c0 and 0.5a0 + 0b0± 0.39c0, respectively. Unprecedented among the HLSs, two monoclinic materials are made up of fer layers which possess a significant amount of ordered defects within the layer. The ordered defects involve one particular Si-O-Si bridge which is, to a fraction of ca. 50%, hydrolyzed to form nests of two ≡Si-OH groups. When heated to 500-600 °C in air, the HLSs condense to form framework silicates. Although all layered precursors were moderately to well ordered, the resulting framework structures were of quite different crystallinity. The orthorhombic materials RUB-36, -38 and -48, general formula SDA4Si36O72(OH)4, which possess very strong hydrogen bonds (d[O···O] ≈ 2.4 Å), transform into a fairly or well ordered CDO-type silica zeolite RUB-37. The monoclinic materials RUB-20 and -40, general formula SDA2Si18O36(OH)2OH, possessing medium strong hydrogen bonds (d[O···O] ≈ 2.65 Å) are transformed into poorly ordered framework silicates. Some rules of thumb can be established concerning the successful zeolite synthesis via a topotactic condensation of layered precursors. Favourably, the precursor (i) possesses already a well ordered structure without defects, (ii) contains strong inter-layer hydrogen bonds and does not contain strong intra-layer hydrogen bonds and (iii) contains a suitable cation. The nature of the organic cation (size, geometry, flexibility, thermal stability) plays a key role in the formation of a microporous tectosilicate with well ordered structure. RUB-36 which meets these criteria yields a well ordered condensation product (RUB-37).


Which therapies will move to the front line for multiple myeloma?
Despite substantial progress, multiple myeloma (MM) remains an incurable disease. Recently the availability of several novel drugs with different and innovative mechanisms of action (daratumumab, elotuzumab, carfilzomib, ixazomib, and panobinostat) has increased the therapeutic options but has also increased complexity in the management of patients with MM. Areas covered: The outstanding results observed in the relapsed setting with regimens including these new drugs has provided the investigators with several treatment options that are being tested also in patients with newly diagnosed MM. Fully published phase 2 and randomized, phase 3 trials including new drugs in patients with relapsed and/or refractory MM have been reviewed. In addition, the progressive incorporation of these new drugs in the front-line treatment of MM and the potential impact of these new therapies in the management of patients with newly diagnosed MM has also been addressed. Expert commentary: In the near future, several novel anti-MM drugs will move from the relapsed to the front-line setting. While the increasing range of effective therapeutic agents is very encouraging it adds to the complexity of treatment decisions and prospective trials are needed to help clinicians to determine which could be the best therapeutic approaches for the different subgroups of patients with newly diagnosed MM.


Control of cell survival and proliferation of postnatal PSA-NCAM(+) progenitors.
In the present work, we studied the effects of several growth factors on survival and proliferation of freshly isolated neural progenitors expressing the polysialylated form of neural cell adhesion molecule (PSA-NCAM). Cells were obtained from postnatal day 2 rat forebrain, using isolation method. We found that (1) insulin-like growth factor 1 (IGF-1) exerts a powerful survival effect by inhibiting apoptotic cell death, (2) epidermal growth factor (EGF) strongly increases cell proliferation, (3) the combination of IGF-1 plus EGF promotes cellular expansion, (4) basic fibroblast growth factor displays only a weak mitogenic effect, and (5) platelet-derived growth factor-AA (PDGF-AA) has no effect on cell survival and proliferation. These results suggest that the postnatal PSA-NCAM(+) progenitors characterized in the present work may represent a transitional stage, between the embryonic EGF-responsive neural progenitors and the postnatal PSA-NCAM(+) progenitors already described that are PDGF-responsive. For these "early PSA-NCAM(+) progenitors," insulin-like growth factor 1 and EGF seem to play a pivotal role in the control of cell death and cell proliferation.


Inhibition of carotid pressor response by left aortic depressor nerve in dogs.
In 12 conscious dogs, the mean increase of 26 mmHg in arterial pressure during carotid occlusion was augmented by 52 mmHg after section of the left cervical vagus nerve and 6 mmHg after right vagal section. In 18 anesthetized dogs, in which the cervical vagal nerves were reversibly cold blocked, corresponding values were 33, 28, and 6 mmHg, respectively. In nine of these dogs, this left-sided dominance was present after bilateral section of the vagal cardiopulmonary afferents; it was absent after bilateral section of the aortic nerves in the other nine dogs. In five dogs on cardiopulmonary bypass with heart and lungs excluded, pressure within the isolated aorta and major intrathoracic arteries was raised from 120 to 220 mmHg. The resultant hypotension reflexly induced by activation of aortic baroreceptors was reduced by left but not by right vagal cold block. It was concluded that, in the dog, the left aortic nerve provided the major inhibition of the increase in arterial pressure after carotid occlusion.


Hallmarks of Splicing Defects in Cancer: Clinical Applications in the Era of Personalized Medicine.
Alternative splicing promotes proteome diversity by using limited number of genes, a key control point of gene expression. Splicing is carried out by large macromolecular machineries, called spliceosome, composed of small RNAs and proteins. Alternative splicing is regulated by splicing regulatory cis-elements in RNA and trans-acting splicing factors that are often tightly regulated in a tissue-specific and developmental stage-specific manner. The biogenesis of ribonucleoprotein (RNP) complexes is strictly regulated to ensure that correct complements of RNA and proteins are coordinated in the right cell at the right time to support physiological functions. Any perturbations that impair formation of functional spliceosomes by disrupting the cis-elements, or by compromising RNA-binding or function of trans-factors can be deleterious to cells and result in pathological consequences. The recent discovery of oncogenic mutations in splicing factors, and growing evidence of the perturbed splicing in multiple types of cancer, underscores RNA processing defects as a critical driver of oncogenesis. These findings have resulted in a growing interest in targeting RNA splicing as a therapeutic approach for cancer treatment. This review summarizes our current understanding of splicing alterations in cancer, recent therapeutic efforts targeting splicing defects in cancer, and future potentials to develop novel cancer therapies.


Arithmetic facts storage deficit: the hypersensitivity-to-interference in memory hypothesis.
Dyscalculia, or mathematics learning disorders, is currently known to be heterogeneous (Wilson & Dehaene, ). While various profiles of dyscalculia coexist, a general and persistent hallmark of this math learning disability is the difficulty in memorizing arithmetic facts (Geary, Hoard & Hamson, ; Jordan & Montani, ; Slade & Russel, ). Arithmetic facts are simple arithmetic problems that are solved by direct retrieval from memory. Recently, De Visscher and Noël () showed hypersensitivity-to-interference in memory in an adult suffering from a specific deficit of arithmetic facts storage. According to the authors, arithmetic facts share many features. The overlapping of these features between arithmetic facts may provoke interference. Consequently, learners who are hypersensitive-to-interference could have considerable difficulties in storing arithmetic facts. The present study aims at testing this new hypothesis on fourth-grade children who are learning multiplication tables. Among 101 children that were assessed, 23 low arithmetic facts learners were selected because of their low score in arithmetic facts fluency (controlling for processing speed). Twenty-three control children were selected, matched for classroom, gender, and age. In addition to a subtest of global reasoning, these participants were given a multiplication production task and a memorization task of low- and high-interference associations. The results show that children with low arithmetic fluencies experience hypersensitivity-to-interference in memory compared with children with typical arithmetic fluencies.


Extremity lesions in the Intergroup Rhabdomyosarcoma Study (IRS-I): a preliminary report.
The sites in which rhabdomyosarcoma occurs most frequently in children and young adults are the head and neck, genitourinary tract, and the extremities. Among these three sites, tumors of the extremities have been associated with the highest relapse rate and lowest survival rate in patients treated by protocols of the Intergroup Rhabdomyosarcoma Study (IRS). In five of six patients treated by primary extremity amputation, tumor recurred. Seven of 21 patients in Clinical Group I (completely resected tumors), and 9 of 27 patients in Clinical Group II (patients with gross tumor excision but positive lymph nodes, "microscopic residual" disease, or extension beyond the muscle of origin) had relapse. Thirteen of 18 patients (72%) in Clinical Group III (gross residual disease) responded to a chemotherapy-radiotherapy regimen, but ten have subsequently had relapses; and 13 of 18 are dead. Of 30 patients in Clinical Group IV (disseminated disease on entry), 15 initially responded to chemotherapy, but 25 of 30 are dead. The period of surveillance is 2 1/2 to 7 1/2 years, with a mean of 46.3 months at least examination. Increased rates of relapse were seen in patients with extremity tumors, as opposed to tumors in other sites, irrespective of the specific IRS chemotherapy-radiotherapy regimen employed. In Clinical Group I (nonamputation), relapse rates by histologic subtype of rhabdomyosarcoma were alveolar subtype, 5/8; embryonal, 1/7; and all other subtypes, 1/6. Clinical Group II, relapse rates were alveolar, 6/12; embryonal, 5/11; all other subtypes, 3/10.


Antitumor effects due to irreversible stoppage of tumor tissue blood flow: evaluation of a novel combretastatin A-4 derivative, AC7700.
The relation between tumor tissue blood flow (tBF) reduction and antitumor effects was investigated. Changes in tBF of normal tissues (liver, kidney cortex, bone marrow and brain cortex) and tumors (Yoshida sarcoma subline, LY80 and Sato lung carcinoma, SLC) due to i.v. administration of AC7700 (1, 3, 10 mg/kg), one of the combretastatin A-4 derivatives, were measured with the hydrogen clearance method. The change in blood flow in tumor microfoci was also observed directly using a rat transparent chamber. Chemotherapy against the solid tumors (LY80, SLC) was performed by administering AC7700 7 times at intervals of 3 days and the effect on the tumor growth, the histological effect, the effect on lymph node metastasis and the survival rate were investigated. Tumor tBF showed a dose-dependent response to AC7700. Although tumor tBF decreased markedly at a dose of 1 mg/kg, it tended to recover partly within several hours. At 10 mg/kg, however, tumor tBF completely stopped within approximately 30 min and never recovered in many regions. The irreversible stoppage of tumor tBF was observed in large s.c. tumors and in microfoci as well. On the other hand, in normal tissues, tBF changes due to AC7700 were not uniform. In the liver, although tBF decreased by approximately 50% at 10 mg/kg AC7700, it recovered within 8 h. In the brain, although the mean maximum reduction was 35%, the blood flow recovered to the original level within 24 h. The blood flow in the kidney cortex did not change at all. In the bone marrow, tBF decreased by approximately 80%. Generally, the blood flow reduction in normal tissues tended to be reversible. The effect on tumor growth and the histological effect were also dependent on the dose of AC7700. The tumor growth was markedly inhibited by 10 mg/ kg AC7700 and extensive necrosis was induced. Lymph node metastases were significantly inhibited and survival was prolonged significantly. In the control group, all 8 SLC tumor-bearing rats died of cancer, the presence of which was verified by gross and microscopic evaluation, within 45 days after tumor implantation. On the other hand, in the treated group, 2 of 8 rats recovered completely and survived. No obvious side effects such as body weight loss, anemia or diarrhea were observed at the dose used in this experiment. From these results, we conclude that strong antitumor effects are obtained by stopping tumor tBF irreversibly and by shutting off the nutritional supply into tumor tissue. AC7700 has been demonstrated to be a promising anticancer compound which has such an action.


A novel triple immunoenzyme staining enables simultaneous identification of all muscle fiber types on a single skeletal muscle cryosection from normal, denervated or reinnervated rats.
Triple immunofluorescence staining has recently been developed to simultaneously identify all muscle fibers on a single cryosection which is helpful for clinical and basic research, but it has disadvantages such as fast photobleaching and unclear outlines of muscle fibers. Triple immunoenzyme staining (TIE) is likely to avoid these disadvantages. In this study, we aimed to establish a sensitive and specific TIE technique to identify fiber types in normal, denervated, and reinnervated rat muscles, and to develop a systematic sampling method for muscle fiber quantification. Tibialis anterior and soleus from normal, denervated, and reinnervated Lewis rat hind limbs were used. Five consecutive cryosections were cut from each muscle, including one for TIE and four for single immunoenzyme staining (SIE). The TIE was performed using the polymerized reporter enzyme staining system for the first two antigens (A4.74 for MyHC-IIA, BA-F8 for MyHC-I) and alkaline phosphatase staining system for the third antigen (BF-F3 for MyHC-IIB), followed by corresponding detective systems and respective chromogens. The type of muscle fibers was quantified by systematic sampling at 12.5%, 25%, 33% and 50% of all muscle fibers, and was compared with that acquired from counting all the fibers (100%). All muscle fiber phenotypes, including pure and hybrid, could be simultaneously identified on a single TIE cryosection with clear outlines. The fiber types on TIE slides matched well with their respective counterpart on the consecutive SIE slides with a 95% match rate. Systematic sampling of 12.5% fibers could represent the true fiber type distribution of the entire muscle section. Our results suggest that novel TIE can effectively visualize fiber types in normal, denervated or reinnervated rat muscles.


Contact sensitization to modern dressings: a multicentre study on 354 patients with chronic leg ulcers.
Modern dressings (MDs) may have a low sensitization rate, but there is a lack of prospective studies in patients with chronic leg ulcers (CLUs) to evaluate this. To determine the rate of sensitization (contact allergy) to MDs and substances present in dressings. A prospective multicentre study was carried out in patients with CLUs at five French dermatology departments; patch tests were performed with the European baseline series and with an additional 27 individual allergens and 10 MDs. Among 354 patients (226 women and 128 men) with CLUs, 59.6% had at least one positive patch test reaction to an MD and 19% had at least one sensitization to an MD. The number of positive test reactions per patient was correlated with the duration of ulcerative disease, but not with ulcer duration, the cause of the ulcer, or the presence of surrounding eczematous lesions. For 11 of 45 patients sensitized to Ialuset cream®, more detailed information could be obtained with sensitization to sodium dehydroacetate (5 cases) or Lanette SX® (3 cases). Sensitization to MDs is not rare. It is absolutely necessary to label all components of MDs on their packaging and to avoid some sensitizing molecules, such as colophonium derivatives or any strong sensitizers.


Education News.
First responders need hands-on experience with pediatric airway management, but the impact of a learner program in the operating room (OR) is unknown. We developed, implemented, and evaluated a pediatric airway "rotator" (PAR) program for 8 multidisciplinary groups to obtain this experience. This quality improvement pilot was conducted in the pediatric ORs from November 2017 to January 2018. We surveyed learner group leaders and anesthesia teachers about their PAR airway management expectations and developed a universal set of prerequisites, objectives, and simulation experiences. Airway management skills were assessed in a group of PARs at baseline. During implementation, another group of PARs completed prerequisites and reviewed objectives before coming to the OR for simu-lation using an infant mannequin. Then they entered the OR for "live" airway management. A comparison of preintervention and postintervention skills suggested an improvement in performance for most airway management domains except laryngeal mask airway insertion, which stayed about the same, and intubation, which decreased in the postintervention group. In the postassessment surveys, the PARs indicated that the interventions were helpful to their learning, and the anesthesia teachers' responses indicated that the primary goals to improve PARs' preparedness, airway management, and communication skills were achieved.


Pilot study of sternal plating for primary closure of the sternum in cardiac surgical patients.
Postoperative sternal wound complications are a significant problem in high-risk patients. In addition to closure with conventional wires, several systems involving rigid fixation with metal plates are currently available. The rapid sternal closure system (Talon) is approved for stabilization and fixation of the anterior chest wall. Anecdotal evidence suggests that use of the Talon may result in improved postoperative recovery. Fifty-one cardiac surgical patients at higher risk for sternal wound complications were enrolled at two sites. Subjects were randomized to insertion of Talons (n = 28) or wires only (control, n = 23) for sternal closure. The primary endpoint was a comparison between study groups of the percent of baseline incentive spirometry volume through postoperative day 7. Secondary endpoints included other measures of quality of recovery, sternal wound infection, and nonunion. The percentage of preoperative incentive spirometry volume achieved was higher in the Talon arm (67% ± 32%) versus control (58% ± 24%); however, this was not statistically significant (P = 0.41). Use of the Talon was associated with decreased use of opiates (21.3 ± 11.8 vs. 25.4 ± 21.6 mg, P = 0.44), increased ability to ambulate 1000 ft on postoperative day 5 (25% vs. 13%, P = 0.28), and decreased duration of mechanical ventilation (median 0.5 vs 1.0 days, P = 0.24) and hospital length of stay (4.5 ± 3.2 vs. 5.3 ± 4.0 days, P = 0.40). One superficial sternal wound infection was observed in each study arm. There were no cases of nonunion. In this pilot study, the primary endpoint was not statistically different between the treatment groups. Use of the Talon was associated with trends toward benefit in endpoints consistent with enhanced postoperative recovery, highlighting a need for additional data from larger randomized trials.


Empty nest or revolving door? A prospective study of women's quality of life in midlife during the phase of children leaving and re-entering the home.
This study documents changes in household composition and effects on women's quality of life of children leaving and returning home. A 9-year annual prospective study of a population-based sample of mid-aged Australian-born women who were premenopausal at baseline (N = 438) was conducted. Documentation was made of household composition and change, well-being, bothersome symptoms, daily hassles, feelings for partner and frequency of sexual activities. There was an increase in the number of women living alone, and a reduction in number of households in which there were children or parents. Each year > 25% of women reported a change in household composition. In the first year after the last child departed (N = 155), there was an improvement in women's positive mood and total well-being and a reduction in negative mood and the number of daily hassles. This improvement in mood was confined to those women who at baseline were not worried about children leaving home. In the first year after children return home there was a trend towards reduced frequency of sexual activities but no mood changes. For the majority of women, the departure of the last child from the household leads to positive changes in women's mood state and a reduced number of daily hassles. Return of offspring may have an adverse effect on sexual relating of the parents.


Population genomics of a forest fungus reveals high gene flow and climate adaptation signatures.
Genome sequencing of spatially distributed individuals sheds light on how evolution structures genetic variation. Populations of Phellopilus nigrolimitatus, a red-listed wood-inhabiting fungus associated with old-growth coniferous forests, have decreased in size over the last century due to a loss of suitable habitats. We assessed the population genetic structure and investigated local adaptation in P. nigrolimitatus, by establishing a reference genome and genotyping 327 individuals sampled from 24 locations in Northern Europe by RAD sequencing. We revealed a shallow population genetic structure, indicating large historical population sizes and high levels of gene flow. Despite this weak substructuring, two genetic groups were recognized; a western group distributed mostly in Norway and an eastern group covering most of Finland, Poland and Russia. This substructuring may reflect coimmigration with the main host, Norway spruce (Picea abies), into Northern Europe after the last ice age. We found evidence of low levels of genetic diversity in southwestern Finland, which has a long history of intensive forestry and urbanization. Numerous loci were significantly associated with one or more environmental factors, indicating adaptation to specific environments. These loci clustered into two groups with different associations with temperature and precipitation. Overall, our findings indicate that the current population genetic structure of P. nigrolimitatus results from a combination of gene flow, genetic drift and selection. The acquisition of similar knowledge especially over broad geographic scales, linking signatures of adaptive genetic variation to evolutionary processes and environmental variation, for other fungal species will undoubtedly be useful for assessment of the combined effects of habitat fragmentation and climate change on fungi strongly bound to old-growth forests.


Effect of asiaticoside on 99mTc-tetrofosmin and 99mTc-sestamibi uptake in MCF-7 cells.
This study was done to examine the effect of asiaticoside on MCF-7 cell uptake of (99m)Tc-tetrofosmin ((99m)Tc-Tfos) and (99m)Tc-sestamibi ((99m)Tc-MIBI). The 3-(4,5-dimethylthiozol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was used to evaluate the effect of a 50% inhibitory concentration of asiaticoside on MCF-7 cell proliferation. MCF-7 cells were treated with 10, 20, 30, 40, and 50 μM asiaticoside for 48 h and then incubated with 59.2 MBq of either (99m)Tc-Tfos or (99m)Tc-MIBI tracer for 60 min. The uptake of the tracers was measured with a dose calibrator. The 50% inhibitory concentration of asiaticoside for MCF-7 cells was determined with the MTT assay to be 40 μM. The uptake results were expressed as the mean ± SE radioactivity in MBq/mg of protein, and P values were also calculated (P values of 0.03 indicated significant differences). In the control (no asiaticoside) and at 10, 20, 30, 40, and 50 μM asiaticoside, the mean levels of (99m)Tc-Tfos uptake were 0.79 (SE, 0.059) (P = 0.14), 0.84 (SE, 0.057) (P = 0.60), 0.47 (SE, 0.034) (P = 0.03), 0.40 (SE, 0.050) (P = 0.03), 0.37 (SE, 0.050) (P = 0.03), and 0.15 (SE, 0.023) (P = 0.03), respectively; the mean levels of (99m)Tc-MIBI uptake were 0.95 (SE, 0.007) (P = 0.14), 0.81 (SE, 0.009) (P = 0.60), 0.79 (SE, 0.019) (P = 0.03), 0.63 (SE, 0.004) (P = 0.03), 0.13 (SE, 0.006) (P = 0.03), and 0.07 (SE, 0.008) (P = 0.03), respectively. Asiaticoside concentrations of 10, 20, 30, 40, and 50 μM revealed the uptake kinetics for both (99m)Tc-Tfos and (99m)Tc-MIBI in MCF-7 cells. (99m)Tc-Tfos and (99m)Tc-MIBI showed similar trends; the radioactivity uptake was dose dependent, and asiaticoside inhibited 16% and 47% of (99m)Tc-Tfos uptake and (99m)Tc-MIBI uptake in MCF-7 cells, respectively. This study showed that asiaticoside, acting as a biochemical modulator, may induce apoptosis and enhance antitumor activity in MCF-7 cells, as determined by (99m)Tc-Tfos and (99m)Tc-MIBI uptake. These findings are promising for cancer chemotherapy. Future studies should be performed to confirm our findings and to further delineate the clinical role of asiaticoside.


Carbon monoxide intoxication: What we know.
Carbon monoxide (CO) is a toxic, color-, taste- and odorless gas with fatal consequences if undetected. Intoxication caused by CO is frequent possibly leading to a high morbidity and mortality. The disease involves multiple organ systems without a typical clinical presentation. The clinical picture is furthermore unrelated to levels of carboxyhemoglobin - the routine biomarker. Therefore the diagnosis and treatment can be very demanding. This article in detail reviews epidemiology, symptoms, diagnosis and the therapy of this multidisciplinary challenge.


Malignant fibrous histiocytoma of the glans penis: a case report.
Malignant fibrous histiocytoma has been regarded as the most common sarcoma of older adults. However, recent opinion regards pleomorphic malignant fibrous histiocytoma as an undifferentiated high grade pleomorphic sarcoma not otherwise classifiable utilizing current techniques available in surgical pathology. Notwithstanding controversy regarding its nomenclature, malignant fibrous histiocytoma involving the penis is exceedingly rare, with only 4 cases previously described, to our knowledge. An uncircumcised 73-year-old male presented with a painless, granular, partially necrotic lesion beneath the penile foreskin. There was no history of sexually transmitted disease, constitutional symptoms or dysuria. Examination of penile shaft, testicles, spermatic cord and inguinal lymph nodes were unremarkable. Biopsy revealed a markedly pleomorphic sarcoma. Subsequent, partial penectomy revealed the same lesion with an adjacent area of squamous cell carcinoma in situ. Malignant fibrous histiocytoma remains a diagnosis of exclusion. The investigation requires extensive tumor sampling in search of areas of differentiation and a complete battery of immunohistochemical markers. Therapeutically important entities in the differential diagnosis that must be ruled out include other poorly differentiated sarcomas, sarcomatoid squamous cell carcinoma and desmoplastic melanoma.


Assessment of the quality of measures of child oral health-related quality of life.
Several measures of oral health-related quality of life have been developed for children. The most frequently used are the Child Perceptions Questionnaire (CPQ), the Child Oral Impacts on Daily Performances (C-OIDP) and the Child Oral Health Impact Profile (COHIP). The aim of this study was to assess the methodological quality of the development and testing of these three measures. A systematic search strategy was used to identify eligible studies published up to December 2012, using both MEDLINE and Web of Science. Titles and abstracts were read independently by two investigators and full papers retrieved where the inclusion criteria were met. Data were extracted by two teams of two investigators using a piloted protocol. The data were used to describe the development of the measures and their use against existing criteria. The methodological quality and measurement properties of the measures were assessed using standards proposed by the Consensus-based Standards for the Selection of Health Measurement Instruments (COSMIN) group. The search strategy yielded 653 papers, of which 417 were duplicates. Following analysis of the abstracts, 119 papers met the inclusion criteria. The majority of papers reported cross-sectional studies (n = 117) with three of longitudinal design. Fifteen studies which had used the original version of the measures in their original language were included in the COSMIN analysis. The most frequently used measure was the CPQ. Reliability and construct validity appear to be adequate for all three measures. Children were not fully involved in item generation which may compromise their content validity. Internal consistency was measured using classic test theory with no evidence of modern psychometric techniques being used to test unidimensionality of the measures included in the COSMIN analysis. The three measures evaluated appear to be able to discriminate between groups. CPQ has been most widely tested and several versions are available. COHIP employed a rigorous development strategy but has been tested in fewer populations. C-OIDP is shorter and has been used successfully in epidemiological studies. Further testing using modern psychometric techniques such as item response theory is recommended. Future developments should also focus on the development of measures which can evaluate longitudinal change.


Sensitivity and Specificity of Pure-Tone and Subjective Hearing Screenings Using Spanish-Language Questions.
Purpose The purpose of this study is to determine the sensitivities and specificities of different audiometric hearing screening criteria and single-item and multi-item hearing disability questionnaires among a group of Spanish-speaking adults in a rural community. Method Participants were 131 predominantly older (77% 65+ years) Hispanic/Latinx adults (98%). A structured Spanish-language interview and pure-tone threshold test data were analyzed for each participant. The sensitivities and specificities of three single questions and the Hearing Handicap Index for the Elderly-Screening (HHIE-S; Ventry & Weinstein, 1983) in Spanish, as well as three audiometric screening criteria, were evaluated in relation to the pure-tone threshold test for detecting hearing loss. Results Sensitivity and specificity of audiometric screening criteria varied, but the highest sensitivity was found for the criterion of > 25 dB HL at 1-4 kHz in either ear. The single self-perception question, "¿Cree usted que tiene pérdida de audición? (Do you think you have a hearing loss?)," was shown to be the most sensitive self-report screening compared to other single-item questions and the HHIE-S. This single question was as sensitive as an audiometric screening to detect a moderate hearing loss (> 40 dB HL in either ear). Results from the Spanish HHIE-S indicated poor performance to detect hearing loss in this population, consistent with previous research. Conclusions Among older Spanish-speaking adults, self-reported hearing status had varying sensitivities depending on the question asked. However, of the tools evaluated, the self-perception question proved to be a more sensitive and specific tool than a multi-item screen. Objective audiometric testing (> 25 dB HL) resulted in the highest sensitivity to detect a mild hearing loss.


High rate of infection control with one-stage revision of septic knee prostheses excluding MRSA and MRSE.
The rate of infection control for one-stage revision of infected knee arthroplasties is unclear as are the factors influencing infection control. Such factors include duration of infection and the type of infected prosthesis. We therefore determined: (1) the rate of infection control with one-stage revision of septic knee prostheses, (2) the clinical knee scores that can be achieved, (3) whether the duration of infection or the type of prosthesis influence the level of infection control, and (4) whether different types of prostheses influence the knee scores. We retrospectively reviewed prospectively collected data from 63 patients who underwent one-stage revisions of septic knee endoprostheses (six unicondylar, 37 primary total knee replacement prostheses, and 20 hinged knee endoprostheses) between 2004 and 2006. All were treated locally and systemically with microorganism-specific antibiotics. For this study we excluded patients with Methicillin-resistant Staphylococcus aureus and Methicillin-resistant Staphylococcus epidermidis or unknown microorganisms. The patients were examined for infection every 3 months and Oxford and Knee Society scores were assessed at the same time. The minimum followup was 24 months (mean followup, 36 months; range, 24-70 months). None of the patients with replacement unicondylar and primary total knee replacement prostheses had recurrence of infection. Three of the 20 patients with the hinged infected knee prostheses had recurrences; these three patients had chronic infections and had undergone two to three revision operations during at least a 5-year period. The likelihood of infection control was influenced by the duration of infection. The mean Knee Society knee score 24 months after surgery was 72 points (range, 20-98 points), the Knee Society function score was 71 points (range, 10-100 points), and the Oxford-12 knee score was 27 points (range, 13-44 points). One-stage revision of septic knee prostheses achieved an infection control rate of 95% and higher knee scores than reported for two-stage revisions. Higher rates of recurrent infection appeared to be associated with long-term chronic infections of hinged prostheses.


SWEPT-SOURCE AND SPECTRAL DOMAIN OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY VERSUS DYE ANGIOGRAPHY IN THE MEASUREMENT OF TYPE 1 NEOVASCULARIZATION.
To compare the area of Type 1 neovascularization in patients with age-related macular degeneration calculated on spectral domain optical coherence tomography angiography (SD-OCTA), swept-source OCTA, and indocyanine green angiography (ICGA). Cross-sectional study enrolling patients with neovascular age-related macular degeneration with Type 1 neovascularization. During the same visit, ICGA (Spectralis HRA, Heidelberg, Germany), 3 × 3-mm or 6 × 6-mm SD-OCTA (CIRRUS AngioPlex model 5000; Carl Zeiss Meditec, Inc, Dublin, OH), and 3 × 3-mm or 6 × 6-mm swept-source OCTA (Plex Elite 9000; Carl Zeiss Meditec, Inc) were performed. Neovascularization areas were compared among the three instruments. The degree of consistency between measurements was investigated through the two-way mixed intraclass correlation, whereas the intermethod agreement was expressed by the Bland-Altman analysis. Mean difference and 95% confidence intervals are provided. Eighteen eyes of 14 white patients (10 females, 83.3%) were included in the study. The neovascularization area measured on ICGA was higher compared to that measured on both SD-OCTA (P = 0.008) and swept-source OCTA (P = 0.008), whereas no differences were found between the two OCTA. Similar results were achieved analyzing 3 × 3-mm and 6 × 6-mm scan separately. Lowest reliability resulted from the ICGA versus SD-OCTA pair (intraclass correlation = 0.786, confidence interval = 0.500-0.915). Spectral domain OCTA and swept-source OCTA exhibited an excellent agreement (mean difference = 0.2). Swept-source OCTA offered qualitatively better images of the neovascularization, compared with SD-OCTA. Better visualization of the extent of neovascularization is obtained using SS-OCT or SD-OCT compared with ICGA, which may be influenced by choroidal permeability and dye leakage. Neovascularization area on OCTA may become an objective parameter in the follow-up of age-related macular degeneration patients, along with traditional imaging techniques.


Molecular epidemiology of subgroup C avian pneumoviruses isolated in the United States and comparison with subgroup a and B viruses.
The avian pneumovirus (APV) outbreak in the United States is concentrated in the north-central region, particularly in Minnesota, where more outbreaks in commercial turkeys occur in the spring (April to May) and autumn (October to December). Comparison of the nucleotide and amino acid sequences of nucleoprotein (N), phosphoprotein (P), matrix (M), fusion (F), and second matrix (M2) genes of 15 U.S. APV strains isolated between 1996 and 1999 revealed between 89 and 94% nucleotide sequence identity and 81 to 95% amino acid sequence identity. In contrast, genes from U.S. viruses had 41 to 77% nucleotide sequence identity and 52 to 78% predicted amino acid sequence identity with European subgroup A or B viruses, confirming that U.S. viruses belonged to a separate subgroup. Of the five proteins analyzed in U.S. viruses, P was the most variable (81% amino acid sequence identity) and N was the most conserved (95% amino acid sequence identity). Phylogenetic comparison of subgroups A, B, and C viruses indicated that A and B viruses were more closely related to each other than either A or B viruses were to C viruses.


Effect of antiscalants on precipitation of an RO concentrate: metals precipitated and particle characteristics for several water compositions.
Inland brackish water reverse osmosis (RO) is economically and technically limited by the large volume of salty waste (concentrate) produced. The use of a controlled precipitation step, followed by solid/liquid separation (filtration), has emerged as a promising side-stream treatment process to treat reverse osmosis concentrate and increase overall system recovery. The addition of antiscalants to the RO feed prevents precipitation within the membrane system but might have a deleterious effect on a concentrate treatment process that uses precipitation to remove problematic precipitates. The effects of antiscalant type and concentration on salt precipitation and precipitate particle morphology were evaluated for several water compositions. The primary precipitate for the synthetic brackish waters tested was calcium carbonate; the presence of magnesium, sulfate, minor ions, and antiscalant compounds affected the amount of calcium precipitated, as well as the phases of calcium carbonate formed during precipitation. Addition of antiscalant decreased calcium precipitation but increased incorporation of magnesium and sulfate into precipitating calcium carbonate. Antiscalants prevented the growth of nucleated precipitates, resulting in the formation of small (100-200 nm diameter) particles, as well as larger (6-10 microm) particles. Elemental analysis revealed changes in composition and calcium carbonate polymorph with antiscalant addition and antiscalant type. Results indicate that the presence of antiscalants does reduce the extent of calcium precipitation and can worsen subsequent filtration performance.


N termini of apPDE4 isoforms are responsible for targeting the isoforms to different cellular membranes.
Phosphodiesterases (PDEs) are known to play a key role in the compartmentalization of cAMP signaling; however, the molecular mechanisms underlying intracellular localization of different PDE isoforms are not understood. In this study, we have found that each of the supershort, short, and long forms of apPDE4 showed distinct localization in the cytoplasm, plasma membrane, and both plasma membrane and presynaptic terminals, respectively. The N-terminal 20 amino acids of the long form of apPDE4 were involved in presynaptic terminal targeting by binding to several lipids. In addition, the N terminus of the short form of apPDE4 bound to several lipids including phosphoinositols, thereby targeting the plasma membrane. Overexpression of the long and the short forms, but not the supershort form attenuated 5-HT-induced membrane hyperexcitability. Finally, the knockdown of apPDE4s in sensory neurons impaired both short-term and long-term facilitation. Thus, these results suggest that apPDE4s can participate in the regulation of cAMP signaling through specific subcellular localization by means of lipid binding activities.


Transglutaminase 2 accelerates vascular calcification in chronic kidney disease.
Transglutaminase 2 (TGM2) is a calcium-dependent enzyme that can cross-link nearly all extracellular matrix (ECM) proteins and can facilitate cell-ECM interaction through integrins. Given the importance of the ECM in vascular calcification we tested the hypothesis that increased TGM2 activity may accelerate vascular calcification in chronic kidney disease (CKD). We utilized thoracic aortas and vascular smooth muscle cells (VSMC) from the Cy/+ rat, a model of progressive CKD that develops arterial calcification on a normal phosphorus diet, compared to normal rats. VSMC isolated from CKD rats had increased expression and activity of TGM2 compared to cells from normal rats. The increased calcification and expression of alkaline phosphatase activity observed in VSMC from CKD rats compared to normal was inhibited in a dose-dependent manner with the TGM inhibitors cystamine and Z006. Matrix vesicles (MV) from CKD rat VSMC also had increased TGM2 expression and the calcification of MV on type I collagen could be inhibited with cystamine and accelerated by exogenous cross-linking of fibronectin or type I collagen with TGM2. Finally, the calcification of aorta rings from CKD rats in ex vivo cultures was inhibited with TGM2 inhibitor. These data demonstrate a role of TGM2 in the pathogenesis of vascular calcification in CKD through enhancement of MV-ECM calcification.


Human cytomegalovirus glycoprotein complex gH/gL/gO uses PDGFR-α as a key for entry.
Herpesvirus gH/gL envelope glycoprotein complexes are key players in virus entry as ligands for host cell receptors and by promoting fusion of viral envelopes with cellular membranes. Human cytomegalovirus (HCMV) has two alternative gH/gL complexes, gH/gL/gO and gH/gL/UL128,130,131A which both shape the HCMV tropism. By studying binding of HCMV particles to fibroblasts, we could for the first time show that virion gH/gL/gO binds to platelet-derived growth factor-α (PDGFR-α) on the surface of fibroblasts and that gH/gL/gO either directly or indirectly recruits gB to this complex. PDGFR-α functions as an entry receptor for HCMV expressing gH/gL/gO, but not for HCMV mutants lacking the gH/gL/gO complex. PDGFR-α-dependent entry is not dependent on activation of PDGFR-α. We could also show that the gH/gL/gO-PDGFR-α interaction starts the predominant entry pathway for infection of fibroblasts with free virus. Cell-associated virus spread is either driven by gH/gL/gO interacting with PDGFR-α or by the gH/gL/UL128,130,131A complex. PDGFR-α-positive cells may thus be preferred first target cells for infections with free virus which might have implications for the design of future HCMV vaccines or anti-HCMV drugs.


Parenting and the parent-child relationship in families of children with mild to borderline intellectual disabilities and externalizing behavior.
This cross-sectional study examined the association between parenting behavior, the parent-child relationship, and externalizing child behavior in families of children with mild to borderline intellectual disabilities (MBID). The families of a child with MBID and accompanying externalizing behavior problems (n=113) reported more positive discipline and physical punishment but less involvement, less positive parenting, less monitoring, a lower sense of parenting competence, less acceptance of the child, and less closeness to the child than the families of a child with MBID and no accompanying externalizing behavior problems (n=71). The parent-child relationship was most strongly associated with externalizing child behavior, over and above parenting behaviors. In addition, the parent-child relationship was found to be associated with parenting behavior, over and above the child's externalizing behavior. Our results highlight the importance of both the parent-child relationship and parenting behavior in connection with the occurrence of externalizing behavior problems on the part of children with MBID. Parenting behavior and the parent-child relationship may thus be promising targets for interventions with this group of children.


Measuring individual plate waste in school lunches. Visual estimation and children's ratings vs. actual weighing of plate waste.
Weighing individual plate waste is time consuming and often impractical. As alternatives, two indirect measures were evaluated-visual estimation and children's ratings of plate waste. Visual estimations were highly correlated with percent waste (r = 0.93) and were quite accurate. Ratings by children were less accurate but were still considered a useful indirect measure that should be further developed.


The effect of short messaging service text on non-attendance in a general ophthalmology clinic.
To our knowledge there have been no previous studies that have examined the effect of short messaging service (SMS) text messaging reminders to both mobile and landlines on the 'did not attend' (DNA) rate in adult hospital clinic attendees. Our aim was to determine the effectiveness of a text messaging reminder in improving attendance in return general ophthalmology clinic patients. Ophthalmology clinic patients requiring a follow-up appointment were invited to enter the study. An information leaflet was provided and patients were contacted two weeks before their scheduled appointment by way of a customized text message to either the mobile phone or landline. The non-attendance rate compared with historic non-attendance rate was recorded. Two hundred and one patients were recruited. The historic DNA rate was 12%. The DNA rate in the SMS text reminder group was reduced to 5.5% (11 patients). The historic 'Could not attend' (CNA) rate of 6% had been reduced to 2% (4 patients). Forty-seven percent of patients used mobile phone technology with text messaging capability and 69% responded to the text reminder. In conclusion, routine SMS texting is a cost-effective means of reducing DNAs and should become standard practice. In addition, two-way messaging could allow for further efficiency as advance notification of patient cancellations facilitates re-scheduling of alternative patients.


The use of stereotactic radiosurgery for brain metastases from breast cancer: who benefits most?
Brain metastases (BM) from primary breast cancer can arise despite use of systemic therapies that provide excellent extracranial disease control. Local modalities for treating BM include surgery, whole brain radiation therapy (WBRT), and stereotactic radiosurgery (SRS). We sought to determine the benefits of SRS for management of BM arising from different biologic breast cancer subtypes. We reviewed records of 131 patients who received SRS for breast cancer BM between 2001 and 2013. Survival was estimated by the Kaplan-Meier method. Effects of tumor biology, number and location of lesions, and number of SRS sessions on survival were evaluated by Cox proportional hazards regression. Of the 122 patients with subtypes available, 41 patients (31%) were classified as estrogen receptor positive/HER2 negative (ER(+)HER2(-)); 30 patients (23%), ER(+)HER2(+); 23 patients (18%), ER(-)HER2(+); and 28 patients (21%), ER(-)HER2(-) (or triple negative breast cancer, TNBC). Median age at first SRS was 50 years. Median overall survival for ER(+)HER2(-), ER(+)HER2(+), ER(-)HER2(+), and TNBC was 16, 26, 23, and 7 months, respectively (p < 0.001 for difference between groups). Patients with TNBC had the shortest time to retreatment with WBRT or SRS or death with hazard ratio of 3.12 (p < 0.001) compared to ER(+)HER2(-). In all subtypes other than TNBC, SRS can provide meaningful control of BM even in the setting of multiple lesions and may be worth repeating for new lesions that develop metachronously. For patients with TNBC, prognosis is guarded following SRS, and there is an urgent need to develop more effective treatment strategies.


Risk of vertical transmission of hepatitis B after amniocentesis in HBs antigen-positive mothers.
Despite appropriate immunoprophylaxis, HBV vertical transmission (VT) occurs in 5-10% of infants born to HBs-antigen (HBsAg)+ mothers. We investigated whether amniocentesis increases the risk of transmission. We performed a case-control study on infants who were born to HBsAg+ mothers without antiviral exposure and completed appropriate immunization. Infants born to mothers with amniocentesis were compared to those without amniocentesis to assess VT rates, which were defined by the percentage of infants with HBsAg positivity when they were 7-12 months old. Of the 642 consecutive infants enrolled, 63 infants with amniocentesis were compared with 198 matched infants selected from the remaining 579 infants without amniocentesis. There was a higher VT rate in infants with amniocentesis than in those without amniocentesis (6.35% vs. 2.53%; p=0.226). Maternal HBV DNA levels before amniocentesis were further stratified to <500 copies/ml, 500-6.99 log10 copies/ml, and ⩾ 7 log10 copies/ml for subset analyses. There were no significant differences in the VT rates between the amniocentesis group and the control group if the maternal HBV DNA levels were <6.99 log10 copies/ml. However, a significantly higher VT rate was observed in the amniocentesis group vs. the control group if the maternal HBV DNA levels were ⩾ 7 log10 copies/ml (50% vs. 4.5%, respectively, p=0.006). According to baseline value risk analyses, performing amniocentesis on highly viremic mothers was a risk factor for HBV transmission (OR=21.3, 95% CI: 2.960-153.775). Amniocentesis performed on HBsAg+ mothers with HBV DNA ⩾ 7 log10 copies/ml significantly increased the frequency of VT. HBsAg+ women who plan to have amniocentesis should be evaluated for the risk of VT and stratified according to their HBV DNA levels. Further prospective studies are warranted to verify our findings.


Association between a lifestyle score and all-cause mortality: a prospective analysis of the Chilean National Health Survey 2009-2010.
To investigate the association between a lifestyle score and all-cause mortality in the Chilean population. Prospective study. The score was based on seven modifiable behaviours: salt intake, fruit and vegetable intake, alcohol consumption, sleep duration, smoking, physical activity, and sedentary behaviours. 1-point was assigned for each healthy recommendation. Points were summed to create an unweighted score from 0 (less healthy) to 7 (healthiest). According to their score, participants were then classified into: less healthy (0-2 points), moderately healthy (3-4 points), and the healthiest (5-7 points). Associations between the categories of lifestyle score and all-cause mortality were investigated using Cox proportional hazard models adjusted for confounders. Nonlinear associations were also investigated. 2,706 participants from the Chilean National Health Survey 2009-2010. After a median follow-up of 10.9 years, 286 (10.6%) participants died. In the maximally adjusted model, and compared with the healthiest participants, those less healthy had 2.55 (95% CI: 1.75 to 3.71) times higher mortality risk due to any cause. Similar trends were identified for the moderately healthy group. Moreover, there was a significant trend toward increasing the mortality risk when increasing unhealthy behaviours (HR model 3: 1.61 [95% CI: 1.34 to 1.94]). There was no evidence of nonlinearity between the lifestyle score and all-cause mortality. Individuals in the less healthy lifestyle category had higher mortality risk than the healthiest group. Therefore, public health strategies should be implemented to promote adherence to a healthy lifestyle across the Chilean population.


[Evaluation of a semisolid medium for preserving microorganisms of the Enterobacteriaceae family].
26 bacterial strains from the Enterobacteriaceae family were studied to evaluate the maintenance of the cultural. tinctorial and biochemical properties of the microorganisms originally preserved in the semisolid medium of conservation since the end of the 1980's. 22 of them were viable, showing their survival for more than 10 years. The microorganisms have been maintained in this medium since their introduction into the Laboratory of Collection of Microbial Cultures of the National Institue of Hygiene. Epidemiology and Microbiology of Cuba. They have been used as pattern strains in the internal control of the quality, of reagents and culture media produced in this center for their further use in the microbiological evaluation of environmental samples This medium gives good results for the conservartion of strains of Enterobaceriaceae and may be used in laboratories with scarce resources.


[Thermal denaturation and nuclease degradation of complexes of stellins A and B with DNA].
The soluble complexes of stellins A and B-protamines from Acipenser stellatus-with DNA were obtained by direct mixing in 2,5.10(-4) M EDTA, pH 8,0. The differential curves of melting of the complexes reveal two transitions at Tmelt.1=49+/-1 degree and Tmelt.2=90+/-1 degree, corresponding to melting of DNA regions of free and protamine-bound DNA regions. The number of amino acid residues per one nucleotide in the protein-binding sites of DNA is 1,30 and 1,22 for the stellin A- and stellin B-DNA complexes, respectively. It was demonstrated that under denaturation the DNA filaments do not break apart completely. Data from the analysis of products of the complexes hydrolysis by DNAse I allowed to postulate a selective binding of the protamines to the AT-pairs of DNA. This assumption was confirmed by changes in the melting curves under different protein/DNA ratios.


[Serological tests of functional activity of the digestive system (gastrin, pepsinogen-I, trypsin), general IgE and serum cortisol levels in children with hepatitis A and B].
The mild form of hepatitis A and B with children is attended by a functional activity of pancreatic gland (tripsin), mucous coats of stomach and duodenum (gastrin) which permits to consider them as a factor of the risk of digestive organs combined pathology starting with the disease acuity. Differences in gastrin levels with children depending on hepatitis etiology were specified. Highest levels of gastrin were observed with persons suffering from hepatitis B.


European Association of Nuclear Medicine Focus 5: Consensus on Molecular Imaging and Theranostics in Prostate Cancer.
In prostate cancer (PCa), questions remain on indications for prostate-specific membrane antigen (PSMA) positron emission tomography (PET) imaging and PSMA radioligand therapy, integration of advanced imaging in nomogram-based decision-making, dosimetry, and development of new theranostic applications. We aimed to critically review developments in molecular hybrid imaging and systemic radioligand therapy, to reach a multidisciplinary consensus on the current state of the art in PCa. The results of a systematic literature search informed a two-round Delphi process with a panel of 28 PCa experts in medical or radiation oncology, urology, radiology, medical physics, and nuclear medicine. The results were discussed and ratified in a consensus meeting. Forty-eight statements were scored on a Likert agreement scale and six as ranking options. Agreement statements were analysed using the RAND appropriateness method. Ranking statements were analysed using weighted summed scores. After two Delphi rounds, there was consensus on 42/48 (87.5%) of the statements. The expert panel recommends PSMA PET to be used for staging the majority of patients with unfavourable intermediate and high risk, and for restaging of suspected recurrent PCa. There was consensus that oligometastatic disease should be defined as up to five metastases, even using advanced imaging modalities. The group agreed that [177Lu]Lu-PSMA should not be administered only after progression to cabazitaxel and that [223Ra]RaCl2 remains a valid therapeutic option in bone-only metastatic castration-resistant PCa. Uncertainty remains on various topics, including the need for concordant findings on both [18F]FDG and PSMA PET prior to [177Lu]Lu-PSMA therapy. There was a high proportion of agreement among a panel of experts on the use of molecular imaging and theranostics in PCa. Although consensus statements cannot replace high-certainty evidence, these can aid in the interpretation and dissemination of best practice from centres of excellence to the wider clinical community. There are situations when dealing with prostate cancer (PCa) where both the doctors who diagnose and track the disease development and response to treatment, and those who give treatments are unsure about what the best course of action is. Examples include what methods they should use to obtain images of the cancer and what to do when the cancer has returned or spread. We reviewed published research studies and provided a summary to a panel of experts in imaging and treating PCa. We also used the research summary to develop a questionnaire whereby we asked the experts to state whether or not they agreed with a list of statements. We used these results to provide guidance to other health care professionals on how best to image men with PCa and what treatments to give, when, and in what order, based on the information the images provide.


Functional outcome after thoracoabdominal aortic aneurysm repair.
Repair of thoracoabdominal aortic aneurysms (TAAAs) is performed for the improvement of long-term survival and the preservation of function. The determination of functional outcome and the identification of predictors of survival and functional recovery after TAAA repair are key to proper patient selection. This retrospective review of clinical data was performed in an academic medical center. The demographics, Crawford aneurysm type (I-18, II-33, III-22, IV-28), preoperative risk factors, operative characteristics, and postoperative complications and outcomes were recorded from the medical records for 101 consecutive patients who underwent TAAA repair (58 elective and 43 urgent/emergent). Functional status and living situation at hospital discharge and 12 months after discharge were determined from follow-up examination records or telephone contact with surviving patients. The patients then were categorized into "good" (survival, home, discharge to rehabilitation center, ambulatory) or "bad" (death, discharge to or residence in a long-term care facility, non-ambulatory) outcomes. The postoperative mortality rate was 17.8% (10% in elective cases and 28% in urgent cases), and significant postoperative complications occurred in 77% of the cases (pulmonary complications in 41%, renal complications in 28%, and cord injury in 12%). The mean length of stay was 22.8 + 23.6 days, and at discharge, 80% of the patients were sent to home or rehabilitation and 20% were sent to long-term care facilities. At 1 year, 15 additional patients had died. All but two patients who had been initially discharged to rehabilitation had returned home, but only two patients who had been discharged to long-term care facilities had returned home and both were nonambulatory. Therefore, the survival rate at 1 year was 67%, and only 52.4% of the patients had a "good" outcome at 1 year (survival rate was 78% and rate of "good" outcome was 63% in patients who underwent elective TAAA repair). Independent predictors of postoperative death and "bad" outcome were age more than 75 years, preoperative heart disease, duration of visceral ischemia, use of left atrial femoral bypass graft, postoperative renal dysfunction, and number of organs failing after surgery. Survival and good functional outcome after TAAA repair is significantly less common than expected and is primarily predicted with intraoperative factors and postoperative complications. Improved operative techniques and limitation of visceral ischemia reperfusion injury may improve outcome after TAAA repair.


Genomic Variations Underlying Speciation and Niche Specialization of Shewanella baltica.
Shewanella baltica was the dominant culturable nitrate-reducing bacterium in the eutrophic and strongly stratified Baltic Sea in the 1980s, where it primarily inhabited the oxic-anoxic transition zone. The genomic structures of 46 of these isolates were investigated through comparative genomic hybridization (CGH), which revealed a gradient of genomic similarity, ranging from 65% to as high as 99%. The core genome of the S. baltica species was enriched in anaerobic respiration-associated genes. Auxiliary genes, most of which locate within a few genomic islands (GIs), were nonuniformly distributed among the isolates. Specifically, hypothetical and mobile genetic element (MGE)-associated genes dominated intraclade gene content differences, whereas gain/loss of functional genes drove gene content differences among less related strains. Among the major S. baltica clades, gene signatures related to specific redox-driven and spatial niches within the water column were identified. For instance, genes involved in anaerobic respiration of sulfur compounds may provide key adaptive advantages for clade A strains in anoxic waters where sulfur-containing electron acceptors are present. Genes involved in cell motility, in particular, a secondary flagellar biosynthesis system, may be associated with the free-living lifestyle by clade E strains. Collectively, this study revealed characteristics of genome variations present in the water column and active speciation of S. baltica strains, driven by niche partitioning and horizontal gene transfer (HGT).IMPORTANCE Speciation in nature is a fundamental process driving the formation of the vast microbial diversity on Earth. In the central Baltic Sea, the long-term stratification of water led to formation of a large-scale vertical redoxcline that provided a gradient of environmental niches with respect to the availability of electron acceptors and donors. The region was home to Shewanella baltica populations, which composed the dominant culturable nitrate-reducing bacteria, particularly in the oxic-anoxic transition zone. Using the collection of S. baltica isolates as a model system, genomic variations showed contrasting gene-sharing patterns within versus among S. baltica clades and revealed genomic signatures of S. baltica clades related to redox niche specialization as well as particle association. This study provides important insights into genomic mechanisms underlying bacterial speciation within this unique natural redoxcline.


Community response to construction noise in three central cities of Zhejiang province, China.
As a common source of environmental noise in China and many developing countries worldwide, construction work provokes many complaints and deterioration in acoustic climate quality. This paper describes research to obtain an improved understanding of people's community response to, and evaluation of, construction noise in three central cities of Zhejiang province, China. This involved carrying out a social survey using standard questionnaires developed by the International Commission on Biological Effects of Noise (ICBEN). A dose-response relationship model is established using a quadratic polynomial regression analysis based on construction noise exposure measurements from 40 construction sites in Hangzhou, Ningbo and Wenzhou. The results of the study indicate that the majority of people have a negative attitude to construction noise; the noise ranges between 60 dB and 80 dB (compared with 50 dB-70 dB traffic noise in Tianjin), with the percentage of highly annoyed people affected increasing from 15%-20% to 30%-40% over the range. There also different levels of annoyance depending on the time of day, and the location and activities of those affected. Other cultural differences are also apparent both between Ningbo/Wenzhou and the more urbane citizens of Hangzhou, and the Chinese people and their more noise-tolerant EU and Vietnam counterparts. The findings of this study provide a new perspective for the study of construction noise that can help local governments have an improved understanding of how residents react to construction noise for the purpose of selecting construction noise-mitigation projects and introducing construction noise-control regulations.


Changes in serum amylase and its isoenzymes after whole body irradiation.
A study was carried out to assess the effect of total body irradiation on pancreatic and parotid isoenzymes of amylase in patients about to undergo bone-marrow transplantation who had received high-dose cyclophosphamide. Twelve patients were studied, enzyme activity being measured before and at various times after total body irradiation. Serum total amylase activity rose rapidly within 12 hours of irradiation to a maximum at 36 hours, returning to normal by six days; most of the increase was derived from salivary damage, with a much smaller pancreatic component. These results confirm that radiation produces acute changes in amylase activity, which may be of use in assessing radiation-induced damage.


Stabilization of Protein-Protein Interactions in chemical biology and drug discovery.
More than 300,000 Protein-Protein Interactions (PPIs) can be found in human cells. This number is significantly larger than the number of single proteins, which are the classical targets for pharmacological intervention. Hence, specific and potent modulation of PPIs by small, drug-like molecules would tremendously enlarge the "druggable genome" enabling novel ways of drug discovery for essentially every human disease. This strategy is especially promising in diseases with difficult targets like intrinsically disordered proteins or transcription factors, for example neurodegeneration or metabolic diseases. Whereas the potential of PPI modulation has been recognized in terms of the development of inhibitors that disrupt or prevent a binary protein complex, the opposite (or complementary) strategy to stabilize PPIs has not yet been realized in a systematic manner. This fact is rather surprising given the number of impressive natural product examples that confer their activity by stabilizing specific PPIs. In addition, in recent years more and more examples of synthetic molecules are being published that work as PPI stabilizers, despite the fact that in the majority they initially have not been designed as such. Here, we describe examples from both the natural products as well as the synthetic molecules advocating for a stronger consideration of the PPI stabilization approach in chemical biology and drug discovery.


Prokaryotic BirA ligase biotinylates K4, K9, K18 and K23 in histone H3.
BirA ligase is a prokaryotic ortholog of holocarboxylase synthetase (HCS) that can biotinylate proteins. This study tested the hypothesis that BirA ligase catalyzes the biotinylation of eukaryotic histones. If so, this would mean that recombinant BirA ligase is a useful surrogate for HCS in studies of histone biotinylation. The biological activity of recombinant BirA ligase was confirmed by enzymatic biotinylation of p67. In particular, it was found that BirA ligase biotinylated both calf thymus histone H1 and human bulk histone extracts. Incubation of recombinant BirA ligase with H3-based synthetic peptides showed that lysines 4, 9, 18, and 23 in histone H3 are the targets for the biotinylation by BirA ligase. Modification of the peptides (e.g., serine phosphorylation) affected the subsequent biotinylation by BirA ligase, suggesting crosstalk between modifications. In conclusion, this study suggests that prokaryotic BirA ligase is a promiscuous enzyme and biotinylates eukaryotic histones. Moreover the biotinylation of histones by BirA ligase is consistent with the proposed role of human HCS in chromatin.


Deliberating the risks of nanotechnologies for energy and health applications in the United States and United Kingdom.
Emerging nanotechnologies pose a new set of challenges for researchers, governments, industries and citizen organizations that aim to develop effective modes of deliberation and risk communication early in the research and development process. These challenges derive from a number of issues including the wide range of materials and devices covered by the term 'nanotechnology', the many different industrial sectors involved, the fact that many areas of nanotechnology are still at a relatively early stage of development, and uncertainty about the environmental, health and safety impacts of nanomaterials. Public surveys have found that people in the United States and Europe currently view the benefits of nanotechnologies as outweighing their risks although, overall, knowledge about nanotechnology remains very low. However, surveys cannot easily uncover the ways that people will interpret and understand the complexities of nanotechnologies (or any other topic about which they know very little) when asked to deliberate about it in more depth, so new approaches to engaging the public are needed. Here, we report the results of the first comparative United States-United Kingdom public engagement experiment. Based upon four concurrent half-day workshops debating energy and health nanotechnologies we find commonalities that were unexpected given the different risk regulatory histories in the two countries. Participants focused on benefits rather than risks and, in general, had a high regard for science and technology. Application context was much more salient than nation as a source of difference, with energy applications viewed in a substantially more positive light than applications in health and human enhancement in both countries. More subtle differences were present in views about the equitable distribution of benefits, corporate and governmental trustworthiness, the risks to realizing benefits, and in consumerist attitudes.


Quantification of antipsychotic biotransformation in brain microvascular endothelial cells by using untargeted metabolomics.
Most studies of antipsychotic-therapies have highlighted the discrepancy between plasma and brain pharmacokinetics of antipsychotics, but how the drug changes through the blood brain barrier (BBB) has not been investigated. Cell-based metabolomics using liquid chromatography-mass spectrometry (LC-MS) combined with multivariate data analysis were applied for screening of antipsychotic metabolites in the BBB. We applied this approach to analyze the antipsychotic biotransformation in brain microvascular endothelia cells (BMVECs), the main component of the BBB. From this study, five, four, three, and one metabolite of chlorpromazine, clozapine, haloperidol and risperidone, respectively, were locally metabolized on the BMVECs. These results confirm that there is a drug biotransformation process within the BBB and show that drug metabolite screening employed cell-based metabolomics using LC-MS, combined with multivariate analysis in the study of BMVECs exposed to antipsychotics can provide a way to screen drug metabolites in the BBB.


Quantification of intensity variations in functional MR images using rotated principal components.
In functional MRI (fMRI), the changes in cerebral haemodynamics related to stimulated neural brain activity are measured using standard clinical MR equipment. Small intensity variations in fMRI data have to be detected and distinguished from non-neural effects by careful image analysis. Based on multivariate statistics we describe an algorithm involving oblique rotation of the most significant principal components for an estimation of the temporal and spatial distribution of the stimulated neural activity over the whole image matrix. This algorithm takes advantage of strong local signal variations. A mathematical phantom was designed to generate simulated data for the evaluation of the method. In simulation experiments, the potential of the method to quantify small intensity changes, especially when processing data sets containing multiple sources of signal variations, was demonstrated. In vivo fMRI data collected in both visual and motor stimulation experiments were analysed, showing a proper location of the activated cortical regions within well known neural centres and an accurate extraction of the activation time profile. The suggested method yields accurate absolute quantification of in vivo brain activity without the need of extensive prior knowledge and user interaction.


What impact do chronic disease self-management support interventions have on health inequity gaps related to socioeconomic status: a systematic review.
The social gradient in chronic disease (CD) is well-documented, and the ability to effectively self-manage is crucial to reducing morbidity and mortality from CD. This systematic review aimed to assess the moderating effect of socioeconomic status on self-management support (SMS) interventions in relation to participation, retention and post-intervention outcomes. Six databases were searched for studies of any design published until December 2018. Eligible studies reported on outcomes from SMS interventions for adults with chronic disease, where socioeconomic status was recorded and a between-groups comparison on SES was made. Possible outcomes were participation rates, retention rates and clinical or behavioural post-intervention results. Nineteen studies were retrieved, including five studies on participation, five on attrition and nine studies reporting on outcomes following SMS intervention. All participation studies reported reduced engagement in low SES cohorts. Studies assessing retention and post-intervention outcomes had variable results, related to the diversity of interventions. A reduction in health disparity was seen in longer interventions that were individually tailored. Most studies did not provide a theoretical justification for the intervention being investigated, although four studies referred to Bandura's concept of self-efficacy. The limited research suggests that socioeconomic status does moderate the efficacy of SMS interventions, such that without careful tailoring and direct targeting of barriers to self-management, SMS may exacerbate the social gradient in chronic disease outcomes. Screening for patient disadvantage or workload, rather than simply recording SES, may increase the chances of tailored interventions being directed to those most likely to benefit from them. Future interventions for low SES populations should consider focussing more on treatment burden and patient capacity. PROSPERO registration CRD42019124760. Registration date 17/4/19.


Cobble community DNA as a tool to monitor patterns of biodiversity within kelp forest ecosystems.
Kelp forest ecosystems dominate 150,000 km of global temperate coastline, rivalling the coastal occurrence of coral reefs. Despite the astounding biological diversity and productive ecological communities associated with kelp forests, patterns of species richness and composition are difficult to monitor and compare. Crustose coralline algae are a critically important substrate for propagule settlement for a range of kelp forest species. Coralline-covered cobbles are home to hundreds of species of benthic animals and algae and form a replicable unit for ecological assays. Here, we use DNA metabarcoding of bulk DNA extracts sampled from cobbles to explore patterns of species diversity in kelp forests of the central California coast. The data from 97 cobbles within kelp forest ecosystems at three sites in Central California show the presence of 752 molecular operational taxonomic units (MOTUs) and 53 MOTUs assigned up to the species level with >95% similarity to current databases. We are able to detect spatial patterns of important management targets such as abalone recruits, and localized abundance of sea stars in 2012. Comparison of classic ecological surveys of these sites reveals large differences in species targets for these two approaches. In order to make such comparisons more quantitative, we use Presence/Absence Metabarcoding, using the fraction of replicate cobbles showing a species as a measure of its local abundance. This approach provides a fast and repeatable survey method that can be applied for biodiversity assessments across systems to shed light on the impact of different ecological disturbances and the role played by marine protected areas.


Oligosaccharide Metabolism and Lipoteichoic Acid Production in Lactobacillus gasseri and Lactobacillus paragasseri.
Lactobacillus gasseri and Lactobacillus paragasseri are human commensal lactobacilli that are candidates for probiotic application. Knowledge of their oligosaccharide metabolic properties is valuable for synbiotic application. The present study characterized oligosaccharide metabolic systems and their impact on lipoteichoic acid (LTA) production in the two organisms, i.e., L. gasseri JCM 1131T and L. paragasseri JCM 11657. The two strains grew well in medium with glucose but poorly in medium with raffinose, and growth rates in medium with kestose differed between the strains. Oligosaccharide metabolism markedly influenced their LTA production, and apparent molecular size of LTA in electrophoresis recovered from cells cultured with glucose and kestose differed from that from cells cultured with raffinose in the strains. On the other hand, more than 15-fold more LTA was observed in the L. gasseri cells cultured with raffinose when compared with glucose or kestose after incubation for 15 h. Transcriptome analysis identified glycoside hydrolase family 32 enzyme as a potential kestose hydrolysis enzyme in the two strains. Transcriptomic levels of multiple genes in the dlt operon, involved in D-alanine substitution of LTA, were lower in cells cultured with raffinose than in those cultured with kestose or glucose. This suggested that the different sizes of LTA observed among the carbohydrates tested were partly due to different levels of alanylation of LTA. The present study indicates that available oligosaccharide has the impact on the LTA production of the industrially important lactobacilli, which might influence their probiotic properties.


[Hepatotoxicity of isaxonine phosphate: 4 cases of severe subacute hepatitis].
Isaxonine phosphate is known to induce acute hepatitis which in most cases is reversible after withdrawal of the drug. The authors describe 4 new cases of hepatitis which differ from those previously reported by their evolutive and pathological features. In 3 cases, the outcome was fatal within a delay of 15-40 days despite discontinuation of the drug, and was associated with hepatic encephalopathy and ascites. In the 4 cases plasma concentration of alanine- and aspartate-aminotransferases were initially increased (up to 33 X upper normal range) and decreased to normal values in 2 cases. Plasma bilirubin levels were also elevated at first and continued to increase during the first 15 days of evolution. Pathological examination of the liver showed mild necrosis, sometimes with a piecemeal or a bridging aspect, marked fibrosis infiltrated with mononuclear and neutrophil polymorphonuclear cells and a conspicuous biliary neogenesis. In these particular cases of hepatitis due to isaxonine phosphate, occurrence in women, increased serum immunoglobulin levels, presence of autoantibodies, clinical and pathological aspects resembling those observed in iproniazid hepatitis may be suggestive of an immunological, or even autoimmune, mechanism.