Catheter ablation of bundle branch reentrant ventricular tachycardia.
Bundle branch reentrant ventricular tachycardia (BBR-VT) is a form of macroreentrant tachycardia involving the bundle of His, both bundle branches, and the ventricular myocardium in the circuit. It generally occurs in the background of dilated cardiomyopathy, prior valve surgery, or other cardiac disease with an underlying His-Purkinje system (HPS) disease. Clinically, BBR-VT usually results in marked hemodynamic compromise and often presents with syncope, presyncope, or sudden cardiac arrest. When a ventricular tachycardia is induced, the presence of His deflections preceding every ventricular deflection should alert one to the possibility of this entity. It is important to show that oscillations in the H-H cycle length results in variations in V-V cycle length. Entrainment of the tachycardia from atrium and right ventricular apex and characteristics of postpacing intervals can be used to differentiate this arrhythmia from intramyocardial reentry and supraventricular tachycardia with aberrancy. Right bundle branch ablation usually cures the tachycardia, and recurrence is uncommon. The underlying cardiac disease and ventricular dysfunction dictate the prognosis and choice of device therapy in these patients.


Characterization of olfactory receptor repertoires provides insights into the high-altitude adaptation of the yak based on the chromosome-level genome.
Olfaction in vertebrates plays pivotal parts in many aspects, such as localizing prey or food, mating behavior, avoiding predators, and social communication. Yak (Bos grunniens) is the only Bos species that can thrive in high-altitude areas. In view of the critical role of olfactory receptors (ORs) in the specific recognition of diverse stimuli, investigating the evolutionary dynamics of ORs in the yak means a lot. In this study, we used the chromosome-level genome of the yak to identify the ORs genes and discussed the effects of high altitude on the yak's olfaction by comparing the yak with other low-altitude living Bos species (Bos frontalis (gayal), Bos gaurus (gaur), Bos indicus (zebu) and Bos taurus (cattle)). The yak had 400 OR genes, including 264 functional genes, 16 partial genes and 120 OR pseudo genes. There were 387 OR genes mapped to yak 31 chromosomes, and chromosomes 13 and 8 had the most OR genes and functional OR genes. Among these five Bos species, yak had the least number of OR gene subfamilies, OR genes and functional OR genes, while the total number of OR genes in gayal (n = 784) was almost twice as many as that of yak, indicating that the olfaction of yak may be less developed. In addition, the phylogenetic relationships of the functional Bos OR genes were illustrated, which comprised 79 families and 466 subfamilies distributed in two classes (Class I and Class II). There were 76 OR gene subfamilies shared by these five Bos species and 17 OR gene subfamilies were unique to the yak. The potential odor specificity of 44 yak OR genes was identified through the similarity to human OR protein sequences. Remarkably, yak lacks β-ionone and Isovaleric acid(IVA)-related ORs, which may be related to the decline of high-altitude herbaceous plant diversity and underdeveloped yak sweat glands. The conserved motifs of OR genes were highly conserved in Bos species. These results provided a solid foundation for further studies on the molecular mechanisms of the yak's adaptation to the high-altitude environment in olfaction.


A study on the association of rs7950273 polymorphism in the PDGFD with ischaemic stroke in the Chinese Han population.
The association between the platelet-derived growth factor D (PDGFD) gene and atherosclerosis has been widely proven, whereas the relationship between the PDGFD gene and ischaemic stroke remains unconfirmed. A case-control study was performed to further evaluate the association of the C → G mutation of rs7950273 in the PDGFD gene with ischaemic stroke (IS) in a Chinese Han population. This study recruited 3033 cases and 2807 controls from general hospitals in the southern, central and northern areas of China. The MGB probe and Taqman 7900HT Sequence Detection System were applied for genotyping. Genotype was not significantly associated with ischaemic stroke in total. After adjustment for gender, age, BMI, hypertension, diabetes mellitus and smoking, the CG and GG genotypes were still not associated with ischaemic stroke (p = 0.892 and p = 0.582 for CG and GG, respectively). This study suggests that the polymorphism of rs7950273 in the PDGFD gene is not associated with ischaemic stroke in the Chinese Han population. Further studies on the gene-gene and gene-environment interactions for the PDGFD gene and ischaemic stroke are needed.


Relationship between plasma resistin concentrations, inflammatory chemokines, and components of the metabolic syndrome in adults.
Recent data suggest that resistin, an adipocyte-derived cytokine, has a putative role in inflammatory processes and metabolic derangements. In vitro data suggest that resistin stimulates the production of inflammatory chemokines, yet the relationship in vivo is largely unknown. The purpose of this study was to determine if a relationship exists between plasma resistin concentrations, plasma inflammatory chemokine aged concentrations (ie, monocyte chemoattractant protein 1 [MCP-1] and epithelial neutrophil activator 78 [ENA-78]), and components of the metabolic syndrome in nondiabetic subjects without known cardiovascular disease (CVD). Plasma samples were obtained from nondiabetic subjects (N = 123) aged 18 to 55 years without known CVD or CVD risk equivalents. The presence of the metabolic syndrome was assessed using consensus guidelines. Fasting plasma resistin, MCP-1, ENA-78, and high-sensitivity C-reactive protein (hs-CRP) concentrations were analyzed. The study population consisted of 67.5% women and 68.3% Caucasians (mean age = 44 +/- 7 years and mean body mass index = 33.3 +/- 6 kg/m(2)). The metabolic syndrome was present in 46.3% of study participants. Resistin concentrations were significantly correlated with white blood cell count (r = 0.326, P < .001), hs-CRP concentrations (r = 0.293, P = .005), MCP-1 concentrations (r = 0.251, P = .005), body mass index (r = 0.193, P = .033), and high-density lipoprotein cholesterol (r = -0.182, P = .044). Resistin concentrations were 1.21 times higher in subjects with the metabolic syndrome compared with those without the metabolic syndrome (P = .003). In stepwise regression analysis, white blood cell count (P < .001) and MCP-1 concentrations (P = .002) were significantly associated with resistin concentrations, independent of hs-CRP, sex, body mass index, presence of the metabolic syndrome, and high-density lipoprotein cholesterol. Data from our cross-sectional study demonstrate that plasma resistin concentrations are associated with circulating chemokine markers of inflammation, namely, MCP-1, and white blood cell count in nondiabetic adults without CVD. Future studies examining the causal relationship between plasma resistin concentrations, chemokine markers of inflammation, CVD, and diabetes are warranted.


The effects of methylphenidate on various types of activity level and attention in hyperkinetic children.
The effects of methylphenidate on a number of objective measures of activity level and attention were assessed on three repeated occasions in four types of settings: free play, movie viewing, testing, and restricted play periods. Subjects were 36 boys between 5 and 12 years of age and of average intelligence. Of these, 18 were diagnosed as hyperkinetic and participated in a double-blind drug-placebo crossover design. The remaining 18 boys, matched in age and IQ with the hyperkinetic children, served as a control group and received no drugs. Results indicated that compared to placebo, methylphenidate significantly reduced wrist, ankle, locomotor, and seat movement activity in the hyperkinetic children regardless of the type of setting in which the measures were taken. Relatively fewer significant drug effects were noted on the measures of concentration or attention. While concentration to reaction time, maze performance, and a movie viewing task improved during drug treatment, the length of attention to toys in free play was not significantly improved. Parental ratings of activity level were also improved by the drug. The hyperkinetic children were also observed to increase their level of task-irrelevant activity over time while control children remained relatively stable in activity over repeated assessment. Despite the positive drug effects, clinical observations suggested that methylphenidate may have reduced the interest of some children in their environment.


Streptococci isolated from various skin lesions: the interaction with Staphylococcus aureus strains.
We isolated 73 streptococcus strains (41 from infections, and 32 from colonization) from various skin diseases between March, 1994, and June, 1998. In 29 out of 41 cases of infective origin, Staphylococcus aureus strains were simultaneously isolated. Twenty-four out of 28 patients with impetigo were suffering from atopic dermatitis. We confirmed that impetigo lesions where Streptococcus pyogenes was dominant in number always showed thick-walled pustules on an erythematous base; these skin lesions were considered to be an early manifestation of streptococcal impetigo. We further confirmed that thick-crusted lesions in streptococcal impetigo, where S. aureus exceeded S. pyogenes in number, were a late manifestation. Antimicrobial agents such as minocycline, fusidic acid, ofloxacin and tosufloxacin, were more effective against S. aureus strains than against beta-hemolytic streptococcal strains. In contrast, ampicillin, cefdinir, imipenem, erythromycin and vancomycin were more effective against beta-hemolytic streptococcal strains.


Can ecological history influence response to pollutants? Transcriptomic analysis of Manila clam collected in different Venice lagoon areas and exposed to heavy metal.
Chronic exposure to environmental pollutants can exert strong selective pressures on natural populations, favoring the transmission over generations of traits that enable individuals to survive and thrive in highly impacted environments. The lagoon of Venice is an ecosystem subject to heavy anthropogenic impact, mainly due to the industrial activities of Porto Marghera (PM), which led to a severe chemical contamination of soil, groundwater, and sediments. Gene expression analysis on wild Manila clams collected in different Venice lagoon areas enabled to identify differences in gene expression profiles between clams collected in PM and those sampled in clean areas, and the definition of molecular signatures of chemical stress. However, it remains largely unexplored to which extent modifications of gene expression patterns persists after removing the source of contamination. It is also relatively unknown whether chronic exposure to xenobiotics affects the response to other chemical pollutants. To start exploring such issues, in the present study a common-garden experiment was coupled with transcriptomic analysis, to compare gene expression profiles of PM clams with those of clams collected in the less impacted area of Chioggia (CH) during a period under the same control conditions. Part of the two experimental groups were also exposed to copper for seven days to assess whether different "ecological history" does influence response to such pollutant. The results obtained suggest that the chronic exposure to chemical pollution generated a response at the transcriptional level that persists after removal for the contaminated site. These transcriptional changes are centered on key biological processes, such as defense against either oxidative stress or tissue/protein damage, and detoxification, suggesting an adaptive strategy for surviving in the deeply impacted environment of Porto Marghera. On the other hand, CH clams appeared to respond more effectively to copper exposure than PM animals, proposing that chronic exposure to chemical toxicants either lowers the sensitivity to additional toxicants or blunts the capacity to respond to novel chemical challenges in PM clams.


Inactivation of glutathione peroxidase by nitric oxide. Implication for cytotoxicity.
S-nitro-N-acetyl-DL-penicillamine (SNAP), a nitric oxide (NO) donor, inactivated bovine glutathione peroxidase (GPx) in a dose- and time-dependent manner. The IC50 of SNAP for GPx was 2 microM at 1 h of incubation and was 20% of the IC50 for another thiol enzyme, glyceraldehyde-3-phosphate dehydrogenase, in which a specific cysteine residue is known to be nitrosylated. Incubation of the inactivated GPx with 5 mM dithiothreitol within 1 h restored about 50% of activity of the start of the SNAP incubation. A longer exposure to NO donors, however, irreversibly inactivated the enzyme. The similarity of the inactivation with SNAP and reactivation with dithiothreitol of GPx to that of glyceraldehyde-3-phosphate dehydrogenase, suggested that NO released from SNAP modified a cysteine-like essential residue on GPx. When U937 cells were incubated with 100 microM SNAP for 1 h, a significant decrease in GPx activity was observed although the change was less dramatic than that with the purified enzyme, and intracellular peroxide levels increased as judged by flow cytometric analysis using a peroxide-sensitive dye. Other major antioxidative enzymes, copper/zinc superoxide dismutase, manganese superoxide dismutase, and catalase, were not affected by SNAP, which suggested that the increased accumulation of peroxides in SNAP-treated cells was due to inhibition of GPx activity by NO. Moreover, stimulation with lipopolysaccharide significantly decreased intracellular GPx activity in RAW 264.7 cells, and this effect was blocked by NO synthase inhibitor N omega-methyl-L-arginine. This indicated that GPx was also inactivated by endogenous NO. This mechanism may at least in part explain the cytotoxic effects of NO on cells and NO-induced apoptotic cell death.


[Feasibility, morbidity and survival of surgery combined with HIPEC in the management of recurrent ovarian cancer].
The management of recurrent ovarian cancer is based on intravenous chemotherapy with or without debulking surgery. The hyperthermic intraperitoneal chemotherapy (HIPEC) is sometimes proposed as a complement to complete surgery. The purpose of this study was to evaluate the feasibility, morbidity and survival of HIPEC associated with complete surgical cytoreduction in the management of patients with a first recurrence of ovarian cancer. Between 2005 and 2010, 27 patients underwent surgery for a recurrence of ovarian cancer. Among them, 17 patients (63%) have received HIPEC. Sixteen patients (94%) were completely resected after surgery. No patient died postoperatively. Two patients had intraoperative complications: a bladder injury and a section of the ureter. Eight patients had postoperative complications including 3 grade 3 or higher (two organ failure and one reoperation). Fifteen patients had a recurrence with a median DFS of 11.9 months (95% CI [5.4-32.9]) from the HIPEC. The median overall survival from diagnosis was 107.8 months. These results showed that the association of HIPEC with a complete cytoreduction for recurrent ovarian cancer presents acceptable morbidity and survival. The results of the ongoing French multicenter study (CHIPOR) are expected to generalize this support.


Ultrasonic vocalizations in rat pups: effects of serotonergic ligands.
Ligands with varying intrinsic activity and selectivity for the various subtypes of the serotonin receptor were tested in the rat pup ultrasonic vocalization (USV) model, a putative animal model reflecting anxiety. USV were elicited by isolating rat pups from their mother and littermates by placing them on a warm (37 degrees C) or a cold (18 degrees C) plate. Concurrently, the negative geotaxic (NG) response and rectal temperature were determined to assess the potentially sedative and hypothermic effects of putative anxiolytics. USV were reduced at low doses and in both temperature conditions by the full 5-HT1A receptor agonists flesinoxan and 8-OH-DPAT (8-hydroxy-2-(di-n-propylamino) tetralin.HBr) and the partial 5-HT1A receptor agonists buspirone, ipsapirone and BMY 7378 (2-[4-[4-[2-pyrimidinyl]-1,2-piperazinyl]butyl]-1,2-benzi-isoth iozol-3-(2H)one-1,1-dioxide. 2HCl). The 5-HT1A receptor antagonists NAN-190 (1-(2-methoxyphenyl)-4-[4-(2-phtalimido)-butyl]piperazide.2H Cl), (+/-)-WAY 100,135 (+/-)-(N-tert-butyl-3(4-(2-methoxy phenyl)piperazin-1 -yl)-2-phenyl propionamine.2HCl), and ((S)-UH-301 (S)-5-fluoro-8-hydroxy-2-(di-n-propyl-amino)tetralin.HBr) reduced USV at higher doses and only in one of both test conditions. The selective 5-HT1A receptor antagonist DU 125530 (2-[4-[4[(7-chloro-2,3dihydro-4-benzodioxin-5-yl)-1-piperazi nyl]butyl]-1,2-benzisothiazol-3(2H)-one-1,1, dioxide, monomesylate), did not influence USV at the cold plate up to high doses, although concomitantly the negative geotaxis was disturbed. The negative geotaxis was impaired after all 5-HT1A receptor ligands, except BMY 7378 and (+/-)-WAY 100,135. Hypothermia coincided with USV-suppression, except for NAN-190 and (S)-UH-301. The USV-suppressing action of flesinoxan (3 mg/kg) could be antagonized by DU 125530, but not its NG effect. However, the hypothermia induced by flesinoxan was antagonized by DU 125530. USV were also suppressed by the 5-HT uptake inhibitors fluvoxamine (both warm and cold plate) and clomipramine (only warm plate). The tricyclic antidepressant imipramine only decreased USV on the cold plate, however, in a U-shaped dose-response curve. At the highest dose tested, no decrease was present. The 5-HT uptake stimulant tianeptine reduced USV under both conditions. Fluvoxamine had no side effects, clomipramine induced hypothermia and tianeptine clearly had sedative properties. The 5-HT1B/2C receptor agonist TFMPP (trifluorometaphenylpiperazine) stimulated USV at a low dose at the cold plate and suppressed USV at a high dose under both conditions. The 5-HT2A/2C receptor antagonist ketanserine enhanced USV at low doses under both conditions and had no effect at a higher dose. Concurrently heavy sedation and hypothermia occurred. The 5-HT3 receptor agonist phenylbiguanide and the 5-HT3 receptor antagonist ondansetron had no effect in this paradigm. Clearly, subtypes of the 5-HT receptor affect rat pup USV differentially.


The effect of freeze-drying parameters and formulation composition on IgG stability during drying.
The objective of this study was to explore the effects of freeze-drying parameters and formulation composition on polyclonal IgG stability during processing. Samples were freeze-dried with different primary drying pressures and secondary drying heating rates. After drying, changes in IgG in vitro binding activity, monomer recovery, average particle size, and polydispersity were studied from the rehydrated lyophilizates. Significant trends were not observed in binding activities or monomer recoveries, but increases in particle size and polydispersity were observed when using lower primary drying pressure. This effect could no longer be observed when sodium phosphate buffer was removed from the formulation. Altering the secondary drying heating rates did not result in any measurable changes in protein stability.


Isocitrate dehydrogenase-mutant glioma: Evolving clinical and therapeutic implications.
The metabolic genes isocitrate dehydrogenase 1 (IDH1) and IDH2 are commonly mutated in low-grade glioma and in a subset of glioblastoma. These mutations co-occur with other recurrent molecular alterations, including 1p/19q codeletions and tumor suppressor protein 53 (TP53) and alpha thalassemia/mental retardation (ATRX) mutations, which together help to define a molecular signature that aids in the classification of gliomas and helps to better predict clinical behavior. A confluence of research suggests that glioma development in IDH-mutant and IDH wild-type tumors is driven by different oncogenic processes and responds differently to current treatment paradigms. Herein, the authors discuss the discovery of IDH mutations and associated molecular alterations in glioma, review clinical features common to patients with IDH-mutant glioma, and highlight current understanding of IDH mutation-driven gliomagenesis with implications for emerging treatment strategies. Cancer 2017;123:4535-4546. © 2017 American Cancer Society.


Temporal succession of soil antibiotic resistance genes following application of swine, cattle and poultry manures spiked with or without antibiotics.
Land application of animal manure is a common agricultural practice potentially leading to dispersal and propagation of antibiotic resistance genes (ARGs) in environmental settings. However, the fate of resistome in agro-ecosystems over time following application of different manure sources has never been compared systematically. Here, soil microcosm incubation was conducted to compare effects of poultry, cattle and swine manures spiked with or without the antibiotic tylosin on the temporal changes of soil ARGs. The high-throughput quantitative PCR detected a total of 185 unique ARGs, with Macrolide-Lincosamide-Streptogramin B resistance as the most frequently encountered ARG type. The diversity and abundance of ARGs significantly increased following application of manure and manure spiked with tylosin, with more pronounced effects observed in the swine and poultry manure treatments than in the cattle manure treatment. The level of antibiotic resistance gradually decreased over time in all manured soils but was still significantly higher in the soils treated with swine and poultry manures than in the untreated soils after 130 days' incubation. Tylosin-amended soils consistently showed higher abundances of ARGs than soils treated with manure only, suggesting a strong selection pressure of antibiotic-spiked manure on soil ARGs. The relative abundance of ARGs had significantly positive correlations with integrase and transposase genes, indicative of horizontal transfer potential of ARGs in manure and tylosin treated soils. Our findings provide evidence that application of swine and poultry manures might enrich more soil ARGs than cattle manure, which necessitates the appropriate treatment of raw animal manures prior to land application to minimise the spread of environmental ARGs.


Comprehensive characterization of posttranscriptional impairment-related 3'-UTR mutations in 2413 whole genomes of cancer patients.
The 3' untranslated region (3'-UTR) is the vital element regulating gene expression, but most studies have focused on variations in RNA-binding proteins (RBPs), miRNAs, alternative polyadenylation (APA) and RNA modifications. To explore the posttranscriptional function of 3'-UTR somatic mutations in tumorigenesis, we collected whole-genome data from 2413 patients across 18 cancer types. Our updated algorithm, PIVar, revealed 25,216 3'-UTR posttranscriptional impairment-related SNVs (3'-UTR piSNVs) spanning 2930 genes; 24 related RBPs were significantly enriched. The somatic 3'-UTR piSNV ratio was markedly increased across all 18 cancer types, which was associated with worse survival for four cancer types. Several cancer-related genes appeared to facilitate tumorigenesis at the protein and posttranscriptional regulation levels, whereas some 3'-UTR piSNV-affected genes functioned mainly via posttranscriptional mechanisms. Moreover, we assessed immune cell and checkpoint characteristics between the high/low 3'-UTR piSNV ratio groups and predicted 80 compounds associated with the 3'-UTR piSNV-affected gene expression signature. In summary, our study revealed the prevalence and clinical relevance of 3'-UTR piSNVs in cancers, and also demonstrates that in addition to affecting miRNAs, 3'-UTR piSNVs perturb RBPs binding, APA and m6A RNA modification, which emphasized the importance of considering 3'-UTR piSNVs in cancer biology.


Initial management of severe hyperglycemia in patients with type 2 diabetes: an observational study.
Current guidelines recommend insulin for patients with type 2 diabetes (T2D) and severe hyperglycemia, but this recommendation lacks sufficient evidence and poses practical challenges. It is unclear whether non-insulin treatments are effective in this setting. The objective of this study was to describe treatment strategies of T2D patients with severe hyperglycemia and identify which initial treatments, interventions, or patient characteristics correlated with successful glucose lowering. This was a retrospective cohort study of 114 patients with T2D and a glycosylated hemoglobin (A1C) ≥12%. Changes in A1C were compared between patients started on non-insulin medications versus insulin-based regimens. Regression analysis was performed to assess predictors of success in achieving A1C ≤9% within 1 year. The main outcomes measures were change in A1C from baseline and predictors of success in achieving A1C ≤9% within 1 year. At baseline, 43 patients (37.7%) started one or more non-insulin medications; 71 (62.3%) started insulin. Fifty-eight patients (50.8%) achieved an A1C ≤9%. Predictors of success were newly diagnosed T2D, certified diabetes educator (CDE) visits, and less time to follow-up A1C; insulin therapy was not. Change in A1C was significantly better in the non-insulin cohort compared to the insulin cohort (-4.5% vs. -2.8%, p = 0.001). Newly diagnosed patients were less likely to start insulin therapy (20.8% vs. 73.3%, p < 0.001), less likely to use insulin at any point (29.2% vs 81.1%, p < 0.001), and more likely to achieve an A1C ≤9% compared to patients with established T2D (87.5% vs 41.1%, p < 0.001). Insulin therapy was used in roughly two-thirds of patients with severe hyperglycemia, but did not result in better glycemic control compared to non-insulin regimens. Rapid follow-up, more CDE visits, and a new diabetes diagnosis were predictors of successful glucose lowering. Patients with T2D and severe hyperglycemia, particularly those newly diagnosed, may be managed with non-insulin therapy.


International nurse education research collaboration during the COVID-19 pandemic: Researchers' perspectives.
International research collaborations in nurse are increasing. However, collaborations in international nurse education research are limited compared to clinical nurse studies. This paper presents the experiences of seven investigators of a multi-country study while conducting collaborative research among nurse students across five continents. This paper aims to describe the experiences and challenges of conducting an international nurse education research and to propose recommendations to enhance these collaborative research experiences. Narrative perspectives from nurse educators on the international nurse collaborative experience were described in this discussion paper. International collaboration in nurse education research was a positive and enriching experience. While several challenges were experienced by the collaborators, the presence of facilitating factors, benefits of collaboration, and opportunities for personal and professional growth and development outweighed the challenges. Team leader attributes, active engagement, commitment, genuine interest, and cultural sensitivity are essential in creating a successful international nurse research project. International collaborative nurse research fosters expansion of nurse knowledge through sharing of expertise and development of culturally diverse perspectives.


Enantioselective Silver-Catalyzed Cascade Synthesis of Fused Lactone and Lactam Oxazolines.
A new and highly stereoselective cascade reaction between isocyanoacetate esters and α-hydroxy and α-amino ketones has been developed. A cinchona alkaloid derived aminophosphine/silver(I) catalyst complex promoted the reaction and enabled the ready synthesis of fused bicyclic γ-lactone and γ-lactam oxazolines with high enantiocontrol (up to 99% ee).


Salivary microbiome profiles of oral cancer patients analyzed before and after treatment.
Treating oral squamous cell carcinoma (OSCC) introduces new ecological environments in the oral cavity. This is expected to cause changes in the oral microbiome. The purpose of this study was to gain new information on the salivary microbiome of OSCC patients in order to improve the aftercare of OSCC patients. The aims of this study were to investigate possible changes in the salivary microbiome profiles of OSCC patients before and after cancer treatment and to compare these changes with the profiles of healthy controls. Paraffin-stimulated whole saliva samples were collected, and the salivary flow rate was measured from 99 OSCC patients prior to surgical resection of the tumor and other adjuvant therapy. After treatment, 28 OSCC patients were re-examined with a mean follow-up time of 48 months. In addition, 101 healthy controls were examined and sampled. After DNA extraction and purification, the V4 hypervariable region of the 16S rRNA gene was amplified and sequenced using Illumina MiSeq. The merged read pairs were denoised using UNOISE3, mapped to zero-radius operational taxonomic units (zOTUs), and the representative zOTU sequences were assigned a taxonomy using HOMD. Descriptive statistics were used to study the differences in the microbial profiles of OSCC patients before and after treatment and in comparison to healthy controls. At baseline, the OSCC patients showed a higher relative abundance of zOTUs classified as Streptococcus anginosus, Abiotrophia defectiva, and Fusobacterium nucleatum. The microbial profiles differed significantly between OSCC patients and healthy controls (F = 5.9, p < 0.001). Alpha diversity of the salivary microbiome of OSCC patients was decreased at the follow-up, and the microbial profiles differed significantly from the pre-treatment (p < 0.001) and from that of healthy controls (p < 0.001). OSCC patients' salivary microbiome profile had a higher abundance of potentially pathogenic bacteria compared to healthy controls. Treatment of the OSCC caused a significant decrease in alpha diversity and increase in variability of the salivary microbiome, which was still evident after several years of follow-up. OSCC patients may benefit from preventive measures, such as the use of pre- or probiotics, salivary substitutes, or dietary counseling. Video Abstract.


Childhood narcolepsy and autism spectrum disorders: four case reports.
Childhood narcolepsy is associated with various emotional, behavioural and cognitive dysfunctions as well as with psychiatric and neurodevelopmental disorders: anxiety, depression, attention deficit hyperactivity disorder and psychosis. A relationship between these conditions is unclear - comorbidity or similar pathophysiological mechanisms can be suggested. We reported four children with narcolepsy type 1 (NT1) and autism spectrum disorder (ASD) - Asperger syndrome (AS). To the best of our knowledge co-occurrence of NT1 and AS has not been described in the literature as noted in this report.


Chemoradiation for elderly patients (≥ 65 years) with esophageal cancer: a retrospective single-center analysis.
Present studies on the efficacy and safety of curative chemoradiation therapy (CRT) with esophageal cancer reflect heterogenous results especially in elderly patients. The aim of this study was to evaluate the toxicity and efficacy of CRT in patients ≥ 65 years. In a cohort, the focus centered around treatment-related toxicity (CTCAE Grade > 3), overall survival as well as progression free survival, comparing these rates in-between patients older than 70 years to those younger than 70 years. A total of 67 patients older than 65 years (34 (50.7%) were older than 70 years) met the inclusion criteria for retrospective analysis (period from January 2013 to October 2017). Treatment consisted of radiotherapy and chemotherapy with carboplatin/paclitaxel or fluorouracil (5-FU)/cisplatin with the intention of neoadjuvant or definite chemoradiation. A sum of 67 patients received CRT (44 (65.6%) patients in neoadjuvant, 23 (34.4%) in definite intent). Of these, 22 and 12 patients were older than 70 years (50% and 52.2% in both treatment groups, respectively). Median age was 71 years and patients had a good physical performance status (ECOG 0: 57.6%, ECOG 1: 27.3%). Median follow-up was 24 months. Most patients had advanced tumour stages (T3 stage: n = 51, 79.7%) and nodal metastasis (N1 stage: n = 54, 88.5%). A subgroup comparison was conducted between patients aged ≤ 70 years and > 70 years. In severe (CTCAE Grade 3-5) toxicities (acute and late), no significant differences were observed between both patient groups (< 70 years vs. > 70 years). 21% had acute grade 3 events, 4 patients (4%) had grade 4 events, and two patients (3%) had one grade 5 event. Late toxicity after CRT was grade 1 in 13 patients (22%), grade 2 in two (3%), grade 3 in two (3%), grade 4 in four (7%), and grade 5 in one (2%). Median overall survival (OS) of all patients was 30 months and median progression-free survival (PFS) was 16 months. No significant differences were seen for OS (32 months vs. 25 months; p = 0.632) and PFS (16 months vs. 12 months; p = 0.696) between older patients treated with curative intent and younger ones. Trimodal therapy significantly prolonged both OS and PFS (p = 0.005; p = 0.018), regardless of age. CRT in elderly patients (≥ 65 years) with esophageal cancer is feasible and effective. Numbers for acute and late toxicities can be compared to cohorts of younger patients (< 65 years) with EC who received the same therapies. Age at treatment initiation alone should not be the determining factor. Instead, functional status, risk of treatment-related morbidities, life expectancy and patient´s preferences should factor into the choice of therapy.


Enzyme targets for drug design of new anti-virulence therapeutics.
Society has benefitted greatly from the use of antibiotics. Unfortunately, the misuse of these valuable molecules has resulted in increased levels of antibiotic resistance, a major global and public health issue. This resistance and the reliance on a small number of biological targets for the development of antibiotics emphasizes the need for new targets. A critical aspect guiding the development of new antimicrobials through a rational structure-guided approach is to understand the molecular structures of specific biological targets of interest. Here we give an overview of the structures of bacterial virulence enzyme targets involved in protein folding, peptidoglycan biosynthesis and cell wall modification. These include enzymes of the thiol-disulphide oxidoreductase pathway (DSB enzymes), peptidyl-proly cis/trans isomerases (Mips), enzymes from the Mur pathway and enzymes involved in lipopolysaccharide modification (EptA and ArnT). We also present progress towards inhibitor design of these targets for the development of novel anti-virulence therapeutic agents.


Water requirement of Urban Green Infrastructure under climate change.
The increased uncertainty of rainfall and high urban temperatures resulting from climate change present challenges for water management in Urban Green Infrastructure (UGI). UGI is an important component of cities, and it plays a crucial role in addressing various environmental issues (e.g., floods, pollutants, heat islands, etc.). Effective water management of UGI is essential to ensure its environmental and ecological benefits in the face of climate change. However, previous studies have not adequately investigated water management strategies for UGI under climate change scenarios. This study aims to estimate the current and future water requirement and effective rainfall (rainwater stored in the soil and plant roots available for plant evapotranspiration) to determine the irrigation requirement of UGI during periods of rainfall deficit under current and future climate conditions. The results indicate that the water requirement for UGI will continue to increase under both RCP4.5 and RCP8.5 climate scenarios, with a larger increase projected under RCP8.5. For instance, the average annual water requirement for UGI in Seoul, South Korea is currently 731.29 mm, and it is projected to increase to 756.45 mm (RCP4.5) and 816.47 mm (RCP8.5) during the period of 2081-2100, assuming low managed water stress condition. In addition, the water requirement of UGI in Seoul is the highest in June (approximately 125-137 mm) and the lowest in December or January (about 5-7 mm). While irrigation is unnecessary in July and August due to sufficient rainfall, other months in Seoul require irrigation when rainfall is insufficient. For example, continuous insufficient rainfall from May to June 2100 and April to June 2081 would need >110 mm (RCP4.5) of irrigation requirement even under high managed water stress condition. The findings of this study provide a theoretical foundation for water management strategies in current and future UGI settings.


Immunization of mice and rabbits by intrasplenic deposition of nanogram quantities of protein attached to Sepharose beads or nitrocellulose paper strips.
Two novel immunization methods designed for immunization with small quantities of antigen, immobilized on a solid matrix and without the use of adjuvant, are presented. The major test antigen used in order to evaluate these methods was bovine serum albumin (BSA). It was deposited in the spleen of mice and rabbits, either attached to Sepharose beads (Pharmacia Sepharose 4B) or to nitrocellulose (NC) paper strips (Millipore). BSA was attached to NC by direct application or by electroblotting after SDS-polyacrylamide gel electrophoresis. The antibody response in mouse and rabbit serum, after intrasplenic immunizations with various quantities of antigen, was analyzed in an ELISA standard procedure. In mice, an antibody response in serum was detected after three intrasplenic immunizations with a total quantity of 73.6 ng BSA bound to Sepharose beads and after two immunizations with a total quantity of 800 ng BSA attached to NC. Determination of the antigen-binding to NC and the clearance rate of antigen attached to NC deposited in the spleen of mice was performed with 125I-labeled BSA. In rabbits, an antibody response in serum was detected after a single intrasplenic immunization with 2.6 micrograms BSA attached to NC. When testing human insulin and sheep prolactin, attached to NC, as antigens in intrasplenic immunization of rabbits, an antibody response was found after a total quantity of 3.2 micrograms insulin and 10.5 micrograms prolactin, respectively.


Effect of TSH in human thyroid cells: evidence for both mitogenic and antimitogenic effects.
The well-known mitogenic effects of TSH observed in vivo on the thyroid are not always reproducible of human thyroid cells in vitro where conflicting results have been obtained. In order to clarify this issue, we have used primary cultures of human thyroid cells obtained from normal tissue and maintained in serum-free medium for several days. In this in vitro model we have studied the effect of TSH on growth by measuring three different parameters: [3H]-thymidine incorporation, cell counts, and DNA measurement. Monolayer cultures were plated at both low and high cell density (2 x 10(4) and 8 x 10(4) cells/25 mm well, respectively). Although at either cell density cultures were equally able to functionally respond to TSH in terms of cAMP accumulation a significant growth response to TSH was observed only in low density cultures. In high density cultures TSH had an antimitogenic effect. Moreover, TSH potentiated the mitogenic effect of insulin only in low density cultures. In contrast to TSH, FCS induced a similar proliferative response at both high and low cell density. Following TSH stimulation, cAMP content was always increased, paralleling the effect of growth in low density but not in high density cultures. The cAMP analogues dibutyryl-cAMP and 8-bromo-cAMP, as well as cholera toxin and forskolin, did not mimic the mitogenic effect of TSH but had an antiproliferative effect. In addition, these agents blunted the proliferative effect of insulin. These data suggest that in thyroid cells TSH is able to elicit both a mitogenic and an antimitogenic effect depending on the environmental conditions such as cell density.(ABSTRACT TRUNCATED AT 250 WORDS)


Trichophyton violaceum abscesses.
Two patients with deep cold abscesses due to Trichophyton violaceum are described. Both have depressed cellular immunity.


The impact of predation on the viburnum whitefly, (Aleurotrachelus jelinekii).
In association with a detailed study of the population dynamics of the viburnum whitefly, Aleurotrachelus jelinekii, observations were made on the predators including spiders and five species of insect, notably the mirid Campyloneura virgula and the neuropteran Conwentzia psociformis. Although the species richness of the predator guild was positively correlated with prey population density, at the individual level there was little evidence over twelve years of a density dependent relationship. In these populations natural enemies do not seem to play an important role in the dynamics.


An adult case of nephrotic syndrome presenting with pulmonary artery thrombosis: a case report.
Pulmonary artery thrombosis is one of the most important complications in patients with nephrotic syndrome. It is well known among nephrologists, however, that this possibly lethal complication very rarely occurs before the diagnosis of nephrotic syndrome. A 21-year-old Japanese woman who had no specific medical history consulted a primary care clinic. Although she had been aware of the edema of her lower extremities for 2 weeks, her chief complaints were palpitations and chest pain, which had started the day before. An electrocardiogram and chest radiograph did not reveal any specific abnormalities. Because her etiology was not clear, she was referred to an emergency division in a hospital 2 days later. Although arterial blood gas analysis did not reveal hypoxemia, computed tomography revealed thrombi of the bilateral pulmonary arteries and left iliac vein. At this point, a laboratory examination confirmed the diagnosis of nephrotic syndrome. Subsequently, she was admitted, and anticoagulant therapy was initiated immediately. The next day, oral corticosteroid therapy was initiated, and an inferior vena cava filter was placed internally. Her proteinuria resolved after 3 weeks of treatment. The prompt and complete response to corticosteroid therapy suggested that minimal change disease was the etiology of the nephrotic syndrome and pulmonary artery thrombosis. An awareness regarding the complication of pulmonary artery thrombosis in nephrotic syndrome is important not only for nephrologists but for all clinicians. Contrast-enhanced computed tomography is crucial to detect pulmonary artery thrombosis.


Potential for the Biodegradation of Atrazine Using Leaf Litter Fungi from a Subtropical Protection Area.
The intense use of pesticides in agricultural activities for the last several decades has caused contamination of the ecosystems connected with crop fields. Despite the well-documented occurrence of pesticide biodegradation by microbes, natural attenuation of atrazine (ATZ), and its effects on ecological processes in subtropical forested areas, such as Iguaçu National Park located in Brazil, has been poorly investigated. Subtropical environments sustain a great degree of fungal biodiversity, and the patterns and roles of these organisms should be better understood. This work aimed to evaluate nine ligninolytic-producer fungi isolated from the INP edge to degrade and detoxify ATZ solutions. ATZ degradation and the main metabolites produced, including deisopropylatrazine and deethylatrazine (DEA), were analyzed using dispersive liquid-liquid microextraction followed by gas chromatography-mass spectrometer. Four fungi were able to degrade ATZ to DEA, and the other five showed potential to grow and facilitate ATZ biodegradation. Furthermore, two strains of Fusarium spp. showed an enhanced potential for detoxification according to the Allium cepa (onion) test. Although the isolates produced ligninolytic enzymes, no ligninolytic activity was observed in the biodegradation of ATZ, a feature with ecological significance. In conclusion, Ascomycota fungi from the INP edge can degrade and detoxify ATZ in solution. Increasing the knowledge of biodiversity in subtropical protected areas, such as ecosystem services provided by microbes, enhances ecosystem conservation.


Production of IL-1-mimicking anti-idiotypic antibodies in rabbits in response to IL-1 immunization.
This report describes the characterization of immunoglobulins with interleukin-1 (IL-1)-like activity from the serum of rabbits immunized with partially purified mouse IL-1. Early after immunization, immune sera were found to contain anti-IL-1 antibodies (idiotypes) that inhibited IL-1 bioactivity (augmented-proliferation of PHA-stimulated thymocytes). Later, anti-idiotypic antibodies appeared that mimicked IL-1 activity. These IL-1-like antibodies were affinity purified either on an anti-IL-1-enriched Ig-Sepharose 4B column from an early bleed or sequentially on anti-Ig and Protein A immunoadsorbent columns. By ELISA anti-idiotypic antibodies specifically bound to rabbit anti-IL-1 antibodies. Functionally, IL-1 mimicking antibodies were reproducibly effective in augmenting the in vitro proliferation of PHA-stimulated thymocytes or Con A-stimulated D10 cells. On the other hand, they did not support proliferation of the IL-2-dependent CTLL-2 cells. The ability of IL-1-mimicking antibodies to enhance thymocyte proliferation could be blocked by functional site related anti-IL-1 antibodies. By Western blot, 125I-labeled IL-1 and IL-1-mimicking antibodies bound to a similar 23 Kd mol. wt protein material recovered from the lysate of thymocytes stimulated with PHA for 48 h. That the observed bioactivity could be attributed to antibody molecules and not to contaminant IL-1 was ascertained by several methods, namely (1) SDS-PAGE analysis of 125I-labeled material and (2) resistance to loss of bioactivity by lyophilization. Furthermore, as neither Ig-anti-Ig nor BSA-anti-BSA complexes mimicked IL-1-augmented thymocyte proliferation, a non-specific effect due to immune complexes could be excluded. The occurrence of antibodies mimicking several of the IL-1 functions induced following IL-1 immunization suggests a potential role for the idiotypic network in modulating cytokine activities and a possible link between regulation of the immune system by cytokines and immunoglobulin idiotypes.


[Eczema and its treatment in older adults].
Eczema encompass a wide range of dermatoses that can affect elderly patients in particular. Common differential diagnoses in elderly patients include asteatotic eczema, late-onset atopic dermatitis, allergic contact dermatitis, early phases of mycosis fungoides, eczematous and pruriginous variants of premonitory bullous pemphigoid, as well as eczematized scabies and post-scabietic eczema. Given the partly overlapping clinical presentations, accurate diagnosis plays a crucial role in the management of these conditions. Therapeutic options depend on the underlying disease and necessitate an individualized approach. This review presents relevant types of eczema in older adults together with diagnostic and therapeutic approaches. In addition to confirming the diagnosis and selecting the appropriate treatment, aspects relevant to the care of older patients should be incorporated into the tailored therapeutic approach.


Gas chromatography quadrupole time-of-flight mass spectrometry determination of benzotriazole ultraviolet stabilizers in sludge samples.
In this research, a simplified procedure for the selective determination of nine benzotriazole UV stabilizers (BUVSs) in sludge from urban sewage treatment plants is presented. Analytes were extracted from the sample using the matrix solid-phase dispersion (MSPD) technique and further determined by gas chromatography (GC) with quadrupole time-of-flight mass spectrometry (QTOF-MS). Highly selective chromatographic records were attained considering a mass window of 0.005Da, centred in the quantification product ion corresponding to each compound. Moreover, the availability of accurate ion product scan MS/MS spectra permitted to confirm the identities of peaks observed in extracted ion MS/MS chromatograms. As a result, a straightforward sample preparation procedure combining extraction and clean-up in the same step, and consuming just 10mL of ethyl acetate, sufficed to deal with complex sludge samples. The developed method attained limits of quantification (LOQs) between 2ngg(-1) and 10ngg(-1), referred to freeze-dried sludge, and recoveries from 70% to 111%, with standard deviations from 2% to 13%. Analysis of sludge samples and certified reference materials confirmed the existence of residues of eight out of nine BUVSs. UV-326, UV-328 and UV-234 displayed the highest occurrence frequencies and individual concentrations above 100ngg(-1) in several samples.


Herbal remedies for menopausal symptoms: are we cautious enough?
To evaluate adverse effects of herbal remedies consumed by menopausal women for control of the climacteric syndrome. We examined the long term safety and herb-drug interactions of commonly used herbal therapy such as soy, black cohosh, dong quai, ginseng and vitamin E. Even carefully designed studies on herbal treatments for vasomotor menopausal symptoms never addressed specifically safety issues. Sporadic reports show dangerous adverse effects of these herbal preparations as well as hazardous interactions between botanic compounds and conventional medications. The unrestricted sale of plant products constitutes a new situation for physicians with little training in phytotherapy. The qualitative and quantitative diversity of the commercially available preparations, the absence of precise prescribing guidelines, and the risk of self-prescribed medication justify the introduction of 'phyto-vigilance'. Physicians should warn their patients about the lack of evidence regarding safety and possible interactions of herbal remedies with concurrent medications.


A multiscale systems perspective on cancer, immunotherapy, and Interleukin-12.
Monoclonal antibodies represent some of the most promising molecular targeted immunotherapies. However, understanding mechanisms by which tumors evade elimination by the immune system of the host presents a significant challenge for developing effective cancer immunotherapies. The interaction of cancer cells with the host is a complex process that is distributed across a variety of time and length scales. The time scales range from the dynamics of protein refolding (i.e., microseconds) to the dynamics of disease progression (i.e., years). The length scales span the farthest reaches of the human body (i.e., meters) down to the range of molecular interactions (i.e., nanometers). Limited ranges of time and length scales are used experimentally to observe and quantify changes in physiology due to cancer. Translating knowledge obtained from the limited scales observed experimentally to predict patient response is an essential prerequisite for the rational design of cancer immunotherapies that improve clinical outcomes. In studying multiscale systems, engineers use systems analysis and design to identify important components in a complex system and to test conceptual understanding of the integrated system behavior using simulation. The objective of this review is to summarize interactions between the tumor and cell-mediated immunity from a multiscale perspective. Interleukin-12 and its role in coordinating antibody-dependent cell-mediated cytotoxicity is used illustrate the different time and length scale that underpin cancer immunoediting. An underlying theme in this review is the potential role that simulation can play in translating knowledge across scales.


Efficacy and safety of 4-aminopyridine in patients with long-term spinal cord injury: a randomized, double-blind, placebo-controlled trial.
To study the efficacy and safety of 4-aminopyridine (4-AP), and to document sensorimotor changes after discontinuation of the drug in patients with long-term spinal cord injury. Randomized, double-blind, placebo-controlled trial. Clinical research unit. Twenty-seven patients with long-term spinal cord injury. Patients were randomized to receive either oral 4-AP 5 mg/day, which was increased by 5 mg/week to a maximum dosage of 30 mg/day, or placebo for 12 weeks. They switched to the opposite treatment for the next 12 weeks. Twenty-five patients finished the study. The results from the first 12 weeks were used to test efficacy. Positive gains in motor function, sensation, and independence occurred more frequently in patients receiving 4-AP (69%) than those receiving placebo (46%). Significant functional improvement was also noted in those treated with 4-AP (chi2, p=0.042). When each evaluation scale was considered separately, significant improvement was seen only in motor function (4-AP 92% vs placebo 46%, Fisher exact test, p=0.03). Persistent effects of the drug were assessed at week 24 in the group that initially received 4-AP. A persistent, significant 4-AP effect was observed in evaluations of sensation and independence (67% and 83% of patients, respectively; Wilcoxon signed rank test, p=0.032 and 0.042, respectively). Fourteen (56%) patients had 26 adverse reactions. One moderate adverse reaction--posterior tibial artery vasospasm--and 25 mild adverse reactions, such as dry mouth, dizziness, nausea, gastritis, oral and peripheral paresthesia, resolved adequately. Six (24%) patients experienced transitory alterations of enzyme levels (alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and creatine kinase) and thrombocytopenia. Patients who received 4-AP showed significant improvement in motor function, and a persistent effect on sensation and independent function occurred. The drug is safe; however, after starting 4-AP therapy, patients must be carefully monitored for the possible occurrence of peripheral vasospasm.


When schizophrenia comes marching home.
Deinstitutionalization of the chronically mentally ill has only recently been recognized as a phenomenon which may not be in the best interests of the patients involved. The reasons for this include the lack of adequate community-based resources for domiciliary, treatment, and rehabilitative services, plus the response of society to deviant behavior. However, the most fundamental problem is likely to be the severity of the illnesses with which we are concerned, so that the solution cannot be as simple as the sending "home" of the long-term patients. Prevention of institutionalization is seen as a more feasible goal than its cure. This requires a comprehensive program incorporating, among other things, a recognition of the necessary role of the mental hospital, and the need to improve the quality of care provided therein.


Pannexin-1-mediated intracellular delivery of muramyl dipeptide induces caspase-1 activation via cryopyrin/NLRP3 independently of Nod2.
Muramyl dipeptide (MDP), the microbial activator of nucleotide-binding oligomerization domain 2 (Nod2), induces NF-kappaB and MAPK activation, leading to the production of multiple anti-bacterial and proinflammatory molecules. In addition, MDP has been implicated in IL-1beta secretion through the regulation of caspase-1. However, the mechanisms that mediate caspase-1 activation and IL-1beta secretion in response to MDP stimulation remain poorly understood. We show here that fluorescent MDP molecules are internalized in primary macrophages and accumulate in granular structures that colocalize with markers of acidified endosomal compartments. The uptake of MDP was Nod2-independent. Upon ATP stimulation, labeled MDP was rapidly released from acidified vesicles into the cytosol, a process that required functional pannexin-1. Caspase-1 activation induced by MDP and ATP required pannexin-1 and Cryopyrin but was independent of Nod2. Conversely, induction of pro-IL-1beta mRNA by MDP stimulation was abolished in Nod2-deficient macrophages but unimpaired in macrophages lacking Cryopyrin. These studies demonstrate a Nod2-independent mechanism mediated through pore-forming pannexin-1 that is required for intracellular delivery of MDP to the cytosol and caspase-1 activation. Furthermore, the work provides evidence for distinct roles of Nod2 and Cryopyrin in the regulation of MDP-induced caspase-1 activation and IL-1beta secretion.


The use of clays to sequestrate organic pollutants. Leaching experiments.
Leaching experiments are performed from clay-pollutant systems in order to evaluate the capability of clays to sequestrate organic pollutants from wastewaters. Reference kaolinite KGa-1b, montmorrillonite SWy-2 and reference soil BCR-700 are the sorbent materials. 2,4,6-trichloroaniline (2,4,6-TCA) and 4-chlorophenol (4-CP) are the typical pollutants, sorbed at amounts of 10.0 mg g(-1) and 5.8 mg g(-1) on SWy-2 and 7.3 mg g(-1) and 2.2 mg g(-1) on KGa-1b, respectively. The leaching agents are ultrapure water and model solutions of acid rain and surface waters that simulate meteoric leaching. 1.0mM HNO(3), 1.0mM H(2)SO(4) solutions and a methanol/water 50/50 (v/v) mixture simulate leaching agents of industrial source. The results are compared and the preferential capability of the clays to sequestrate the more lipophilic 2,4,6-TCA is evidenced. The bond interactions are discussed and explained through preferential adsorption reactions. For montmorrillonite also a simultaneous intercalation in the phyllosilicate interlayer is proposed.


Maternal obesity results in decreased syncytiotrophoblast synthesis of palmitoleic acid, a fatty acid with anti-inflammatory and insulin-sensitizing properties.
The fetus is dependent on delivery of fatty acids (FAs) by the syncytiotrophoblast, the transporting epithelium of the human placenta. Obese pregnant women have dyslipidemia; however, whether obesity impacts placental lipid transport and metabolism remains to be fully established. Palmitoleic acid (POA), an FA with anti-inflammatory and insulin-sensitizing properties, is synthesized from palmitic acid (PA) catalyzed by stearoyl-coenzyme A desaturase (SCD) activity. We hypothesized that the uptake and incorporation of FAs and POA synthesis are reduced in primary human trophoblasts (PHTs) isolated from pregnancies complicated by maternal obesity. Villous cytotrophoblasts were isolated from 7 placentas of obese [body mass index (BMI) = 37.5 ± 1.9] and 12 normal (BMI = 23.6 ± 0.6) mothers. FA uptake and incorporation were assessed using uniformly labeled (U[13C])-FA mixtures of PA, oleic acid (OA), linoleic acid, and docosahexaenoic acid. Cellular [13C] FAs were quantified both in total cellular lipids and in lipid classes by GC-MS. Uptake and incorporation of [13C] FAs in total cellular lipids were not different in PHTs isolated from obese mothers compared with normal mothers. Only the concentration of OA was increased in the triglyceride fraction (P < 0.05) if the mother was obese. We found an isotopic enrichment of POA after U[13C]-PA treatment, demonstrating SCD activity in PHT cells. Labeled POA content and the POA:PA ratio were significantly lower in PHTs isolated from placentas of obese mothers compared with normal, healthy controls. Decreased syncytiotrophoblast POA synthesis may contribute to insulin resistance and low-grade inflammation in the mother, placenta, or fetus (or a combination of the 3) in pregnancies complicated by obesity.-Ferchaud-Roucher, V., Barner, K., Jansson, T., Powell, T. L. Maternal obesity results in decreased syncytiotrophoblast synthesis of palmitoleic acid, a fatty acid with anti-inflammatory and insulin-sensitizing properties.


The role of neurotoxins in the periorbital and midfacial areas.
Initially popularized for the treatment of strabismus and blepharospasm, injection of botulinum neurotoxin has become the most commonly performed cosmetic treatment in the United States. Injection techniques have been particularly well-studied in the midface and periocular region, and patient satisfaction tends to be very high. We review the salient differences among available neurotoxins, how to optimally reconstitute them, how to inject the forehead, glabella, lateral canthal lines ("crow's feet"), infralid region, and transverse nasal lines ("bunny lines"), how to sculpt the brow, and how to manage potential complications.


A rare presentation of soft tissue chondroma: A case report.
Extraskeletal chondroma (ESC) is a benign, slow-growing cartilaginous tumor arising from tenosynovial sheaths. The aim of this article is to report and discuss a case of ESC affecting upper thigh. A 41-year-old male presented with a swelling in the medial aspect of the left thigh. On clinical examination, there was a 10 × 15 cm non-tender, hard, ill-defined mass in the medial aspect of the left upper thigh. Ultrasound showed a large well defined thick wall mass, located inside gracillis or adductor muscles. Magnetic resonance imaging showed a large well defined mass involving the adductor compartment of the upper thigh. The patient underwent wide local excision under spinal anesthesia. The histopathological examination of the specimen revealed binucleated chondrocytes with dots of calcification confirming ESC. There are many theories trying to explain the origin of ESC, as some authors think that it originates from the pluripotent cells of the tenosynovium, while others state that it may be derived from metaplasia of the tendon sheath. In this case, the lesion was completely surrounded by muscle fibers away from the nearby tendons. Extraskeletal chondroma is a rare benign lesion, although mostly affect the upper extremities, it can be found anywhere in the body, histopathological examination of the specimen is the diagnostic method of choice.


Spatial performance and perceptual asymmetries in beginning readers: shift of hand advantage in dichhaptic tasks.
The stability of perceptual asymmetries was studied in two groups of 6-year-old, right-handed children (normal, NL, and poor, PL) learning reading, by means of two experiments occurring at a year's interval (Experiment I and Experiment II). A dichhaptic procedure derived from S. F. Witelson's method (1974, Cortex, 10, 3-17) was used. With group data, perceptual asymmetries were stable over time, whereas with individual data, perceptual asymmetries were highly variable. NL children demonstrated a left-hand advantage at the group level in both Experiment I and Experiment II, with relatively little individual evolution over time. No significant hand advantage was found in PL children in Experiment I, but dramatic alterations occurred in Experiment II where all PL children shifted to a left-hand advantage. This shift was accompanied by an improvement in spatial performance. Such changes in perceptual asymmetry might be of an adaptive nature. Individual changes across time may be related to developmental plasticity (cerebral maturation) and/or neurocognitive flexibility (differential activation of cerebral subsystems).


[Propositions for the selection and the delineation of peritumoral microscopic disease volumes in oral cavity and oropharyngeal cancers (lymph nodes excluded)].
This article reviews the concept of selectivity in peritumoral microscopic disease to be included in the Clinical Target Volume (CTV) for elective treatment for oral cavity and oropharyngeal squamous cell carcinoma, using the local tumoral spread. The objective of the present article is to present a procedure for the delineation of the target volumes, required for an appropriate application of 3-DCRT and IMRT for head and neck cancers. These propositions are for the delineation of microscopic peritumoral target volumes when external beam irradiation is required. CTVs are illustrated on CT sections.


Effects of dietary fish oil on plasma high density lipoprotein. Electron spin resonance and fluorescence polarization studies of lipid ordering and dynamics.
Dietary fish oils are implicated in reducing the incidence of coronary heart disease, perhaps by altering the properties of plasma lipoproteins. The hypothesis that omega-3 polyunsaturated fatty acids (PUFA) in fish oils produce changes in lipid ordering and dynamics within high density lipoprotein (HDL), thereby potentially modifying cholesterol transport, is investigated here. Rabbits were fed a diet supplemented with either 10% (by weight) menhaden oil (MO), a fish oil rich in omega-3 PUFAs, or hydrogenated cottonseed oil for a period of 12 weeks. HDL was isolated by sequential flotation ultracentrifugation from plasma drawn every 2 weeks. Gas chromatography confirmed that the predominant omega-3 PUFAs of fish oils, eicosapentaenoic 20:5 and docosahexaenoic 22:6 acids, were only incorporated into the triglyceride, phospholipid, and cholesteryl ester constituents of lipoproteins from rabbits on the MO diet. ESR of 5- and 16-doxyl stearic acids demonstrates that molecular order and dynamics within the outer monolayer of HDL is virtually unaffected. In contrast, ESR of cholesteryl 12-doxyl stearate indicates order is less within the inner apolar core of the lipoprotein for the MO diet than for the hydrogenated cottonseed oil diet. Fluorescence polarization of 1,6-diphenyl-1,3,5-hexatriene supports this finding. The greater disorder detected within HDL from rabbits fed fish oil may result in an enhancement of cholesterol exchange between lipoproteins and between lipoproteins and cells, which may have anti-atherogenic ramifications.


Risk factors associated with albuminuria in Rwanda: results from a STEPS survey.
Non-communicable diseases (NCDs) are a growing burden which affects every part of the world, including developing countries. Chronic kidney disease (CKD) has varied etiology which can result from or complicate other NCDs such as diabetes and cardiovascular diseases. The growing prevalence of NCDs coupled with the increasing age in most developing countries, has seen a marked increase of CKD in these settings. CKD has been described as "the most neglected NCD" and greatly affects the quality of life of patients. It also places a huge economic burden on societies. However, few epidemiological data exist, particularly in sub-Saharan Africa. Assessment of the prevalence of albuminuria as a marker of kidney damage and CKD progression and its main risk factors was thus needed in Rwanda. This study analyzed data collected during the first STEPwise approach to NCD risk factor Surveillance (STEPS) survey in Rwanda, conducted from 2012 to 2013, to assess the prevalence of albuminuria. A multistage cluster sampling allowed to select a representative sample of the general population. Furthermore, descriptive, as well as univariable analyses and multiple logistic regression were performed to respond to the research question. This survey brought a representative sample of 6,998 participants, among which 4,384 (62.65%) were female. Median age was 33 years (interquartile range, IQR 26-44), and over three quarters (78.45%) lived in rural areas. The albuminuria prevalence was 105.9 per 1,000 population. Overall, semi-urban and urban residency were associated with lower odds of CKD (odds ratio, OR 0.36, CI 0.23-0.56, p<0.001 and OR 0.34, CI 0.23-0.50, p<0.001, respectively) than rural status. Being married or living with a partner had higher odds (OR 1.44 (CI 1.03-2.02, p=0.031) and OR 1.62 (CI 1.06-2.48, p=0.026), respectively) of CKD than being single. Odds of positive albuminuria were also greater among participants living with human immunodeficiency virus (HIV) (OR 1.64, CI 1.09- 2.47, p=0.018). Gender, age group, smoking status and vegetable consumption, body mass index (BMI) and hypertension were not associated with albuminuria. The albuminuria prevalence was estimated at 105.9 per 1,000 in Rwanda. Rural residence, partnered status and HIV positivity were identified as main risk factors for albuminuria. Increased early screening of albuminuria to prevent CKD among high-risk groups, especially HIV patients, is therefore recommended.


Reducing the risk of healthcare-acquired infection.
Many patients experience increased hospital stays, poor health outcomes, or die each year, as a result of healthcare-acquired infections. Evonne Curran discusses the most common types of infection and suggests how nurses can minimise the risks of infection in clinical settings.


Energy transfer across magnetopause under dawn-dusk IMFs.
A parametric study on the energy transfer of the solar wind across the magnetopause entering the magnetosphere is conducted using a global magnetohydrodynamic numerical simulation. The characteristics of the mechanical and electromagnetic energy distribution under the dawn-dusk interplanetary magnetic fields (IMFs) are investigated by analyzing magnetic reconnection and viscous effect, and compared with the radial and north-south IMFs. It is shown that (1) the interactions at the magnetopause and the transfer of energy across this boundary move in relation to the IMF orientation. (2) For the duskward IMF, the mechanical energy flow clearly enters the equatorial and low-latitude regions on the dayside, and the electromagnetic energy flow has a small inflow on the equatorial and low latitudes of the dayside. A significant energy inflow appears on the dawn side in the northern hemisphere and the dusk side in the southern hemisphere near the polar cusp. (3) The energy distribution characteristics across the magnetopause under dawn-dusk IMFs are mirror symmetric about the [Formula: see text] plane. (4) For a magnetic field of 5 nT, the electromagnetic energy input under the dawn-dusk IMFs is twice as large as the mechanical energy and the electromagnetic energy under the radial IMF, which is five times as large as the electromagnetic energy during the pure northward IMF, but only half as large as the electromagnetic energy under the pure southward IMF. The mechanical energy input under dawn-dusk IMFs has the same magnitude as that under radial and north-south IMFs. The magnitude of the energy transfer rate for the dawn IMF and dusk IMF (about 3.5%) is between 1.71% for the northward IMF and 4.95% for the southward IMF, but higher than 2.22% for the radial IMF. The Akasofu-type energy-coupling formula, [Formula: see text], underestimates the energy input from the solar wind under [Formula: see text] dominated IMF.


Increase of bone marrow lymphocytes in systemic mastocytosis: reactive lymphocytosis or malignant lymphoma? Immunohistochemical and molecular findings on routinely processed bone marrow biopsy specimens.
To clarify the nature (reactive or neoplastic) of lesional, perifocally aggregated lymphocytes in bone marrow infiltrates of systemic mastocytosis (SM), the histopathology of which can resemble malignant lymphoma with focal bone marrow involvement, particularly low grade malignant B cell lymphoma of lymphoplasmacytic immunocytoma subtype, which frequently exhibits increased mast cell (MC) numbers. Thirteen cases of SM and three of lymphoplasmacytic immunocytoma with predominant focal bone marrow infiltration were investigated. Immunostaining of formalin fixed, paraffin wax embedded bone marrow specimens was performed using antibodies against CD2, CD5, CD20, CD23, and CD25; kappa and lambda immunoglobulin light chains; and MC markers chymase, tryptase, and CD117 (KIT). Monoclonal rearrangements of IgH and TCRgamma were studied using seminested polymerase chain reaction (PCR). c-kit point mutation Asp816-Val was detected by PNA mediated PCR clamping and hybridisation probes. The lymphocytic clusters in SM contained nearly equal numbers of mature T and B cells, the latter with no coexpression of aberrant antigens, such as CD5 or CD23. Most MCs in SM cases constantly coexpressed tryptase, CD25, and CD117. No monoclonal rearrangements were seen for IgH or TCRgamma. In contrast, B cells from immunocytomas showed light chain restriction and monoclonal rearrangement for IgH, confirming their neoplastic nature. c-kit point mutation Asp816-Val was found in ten of 13 SM cases, but in none of the three immunocytomas. Focal accumulations of lymphocytes in the bone marrow of SM are reactive in nature and could be termed lymphocytosis. A diagnosis of SM-AHNMD/immunocytoma should not be made.


Hemophagocytic syndrome in children with acute monoblastic leukemia-another cause of fever of unknown origin.
Intensification of antileukemic treatment and progress in supportive management have improved the survival rates of children with acute myeloid leukemia (AML). However, morbidity and early mortality in these patients are still very high, especially in children with acute monoblastic leukemia (AML FAB M5). Inflammatory syndromes complicating the management of these children after application of cytosine arabinoside and due to hyperleukocytosis at initial presentation have been reported. Hemophagocytic lymphohistiocytosis (HLH) has been described as a serious and life-threatening acute complication during treatment of different oncologic entities; however, data on HLH in children with AML FAB M5 are extremely rare. A retrospective study of all children with AML FAB M5 treated at our institution between 1993 and 2013 was performed to describe the clinical characteristics of patients who developed an inflammatory syndrome with HLH during oncologic treatment. Three of 10 children developed an inflammatory syndrome with fever, elevation of C-reactive protein, hyperferritinemia, elevation of soluble interleukin-2, and hemophagocytosis during prolonged aplasia following the first cycle of chemotherapy not responding to broad-spectrum antibiotics. No infectious agents could be identified; the initial symptoms occurred 17, 18, and 28 days after diagnosis of AML, respectively. The children immediately responded to dexamethasone; however, the same syndrome was observed again after the second cycle of chemotherapy and, in one patient, also after the third cycle. Treating physicians should be aware of an inflammatory syndrome resembling HLH in children with monoblastic leukemia since this problem might extremely complicate management and supportive care of these children. The co-incidence of monoblastic leukemia with HLH might be explained by cytokines released from the monoblastic leukemic cells themselves.


Evaluation of Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy for Peritoneal Carcinomatosis of Colorectal Origin in the Era of Value-Based Medicine.
Peritoneal spread from colorectal cancer is second only to the liver as a site for metastasis. Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) is a well-established treatment option for patients with peritoneal carcinomatosis (PC) of colorectal origin. However, due to concerns regarding both its clinical benefit and high cost, its universal adoption as the standard of care for patients with limited peritoneal dissemination has been slow. The purpose of this review was to clarify the clinical utility and cost effectiveness of CRS-HIPEC in the treatment of colorectal PC using the framework of value-based medicine, which attempts to combine both benefit and cost into a single quantifiable metric. Our comprehensive review of the clinical outcomes and cost effectiveness of CRS-HIPEC demonstrate that it is a highly valuable oncologic therapy and a good use of healthcare resources.


Preclinical study of a "tailor-made" combination of NK4-expressing gene therapy and gefitinib (ZD1839, Iressa) for disseminated peritoneal scirrhous gastric cancer.
We evaluated the effect of a "tailor-made" chemo-gene therapy in scirrhous gastric cancer (SGC)-bearing nude mice. For this tailor-made approach, we first selected gefitinib (epidermal growth factor receptor-tyrosine kinase inhibitor)-sensitive SGC cell lines, and 5/8 cell lines demonstrated various degrees of gefitinib-sensitivity. In the highly gefitinib-sensitive NUGC-4, the biological response to NK4 (HGF antagonist/angiogenesis inhibitor) was examined. Subsequently, the composition of an NK4-expressing ternary complex (cationic lipid/nucleic acid/HMG-1, 2 protein) was optimized for maximum transfection activity in NUGC-4. Finally, mice were peritoneally coinoculated with NUGC-4 and scirrhous-associated gastric fibroblasts, NF22, on day 0. Animal models were orally administrated gefitinib (50 mg/kg/day, on days 7-28), and peritoneally NK4-expressing ternary complex (on days 14, 21 and 28). NK4-expression suppressed the gefitinib-resistance induced by the interaction between fibroblasts and SGC, and eventually, this tailor-made combination synergistically decelerated the disease progression by inhibiting proliferative, angiogenic and antiapoptotic effects in tumor tissues. On day 28, both the hemoglobin concentration (g/dl) (control (n = 8), 11.9; treated (n = 8), 17.3; p = 0.0014) and the numbers of mice in good condition (control, 2; treated, 8; p = 0.0012) were significantly greater, and the abdominal girth (mm) (control, 81.1; treated, 70.3; p = 0.0036) was significantly reduced. The median points of bloody ascite-free survival time (days) (control, 22; treated, 44; p < 0.0001) and time to euthanasia (days) (control, 36.5; treated, 56; p < 0.0001) were also significantly prolonged. This combination is a potentially useful approach to the treatment of peritoneal gefitinib-sensitive SGC dissemination.


Retraction.
Retraction: "The lncRNA SNHG3 accelerates papillary thyroid carcinoma progression via the miR-214-3p/PSMD10 axis", by Guoqing Sui, Butian Zhang, Dan Fei, Hui Wang, Feng Guo, and Qiang Luo, J Cell Physiol. 2020; 6615-6624: The above article, published online on 11 February 2020 in Wiley Online Library (https://onlinelibrary.wiley.com/doi/10.1002/jcp.29557) has been retracted by agreement between the authors, the journal's Editor in Chief, Prof. Dr. Gregg Fields, and Wiley Periodicals LLC. The retraction has been agreed after an investigation based on public allegations. The authors stated that unintentional errors occurred during the research process, and the experimental results cannot be verified.


Pathological findings in a Dachshund-cross dog with neuroaxonal dystrophy.
Neuroaxonal dystrophy (NAD) is a neurodegenerative condition affecting humans and animals characterized by the widespread presence of swollen axons (spheroids). Herein, we report the pathological findings in a case of neuroaxonal dystrophy in a Dachshund-cross puppy, which was euthanized because of a proprioceptive positioning deficits and irreversible ataxia of the hind limbs. Histologically, there was a bilaterally symmetric neuroaxonal dystrophy with eosinophilic axonal spheroids exclusively localized at the level of the ventral posterior lateral nucleus of the thalamus, medial lemniscus, gracilis nucleus, medial cuneatus nucleus in the brain as well as the gracilis and cuneatus fasciculi throughout the spinal cord. To the authors' knowledge, this is the first report of canine neuroaxonal dystrophy with this exclusive and specific localization only in the neuronal circuit implicated in the transmission of conscious proprioceptive information.


Lack of an association between granuloma annulare and type 2 diabetes mellitus.
Conflicting reports have been published regarding whether a relationship exists between granuloma annulare (GA) and diabetes mellitus (DM). To evaluate the prevalence of DM in patients with GA using a case-control design. The incidence of DM was determined in 126 patients with GA. Fifty of the 126 patients with GA were further compared with an age-, sex- and race-matched population of psoriasis patients seen during a similar time period in the same clinical setting. Eleven (9%) of 126 GA patients suffered from type 2 DM. In the matched comparison of 50 patients, 11 (22%) GA patients and 10 (20%) psoriasis patients suffered from type 2 DM. This case-control study failed to reveal any statistically significant correlation between GA and type 2 DM.


Attenuation and soil biodegradation of fungicides by using vegetated buffer strips in vineyards during a simulated rainfall-runoff event.
Rainfall-runoff events occurring in vineyard fields can result in pesticide ground losses and the subsequent pollution of surface water bodies, derivate from the crop protection spray applications. In this study, the capacity of vegetated buffer strips (BS) to prevent surface water pollution due to the application of five fungicide products typically used in vineyards (copper, dimethomorph, oxathiapiprolin, zoxamide, acibenzolar-s-methyl, and laminarin) following a simulated run-off event has been assessed, and compared to that from a bare ground soil (BG). Two strips (5 m in length, each), one with vegetation and the other without were built up, and two different experiments were performed, a runoff event and a soil fungicide degradation kinetic evaluation. The runoff results show that fungicide mass retention in the strips ranged from 73 to 98% and that the presence of vegetation in BS increased the fungicide mass retention in the strips by almost 10% (on average) in comparison to the unvegetated strip. Moreover, soil degradation studies highlighted that the presence of vegetation reduces significantly the half-time life of almost all the studied fungicides by 55%, on average. Eight fungicide transformation products (TPs) were identified following a runoff event in the soil strips, but the abundance of these TPs was up to 78% lower in vegetated strips. These results highlight the effectiveness of using vegetated buffer zones in vineyards to protect aquatic ecosystem pollution.


Limitation-induced fluorescence enhancement of carbon nanoparticles and their application for glucose detection.
Rational design of detection strategy is the key to high-performance fluorescence analysis. In this article, we found that the glucose-induced limitations can greatly enhance the fluorescence of functionalized carbon nanoparticles (CNPs), which are synthesized through one-step thermal pyrolysis method using phenylboronic acid derivative as the precursors. The glucose can assembly onto the surface of the CNPs to form a "shell", limiting the surfaces' intramolecular rotation and reducing non-radiative decay, which hence resulted in enhanced fluorescence of the CNPs. Under optimal conditions, the fluorescence intensity of the CNPs is nearly 70-fold enhanced, and the method has low detection limit (10 μM) and linear response in the concentration range from 50 μM to 2000 μM. Based on this interesting "target-triggered limitation-induced fluorescence enhancement" phenomenon, a simple and effective non-enzymatic fluorescence enhancement method was developed and successfully applied to the determination of glucose in spiked serum samples. This work provides new insight into the design of fluorescence-enhanced detection strategies based on the limitation-induced property.


Discrimination between intensity and affective pain descriptors: a psychophysiological evaluation.
The current study utilized a differential classical conditioning paradigm to test subjects' abilities to autonomically differentiate between pain descriptors that had previously been designated as belonging to the intensity or affective dimensions of pain perception. Twenty-one subjects were first tested for differences in spontaneous skin conductance responses (SCRs) and possible habituation to visual presentations of 23 intensity or affective pain descriptors. The classical conditioning procedure consisted of 46 12-sec visual trials. Each of the 23 pain descriptors was presented twice to each subject. Results indicated no differences in spontaneous SCR to intensity or affective descriptors and a clear habituation of response across trials. Results also indicated that the utilization of a differential classical conditioning paradigm produced an overall difference in SCR to the two sets of pain descriptors. The intensity-conditioned subjects demonstrated greater SC responsivity (P less than 0.0004) to intensity-related descriptors than to affective descriptors, and affective-conditioned subjects displayed greater skin conductance responsivity (P less than 0.0004) to affective pain descriptors than to pain intensity descriptors. These results provide psychophysiological support for a multidimensional conceptualization of pain and suggest the utility of classically conditioned autonomic responses in the further development and refinement of verbal pain descriptor scales.


Drinking milk or water has no effect on the severity of optokinetic rotation-induced symptoms of motion sickness.
The present study investigated the effects of drinking milk or water before viewing an optokinetic rotation drum on the severity of motion sickness and abnormal gastric myoelectric activity. There were 27 subjects who drank 300 ml of milk or water, or drank nothing, in three separate sessions with 2-d intervals between every two sessions. Subjects in each session then viewed a vertically striped optokinetic rotation drum for 16 min. Symptoms of motion sickness and electrogastrograms (EGGs) were measured. Subjects reported no significant difference in symptoms of motion sickness among sessions of drinking milk, water, or nothing. EGG recordings indicated that subjects in sessions of drinking milk and water significantly increased normal gastric myoelectric activity at EGG 3 cycles per minute (cpm). Subjects in all three sessions increased abnormal EGG activity at 4-9 cpm during drum rotation period, however, the ratios of EGG 4-9 cpm of drum rotation and baseline periods were not significantly different among sessions. These results demonstrated that drinking milk or water before viewing an optokinetic rotation drum exhibited no effect on the severity of symptoms of motion sickness and abnormal gastric myoelectric activity.


Duration of benefit per Dose: Carbidopa-Levodopa immediate release vs. extended release capsules (Rytary®).
For patients with Parkinson's disease, clinicians commonly assess duration of benefit for individual doses of levodopa in order to consider medication changes. To determine the mean duration of ON time per dose and mean duration of ON time without troublesome dyskinesia (WoTD) per dose of CD-LD IR vs. CD-LD ER in the ADVANCE-PD trial. We performed a post hoc analysis of the ADVANCE-PD trial. Mean ON time per dose and ON time WoTD was calculated at baseline and end-of-study (EOS). Changes were compared between CD-LD IR and CD-LD ER (Rytary®) treatment groups using an ANCOVA model. Mean (SD) baseline ON time per dose of CD-LD IR (n = 393) was 2.20 h. Patients randomized to double-blind treatment with CD-LD IR (n = 192) experienced an increase in mean ON time per dose from baseline to EOS from 2.24 h to 2.38 h. In comparison, patients randomized to double-blind treatment with CD-LD ER (n = 201) experienced an increase in mean ON time per dose from baseline (on CD-LD IR) to EOS (on CD-LD ER) from 2.17 h to 3.55 h. Conversion and optimization with CD-LD ER increased ON time per dose by 1.21 h more than optimization of CD-LD IR (p < 0.0001). Similarly, CD-LD ER increased ON time WoTD per dose by 1.16 h more than CD-LD IR (p < 0.0001). In the ADVANCE-PD trial, CD-LD ER significantly increased ON time per dose compared to CD-LD IR (+1.21 h, p < 0.0001) and provided significantly more ON time per dose (3.55 h vs 2.38 h, p < 0.0001).


The inhibition by bromothymol blue of anion translocation across the mitochondrial membrane.
1. In rat liver mitochondria bromothymol blue inhibited the exchange of [14C]succinate for succinate, malonate, L-malate and inorganic phosphate; the [14C]citrate/citrate and [14C]citrate/malate exchange reactions and the phosphate/hydroxyl exchange were also inhibited by this dye. The inhibition of the rate of succinate, citrate and phosphate uptake by bromothymol blue is found to be competitive. 2. The degree of inhibition by bromothymol blue of the ]14C]succinate/malonate exchange reaction was pH dependent. It has been shown that the inhibition increased linearly while the pH was increased from 6.0 to 8.2. However, the binding rate of bromothymol blue to the mitochondria decreased with the rising pH of the medium. It is concluded that the binding of acidic bromothymol blue was not essential for the inhibitory effect. 3. Other sulfonephthalein derivatives also inhibited [14C]succinate/malonate exchange reaction. At pH 7.2 the relative order of the strength of the inhibitory action of the sulfonephthalein compounds tested was: thymol blue greater than bronocresol green greater than bromothymol blue greater than phenol red greater than bromocresol purple. The results do not indicate any correlation between the pK values of pH values of pH indicators and their extents of inhibition. 4. It is suggested that the negatively charged bromothymol blue interacts with the positively charged centers of the anion carrier systems causing inhibition of membrane permeability for anions.


Optical coherence tomography angiography in patients with polypoidal choroidal vasculopathy.
To report the characteristics of polypoidal choroidal vasculopathy (PCV) based on optical coherence tomography angiography (OCTA) results. A retrospective, cross-sectional case series was conducted. Patients treated for PCV were evaluated with the OCTA system. The OCTA images of these patients were compared with those from indocyanine green angiography (ICGA). All eyes of consecutive patients with PCV were included. The mean age of the patients (five men and two women) was 67.86 ± 14.02 years. The mean number of anti-vascular endothelial growth factor injections was 10.43 ± 10.01. OCTA demonstrated branched vascular networks, which were detected by ICGA; however, polyps were not revealed consistently by OCTA. A total of 24 polyps were detected in seven eyes from seven patients by hyper-fluorescence on ICGA. However, only 12 polyps (50 %) were hyper-reflective on OCTA. PCV polyps were not detected as consistently by OCTA as by ICGA. This suggests that the polyps were detected differently by OCTA depending on blood flow in the polyp.


Prediction of Cyclic Fatigue Life of Nickel-Titanium Rotary Files by Virtual Modeling and Finite Elements Analysis.
The finite element method (FEM) has been proposed as a method to analyze stress distribution in nickel-titanium (NiTi) rotary instruments but has not been assessed as a method of predicting the number of cycles to failure (NCF). The objective of this study was to predict NCF and failure location of NiTi rotary instruments by FEM virtual simulation of an experimental nonstatic fatigue test. ProTaper Next (PTN) X1, X2, and X3 files (Dentsply Maillefer, Baillagues, Switzerland) (n = 20 each) were tested to failure using a customized fatigue testing device. The device and file geometries were replicated with computer-aided design software. Computer-aided design geometries (geometric model) were imported and discretized (numeric model). The typical material model of an M-Wire alloy was applied. The numeric model of the device and file geometries were exported for finite element analysis (FEA). Multiaxial random fatigue methodology was used to analyze stress history and predict instrument life. Experimental data from PTN X2 and X3 were used for virtual model tuning through a reverse engineering approach to optimize material mechanical properties. Tuned material parameters were used to predict the average NCF and failure locations of PTN X1 by FEA; t tests were used to compare FEA and experimental findings (P < .05). Experimental NCF and failure locations did not differ from those predicted with FEA (P = .098). File NCF and failure location may be predicted by FEA. Virtual design, testing, and analysis of file geometries could save considerable time and resources during instrument development.


Sensitive high-performance liquid chromatographic determination of ionic drugs in biological fluids with short-wavelength ultraviolet detection using column switching combined with ion-pair chromatography: application to basic compounds.
A highly sensitive and selective high-performance liquid chromatographic method with short-wavelength UV detection is described for the determination of ionic compounds in biological fluids, which was applied to two basic compounds, 2-(3-[4-(4-fluorophenyl)-1-piperazinyl]propyl)-6,7,8,9-tetrahydro-2H-nap htho [2,3-b][1,4]oxazin-3(4H)-one (I) and methyl 2-(4-diphenylmethyl-1-piperazinyl)ethyl (+/-)-1,4-dihydro-2,6-dimethyl-4-(m-nitrophenyl)-3,5-pyridinedicarboxyla te (II), in human serum. The method is based on the combination of the column-switching technique and ion-pair chromatography. In the first ODS column, the analyte is pre-separated from endogenous substances in serum by ion-pair chromatography. After column switching, in the second ODS column the heart-cut fraction containing the analyte is further separated by non-ion-pair chromatography from coeluted endogenous substances from the first ODS column. The proposed method offered high sensitivity and selectivity with UV detection at 215 nm for I and 230 nm for II. The detection limits were 0.2 ng/ml for both I and II using 1 ml of serum. The principle of the proposed method would be applicable to both acidic and basic compounds in biological fluids with a suitable ion-pair reagent.


Degradative activities in a recombinant chinese hamster ovary cell culture.
Two degradative activities were found in a recombinant Chinese hamster ovary cell culture. These activities became more dominant under high cell density and extended running time, as achieved in a semi-continous perfusion culture. The first, insulin degradative activity caused a growth upset in the 3rd cycle of the perfusion culture and shortened the length of the bioreactor process. The second activity, derived from the neutral pH stable sialidase, was found to affect the integrity of the carbohydrate structure of the recombinant protein, causing increase in heterogeneity in molecular weight and pI of the glycoforms. The most efficient way to overcome these problems may be the use of genetically altered 'designer cells' as the production cell line.


Simple and Fast SEC-Based Protocol to Isolate Human Plasma-Derived Extracellular Vesicles for Transcriptional Research.
Extracellular vesicles (EVs) are membranous structures that protect RNAs from damage when circulating in complex biological fluids, such as plasma. RNAs are extremely specific to health and disease, being powerful tools for diagnosis, treatment response monitoring, and development of new therapeutic strategies for several diseases. In this context, EVs are potential sources of disease biomarkers and promising delivery vehicles. However, standardized and reproducible EV isolation protocols easy to implement in clinical practice are missing. Here, a size exclusion chromatography-based protocol for EV-isolation from human plasma was optimized. We propose a workflow to isolate EVs for transcriptional research that allows concomitant analysis of particle number and size, total protein, and quantification of a major plasma contaminant. This protocol yields 7.54 × 109 ± 1.22 × 108 particles, quantified by nanoparticle tracking analysis, with a mean size of 115.7 ± 11.12 nm and a mode size of 83.13 ± 4.72 nm, in a ratio of 1.19 × 1010 ± 7.38 × 109 particles/μg of protein, determined by Micro Bicinchoninic Acid (BCA) Protein Assay, and 3.09 ± 0.7 ng RNA, assessed by fluorescence-based RNA-quantitation, from only 900 μL of plasma. The protocol is fast and easy to implement and has potential for application in biomarkers research, therapeutic strategies development, and clinical practice.


The effect of oxidative stress on accumulation of apolipoprotein E3 and E4 in a cell culture model of beta-amyloid angiopathy (CAA).
Apolipoprotein E (apoE) is a multifunctional molecule that is active during brain development, maintenance, and injury. Allele epsilon 4 of apoE is recognized as a risk factor for beta-amyloidosis, but the responsible mechanisms are not clear. Recently, we showed that vascular smooth muscle cells (SMCs) from epsilon 4/ epsilon 4 carriers are the most susceptible to oxidative protein damage that was associated with the appearance of apoE-Abeta-immunoreactive granules in cells. Here, we demonstrate that apoE4 is more readily accumulated in SMCs treated with ferrous ions than is apoE3. ApoE accumulated in lysosomes in the form of monomers, dimers, apoE-containing complexes, and apoE fragments. ApoE4 and apoE4-containing complexes persisted in SMCs longer than apoE3 and its complexes. Both isoforms of apoE stimulated formation of apoE-Abeta deposits and increased immobilization of iron in cultures treated with ferrous ions. The accumulation of apoE-Abeta deposits in lysosomes was associated with the appearance of lipid peroxidation products such as malondialdehyde and 4-hydroxynonenal-2-nonenal. The higher cellular accumulation of apoE4 than apoE3 in SMCs exposed to oxidative stress may facilitate development of beta-amyloid angiopathy that is more frequent in epsilon 4/ epsilon 4 carriers.


gamma Rays from close binaries in the quiet stage.
THE presence of rotating neutron stars in binary systems is revealed by the existence of X-ray pulsators which are generally associated with massive companions. The evolutionary history of these systems is now relatively clear (see ref. 1 and refs therein). The X-ray phase, which corresponds to accretion on the neutron star of a strong stellar wind \M approximately 10(-6) M(\circ) yr(-1), is preceded by a much longer quiet state, where the primary is unevolved, possibly with a weak wind, \M approximately 10(-9) M(\circ) yr(-1) and the rotational energy loss of the neutron star inhibits accretion. However, with the only exception of PSR1913 + 16, radio pulsars are not found in binary systems. Here, motivated by the recent discovery of gamma-ray emission from slow pulsars(2,3), we suggest (gamma)-ray observations as a way of detecting binaries in the quiet state and compare the expected number with the COS B results. We refer to the review of van den Heuvel(1) where, as a representative case, a system of initial mass 20 + 8 M(\circ) and orbital period 4.7 d is considered. After the first stage of mass exchange and the supernova explosion, one has a neutron star with an unevolved companion of 22.7 M(\circ). The period is now P = 12.6 d. The primary remains on the main sequence (quiet stage) for t(ms) = 3.6 x 10(6)yr. The X-ray phase occurs after the star has left the main sequence, but before it fills its Roche lobe, as an excessive mass transfer absorbs the X-ray emission. Its duration is t(x) approximately 10(4)yr.