Significance of coexistent granulomatous inflammation and lung cancer.
Coexistence of lung cancer and granulomatous inflammation in the same patient confuses clinicians. We aimed to document the prevalence, clinicopathological features, treatment outcomes and prognosis in patients with coexisting granulomatous inflammation undergoing curative lung resection for lung cancer, in a tuberculosis (TB)-endemic country. An observational cohort study of patients with lung cancer undergoing curative resection between 2012 and 2015 in a tertiary centre in Singapore. One hundred and twenty-seven patients underwent lung resection for cancer, out of which 19 (14.9%) had coexistent granulomatous inflammation in the resected specimen. Median age was 68 years and 58.2% were males. Overall median (range) survival was 451 (22-2452) days. Eighteen (14%) patients died at median duration of 271 days after surgery. The postsurgery median survival for those alive was 494 (29-2452) days in the whole group. Subgroup analysis did not reveal any differences in age, gender, location of cancer, radiological features, type of cancer, chemotherapy, history of TB or survival in patients with or without coexistent granulomatous inflammation. Incidental detection of granulomatous inflammation in patients undergoing lung resection for cancer, even in a TB-endemic country, may not require any intervention. Such findings may be due to either mycobacterial infection in the past or 'sarcoid reaction' to cancer. Although all patients should have their resected specimen sent for acid-fast bacilli culture and followed up until the culture results are reported, the initiation of the management of such patients as per existing lung cancer management guidelines does not affect their outcome adversely.


Cell sourcing and culture conditions for fibrin-based valve constructs.
Cell sourcing for tissue-engineered heart valves remains a critical issue. In this work, human dermal fibroblasts (HDF) or porcine valve interstitial cells (PVIC) were entrapped in adherent fibrin disk constructs and harvested at 3 and 5 weeks. We compared the fibrin remodeling abilities of each cell type in Dulbecco's Modified Eagle's Medium (DMEM) and DMEM/F12 supplemented with transforming growth factor beta (TGF), and the response of PVIC to DMEM/F12 supplemented with fibroblast growth factor (FGF), a combination of FGF and TGF, and TGF with varying ascorbic acid (AA) concentrations. Culture media were supplemented with serum, insulin, AA, a fibrinolysis inhibitor, and antibiotics. DMEM maximized collagen and elastin deposition by HDF, while DMEM/F12 with FGF yielded the highest fibrin remodeling response by PVIC. HDF degraded fibrin slower than PVIC, and PVIC constructs had higher cellularity than HDF constructs in DMEM and DMEM/F12 at 3 weeks. FGF addition increased collagen content, collagen deposited per cell, and collagen as percentage of total protein compared to medium supplemented with TGF or TGF and FGF. AA addition increased collagen deposition by PVIC, but there was no dose dependence between 50 and 150 microg/mL AA. These results collectively show that PVIC are able to remodel fibrin faster and exhibit greater mechanical stiffening compared to HDF. Conditions for increased collagen deposition are also identified toward the engineering of valve constructs.


Hemangioblastomas of the central nervous system--immunohistochemical and ultrastructural study.
Immunohistochemical studies using immunoperoxidase staining for glial fibrillary acidic protein (GFAP), S-100 protein, and factor VIII-related antigen (VIII-RAg) were performed on 10 hemangioblastomas of the central nervous system to determine the origin of stromal cells. No cytoplasmic immunoreactivity for anti-GFAP, anti-S-100 protein, or anti-VIII-RAg was detected in most stromal cells. A small number of GFAP-positive cells were found only in the periphery of the tumor; they were thought to be trapped astrocytes or stromal cells taking up GFAP. Most stromal cells had abundant, clear cytoplasm with some microfilaments and lipid vacuoles. Cylindrical cytoplasmic processes and intermediate junctions were observed in some stromal cells, but most cells did not possess any junctional device. No stromal cell possessed any feature clearly suggesting endothelial cells or pericytes. Our immunohistochemical and ultrastructural investigations did not support the theories of stromal cell origin from astrocytes or endothelial cells. We concluded that stromal cells can be regarded as an aberrant cell type of angiogenic mesenchymal derivation.


Droplet plume emission during plasmonic bubble growth in ternary liquids.
Plasmonic bubbles are of great relevance in numerous applications, including catalytic reactions, micro/nanomanipulation of molecules or particles dispersed in liquids, and cancer therapeutics. So far, studies have been focused on bubble nucleation in pure liquids. Here we investigate plasmonic bubble nucleation in ternary liquids consisting of ethanol, water, and trans-anethole oil, which can show the so-called ouzo effect. We find that oil (trans-anethole) droplet plumes are produced around the growing plasmonic bubbles. The nucleation of the microdroplets and their organization in droplet plumes is due to the symmetry breaking of the ethanol concentration field during the selective evaporation of ethanol from the surrounding ternary liquids into the growing plasmonic bubbles. Numerical simulations show the existence of a critical Marangoni number Ma (the ratio between solutal advection rate and the diffusion rate), above which the symmetry breaking of the ethanol concentration field occurs, leading to the emission of the droplet plumes. The numerical results agree with the experimental observation that more plumes are emitted with increasing ethanol-water relative weight ratios and hence Ma. Our findings on the droplet plume formation reveal the rich phenomena of plasmonic bubble nucleation in multicomponent liquids and help to pave the way to achieve enhanced mixing in multicomponent liquids in chemical, pharmaceutical, and cosmetic industries.


Species differences in the metabolism of norephedrine in man, rabbit and rat.
1. (+/-)-2-Amino-1-phenyl[1-(14)C]propan-1-ol ([(14)C]norephedrine) was administered orally to man, rat and rabbit and the metabolites excreted in the urine were identified and measured. Pronounced species differences in the metabolism of the drug were found. 2. Three male human subjects, receiving 25mg each of [(14)C]norephedrine hydrochloride, excreted over 90% of the (14)C in the first day. The main metabolite was the unchanged drug (86% of the dose) and minor metabolites were hippuric acid and 4-hydroxynorephedrine. 3. In rats given 12mg of the drug/kg almost 80% of the (14)C administered was excreted in the first day. The major metabolites in the urine were the unchanged drug (48% of the dose), 4-hydroxynorephedrine (28%) and trace amounts of side-chain degradation products. 4. Rabbits given 12mg of the drug/kg excreted 85-95% of the dose of (14)C in the urine in the first 24h after dosing. The major metabolites in the urine were conjugates of 1,2-dihydroxy-1-phenylpropane (31% of the dose) and of 1-hydroxy-1-phenylpropan-2-one (27%) and hippuric acid (20%). The unchanged drug was excreted in relatively small amounts (8%).


CISK attenuates degradation of the chemokine receptor CXCR4 via the ubiquitin ligase AIP4.
HER2 overexpression in cancers causes hyperactivation of the PI 3-kinase pathway and elevated levels of the chemokine receptor CXCR4, which is strongly associated with increased metastatic potential. Here, we provide evidence that the cytokine-independent survival kinase CISK is activated downstream of the PI 3-kinase-dependent kinase PDK1 on endosomes and negatively regulates the lysosomal degradation of CXCR4. We demonstrate that CISK prevents CXCR4 degradation by inhibiting sorting of the receptor from early endosomes to lysosomes. In contrast, CISK does not interfere with ligand-induced degradation of epidermal growth factor receptors. CISK strongly interacts and colocalizes with the E3 ubiquitin ligase AIP4, which is important for the ubiquitin-dependent lysosomal degradation of CXCR4. Moreover, the observed inhibition is both dependent on the interaction between CISK and AIP4 and on the activation status of CISK. Consistent with this, an activated form of CISK but not of the related kinase SGK1 phosphorylates specific sites of AIP4 in vitro. Taken together, these results reveal a critical function of CISK in specifically attenuating ubiquitin-dependent degradation of CXCR4, and provide a mechanistic link between the PI 3-kinase pathway and CXCR4 stability.


Secretion of ferritin by rat hepatoma cells and its regulation by inflammatory cytokines and iron.
The possibility that serum ferritin is a secreted protein and an acute phase reactant regulated by inflammatory hormones and iron was examined in a hepatic cell line that secretes plasma proteins. Differentiated rat hepatoma cells released albumin and ferritin into the medium, as determined by rocket immunoelectrophoresis and isolation of ferritin by standard procedures plus immunoaffinity chromatography, following labeling with radioactive amino acid. Administration of interleukin-1-beta (IL-1) or tumor necrosis factor-alpha (TNF) doubled the amounts of ferritin released into the medium over 24 and 48 hours. Together, the cytokines had more than an additive effect. Albumin secretion was diminished by IL-1, but not TNF. Iron, administered as an iron dextran complex or as a 1:1 chelate with nitrilotriacetate (Fe-NTA), also enhanced ferritin release, but had no effect on albumin. Intracellular ferritin concentrations did not change significantly with cytokine treatment, but increased in response to iron. With or without treatments, release of ferritin and albumin from cells into the medium was inhibited by brefeldin A, an inhibitor of Golgi function. The effect of each of the cytokines and of iron on ferritin and albumin was also blocked by dichlorofuranosylbenzimidazole (DRB), an inhibitor of transcription. The stimulatory effect of Fe-NTA on ferritin secretion was diminished by TNF, and this was partially counteracted by IL-1, indicating additional regulatory complexity. These results show for the first time that hepatic cells secrete ferritin, that this ferritin secretion is regulated by iron and inflammatory cytokines, and that the mechanisms of regulation differ from those for intracellular ferritin. The results would explain why serum ferritin increases in inflammation or when iron flux is enhanced.


Novel Quinolizine AIE System: Visualization of Molecular Motion and Elaborate Tailoring for Biological Application.
Molecular motions are ubiquitous in nature and they immutably play intrinsic roles in all actions. However, exploring appropriate models to decipher molecular motions is an extremely important but very challenging task for researchers. Considering aggregation-induced emission (AIE) luminogens possess their unique merits to visualize molecular motions, it is particularly fascinating to construct new AIE systems as models to study molecular motion. Herein, a novel quinolizine (QLZ) AIE system was constructed based on the restriction intramolecular vibration (RIV) mechanism. It was demonstrated that QLZ could act as an ideal model to visualize single-molecule motion and macroscopic molecular motion via fluorescence change. Additionally, further elaborate tailoring of this impressive core achieved highly efficient reactive oxygen species production and realized fluorescence imaging-guided photodynamic therapy applications, which confirms the great application potential of this new AIE-active QLZ core. Therefore, this work not only provides an ideal model to visualize molecular motion but also opens a new way for the application of AIEgens.


Born digital or fossilised digitally? How born digital data systems continue the legacy of social violence towards LGBTQI + communities: a case study of experiences in the Republic of Ireland.
The AI and Society discourse has previously drawn attention to the ways that digital systems embody the values of the technology development community from which they emerge through the development and deployment process. Research shows how this effect leads to a particular treatment of gender in computer systems development, a treatment which lags far behind the rich understanding of gender that social studies scholarship reveals and people across society experience. Many people do not relate to the narrow binary gender options of male or female, and many people express their gender identity in much richer ways than the sex/gender binary female/woman and male/man Boolean terms will allow. We ask: are "born-digital" gendered datasets in digital systems experienced as marginalising by those who express their identity beyond the male/female binary? Case Study: Ireland. To answer this universal question, this paper presents the findings of an empirical case study of people in Ireland with diverse gender identities and expressions, and their experiences with public data systems and new technologies. In spite of great social changes in Ireland which have led to constitutional change in favour of LGBTQI + people, born-digital systems were experienced by respondents as embodying socio-cultural values which were no longer accepted in society at large. For many of the respondents, digital technologies routinely marginalise them in all kinds of ways. These systems keep alive violence and oppression long after civil rights have been enshrined in constitutional law. This study is just one example of the way assumptions about digital are disengaged from society-at-large. It is a call to arms to all who are passionate about socially-responsible technology.


TET2 gene mutation is unfavorable prognostic factor in cytogenetically normal acute myeloid leukemia patients with NPM1+ and FLT3-ITD - mutations.
Cytogenetically normal acute myeloid leukemia (cn-AML) is a group of heterogeneous diseases. Gene mutations are increasingly used to assess the prognosis of cn-AML patients and guide risk-adapted treatment. In the present study, we analyzed the molecular genetics characteristics of 373 adult cn-AML patients and explored the relationship between TET2 gene mutations or different genetic mutation patterns and prognosis. We found that 16.1 % of patients had TET2 mutations, 31.6 % had FLT3 internal tandem duplications (ITDs), 6.2 % had FLT3 tyrosine kinase domain mutations, 2.4 % had c-KIT mutations, 37.8 % had NPM1 mutations, 11.3 % had WT1 mutations, 5.9 % had RUNX1 mutations, 11.5 % had ASXL1 mutations, 3.8 % had MLL-PTDs, 7.8 % had IDH1 mutations, 7.8 % had NRAS mutations, 12.3 % had IDH2 mutations, 1.6 % had EZH2 mutations, and 14.7 % had DNMT3A mutations, while none had CBL mutations. Gene mutations were detected in 76.94 % (287/373) of all patients. In the NPM1m(+) patients, those with TET2 mutations were associated with a shorter median overall survival (OS) as compared to TET2 wild-type (wt) patients (9.9 vs. 27.0 months, respectively; P = 0.023); Interestingly, the TET2 mutation was identified as an unfavorable prognostic factor and was closely associated with a shorter median OS as compared to TET2-wt (9.5 vs. 32.2 months, respectively; P = 0.013) in the NPM1m(+)/FLT3-ITDm(-) patient group. Thus, identification of TET2 combined with classic NPM1 and FLT3-ITD mutations allowed us to stratify cn-AML into distinct subtypes.


Paraburkholderia phytofirmans PsJN Protects Arabidopsis thaliana Against a Virulent Strain of Pseudomonas syringae Through the Activation of Induced Resistance.
Paraburkholderia phytofirmans PsJN is a plant growth-promoting rhizobacterium (PGPR) that stimulates plant growth and improves tolerance to abiotic stresses. This study analyzed whether strain PsJN can reduce plant disease severity and proliferation of the virulent strain Pseudomonas syringae pv. tomato DC3000, in Arabidopsis plants, through the activation of induced resistance. Arabidopsis plants previously exposed to strain PsJN showed a reduction in disease severity and pathogen proliferation in leaves compared with noninoculated, infected plants. The plant defense-related genes WRKY54, PR1, ERF1, and PDF1.2 demonstrated increased and more rapid expression in strain PsJN-treated plants compared with noninoculated, infected plants. Transcriptional analyses and functional analysis using signaling mutant plants suggested that resistance to infection by DC3000 in plants treated with strain PsJN involves salicylic acid-, jasmonate-, and ethylene-signaling pathways to activate defense genes. Additionally, activation occurs through a specific PGPR-host recognition, being a necessary metabolically active state of the bacterium to trigger the resistance in Arabidopsis, with a strain PsJN-associated molecular pattern only partially involved in the resistance response. This study provides the first report on the mechanism used by the PGPR P. phytofirmans PsJN to protect A. thaliana against a widespread virulent pathogenic bacterium.


In vitro inhibition of biophysical surface properties and change in ultrastructures of exogenous pulmonary surfactant by albumin or fibrinogen.
In order to observe the effects of serum albumin and fibrinogen on biophysical surface properties and the morphology of pulmonary surfactant in vitro, we measured the surface adsorption rate, dynamic minimum and maximum surface tension (min-, max-ST) by Pulsating Bubble Surfactometer, and demonstrated ultrastructures on a series of mixtures with varying concentrations of albumin or fibrinogen and Surfactant-TA. The albumin and fibrinogen significantly inhibited the adsorption rate and ST-lowering properties of surfactant through increasing STs of adsorption rate, min-ST, and max-ST. The characteristic morphology of the Surfactant-TA changed from lamellar rod-like structure with open ends into spherical structures with loss of their open ends by mixing with albumin or fibrinogen. These inhibitory effects of albumin and fibrinogen on surface properties of surfactant were dependent upon the increasing concentration of albumin or fibrinogen. We concluded that albumin and fibrinogen significantly altered surfactant function and its ultrastructural morphology in vitro. These findings support the concept that albumin and fibrinogen-induced surfactant dysfunction may play an important role in the pathophysiology of adult respiratory distress syndrome, and this adverse effect of albumin and fibrinogen on surfactant might be overcome by administration of large doses of exogenous surfactant.


Cytotoxic effect of silica nanoparticles against hepatocellular carcinoma cells through necroptosis induction.
Hepatocellular carcinoma (HCC) is a common cancer that affects people worldwide with high morbidity and mortality, and its resistance to current chemotherapeutic drugs is a serious concern. Cytotoxicity of silica nanoparticles (Nano-SiO2) towards cancer cells has been reported previously, but the specific mechanism is not fully clear. In this study, Nano-SiO2 showed a remarkable cytotoxic effect against HCC cells, regardless of whether the cells were drug resistant or not. Further study showed that Nano-SiO2 treatment leads to cell cycle arrest, apoptosis enhancement and necroptosis induction in the HCC cells. RNA-seq data, together with bioinformatics analysis, revealed that a series of genes involved in cancer cell death could be regulated by Nano-SiO2, among which ZBP-1 was up-regulated the most by Nano-SiO2 treatment. The siRNA based experiments demonstrated that ZBP-1 might play a key role in mediating Nano-SiO2 cytotoxic functions against HCC cells. These results have evidently signified the anti-tumor potential of Nano-SiO2 in the treatment of HCC.


PFOS and PCB 153 have direct adverse effects on neonatal testis modeled using a coculture of primary gonocyte and sertoli cells.
Perfluorooctane sulfonate (PFOS) is widely used in industry; it is nonbiodegradable and persistent in the human body and in the environment. Although reports have indicated that young people might have higher PFOS levels in serum or blood than do older people, its adverse effects on neonatal testicular cells had not been investigated previously. PCB 153 is one of the most prevalent polychlorinated biphenyl (PCB) congeners in biological tissues, but the direct adverse effect of PCB 153 on neonatal testis remains unclear. In this study, we exposed a neonatal Sertoli cell/gonocyte coculture system to PFOS and PCB 153 individually at concentrations of 0, 1, 10, 50, and 100 μM for 24 h. Exposure to either compound reduced the cell viability and induced the production of reactive oxygen species (ROS) in dose-dependent manners, with PCB 153 having a greater effect than PFOS. Whereas PCB 153 induced apoptosis significantly from 10 μM, PFOS induced no obvious change. Morphologically, both PCB 153 and PFOS induced changes in the vimentin and actin filaments in the Sertoli cells, as investigated using confocal argon ion laser scanning microscopy; here, PFOS exhibited a more dramatic effect than did PCB 153. Furthermore, doses of 50 μM for PFOS and 10 μM for PCB 153 were the key concentrations that produced significant differences between the control and exposure groups. We suggest that both PCB 153 and PFOS directly affect neonatal gonocyte and Sertoli cells; the production of ROS and the change in the cytoskeleton in Sertoli cells might be causes.


When Broca experiences the Janus syndrome: an ER-fMRI study comparing sentence comprehension and cognitive sequence processing.
The determining of brain regions that exhibit specific activity during sentence comprehension compared to other non-linguistic cognitive tasks constitutes one of the important challenges in the domain of functional neuroimaging of the faculty of language. In the current paper we report an event-related functional magnetic resonance imaging (ER-fMRI) experiment, in which we directly compared the cerebral basis of sentence comprehension on the one hand, and of abstract sequence processing on the other hand. Previous experimental work done in our group, as well as different observations from recent behavioural, neurophysiological and functional neuroimaging experiments led us to propose the hypothesis that both of these tasks would share certain computational properties. Thus, this experiment was designed to show which brain regions would be implicated in both tasks and compare them to brain regions that would be specifically engaged in sentence comprehension. Results from this experiment suggest that distinct sub-regions in the left prefrontal cortex, potentially including Broca's area show distinct activation patterns during both of these tasks. Results are discussed in the context of a construction-based model of sentence processing (see Dominey and Hoen, 2006, this issue) that is based on a dual-path processing mechanism separating function and content information processing. We propose and discuss the hypothesis that subparts of Broca's area BA 44 and BA 45 would respectively be implicated in two different aspects of sentence comprehension: i) a general structure mapping capability and ii) the online integration of semantic representations onto structural constraints.


Tomato glycosyltransferase Twi1 plays a role in flavonoid glycosylation and defence against virus.
Secondary metabolites play an important role in the plant defensive response. They are produced as a defence mechanism against biotic stress by providing plants with antimicrobial and antioxidant weapons. In higher plants, the majority of secondary metabolites accumulate as glycoconjugates. Glycosylation is one of the commonest modifications of secondary metabolites, and is carried out by enzymes called glycosyltransferases. Here we provide evidence that the previously described tomato wound and pathogen-induced glycosyltransferase Twi1 displays in vitro activity toward the coumarins scopoletin, umbelliferone and esculetin, and the flavonoids quercetin and kaempferol, by uncovering a new role of this gene in plant glycosylation. To test its activity in vivo, Twi1-silenced transgenic tomato plants were generated and infected with Tomato spotted wilt virus. The Twi1-silenced plants showed a differential accumulation of Twi1 substrates and enhanced susceptibility to the virus. Biochemical in vitro assays and transgenic plants generation proved to be useful strategies to assign a role of tomato Twi1 in the plant defence response. Twi1 glycosyltransferase showed to regulate quercetin and kaempferol levels in tomato plants, affecting plant resistance to viral infection.


A cellular model reflecting the phenotypic heterogeneity of mutant HRAS driven squamous cell carcinoma.
Squamous cell carcinomas have a range of histopathological manifestations. The parameters that determine this clinically observed heterogeneity are not fully understood. Here, we report the generation of a cell culture model that reflects part of this heterogeneity. We have used the catalytic subunit of human telomerase hTERT and large T to immortalize primary UV-unexposed keratinocytes. Then, mutant HRAS G12V has been introduced to transform these immortal keratinocytes. When injected into immunosuppressed mice, transformed cells grew as xenografts with distinct histopathological characteristics. We observed three major tissue architectures: solid, sarcomatoid and cystic growth types, which were primarily composed of pleomorphic and basaloid cells but in some cases displayed focal apocrine differentiation. We demonstrate that the cells generated represent different stages of skin cancerogenesis and as such can be used to identify novel tumor-promoting alterations such as the overexpression of the PADI2 oncogene in solid-type SCC. Importantly, the cultured cells maintain the characteristics from the xenograft they were derived from while being amenable to manipulation and analysis. The availability of cell lines representing different clinical manifestations opens a new tool to study the stochastic and deterministic factors that cause case-to-case heterogeneity despite departing from the same set of oncogenes and the same genetic background.


Effect of chronic co-administration of metformin and vitamin C on plasma glucose and lipid concentrations in normal rats.
In clinical setting, uncomplicated diabetes mellitus type 2 is managed with anti-oxidants (e.g. ascorbic acid, alpha-tocopherol, etc.) with standard oral hypoglycaemic agents, which is aimed at limiting its glucose auto-oxidation and lipid peroxidation complications. The current study is an experimental animal study aimed at investigating the effect of co-administration of metformin and ascorbic acid (Vitamin C) on plasma glucose and lipid levels in non-diabetic rats which could serve as a template for future studies in this area. The hypoglycaemic and hypolipidaemic activities of metformin, ascorbic acid, and metformin-ascorbic acid combination were studied in 4 groups consisting of 6 rats per group and weighing 120 - 155 g, by administering oral doses of 5, 10 and 15 (for co-administration) mg/kg/day of the drugs, respectively, for 30 days. The acute oral toxicity of the combination was also conducted using limit dose test of Up and Down Procedure of Acute Oral Toxicity test. Results of the study showed that metformin and metformin-ascorbic acid combination induced significant and comparable hypoglycaemia. The drug combination also lowered plasma total cholesterol, low density lipoprotein-cholesterol (LDL-c), very low density lipoprotein-cholesterol (VLDL-c) significantly but had no effect on plasma high density lipoprotein-cholesterol (HDL-c). The LD50 estimate of the drug combination was greater than 5000 mg/kg body weight/oral route. The results of this study suggest the drug combination could have hypoglycaemic and lipid-lowering effects.


Status epilepticus and the use of continuous EEG monitoring in the intensive care unit.
Status epilepticus (SE) is one of the major neurologic emergencies. Newer data about the genesis and treatment of this condition are available to help improve our understanding and management. Approximately 150,000 cases of generalized convulsive SE occur in the United States each year. Clinically apparent seizures complicate about 8% of intensive care unit admissions, and another 10% of ICU patients suffer electrographic seizures in the course of another critical illness. Some of these cases result from previously under-recognized epileptogenic effects of commonly used drugs, such as cefepime. Continuous EEG (cEEG) recording is necessary for both diagnosis and management in these patients, especially since anticonvulsant drugs may abolish motor activity without stopping seizures. Recent studies have underscored the utility of benzodiazepines as the first-line agents for SE termination. The recently published Rapid Anticonvulsant Medication Prior to Arrival Trial (RAMPART) demonstrates that the more rapidly treatment is administered, the more effective it will be. When SE fails to respond to usual doses of benzodiazepines, it should be considered refractory to conventional anticonvulsants, and a general anesthetic approach is likely to be necessary. While definitions have varied, patients should be managed for SE after 5 minutes of seizure activity. Management of a patient with SE involves three phases: termination of SE, prevention of recurrence, and treatment of complications. The typical anticonvulsants have limited ability to terminate SE; lorazepam is the most useful, controlling SE in 65% of patients experiencing generalized convulsive SE. If the first conventional anticonvulsant fails, others are unlikely to be useful, and one of the newer anticonvulsants or a general anesthetic agent should be considered. EEG is crucial in the diagnosis and classification of potential seizures. cEEG monitoring helps to guide anticonvulsant therapy in patients with SE and those with frequent seizures. In addition, cEEG has the potential for presymptomatic diagnosis of delayed neurologic deterioration in patients with subarachnoid hemorrhage and for the differential diagnosis of stroke subtypes, especially when cEEG is subjected to signal processing.


Differential Impact of Inhibitory G-Protein Signaling Pathways in Ventral Tegmental Area Dopamine Neurons on Behavioral Sensitivity to Cocaine and Morphine.
Drugs of abuse engage overlapping but distinct molecular and cellular mechanisms to enhance dopamine (DA) signaling in the mesocorticolimbic circuitry. DA neurons of the ventral tegmental area (VTA) are key substrates of drugs of abuse and have been implicated in addiction-related behaviors. Enhanced VTA DA neurotransmission evoked by drugs of abuse can engage inhibitory G-protein-dependent feedback pathways, mediated by GABAB receptors (GABABRs) and D2 DA receptors (D2Rs). Chemogenetic inhibition of VTA DA neurons potently suppressed baseline motor activity, as well as the motor-stimulatory effect of cocaine and morphine, confirming the critical influence of VTA DA neurons and inhibitory G-protein signaling in these neurons on this addiction-related behavior. To resolve the relative influence of GABABR-dependent and D2R-dependent signaling pathways in VTA DA neurons on behavioral sensitivity to drugs of abuse, we developed a neuron-specific viral CRISPR/Cas9 approach to ablate D2R and GABABR in VTA DA neurons. Ablation of GABABR or D2R did not impact baseline physiological properties or excitability of VTA DA neurons, but it did preclude the direct somatodendritic inhibitory influence of GABABR or D2R activation. D2R ablation potentiated the motor-stimulatory effect of cocaine in male and female mice, whereas GABABR ablation selectively potentiated cocaine-induced activity in male subjects only. Neither D2R nor GABABR ablation impacted morphine-induced motor activity. Collectively, our data show that cocaine and morphine differ in the extent to which they engage inhibitory G-protein-dependent feedback pathways in VTA DA neurons and highlight key sex differences that may impact susceptibility to various facets of addiction.


[Progress in biosynthesis of santalene and santalol].
Santalene and santalol are the main components of valuable perfume sandalwood essential oil, and have good antibacterial, anti-oxidation and anti-tumor activities. Commercial sandalwood essential oil is mainly extracted from sandalwood tree that grows slowly and is difficult to cultivate. In addition, the extraction recovery of sandalwood essential oil from sandalwood tree is too low to meet the market demand. These factors make sandalwood essential oil expensive. An option is to use genetic engineering and molecular biological methods to heterologously express related synthase of santalene and santalol in microbial host. In this paper, the biosynthesis progress of santalene and santalol synthase, as well as the optimization of mevalonate metabolic pathways in the hosts are summarized. Furthermore, the strategies of applying protein engineering technology to carry out orthomutation of santalene synthase were also discussed, to provide reference for the optimal biosynthesis of santalene and santalol.


Polynomials to model the growth of young bulls in performance tests.
The use of polynomial functions to describe the average growth trajectory and covariance functions of Nellore and MA (21/32 Charolais+11/32 Nellore) young bulls in performance tests was studied. The average growth trajectories and additive genetic and permanent environmental covariance functions were fit with Legendre (linear through quintic) and quadratic B-spline (with two to four intervals) polynomials. In general, the Legendre and quadratic B-spline models that included more covariance parameters provided a better fit with the data. When comparing models with the same number of parameters, the quadratic B-spline provided a better fit than the Legendre polynomials. The quadratic B-spline with four intervals provided the best fit for the Nellore and MA groups. The fitting of random regression models with different types of polynomials (Legendre polynomials or B-spline) affected neither the genetic parameters estimates nor the ranking of the Nellore young bulls. However, fitting different type of polynomials affected the genetic parameters estimates and the ranking of the MA young bulls. Parsimonious Legendre or quadratic B-spline models could be used for genetic evaluation of body weight of Nellore young bulls in performance tests, whereas these parsimonious models were less efficient for animals of the MA genetic group owing to limited data at the extreme ages.


[Two new Ctenophthalmus (Insecta: Siphonaptera: Ctenophthalmidae) from Tanzania].
During a recent epidemiological study of Lushoto plague focus, some uncommon specimens of fleas or even totally new species were collected. In this paper, we describe one of those, Ctenophthalmus (Ethioctenophthalmus) teucqae n. sp. Microscopic observation of comparison specimens deposited at National History Museum (London) allows us to create a sub-species, C. (E.) teucqae shumeensis n. ssp.


Gut instincts: CYP3A4 and intestinal drug metabolism.
First-pass metabolism is a common cause of incomplete and variable absolute bioavailability for an orally dosed drug. The drug-metabolizing enzyme CYP3A4 is often implicated in this process, resulting, in some cases, in systemic exposures of less than 15% of the administered dose. By creating an elegant CYP3A4-transgenic mouse model, van Herwaarden et al. show in this issue of the JCI that first-pass metabolism of the anticancer agent docetaxel by the gut wall, and not the liver, is likely to be the major cause of its low oral bioavailability in humans (see the related article beginning on page 3583). This study helps explain interpatient differences in efficacy and safety following oral therapy with approved CYP3A4 substrates and provides a powerful new tool for preclinical predictions of first-pass metabolism for new drugs in development.


Design of Biopharmaceutical Formulations Accelerated by Machine Learning.
In addition to activity, successful biological drugs must exhibit a series of suitable developability properties, which depend on both protein sequence and buffer composition. In the context of this high-dimensional optimization problem, advanced algorithms from the domain of machine learning are highly beneficial in complementing analytical screening and rational design. Here, we propose a Bayesian optimization algorithm to accelerate the design of biopharmaceutical formulations. We demonstrate the power of this approach by identifying the formulation that optimizes the thermal stability of three tandem single-chain Fv variants within 25 experiments, a number which is less than one-third of the experiments that would be required by a classical DoE method and several orders of magnitude smaller compared to detailed experimental analysis of full combinatorial space. We further show the advantage of this method over conventional approaches to efficiently transfer historical information as prior knowledge for the development of new biologics or when new buffer agents are available. Moreover, we highlight the benefit of our technique in engineering multiple biophysical properties by simultaneously optimizing both thermal and interface stabilities. This optimization minimizes the amount of surfactant in the formulation, which is important to decrease the risks associated with corresponding degradation processes. Overall, this method can provide high speed of converging to optimal conditions, the ability to transfer prior knowledge, and the identification of new nonlinear combinations of excipients. We envision that these features can lead to a considerable acceleration in formulation design and to parallelization of operations during drug development.


Is antisocial personality disorder continuous or categorical? A taxometric analysis.
Although the DSM-IV-TR is organized into discrete disorders, the question of whether a given disorder possesses a dimensional or a categorical latent structure is an empirical one that can be examined using taxometric methods. The objective of this study was to ascertain the latent structure of antisocial personality disorder (ASPD). Participants were 1146 male offenders incarcerated in state prisons (n=569), or court-ordered to residential drug treatment (n=577). Participants were interviewed using the Structured Clinical Interview for DSM-IV Axis II Personality Disorders (SCID-II) to assess ASPD symptoms; they also completed the Personality Diagnostic Questionnaire-4 (PDQ-4) ASPD scale. Taxometric analyses were performed to examine whether ASPD is underpinned by a discrete category or a dimensional construct. Multiple taxometric procedures using two different sets of indicators provided no evidence that ASPD has a taxonic latent structure. Instead, the results were far more consistent with the proposition that ASPD exists on a continuum, regardless of whether it is assessed using a structured interview or a self-report measure. Evidence that ASPD is dimensional suggests that it is best studied using continuous measures and that dichotomizing individuals into ASPD versus non-ASPD groups will typically result in decreased statistical power. The findings are also consistent with a multifactorial etiology for ASPD and with recent attempts to conceptualize ASPD within the framework of extant dimensional models of personality.


Cervical vertebral maturation and its relationship to circum-pubertal phases of the dentition in a cohort of Portuguese individuals.
To explore the relationship between individual skeletal maturity as assessed by Cervical Vertebral Maturity method (CVM), circum-pubertal phases of the dentition (early mixed, intermediate mixed, late mixed and early permanent) and chronlogical age in a cohort of Portuguese individuals. This was a retrospective cross-sectional study. The sample comprised 300 Caucasian Portuguese subjects aged 6 to 16 years, (137 boys and 163 girls). All the participants had good quality panoramic and lateral cephalometric radiographs. Subject skeletal maturity was evaluated using the CVM method. Dental age evaluation was determined by using panoramic radiographs and dental casts. Descriptive statistics (absolute and relative frequencies) and percentages were obtained for the prevalence of the CVM stages in the various phases of the dentition and for the different ages for each of males and females. Prepubertal stage 1 (CS1) was predominently observed in the early mixed dentition phase followed by the intermediate mixed dentition phase. While, the CS1 stage was found in all the other phases of tooth development. There was a wide distribution of all CVM stages in the late mixed dentition and early permanent dentition phases. While, the CS3 stage was predominantly present in both the late mixed dentition and in the early permanent dentition phases. Moreover, the chronological age did not seem to be an accurate indicator in differentiating between the pre-pubertal and the pubertal growth spurt stages. Early mixed dentition phase could determine with a high accuracy the prepubertal skeletal maturity stage (CS1), Furthermore, the chronological age did not seem to be an accurate indicator in differentiating between the pre-pubertal and the pubertal growth spurt stages. Key words:Cervical vertebrae, cephalometric, panoramic, tooth calcification, portuguese.


Adaptively Placed Multi-Grid Scene Representation Networks for Large-Scale Data Visualization.
Scene representation networks (SRNs) have been recently proposed for compression and visualization of scientific data. However, state-of-the-art SRNs do not adapt the allocation of available network parameters to the complex features found in scientific data, leading to a loss in reconstruction quality. We address this shortcoming with an adaptively placed multi-grid SRN (APMGSRN) and propose a domain decomposition training and inference technique for accelerated parallel training on multi-GPU systems. We also release an open-source neural volume rendering application that allows plug-and-play rendering with any PyTorch-based SRN. Our proposed APMGSRN architecture uses multiple spatially adaptive feature grids that learn where to be placed within the domain to dynamically allocate more neural network resources where error is high in the volume, improving state-of-the-art reconstruction accuracy of SRNs for scientific data without requiring expensive octree refining, pruning, and traversal like previous adaptive models. In our domain decomposition approach for representing large-scale data, we train an set of APMGSRNs in parallel on separate bricks of the volume to reduce training time while avoiding overhead necessary for an out-of-core solution for volumes too large to fit in GPU memory. After training, the lightweight SRNs are used for realtime neural volume rendering in our open-source renderer, where arbitrary view angles and transfer functions can be explored. A copy of this paper, all code, all models used in our experiments, and all supplemental materials and videos are available at https://github.com/skywolf829/APMGSRN.


Phage therapy: Should bacterial resistance to phages be a concern, even in the long run?
Bacteriophage therapy, the use of viruses that infect bacteria as antimicrobials, has been championed as a promising alternative to conventional antibiotics. Although in the laboratory bacterial resistance against phages arises rapidly, resistance so far has been an only minor problem for the effectiveness of phage therapy. Resistance to antibiotics, however, has become a major issue after decades of extensive use. Should we expect similar problems after long-term use of phages as antimicrobials? Like antibiotics, phages are often noted to be drivers of bacterial evolution. Should we expect phage-treated pathogens to develop a general resistance to phages over time, a resistance against which only, for example, hypothetically co-evolved phages might be infective? Here we argue that the global infection patterns of phages suggest that this is not necessarily a concern as environmental phages often can infect bacteria with which those phages lack any recent co-evolutionary history.


Pain management in older adults: prevention and treatment.
The release of guidelines in 1998 by the American Geriatrics Society on "The Management of Chronic Pain in Older Persons" was a breakthrough in helping to manage pain in this population. Already advances have fostered a need to update recommendations. This article focuses on the treatment strategies available for seniors that are likely to help to fulfill the obligation to relieve pain and suffering in patients. A review was done of the literature using Medline and other search techniques. New pain scales have been developed with seniors in mind and greater testing of older scales in elderly populations have helped to identify measures of pain more suited to frail seniors. Advances in cyclooxygenase inhibition selectivity, alternative medicine, and progress in the identification of nonopioid pain receptors and the development of products to target them are just a few of changes that have altered the way clinicians think about treating pain. The use of hospice in end-of-life palliative care is a valuable resource for clinicians managing pain at that phase in care as well. Tools are available to prevent and treat pain successfully in seniors. Educating clinicians about available assessment tools, techniques and interventions may be the biggest challenge to comforting the older adult in pain.


[Tubulo-interstitial syndrome in children with hemolytic-uremic syndrome].
As many as 53 patients with the hemolyticouremic syndrome in the acute stage were examined and treated as were 29 patients in the long-term observation period (after 12-18 months). The characteristic features of the urinary syndrome in the acute and long-term observation period and the nephrobiopsy data 12-18 months after the hemolyticouremic syndrome point out that the tubulointerstitial component is of paramount importance in the impairment of the kidneys in patients with the hemolyticouremic syndrome.


An evaluation of the Mobin-Uddin umbrella in the prevention of pulmonary thromboembolism.
A vena caval umbrella was implanted in twenty-eight patients for the prevention of recurrent pulmonary embolism. Eighteen of these patients were catastrophically ill at the time of reimplantation. Thirteen patients died after implantation, one from a recurrent pulmonary embolus originating in the vena cava. There have been two additional recurrent nonfatal emboli. Three of the thirteen long-term survivors had significant lower extremity edema. Our experience and that of others indicates that the inferior vena caval umbrella is comparable to other methods of incomplete interruption in terms of effectiveness, morbidity, and mortality. Its unique technical advantage is the simplicity of insertion in severely ill patients in whom abdominal surgery is undesirable.


Nutrition knowledge of adolescents in a family setting in Geelong, Australia.
A family study of nutrition knowledge was carried out in 213 families in the city of Geelong, Victoria, Australia. On average, mothers had the highest number of correct answers [mean 8.0 (S.D. 1.4)] followed by fathers [mean 7.8 (S.D. 1.5)], adolescent girls [mean 6.4 (S.D. 1.8)] and adolescent boys [mean 6.2 (S.D. 1.5)]. A highly significant difference, in the score obtained, was found between parents and adolescents (p < 0.001). On average, the percentage of 'do not know' answers was twice as high among adolescents (26%) as among parents (11%). Negative correlations which ranged from -0.10 for girls to -0.23 for fathers were found between the knowledge score obtained by the subjects and socioeconomic status. Parents' knowledge score was independent of their educational level (p > 0.05). Mothers with TAFE (Technical And Further Education) qualifications obtained the highest score (8.7).


The impact of childhood parental quality on mental health outcomes in older adults.
Parental bonding is cited as a determinant of mental health outcomes in childhood, adolescence and early-mid adulthood. Examination of the long-term impact for older adults is limited. We therefore examine the long-term risk of perceived poor parental bonding on mental health across the lifespan and into early-old age. Participants (N = 1255) were aged 60-64 years of age and drawn from the Australian Life Histories and Health study. Quality of parental bonding was assessed with the Parental Bonding Instrument (PBI). Self-reported history of doctors' mental health diagnoses and current treatment for each participant was recorded. Current depression was assessed with the Centre for Epidemiologic Studies Depression-8 (CESD-8). Due to known gender differences in mental health rates across the lifespan, analyses were stratified by sex. A bi-factor analysis of the PBI in a structural equation framework indicated perceived Poor Parental Quality as a risk for both ever and current depression for both sexes. For males, Over-Protective Fathers were a risk for ever and current depression, whilst overall Poor Parental Quality was a risk for reporting current depression treatment. Whilst a number of the risks associated with current depression and treatment were attenuated when controlling for current mood, parental quality remained a significant risk for having reported a lifetime diagnosis for depression and anxiety for men. Our results extend the existing literature base and demonstrate that mental health risk attributed to poor perceived parental quality continues across the life-course and into early-old age.


In utero surgery for cleft lip/palate: minimizing the "Ripple Effect" of scarring.
Surgical intervention is currently performed on highly selected fetuses with anatomical deformities that have a high mortality or severe morbidity when treated postnatally. In the future, in utero surgical intervention for non-life-threatening disease may become possible as fetal surgery becomes safer for the mother and fetus. Fetal cleft repair is an attractive intervention for plastic surgeons because it affords the potential to provide a scarless repair and correct the primary deformity. Furthermore, scarless fetal lip and palate repairs may prevent the ripple effect of postnatal scarring with its resultant secondary dentoalveolar and midface growth deformities. These potential benefits can dramatically reduce the number of postnatal reconstructive procedures in children with facial clefts. The rationale for a prenatal treatment approach to the patient with cleft lip/palate and the experimental evidence to support in utero intervention are discussed in this article.


The stathmokinetic and morphological response of the hamster respiratory epithelium to intralaryngeal instillations of saline and ferric oxide in saline.
Ferric oxide (Fe2O3) and saline, substances which enhance lung tumor development when intratracheally instilled with certain carcinogens, were studied for their effects on respiratory epithelial cell proliferation in Syrian golden hamsters. Groups of hamsters were given intralaryngeal instillations of 0.2 ml saline or 3 mg Fe2O3 in 0.2 ml saline (Fe2O3-saline) once a week for 5, 10, or 15 weeks; an additional group of hamsters received a single Fe2O3-saline instillation. Epithelial mitotic rates (MR, 6 hr colchicine blockade) for the midtrachea, left intrapulmonary bronchus, and left lung bronchioles were determined 32 hr after the last instillation for each group. No change in the MR was seen at any airway level for any of the saline-treated groups. There was also no change in the MR of the trachea or bronchus for any of the groups treated with Fe2O3-saline. The MR of the bronchioles was increased after 5 instillations of Fe2O3-saline. Fe2O3-saline instillations also caused bronchioloalveolar hyperplasia (BAH) to develop by 5 instillations, but after 10 and 15 treatments BAH was less prominent. These data indicate that intralaryngeal Fe2O3-saline instillations result in focal cell injury followed by proliferation in the distal airways, but multiple long-term treatments produce an adaptive response of the respiratory epithelium.


Atrial selectivity in Na+channel blockade by acute amiodarone.
Na(+) channel blockers are often used to treat atrial fibrillation (AF), but may sometimes cause ventricular contractile dysfunction. However, amiodarone, a multi-channel blocker with Na(+) channel block, causes less contractile dysfunction. In this study, we tested the hypothesis that Na(+) channel block by amiodarone is selective in atrial myocytes (AM) compared with ventricular myocytes (VM). Na(+) currents (INa) were measured using whole-cell patch-clamp technique in isolated rabbit AM and VM. Amiodarone inhibited INa in AM (IC50: 1.8 ± 1.1 μM; n = 8) much more than in VM (40.4 ± 11.9 μM; n = 7, P < 0.01). Amiodarone at 10 μM shifted the steady-state inactivation relationship in AM (-16.2 ± 1.7 mV shift, n = 12) compared with VM (-5.9 ± 0.7 mV shift; n = 13; P < 0.01). For mexiletine, the inhibition of INa and inactivation curve shifts were comparable for AM and VM. The effects of amiodarone and mexiletine on conduction velocity (CV) in Langendorff-perfused rabbit hearts were evaluated using an optical mapping system. The decrease of CV by 3 μM amiodarone was significantly larger in the atrium (-18.9 ± 3.8% change; n = 5) compared with the ventricle (-3.7 ± 3.7%; n = 5; P < 0.01). In contrast, mexiletine reduced CV equally in the atrium and the ventricle. Amiodarone preferentially inhibits INa of AM compared with VM. Atrial selective Na(+) channel block by amiodarone may contribute to treating AF with less effect on ventricular contractility than other Na(+) channel blockers.


Culture of ascitic ovarian cancer cells as a clinically-relevant ex vivo model for the assessment of biological therapies.
There are few in vitro models of human ovarian cancer suitable for the assessment of biological therapies. We have established short-term cultures of ovarian carcinoma cells from ascites, maintained in suspension in ascitic fluid to help preserve the original tumor cell microenvironment. We assessed the effects of a potential biological therapeutic agent, interferon-alpha (IFN alpha), on ovarian cell phenotype. In total, eight cultures were established from seven patients. Quantitative changes in cell surface phenotype were determined by flow cytometry for HLA-ABC, HLA-DR, TAG72, CA125, HMFG1 and HMFG2 antigens. The amount of CA125 antigen shed into the culture media was also assessed. Variations in cell surface phenotype between specimens probably reflected the specific cytokine milieu of the ascites as well as idiotypic differences between tumors. Nevertheless, there were consistent phenotypic responses to IFN alpha, with up-regulation of MHC Class I but down-regulation of the HMFG1 and HMFG2 antigens from the cell surface. The results suggest that this approach may be useful in patient selection and for optimizing biological therapies, as it enables patients' individual tumor responses to exogenous cytokine to be studied against the background of the endogenous cytokine milieu.


Modification of topA in Synechococcus sp. PCC 7942 resulted in mutants capable of growing under low but not high concentration of CO2.
Insertion of a cartridge encoding kanamycin resistance within an open reading frame, ORF839, in the cyanobacterium Synechococcus sp. PCC 7942 resulted in merodiploids bearing both the normal and the modified ORF839, suggesting that its gene product is essential for growth. In the absence of kanamycin the mutants were able to grow like the wild type, but in its presence the mutants grew under 0.015% CO2 in air but not under 5% CO2 in air. ORF839, identified in this study, is highly homologous to topA encoding topoisomerase I in several organisms, but it does not contain the zinc-binding motif identified in the C-terminal region of the enzyme from Escherichia coli.


Neuropathological and neuroradiological spectrum of pediatric malignant gliomas: correlation with outcome.
The diagnostic accuracy and reproducibility for glioma histological diagnosis are suboptimal. To characterize radiological and histological features in pediatric malignant gliomas and to determine whether they had an impact on survival. We retrospectively reviewed a series of 96 pediatric malignant gliomas. All histological samples were blindly and independently reviewed and classified according to World Health Organization 2007 and Sainte-Anne classifications. Radiological features were reviewed independently. Statistical analyses were performed to investigate the relationship between clinical, radiological, and histological features and survival. Cohort median age was 7.8 years; median follow-up was 4.8 years. Tumors involved cerebral hemispheres or basal ganglia in 82% of cases and brainstem in the remaining 18%. After histopathological review, low-grade gliomas and nonglial tumors were excluded (n = 27). The World Health Organization classification was not able to demonstrate differences between groups and patients survival. The Sainte-Anne classification identified a 3-year survival rate difference between the histological subgroups (oligodendroglioma A, oligodendroglioma B, malignant glioneuronal tumors, and glioblastomas; P = .02). The malignant glioneuronal tumor was the only glioma subtype with specific radiological features. Tumor location was significantly associated with 3-year survival rate (P = .005). Meningeal attachment was the only radiological criteria associated with longer survival (P = .02). The Sainte-Anne classification was better able to distinguish pediatric malignant gliomas in terms of survival compared with the World Health Organization classification. In this series, neither of these 2 histological classifications provided a prognostic stratification of the patients.


Safety and efficacy of a feed additive consisting of iron chelate of ethylenediamine for all animal species (Zinpro Animal Nutrition (Europe), Inc.).
Following a request from the European Commission, EFSA was asked to deliver a scientific opinion on the safety and efficacy of iron chelate of ethylenediamine (Iron-EDA-Cl) as a feed additive for all animal species. The EFSA Panel on Additives and Products or Substances used in Animal Feed (FEEDAP) identified several issues related to the data provided concerning the chemical characteristics of the additive. Based on the information provided, the FEEDAP Panel considered unlikely that the additive consists only of iron monochelate of EDA, but of several coexisting (iron) species; therefore, in the absence of adequate experimental data and owing to the uncertainties identified, the Panel cannot conclude on its identity and characterisation. The FEEDAP Panel concludes that the additive is safe for poultry for fattening and reared for laying/breeding, but cannot conclude on the safety for other animal species/categories. The FEEDAP Panel cannot conclude on the safety of the additive for the consumer or the environment. The FEEDAP Panel concludes that handling the additive poses a risk to users by inhalation. The additive should be considered as non-irritant for the skin but irritant for the eyes and skin sensitiser. The FEEDAP Panel cannot conclude on the efficacy of the additive.


Impact of intraoperative MRI on outcomes in epilepsy surgery: preliminary experience of two years.
To determine the impact of intraoperative magnetic resonance imaging (iMRI) in epilepsy surgeries on the extent of surgical resection and seizure outcome along with its feasibility and limitations. Patients with pharmacoresistant epilepsy (PRE), who underwent surgeries in operating theater equipped with high-field 1.5-Tesla MRI, were evaluated for extent of resection, operative time, scanning time, pathologies, resultant extra resection, and seizure outcomes. Thirty-nine patients with mean age of 18 (range: 3-65) years with PRE underwent surgical intervention. Mean duration of epilepsy was 10.2 years. Surgical interventions included tumor resection (31%), resection of focal cortical dysplasia (28%), mesial temporal lobe surgeries (18%), and disconnection surgeries (23%). iMRI alone, apart from navigation and electrophysiology, improved resection rates in 13% (5 out of 39) of these patients. In lesional group, iMRI modified operative strategy resulting in increased resections in 21% (5/23) patients. Complete resection was observed in 87% of patients. iMRI scanning time constituted 25% (mean: 72 ± 21 min) of time spent under anesthesia by the patient. Major and minor complications were observed in 2.5% and 7.5% of patients, respectively. The mean follow-up was 14 months. Favorable postoperative seizure control (Engel Classes I and II) was achieved in 85% and complete seizure freedom was achieved in 77% of patients (Engel Class IA) at 1-year follow-up. iMRI increases the extent of resection mainly in lesional epilepsy surgeries translating into good seizure outcomes but not found to be much beneficial in prototype mesial temporal sclerosis surgeries and disconnection surgeries.


Comparison of histamine and methacholine for use in bronchial challenge tests in community studies.
Measurement of bronchial reactivity is widely used in epidemiological surveys. Histamine has been compared with methacholine inhalation challenge in two samples of adults from a small town to determine which is the better agent for use in community studies. Increasing doses of histamine and methacholine were given, up to a maximum of 4 and 12 mumol respectively, according to the method of Yan et al, the provocative dose of agonist causing a 20% fall in FEV1 (PD20) being measured. More subjects had a measurable PD20 with methacholine than with histamine, both in a random sample of 108 subjects (25 v 11 subjects, p less than 0.01) and in an additional 95 subjects selected because of wheeze in the last 12 months (67 v 48 subjects, p less than 0.01). Side effects were mild with both agents but histamine caused voice change in more subjects (21% v 11%). Repeatability was assessed in a further group of subjects with wheeze in the last year. The 95% range for a single estimation of PD20 in subjects with a measured PD20 on at least one occasion was +/- 2.5 doubling doses for histamine (n = 25) and +/- 2.1 doubling doses for methacholine (n = 33). Thus methacholine has advantages over histamine for community studies of bronchial reactivity as it is possible to use doses that produce more PD20 measurements with fewer side effects.


Cholesterol-lowering effect of garlic extracts and organosulfur compounds: human and animal studies.
The medicinal use of garlic dates back thousands of years, but there was little scientific support of its therapeutic and pharmacologic properties until recently. In the past decade, the cancer-protective effects of garlic have been well established by epidemiologic studies and animal experiments. However, the cardiovascular-protective properties of garlic are less well understood. In particular, despite the reported hypocholesterolemic effect of garlic, the mechanism of the effect is unclear. In a recent randomized, double-blind, placebo-controlled intervention study, we showed that aged garlic extract (AGE) supplementation was effective in lowering plasma concentration of total cholesterol by 7% and LDL cholesterol by 10% in hypercholesterolemic men compared with subjects consuming a placebo. Supplementation of AGE in animal diets similarly reduced plasma concentrations of total cholesterol and triacylglycerol by 15 and 30%, respectively. In subsequent experiments using cultured rat hepatocytes, we found 44--87% inhibition of cholesterol synthesis by the water-extractable fraction (WEF), methanol-extractable fraction (MEF) and petroleum ether-extractable fraction (PEF) of fresh garlic, and Kyolic (liquid form of AGE). These observations suggested that hydrophilic and hydrophobic compounds of garlic are inhibitory to cholesterol synthesis. Because S-allylcysteine (SAC) alone was less potent than Kyolic, which contains SAC and other sulfur compounds, a maximal inhibition appears to require a concerted action of multiple compounds of garlic. In a series of experiments, we further characterized the inhibitory potency of individual water-soluble and lipid-soluble compounds of garlic. Among water-soluble compounds, SAC, S-ethylcysteine (SEC), and S-propylcysteine (SPC) inhibited cholesterol synthesis by 40--60% compared with 20--35% by gamma-glutamyl-S-allylcysteine (GSAC), gamma-glutamyl-S-methylcysteine (GSMC) and gamma-glutamyl-S-propylcysteine (GSPC). Lipid-soluble sulfur compounds (i.e., diallyl sulfide, diallyl disulfide, diallyl trisulfide, dipropyl sulfide and dipropyl trisulfide) at low concentrations (0.05--0.5 mol/L) slightly (10--15%) inhibited cholesterol synthesis but became highly cytotoxic at high concentrations (1.0--4.0 mol/L). All water-soluble compounds, except S-allylmercaptocysteine, were not cytotoxic, judging from the release of cellular lactate dehydrogenase into the culture medium. Taken together, the results of our studies indicate that the cholesterol-lowering effects of garlic extract, such as AGE, stem in part from inhibition of hepatic cholesterol synthesis by water-soluble sulfur compounds, especially SAC.


Acquired hyperexcitable peripheral nerve disorders: Clinical and laboratory features, therapeutic responses, and long-term follow-up.
Hyperexcitable peripheral nerve disorders (HPNDs) are rare. Although their clinical and laboratory features have been well studied, information on treatment and follow-up is limited. The aim of this study is to explore the long-term clinical, investigative, and therapeutic profile of patients with acquired HPNDs. This study retrospectively analyzed patients from a single tertiary care center with HPND (January 2012 to January 2022). Patients were recruited according to published inclusion and exclusion criteria. Details of clinical features, diagnostic tests, therapeutic interventions, and follow-up were recorded. This study included patients with follow-up of 2 or more years. A total of 32 patients (M = 26, F = 6) were studied. The common clinical features included myokymia, neuropathic or shock-like pain, cramps, sleep disturbances, encephalopathy, cerebellar ataxia, and seizures. A total of 81.25% of patients responded favorably to corticosteroids and membrane stabilizers. Among the nonresponders, five received intravenous immunoglobulin (IVIG), and one received plasma exchange (PLEX). Two patients required rituximab due to poor responses to the above treatments. The mean duration of response was 6 weeks (4-24 weeks) from the initiation of treatment. All patients had favorable outcomes, reaching clinical remission within 1-5 years from the initiation of treatment. Only two patients had relapses. Immunotherapy could be stopped in 78% of patients within 3 years and 100% by 5 years. Chronic immunosuppression starting with corticosteroids is required for satisfactory outcomes of HPNDs. These disorders usually run a monophasic course, and relapses are uncommon.


Extensive syncytium formation mediated by the reovirus FAST proteins triggers apoptosis-induced membrane instability.
The fusion-associated small transmembrane (FAST) proteins of the fusogenic reoviruses are the only known examples of membrane fusion proteins encoded by non-enveloped viruses. While the involvement of the FAST proteins in mediating extensive syncytium formation in virus-infected and -transfected cells is well established, the nature of the fusion reaction and the role of cell-cell fusion in the virus replication cycle remain unclear. To address these issues, we analyzed the syncytial phenotype induced by four different FAST proteins: the avian and Nelson Bay reovirus p10, reptilian reovirus p14, and baboon reovirus p15 FAST proteins. Results indicate that FAST protein-mediated cell-cell fusion is a relatively non-leaky process, as demonstrated by the absence of significant [3H]uridine release from cells undergoing fusion and by the resistance of these cells to treatment with hygromycin B, a membrane-impermeable translation inhibitor. However, diminished membrane integrity occurred subsequent to extensive syncytium formation and was associated with DNA fragmentation and chromatin condensation, indicating that extensive cell-cell fusion activates apoptotic signaling cascades. Inhibiting effector caspase activation or ablating the extent of syncytium formation, either by partial deletion of the avian reovirus p10 ecto-domain or by antibody inhibition of p14-mediated cell-cell fusion, all resulted in reduced membrane permeability changes. These observations suggest that the FAST proteins do not possess intrinsic membrane-lytic activity. Rather, extensive FAST protein-induced syncytium formation triggers an apoptotic response that contributes to altered membrane integrity. We propose that the FAST proteins have evolved to serve a dual role in the replication cycle of these fusogenic non-enveloped viruses, with non-leaky cell-cell fusion initially promoting localized cell-cell transmission of the infection followed by enhanced progeny virus release from apoptotic syncytia and systemic dissemination of the infection.


Reassessment of the Upper Fremont Glacier Ice-Core Chronologies by Synchronizing of Ice-Core-Water Isotopes to a Nearby Tree-Ring Chronology.
The Upper Fremont Glacier (UFG), Wyoming, is one of the few continental glaciers in the contiguous United States known to preserve environmental and climate records spanning recent centuries. A pair of ice cores taken from UFG have been studied extensively to document changes in climate and industrial pollution (most notably, mid-19th century increases in mercury pollution). Fundamental to these studies is the chronology used to map ice-core depth to age. Here, we present a revised chronology for the UFG ice cores based on new measurements and using a novel dating approach of synchronizing continuous water isotope measurements to a nearby tree-ring chronology. While consistent with the few unambiguous age controls underpinning the previous UFG chronologies, the new interpretation suggests a very different time scale for the UFG cores with changes of up to 80 years. Mercury increases previously associated with the mid-19th century Gold Rush now coincide with early-20th century industrial emissions, aligning the UFG record with other North American mercury records from ice and lake sediment cores. Additionally, new UFG records of industrial pollutants parallel changes documented in ice cores from southern Greenland, further validating the new UFG chronologies while documenting the extent of late 19th and early 20th century pollution in remote North America.


NF1 regulatory element functions as a repressor of tissue plasminogen activator expression.
Analysis of the distribution of endothelial cell tissue plasminogen activator (tPA) in the vasculature of rodents and primates demonstrated that tPA is constitutively expressed predominantly in small artery endothelial cells of brain and lung. The regulatory elements responsible for the highly selective expression of arterial endothelial cell tissue plasminogen activator were sought. Transcription factor binding sites were defined by electrophoretic mobility-shift assay (EMSA) analysis using rat lung and brain nuclear extracts and the tPA promoter sequence from -609 to +37 bp. Protein binding to the promoter was found to be mediated by an NF1 site between -158 and -145 bp upstream from the transcriptional start site. Specific binding was confirmed through mutational analysis and competition binding studies. Infection of endothelial cells with a tPA promoter-green fluorescent protein (GFP) (-609 to +37 bp) reporter construct resulted in expression of the GFP, whereas no expression was found in smooth muscle cells. Mutation of the NF1 site increased the GFP expression indicating that the element acts as a repressor. These results suggest that the 600 bp of the tPA promoter upstream of the transcription start site conveys cell specificity to tPA expression and that an NF1 site within this region acts as a repressor.


Transjugular intrahepatic portosystemic shunt for the treatment of portal hypertension in noncirrhotic patients with portal cavernoma.
Background. The purpose of this study was to evaluate the safety and efficacy of transjugular intrahepatic portosystemic shunt (TIPS) placement in the management of portal hypertension in noncirrhotic patients with portal cavernoma. Methods. We conducted a single institution retrospective analysis of 15 noncirrhotic patients with portal cavernoma treated with TIPS placement. 15 patients (4 women and 11 men) were evaluated via the technical success of TIPS placement, procedural complications, and follow-up shunt patency. Results. TIPS placement was technically successful in 11 out of 15 patients (73.3%). Procedure-related complications were limited to a single instance of hepatic encephalopathy in one patient. In patients with successful shunt placement, the portal pressure gradient decreased from 25.8 ± 5.7 to 9.5 ± 4.2 mmHg (P < 0.001). TIPS dysfunction occurred in two patients during a median follow-up time of 45.2 months. Revision was not performed in one patient due to inadequate inflow. The other patient died of massive gastrointestinal bleeding in a local hospital. The remaining nine patients maintained functioning shunts through their last evaluation. Conclusions. TIPS is a safe and effective therapeutic treatment for noncirrhotic patients with symptomatic portal hypertension secondary to portal cavernoma.


Upper extremity kinematics: development of a quantitative measure of impairment severity and dissimilarity after stroke.
Strokes are a leading cause of disability worldwide, with many survivors experiencing difficulty in recovering upper extremity movement, particularly hand function and grasping ability. There is currently no objective measure of movement quality, and without it, rehabilitative interventions remain at best informed estimations of the underlying neural structures' response to produce movement. In this article, we utilize a novel modification to Procrustean distance to quantify curve dissimilarity and propose the Reach Severity and Dissimilarity Index (RSDI) as an objective measure of motor deficits. All experiments took place at the Medstar National Rehabilitation Hospital; persons with stroke were recruited from the hospital patient population. Using Fugl-Meyer (FM) scores and reach capacities, stroke survivors were placed in either mild or severe impairment groups. Individuals completed sets of reach-to-target tasks to extrapolate kinematic metrics describing motor performance. The Procrustes method of statistical shape analysis was modified to identify reaching sub-movements that were congruous to able-bodied sub-movements. Movement initiation proceeds comparably to the reference curve in both two- and three-dimensional representations of mild impairment movement. There were significant effects of the location of congruent segments between subject and reference curves, mean velocities, peak roll angle, and target error. These metrics were used to calculate a preliminary RSDI score with severity and dissimilarity sub-scores, and subjects were reclassified in terms of rehabilitation goals as Speed Emphasis, Strength Emphasis, and Combined Emphasis. The modified Procrustes method shows promise in identifying disruptions in movement and monitoring recovery without adding to patient or clinician burden. The proposed RSDI score can be adapted and expanded to other functional movements and used as an objective clinical tool. By reducing the impact of stroke on disability, there is a significant potential to improve quality of life through individualized rehabilitation.


Quantification of tumour evolution and heterogeneity via Bayesian epiallele detection.
Epigenetic heterogeneity within a tumour can play an important role in tumour evolution and the emergence of resistance to treatment. It is increasingly recognised that the study of DNA methylation (DNAm) patterns along the genome - so-called 'epialleles' - offers greater insight into epigenetic dynamics than conventional analyses which examine DNAm marks individually. We have developed a Bayesian model to infer which epialleles are present in multiple regions of the same tumour. We apply our method to reduced representation bisulfite sequencing (RRBS) data from multiple regions of one lung cancer tumour and a matched normal sample. The model borrows information from all tumour regions to leverage greater statistical power. The total number of epialleles, the epiallele DNAm patterns, and a noise hyperparameter are all automatically inferred from the data. Uncertainty as to which epiallele an observed sequencing read originated from is explicitly incorporated by marginalising over the appropriate posterior densities. The degree to which tumour samples are contaminated with normal tissue can be estimated and corrected for. By tracing the distribution of epialleles throughout the tumour we can infer the phylogenetic history of the tumour, identify epialleles that differ between normal and cancer tissue, and define a measure of global epigenetic disorder. Detection and comparison of epialleles within multiple tumour regions enables phylogenetic analyses, identification of differentially expressed epialleles, and provides a measure of epigenetic heterogeneity. R code is available at github.com/james-e-barrett.


Nonlinear properties of stretch reflex studied in the decerebrate cat.
1. Pairs of brief stretches or a series of stretches at random intervals (Poisson process) were applied to a slow (soleus) and a fast (plantaris) muscle in decerebrate cats to analyze the nonlinear effects of one stretch on the reflex responses to subsequent stretches. Neural activity, electromyogram (EMG), and force were recorded. The reflex responses due to stretch were compared with reflexes as a result of electrical stimulation of nerves. Nonlinearities of muscle were also examined in the absence of reflexes. Short-latency neural activity produced by the stimuli at all intervals studied was quite constant, so changes in sensory activity cannot account for the nonlinearities. Three phases of nonlinear interactions were observed, and mechanisms for these nonlinearities are suggested. 2. For short intervals (less than 100 ms) following a stretch the force and EMG produced by a second stretch is depressed. This early depression could be due to the after hyperpolarization of the motoneuron cel body or to synaptic mechanisms, since the depression of EMG is seen with electrical stimulation of Ia sensory, but not alpha-motor axons. In addition, a second stretch can disrupt the reflex contraction produced by the first stretch if it occurs at a time when new actomyosin bonds are not readily formed. Because of this force suppression, the total reflex force produced in response to two stretches may be less than the response to a single stretch. 3. For intervals between 100 and 300 ms the force and EMG produced by a second stretch is enhanced. This potentiation is also seen with electrical stimulation of large sensory but not motor axons and could result from a synchronization of motoneuronal excitability cycles. It is more prominent in the homogeneous (soleus) muscle than the mixed (plantaris) muscle, probably because the motoneuron cell bodies will reach a period of high excitability at more nearly the same time in the homogeneous muscle. 4. For longer intervals the force produced by a second stretch is reduced even when the EMG is close to control values. This late depression is also observed with electrical stimulation of cut motor axons and therefore arises from the contractile properties of muscles. 5. With a random series of stretches, the same time course of nonlinear interactions is observed. However, as the mean rate of the random stretches is increased, the average response of the reflex decreases. Thus, the stretch reflex will be most effective in correcting for occasional perturbations to a movement, rather than for continuously varying disturbances.


[Lipid peroxidation in the rat liver following skeletal injury].
We assessed the concentrations of the products of lipid peroxidation (conjugated dienes--CD, malone dialdegide--MDA), the activity of catalase and the total lipids in the rat liver following tibial fractures. The experiment was carried out using sixty adult male Wistar rats. In group 1 (n = 30), tibial fractures were modeled and fixed with the apparatus of external fixation. In control group 2 (n = 30), the external apparatus was applied to the tibias but the fractures were not modeled. In group 1 animals, the absolute concentrations of CD and MDA were statistically reduced at each time-point studied. The concentration of CD in group 2 was significantly lower on day 3 while the level of MDA up to day 14 of the experiment than in the intact rats. The level of total lipids on days 3 and 7 was decreased in group 1 while in group 2 it was lower than the intact values on days 3 through 14. The catalase activity in group 1 was statistically elevated from day 7 of the experiment as compared to the intact rats. No significant changes in the activity of catalase were found in group 2 at all time-points of the experiment.


Heterogeneity of glycine receptors and their messenger RNAs in rat brain and spinal cord.
Messenger RNAs isolated from adult or newborn rat spinal cord were fractionated in a sucrose gradient. The fractions were injected into Xenopus oocytes to determine their potencies for expression of glycine receptors (GlyRs), which were then examined electrophysiologically. The sedimentation profiles disclosed two classes of GlyR mRNAs, one heavy and the other light. The adult spinal cord was rich in heavy GlyR mRNA, whereas the light GlyR mRNA was more abundant in neonatal spinal cord and in adult cerebral cortex. Glycine receptors encoded by heavy and light mRNAs of adult spinal cord showed some electrophysiological differences. Thus there are two types of GlyRs encoded by mRNAs of different sizes, and the expression of these mRNAs is developmentally regulated. A tissue- and age-dependent distribution of heterogeneous GlyR mRNAs may imply diverse roles of the GlyRs in neuronal function in the central nervous system.


Dopaminergic control of striatal 5-HT level at normobaric condition and at pressure.
High pressure of helium-oxygen (He-O2) increases the extracellular levels in both serotonine and dopamine in the rat striatum. Some motor symptoms evoked by high pressure (i.e., LMA) are known to be reduced by intrastriatal infusions of D1-like (SCH23390, 1 microM) or D2-like (Sulpiride, 1 microM) dopaminergic antagonists. Other studies have also reported that serotoninergic antagonists reduce the motor perturbation at pressure. However, it remains unknown whether the changes in serotoninergic neurotransmission may contribute to the beneficial effects of intrastriatal administration of a dopaminergic antagonist. The present study reports the effects of SCH23390 and sulpiride on serotonin levels in the striatum of rats exposed to 8 MPa of He-O2. Both sulpiride and SCH23390 reduced pressure-induced striatal 5-HT increase. Our data suggest that D1-like and D2-like receptors have similar effects on a pressure-evoked striatal 5-HT increase. Thus, reduction in serotoninergic neurotransmission may be one mechanism by which dopaminergic antagonists reduce motor symptoms at pressure.


Short cut of protein purification by integration of cell-disrupture and affinity extraction.
Screening strategies based on functional genomics require the isolation of gene products of several hundred cDNA clones in a fast and versatile manner. Conventional purification strategies will fail to accomplish this goal within a reasonable time frame. In order to short-cut these procedures, we have developed a combination of cell disintegration and affinity technique for rapid isolation and purification. For our purpose, tagged proteins have been produced in yeast by fusing the FLAG-sequence adjacent to the 5' end of cDNAs coding for the respective protein. The example of an over-expressed FLAG-tagged fusion protein, human serum albumin (HSA), was released into the cytoplasm. Detection and purification of the FLAG-fusion protein were carried out by using a mouse monoclonal antibody directed against the FLAG-peptide. For purification purposes, the antibody was immobilized on PROSEP magnetic glass beads. These magnetic glass beads with 500 microns diameter have been investigated for disintegration of yeast and simultaneous capturing of the target protein. After 60 s, 90% of the maximal disintegration level was achieved when a ratio of 20 microliters yeast cell suspension and 100 microliters glass are vortexed. After a wash step, the FLAG-fusion proteins have been eluted with chelating agents such as EDTA. The short-cut procedure has been compared to a conventional purification strategy using an affinity chromatography process. Due to the highly favorable binding characteristics of the applied immunoaffinity sorbent the yield observed in batch operation was 90% and purity in the range of 70-80%.


Troponin I Tyrosine Phosphorylation Beneficially Accelerates Diastolic Function.
A healthy heart is able to modify its function and increase relaxation through posttranslational modifications of myofilament proteins. While there are known examples of serine/threonine kinases directly phosphorylating myofilament proteins to modify heart function, the roles of tyrosine (Y) phosphorylation to directly modify heart function have not been demonstrated. The myofilament protein TnI (troponin I) is the inhibitory subunit of the troponin complex and is a key regulator of cardiac contraction and relaxation. We previously demonstrated that TnI-Y26 phosphorylation decreases calcium-sensitive force development and accelerates calcium dissociation, suggesting a novel role for tyrosine kinase-mediated TnI-Y26 phosphorylation to regulate cardiac relaxation. Therefore, we hypothesize that increasing TnI-Y26 phosphorylation will increase cardiac relaxation in vivo and be beneficial during pathological diastolic dysfunction. The signaling pathway involved in TnI-Y26 phosphorylation was predicted in silico and validated by tyrosine kinase activation and inhibition in primary adult murine cardiomyocytes. To investigate how TnI-Y26 phosphorylation affects cardiac muscle, structure, and function in vivo, we developed a novel TnI-Y26 phosphorylation-mimetic mouse that was subjected to echocardiography, pressure-volume loop hemodynamics, and myofibril mechanical studies. TnI-Y26 phosphorylation-mimetic mice were further subjected to the nephrectomy/deoxycorticosterone acetate model of diastolic dysfunction to investigate the effects of increased TnI-Y26 phosphorylation in disease. Src tyrosine kinase is sufficient to phosphorylate TnI-Y26 in cardiomyocytes. TnI-Y26 phosphorylation accelerates in vivo relaxation without detrimental structural or systolic impairment. In a mouse model of diastolic dysfunction, TnI-Y26 phosphorylation is beneficial and protects against the development of disease. We have demonstrated that tyrosine kinase phosphorylation of TnI is a novel mechanism to directly and beneficially accelerate myocardial relaxation in vivo.


Mesenchymal tumours of the pleura: review and update.
Primary mesenchymal tumours of the pleura are uncommon and can be diagnostically challenging due to their overlapping histopathologic and immunophenotypic features. Herein we discuss selected mesenchymal tumours of the pleura, including solitary fibrous tumour, calcifying fibrous tumour, desmoid fibromatosis, synovial sarcoma, schwannoma, malignant peripheral nerve sheath tumour, inflammatory myofibroblastic tumour, follicular dendritic cell sarcoma, epithelioid hemangioendothelioma, and desmoplastic small round cell tumour. We review their clinicopathologic characteristics, along with an update on the relevant immunohistochemical and molecular features.


Neutrophil-to-lymphocyte ratio in chronic obstructive pulmonary disease: a retrospective study.
Chronic obstructive pulmonary disease (COPD) is a common chronic inflammatory disease of the lung with a high mortality and morbidity rate. Some of the inflammatory markers such as C-reactive protein (CRP), leukocyte count are associated with COPD. In this study, we aimed to evaluate the role of neutrophil-to-lymphocyte ratio (NLR) in COPD patients comparing with the other well-known inflammatory markers. We retrospectively enrolled the laboratory results of 269 COPD patients of which 178 patients at stable period and 91 patients during acute exacerbation and 50 sex- and age- matched healthy controls. We found that NLR values of the stable COPD patients were significantly higher than those of the controls (P < 0.001). During acute exacerbation of the disease there was a further increase compared to stable period (P < 0.001). NLR values were also positively correlated with serum CRP levels and red cell distribution width (RDW) and negatively correlated with mean platelet volume (MPV) in both COPD groups. In conclusion, NLR could be considered as a new inflammatory marker for assessment of inflammation in COPD patients with its quick, cheap, easily measurable property with routine complete blood count analysis.


Short pulse generation using a passively mode locked single InGaAsP/InP quantum well laser.
We report on subpicosecond pulse generation using passively mode locked lasers (MLL) based on a low optical confinement single InGaAsP/InP quantum well active layer grown in one epitaxial step. Systematic investigation of the performances of two-section MLLs emitting at 1.54 microm evidenced pulse width of 860 fs at 21.31 GHz repetition rate, peak power of approximately 500 mW and a time-bandwith product of 0.57. A 30 kHz linewidth of the photodetected radio-frequency electrical spectrum is further demonstrated at 21 GHz which is, to our knowledge, the lowest value ever reported for a quantum well device.


Molecular karyotypes for Alternaria plant pathogens known to produce host-specific toxins.
There are at least ten plant diseases caused by Alternaria species in which host-specific toxins (HSTs) are responsible for fungal pathogenicity. Of these HST-producers, seven are considered distinct pathotypes of the species Alternaria alternata, and the remaining three are among other species of pathogenic Alternaria. Inter- and intra-specific variation among Alternaria taxa, including HST-producers, was determined by electrophoretic karyotyping using pulsed-field gel electrophoresis. A. alternata including seven pathotypes of A. alternata and eight non-pathogenic strains had 9-11 chromosomal bands with estimated sizes ranging from 0.4 to 5.7 Mb. In contrast, Alternaria species that are morphologically distinct from A. alternata had 8-10 bands with sizes between 0.9 and 5.7 Mb. Estimated genome sizes of A. alternata and other Alternaria species ranged from 28.8 to 33.6 Mb and 25.1 to 30.7 Mb, respectively. Other species of pathogenic Alternaria were difficult to differentiate from A. alternata on the basis of chromosome-size polymorphisms alone, but Southern analysis using rDNA as a probe could, in some cases, differentiate between them. These results were cytologically confirmed by 4',6-diamidino-2-phenylindole (DAPI) staining and fluorescence in situ hybridization with a rDNA probe for mitotic metaphase chromosomes prepared by the germ-tube burst method.


Reactive oxygen species stimulate VEGF production from C(2)C(12) skeletal myotubes through a PI3K/Akt pathway.
Vascular endothelial growth factor (VEGF) is a potent angiogenic stimulus, the expression of which increases in skeletal muscle after exercise. Because exercise is also accompanied by increased intramuscular reactive oxygen species (ROS) generation, we tested the hypothesis that ROS stimulate VEGF production from skeletal myotubes. Differentiated C(2)C(12) skeletal myotubes exposed to ROS-producing agents exhibited a concentration-dependent increase in VEGF production, whereas undifferentiated myoblasts did not respond to oxidants. Moreover, conditioned medium from ROS-treated myotubes increased the bovine lung microvascular cell proliferation rate. To study the mechanism(s) involved in the stimulation of VEGF production by ROS, myotubes were pretreated with a selective phosphatidylinositol 3-kinase (PI3K) inhibitor, LY-294002, before being exposed to hydrogen peroxide or pyrogallol. LY-294002 attenuated both Akt phosphorylation and VEGF production. In addition, oxidants increased nuclear factor-kappaB-dependent promoter activity in transiently transfected myotubes; however, pretreatment with the pharmacological inhibitor of nuclear factor-kappaB, diethyldithiocarbamate, did not affect the oxidant-stimulated VEGF release. We conclude that ROS induce VEGF release from myotubes via a PI3K/Akt-dependent pathway.


What lies beneath: a retrospective, population-based cohort study investigating clinical and resource-use characteristics of institutionalized older people in Catalonia.
Planning population care in a specific health care setting requires deep knowledge of the clinical characteristics of the target care recipients, which tend to be country specific. Our area virtually lacks any descriptive, far-reaching publications about institutionalized older people (IOP). We aimed to investigate the demographic and clinical characteristics of institutionalized older people (IOP) ≥65 years old and compare them with those of the rest of the population of the same age. Retrospective analysis (total cohort approach) of clinical and resource-use characteristics of IOP and non-IOP older than 65 years in Catalonia (North-East Spain). Variables analysed included age and sex, diagnoses, morbidity burden-using Adjusted Morbidity Groups (GMA, Grupos de Morbilidad Ajustada)-, mortality, use of resources, and medications taken. All data were obtained from the administrative database of the local healthcare system. This study included 93,038, 78,458, 68,545 and 67,456 IOP from 2011, 2013, 2015 and 2017, respectively. In this interval, an increase in median age (83 vs. 87 years), in women (68.64% vs. 72.11%) and in annual mortality (11.74% vs. 20.46%) was observed. Compared with non-IOP (p < 0.001 in all comparisons), IOP showed a higher annual mortality (20.46% vs. 3.13%), a larger number of chronic diseases (specially dementia: 46.47% vs. 4.58%), higher multimorbidity (15.2% vs. 4.2% with GMA of maximum complexity), and annual admissions to acute care (47.6% vs. 27.7%) and skilled nursing facilities (27.8% vs. 7.4%), mean length of hospital stay (10.0 vs. 7.2 days) and mean of medications taken (11.7 vs. 8.0). There is a growing gap between the clinical and demographic characteristics of age-matched IOP and non-IOP, which overlaps with a higher mortality rate of IOP. The profile of resources utilization of IOP compared with non-IOP strongly suggests a deficiency of preventive actions and stresses the need to rethink the care model for IOP from a social and health care perspective.


An open-label pilot study of the use of rivastigmine to promote functional recovery in patients with unilateral spatial neglect due to first ischemic stroke.
The aim of this study was to evaluate the efficacy and safety of rivastigmine as add-on treatment to specific cognitive rehabilitation for unilateral spatial neglect (USN). Twenty patients were randomly assigned either to rehabilitation treatment only (No-RIV) or to rivastigmine (3 mg twice a day, for 8 weeks) add-on treatment (RIV+,). USN and functional status were evaluated by means of specific and validated instruments at baseline, at discharge and at one-month follow up. Compared with the untreated patients, the RIV+ subjects, at discharge, recorded significantly better discharge scores and higher effectiveness on two of the scales. However, subsequent further improvement of the No-RIV patients meant that at follow up there was no significant difference between the two groups. No other statistically significant difference was found. Rivastigmine as add-on treatment to specific cognitive training for USN may improve and accelerate recovery on some specific impairment tests as compared with cognitive training alone.


Evidence-based medicine in migraine prevention.
Migraine headache is a chronic, painful, disabling and potentially progressive, condition primarily occurring in early and middle adulthood. For many patients, daily activities are impaired by the sudden and unpredictable occurrence of migraine attacks. In recent years, significant progress has been made in the field of migraine treatment. For the acute treatment of migraine attacks, 5-hydroxytryptophan(1B/D) agonists (so called triptans), were the most innovative development, successfully aborting attacks in less than 1 h. The search for innovative drugs usable for migraine prevention, however, was less successful, mainly due to the lack of reliable and predictive animal models. Recently, neuromodulators such as valproic acid and topiramate, initially developed as anticonvulsants, have been shown in large clinical trials to be effective in the prevention of migraine. As for the acute treatment of migraine attacks more than 10 years ago, large clinical trial programs are now setting new standards for evidence-based medicine in migraine prevention. This review summarizes the current options in migraine prevention with special emphasis on clinical trial design and new developments such as topiramate.


A generalized "cut and projection" algorithm for the generation of quasiperiodic plasmonic concentrators for high efficiency ultra-thin film photovoltaics.
This report will present a generalized two-dimensional quasiperiodic (QP) tiling algorithm based on de Bruijn's "cut and projection" method for use in plasmonic concentrator (PC) / photovoltaic hybrid devices to produce wide-angle, polarization-insensitive, and broadband light absorption enhancement. This algorithm can be employed with any PC consisting of point-like scattering objects, and can be fine-tuned to achieve a high spatial density of points and high orders of local and long-range rotational symmetry. Simulations and experimental data demonstrate this enhancement in ultra-thin layers of organic photovoltaic materials resting on metallic films etched with arrays of shallow sub-wavelength nanoholes. These devices work by coupling the incident light to surface plasmon polariton (SPP) modes that propagate along the dielectric / metal interface. This effectively increases the scale of light-matter interaction, and can also result in constructive interference between propagating SPP waves. By comparing PCs made with random, periodic, and QP arrangements, it is clear that QP is superior in intensifying the local fields and enhancing absorption in the active layer.