Expression of a novel NAC domain-containing transcription factor (CaNAC1) is preferentially associated with incompatible interactions between chili pepper and pathogens.
We aim to isolate genes in chili pepper that are regulated during the hypersensitive response to infection by nonhost pathogens, with a view to elucidating the defense responses against pathogen attack. Among the 90 transcription factors initially characterized by reverse RNA gel blot analysis, a cDNA clone, CaNAC1 (Capsicum annuum NAC1) containing the plant-specific NAC domain motif was further characterized. Expression of the CaNAC1 gene was rapidly and specifically induced during incompatible interactions between pepper and bacterial or viral pathogens. Additionally, this gene was strongly induced by exogenously applied salicylic acid and ethephon, whereas methyl jasmonate only had a transient effect. A CaNAC1-smGFP (soluble modified green fluorescent protein) fusion protein localized to the nucleus following transfection into the epidermis of onion. Using the yeast system, we further disclose that the transcription activation domain of CaNAC1 is located in the C-terminal half of the protein. Our results collectively suggest that the plant-specific NAC domain protein, CaNAC1, may play a role in the regulation of defense responses in plants.


Managing hospitalized patients with bacterial infections: the price-to-pay upon site of infection.
Infections impose a significant burden on healthcare costs worldwide. We aimed to explore antibiotic- and hospital-related costs of infections needing admission in a tertiary university hospital in Greece. We performed a prospective cohort study in the medical care unit of a tertiary university hospital in Greece, for the period May 2016 to May 2018. Patients admitted with respiratory, urinary, gastrointestinal tract, skin, soft tissue and bone infections or primary bacteremia were included in this study. Costs of hospitalization and unit cost of antibiotic regimen were retrieved from a database for Greek hospitals containing data for each International Classification of Diseases (ICD-10) code and the national formulary respectively, and manually calculated for each patient. Antibiotic costs represent approximately 14-40% of total hospital-related costs depending on infection studied. Skin, soft tissue and bone infections and primary bacteremia led hospital- and antibiotic-related costs, with median costs of €6370 (interquartile range (IQR) 3330.90-11 503.90), €2519.90 (IQR 431.50-8371.10), €4418.10 (IQR 2335-8281.90) and €1394.30 (IQR 519.12-6459.90), respectively. Antibiotic- and hospital-related costs significantly differs with site of infection (p<0.0001). Length of stay is strongly correlated with antibiotic- and hospital-related costs, while site of infection is moderately related to antibiotic cost (eta value 0.445), and hospital-related cost (eta value 0.387). Healthcare-related costs vary substantially depending on site of infection. Information about real-life costs can drive best decisions and help to reduce healthcare expenditures.


Factor Xa inhibitor rivaroxaban suppresses experimental abdominal aortic aneurysm progression via attenuating aortic inflammation.
Rivaroxaban is a specific factor Xa (FXa) inhibitor for venous thromboembolism treatment. Recently, increasing evidence have reported the beneficial effects of rivaroxaban on treating cardiovascular disorders such as coronary and peripheral artery disease. However, its potential influence on abdominal aortic aneurysm (AAA) remains unclear. This study aims to investigate whether rivaroxaban treatment could attenuate experimental AAA progression and its related mechanisms. In human aneurysmal aorta, FXa protein expression was significantly upregulated. Further investigations identified a positive correlation among plasma FXa level, AAA severity (the maximal aortic diameter), and intra-aneurysmal thrombus percentage. In Ang II (angiotensin II)-infused ApoE-/- mice, the administration of high dose rivaroxaban (15 mg/kg/d) for 14 days significantly reduced the maximal aortic diameter, while low dose rivaroxaban (5 mg/kg/d) did not display such a protective role. Although rivaroxaban treatments reduced the incidence of AAA and thrombus formation, these differences did not reach statistical significance. Immunohistochemistry revealed a pronounced aortic remodeling including increased collagen content and enhanced elastin degradation in Ang II-induced AAAs, which was inhibited by high dose rivaroxaban treatment. Further analysis demonstrated that rivaroxaban exerted its protective effects by decreasing leukocyte infiltration, inflammatory cytokines expression, and matrix metalloproteinases (MMPs) expression in the aortic wall. The inhibitory effect of rivaroxaban on aneurysm development was also observed in calcium chloride-induced AAA model. Mechanistically, in human aortic endothelial cells, FXa stimulation increased the expression of inflammatory cytokines (interleukin (IL)-1β, IL-6, IL-8, monocyte chemoattractant protein-1) and adhesive molecules, which were all reversed by the cotreatment of rivaroxaban. Subsequent monocyte-endothelial cell interaction was enhanced after FXa stimulation and was alleviated by rivaroxaban cotreatment. In addition, FXa induced a significantly heightened expression of MMP2 in human aortic endothelial cells, which was ameliorated by rivaroxaban coadministration. Rivaroxaban attenuated both angiotensin II- and calcium chloride-induced abdominal aortic aneurysm (AAA) progressions, through inhibiting aortic remodeling and inflammation. Rivaroxaban could be a promising therapeutic agent in attenuating AAA development by counteracting FXa-induced aortic wall inflammation.


Capillary CAA and perivascular Aβ-deposition: two distinct features of Alzheimer's disease pathology.
Cerebral amyloid angiopathy (CAA) is frequently seen in Alzheimer's disease (AD) cases and represents one of its histopathological hallmarks. CAA is characterized by amyloid β-protein (Aβ) deposits within vessel walls. In addition to arteries and veins capillaries can also be affected. Aβ deposition into the capillary wall is, thereby, known as capillary CAA (capCAA) and strongly associated with the apolipoprotein E APOEε4 allele as a risk factor. Aβ deposits along the pericapillary glia limitans are described as pericapillary Aβ (pericapAβ: synonymous with pericapillary CAA in other studies). Here, we studied the relationship between pericapAβ and capCAA in 58 human autopsy cases. Although pericapAβ and capCAA were more frequently found in AD cases compared to controls and although they exhibited a correlation to one another, detailed analysis revealed that there is a significant number of cases with pericapAβ lacking capCAA and vice versa. Moreover, single capillaries show either both pathologies or pericapAβ or capCAA only. There was no local association between these pathologies when analyzing multiple capillaries in each given case. Moreover, pericapAβ predominantly exhibited Aβ(42) whereas capCAA contained both Aβ(42) and Aβ(40). These differences as well as differences in the related astroglial reaction indicate that pericapAβ and capCAA are not directly linked. PericapAβ appears to represent initial Aβ accumulation along the glia limitans that is involved in the perivascular drainage of apoE and Aβ regardless of the APOE genotype whereas capCAA could be explained by a limited transendothelial clearance of apoE4-Aβ complexes compared to apoE2/3-Aβ complexes.


Chronic lathyrism and atheromatosis in the rat. Study of the V.L.D.L. and plasma and arterial wall lipids.
Temporary chronic administration of Beta-amino-propionitrile (B.A.P.N.) produced morphological and biochemical changes of the aortic wall of rat as well as abnormalities of the plasma lipid levels. A hyperlipidic diet resulted in the blood plasma lipid abnormalities as B.A.P.N. intoxication. Nine weeks of B.A.P.N. followed by 42 weeks of a hyperlipidic diet increased the aortic cholesterol level and induced an atheroma. The diet alone produced only an endothelial lipid overload. The structure of arterial wall played the decisive role in atherogenesis.


Brain-derived neurotrophic factor from follicular fluid is positively associated with rate of mature ooocytes collected and cleavage rate in intracytoplasmic sperm injection patients.
The aim of the study was to evaluate the correlation between BDNF and oocyte maturation and to verify whether BDNF could predict in vitro fertilization (IVF) outcome. The follicle fluid (FF) for BDNF, E(2) and P assay were obtained from 59 patients undergoing intracytoplasmic sperm injection (ICSI). The women were divided into two groups by pregnancy outcome and their clinical and lab data were compared. And the correlation of BDNF with E(2), P, age, and IVF data were analyzed. Positive correlation was observed between BDNF and E(2) concentration in FF. BDNF was positively correlated with the rate of mature oocytes collected and cleavage rate. The BDNF in FF could not predict IVF outcome, but BDNF in FF might play an important role in the maturation of oocyte and development of oocyte into preimplantation embryo.


Inaccuracy of Wolff-Parkinson-white accessory pathway localization algorithms in children and patients with congenital heart defects.
ECG algorithms used to localize accessory pathways (AP) in patients with Wolff-Parkinson-White (WPW) syndrome have been validated in adults, but less is known of their use in children, especially in patients with congenital heart disease (CHD). We hypothesize that these algorithms have low diagnostic accuracy in children and even lower in those with CHD. Pre-excited ECGs in 43 patients with WPW and CHD (median age 5.4 years [0.9-32 years]) were evaluated and compared to 43 consecutive WPW control patients without CHD (median age 14.5 years [1.8-18 years]). Two blinded observers predicted AP location using 2 adult and 1 pediatric WPW algorithms, and a third blinded observer served as a tiebreaker. Predicted locations were compared with ablation-verified AP location to identify (a) exact match for AP location and (b) match for laterality (left-sided vs right-sided AP). In control children, adult algorithms were accurate in only 56% and 60%, while the pediatric algorithm was correct in 77%. In 19 patients with Ebstein's anomaly, diagnostic accuracy was similar to controls with at times an even better ability to predict laterality. In non-Ebstein's CHD, however, the algorithms were markedly worse (29% for the adult algorithms and 42% for the pediatric algorithms). A relatively large degree of interobserver variability was seen (kappa values from 0.30 to 0.58). Adult localization algorithms have poor diagnostic accuracy in young patients with and without CHD. Both adult and pediatric algorithms are particularly misleading in non-Ebstein's CHD patients and should be interpreted with caution.


The nose is hungrier than the eyes.
Vision and olfaction are the main sensory channels for appraising food prior to eating. Motivational models often assume that these sensory channels function in an equivalent manner. We tested this notion by asking participants to rate their desire for some snacks only via smell and others only via vision. In the next phase, participants consumed a small sample of every snack, now with all of the senses available, rating liking and desire for more. After consuming a meal, participants repeated the desire/liking test. Sensing via olfaction, relative to vision, led to greater desire ratings irrespective of state. When hungry, judgments of liking and desire for more were higher for foods that were initially smelled relative to those that were initially seen. Across the meal, visually based desire ratings declined more than those based on smell, relative to ratings made when the snacks were tasted. Together, this suggests motivational equivalence does not hold for olfaction and vision. We suggest this may be due to a greater reliance on memory for generating visually based desire.


Randomised trial of infant sleep location on the postnatal ward.
To determine whether postnatal mother-infant sleep proximity affects breastfeeding initiation and infant safety. Randomised non-blinded trial analysed by intention to treat. Postnatal wards of the Royal Victoria Hospital (RVI), Newcastle upon Tyne, UK. 64 newly delivered mother-infant dyads with a prenatal intention to breastfeed (vaginal deliveries, no intramuscular or intravenous opiate analgesics taken in the preceding 24 h). Infants were randomly allocated to one of three sleep conditions: baby in mother's bed with cot-side; baby in side-car crib attached to mother's bed; and baby in stand-alone cot adjacent to mother's bed. Breastfeeding frequency and infant safety observed via night-time video recordings. During standardised 4-h observation periods, bed and side-car crib infants breastfed more frequently than stand-alone cot infants (mean difference (95% confidence interval (CI)): bed v stand-alone cot = 2.56 (0.72 to 4.41); side-car crib v stand-alone cot = 2.52 (0.87 to 4.17); bed v side-car crib = 0.04 (-2.10 to 2.18)). No infant experienced adverse events; however, bed infants were more frequently considered to be in potentially adverse situations (mean difference (95% CI): bed v stand-alone cot = 0.13 (0.03 to 0.23); side-car crib v stand-alone cot = 0.04 (-0.03 to 0.12); bed v side-car crib = 0.09 (-0.03-0.21)). No differences were observed in duration of maternal or infant sleep, frequency or duration of assistance provided by staff, or maternal rating of postnatal satisfaction. Suckling frequency in the early postpartum period is a well-known predictor of successful breastfeeding initiation. Newborn babies sleeping in close proximity to their mothers (bedding-in) facilitates frequent feeding in comparison with rooming-in. None of the three sleep conditions was associated with adverse events, although infrequent, potential risks may have occurred in the bed group. Side-car cribs are effective in enhancing breastfeeding initiation and preserving infant safety in the postnatal ward.


Prostaglandin E2 restrains human Treg cell differentiation via E prostanoid receptor 2-protein kinase A signaling.
Regulatory T cells (Treg cells) belong to a class of immunosuppressive cells that control the pathological changes of autoimmunity and inflammation. Prostaglandin E2 (PGE2) is a potent lipid mediator of immune inflammation including rheumatoid arthritis (RA) that exerts its effects via four subtypes of G-protein-coupled receptors (EP1-4). The ability of PGE2 to regulate human Treg differentiation has not yet been reported. In the current study, we investigated the effects of PGE2 on the differentiation of naïve T cells from healthy and RA patients into Treg cells and the intracellular signaling involved in this process in vitro. Our data indicate that PGE2 negatively influenced the percentage of Treg cells and Foxp3 mRNA expression. The regulatory effects of PGE2 were associated with increased intracellular cAMP levels and PKA activity. EP2 receptors may mediate the inhibitory role of PGE2, since PGE2 actions were mimicked by EP2 agonist (Butaprost) and cAMP agonist (Sp-8-CPT-cAMPS) but were reversed by an EP2 antagonist (PF-04418948) and a PKA inhibitor (H-89). PGE2 negatively modulated the expression of cytotoxic T lymphocyte antigen-4 (CTLA-4) and glucocorticoid-induced tumor necrosis factor receptor-related protein (GITR), as well as the production of interleukin (IL)-10 by Treg cells via EP2 receptors and cAMP/PKA signaling. All these findings indicate that PGE2 can inhibit Treg differentiation mediated through the EP2-cAMP/PKA signaling pathway, and suggest novel immune-based therapies for use in RA treatment.


Perimeter and carvacrol-loading regulate angiogenesis and biofilm growth in 3D printed PLA scaffolds.
Carvacrol is a natural low-cost compound derived from oregano which presents anti-bacterial properties against both Gram-positive and Gram-negative bacteria. In this work, carvacrol-loaded PLA scaffolds were fabricated by 3D printing as platforms to support bone tissue regeneration while preventing biofilm development. Scaffolds were printed with or without a perimeter (lateral wall) mimicking the cortical structure of bone tissue to further evaluate if the lateral interconnectivity could affect the biological or antimicrobial properties of the scaffolds. Carvacrol incorporation was performed by loading either the PLA filament prior to 3D printing or the already printed PLA scaffold. The loading method determined carvacrol localization in the scaffolds and its release profile. Biphasic profiles were recorded in all cases, but scaffolds loaded post-printed released carvacrol much faster, with 50-80% released in the first day, compared to those containing carvacrol in PLA filament before printing which sustained the release for several weeks. The presence or absence of the perimeter did not affect the release rate, but total amount released. Tissue integration and vascularization of carvacrol-loaded scaffolds were evaluated in a chorioallantoic membrane model (CAM) using a novel quantitative micro-computed tomography (micro-CT) analysis approach. The obtained results confirmed the CAM tissue ingrowth and new vessel formation within the porous structure of the scaffolds after 7 days of incubation, without leading to hemorrhagic or cytotoxic effects. The absence of lateral wall facilitated lateral integration of the scaffolds in the host tissue, although increased the anisotropy of the mechanical properties. Scaffolds loaded with carvacrol post-printing showed antibiofilm activity against Staphylococcus aureus and Pseudomonas aeruginosa as observed in a decrease in CFU counting after biofilm detachment, changes in metabolic heat measured by calorimetry, and increased contact killing efficiency. In summary, this work demonstrated the feasibility of tuning carvacrol release rate and the amount released from PLA scaffolds to achieve antibiofilm protection without altering angiogenesis, which was mostly dependent on the perimeter density of the scaffolds.


Bis[3,5-di-fluoro-2-(pyridin-2-yl)phen-yl](4,4'-di-meth-oxy-2,2'-bi-pyridine)-iridium(III) hexa-fluorido-phosphate.
The title cyclo-metalated distorted octa-hedral iridium complex, [Ir(C11H6F2N)2(C12H12N2O2)]PF6, exhibits elongated Ir-N bonds to the dimeth-oxy bi-pyridine ligand [2.128 (3) and 2.136 (3) Å] where these nitro-gen atoms are trans to the Ir-C bonds of the two cyclo-metalating di-fluoro-phenyl-pyridine ligands. The angles between the mean planes of the phenyl and pyridyl fragments within the individual ligands range from 3.5 (2) to 11.4 (2)° to deviate slightly from coplanarity.


Addiction of mesenchymal phenotypes on the FGF/FGFR axis in oral squamous cell carcinoma cells.
The epithelial-mesenchymal transition (EMT) is a crucial morphological event that occurs during epithelial tumor progression. ZEB1/2 are EMT transcription factors that are positively correlated with EMT phenotypes and breast cancer aggressiveness. ZEB1/2 regulate the alternative splicing and hence isoform switching of fibroblast growth factor receptors (FGFRs) by repressing the epithelial splicing regulatory proteins, ESRP1 and ESRP2. Here, we show that the mesenchymal-like phenotypes of oral squamous cell carcinoma (OSCC) cells are dependent on autocrine FGF-FGFR signaling. Mesenchymal-like OSCC cells express low levels of ESRP1/2 and high levels of ZEB1/2, resulting in constitutive expression of the IIIc-isoform of FGFR, FGFR(IIIc). By contrast, epithelial-like OSCC cells showed opposite expression profiles for these proteins and constitutive expression of the IIIb-isoform of FGFR2, FGFR2(IIIb). Importantly, ERK1/2 was constitutively phosphorylated through FGFR1(IIIc), which was activated by factors secreted autonomously by mesenchymal-like OSCC cells and involved in sustained high-level expression of ZEB1. Antagonizing FGFR1 with either inhibitors or siRNAs considerably repressed ZEB1 expression and restored epithelial-like traits. Therefore, autocrine FGF-FGFR(IIIc) signaling appears to be responsible for sustaining ZEB1/2 at high levels and the EMT phenotype in OSCC cells.


Renal and circulatory dysfunction in cirrhosis: current management and future perspectives.
Chronic liver diseases are amongst the top leading causes of death in Europe as well as in other areas of the world. Chronic liver diseases are characterized by unrelenting progression of liver inflammation and fibrosis over a prolonged period of time, usually more than 20 years, which may eventually lead to cirrhosis. Advanced cirrhosis leads to a complex syndrome of chronic liver failure which involves many different organs besides the liver, including the brain, heart and systemic circulation, adrenal glands, lungs, and kidneys. The high morbidity and mortality secondary to chronic liver failure is due to complications related to the dysfunction of these organs, either alone or, more frequently, in combination. Understanding the mechanisms leading to organ dysfunction is crucial to the development of strategies for treatment and prevention of complications of cirrhosis. This article reviews our current knowledge, as well as future perspectives, on the management of circulatory and renal dysfunction in chronic liver failure.


Color Doppler evaluation of the ocular arterial flow changes in chronic obstructive pulmonary disease.
To evaluate the hemodynamic changes in the extraocular orbital vessels of the patients with chronic obstructive pulmonary disease (COPD), using color Doppler ultrasonography (CDU) technique, and to compare the results with those of healthy control subjects. Forty-five patients with COPD and 17 healthy control subjects were included in this study. Patients with COPD were classified according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD). Fifteen patients of stage I COPD (mild airflow limitation), stage II COPD (worsening airflow limitation) or stage III COPD (severe airflow limitation) were enrolled into Group I, II and III, respectively. End tidal carbon dioxide (EtCO(2)), peripheral oxygen saturation (SpO(2)), pulse rate (PR) and respiratory rate (RR) were measured by using capnograph/pulse oximeter in all patients. Measurements were performed in only one randomly chosen eye of each participant. The peak systolic velocity (PSV), end-diastolic velocity (EDV), and resistance index (RI) were measured in the ophthalmic artery (OA), central retinal artery (CRA), lateral short posterior ciliary artery (LPCA) and medial short posterior ciliary artery (MPCA), using CDU technique. The PSV measurements of the OA were significantly higher in Groups II and III compared to control group (p < 0.01, p < 0.001, respectively). The RI values from OA and CRA were significantly higher in Group II and III than the control group (p < 0.05). The RI values of LPCA and MPCA were also significantly higher in Group II than the control subjects (p < 0.05). When RI values were compared, mean values of LPCA and MPCA were significantly lower in Group III than in Group II (p < 0.05). There were no significant differences between Group I and control patients about PSVs, EDVs and RI values of all arteries Statistically significant correlations were found for the EtCO(2) with PSV (r = 0.53, p < 0.01) and EDV (r = 0.51, p < 0.01) of the OA. Statistically significant correlations were also found for the SpO2 with RI (r = -0.34, p < 0.05) in the OA. We concluded that COPD is associated with impaired retrobulbar hemodynamics, especially in the ophthalmic artery. Moreover, central retinal and posterior ciliary arteries with increased resistance are also found to be affected when compared with healthy control eyes.


Role of the insulin-like growth factor 1 axis and visceral adiposity in oesophageal adenocarcinoma.
Epidemiological studies have linked obesity with many cancers. The insulin-like growth factor (IGF) 1 axis may be an important mediator in obesity-associated cancer. This study examined the relationship between IGF-1 and its receptor (IGF-1R) in oesophageal adenocarcinoma, a cancer strongly linked to obesity. Patients with oesophageal adenocarcinoma considered suitable for attempted curative treatment were studied. Visceral adiposity was defined by waist circumference or visceral fat area. Free and total IGF-1 in serum were measured by enzyme-linked immunosorbent assay. Quantitative polymerase chain resection was used to determine mRNA expression of IGF-1 and IGF-1R in resected tumour samples. IGF-1R expression in tissue microarrays (TMAs) was quantified by immunohistochemistry. A total of 220 patients were studied. Total and free IGF-1 levels were significantly increased in the serum of viscerally obese patients. Gene expression analysis revealed a significant association between obesity status and both IGF-1R (P = 0·021) and IGF-1 (P = 0·031) in tumours. TMA analysis demonstrated that IGF-1R expression in resected tumours was significantly higher in viscerally obese patients than in those of normal weight (P = 0·023). Disease-specific survival was longer in patients with negative IGF-1R expression than in those with IGF-1R-positive tumours (median 60·0 versus 23·4 months; P = 0·027). This study highlighted the association of the IGF axis with visceral obesity, and a potential impact on the biology of oesophageal adenocarcinoma through its receptor. Targeting the IGF axis may have a rationale in future studies.


Prediction of Trauma Mortality Incorporating Pre-injury Comorbidities Into Existing Mortality Scoring Indices.
The purpose of the study is to develop a comprehensive risk score of mortality in trauma victims that can predict the in-hospital mortality better than trauma injury severity score (TRISS) and A Severity Characterization of Trauma (ASCOT) score. All hospitalized trauma patients, between the ages of 16 and 89 years old were included in the study. The National Trauma Quality Improvement Program (TQIP) database of the calendar year 2011-2016 was accessed for the development of a traum mortality scoring system (TMS). The prediction of mortality was tested by creating a receiver operating characteristics (ROC) curve and an area under the curve (AUC). ROCs and AUCs of TMS were compared with TRISS and ASCOT score. The AUC of TMS (0.892, 95% CI: 0.888-0.896) was better than TRISS (0.864, 95% CI: 0.859-0.869, P <0.0001) and ASCOT (0.841, 95% CI: 0.835-0.846, P <0.0001), respectively, in blunt injury. Similarly, TMS prediction (AUC: 0.949, 95% CI: 0.940-0.958) was better in penetrating injury when compared with TRISS (0.942, 95% CI: 0.934-0.951, P = 0.030) and ASCOT (0.924, 95% CI: 0.912-0.936, P <0.0001), respectively. TMS can predict the in-hospital mortality better than TRISS and ASCOT.


Promoter regions of the human X-linked housekeeping genes PRPS1 and PRPS2 encoding phosphoribosylpyrophosphate synthetase subunit I and II isoforms.
The 5' regions of the human phosphoribosylpyrophosphate synthetase subunit I and II genes (PRPS1 and PRPS2, respectively) were isolated and sequenced. A comparison of the nucleotide sequences between human and rat PRPS1 genes revealed that the sequences around the transcription initiation sites were conserved over 56 nucleotides, and that a TATA-like sequence, a CCAAT box and three putative Sp1 binding sites were present at almost the same positions in the GC-rich sequences. Two major transcription initiation sites were localized in the human PRPS1, one of the two was located 27 nucleotides downstream from the TATA-like sequence, while the upstream initiation site was in the TATA-like sequence. The promoter region of the human PRPS2 gene was also GC-rich and contained a TATA-like sequence, four Sp1 binding sites and a homopyrimidine stretch. The initiation sites were localized at 90 nucleotides upstream from the ATG initiation codon. Chloramphenicol acetyltransferase (CAT)/promoter fusion assays showed that a 2.0 kb region (human PRPS1) and a 1.1 kb region (human PRPS2) possessed the promoter activities in four cell lines. The CAT activities in the three human cell lines tended to correlate with the steady-state mRNA levels of the PRPS1 and PRPS2 genes. These results suggest that the 5' flanking regions cloned contribute to the cell-differential expression of these two genes.


Histone deacetylase 1 interacts with HIV-1 Integrase and modulates viral replication.
HIV-1 hijacks the cellular machinery for its own replication through protein-protein interactions between viral and host cell factors. One strategy against HIV-1 infection is thus to target these key protein complexes. As the integration of reverse transcribed viral cDNA into a host cell chromosome is an essential step in the HIV-1 life cycle, catalyzed by the viral integrase and other important host factors, we aimed at identifying new integrase binding partners through a novel approach. A LTR-derived biotinylated DNA fragment complexed with the integrase on magnetic beads was incubated with extracts from integrase-expressing 293 T cells. Liquid chromatography-mass spectrometry/mass spectrometry and co-immunoprecipitation/pull-down experiments were used for the identification of binding partners. Transfections of histone deacetylase 1 (HDAC1) expression vectors and/or specific siRNA were conducted in HeLa-CD4 and 293 T cells followed by infection with fully infectious NL4-3 and luciferase-expressing pseudotyped viruses or by proviral DNA transfection. Fully infectious and pseudotyped viruses produced from HDAC1-silenced 293 T cells were tested for their infectivity toward HeLa-CD4 cells, T cell lines and primary CD4+ T cells. Late RT species and integrated viral DNA were quantified by qPCR and infectivity was measured by luciferase activity and p24 ELISA assay. Results were analyzed by the Student's t-test. Using our integrase-LTR bait approach, we successfully identified new potential integrase-binding partners, including HDAC1. We further confirmed that HDAC1 interacted with the HIV-1 integrase in co-immunoprecipitation and pull-down experiments. HDAC1 knockdown in infected HeLa cells was shown to interfere with an early preintegration step of the HIV-1 replication cycle, which possibly involves reverse transcription. We also observed that, while HDAC1 overexpression inhibited HIV-1 expression after integration, HDAC1 knockdown had no effect on this step. In virus producer cells, HDAC1 knockdown had a limited impact on virus infectivity in either cell lines or primary CD4+ T cells. Our results show that HDAC1 interacts with the HIV-1 integrase and affects virus replication before and after integration. Overall, HDAC1 appears to facilitate HIV-1 replication with a major effect on a preintegration step, which likely occurs at the reverse transcription step.


Schneider's first rank symptoms--prevalence, diagnostic use and prognostic implications.
An evaluation of the prevalence of Schneiderian first-rank symptoms, and their diagnostic and prognostic value is described. 35.2 per cent of schizophrenic patients had first-rank symptoms. The presence of first-rank symptoms did not indicate either chronicity of illness or a poor outcome.


Fibrinogen for the prediction of severe maternal complications in placental abruption with fetal death after 24 weeks of gestation.
To assess the correlation between standard laboratory indicators at admission and severe maternal complications due to placental abruption (PA) with intrauterine fetal death (IUFD) after 24 weeks. Retrospective study in three French tertiary referral hospitals. Correlation of laboratory indicators at admission (platelet count, prothrombin, activated partial thromboplastin time, fibrinogen) and severe maternal complications (massive transfusion, multiple organ failure, hysterectomy, or maternal deaths) in patients with PA and IUFD. Over 12 years, we identified 27/344 (7.8%) pregnant women presenting PA with IUFD. No patient had coagulopathy at admission. Fifteen individuals (55.5%) underwent delivery by cesarean section before or during labor. Fifteen individuals (55.5%) presented severe complications, and 17/27 (63%) lost more than 1 L of blood during delivery. Fibrinogen level was shown to be the laboratory indicator most correlated with severe complications (r = -0.52, P = 0.01). The receiver operating characteristic curve of fibrinogen less than 1.9 g/L in the prediction of severe complications (area under the curve = 0.80, 95% confidence interval [CI] 0.54-0.97) showed both a sensitivity and specificity of 83% (95% CI 54%-96%). In cases of IUFD with PA, fibrinogen levels at admission had a prognostic value for the prediction of severe maternal complications.


Disability culture in West Africa: qualitative research indicating barriers and progress in the greater Accra region of Ghana.
In 2006, Ghana passed a Disability Rights Bill which proposes that by 2016 Ghana will provide disabled persons in the country with a variety of services and equal employment opportunities. This article presents interviews conducted with community leaders from the Greater Accra region of Ghana in 2009, examining the current views of persons with disabilities in the country. Using qualitative analytic methods, these interviews were coded for themes and examined in relation to historical perceptions of disabled persons in Ghana. The results suggest that there appears to be a growing acceptance that people with disabilities have rights as human beings and that the Disability Rights Bill is a positive step in the right direction for Ghana. There was no consensus, however, on what these basic rights entail, and who is responsible for enforcing and funding new policies. A potential barrier to progress included non-biologically based beliefs about what causes disability, which were reported to resonate strongly with many Ghanaians.


Scoring System Based on Post-Transplant Complications in Patients after Allogeneic Hematopoietic Cell Transplantation for Myelodysplastic Syndrome: A Study from the SFGM-TC.
We developed a prognostic scoring system to evaluate the prognosis of myelodysplastic syndrome (MDS) patients surviving more than 100 days allogeneic hematopoietic cell transplantation after (allo-HCT). We performed a landmark analysis on a derivation cohort of 393 cases to identify prognostic factors for 3-year overall survival. Potential predictor variables included demographic and clinical data, transplantation modalities and early post-transplant complications. The scoring system was tested against a validation cohort which included 391 patients. Complications occurring before day 100 such as relapse [HR = 6.7; 95%CI, 4.5-10.0] (4 points), lack of platelet recovery [HR, 3.6; 95%CI, 2.2-5.8] (2 points), grade-II acute GVHD [HR = 1.7; 95%CI, 1.2-2.5] (1 point) and grade-III/IV [HR = 2.6; 95%CI, 1.8 -3.8] (2 points) were the only independent predictors of 3-year OS. The 3-year OS associated with low (0), intermediate (1-3) and high (≥4) risk scores was respectively 70%, 46% and 6%. The model performed consistently in both cohorts, with good calibration. This post-transplant scoring system is a powerful predictor of outcome after allo-HCT for MDS, and can provide useful guidance for clinicians. Additional studies are required to evaluate this scoring system for other hematologic malignancies.


Photodegradation of the fungicide thiram in aqueous solutions. Kinetic studies and identification of the photodegradation products by HPLC-MS/MS.
In this study, the relevance of photodegradation processes on the persistence of the fungicide thiram in waters was investigated. The photodegradation of thiram in Milli-Q water and in aqueous solutions of humic and fulvic acids, as well as the photodegradation in spiked river water were studied. Both pure thiram and one of its commercial formulations were used to prepare the solutions which were irradiated in a solar light simulator. In general, thiram photodegradation follows pseudo-first order kinetics. The half-life time of thiram 2mgL(-1) in Milli-Q water was 28min. However, the degradation rate of thiram was significantly increased (p=0.02) by the inert components of the thiram commercial formulation as well as by commercial humic acids and by fulvic acids isolated from river water (p<0.004). Thus, the half-life time of thiram decreased to 24min in the presence of the inert formulation components, while, in the presence of both humic and fulvic acids (10mgL(-1)) it decreased to 22min. Furthermore, thiram photodegradation in natural river water showed that there is a significant enhancement of the degradation rate constant of thiram relatively to Milli-Q water, corresponding to a decrease of about 38% in its half-life time. This increase of the degradation rate in river water seems to be higher than that observed in the presence of FA, suggesting that beyond organic matter, other natural river components can increase the thiram photodegradation rate. These results allow us to conclude that photodegradation by solar radiation can be an important degradation pathway of thiram in natural waters. HPLC-MS/MS allowed to identify, for the first time, three products of the photodegradation of thiram in aqueous solution. Three compounds were identified and their structure was corroborated by the MS(n) spectra fragmentation profile. Pathways for the formation of the products from thiram photodegradation are proposed and discussed.


M1 muscarinic receptor activation decreases alcohol consumption via a reduction in consummatory behavior.
Muscarinic acetylcholine receptors (mAChRs) have been shown to mediate alcohol consumption and seeking. Both M4 and M5 mAChRs have been highlighted as potential novel treatment targets for alcohol use disorders (AUD). Similarly, M1 mAChRs are expressed throughout reward circuitry, and their signaling has been implicated in cocaine consumption. However, whether the same effects are seen for alcohol consumption, or whether natural reward intake is inadvertently impacted is still unknown. To determine the role of M1 mAChRs in alcohol consumption, we tested operant self-administration of alcohol under both fixed ratio (FR3) and progressive ratio (PR3-4) schedules. Enhancing M1 mAChR signaling (via the M1 PAM-Agonist PF-06767832, 1 mg/kg, i.p.) reduced operant alcohol consumption on a fixed schedule but had no effect on motivation to acquire alcohol. To determine whether these actions were specific to alcohol, we examined the effects of M1 enhancement on natural reward (sucrose) self-administration. Systemic administration of PF-06767832 (1 mg/kg, i.p.) also reduced operant sucrose self-administration, suggesting the actions of the M1 receptor may be non-selective across drug and natural rewards. Finally, to understand whether this reduction extended to natural consummatory behaviors, we assessed home cage standard chow and water consumption. M1 enhancement via systemic PF-06767832 administration reduced food and water consumption. Together our results suggest the M1 PAM-agonist, PF-06767832, non-specifically reduces consummatory behaviors that are not associated with motivational strength for the reward. These data highlight the need to further characterize M1 agonists, PAMs, and PAM-agonists, which may have varying degrees of utility in the treatment of neuropsychiatric disorders including AUD.


A comparison of colorectal cancer screening uptake among average-risk insured American Indian/Alaska Native and white women.
American Indian and Alaska Native (AI/AN) women have among the lowest rates of colorectal cancer (CRC) screening. Whether screening disparities persist with equal access to health care is unknown. Using administrative data from 1996-2007, we compared CRC screening events for 286 AI/AN and 14,042 White women aged 50 years and older from a health maintenance organization in the Pacific Northwest of the U.S. The proportion of AI/AN and White women screened for CRC at age 50 was similar (13.3% vs. 14.0%, p =.74). No differences were seen in the type of screening test. Time elapsed to first screening among AI/AN women who were not screened at age 50 did not differ from White women (hazard ratio 1.0, 95% confidence interval 0.8-1.3). Uptake for CRC screening was similar among insured AI/AN and White women, suggesting that when access to care is equal, racial disparities in screening diminish.


Universal red blood cells--enzymatic conversion of blood group A and B antigens.
Accidental transfusion of ABO-incompatible red blood cells (RBCs) is a leading cause of fatal transfusion reactions. To prevent this and to create a universal blood supply, the idea of converting blood group A and B antigens to H using specific exo-glycosidases capable of removing the immunodominant sugar residues was pioneered by Goldstein and colleagues at the New York Blood Center in the early 1980s. Conversion of group B RBCs to O was initially carried out with alpha-galactosidase extracted from coffee beans. These enzyme-converted O (ECO) RBCs appeared to survive normally in all recipients independent of blood group. The clinical trials moved from small infusions to single RBC units and finally multiple and repeated transfusions. A successful phase II trial utilizing recombinant enzyme was reported by Kruskall and colleagues in 2000. Enzymatic conversion of group A RBCs has lagged behind due to lack of appropriate glycosidases and the more complex nature of A antigens. Identification of novel bacterial glycosidases with improved kinetic properties and specificities for the A and B antigens has greatly advanced the field. Conversion of group A RBCs can be achieved with improved glycosidases and the conversion conditions for both A and B antigens optimized to use more cost-efficient quantities of enzymes and gentler conditions including neutral pH and short incubation times at room temperature. Of the different strategies envisioned to create a universal blood supply, the ECO concept is the only one, for which human clinical trials have been performed. This paper discusses some biochemical and clinical aspects of this developing technology.


Electrode placement over the innervation zone affects the low-, not the high-frequency portion of the EMG frequency spectrum.
The purpose of this study was to use a wavelet-based signal processing technique to examine the influence of electrode placement over the innervation zone (IZ) on the shape of the electromyographic (EMG) frequency spectrum. Ten healthy males (mean+/-SD age=23.6+/-3.0 years) performed isometric muscle actions of the dominant leg extensors at 10%, 40%, 70%, and 100% of the maximum voluntary contraction (MVC). Surface EMG signals were detected simultaneously from the vastus lateralis with two bipolar electrode arrangements. One of the electrode arrangements had its center point located directly over the IZ, while the other arrangement had its center point distal to the IZ (i.e., 20 mm away). All EMG signals were processed with a wavelet-based procedure. The results showed that for all isometric torque levels, the EMG signals from the distal electrode arrangement demonstrated greater total intensity values than those for the IZ arrangement for frequencies ranging from approximately 2 to 110 Hz. There were no consistent differences, however, between the IZ and distal electrode arrangements for total EMG intensity values above 110 Hz. Thus, these findings indicated that electrode placement over the IZ affected primarily the low-, rather than the high-frequency portion of the EMG frequency spectrum.


Job characteristics and staying engaged in work of nurses: Empirical evidence from Malaysia.
The purpose of this study is to examine the relationship between job characteristics (job autonomy, job feedback, skill variety, task identity, task significance) and work engagement of nurses in Malaysia. A survey using self-administered questionnaires was used to collect data from a sample of 856 staff nurses working in eight public hospitals in Malaysia. A shortened nine-item version of the Utrecht Work Engagement Scale(UWES-9) was used to measure work engagement. The UWES-9 comprises three dimensions, which was measured with three items each: vigor, dedication, and absorption. Job characteristics (job autonomy, job feedback, skill variety, task identity, task significance) were measured with the corresponding subscales of the Job Diagnostic Survey. Each subscale consisted of three items. Hypotheses were tested using hierarchical regression analysis. Findings indicated that all the five demographic variables (age, marital status, education, organizational tenure, job tenure) were unrelated to work engagement. The results further revealed that job autonomy (β = 0.19, P < 0.01), job feedback (β = 0.10, P < 0.01), task identity (β = 0.13, P < 0.01), and task significance (β = 0.08, P < 0.05) were positively related to work engagement. Skill variety (β = 0.03, P > 0.05), however, did not affect work engagement. Job autonomy, job feedback, task identity, and task significance are important factors in predicting work engagement. The findings of this study highlighted the need to incorporate these core dimensions in nursing management to foster work engagement.


Thermopreferendum of the rat: inter- and intra-subject variabilities.
The thermopreferendum of male hooded rats was studied in a temporal thermal gradient. The preferred ambient temperature was found to be approximately 19 degrees C. In addition to the thermopreferendum, three other physiological functions (resting body temperature, daily food intake, and daily ambulatory activity) were each measured in eight rats for 8 days. Overall variability of the thermopreferendum data was higher than that of body temperature and food intake data but lower than the variability of ambulatory activity data. Coefficients of inter- and intrasubject variabilities were computed for each of the four variables. Inter-subject variability was equivalent in all variables, but intrasubject variability was smaller for thermopreferendum and activity than for food intake and core temperature. The thermopreferendum of 19 degrees C is consistent with previously published results but inconsistent with the available data on the thermoneutral zone of the rat (27-28 degrees C). The cause of this inconsistency remains to be determined.


Confocal imaging of changes in glial calcium dynamics and homeostasis after mechanical injury in rat spinal cord white matter.
Periaxonal glia play an important role in maintaining axonal function in white matter. However, little is known about the changes that occur in glial cells in situ immediately after traumatic injury. We used fluo-3 and confocal microscopy to examine the effects of localized (<0.5 mm) mechanical trauma on intracellular calcium (Ca(i)(2+)) levels in glial cells in a mature rat spinal cord white matter preparation in vitro. At the injury site, the glial Ca(i)(2+) signal increased by 300-400% within 5 min and then irreversibly declined indicating cell lysis and death. In glial cells at sites adjacent to the injury (1.5-2 mm from epicenter), Ca(i)(2+) levels peaked at 10-15 min, and thereafter declined but remained significantly above rest levels. At distal sites (6-9 mm), Ca(i)(2+) levels rose and declined even slower, peaking at 80-90 min. Injury in zero calcium dampened Ca(i)(2+) responses, indicating a role for calcium influx in the generation and propagation of the injury-induced Ca(i)(2+) signal. By 50-80 min post-injury, surviving glial cells demonstrated an enhanced ability to withstand supraphysiological Ca(i)(2+) loads induced by the calcium ionophore A-23187. Glial fibrillary acidic protein (GFAP) and CNPase immunolabeling determined that the glial cells imaged with fluo-3 included both astrocytes and oligodendrocytes. These data provide the first direct evidence that the effects of localized mechanical trauma include a glial calcium signal that can spread along white matter tracts for up to 9 mm within less than 3 h. The results further show that trauma can enhance calcium regulation in surviving glial cells in the acute post-injury period.


STAT3-mediated coincidence detection regulates noncanonical immediate early gene induction.
Signaling pathways interact with one another to form dynamic networks in which the cellular response to one stimulus may depend on the presence, intensity, timing, or localization of other signals. In rare cases, two stimuli may be simultaneously required for cells to elicit a significant biological output. This phenomenon, generally termed "coincidence detection," requires a downstream signaling node that functions as a Boolean AND gate to restrict biological output from a network unless multiple stimuli are received within a specific window of time. Simultaneous activation of the EGF receptor (EGFR) and a thrombin receptor (protease-activated receptor-1, PAR-1) increases the expression of multiple immediate early genes (IEGs) associated with growth and angiogenesis. Using a bioinformatic comparison of IEG promoter regions, we identified STAT3 as a critical transcription factor for the detection of coincident EGFR/PAR-1 activation. EGFR activation induces classical STAT3 Tyr(705) phosphorylation but also initiates an inhibitory signal through the PI3K-AKT signaling axis that prevents STAT3 Ser(727) phosphorylation. Coincident PAR-1 signaling resolves these conflicting EGF-activated pathways by blocking AKT activation and permitting GSK-3α/β-dependent STAT3 Ser(727) phosphorylation and STAT3-dependent gene expression. Functionally, combinatorial EGFR/PAR-1 signaling suppresses EGF-induced proliferation and thrombin-induced leukocyte adhesion and triggers a STAT3-dependent increase in endothelial cell migration. This study reveals a novel signaling role for STAT3 in which the simultaneous presence of extracellular EGF and thrombin is detected at the level of STAT3 post-translational modifications. Collectively, our results describe a novel regulatory mechanism in which combinatorial EGFR/PAR-1 signaling regulates STAT3-dependent IEG induction and endothelial cell migration.


Relationships between changes in abdominal fat distribution and insulin sensitivity during a very low calorie diet in abdominally obese men and women.
Little is known about the association between abdominal obesity and insulin sensitivity during rapid weight loss. We assessed the role of visceral and subcutaneous fat as determinants of insulin sensitivity during rapid weight loss in obese persons with the metabolic syndrome. Twenty abdominally obese individuals [11 women and 9 men, body mass index (BMI) 35.8+/-3.5 kg/m2] with the metabolic syndrome underwent a very-low-calorie diet (VLCD) for nine weeks. At baseline, the computed tomography (CT) measured area of total (r=-0.50, p=0.033) and visceral fat tissue (r=-0.48, p=0.043), but not that of subcutaneous fat tissue (r=-0.34, p=0.17), correlated with insulin sensitivity as assessed by the quantitative insulin sensitivity check index after adjusting for sex and age. The 18 subjects who completed the study lost 14.8 kg during the VLCD. Total, visceral and subcutaneous abdominal fat tissue decreased by 22%, 29% and 17%, respectively. The decrease in total (r=-0.51, p=0.035) and subcutaneous abdominal fat (r=-0.57, p=0.017), but not visceral fat (r=0.11, p=0.68), correlated with the increase in insulin sensitivity. Waist circumference did not offer any additional information concerning abdominal fat distribution or insulin sensitivity compared with that provided by BMI at baseline or after weight loss. The waist/hip ratio was not associated with the CT measures of abdominal fat distribution or insulin sensitivity. Total abdominal fat may be more important than its compartmentalisation in abdominally obese individuals with the metabolic syndrome. In this subgroup of individuals with obesity, the measurement of waist circumference and the waist/hip ratio offered little additional information over that provided by BMI at baseline or after weight loss.


Plasmonic Optoelectronic Memristor Enabling Fully Light-Modulated Synaptic Plasticity for Neuromorphic Vision.
Exploration of optoelectronic memristors with the capability to combine sensing and processing functions is required to promote development of efficient neuromorphic vision. In this work, the authors develop a plasmonic optoelectronic memristor that relies on the effects of localized surface plasmon resonance (LSPR) and optical excitation in an Ag-TiO2 nanocomposite film. Fully light-induced synaptic plasticity (e.g., potentiation and depression) under visible and ultraviolet light stimulations is demonstrated, which enables the functional combination of visual sensing and low-level image pre-processing (including contrast enhancement and noise reduction) in a single device. Furthermore, the light-gated and electrically-driven synaptic plasticity can be performed in the same device, in which the spike-timing-dependent plasticity (STDP) learning functions can be reversibly modulated by visible and ultraviolet light illuminations. Thereby, the high-level image processing function, i.e., image recognition, can also be performed in this memristor, whose recognition rate and accuracy are obviously enhanced as a result of image pre-processing and light-gated STDP enhancement. Experimental analysis shows that the memristive switching mechanism under optical stimulation can be attributed to the oxidation/reduction of Ag nanoparticles due to the effects of LSPR and optical excitation. The authors' work proposes a new type of plasmonic optoelectronic memristor with fully light-modulated capability that may promote the future development of efficient neuromorphic vision.


The Evolution of Policy Instruments for Air Pollution Control in China: A Content Analysis of Policy Documents from 1973 to 2016.
China's portfolio of air-pollution control policy instruments has gradually broadened since the 1970s from regulatory instruments to include numerous market-based and voluntary policy instruments. We demonstrate this broadened portfolio of policy instruments for air-pollution control with a computer-assisted content analysis of 148 central-level policy documents from 1973 to 2016. We identify 20 types of policy instruments in these documents, and analyze such things as their historical evolution, main subjects, frequency of use, and whether they were issued by a single agency or jointly with other agencies. Prior research has found several factors complicating the diversification of policy instruments in China, including the late start of coordinated governance of air pollution, overreliance on regulatory instruments, insufficient use of market-based and voluntary instruments, the high cost of collecting shared information on a web-based platform, and the choice of policy instruments resulting from the "campaign-style" of governance. Given such challenges, we expected the policy documents to show little diversification of policy instruments and little coordination among agencies. The content analysis results show, however, a gradual shift from a centralized, regulatory model to an increasingly coordinated model using a diverse portfolio of policy instruments.


Is previous thoracic sympathectomy a risk factor for exertional heat stroke?
We report the case of a physically fit young man who presented with severe, life-threatening heat stroke after running a 10 km road race. He had previously received bilateral thoracic sympathectomy for axillary hyperhidrosis at another hospital, and was known to have upper body and limb anhidrosis. Thoracic sympathectomy can result in reduced sweating and disturbed peripheral vascular and heart rate responses. Patients should be warned that these mechanisms may play a role in the development of exertional heat stroke.


Purification and characterization of four beta-expansins (Zea m 1 isoforms) from maize pollen.
Four proteins with wall extension activity on grass cell walls were purified from maize (Zea mays) pollen by conventional column chromatography and high-performance liquid chromatography. Each is a basic glycoprotein (isoelectric point = 9.1-9.5) of approximately 28 kD and was identified by immunoblot analysis as an isoform of Zea m 1, the major group 1 allergen of maize pollen and member of the beta-expansin family. Four distinctive cDNAs for Zea m 1 were identified by cDNA library screening and by GenBank analysis. One pair (GenBank accession nos. AY104999 and AY104125) was much closer in sequence to well-characterized allergens such as Lol p 1 and Phl p 1 from ryegrass (Lolium perenne) and Phleum pretense, whereas a second pair was much more divergent. The N-terminal sequence and mass spectrometry fingerprint of the most abundant isoform (Zea m 1d) matched that predicted for AY197353, whereas N-terminal sequences of the other isoforms matched or nearly matched AY104999 and AY104125. Highly purified Zea m 1d induced extension of a variety of grass walls but not dicot walls. Wall extension activity of Zea m 1d was biphasic with respect to protein concentration, had a broad pH optimum between 5 and 6, required more than 50 micro g mL(-1) for high activity, and led to cell wall breakage after only approximately 10% extension. These characteristics differ from those of alpha-expansins. Some of the distinctive properties of Zea m 1 may not be typical of beta-expansins as a class but may relate to the specialized function of this beta-expansin in pollen function.


Extracellular material secreted by human colonic adenocarcinoma cell lines promotes spreading in serum-free medium and induces neurite outgrowth of PC-12 cells.
A completely defined medium has been designed to promote cell proliferation of 2 colonic adenocarcinoma cell lines of epithelial origin (HT 29 and HRT 18). The spreading of both cell types, especially of HT 29 cells, was not possible in a serum-free medium supplemented with growth factors. Spreading was obtained in a defined medium (a 1/1 mixture of DMEM and F12 media supplemented with 5 micrograms/ml transferrin, 5 ng/ml EGF, 10 ng/ml selenite and 15 mM HEPES pH 7.3) with an extracellular matrix-like material (ECM) secreted by the cells themselves. The properties of the ECM have been studied: ECM secreted by the 2 cell lines induced very quick spreading of HT 29 and HRT 18 cells (1 to 2 hr vs. 12 to 24 hr in serum-supplemented medium). ECM induced morphological differentiation of a rat pheochromocytoma cell line (PC 12). PC-12 cells grown under these conditions began to develop neurite extensions as early as 2 hr after seeding.


Meta-analysis of echocardiographic quantification of left ventricular filling pressure.
The clinical reliability of echocardiographic surrogate markers of left ventricular filling pressures (LVFPs) across different cardiovascular pathologies remains unanswered. The main objective was to evaluate the evidence of how effectively different echocardiographic indices estimate true LVFP. Design: this is a systematic review and meta-analysis. Scopus, PubMed and Embase. Eligibility criteria for selecting studies were those that used echocardiography to predict or estimate pulmonary capillary wedge pressure or left ventricular end-diastolic pressures. Twenty-seven studies met criteria. Only eight studies (30%) reported both correlation coefficient and bias between non-invasive and invasively measured LVFPs. The majority of studies (74%) recorded invasive pulmonary capillary wedge pressure as a surrogate for left ventricular end-diastolic pressures. The pooled correlation coefficient overall was r = 0.69 [95% confidence interval (CI) 0.63-0.75, P < 0.01]. Evaluation by cohort demonstrated varying association: heart failure with preserved ejection fraction (11 studies, n = 575, r = 0.59, 95% CI 0.53-0.64) and heart failure with reduced ejection fraction (8 studies, n = 381, r = 0.67, 95% CI 0.61-0.72). Echocardiographic indices show moderate pooled association to invasively measured LVFP; however, this varies widely with disease state. In heart failure with preserved ejection fraction, no single echocardiography-based metric offers a reliable estimate. In heart failure with reduced ejection fraction, mitral inflow-derived indices (E/e', E/A, E/Vp, and EDcT) have reasonable clinical applicability. While an integrated approach of several echocardiographic metrics provides the most promise for estimating LVFP reliably, such strategies need further validation in larger, patient-specific studies.


DESCRIPTION OF PROVING INTENTIONAL HOMICIDES INVOLVING POISONOUS SUBSTANCES: THE RELATIONSHIP OF MEDICAL AND PROCEDURAL CONTEXTS.
The purpose of the study is to provide the description of proving intentional homicides involving poisonous substances based on the structural analysis of the medical and criminal procedure criteria of the relevant process. The practical basis for the research is the statistical and analytical materials of the Ministry of Internal Affairs of Ukraine and the National Police of Ukraine, the Prosecutor's General Office, the State Judicial Administration of Ukraine for 2016-2021; summarized data from the study of 20 materials of criminal proceedings (primarily resolutions on the appointment of forensic and other examinations), materials of mass media. As a result of the research, it was established that the medical description of the concept of poison and possible variants of its use are urgently needed, including during the implementation of the versioning procedure in the pre-trial investigation, as well as establishing the identity of the perpetrator or the list of other similar offenses (committed in a similar way). The views of scientists on the understanding of the concept of poison, including lethal agents are characterized; a number of explanations regarding the use of special knowledge in the pre-trial investigation of intentional homicides involving poisonous substances are also provided.


Height and life satisfaction: Evidence from 27 nations.
To evaluate the effect of height on life satisfaction. We use data from a recent multi-country survey that was conducted in 27 nations. Our main finding is that height does have a strong positive effect on life satisfaction. These findings remain positive and significant when we use a comprehensive set of well-known covariates of life-satisfaction at both the individual and country levels. These findings also remain robust to alternative statistical specifications. From a theoretical standpoint, our findings suggest that height is important in explaining life-satisfaction independent of other well-known determinants. From a methodological standpoint, the findings of this study highlight the need to explicitly control for the effect of heights in studies on subjective well-being, happiness, and life-satisfaction.


Transfusion of predonated autologous blood in elective cardiac surgery.
Despite blood conservation techniques, the average transfusion requirement in patients undergoing elective cardiac surgical procedures remains 1 to 3 units. We studied the efficacy of predonated autologous blood in decreasing homologous transfusion in two matched groups of 58 patients each. Group 1 received homologous blood perioperatively, and Group 2 was transfused with predonated autologous blood. An average of 1.97 units was predonated in Group 2 over 18 days. This resulted in a decline in whole blood hemoglobin concentration of 2.2 gm/dl. No complications resulted from phlebotomy in this ambulatory population consisting predominantly of patients with coronary artery disease. Transfusion of an average of 1.7 units of autologous blood in Group 2 reduced the volume of homologous transfusion by 46% compared with Group 1 (p less than .01). In Group 1, 38% of patients required no homologous transfusion compared with 64% in Group 2 (p less than .02). There were no complications related to autologous blood transfusion. Total transfusion requirement was related to the length of cardiopulmonary bypass. We conclude that autologous predonation is a simple, safe, and cost-effective method of reducing homologous transfusion and thereby decreasing the risk of transfusion-related reactions and infections.


Cyclin-dependent kinase 4/6 inhibitors require an arcuate-to-paraventricular hypothalamus melanocortin circuit to treat diet-induced obesity.
The arcuate nucleus (ARC) of the hypothalamus comprises two antagonistic neuron populations critical for energy balance, namely, the anorexigenic pro-opiomelanocortin (POMC) and the orexigenic agouti-related peptide (AgRP) neurons that act as agonists and antagonists, respectively, for neurons expressing the type IV melanocortin receptor (MC4R) (Andermann ML and Lowell BB. Neuron 95: 757-778, 2017). MC4R activation increases energy expenditure and decreases food intake during positive energy balance states to prevent diet-induced obesity (DIO). Work from our group identified aberrant neuronal cell cycle events both as a novel biomarker and druggable target in the ARC for the treatment of DIO, demonstrating pharmacological restoration of retinoblastoma protein function in the ARC using cyclin-dependent kinase 4/6 (CDK4/6) inhibitors could treat DIO in mice by increasing lipid oxidation to selectively decrease fat mass. However, the role of CDK4/6 inhibitors on food intake was not examined. Four-week-old Mc4r-loxTB mice were continuously administered high-fat diet (60% kcal fat). At 8 wk of age, animals were administered 60 mg/kg abemaciclib orally or a saline control and monitored every 2 wk for fat mass changes by MRI. At 11 wk of age, all animals were injected bilaterally in the paraventricular hypothalamus with AAV8 serotype virus expressing a Cre-mCherry and monitored for another 5 wk. Restoration of Mc4r expression in the paraventricular hypothalamic nucleus (PVN/PVH) reduced food intake in hyperphagic obese mice when given CDK4/6 inhibitor therapy. The reduced food intake was responsible for reduced fat mass in mice treated with abemaciclib. These results indicate that targeting POMC neurons could be an effective strategy in treating diet-related obesity.NEW & NOTEWORTHY We have defined some of the necessary components to prevent high-fat diet-induced obesity at the molecular and cellular level. Within POMC neurons, the retinoblastoma protein must remain active and prevented from phosphoinactivation by cyclin-dependent kinases. The downstream neurons within the PVH must also properly express MC4R for the circuit to appropriately regulate feeding behavior.


Novel genotypes of Coxiella burnetii identified in isolates from Australian Q fever patients.
Coxiella burnetii, the causative agent of Q fever, was first discovered in Australia in 1937. However, little is known about the strains of C. burnetii present in this country. In this study, six published genotyping methods were applied to 42 isolates from Australian patients with acute (n=39) and chronic (n=3) Q fever. All the isolates contained the plasmid QpRS and lacked the acute disease antigen A (adaA) gene. Two methods of genotyping based on single nucleotide polymorphisms (SNPs) also failed to discriminate between the isolates. However, results from the method based on SNPs within the multi-spacer sequence typing (MST) loci determined a novel MST genotype, with the Australian isolates forming a unique phylogenetic clade. Multi-locus variable number of tandem repeats (VNTR) analysis (MLVA) determined 14 genotypes, all of which were novel compared with those previously identified in strains from other countries. Many of these were single locus variants, differing from each other at just one of the 15 loci tested. Our results show that the Australian isolates exhibit significant diversity from previously characterised strains, but are genetically closely related to each other, supporting a model of evolution by clonal expansion in a geographically isolated location.


The complex business of adapting effective interventions to new populations: an urban to rural transfer.
To assess the effectiveness of a relatively unaltered version of a sexual risk reduction intervention previously shown to be effective among urban youth, "Original Focus on Kids" (OFOK), compared with a version modified for West Virginia (WVFOK) and a control condition (training in environmental conservation), in altering protective sexual behaviors and perceptions among rural, Appalachian youth. Nine hundred ninety-nine youth aged 12 to 16 years from 12 rural counties in West Virginia. Randomized, controlled, longitudinal trial of a theory-based prevention intervention. Outcomes were self-reported sexual behaviors and perceptions assessed at baseline, 3, 6, and 9 months postintervention. Both WVFOK and OFOK positively affected perceptions of abstinence but not behaviors. OFOK significantly enhanced some perceptions of condom use compared with both control youth and WVFOK youth, but again, not behaviors. Overall, neither version was as effective as FOK had been in the original urban setting. The less altered version (OFOK) was more effective, especially with regard to condom-use perceptions, in this new population and cultural setting than the more culturally altered version (WVFOK). In several of the implementation settings, neither version was delivered as intended by the researchers because of logistic issues. Although many of these changes were seemingly minor, such deviations may have significant impact on intervention effect.


A cytogenetic survey of 200 unclassifiable mentally retarded children with congenital anomalies and 200 normal controls.
A cytogenetic survey was carried out on 200 patients with mental retardation and multiple congenital anomalies, and on 200 normal adult controls. Patients with a known syndrome were excluded from the survey. Chromosome analyses were carried out on 'blind-coded' slides using the ASG banding technique as the routine stain. After the initial analyses (at least 15 cells per person) the slides were decoded, destained and reused for C and Q band polymorphism studies. Five major chromosome abnormalities were detected in the patient group during the survey. They included three patients with de novo, apparently balanced, reciprocal translocations, karyotypes 46,XY,rcp(3;16)(q21;p12); 46,XX,rcp(5;8)(p15;q22); and 46,XX,rcp(5;12)(p11;q24); one with karyotype 47,XX,+mar and one with karyotype 46,XX,der(13),t(13;?)(q34;?). One additional patient whose karyotype in lymphocytes was 46,XX,inv(9)(p11;q13) was found to have a mosaic karyotype 46,XX,inv(9)(p11;q13)/46,XX,inv(9) (p11;q13), der(12),t(12;?)p13;?) in cultured skin fibroblasts. None of the 200 controls had a major chromosome abnormality. From the combined results of this and previous surveys it is now apparent that about 6.2% of the unclassifiable mentally retarded patients with three or more congenital anomalies and about 0.7% of the controls reveal major chromosome abnormalities.


A critical analysis of the Sacks-Vine gastrostomy tube: a review of 120 consecutive procedures.
Results from 120 patients managed with a Sacks-Vine gastrostomy tube were analyzed. In our experience, this device can be successfully placed in almost all cases (96%), and has a low rate for procedure-related mortality (0.8%) and major (4.4%) and minor (12.4%) complications. Advantages and problems associated with this feeding catheter are discussed. The Sacks-Vine gastrostomy tube is a reasonable alternative to other catheters placed by different methods.


Long-Term Outcomes After Surgical Pulmonary Arterioplasty and Risk Factors for Reintervention.
Although surgical patch arterioplasty is the conventional therapy for branch pulmonary artery (PA) stenosis, limited data exist on long-term outcomes. We examined the incidence of and risk factors for reintervention after surgical arterioplasty for branch PA stenosis in biventricular congenital heart disease. This retrospective cohort study included patients with 2-ventricle physiology who underwent patch arterioplasty for PA stenosis at a single high-volume congenital heart center during a 10-year period. Freedom from surgical or percutaneous reintervention for recurrent PA stenosis was evaluated. Univariate and multivariable Cox regression analyses were performed to determine risk factors for reintervention. Among 135 patients, the median age at patch arterioplasty was 0.9 years. Survival to hospital discharge (or 30 days postoperatively) was 96%. During a median follow-up period of 4.0 years, reintervention for PA stenosis occurred in 38 of 115 patients (33%) at a median time to reintervention of 1.4 years. The overall 10-year reintervention rate was 54%. In univariate analysis, age less than 30 days at initial arterioplasty, congenital PA stenosis (vs acquired), and bilateral PA stenosis (vs unilateral) were significantly associated with reintervention. In multivariable analysis, neonatal age (adjusted hazard ratio, 3.6; p = 0.002) and bilateral PA stenosis (adjusted hazard ratio, 2.8; p = 0.005) remained independently associated with reintervention. Long-term reintervention for recurrent PA stenosis after patch arterioplasty is common. Patients with bilateral PA stenosis or age younger than 30 days at the time of the index pulmonary arterioplasty are at higher risk for reintervention. These patients may benefit from frequent monitoring or novel approaches to repair.


Disparity-induced accommodation in late-onset myopia.
The effect of disparity-vergence on the accommodation response (AR) was measured in 10 late-onset myopes (LOMs) and 10 emmetropic subjects during the course of a 10 minute near-vision task (working distance 33 cm). Disparity was induced by the introduction of 3 and 6 delta base-out prisms placed before the right eye, and the resulting AR for the left eye was measured at 1 min intervals using an objective infra-red optometer. LOMs showed a significant increase in AR with increasing disparity whereas emmetropes showed no significant difference in AR for all disparity conditions. The implications of these findings are discussed with reference to the aetiology of late-onset myopia.


Microfluidic cytometer based on dual photodiode detection for cell size and deformability analysis.
Cellular mechanical properties play an important role in disease diagnosis. Distinguishing cells based on their mechanical properties provides a potential method for label-free diagnosis. In this work, a convenient and low-cost microfluidic cytometer was developed to study cell mechanical properties and cell size based on the change of transmission intensity, using a low-cost commercial laser as a light source and two photodiodes as detectors. The cells pass through a narrow microchannel with a width smaller than the cell dimension, integrated in a polydimethylsiloxane chip, below which the laser is focused. The transit time of individual cells is measured by the time difference detected by two photodiodes. This device was used to study the difference in cell mechanical properties between HL60 cells treated with and without Cytochalasin D. Furthermore, it was also applied to distinguish cells with different diameters, HL60 cells and red blood cells, by measuring the transmission intensity.


A theoretical method to predict DNA permutation gel electrophoresis from the sequence.
The gel electrophoretic permutation assays of DNA fragments experimentally investigated by different authors were theoretically reproduced using our theoretical model of sequence-dependent curvature. The general pattern of agreement obtained suggests that our method can be usefully adopted as an alternative to the experimental assay, in particular where the lack of a sufficient number of unique restriction sites in the fragment prevents the correct localization of the main bend site.


The association of neuroblastoma with myoclonic encephalopathy of infants: the use of magnetic resonance as an imaging modality.
The association of neural crest tumors with myoclonic encephalopathy of infants has been well described. Since these tumors often are clinically occult the diagnostic modalities used to identify these lesions need to be sensitive. We describe a child with neuroblastoma associated with infantile myoclonic encephalopathy in whom magnetic resonance imaging identified the lesion while other techniques were unable to demonstrate a mass clearly. Magnetic resonance imaging should be considered as a diagnostic modality when adrenal lesions are suspected but not apparent with other imaging techniques.


Capillarisation and fibre types in hypertrophied m. plantaris in rats of various ages.
Influences of age, overload obtained through denervation of synergists, and training on the capillarisation of the m. plantaris were compared in 5-, 13- and 25-month-old rats in relation to different fibre types. Overload resulted in about 30% hypertrophy in each age group. Age effects were significant only in the deep (more oxidative) region of the muscle. From 5 to 13 months, the percentage of FOG fibres increased at the expense of FG fibres, while the fibre cross-sectional areas (FCSA) of each fibre type increased. From 13 to 25 months, the FCSA of FG fibres decreased, as did the local capillary-to-fibre ratio (LCFR) of each fibre type, indicating capillary loss and a declined capillary density for each fibre type (CFD). Overload effects were identical for both the superficial (more glycolytic) and the deep region for each age group. With overload, FCSA and LCFR of each fibre type increased, while CFD decreased, indicating that capillary proliferation occurred with overload, even at old age, although lagging behind increases in FCSAs. Training showed minor effects.


Short-term dual antiplatelet therapy in diabetic patients admitted for acute coronary syndrome treated with a new-generation drug-eluting stent.
The optimal duration of dual antiplatelet therapy (DAPT) in patients with diabetes mellitus (DM) admitted with acute coronary syndrome (ACS) and treated with a drug-eluting stent (DES) remains unclear. This is a prespecified sub-study from the Randomised Evaluation of short-term DUal antiplatelet therapy in patients with acute Coronary syndromE treated with a new generation DES (REDUCE) trial that was designed to determine the efficacy and safety of short-term versus standard 12 months DAPT in diabetic patients with ACS undergoing percutaneous coronary intervention (PCI) using the COMBO stent. In this study we included ACS diabetic patients enroled in the REDUCE trial treated with the COMBO stent and randomly assigned to either 3 or 12 months of DAPT. The primary study endpoint was the composite of all-cause mortality, myocardial infarction (MI), stent thrombosis (ST), stroke, target vessel revascularisation (TVR), and bleeding complications at 12 and 24 months follow-up. A total of 307 diabetic patients were included, of which 162 (52.8%) in the 3 months DAPT group and 145 (47.2%) in the 12 months DAPT group. Patient characteristics, PCI success, and number of stents used were similar in the 3 and 12 months DAPT groups. Occurrence of the primary study endpoint at 12 and 24 months follow-up was comparable between the two groups (3.1 vs. 3.5%, p = 0.865, and 15.8 vs. 14.9%, p = 0.824, respectively). Moreover, the prevalence of the specific clinical outcome parameters (all-cause mortality), MI, ST, stroke, TVR, and bleeding was similar in both study groups. This sub-analysis shows similar clinical outcomes following 3 months DAPT as compared to 12 months DAPT in diabetic patients undergoing PCI for ACS using the COMBO stent. These results suggest that, even in this particular subset of patients, short duration of DAPT might be considered safe. Future larger studies are warranted to provide more precise estimations in terms of safety and efficacy of short term DAPT in these high-risk patients.


RGMQL: scalable and interoperable computing of heterogeneous omics big data and metadata in R/Bioconductor.
Heterogeneous omics data, increasingly collected through high-throughput technologies, can contain hidden answers to very important and still unsolved biomedical questions. Their integration and processing are crucial mostly for tertiary analysis of Next Generation Sequencing data, although suitable big data strategies still address mainly primary and secondary analysis. Hence, there is a pressing need for algorithms specifically designed to explore big omics datasets, capable of ensuring scalability and interoperability, possibly relying on high-performance computing infrastructures. We propose RGMQL, a R/Bioconductor package conceived to provide a set of specialized functions to extract, combine, process and compare omics datasets and their metadata from different and differently localized sources. RGMQL is built over the GenoMetric Query Language (GMQL) data management and computational engine, and can leverage its open curated repository as well as its cloud-based resources, with the possibility of outsourcing computational tasks to GMQL remote services. Furthermore, it overcomes the limits of the GMQL declarative syntax, by guaranteeing a procedural approach in dealing with omics data within the R/Bioconductor environment. But mostly, it provides full interoperability with other packages of the R/Bioconductor framework and extensibility over the most used genomic data structures and processing functions. RGMQL is able to combine the query expressiveness and computational efficiency of GMQL with a complete processing flow in the R environment, being a fully integrated extension of the R/Bioconductor framework. Here we provide three fully reproducible example use cases of biological relevance that are particularly explanatory of its flexibility of use and interoperability with other R/Bioconductor packages. They show how RGMQL can easily scale up from local to parallel and cloud computing while it combines and analyzes heterogeneous omics data from local or remote datasets, both public and private, in a completely transparent way to the user.


Contact-coupled impact of slender rods: analysis and experimental validation.
To validate models of contact mechanics in low speed structural impact, slender rods were impacted in a drop tower, and measurements of the contact and vibration were compared to analytical and finite element (FE) models. The contact area was recorded using a novel thin-film transfer technique, and the contact duration was measured using electrical continuity. Strain gages recorded the vibratory strain in one rod, and a laser Doppler vibrometer measured speed. The experiment was modeled analytically on a one-dimensional spatial domain using a quasi-static Hertzian contact law and a system of delay differential equations. The three-dimensional FE model used hexahedral elements, a penalty contact algorithm, and explicit time integration. A small submodel taken from the initial global FE model economically refined the analysis in the small contact region. Measured contact areas were within 6% of both models' predictions, peak speeds within 2%, cyclic strains within 12 με (RMS value), and contact durations within 2 μs. The global FE model and the measurements revealed small disturbances, not predicted by the analytical model, believed to be caused by interactions of the non-planar stress wavefront with the rod's ends. The accuracy of the predictions for this simple test, as well as the versatility of the diagnostic tools, validates the theoretical and computational models, corroborates instrument calibration, and establishes confidence that the same methods may be used in experimental and computational study of contact mechanics during impact of more complicated structures. Recommendations are made for applying the methods to a particular biomechanical problem: the edge-loading of a loose prosthetic hip joint which can lead to premature wear and prosthesis failure.


Dynamical crossover line in supercritical water.
Dynamical crossover in water is studied by means of computer simulation. The crossover temperature is calculated from the behavior of velocity autocorrelation functions. The results are compared with experimental data. It is shown that the qualitative behavior of the dynamical crossover line is similar to the melting curve behavior. Importantly, the crossover line belongs to experimentally achievable (P, T) region which stimulates the experimental investigation in this field.


Molecular determinants of thyroid hormone receptor selectivity in a series of phosphonic acid derivatives: 3D-QSAR analysis and molecular docking.
A mathematical study was performed on a set of phosphonic acid derivatives that are substrates for thyroid hormone receptor β (TRβ) and thyroid hormone receptor α (TRα), three-dimensional quantitative structure-activity relationship (3D-QSAR) models using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) methods were employed to investigate the structural requirements for this series of compounds with improved activity. Some descriptors were also employed to significantly improve the performance of the derived models. The CoMFA model for TRβ exhibited Rcv(2) of 0.612, Rpred(2) of 0.7218, whereas CoMSIA model showed Rcv(2) of 0.621, R(2)pred of 0.7358; the CoMFA model for TRα displayed Rcv(2) of 0.678, Rpred(2) of 0.6424, and the CoMSIA model had Rcv(2) of 0.671, Rpred(2) of 0.6932, which indicate that the constructed models are statistically significant. The derived contour maps further pointed out the regions where interactive fields may influence the activity. In order to validate the QSAR models and explore the origin of the selectivity at the amino acid level, molecular docking was developed, and the results indicate that Arg282, Arg320, Asn331, Gly332, Thr329 and His435 for TRβ, but Ala225, Arg228, Met259, Arg262 and His381 for TRα, respectively are important residues. The information obtained from the QSAR models can be used in the design of more potent TR agonists.


Challenges in implementing a successful newborn cystic fibrosis screening program.
To identify necessary components of a successful cystic fibrosis (CF) newborn screening (NBS) program. The approach to CF NBS used by the Massachusetts NBS program was examined. Several key components were identified that should be addressed when a state has made the decision to screen, and well in advance of actual implementation. These components include (1) inclusion of CF center directors in the development process; (2) logistics of choosing a screening algorithm relative to practices in place and community wishes; (3) projections of medical service needs from specific algorithms; (4) identification of critical reporting components; (5) identification of critical follow-up components; and (6) recognition of educational needs. Careful examination of a wide variety of issues is needed to ensure optimal implementation of NBS for CF.


Peribulbar anesthesia for strabismus surgery in adult patients.
To evaluate the efficacy and safety of peribulbar anesthesia during strabismus surgery. Medical records of patients undergoing strabismus surgery and peribulbar anesthesia were reviewed. The overall efficacy of peribulbar anesthesia was evaluated as requirement of supplemental peribulbar anesthesia, impossibility to perform eye muscles surgery due to inadequate efficacy of the block and peribulbar block complications that occurred up to 6 weeks postoperatively. Presence of oculocardiac reflex (OCR) and presence of decreased visual acuity and afferent pupillary defect postoperatively were reported. A total of 510 patients comprised our study group. The total amount of peribulbar injections was 717. Four patients (0.7%) required supplemental injection in the superonasal quadrant. Five of 510 (0.9%) required an anesthesiologic intervention with intravenous atropine. Eighty patients of 510 (15.6%) complained about transitory complete ptosis and/or amaurosis postoperatively. No complications were observed up to 6 weeks postoperatively. Peribulbar anesthesia was an effective and safe option during strabismus surgery in adult patients.


Alterations in metabolic clearance of atrial natriuretic peptides in heart failure: how do they relate to the resistance to atrial natriuretic peptides?
Deficiencies in activity of the atrial natriuretic peptide (ANP) system may be able to explain the disturbed electrolyte and fluid homeostasis occurring in chronic heart failure. Generally, in studies concerning the possible pathophysiologic role of ANP in heart failure, only the circulating levels of the hormone were measured. It has been shown, however, that plasma ANP levels exhibit marked variability attributable to the pulsatory pattern of secretion and to its very short plasma half-life. An evaluation of the main turnover parameters might represent a significant improvement in the assessment of the functioning of the overall ANP system. By using a tracer method, which does not alter the steady-state condition, a disturbed peripheral metabolism of ANP and a resistance to its biologic effects was demonstrated in patients with idiopathic dilated cardiomyopathy, even in those in the asymptomatic phase of the disease, showing ANP circulating levels, atrial pressure and volume, and cardiac index within the normal range. The altered degradation and distribution of ANP in patients with heart failure were demonstrated by a great increase in metabolic clearance (on average, 2.5-fold), production (on average, 6-fold), or both, and by a progressive reduction in the distribution spaces of the hormone when compared with normal subjects at the same sodium intake. The ratio between ANP disposal and the daily excretion of sodium (equal to the sodium intake in subjects at a strictly controlled sodium balance) may give a good index of the biologic activity (natriuresis) of the ANP system. Preliminary studies suggest that an index of biologic activity of the ANP system may be a useful tool for the comparison of the efficacy of different therapeutic strategies in heart failure. Indeed, after a 2-month treatment with an angiotensin-converting enzyme inhibitor, this index was returned to within the normal range, suggesting that the drug was able to "normalize" the peripheral distribution and degradation of the hormone in these patients. Although future studies in a large series of patients will be useful to assess this important issue, the setup of accurate methods able to evaluate the presence and degree of resistance to biologic activity of ANP may be a useful tool in the follow-up evaluation of patients with heart failure, and may pave the way for further progress in the knowledge of more general physiologic and pathophysiologic mechanisms of this important clinical condition.


On the neurology of perception.
The neurological base of biological space and of spatial perception is discussed. The nervous system is viewed as a system controlling behaviour. Movements as elements of behaviour are guided movements: goal-directed, programmed and ordered in space. Perceptual space is derived from directional properties of behaviour. The sense organs are not 'doors of perception', transparent to the alleged properties of the environment. Rather they are used in a centrifugal sense--outward from the organism. They are instrumental in updating a 'map' of the outside world and of the organisms as part of that world. The map is, in essence, a projection of the organism's own behaviour modified by the regularities, constraints and supports encountered in the world. The role of the periphery varies from moment to moment with the organisational level of behaviour. Thus, the sensomotor system is operated for updating the map and also for calibrating movements. At a peripheral level it helps to level out irregularities encountered in the execution of simple movements. All these functions may take place at the same time. Taken together, these considerations serve as an explanation of the fact that we are able to determine the spatial properties of objects although the shape as such is not presented to the sensory surface of the body, nor are the various scanpaths of our exploratory movements a replica of the geometrical properties of the object.


[Aortic inflammatory lesions in Behçet's disease].
The arterial lesions affect about 10% of patients with Behçet's disease (BD). Aortic inflammatory involvement includes predominantly aortic aneurysmal lesions affecting most often the abdominal aorta. They account for the severity of the disease and are a leading cause of death when they hit the aorta or pulmonary arteries. Within the arterial lesions of BD, aortic involvement is, with femoral lesions, the most common site involved (18-28% of patients with vascular disease). Unlike other large vessels vasculitis (i.e. giant cell arteritis and Takayasu's arteritis) diffuse aortitis is observed in less than 5% of patients with BD. Aortic lesions of BD may be asymptomatic (systematic imaging or occasionally associated with other vascular event) or be revealed by the occurrence of abdominal, thoracic or lumbar pain, or an aortic valve insufficiency. Fever is frequently associated. Increase in acute phase reactants is common in these patients. Histological analysis may show infiltration by lymphocytes, neutrophils and plasma cells in the media and adventitia and a proliferation of the vasa vasorum in the media as well as a fibroblastic proliferation. In the later phase, a fibrous thickening of the media and adventitia is observed as well as a proliferation and thickening of the vasa vasorum. The therapeutic management should always include a medical treatment for the control of inflammation (corticosteroids, immunosuppressive drugs and/or biotherapy) and often an endovascular or surgical treatment if the aneurysm is threatening. The choice between endovascular or surgical treatment is considered case by case, depending on the experience of the team, anatomical conditions and of the clinical presentation. In this review, we provide a detailed and updated review of the literature to describe the aortic inflammatory damage associated with Behçet's disease.


Soluble epoxide hydrolase inhibitor promotes the healing of oral ulcers.
Oral ulcers are a lesion in the oral mucosa that impacts chewing or drinking. Epoxyeicosatrienoic Acids (EETs) have enhanced angiogenic, regenerative, anti-inflammatory, and analgesic effects. The present study aims to evaluate the effects of 1-Trifluoromethoxyphenyl-3-(1-Propionylpiperidin-4-yl) Urea (TPPU), a soluble epoxide hydrolase inhibitor for increasing EETs level, on the healing of oral ulcers. The chemically-induced oral ulcers were established in Sprague Dawley rats. The ulcer area was treated with TPPU to evaluate the healing time and pain threshold of ulcers. The expression of angiogenesis and cell proliferation-related protein in the ulcer area was detected using immunohistochemical staining. The effects of TPPU on migration and angiogenesis capability were measured with scratch assay and tube formation. Compared with the control group, TPPU promoted wound healing of oral ulcers with a shorter healing time, and raised pain thresholds. Immunohistochemical staining showed that TPPU increased the expression of angiogenesis and cell proliferation-related protein with reduced inflammatory cell infiltration in the ulcer area. TPPU enhanced cell migration and tube-forming potential in vitro. The present results support the potential of TPPU with multiple biological effects for the treatment of oral ulcers by targeting soluble epoxide hydrolase.


Age-dependent changes in the ultrastructure and in the molecular composition of rat brain microtubules.
An age-dependent increase of a cathepsin D-like protease activity that preferentially degrades high molecular weight microtubule-associated proteins (MAPs) has been previously described. Microtubules (MT) purified from rat brain of different ages in the presence of several protease inhibitors retained undegraded MAPs through cycles of polymerization, and revealed several age-dependent changes in the relative amounts of MAPs and MT-associated kinases. MAP2 immunoreactivity was found significantly lower in MT preparations from aged animals in contrast with a relative increase of tau molecules. In addition, the phosphorylation of MAP2 by its associated cyclic AMP-dependent protein kinase was also altered, consecutively to the partial loss of the enzyme during polymerization cycles and an age-dependent decrease in the ability of the cyclic nucleotide to stimulate MAP2-bound kinase activity. The evidence of an unusually high packing density of sedimented MT from old rat brains further suggested the modification with aging of the physical structure of the arm-like projections of MAPs, in addition to a lower amount in high molecular weight MAPs. These results support the hypothesis of a selective alteration with aging of the mechanical and regulatory properties of brain MT, consecutive to a change in the composition and/or the structure of MAPs.


Stable "zeta" peptides that act as potent antagonists of the high-affinity IgE receptor.
Recently we described a family of peptides, unrelated in sequence to IgE, that form stable beta-hairpins in solution and inhibit IgE activity in the microM range [Nakamura, G. R., Starovasnik, M. A., Reynolds, M. E. & Lowman, H. B. (2001) Biochemistry 40, 9828-9835]. Using an expanded set of peptide-phage libraries, we found a simpler motif, X(2)CPX(2)CYX, for binding to the high-affinity IgE receptor. In solution, one of these peptides spontaneously formed a covalent antiparallel dimer. We subsequently linked these monomers in a single-chain construct on phage and optimized receptor binding. Ultimately, peptides with 30 nM affinity were produced. NMR studies showed that the peptide adopts a stable fold consisting of two "zeta" (zeta)-shaped moieties. Structure-activity analyses reveal a single binding site created by the zeta-dimer, with two tyrosine residues important for structural stability and two proline residues important for Fc epsilon RI binding. The peptides inhibit histamine release from cultured cells and are extremely stable in biological fluids. The zeta peptides appear to act as competitive IgE inhibitors and suggest possibilities for design of novel IgE antagonists.