Misalignment in Community Mental Health Leader and Therapist Ratings of Psychological Safety Climate Predicts Therapist Self-Efficacy with Evidence-Based Practices (EBPs).
Therapist self-efficacy in delivering evidence-based practices (EBPs) is associated with implementation outcomes, including adoption and sustainment in community mental health settings. Inner context organizational climate, including psychological safety, can proximally shape therapist learning experiences within EBP implementation. Psychologically safe environments are conducive to learning behaviors including taking risks, admitting mistakes, and seeking feedback. Organization leaders are instrumental in facilitating psychological safety, but may have differing perspectives of organizational climate than front-line therapists. Discrepant leader and therapist views of psychological safety may have independent associations with therapist EBP learning and implementation outcomes over and above average therapist perceptions of climate. This study examined survey data from 337 therapists and 123 leaders from 49 programs contracted to deliver multiple EBPs within a study examining determinants of sustainment within a large system-driven implementation. Both leaders and therapists completed measures of psychological safety climate and therapists reported on their self-efficacy in delivering multiple EBPs in children's mental health services. Polynomial regression and response surface analysis models were conducted to examine the associations of therapist and leader reports of psychological safety and therapist EBP self-efficacy. Greater discrepancies between leader and therapist reports of psychological safety, in either direction, were associated with lower therapist EBP self-efficacy. Alignment in leader and therapist views of psychological safety climate may impact EBP implementation outcomes. Strategies for improving alignment in perceptions and priorities among organizational members can be included in organizational implementation interventions and may represent unexamined implementation mechanisms of action.


Measuring the Indirect Cost of Illness Using EQ-5D-5L While Accounting for Job Characteristics.
The EQ-5D-5L questionnaire is used to measure treatment effects on the quality of life. For cost-utility analyses, EQ-5D-5L profiles are assigned numbers representing societal preferences (index weights). On the cost side, the indirect costs are frequently included: the value of product lost due to illness-related absences (absenteeism) or diminished productivity (presenteeism). The possibility to use EQ-5D data to estimate absenteeism and presenteeism (A&P) would be useful, if real-world data on A&P are lacking. However, beyond-health factors may also matter for A&P. We aimed to assess how A&P depend on the EQ-5D-5L profile, while accounting for job characteristics (e.g. remote or in-office). We surveyed 756 employed Poles. Respondents reported their job characteristics and evaluated the impact of eight hypothetical EQ-5D-5L profiles on A&P (two blocks of states used). Econometric modelling was used to establish the determinants of A&P. Both A&P increase with health problems as indicated across EQ-5D-5L dimensions (especially mobility and self-care), and this impact differs from the impact on index weight (e.g. pain/discomfort barely impact the A&P). The job characteristics mattered: absenteeism decreases in sedentary occupations and increases in those occupations performed remotely or requiring cooperation, while presenteeism increases in jobs performed remotely and decreases for those requiring creative thinking. The entire EQ-5D-5L profile, not just index weights, should be used to estimate A&P. That job characteristics matter may be relevant in applications, as some diseases concentrate in specific subgroups.


Divergent hepatitis E virus in birds of prey, common kestrel (Falco tinnunculus) and red-footed falcon (F. vespertinus), Hungary.
Hepatitis E virus (HEV), family Hepeviridae, has raised considerable public health concerns because of its zoonotic potential; however, the animal to animal transmissions and the natural chain of hepevirus infections in wildlife are less known. Using random amplification and next generation sequencing technology a novel HEV in birds of prey was serendipitously identified in Hungary. HEV RNA was detected in total of 2 (18%) of the 11 and 1 (14%) of the 7 faecal samples from common kestrels and red-footed falcons, respectively. High faecal viral load (2.03×10(8) genomic copies/ml) measured by qPCR. The complete genome of strain kestrel/MR22/2014/HUN (KU670940) HEV is 7033-nt long including a 35-nt 5'end and a 63-nt 3'end (excluding the poly(A)-tail). Sequence analyses indicated that the ORF1 (4920nt/639 aa), ORF2 (1989nt/662 aa) and ORF3 (360nt/119aa) proteins of kestrel/MR22/2014/HUN shared the highest identity (58.1%, 66.8% and 28.5%) to the corresponding proteins of ferret, rat and human genotype 4 Orthohepeviruses, respectively. Interestingly, the ORF3 protein is potentially initiated with leucine (L) using an alternate, non-AUG (UUG) start codon. This study reports the identification and complete genome characterization of a novel Orthohepevirus species related to mammalian HEVs in birds of prey. It is important to recognize all potential hosts, reservoirs and spreaders in nature and to reconstruct the phylogenetic history of hepeviruses.


Mycotoxins - Their Biosynthesis in Fungi: Biosynthesis of the Trichothecenes.
The biosynthetic pathway as currently postulated for trichothecin, a model 12,13-epoxy-Δ9-trichothecene, involves the following sequence: 3 mevalonic acids → farnesyl pyrophosphate → trichodiene → trichodiol → 12,13-epoxytrichothec-9-ene → trichodermol → 12,13-epoxy,4β, 8a-dihydroxy-trichothec-9-ene → trichothecolone → trichothecin.


A combined mass and energy balance to provide bioindicators of soil microbiological quality.
In this work, a method is proposed to quantify the efficiency of carbon utilization by soil microbes. Microcalorimetry was used to compute the heat yield (Y(Q/X)) of six soil samples collected in the Amazon. A combined mass and energy balance is developed to quantify the enthalpy of the glucose oxidation reaction (Delta(r)H(s)) and the biomass yield (Y(X/S)) from the experimental values of Y(Q/X). Results were compared by graphical analysis to establish the kinetics of the glucose oxidation and the microbial growth reactions in terms of energy dissipation. The correlations found suggest that the measured values for Y(Q/X) and Delta(r)H(s) are biomass yield dependent. The main environmental factors affecting the kinetics of the glucose oxidation and the microbial growth reactions in soils are the initial microbial population and the percentage of nitrogen of the samples. The comparative study among the samples showed that the deforestation of the Primary forests in the Amazon to establish arable lands, affected the efficiency of the carbon utilization by soil microorganisms.


Implementation of Technology-Delivered Diabetes Self-care Interventions in Clinical Care: a Narrative Review.
Evidence is growing for the positive effects of technology-delivered diabetes self-care interventions on behavioral and clinical outcomes. However, our understanding of how to effectively implement these interventions into routine clinical practice is limited. This article provides an overview of the methods and results of studies examining the implementation of technology-delivered diabetes self-care interventions into clinical care. We focus specifically on patient-facing behavioral interventions delivered with technology (e.g., text messaging, apps, websites). Eleven articles were included in the review. Most studies (n = 9) examined barriers and facilitators to implementation, while about half (n = 5) integrated the intervention into clinical care and evaluated implementation and/or effectiveness. Only six studies applied a theory or framework. The most common determinants of implementation were time constraints for clinic staff, familiarity with technology, knowledge of the intervention, and perceived value. We found substantial variation in implementation outcomes, including which were reported, how they were assessed, and the results. In the four studies that evaluated effectiveness, hemoglobin A1c improved. Successful implementation of technology-delivered interventions has the potential to transform healthcare delivery and improve diabetes health on a population level. Promising strategies to address common determinants of implementation include appointing a clinic champion, developing staff training and educational materials, and adapting intervention processes to the clinic context. Future research should evaluate these implementation strategies to understand when and how they impact outcomes. Frameworks such as Reach Effectiveness Adoption Implementation Maintenance (RE-AIM) can help ensure outcomes are systematically reported and allow for comparison across studies.


Effects of prostaglandin endoperoxide analogs on contractile elements in lung and gastrointestinal tract.
Prostaglandin endoperoxides are formed in the lung as intermediate compounds in the biosynthesis of prostaglandins and thromboxanes. The effects of different doses of two analogs of prostaglandin endoperoxide PGH2 were compared with those of PGF2alpha and PGE2 on superfused preparations of isolated trachea, bronchiole, peripheral lung, pulmonary artery and gastrointestinal smooth-muscle tissues. Endoperoxide analogs induced contraction of all smooth-muscle structures in the lung and airway. Compared to PGF2alpha, analog I was approximately 71 times as potent on guinea-pig trachea, 214 times as potent on guinea-pig lung, and 57 times as potent on guinea-pig pulmonary artery. Analog II was moderately less potent on all tissues than analog I. On gastrointestinal smooth-muscle organs, the PGH2 analogs were generally closer in activity to PGF2alpha and PGE2, or even weaker. The findings show that PG endoperoxide analogs are potent constrictors of airways, lung and pulmonary vessels, and suggest that the naturally occurring compounds may participate in the mediation of bronchoconstriction and pulmonary vasoconstriction in disease states.


'Oxygen uptake efficiency slope' in trained and untrained subjects exposed to hypoxia.
We assessed the ability of the oxygen uptake efficiency slope, whether calculated on 100 and 80% of maximal exercise test duration (OUES(100) and OUES(80)), to identify the change in cardiorespiratory capacities in response to hypoxia in subjects with a broad range of V(O2 peak). Four maximal exercise tests were performed in trained (T) and untrained subjects (UT) in normoxia and at 1000, 2500 and 4500 m. The mean reductions in maximal exercise capacities at 4500 m were the same in T subjects for V(O2 peak) (-30%), OUES(80) (-26%) and OUES(100) (-26%) whereas in UT subjects only OUES(100) (-14%), but not OUES(80) (-20%), was lower compared with V(O2 peak) (-21%, p<0.05). OUES(100) and OUES(80) were correlated with V(O2 peak) and the ventilatory anaerobic threshold in both groups. Multiple regression analyses showed that V(O2 peak), OUES(100) and OUES(80) were significantly linked to O(2) arterial-venous difference. The OUES(80) could be considered as an interesting sub-maximal index of cardiorespiratory fitness in normal or hypoxemic subjects unable to reach V(O2 peak).


Challenges in peer review: how to guarantee the quality and transparency of the editorial process in scientific journals.
The editorial process of scientific journals is complex but essential for the dissemination of scientific knowledge. The quality of the process depends on the authors, editors and reviewers, who must have the necessary experience and knowledge to ensure the quality of the published articles. One of the most significant challenges scientific journals face today is the peer review of manuscripts. Editors are responsible for coordinating and overseeing the entire editorial process, from manuscript submission to final publication, and ensuring that articles meet ethical and scientific integrity standards. Editors are also in charge of selecting appropriate reviewers. However, the latter is becoming difficult due to the increasing refusal of expert reviewers to participate in the editorial process. The reasons for it are diverse, but the lack of recognition for review work and reviewer fatigue in the most sought-after reviewers are among the most important. Some of the measures that could be taken to alleviate the problem concern the possibility of professionalizing peer review.


Superoxide signaling and cell death in retinal ganglion cell axotomy: effects of metallocorroles.
Injury to retinal ganglion cell (RGC) axons within the optic nerve causes apoptosis of the soma. We previously demonstrated that in vivo axotomy causes elevation of superoxide anion within the RGC soma, and that this occurs 1-2 days before annexin-V positivity, a marker of apoptosis. Pegylated superoxide dismutase delivery to the RGC prevents the superoxide elevation and rescues the soma. Together, these results imply that superoxide is an upstream signal for apoptosis after axonal injury in RGCs. We then studied metallocorroles, potent superoxide dismutase mimetics, which we had shown to be neuroprotective in vitro and superoxide scavengers in vivo for RGCs. RGCs were retrograde labeled with the fluorescent dye 4Di-10Asp, and then axotomized by intraorbital optic nerve transection. Iron(III) 2,17-bis-sulfonato-5,10,15-tris(pentafluorophenyl)corrole (Fe(tpfc)(SO(3)H)(2)) (Fe-corrole) was injected intravitreally. Longitudinal imaging of RGCs was performed and the number of surviving RGCs enumerated. There was significantly greater survival of labeled RGCs with Fe-corrole, but the degree of neuroprotection was relatively less than that predicted by their ability to scavenge superoxide-This implies an unexpected complexity in signaling of apoptosis by reactive oxygen species.


PNIPAAM modified mesoporous hydroxyapatite for sustained osteogenic drug release and promoting cell attachment.
This work presented a sustained release system of simvastatin (SIM) based on the mesoporous hydroxyapatite (MHA) capped with poly(N-isopropylacrylamide) (PNIPAAM). The MHA was prepared by using cetyltrimethylammonium bromide (CTAB) as a template and the modified PNIPAAM layer on the surface of MHA was fabricated through surface-initiated atom transfer radical polymerization (SI-ATRP). The SIM loaded MHA-PNIPAAM showed a sustained release of SIM at 37 °C over 16 days. The bone marrow mesenchymal stem cell (BMSC) proliferation was assessed by cell counting kit-8 (CCK-8) assay, and the osteogenic differentiation was evaluated by alkaline phosphatase (ALP) activity and Alizarin Red staining. The release profile showed that the release of SIM from MHA-SIM-PNIPAAM lasted 16 days and the cumulative amount of released SIM was almost seven-fold than MHA-SIM. Besides, SIM loaded MHA-PNIPAAM exhibited better performance on cell proliferation, ALP activity, and calcium deposition than pure MHA due to the sustained release of SIM. The quantity of ALP in MHA-SIM-PNIPAAM group was more than two fold than pure MHA group at 7 days. Compared to pure MHA, better BMSC attachment on PNIPAAM modified MHA was observed using fluorescent microscopy, indicating the better biocompatibility of MHA-PNIPAAM.


[Thumb salvage after infected toe-to-hand vascularised transfer with induced membrane technique].
The induced membrane technique of bone reconstruction described by A.C. Masquelet is a well-known and efficient procedure for the lower limbs but is rarely used in the hand. After debridement, the technique consists first in inducing a foreign body membrane by the implantation of a cement methyl methacrylate polymer spacer and then filling the defect by cancellous bone. We report a case of induced membrane to save an infected vascularized custom made toe-to-hand transfer. The second stage was done 3 months after the first. Bone healing was obtained 4 months later. No specific complication was observed. Induced membrane technique seems to be another possibility for bony defects of the hand besides vascularised or non-vascularised grafts. It is essential to apply the principles of the two stages of the procedure, first respecting the foreign body membrane and second stable fixation of the graft. In sepsis, this allows a second surgical debridement without compromising the graft. Masquelet technique, simple and reproducible, seems an effective salvage procedure for bone defects of the thumb.


Mini-pillar microarray for individually electrochemical sensing in microdroplets.
High throughput and high sensitivity are two important aspects in multiple biomarker recognition, drug discovery and relevant biochemical sensing. Here, we integrate mini-pillar microarray with the circuit components toward high-throughput individual electrochemical sensing in microdroplets. On such droplet-microarray-based electrochemical platform, the high adhesion of the mini-pillar can hold a microdroplet (hundreds nanoliter to a few microliter) regardless of rotation and deformation. Each pillar as a unit has a three-electrode to achieve individual electrochemical sensing, and electrodes are integrated on one side to achieve the sequential electrochemical read-out. Qualitative and quantitative electrochemical assessments of multiple glucose concentrations in individual microdroplets are also achieved. Such mini-pillar-based individual electrochemical platform shows great potential in high-throughput and high-sensitive biomolecular recognitions, provides an opportunity to develop miniaturized sensing platform for emerging biological and pathological applications.


Asthma requiring mechanical ventilation. A low morbidity approach.
There is considerable uncertainty about the clinical features, respiratory physiology, and optimal management of patients with asthma requiring mechanical ventilation. Furthermore, the ventilatory and pharmacologic management of asthma requiring mechanical ventilation remain controversial. We hypothesized (1) that there are clinically identifiable and pathophysiologically different subgroups presenting with asthma requiring ventilation; (2) that lower dose steroid therapy (< 400 mg/d intravenous hydrocortisone) is adequate; (3) that permissive hypercapnia is safe; (4) that prolonged paralysis is generally unnecessary; and (5) that clinical outcome would be favorable in patients treated with this approach. Review of medical records and intensive care charts and statistical analysis of findings. ICU of tertiary institution. Thirty-five consecutive cases of life-threatening asthma requiring mechanic ventilation. Three clinical subgroups of ventilation-requiring asthmatics could be identified. Those presenting with steady deterioration (10), those with unstable asthma followed by a sudden "dip" (16), and those with a sudden unexpected dip (9). Patients in the first group had a significantly lower PaCO2 (p < 0.01) at presentation, but required ventilation for longer periods. Those in the second group had a significantly higher PaCO2 (p < 0.01) and required ventilation for a shorter period. Those in the third group had an intermediate PaCO2 level before intubation and the shortest period (p < 0.01) of mechanical ventilation. Five patients experienced their sudden dip after ingesting aspirin. Ten cases received "high" dose hydrocortisone therapy (mean: 980 mg/24 h), and 25 received lower dose hydrocortisone (mean: 341 mg/24 h). No differences in illness severity at presentation or outcome could be detected between these two groups. Mean duration of ventilatory support was 36 h and mean duration of the ICU stay 52.1 h. Muscle relaxation was used in 12 patients for a mean period of 11.1 h. One patient was brain dead on arrival. All others survived. Life threatening asthma is an endpoint for several different clinical patterns of disease. No major clinical advantage could be found in our group of patients when high-dose steroids were used. Long-term use of muscle relaxants and prolonged mechanic ventilation are rarely needed in the management of patients with life-threatening asthma and excellent results can be achieved with a relatively simple management strategy.


Decontamination of broilers with hydrogen peroxide stabilised with glycerol during processing.
Experiments were conducted to assess the effects of different concentrations of hydrogen peroxide stabilised by glycerol solution in potable water on the bacteriological and organoleptic quality of freshly slaughtered broiler carcasses. Skin-pH and colour were measured 3.5 and 24 h after treatment and compared to untreated carcasses. Bacterial colonisation was determined 3.5 and 24 h and, 7 days after treatment, carcasses being stored at 1 degrees C. None of the concentrations used affected the appearance and "bloom" of the carcasses as could be measured by colorimeter and changing of the acidity. Mean microbial counts were significantly reduced (P<0.01) when treated and control broilers were compared. Average reductions of 0.3 up to1.4 log N for the mesophilic aerobic counts were achieved and from 0.4 up to 1.2 log N for Enterobacteriaceae. A 3% w/w solution made from a commercially available stock solution (Glyroxyl), which consists of 44% hydrogen peroxide, 44% demineralised water and 12% glycerol proved to lower colonisation more effectively than a 2% solution.


Effect of retinol and retinoic acid on permeability, electrical resistance and phase transition of lipid bilayers.
Retinol and retinoic acid have been incorporated into the artificial membrane systems, planar bimolecular lipid membranes and liposomes, and their effects on several membrane parameters have been measured. 1. Retinol and retinoic acid increased the permeability of egg lecithin liposomes to K+, I- and glucose when incorporated into the membranes at levels as low as 0.5 membrane mol%. Retinoic acid influenced permeability more than did retinol for each of the solutes tested. 2. Retinol and retinoic acid both decreased the electrical resistance of egg lecithin-planar bimolecular lipid membranes from 0.5 to 8 membrane mol%. Retinoic acid effected a larger change than did retinol. 3. Retinol and retinoic acid increased the permeability of dimyristoylphosphatidylcholine and dipalmitoylphosphatidylcholine liposomes to water at 1.0 and 3.0 membrane mol%. A larger effect on water permeability was measured for retinoic acid than for retinol. 4. Retinol and retinoic acid at 1.0 and 3.0 membrane mol% were shown to lower the phase-transition temperature of liposomes composed of dimyristoylphosphatidylcholine or dipalmitoylphosphatidylcholine. Phase-transition temperatures were monitored by abrupt changes in water permeability and liposome size associated with the transition. Retinoic acid lowered the phase-transition temperature of dimyristoylphosphatidylcholine liposomes more than did retinol, while both retinoids had almost the same effect on dipalmitoylphosphatidylcholine liposomes.


Multiple headspace sampling coupled to a programmed temperature vaporizer to improve sensitivity in headspace-gas chromatography. Determination of aldehydes.
The improvement of sensitivity in headspace (HS) sampling of not very volatile analytes constitutes a challenge that has usually been approached through coupling with additional techniques. Here we propose a new methodology for increasing sensitivity through a multistep approach. This proof of concept is based on direct coupling of a headspace sampler with a programmed temperature vaporizer (PTV) and a gas chromatograph (GC), with mass spectrometry (MS) detection. Analytes are extracted from the same vial in a stepwise procedure, splitting the headspace generation time of conventional HS into four periods and using the PTV to cryogenically trap the analytes during the successive HS samplings. Solvent vent mode is mandatory in order to retain the analytes, purging the gas solvent at an adequate initial low temperature and flash-heating the PTV liner in a quick ramp (720 °C/min), once the HS samplings are finished. Linear aldehydes, from pentanal to decanal, possible biomarkers of several diseases have been selected as model compounds. This multiple HS method has been compared with conventional HS, and it has been validated in terms of linearity, limits of detection, repeatability, reproducibility and accuracy. The limits of detection (LOD) ranged from 0.004 to 0.159 µg/L. Enrichment factors (EF) in relation to the conventional HS method ranged from 3.0 to 6.7, except for pentanal (EF: 0.8), which is too volatile and polar to be trapped in the PTV with the multiple HS methodology. Similar enrichment factors were obtained in a urine sample.


The impact of severity of hypertension on association of PGC-1alpha gene with blood pressure and risk of hypertension.
Little is known about the impact of severity of hypertension on the association of genes with high blood pressure, which may cause the inconsistently reported associations of peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha) gene with blood pressure. A cardiovascular epidemiology survey and genotyping were performed in a population-based sample of 1642 apparently healthy residents (648 men and 994 women aged 35-91 years). After adjusting for age, sex, body mass index, and antihypertensive medication, G482S and +2962A/G polymorphisms were significantly associated with systolic blood pressures in hypertension patients with medication use (p = 0.023 and 0.022 for G482S and +2962A/G respectively) but not in all participants, normotensives, and patients with no medication use. Multivariable logistic models showed that the two polymorphisms were significantly associated with severe hypertension (SBP > or = 160 mm Hg or DBP > or = 100 mm Hg regardless of medication use), with an OR of 0.6(95% confidence interval [CI]: 0.4-0.98) for S482S vs. G482G and an OR of 1.9(95% CI: 1.2-3.0) for +2962G/G vs. +2962A/A, but not with regular hypertension (SBP > or = 140 mm Hg or DBP > or = 90 mm Hg or current use of antihypertensive medications), with an OR of 0.9(95% CI: 0.7-1.2) for S482S vs. G482G and an OR of 0.9(95% CI: 0.7-1.4) for +2962G/G vs. +2962A/A. Haplotype combination analyses showed a significant synthetic effect (OR of severe hypertension for persons with G482X and +2962G/G = 2.6, 95%CI: 1.5-4.4, with reference to persons with S482S and +2962A/X). In this study, we found that G482S and +2962A/G polymorphisms of PGC-1alpha gene were only significantly associated with severe hypertension defined by occasional clinic blood pressure measurements. This finding suggested severe hypertension rather than regular hypertension should be used as the outcome in studies on association of genes with blood pressure or hypertension, in order to have a better power.


High nitrous oxide fluxes from rice indicate the need to manage water for both long- and short-term climate impacts.
Global rice cultivation is estimated to account for 2.5% of current anthropogenic warming because of emissions of methane (CH4), a short-lived greenhouse gas. This estimate assumes a widespread prevalence of continuous flooding of most rice fields and hence does not include emissions of nitrous oxide (N2O), a long-lived greenhouse gas. Based on the belief that minimizing CH4 from rice cultivation is always climate beneficial, current mitigation policies promote increased use of intermittent flooding. However, results from five intermittently flooded rice farms across three agroecological regions in India indicate that N2O emissions per hectare can be three times higher (33 kg-N2O⋅ha-1⋅season-1) than the maximum previously reported. Correlations between N2O emissions and management parameters suggest that N2O emissions from rice across the Indian subcontinent might be 30-45 times higher under intensified use of intermittent flooding than under continuous flooding. Our data further indicate that comanagement of water with inorganic nitrogen and/or organic matter inputs can decrease climate impacts caused by greenhouse gas emissions up to 90% and nitrogen management might not be central to N2O reduction. An understanding of climate benefits/drawbacks over time of different flooding regimes because of differences in N2O and CH4 emissions can help select the most climate-friendly water management regimes for a given area. Region-specific studies of rice farming practices that map flooding regimes and measure effects of multiple comanaged variables on N2O and CH4 emissions are necessary to determine and minimize the climate impacts of rice cultivation over both the short term and long term.


Juniperus rigida Sieb. extract inhibits inflammatory responses via attenuation of TRIF-dependent signaling and inflammasome activation.
Juniperus rigida Sieb. (J. rigida) is used for medicinal purposes in Asian countries to treat inflammation-related disorders, such as neuralgia, dropsy, and gout. The anti-inflammatory effects of J. rigida extract (JR) and its underlying mechanisms were explored both in in vitro cell lines and in vivo metabolic disease models. Lipopolysaccharide (LPS)-stimulated RAW264.7 murine macrophages were used to study the changes in inflammatory responses in vitro. Bone marrow-derived macrophages (BMDMs) were used to study the regulatory effect of JR on inflammasome activation. The murine model for monosodium urate (MSU)-induced peritonitis and high-fat diet (HFD)-induced type 2 diabetes were employed to study the effect of JR on in vivo efficacy. JR suppressed the MSU-induced in vivo inflammatory response by attenuation of proinflammatory cytokines, including interleukin (IL)-1β, IL-6, and tumor necrosis factor-alpha (TNF-α). In the in vitro study, JR suppressed IL-1β secretion via regulation of apoptosis-associated speck-like protein containing a CARD (ASC) oligomerization, leading to the inhibition of inflammasome activation. JR also inhibited the LPS-stimulated release of proinflammatory mediators, such as nitric oxide (NO), TNF-α, and IL-6 in RAW264.7 cells. The inhibitory effects of JR were mediated through the regulation of the TRIF-dependent signaling pathway from JAK1/STAT1 phosphorylation. Furthermore, JR showed inhibitory effects on HFD-induced type 2 diabetes in a mouse model through the regulation of blood glucose and serum IL-1β. Our results indicate that JR attenuates both LPS-stimulated and danger-signal-induced inflammatory responses in macrophages via regulation of the key inflammatory mechanisms, providing scientific support for its traditional use in the treatment of various inflammation-related metabolic disorders.


Impact of intracoronary adenosine administration during primary PCI: A meta-analysis.
Aim of the present study was to evaluate all randomized trials, comparing intracoronary adenosine versus placebo in STEMI patients undergoing primary PCI. PubMed, the Cochrane Library and ISI Web of Knowledge electronic databases were scanned for eligible studies up to February 23rd 2015. The summary measure used was risk ratio (RR) with 95% confidence intervals. A total of 13 studies were eligible, including 1487 patients. Incidence of ST resolution was significantly higher in the IC adenosine group than in the placebo group (RR = 1.20 [1.05–1.38]; p = 0.008). At metaregression, a significant correlation was found between the magnitude of the adenosine-related effect on ST resolution and the mean ischemic time (p = 0.011) or the percentage of patients with the LAD as the infarct-related artery (p = 0.03). Furthermore, we found a larger increase in LVEF (p = 0.02) with a parallel reduction in the incidence of heart failure (HF) (RR = 0.50 [0.28–0.89]; p = 0.02) in the IC adenosine group. Finally, IC adenosine administration was associated with a significantly lower incidence of major adverse cardiac events (MACE) both at short- (RR = 0.62 [0.39–0.98] p = 0.04) and long-term (RR = 0.61 [0.39–0.95] p = 0.03). This is the first meta-analysis demonstrating a clinical benefit for IC adenosine in hard endpoints, such as adverse cardiovascular events, in patients undergoing primary PCI.


Risdiplam for the treatment of adults with spinal muscular atrophy: Experience of the Northern Ireland neuromuscular service.
Risdiplam is the newest available treatment for patients with spinal muscular atrophy (SMA). There is little information on its use in adults. We present the clinical experience of adults with SMA treated with risdiplam through the Early Access to Medicines Scheme (EAMS) in Northern Ireland. All adults with Type 2 SMA attending the regional neuromuscular clinic were offered risdiplam treatment. Patients had assessments of respiratory function, the Epworth Sleepiness Scale (ESS), Quality of Life Measure for People with Slowly Progressive and Genetic Neuromuscular Disease (QOLM), and Egen Klassifikation 2 (EK2) every 3 mo and the Revised Upper Limb Module for SMA (RULM) at baseline and 6 mo. All assessments other than the RULM were carried out virtually. Six of seven patients who were offered risdiplam consented to treatment through the EAMS (five female, one male, mean age 33.7 y). It was generally well tolerated other than skin photosensitivity in all patients. All patients remained on therapy at 9 mo. All reported meaningful improvements in overall strength, sense of wellbeing, and speech quality. There was no change in respiratory function, daytime hypersomnolence, or upper limb function (all p > .05). There was improvement in the QOLM (p = .027) and EK2 (p = .009). Our study raises hopes that risdiplam may be efficacious in adults; however, more systematic studies in larger cohorts are needed before drawing any definitive conclusions. This study also demonstrated the feasibility of virtual assessments.


Naturalistic Parent Teaching in the Home Environment During Early Childhood.
Children's sociocultural experiences in their day-to-day lives markedly play a key role in learning about the world. This study investigated parent-child teaching during early childhood as it naturally occurs in the home setting. Thirty-nine families' naturalistic interactions in the home setting were observed; 1033 teaching sequences were identified based on detailed transcriptions of verbal and non-verbal behavior. Within these sequences, three domains of learning (knowledge, skills, and dispositions) and subtopics were identified and analyzed in relation to gender, child birth order, context, teaching strategies, and learner response. Findings show knowledge, skills, and dispositions were taught equally, marked by the most prominent subtopics taught within each domain, including cognitive (skill), game rule (knowledge), and social rule (disposition). Further, mothers and fathers were found to teach their children equally, however, fathers taught knowledge more than mothers, whereas mothers taught dispositions more than fathers. Differences between domains of learning and subtopics also existed between mother's and father's teaching based on child birth order and gender. This study also assessed the contrast between teaching knowledge, skills, and dispositions by context, parent teaching strategies, and child learner response. Results support the notion that family interactions in the home setting set a stage for children's rich informal learning experiences. Vygotskian sociocultural conceptions underpin this research and findings are discussed using this central theoretical lens.


Identification of genes associated with head and neck carcinogenesis by cDNA microarray comparison between matched primary normal epithelial and squamous carcinoma cells.
In order to identify genes involved in head and neck carcinogenesis, we compared the gene expression profile in matched primary normal epithelial cells and primary head and neck cancer cells from the same patients. A cDNA microarray analysis consisting of 12 530 human genes revealed significant changes in the expression of 213 genes, with 91 genes being up-regulated and 122 being down-regulated. This comprehensive list of genes includes those associated with signal transduction (growth factors), cell structure, cell cycle, transcription, apoptosis, and cell-cell adhesion. Further analysis of nine genes involved in cell-cell interaction, using Western blot and/or reverse transcription (RT)-PCR of four paired cell lines supported the reliability of our microarray analysis. More specifically, our study provides the first evidence that claudin-7 and connexin 31.1 are down-regulated in head and neck squamous cell carcinomas (HNSCC) compared to normal cells. These findings provide a large body of information regarding gene expression profiles associated with head and neck carcinogenesis, and also represent a source of potential targets for HNSCC prevention and/or therapeutics.


Adjuvant treatment strategies for early colon cancer.
Colon cancer remains a major cause of death; however, in the last 3 years a number of trials have been published that have led to changes in the treatment of patients with this disease. Initially, the adjuvant treatment of patients following curative resection was based on their Dukes staging; this is now being refined by consideration of other pathological factors, as well as the investigation of newer prognostic markers such as p53, Ki67 and a number of genes on chromosome 18. Tumours generally develop from the progressive accumulation of genetic events, although some develop through mutation or inactivation of DNA mismatch repair proteins leading to microsatellite instability; this is particularly important in Lynch's syndrome. The loss of gene expression can occur by deletion or mutation of genes or by aberrant methylation of CpG islands. In patients with Dukes C colon cancer the standard of care for adjuvant chemotherapy was previously based on bolus fluorouracil (5-fluorouracil) and folinic acid (leucovorin) administered 5 days per month or weekly for 6 months. Recent studies with a combination of infusional fluorouracil, folinic acid and oxaliplatin have been found to be superior. A further study replacing fluorouracil with oral capecitabine has also demonstrated equivalent disease-free survival. Although some debate remains regarding the benefit of adjuvant treatment for patients with Dukes B colon cancer, the emerging consensus is that, for those patients who are younger and have high-risk features, chemotherapy should be discussed. A number of large vaccine trials have also been conducted in the adjuvant setting and, overall, these have been disappointing. This is a rapidly advancing area of therapy and the results of new trials are awaited to determine whether additional benefits can be achieved with biological therapies such as anti-vascular endothelial growth factor and anti-epithelial growth factor receptor monoclonal antibodies, which have already been shown to be effective in setting of metastatic colon cancer.


Analysis of electrical and mechanical left atrial properties in patients with persistent atrial fibrillation.
The study of left atrial (LA) mechanical function during atrial fibrillation (AFib) can provide valuable information, particularly if such profiling is related to the cavity electrical substrate and conveys prognostic information. To assess if there is any relation between LA mechanical and electrical asynchrony and if such evaluation can be of interest in stratifying AFib patients. 50 patients with persistent AFib who underwent electrical cardioversion (CV) were evaluated with pre-CV atrial electrograms (AEGs). Electrical asynchrony was classified according to Wells' patterns of AEGs, ranging from most organized (I) to most dispersed (III) one. LA mechanical asynchrony was addressed by transthoracic 2D-speckle-tracking echo and quantified according to time-to-peak standard deviation (TP-SD) of wall strains and their peak values (PS) before CV, after 24 h, at 1 month. Pre-CV a linear, inverse relation between TP-SD and PS (p < 0.001) and a direct linear relation between TP-SD and Wells' classes (p = 0.04) were observed. With sinus rhythm TP-SD decreased (p = 0.023) and PS increased (p < 0.001), suggesting improved LA mechanical milieu. A multivariate analysis, testing the effects of baseline variables in predicting post-CV recurrence of AFib, revealed that amount of TP-SD variation pre/24 h post-CV was the only independent predictor at 6 months (p = 0.046). Speckle tracking-derived LA parameters can describe LA wall forces during AFib, categorizing the asynchronous mechanistic profile of AFib that correlates with the degree of the dispersed LA electrical activity. The amount of changes in LA mechanical asynchrony pre/post-CV seems to have prognostic relevance in predicting SR maintenance.


[Epidemiological study of type 1 diabetes in children under 15 years-old in Castilla-La Mancha (Spain)].
We studied the incidence and prevalence of type 1 diabetes in children under 15 years-old in Castilla-La Mancha. Incidence: All new cases in a 12 months period (2007-2008) were included. To calculate the completeness of ascertainment we used the capture-recapture method. The result is expressed in cases/100,000 inhabitants under 15 years old/year. Prevalence: all children under 15 years diagnosed with diabetes on 31(st) of May of 2008 were registered. Results are expressed as cases/1000 inhabitants under 15 years old. The incidence in the Castilla-La Mancha was 27.6/100,000/year, but there was a wide variability among the different provinces: Ciudad Real (34.15), Albacete (28.19), Toledo (26.57), Guadalajara (20.3) and Cuenca (17.6). The prevalence was 1.44/1000 children under 15 years old and 0.21/1000 for the whole population. By provinces: Ciudad Real (1.67), Albacete (1.64), Toledo (1.42), Cuenca (1.02) and Guadalajara (1.01). By sex and age, we found a higher incidence (13/7) and prevalence (22/7) in males under 5 years old. The age group with highest incidence was the 4-9 year-olds, and the highest prevalence was in the 10-14 years group. Both, incidence and prevalence of type 1 diabetes in children under 15 years old in Castilla-La Mancha are high, with a wide range among the different provinces. There is a preponderance in males under 5 years old. The highest prevalence is that of the 10-14 years age group. The highest incidence was in the 5-10 year age group.


Automated liquid operation method for microfluidic heterogeneous immunoassay.
In this work, an automated liquid operation method for multistep heterogeneous immunoassay toward point of care testing (POCT) was proposed. A miniaturized peristaltic pump was developed to control the flow direction, flow time and flow rate in the microliter range according to a program. The peristaltic pump has the advantages of simple structure, small size, low cost, and easy to build and use. By coupling the peristaltic pump with an antibody-coated capillary and a reagent-preloaded cartridge, the complicated liquid handling operation for heterogeneous immunoassay, including sample metering and introduction, multistep reagent introduction and rinsing, could be triggered by an action and accomplished automatically in 12 min. The analytical performance of the present immunoassay system was demonstrated in the measurement of human IgG with fluorescence detection. A detection limit of 0.68 μg/mL IgG and a dynamic range of 2-300 μg/mL were obtained.


Stereoselectivity of the 4-hydroxylation of debrisoquine in man, detected by gas chromatography/mass spectrometry.
A stable isotope assay for the quantification of debrisoquine (1) and its major urinary metabolite 4-hydroxydebrisoquine (2) is described. The method consists of extractive derivatization of 1 and 2 by use of 1,3-diketones, chiral derivatization of the 4-hydroxy group of 2, and gas chromatography/negative ion chemical ionization mass spectrometry in the presence of deuterated analogues of 1 and 2. In comparison with synthetic R-(-)-2 and S-(+)-2 it is shown that in vivo benzylic 4-hydroxylation of 1 is highly stereoselective, leading predominantly to S-(+)-4-hydroxydebrisoquine (enantiomeric excess greater than or equal to 90%).


High-intensity rectangular fiber-coupled diode laser array for solid-state laser pumping.
A high-power diode laser bar coupling scheme with rectangular optical fibers is proposed, and the concept is tested on a scale version: an individual diode laser array and a single rectangular fiber. 60% of the power from a 1-W cw, 213-µm-wide 20-stripe diode array is coupled into a 216 µm × 28 µm 0.66 numerical aperture optical fiber, which produces intensities at the fiber output face of 9.9 kW cm(-2). The elliptical, dual-lobed far-field intensity pattern of the diode laser output, with divergence of 39° × 13° FWHM is converted on passing through the fiber into a single-lobed, nearly circular pattern with a FWHM divergence of 21° × 22°. The beam quality is reduced by only a factor of 30 when this coupling method is used. Alignment tolerances in the three planes of movement are measured and found to be in excess of 10 µm.


[LC/MS/MS Analysis of the Metabolites of Lathyrane Diterpenoids in Caco-2 Cells].
To identify the metabolites of euphorbetin L1,euphorbetin L2,euphorbetin L8 and 6( 17),12( E)-lathyrol-5,15-diacetate-3-phenylacetate in Caco-2 cells by LC/MS/MS. Caco-2 cells were cultured with 100 μg/mol lathyrane diterpenoid for 3,6,12 h,respectively. Then the samples were collected,purified and identified by LC/MS/MS. The major metabolites of euphorbetin L1 were two methylated products which were obtained after hydrolysis of the ester. The major metabolites of euphorbetin L2,euphorbetin L8 and 6( 17),12( E)-lathyrol-5,15-diacetate-3-phenylacetate were hydrolysis products of the ester. The main metabolic pathway of euphorbetin L1 is methylation and hydrolysis of the ester. The main metabolic pathway of euphorbetin L2,euphorbetin L8 and 6( 17),12( E)-lathyrol-5,15-diacetate-3-phenylacetate is hydrolysis of the ester. LC/MS/MS can identify the metabolites of euphorbetin L1,euphorbetin L2,euphorbetin L8 and 6( 17),12( E)-lathyrol-5,15-diacetate-3-phenylacetate in Caco-2 cells quickly and sensitively.


Relationships of the musculocutaneous nerve and the coracobrachialis during coracoid abutment procedure (Latarjet procedure).
The aim of this study was first to define first the anatomical relationships between the musculocutaneous nerve and the coracobrachialis, and then the induced modifications of these relationships by a preglenoid transposition of the vertical part of the coracoid process. Twenty-one embalmed adult trunks and upper limb were dissected. First the coracobrachialis and the musculocutaneous nerve were identified through a deltopectoral approach. We measured the distances between the lateral cord of the brachial plexus and the entry point of the nerve, between the inferior tip of the tip of the coracoid process and the penetration of the nerve or its twigs, and finally the angle between the general axis of the coracobrachialis and the axis of the musculocutaneous nerve. The same measures were performed after the coracoid bone block abutment. Proximal motor branches destined to the coracobrachialis varied from 0 to 3. Mean distance between the lateral cord of the brachial plexus and entry point of the nerve into the muscle was 47.2 mm before and 48.43 mm after the coracoid transfer. Mean angulations between the nerve and the muscle was 121 degrees before and 136 degrees after the transfer of the coracoid process. Mean distance between the inferior tip of the coracoid process and entry point of the nerve into the muscle was 55.7 mm, reduced to 48.6 mm after the coracoid transposition. Finally, the distance between the tip of the coracoid and the first motor twig entering the coracobrachialis was less than 50 mm in 75% of the cases with a mean value of 40.6 mm. Lesion of the musculocutaneous nerve is a known complication of the coracoid bone block abutment procedure (Latarjet-Bristow). From this study we know that they are due to lengthening of the nerve and modification of the penetration angle of the nerve into the coracobrachialis. We also infer that some motor nerve destined to the coracobrachialis might be damaged during the proximal medial release of the muscle after the detachment of the pectoralis minor muscle.


Individually immobilized and surface-modified hydrocarbon-degrading bacteria for oil emulsification and biodegradation.
Effective emulsification plays an important role in the treatment of marine oil spills. The negative effects of chemical surfactants have necessitated a search for alternative dispersant that are sustainable and environmentally-friendly. To identify alternate dispersants, oil-in-seawater emulsions stabilized by hydrocarbon-degrading bacteria were investigated. After individual immobilization and surface-modification, the hydrocarbon-degrading bacteria, Bacillus cereus S-1, was found to produce a stable oil-in-seawater Pickering emulsion, which was similar to particle emulsifiers. The individual immobilization and surface-modification process improved the surface hydrophobicity and wettability of the bacterial cells, which was responsible for their effective adsorption at the oil-water interface. Through effective emulsification, the biodegradation of oil was remarkably facilitated by these treated bacteria, because of the increased interfacial area. By combining the emulsification and biodegradation, the results of this reported work demonstrated a novel approach for developing environmentally-friendly bioremediation technology in the field of oil treatment.


Apparent tick paralysis by Rhipicephalus sanguineus (Acari: Ixodidae) in dogs.
Certain tick species including Ixodes holocyclus can inoculate neurotoxins that induce a rapid, ascending flaccid paralysis in animals. Rhipicephalus sanguineus, the most widespread tick of dogs, is recognized as a vector of several pathogens causing diseases in dogs and humans. A single report suggests its role as cause of paralysis in dogs. This study presents the clinical history of 14 young dogs heavily infested by R. sanguineus (intensity of infestation, 63-328) in an endemic area of southern Italy. During May to June of 2011, dogs were presented at the clinical examination with neurological signs of different degrees (e.g., hind limb ataxia, generalized lethargy, and difficulty in movements). All animals were treated with acaricides and by manual tick removal but ten of them died within a day, displaying neurological signs. The other 4 dogs recovered within 3 days with acaricidal and supportive treatment. Twelve dogs were positive by blood smear examination for Hepatozoon canis with a high parasitemia, two also for Babesia vogeli and two were negative for hemoparasites. Low-grade thrombocytopenia, hypoalbuminemia, and pancytopenia were the haematological alterations most frequently recorded. Other causes of neurological disease in dogs were excluded and the diagnosis of tick paralysis by R. sanguineus was confirmed (ex juvantibus) by early and complete recovery of 4 dogs following acaricidal treatment and tick removal.


Controlling disease outbreaks in wildlife using limited culling: modelling classical swine fever incursions in wild pigs in Australia.
Disease modelling is one approach for providing new insights into wildlife disease epidemiology. This paper describes a spatio-temporal, stochastic, susceptible- exposed-infected-recovered process model that simulates the potential spread of classical swine fever through a documented, large and free living wild pig population following a simulated incursion. The study area (300 000 km2) was in northern Australia. Published data on wild pig ecology from Australia, and international Classical Swine Fever data was used to parameterise the model. Sensitivity analyses revealed that herd density (best estimate 1-3 pigs km-2), daily herd movement distances (best estimate approximately 1 km), probability of infection transmission between herds (best estimate 0.75) and disease related herd mortality (best estimate 42%) were highly influential on epidemic size but that extraordinary movements of pigs and the yearly home range size of a pig herd were not. CSF generally established (98% of simulations) following a single point introduction. CSF spread at approximately 9 km2 per day with low incidence rates (< 2 herds per day) in an epidemic wave along contiguous habitat for several years, before dying out (when the epidemic arrived at the end of a contiguous sub-population or at a low density wild pig area). The low incidence rate indicates that surveillance for wildlife disease epidemics caused by short lived infections will be most efficient when surveillance is based on detection and investigation of clinical events, although this may not always be practical. Epidemics could be contained and eradicated with culling (aerial shooting) or vaccination when these were adequately implemented. It was apparent that the spatial structure, ecology and behaviour of wild populations must be accounted for during disease management in wildlife. An important finding was that it may only be necessary to cull or vaccinate relatively small proportions of a population to successfully contain and eradicate some wildlife disease epidemics.


Effects of caffeine on heart rate and QT variability during sleep.
Administration of caffeine in the evening produces poor sleep. Patients with insomnia have characteristic electrocardiogram (ECG) changes, including increased heart rate (HR), increased sympathetic activity, and decreased parasympathetic activity. Fifteen young adult normal subjects slept in the laboratory for several nights prior to randomization into a caffeine protocol where subjects received caffeine 400 mg 30 min prior to one night of sleep and placebo randomly prior to another night. ECG was sampled at a rate of 500 Hz and recorded onto a PC. Data samples of 256-s periods of the ECG trace were taken from wake (before sleep), stage II, and REM for placebo and caffeine conditions. A peak detection algorithm was used to identify the R-R intervals (in milliseconds) from the ECG. A common QT variability algorithm was used to find the QT interval for each beat using the time-stretch model. The powers for HR and QT series were integrated in the bands of LF (low frequency: 0.04-0.15 Hz) and HF (high frequency: 0.15-0.5 Hz) bands. There was a significant caffeine by sleep stage interaction for LF/HF ratios (F = 4.0; df = 2, 18; P = .04). LF/HF ratios were significantly higher during REM following caffeine administration. There was also a significant caffeine by sleep stage interaction for QTvi (QT variability normalized for mean QT interval divided by HR variability normalized for mean HR; F = 5.6; df = 2, 12; P = .02). QTvi was also significantly higher during REM following caffeine administration. The higher LF/HF ratios and QTvi during REM are most likely due to the sympathetic effects of caffeine. These findings suggest that excessive caffeine intake may result in adverse cardiovascular events in vulnerable subjects.


Disseminated tuberculosis masquerading as a presentation of systemic lupus erythematosus.
Tuberculosis (TB) infection is the endemic in Asia-Pacific region. Miliary TB is a disseminated form which may present similarly as autoimmune conditions. Here we describe a 17-year-old girl who had miliary TB with manifestations mimicking new-onset systemic lupus erythematosus (SLE) including oral ulcers, serositis, cytopenia, proteinuria and raised autoantibody titers. Complex associations between SLE and TB are highlighted. High index of clinical suspicion for TB infection is needed upon presentations resembling immune diseases like SLE.


A digital territory to be appropriated: the state and the nationalization of cyberspace.
Next to land, water, air and space, cyberspace is the complex socio-technical setting often called the 'fifth domain'. Nationalism has taken over the organization of the first four domains, in the form of constructing national states, national territorial waters and national airspace. The basic proposition of this article is that the ideology of nationalism has also infiltrated the fifth domain - cyberspace - in two ways. First, through state-led cyber-nationalism via official government websites that present 'national' achievements and propagate the official state positions on disputes about territory, symbols or history. Second, through individual communities who use the internet to sustain a sense of national belonging and/or to promote and disseminate their nationalist ideals. Both ways are important in an online national identity (re)production framework that, in a fluid, global, modern world, functions supportively towards the traditional national identity (re)production mechanisms. This article aims to examine the patterns of the nationalization of cyberspace through an analysis of state-led institutions and government websites that aim to enhance national identity and the sense of national belonging in a globalized world, as well as to propagate official state positions. It will focus on Greek, Dutch, US and Israeli websites. The term 'nationalization' in this context denotes the ideological charging of the cyber-footprint of the nation: how the internet produces and re-produces the nation, how the users partake in the national community by way of 'consuming' the digitalized national ideology, and the way cyber-nationalism defines people's sense of belonging.


Oxidative turnover increases the rate constant and extent of intramolecular electron transfer in the multicopper enzymes, ascorbate oxidase and laccase.
Using laser flash photolysis of lumiflavin/EDTA solutions containing ascorbate oxidase, we find that the rate constant for intramolecular electron transfer varies from one enzyme preparation to another and is generally a more sensitive measure of the state of the active site than are steady-state assays. Thus, type I copper is initially reduced in a second-order reaction followed by first-order reoxidation by the type II-III trinuclear copper center. The observed rate constant for this intramolecular process in presumably native enzyme is 160 s-1 at pH 7, whereas an enzyme preparation which had less than 20% activity had a rate constant of 2.6 s-1. Other samples of relatively active enzyme showed biphasic intramolecular kinetics intermediate between the above values. The inactive enzyme sample could be reactivated by dialysis against ascorbate or by treatment with ferricyanide, resulting in a corresponding increase in the intramolecular rate constant for type I copper reoxidation to a value comparable to that of native enzyme. Using this same methodology, we have determined that the type I copper in Japanese lacquer tree laccase is reoxidized by the type II-III trinuclear copper center in a first-order (intramolecular) process with rate constants of 1 s-1 at pH 7.0 and 4.9 s-1 at pH 6.0, values which are approximately two orders of magnitude smaller than for ascorbate oxidase. The intramolecular rate constant and enzyme activity for laccase also increased, but only by a factor of 2-6, when the enzyme was treated with ascorbate or ferricyanide, respectively. We further found that intramolecular electron transfer in laccase was completely inhibited by fluoride ion, in contrast to ascorbate oxidase which is unaffected by this ion. These differences in behavior for these two very similar enzymes are rather remarkable, when it is considered that the distance between copper atoms is constrained by the location of the protein-derived copper ligands in the three-dimensional structure, and that the redox potentials of the enzymes are similar. Our results may be interpreted in terms of an interconversion between active and inactive enzyme in which there is a rearrangement of the type II-III trinuclear copper center, resulting in a lowering of the redox potential and a block in electron transfer. Turnover restores the active enzyme conformation.(ABSTRACT TRUNCATED AT 400 WORDS)


[The role of glucose and reactive oxygen species in the development of vascular complications of diabetes mellitus].
Several mechanisms seem to be involved in the development of oxidative stress in the presence of elevated glucose concentrations, namely glucose autoxidation, protein glycation, and the polyol pathway. In diabetes patients reactive oxygen species and advanced glycation end products are able to alter vascular function and disturb cellular homeostasis especially by lipid peroxidation, changes in extracellular matrix and inhibiting synthesis and action of nitric oxide.


Paracrine signaling of human mesenchymal stem cell modulates retinal microglia population number and phenotype in vitro.
Cellular therapy with mesenchymal stem cells (MSC) is emerging as an effective option to treat optic neuropathies. In models of retinal degeneration, MSC injected in the vitreous body protects injured retinal ganglion cells and stimulate their regeneration, however the mechanism is still unknown. Considering the immunomodulating proprieties of MSC and the controversial role of microglial contribution on retinal regeneration, we developed an in vitro co-culture model to analyze the effect of MSC on retinal microglia population. We used whole adult rat retinal explants in co-culture with human Wharton's jelly mesenchymal stem cells (hMSC) separated by a transwell membrane and analyzed hMSC effect on both retinal ganglion cells (RGCs) and retinal microglia. hMSC in co-culture protected RGCs after 3 days in vitro by paracrine signaling. In addition, hMSC reduced microglia population and inhibited the pro-inflammatory phenotype of the remaining microglia. Using a co-culture model, we demonstrated the paracrine effect of hMSC on RGC survival after injury concomitant with a reduction of microglial population. Paracrine signaling of hMSC also changed microglia phenotype and the expression of antiinflammatory factors in the retina. Our results are consistent with a detrimental effect of microglia on RGC survival and regeneration after injury.


The sutureless aortic valve at 1 year: A large multicenter cohort study.
Sutureless aortic valve replacement (AVR) offers an alternative to standard AVR in aortic stenosis. This prospective, single-arm study aimed to demonstrate safety and effectiveness of a bovine pericardial sutureless aortic valve at 1 year. From February 2010 to September 2013, 658 patients (mean age 78.3 ± 5.6 years; 40.0% octogenarian; 64.4% female; mean Society of Thoracic Surgeons score 7.2 ± 7.4) underwent sutureless AVR in 25 European centers. Concomitant cardiac procedures were performed in 29.5% and minimally invasive cardiac surgery in 33.3%. One-year site-reported event rates were 8.1% for all-cause mortality, 4.5% for cardiac mortality, 3.0% for stroke, 1.9% for valve-related reoperation, 1.4% for endocarditis, and 0.6% for major paravalvular leak. No valve thrombosis, migration, or structural valve deterioration occurred. New York Heart Association class improved at least 1 level in 77.5% and remained stable (70.4% New York Heart Association class I or II at 1 year). Mean effective orifice area was 1.5 ± 0.4 cm(2); pressure gradient was 9.2 ± 5.0 mm Hg. Left ventricular mass decreased from 138.5 g/m(2) before surgery to 115.3 g/m(2) at 1 year (P < .001). Echocardiographic core laboratory findings confirmed that paravalvular leak was rare and remained stable during follow-up. The Perceval sutureless valve resulted in low 1-year event rates in intermediate-risk patients undergoing AVR. New York Heart Association class improved in more than three-quarters of patients and remained stable. These data support the safety and efficacy to 1 year of the Perceval sutureless valve in this intermediate-risk population.


[Yellow nail syndrome: description of a case and review of the associated pathology].
The AA. report a case of yellow nail syndrome associated with rheumatoid arthritis and monoclonal gammopathy (IgG-lambda). Because of the great variety of the diseases associated with this syndrome, the AA. suggest to control patients periodically to verify the probable appearance of other clinical manifestations.


Introduction and evaluation of a modular seminar system in gross anatomy teaching at the Hannover Medical School.
We present a new modular seminar system which has been introduced into the gross anatomy teaching at the Hannover Medical School. It consists of seven modules with a clinical emphasis. The new modular seminar system was evaluated by an anonymous questionnaire. The results showed that the seminar system as a whole, and the different modules with one exception were highly appreciated by the students. The evaluation also revealed that the main reason for the success of a module is the manner of the teaching and learning rather than the clinical relevance. Taking into account the results of this evaluation we describe the appropriate style of teaching for use in a seminar. The success of this new approach to small group instruction in Germany should encourage other teachers of anatomy and other undergraduate subjects to consider new methods of teaching.


Elucidation of tautomer structures of 2-acetyltetrahydropyridine using gas chromatography/mass spectrometry and gas chromatography/infrared spectroscopy.
2-Acetyltetrahydropyridine is an important flavor component in heated corn products such as popcorn and corn chips. The compound exists as a mixture of two tautomers that have different flavor/aroma characteristics. The tautomers also exhibit different chromatographic behaviors and are distinguishable spectroscopically. Though their electron ionization mass spectra are different, structure assignment based on low-resolution mass spectra alone has been subject to error. A combination of high resolution exact mass measurement and vapor phase infrared measurement of the separated tautomers was used to unambiguously assign the tautomer structures.


Impact of air gun noise on the behaviour of marine fish and squid.
In this study various species of captive marine fish and one species of squid were exposed to the noise from a single air gun. Six trials were conducted off the coast of Western Australia with each trial using a different noise exposure regime. Noise levels received by the animals ranged between 120 and 184 dB re 1 μPa(2).s (SEL). Behavioural observations of the fish and squid were made before, during and after air gun noise exposure. Results indicate that as air gun noise levels increase, fish respond by moving to the bottom of the water column and swimming faster in more tightly cohesive groups. Significant increases in alarm responses were observed in fish and squid to air gun noise exceeding 147-151 dB re 1 μPa SEL. An increase in the occurrence of alarm responses was also observed as noise level increased.


The chaperone Lhs1 contributes to the virulence of the fish-pathogenic oomycete Aphanomyces invadans.
Oomycetes are fungal-like eukaryotes and many of them are pathogens that threaten natural ecosystems and cause huge financial losses for the aqua- and agriculture industry. Amongst them, Aphanomyces invadans causes Epizootic Ulcerative Syndrome (EUS) in fish which can be responsible for up to 100% mortality in aquaculture. As other eukaryotic pathogens, in order to establish and promote an infection, A. invadans secretes proteins, which are predicted to overcome host defence mechanisms and interfere with other processes inside the host. We investigated the role of Lhs1 which is part of an ER-resident complex that generally promotes the translocation of proteins from the cytoplasm into the ER for further processing and secretion. Interestingly, proteomic studies reveal that only a subset of virulence factors are affected by the silencing of AiLhs1 in A. invadans indicating various secretion pathways for different proteins. Importantly, changes in the secretome upon silencing of AiLhs1 significantly reduces the virulence of A. invadans in the infection model Galleriamellonella. Furthermore, we show that AiLhs1 is important for the production of zoospores and their cluster formation. This renders proteins required for protein ER translocation as interesting targets for the potential development of alternative disease control strategies in agri- and aquaculture.


The Role of the Geneticist and Genetic Counselor in an ACHD Clinic.
There is a growing population of adults with congenital heart disease due to the advancements in surgical repair and medical management. At the same time, the understanding of the genetic basis of both syndromic and isolated congenital heart disease has grown tremendously and is being rapidly translated into changes in clinical care, resulting in an increasing need for incorporation of genetic expertise into the care of adult congenital heart disease patients. Here we review the importance of delivery of genetic information to the adult congenital heart disease population and highlight the shared and distinct roles of clinical geneticists and genetic counselors in provision of services. The adult congenital heart disease patient population has unique needs and clinical geneticists and genetic counselors can play an important role in the diagnostic evaluation and assessment of these patients to provide an accurate etiologic diagnosis and to counsel regarding genetic testing, recurrence risk, family screening, and prenatal diagnosis.


Distribution and size of GABAergic neurons in area 7b and the retroinsular cortex of the monkey.
The distribution of gamma-aminobutyric acid (GABA) neurons was examined in the retroinsular cortex (Ri) and area 7b of the monkey. GABA-immunoreactive somata and puncta were observed in all layers of Ri and area 7b. The densest concentration of these neurons was located in layers I and II. The vast majority (98.9%) of GABA-immunoreactive somata were less than 15 microns in major diameter. These data demonstrate that high concentrations of GABAergic neurons are located in those cortical layers that have been shown to receive afferent projections from corticocortical fibers.


Surface trapping and AFM detection of DNA topological intermediates generated from an oxidative chemical nuclease.
Direct observation of DNA topological intermediates generated from a 'chemical nuclease' treatment has been made by atomic force microscopy (AFM). The intermediates were trapped at the mica-water interface and imaging was carried out in the dynamic force mode. Complete conversion from supercoiled circular state to relaxed circular/linear state has been observed over a time scale of 8 min. Implication of such studies in complementing gel electrophoresis data has been predicted.


Open intercondylar fractures of the distal humerus: Management using a mini-external fixator construct.
Intercondylar fractures of the distal humerus are a challenging entity to treat. Open reduction-internal fixation with plating is well accepted as the standard treatment for these fractures, because it allows early mobilization and prevents joint stiffness. However, this technique may be associated with inferior postoperative results and a higher risk of infection in open fractures. External fixation appears to be an interesting option in such cases, where the results of open reduction-internal fixation with plating may be suboptimal. We present a bilateral uniplanar mini-external fixator construct for the treatment of open intercondylar distal humeral fractures. We managed 8 cases with this external fixation technique, with 6 of 8 patients achieving good to excellent results as determined by Cassebaum's rating system.


Coronary-coronary bypass using the radial artery.
This report describes the conditions and results of coronary-coronary bypass using the radial artery on the right coronary artery. The angiographic and clinical results are excellent.


Tobacco habituated and non-habituated subjects exhibit different mutational spectrums in head and neck squamous cell carcinoma.
Head and neck squamous cell carcinoma (HNSCC) is the sixth most common non-skin cancer in the world. Tobacco chewing is implicated with most of the cases of HNSCC but this type of cancer is increasing in non-tobacco chewers as well. This study was instigated to provide comprehensive variant and gene-level data in HNSCC subjects of the Indian population and fill the gap in the literature on comparative assessment of gene mutations in cancer subjects with a habit of tobacco and those without any habit using targeted amplicon sequencing. We performed targeted Amplicon sequencing of 409 tumor suppressor genes and oncogenes, frequently mutated across many cancer types, including head and neck. DNA from primary tumor tissues and matched blood was analyzed for HNSCC patients with a habit of tobacco and those without any habit. PDE4DIP, SYNE1, and NOTCH1 emerged as the highly mutated genes in HNSCC. A total of 39 candidate causal variants in 22 unique cancer driver genes were identified in non-habitual (WoH) and habitual (WH) subjects. Comparison of genes from both the subjects, showed seven unique cancer driver genes (KIT, ATM, RNF213, GATA2, DST, RET, CYP2C19) in WoH, while WH showed five (IL7R, PKHD1, MLL3, PTPRD, MAPK8) and 10 genes (SETD2, ATR, CDKN2A, NCOA4, TP53, SYNE1, KAT6B, THBS1, PTPRT, and FGFR3) were common to both subjects. In addition to this NOTCH1, NOTCH2, and NOTCH4 gene were found to be mutated only in habitual subjects. These findings strongly support a causal role for tobacco, acting via PI3K and MAPK pathway inhibition and stimulation of various genes leading to oncogenic transformations in case of tobacco chewers. In case of non-tobacco chewers it appears that mutations in the pathway affecting the squamous epithelial lineage and DNA repair genes lead to HNSCC. Somatic mutation in CYP2C19 gene in the non-habitual subjects suggests that this gene may have a tobacco independent role in development and progression of HNSCC. In addition to sharing high mutation rate, NOTCH gene family was found to be mutated only in habitual sample. Further, presence of mutated genes not earlier reported to be involved in HNSCC, suggest that the Indian sub-continent may have different sets of genes, as compared to other parts of the world, involved in the development and progression of HNSCC.


The hallmarks of ovarian cancer: Focus on angiogenesis and micro-environment and new models for their characterisation.
Cancers develop by sustained growth, migration and invasion properties of tumour cells, supported by complex interactions with stromal cells within the tumour micro-environment. This review is focused on the latest discoveries regarding the highlighted role of angiogenesis and tumour micro-environment in ovarian cancer. This cancer milieu encompasses non-cancerous cells present in the tumour or nearby, including vessel-forming cells, fibroblasts and immune cells amongst others that work in a cooperative way with cancer cells, impacting tumour behaviour. Angiogenesis, migration and invasion, and more recently immune evasion, are cancer hallmarks clearly dependent on these supporting cells. Moreover, these stromal cells are more genetically stable than tumour cells and thus represent an attractive therapeutic target. A better understanding of the stromal cells function, and their complex interplay with cancer cells, will open additional areas to target, as the tumour-host interface.


Comparison of custom to standard TKA instrumentation with computed tomography.
There is conflicting evidence whether custom instrumentation for total knee arthroplasty (TKA) improves component position compared to standard instrumentation. Studies have relied on long-limb radiographs limited to two-dimensional (2D) analysis and subjected to rotational inaccuracy. We used postoperative computed tomography (CT) to evaluate preoperative three-dimensional templating and CI to facilitate accurate and efficient implantation of TKA femoral and tibial components. We prospectively evaluated a single-surgeon cohort of 78 TKA patients (51 custom, 27 standard) with postoperative CT scans using 3D reconstruction and contour-matching technology to preoperative imaging. Component alignment was measured in coronal, sagittal and axial planes. Preoperative templating for custom instrumentation was 87 and 79 % accurate for femoral and tibial component size. All custom components were within 1 size except for the tibial component in one patient (2 sizes). Tourniquet time was 5 min longer for custom (30 min) than standard (25 min). In no case was custom instrumentation aborted in favour of standard instrumentation nor was original alignment of custom instrumentation required to be adjusted intraoperatively. There were more outliers greater than 2° from intended alignment with standard instrumentation than custom for both components in all three planes. Custom instrumentation was more accurate in component position for tibial coronal alignment (custom: 1.5° ± 1.2°; standard: 3° ± 1.9°; p = 0.0001) and both tibial (custom: 1.4° ± 1.1°; standard: 16.9° ± 6.8°; p < 0.0001) and femoral (custom: 1.2° ± 0.9°; standard: 3.1° ± 2.1°; p < 0.0001) rotational alignment, and was similar to standard instrumentation in other measurements. When evaluated with CT, custom instrumentation performs similar or better to standard instrumentation in component alignment and accurately templates component size. Tourniquet time was mildly increased for custom compared to standard.


[Hyperthyroidism (author's transl)].
Surgical cure of hyperthyroidism aims at removing enough functioning follicles to prevent hyperthyroidism while leaving sufficient tissue to maintain euthyroidism. In the case of Graves' disease the surgeon is faced with a goiter consisting of uniformly hyperstimulated follicles that are but one of the multiple targets of an immunologic attack. In contrast, autonomous follicles with an intrinsic functional abnormality are the hallmark of multinodular toxic goiter. These follicles may be clustered (toxic adenoma) or spread in different patterns throughout the gland. Partial thyroidectomy provides definite cure. While operating, the surgeon is unable to appreciate the functional quality of the tissue left behind. Thus, both postoperative hypo- and hyperthyroidism may occur independently of the surgical technique.


[Pharmacological effects of Oleum Cinnamomi and water extract of Cortex Cinnamomi in rats with yang-deficiency cold syndrome and the mathematical analysis].
To compare the effects of Oleum Cinnamomi and water extract of Cortex Cinnamomi in rats with yang-deficiency cold syndrome based on mathematical analysis. A total of 48 male Sprague-Dawley rats were randomly divided into 4 groups (normal, model, Oleum Cinnamomi and water extract of Cortex Cinnamomi). Yang-deficiency cold syndrome was induced by hydrocortisone sodium succinate. Oleum Cinnamomi and water extract of Cortex Cinnamomi were given by gastrogavage daily for one week to respective groups. Material metabolism indexes such as glucose (GLU), uric acid (UA), total cholesterol (TC), triacylylyceral (TAG), total protein (TP) and albumin (ALB); energy metabolism indexes such as lactic acid (LAC), lactate dehydrogenase (LDH), succinate dehydrogenase (SDH) and adenosine triphosphatase (ATPase); endocrine system indexes such as corticosteroid (CS), triiodothyronine (T3), tetraiodothyronine (T4), thyroid stimulating hormone (TSH), estradiol (E(2)), vitamin C (VC) and 17-hydroxycorticosteriod (17-OHCS); and immune system indexes such as immunoglobulin M (IgM), immunoglobulin G (IgG), complement 3 (C3) and complement 4 (C4) were measured. And then the data were analyzed by mathematical analysis method. Oleum Cinnamomi and water extract of Cortex Cinnamomi had similar influence on some indexes of material metabolism, energy metabolism and endocrine and immune systems in rats with yang-deficiency cold syndrome. Positive effects were showed in GLU, TC, TAG, TP, ALB, IgM, E(2), CS, VC and 17-OHCS. Water extract of Cortex Cinnamomi had no significant effects on TSH, LAC and SDH, but Oleum Cinnamomi had, while water extract of Cortex Cinnamomi had significant effects on ATPase, LDH and IgG. There is a complex relationship between Oleum Cinnamomi and water extract of Cortex Cinnamomi in their effects on rats with yang-deficiency cold syndrome. They have similar property, however, disparities exist between them to some extent. The exact mechanism needs further research.


Numerical simulation techniques to study the structural response of the human chest following median sternotomy.
The optimal closure technique of median sternotomy remains controversial. The objective of this study was to analyze the structural response of the separated sternum using computer-based numerical discretization techniques, such as finite element methods. Thoracic computer tomographic scans (2.5-mm slices) were segmented, analyzed by image processing techniques, and transferred into a three-dimensional finite element model. In a first approach a linear elastic material model was used; neglecting nonlinear and damage effects of the bones. The influence of muscles and tendons was disregarded. Nonlinear contact conditions were applied between the two sternal parts and between fixation wires and sternum. The structural response of this model was investigated under normal breathing and asymmetric leaning on one side of the chest. Displacement and stress response of the segmented sternum were compared regarding two different closure techniques (single loop, figure-of-eight). The obtained results revealed that for the normal breathing load case the single loop technique is capable of clamping the sternum sufficiently, assuming that the wires are prestressed. For asymmetric loading conditions, such as leaning on one side of the chest, the figure-of-eight loop can substantially reduce the relative longitudinal displacement between the two parts compared with the single loop. The application of numerical simulation techniques using complex computer models enabled the determination of structural behavior of the chest regarding the influence of different closure techniques. They allowed easy and fast modifications and therefore, in contrast to a real physical model, in-depth parameter studies.


Mechanisms and functions of guanylate-binding proteins and related interferon-inducible GTPases: Roles in intracellular lysis of pathogens.
Guanylate-binding proteins (GBPs) are a group interferon-inducible GTPases within the constellation of the dynamin GTPase superfamily. These proteins restrict the replication of intracellular pathogens in both immune and non-immune cells. GBPs and their related family members immunity-related GTPases target and lyse the membrane of the pathogen-containing vacuole, destroying the residential niche of vacuolar protozoal and bacterial pathogens. They also prevent virion infectivity and target replication complexes of ribonucleic acid viruses. The exciting concept that GBPs and immunity-related GTPases can directly target the membrane of bacteria and protozoa has emerged. Rupture and lysis of the pathogen membrane mediates liberation of concealed microbial ligands for activation of innate immune sensing pathways and the inflammasome. Further studies have demonstrated a capacity of GBPs to recruit additional antimicrobial factors, highlighting the complexity of the molecular mechanisms involved in pathogen killing. In this mini-review, we discuss recent advances describing the localisation and functions of GBPs on the host and pathogen membrane. We also highlight unresolved questions related to the regulation of GBPs in cell-autonomous immunity to intracellular pathogens.


Role of butyrogenic Firmicutes in type-2 diabetes.
The aim of this review is to speculate the pre-clinical and clinical evidences indicating the association between butyrate-synthesizing firmicutes and development and progression of type 2 diabetes mellitus. Literature was searched using 'Google Scholar' and 'PubMed' to find out most relevant articles for the scope of this review. Information was also gathered from authentic sources such as the World Health Organisation and the International Diabetes Federation. Evidences suggest that an abnormal perturbation in the gut microbiome characterized by subsided levels of butyrate-producing bacteria may gradually result in the progression of type-2 diabetes; however, the explicit mechanisms underlying and implicating the role of specific butyrate-producing microbes remain unclear. This review explicitly summarizes the role of butyrate-synthesizing firmicutes known to be reduced in the subjects with type-2 diabetes mellitus in host metabolic health and contemplates the putative and reported mechanisms underlying its implication in the pathophysiology of type-2 diabetes mellitus.


Linkage of the gene for cystinosis to markers on the short arm of chromosome 17. The Cystinosis Collaborative Research Group.
Nephropathic cystinosis (MIM 21980) is an autosomal recessive disorder due to defective transport of the amino acid cystine out of lysosomes. Cystine storage leads to acidosis, dehydration, rickets and growth retardation in the first year of life, followed by renal glomerular failure at approximately ten years of age. Renal transplantation is highly successful, but cystine continues to accumulate in other tissues, resulting in complications such as corneal ulcerations and retinal blindness, a distal vacuolar myopathy, delayed puberty, swallowing difficulties, pancreatic deficiency and central nervous system involvement. Treatment with the cysteine-depleting agent, cysteamine (Cystagon), or phosphocysteamine, has proven successful in retarding glomerular deterioration and enhancing growth. Although cystinosis represents the prototypic disorder of lysosomal membrane transport, neither the cystinosis gene nor the lysosomal cystine carrier has been isolated. We now report linkage of the cystinosis gene to markers on the short arm of chromosome 17 (Zmax = 10.89, theta = 0.03) for marker D17S1584. Multipoint analysis and haplotypes in recombinant families suggest that the gene is located between markers D17S1583 and D17S796.


Conventional Polyethylene in Total Hip Arthroplasty in Young Patients: Survivorship, Wear Analysis, and Clinical Outcomes Between 15 and 20 Years.
Total hip arthroplasty (THA) remains a successful procedure for most patients. However, there is a paucity of information regarding the long-term performance of conventional polyethylene (CPE) bearings in young patients undergoing THA. After accounting for incomplete follow-up of a prospective cohort of 123 THAs in patients ≤50 years, we performed a retrospective review of 101 hips in 84 patients (82.1%) with an average 17.1-year follow-up (14.7-19.6 years). Outcomes of interest included linear and volumetric wear, clinical outcome scores, implant survivorship, and patient mortality. Wear rates were calculated using Martell Software. Wear analysis revealed median linear and volumetric wear rates of 0.106 mm/y (confidence interval, 0.079-0.133) and 43.58 mm3/y (confidence interval, 33.4-53.75). The modified Harris hip scores improved by 36 points while University of California, Los Angeles activity scores improved by 2.0 points at 15-year follow-up (P < .0001). Twenty-two hips (21.8%) were revised, 13 of which (12.8%) were for wear-related causes at an average of 14.9 years (range, 9.2-21 years) from index arthroplasty. There was significantly higher mortality in patients with a preoperative diagnosis of inflammatory avascular necrosis (P = .015). Because CPE was commonly used in THA over the last 25 years, it is important to understand its implications on the growing revision burden. Significant concerns exist with regard to the long-term durability of CPE bearings in young, moderately active patients 15 years after THA. These patients should be followed closely for wear-related problems. Our results should be used as a comparison when evaluating the outcomes of more modern bearing surface combinations.


Haematopoietic cell transplantation for blastic plasmacytoid dendritic cell neoplasm: a North American multicentre collaborative study.
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is incurable with conventional therapies. Limited retrospective data have shown durable remissions after haematopoietic cell transplantation (HCT) [allogeneic (allo) or autologous (auto)]. We conducted a multicentre retrospective study in BPDCN patients treated with allo-HCT and auto-HCT at 8 centres in the United States and Canada. Primary endpoint was overall survival (OS). The population consisted of 45 consecutive patients who received an allo-HCT (n = 37) or an auto-HCT (n = 8) regardless of age, pre-transplant therapies, or remission status at transplantation. Allo-HCT recipients were younger (50 (14-74) vs. 67 (45-72) years, P = 0·01) and had 1-year and 3-year OS of 68% [95% confidence interval (CI) = 49-81%] and 58% (95% CI = 38-75%), respectively. Allo-HCT in first complete remission (CR1) yielded superior 3-year OS (versus not in CR1) [74% (95% CI = 48-89%) vs. 0, P < 0·0001]. Allo-HCT outcomes were not impacted by regimen intensity [3-year OS for myeloablative conditioning = 61% (95% CI = 28-83%) vs. reduced-intensity conditioning = 55% (95% CI = 28-76%)]. One-year OS for auto-HCT recipients was 11% (95% CI = 8-50%). These results demonstrate efficacy of allo-HCT in BPDCN, especially in patients in CR1. Pertaining to auto-HCT, our results suggest lack of efficacy against BPDCN, but this observation is limited by the small sample size. Larger prospective studies are needed to better define the role of HCT in BPDCN.


Decreased postoperative myocardial fatty acid oxidation.
Myocardial substrate preferences following cardioplegic arrest for coronary bypass surgery have not been established. Fatty acids are believed to be the major fuel source for aerobic metabolism. Following cardioplegic arrest arterial fatty acid levels are elevated and myocardial fatty acid accumulation without oxidation may contribute to reperfusion injury. Perioperative fatty acid metabolism was evaluated in 18 patients undergoing elective coronary bypass surgery who were randomized to receive either blood (n = 11) or crystalloid (n = 7) cardioplegia. Palmitate labeled with 14carbon was infused perioperatively and arterial and coronary sinus blood samples were obtained to calculate myocardial fatty acid extraction and oxidation before and after cardioplegic arrest. Lactate and glycerol were released from the heart during both blood and crystalloid cardioplegia, suggesting ischemic glycolysis and lipolysis. Myocardial oxygen consumption was depressed and the myocardial consumptions of lactate, glucose, and fatty acids were minimal during the first 60 min after aortic clamp removal in both groups despite high arterial concentrations. Fatty acid oxidation was minimal after blood cardioplegia and was not found after crystalloid cardioplegia. Fatty acids were extracted by the heart, but were not aerobically metabolized following cardioplegic arrest. Myocardial fatty acid accumulation without oxidation may have been deleterious. The inability of the heart to oxidize exogenous fatty acids may reflect altered myocardial exogenous substrate preferences during reperfusion following coronary bypass surgery.


Ciprofloxacin-induced acute liver injury: case report and review of literature.
Ciprofloxacin is a fluorinated quinolone antibiotic with relatively low occurrence of adverse side effects. However, increasing evidence suggests that ciprofloxacin may cause severe liver damage. Until now, 14 cases of ciprofloxacin-associated liver injuries have been reported. We describe a case of a 22-year-old male who developed hepatic failure after intake of ciprofloxacin. The patient had been treated with 2 x 250 mg ciprofloxacin per day. He presented with symptoms of acute liver failure 14 days later. Liver biopsy revealed extensive hepatocellular necrosis involving zones 3 and 2 of hepatic acini and a mixed inflammatory infiltration containing abundant eosinophils. Symptoms resolved after corticoidsteroid therapy. In the present paper, we report the clinico-pathological characteristics of a case of ciprofloxacin-associated acute hepatic failure and discuss the current literature.


[Epidemiological study of pulmonary hydatid cyst in the Ivory Coast. 3 cases].
No cases of echinococcus have been reported up to this time in Ivory Coast, where it has been considered non-existant in either pulmonary or hepatic form. The three cases of pulmonary echinococcus reported here show the classic paucity of clinical symptoms associated with classical radiological findings. The epidemiological research confirms in one case definite infection occurring in Ivory Coast and the other two either in the Ivory Coast or in closely neighbouring areas.


Folic Acid and vitamin B12 supplementation improves coronary flow reserve in elderly subjects with vitamin B12 deficiency.
Major cardiovascular risk factors including hyperhomocysteinemia are frequently associated with decreased coronary flow reserve (CFR), an important physiological parameter of the coronary circulation. This study was designed to determine whether folate (5 mg) and vitamin B12 (500 μg) supplementation in elderly patients with vitamin B12 deficiency improved CFR, while reducing homocysteine levels. Forty-four patients aged >65 years showing serum vitamin B12 concentrations <180 mg/dL were randomized to take either oral folate (5 mg) plus vitamin B12 (500 μg) supplementation (n = 24) or placebo (n = 20) for 8 weeks. The study course consisted of two visits: visit 1 (pretreatment) included the baseline assessment of laboratory profile and CFR values with trans-thoracic Doppler echocardiography. Visit 2 was scheduled 8 weeks later to repeat CFR and laboratory tests after therapy. In the treatment arm, oral supplementation with folate and vitamin B12 significantly improved total cholesterol, serum folate, serum vitamin B12, homocysteine, and insulin resistance. At 8 weeks, the treatment group had a significant increase from baseline in CFR values (baseline: 1.7 ± 0.2; postttreatment: 2.1 ± 0.2, p <0.001) that was not seen in the placebo group (baseline: 1.6 ± 0.2; posttreatment: 1.6 ± 0.2; P = ns). In this study of elderly subjects with vitamin B12 deficiency, supplementation with folate and vitamin B12 was associated with a significant improvement in CFR values.


Human miR-26a-5p regulates the glutamate transporter SLC1A1 (EAAT3) expression. Relevance in multiple sclerosis.
Multiple sclerosis (MS) is an autoimmune disease of the central nervous system, characterized by chronic inflammation, demyelination and scarring as well as a broad spectrum of signs and symptoms. MicroRNA plays pivotal roles in cellular and developmental processes by regulating gene expression at the post-transcriptional level. Increasing evidence suggests the involvement of microRNAs in the pathogenesis of neurodegenerative diseases, including MS. We have already found that the expression of a specific miRNA, hsa-mir-26a-5p (miR-26a), changed during INF-β treatment in responder Relapsing-Remitting MS patients. Functional annotations of mir-26a targets revealed that a number of genes were implicated in Glutamate Receptor Signaling pathway, which is notoriously altered in neurodegenerative diseases as MS. In this study, the different potential targets were subjected to a validation test based on luciferase reporter constructs transfected in an oligodendroglial cell line. In this functional screening, miR-26a was able to interact with SLC1A1 3' UTR suppressing the reporter activity. Transfection of a miR-26a mimic was then shown to decrease the endogenous SLC1A1 mRNA. Afterward, we have evaluated in blood platelets from interferon-β treated Multiple Sclerosis patients the expression of miR-26a and SLC1A1, finding not only their converse expression, but also a responsiveness to interferon-β therapy. Overall, these data suggest that mir-26a and SLC1A1 may play a role in the MS pathogenesis, and may be potential targets for the development of new biomarkers and/or therapeutic tools.


Diagnosis of early-stage rheumatoid arthritis: usefulness of unenhanced and gadolinium-enhanced MR images at 3 T.
Forty-one consecutive unclassified arthritis patients with polyarthralgia including wrist joint were evaluated with 3-T MRI as possible early-stage rheumatoid arthritis (RA). After prospective follow-up, 21 of 41 patients fulfilled the American College of Rheumatology (ACR) criteria. Synovitis was detected in all 21 RA patients (sensitivity=100%) with postcontrast MRI and in 14 patients (67%) with unenhanced MRI when none of them fulfilled ACR diagnostic criteria. Fat-suppressed intermediate-weighted fast spin-echo (FSE) image showed high detection rate of synovitis and bone erosion, whereas FIESTA image clearly delineated joint fluid and bone trabeculae. MRI at 3 T is a potentially powerful tool for discriminating and managing early-stage RA patients.


Understanding visual hallucinations: A new synthesis.
Despite decades of research, we do not definitively know how people sometimes see things that are not there. Eight models of complex visual hallucinations have been published since 2000, including Deafferentation, Reality Monitoring, Perception and Attention Deficit, Activation, Input, and Modulation, Hodological, Attentional Networks, Active Inference, and Thalamocortical Dysrhythmia Default Mode Network Decoupling. Each was derived from different understandings of brain organisation. To reduce this variability, representatives from each research group agreed an integrated Visual Hallucination Framework that is consistent with current theories of veridical and hallucinatory vision. The Framework delineates cognitive systems relevant to hallucinations. It allows a systematic, consistent, investigation of relationships between the phenomenology of visual hallucinations and changes in underpinning cognitive structures. The episodic nature of hallucinations highlights separate factors associated with the onset, persistence, and end of specific hallucinations suggesting a complex relationship between state and trait markers of hallucination risk. In addition to a harmonised interpretation of existing evidence, the Framework highlights new avenues of research, and potentially, new approaches to treating distressing hallucinations.