Mapping Receptor Antibody Endocytosis and Trafficking in Brain Endothelial Cells.
Drug delivery to the brain is a tremendous problem for the academic society and the industry. One solution with a huge potential is to use endocytic receptors as carriers. Here we describe how endocytic activity and subcellular trafficking of a specific receptor in brain endothelial cells can be characterized in three steps. (1) Labeling, endocytosis, and trafficking of a specific receptor at given time points in a pulse-chase experiment. (2) Fixed antibody labeling and co-staining of subcellular markers for image acquisition. (3) Analysis and quantification of co-localization between the receptor and subcellular markers in ImageJ.


Ustekinumab: The "New Kid on the Block" in the Treatment of Psoriatic Arthritis.
Psoriatic arthritis (PsA) is a chronic inflammatory seronegative spondyloarthritis associated with psoriasis. While TNF-α inhibitors have revolutionized the treatment of rheumatic diseases, including PsA, not all patients respond to these agents while others are unsuitable or intolerant to them. Thus, there is a need for additional treatment modalities with a novel mechanism of action. In the past years, the IL-23/Th17 axis has emerged as an important mechanism in the pathogenesis of PsA. Ustekinumab, a fully human IgG1κ monoclonal antibody that targets the common subunit p40 of IL-12 and IL-23, has been shown in clinical trials, to be well-tolerated and effective in patients with active PsA. It improved signs and symptoms of PsA, inhibited radiographic progression and was effective in dactylitis, enthesitis, and skin disease, with a safety profile consistent with the one observed in patients with psoriasis. Moreover, it was to be effective in anti-TNF-α experienced patients, definitely fulfilling an unmet need in the management of PsA.


Immunohistochemical localization of calcium-binding proteins, parvalbumin and calbindin-D 28k, in the adult and developing visual cortex of cats: a light and electron microscopic study.
In the cat primary visual cortex, we investigated with immunohistochemical techniques the developmental changes in the cellular and subcellular localization of the Ca2+-binding proteins parvalbumin (PV) and calbindin-D 28K (CBP), in order to determine whether there is a correlation between the expression of Ca2+-dependent processes and the time course of the critical period for use-dependent plasticity. On the 54th day of gestation and at 1 week postnatally, both calcium-binding proteins were present only in a subpopulation of neurons in layers V and VI. During subsequent maturation, the number of PV(+) and CBP(+) neurons increased significantly and labeled cells were detected in more superficial layers. Moreover, the homogeneous labeling of some CBP(+) neurons in layers IV to VI decreased and changed to a punctate pattern. In adult cats PV(+) neurons were evenly distributed throughout layers II to VI, whereas CBP(+) neurons were concentrated in layers II/III. Only a few immunoreactive cells had morphological features characteristic of pyramidal cells; the large majority were nonpyramidal. Electron microscopy confirmed the presence of PV- and CBP-reaction product within the perikarya, axons, and dendrites of labeled cells. It was associated preferentially with microtubules, postsynaptic densities, and intracellular membranes. Immunoreactive neurons received immunonegative asymmetric synapses on their dendritic shafts and made symmetric synaptic contacts with labeled and unlabeled somata and with unlabeled dendritic shafts. The large number and widespread distribution of immunoreactive neurons implies that PV and CBP play an important role in the regulation of calcium-dependent processes in the visual cortex. Furthermore, the developmental redistribution of PV and CBP points to changes in the organization of Ca2+-dependent processes during maturation.


Muscarinic receptor plasticity in rats lesioned in the nucleus basalis of Meynert.
The present study investigated the effects of chronic treatment with scopolamine (10 mg/kg i.p. for 21 days) on the muscarinic acetylcholine receptors in the frontoparietal cortex of rats, lesioned at the level of the nucleus basalis of Meynert. Ibotenic acid (25 nmol in 0.5 microliters) was injected bilaterally or unilaterally into the area of this nucleus and produced a major impairment of the cortical cholinergic system. These lesions depleted specifically frontoparietal cortical choline acetyltransferase activity. Sham-operated rats were similarly operated but no neurotoxin was injected. The chronic treatment with scopolamine caused a significant increase in the binding of [3H](-)quinuclidinylbenzilate to muscarinic receptors in the frontoparietal cortex of control and sham-operated rats but not in lesioned animals. This increase was due to an up-regulation in the number of muscarinic acetylcholine receptors, without significant change in their affinity. These results suggest that a functional presynaptic cholinergic terminal is necessary for the plasticity of muscarinic receptors in the central nervous system.


A colonial-nesting seabird shows no heart-rate response to drone-based population surveys.
Aerial drones are increasingly being used as tools for ecological research and wildlife monitoring in hard-to-access study systems, such as in studies of colonial-nesting birds. Despite their many advantages over traditional survey methods, there remains concerns about possible disturbance effects that standard drone survey protocols may have on bird colonies. There is a particular gap in the study of their influence on physiological measures of stress. We measured heart rates of incubating female common eider ducks (Somateria mollissima) to determine whether our drone-based population survey affected them. To do so, we used heart-rate recorders placed in nests to quantify their heart rate in response to a quadcopter drone flying transects 30 m above the nesting colony. Eider heart rate did not change from baseline (measured in the absence of drone survey flights) by a drone flying at a fixed altitude and varying horizontal distances from the bird. Our findings suggest that carefully planned drone-based surveys of focal species have the potential to be carried out without causing physiological impacts among colonial-nesting eiders.


Potent dendritic cell vaccine loaded with latent membrane protein 2A (LMP2A).
Epstein-Barr virus (EBV), a potential oncogenic herpesvirus, has been found to be associated with several malignancies. It's critical to elicit cellular immunity of the body to fight against EBV-associated tumor development. Using dendritic cells (DCs) loaded with latent membrane protein 2A (LMP2A) to elicit T cell response against tumor may be one of the most direct and safest immunotherapy approaches. The present study aimed to develop DCs-based cancer vaccine (DC loaded with LMP2A protein) and study its biological characteristics and immune functions. Purified LMP2A protein was extracted from a cell line L929/LMP2A stably expressing LMP2A. LMP2A could be loaded on DCs with no significant changes of the DC surface markers and cytomorphology. The percentage of DCs loaded with LMP2A was above 80%. LMP2A-loaded DCs markedly enhanced the proliferation of antigen-specific CD8+ T and CD4+ T cells by 3H-TdR incorporation assay. Besides, the specific cytotoxicity of the CTLs against LMP2A target cells was also significantly increased. These results indicated that DC-based vaccine loaded with virus antigen could elicit potent CTL response and provide a foundation for further study on the DC-based immunotherapy for nasopharygeal carcinoma and other EBV associated tumors.


Lipoprotein(a) and inflammation- pathophysiological links and clinical implications for cardiovascular disease.
The role of lipoprotein(a) (Lp[a]) as a significant and possibly causal cardiovascular disease (CVD) risk factor has been well established. Many studies, mostly experimental, have supported inflammation as a mediator of Lp(a)-induced increase in CVD risk. Lp(a), mainly through oxidized phospholipids bound to its apolipoprotein(a) part, leads to monocyte activation and endothelial dysfunction. The relationship between Lp(a) and inflammation is bidirectional as Lp(a) levels, besides being associated with inflammatory properties, are regulated by inflammatory stimuli or anti-inflammatory treatment. Reduction of Lp(a) concentration, especially by potent siRNA agents, contributes to partial reversion of the Lp(a) related inflammatory profile. This review aims to present the current pathophysiological and clinical evidence of the relationship between Lp(a) and inflammation.


Modeling of ultrasonic nonlinearities for dislocation evolution in plastically deformed materials: Simulation and experimental validation.
A nonlinear constitutive relationship was established to investigate nonlinear behaviors of ultrasonic wave propagation in plastically damaged media based on analyses of mixed dislocation evolution. Finite element simulations of longitudinal wave propagation in plastically deformed martensite stainless steel were performed based on the proposed nonlinear constitutive relationship, in which the contribution of mixed dislocation to acoustic nonlinearity was considered. The simulated results were validated by experimental measurements of plastically deformed 30Cr2Ni4MoV martensite stainless steels. Simulated and experimental results both reveal a monotonically increasing tendency of the normalized acoustic nonlinearity parameter as a function of plastic strain. Microscopic studies revealed that the changes of the acoustic nonlinearity are mainly attributed to dislocation evolutions, such as dislocation density, dislocation length, and the type and fraction of dislocations during plastic loading.


Non-pharmacological interventions to reduce agitation in dementia.
Every month, DTB scans sources of information on treatments, disease management and other healthcare topics for key items to bring to our readers' attention and help them keep up to date. To do this, we produce succinct, contextualised summaries of the information concerned.


Mental health and itch in burns patients: Potential associations.
The purpose of this study was to investigate the relationship between mental health and self-reported itch in patients with burns across a 6 month time period and to test the hypothesis that poorer mental health outcomes are associated with increased severity of itch. A quantitative study with three time points for data collection was conducted. Participants (232) completed assessments at 1 month, 3 months, and 6 months after burn injury. The Patient and Observer Scar Assessment Scale (POSAS) was used to report itch and the Short Form Health Survey (SF-36) provided an assessment of mental health across time. Only data from the itch and mental health subscales were used in the analysis. To analyze the data a quantile regression model was used. Mental health is significantly associated with itch after adjusting for variation in itch over time (p=0.001). The regression coefficient indicates that as mental health increases by one unit, itch decreases by 0.03. Of importance, the relationship remained significant after adjusting for total burn surface area (p<0.001). These findings suggest there is a relationship between mental health and itch. Given the powerful impact itch can have on an individual's wellbeing health professionals can begin to further investigate itch from a bio-psychosocial perspective. Further research to investigate causal relationships between mental health and itch is important.


Nervous system involvement in SARS-coronavirus infection: a review on lessons learned from the previous outbreaks, ongoing pandemic and what to expect in the future.
Viral infections have been associated with the deleterious damage to nervous system resulting in impairment of the central nervous system as late sequalae infections. Since the outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV2), several studies have reported patients developing adverse neurological signs and symptoms. Like the outbreak of SARS in 2003, the recent outbreak has undermined the norm of the nervous system. This review will summarize the possible mechanism of neurological manifestations, the clinical presentations of patients with such symptoms secondary to SARS coronaviruses, and the prospective role of neurology and neurosurgery practice in managing these symptoms in the current climate.


Detecting HSP90 phosphorylation.
Heat-shock protein 90 (HSP90) is an essential molecular chaperone in eukaryotes. It is important for chaperoning proteins that are important determinants of multistep carcinogenesis. HSP90's ATPase activity is associated with its chaperone function. Co-chaperones as well as posttranslational modifications (phosphorylation, acetylation, and S-nitrosylation) are important for regulating its ATPase activity. Yeast can be used to express and purify HSP90 and also detect its phosphorylation by pan-phosphoserine or phosphothreonine antibodies.


Endovascular Repair of Abdominal Aortic Aneurysms is a Valid Alternative to Open Repair also in Patients Treated Outside of Instructions for Use Criteria.
It remains unclear whether endovascular aneurysm repair, in the long term, is less effective than open surgery due to need for reinterventions and close monitoring. We aimed to evaluate this matter in a real-life cohort. We collected consecutive patients treated with EVAR or OSR between January 2005 and December 2013. Primary outcomes were 30-day, 90-day and long-term all-cause mortality. Secondary outcomes were 30-day reintervention rate and reintervention-free survival. We evaluated also a subpopulation who did not adhere to IFU. The inclusion criteria were met by 416 patients. 258 (62%) received EVAR, while 158 (38%) underwent OSR. The 30- or 90-day mortality was similar between groups (p = 0.272 and p = 0.346), as ARM (p = 0.652). The 30-day reintervention rate was higher in the OSR group (p < 0.001), but during follow-up, it was significantly higher in the EVAR group (log-rank: 0.026). There were 114 (44.2%) non-IFU patients in the EVAR group, and we compared them with OSR group. There was no significant difference in all-cause mortality at 30 or 90 days, nor in the long term (p = 1; p = 1 and p = 0.062). ARM was not affected by the procedure technique (p = 0.136). The short-term reintervention rate was higher in the OSR group (p = 0.003), while in the long-term EVAR, patients experienced more reinterventions (log-rank = 0.0.43). No significant difference in survival was found between EVAR and OSR, independent of adherence to IFU. EVAR may be considered for surgical candidates.


Acidic fibroblast growth factor gene 5' non-coding exon and flanking region from hamster DDT1 cells: identification of the promoter region and transcriptional regulation by testosterone and aFGF protein.
Selected clones of Syrian hamster DDT1-MF2 cells are responsive to testosterone for growth. Heparin binding growth factor 1 (HBGF-1) or acidic fibroblast growth factor (aFGF) can replace testosterone (T) in the stimulation of growth in these cells. This phenomena is correlated with testosterone's ability to elevate aFGF mRNA two- to threefold in DDT1 cells. To better understand the possible mechanisms of regulation of aFGF mRNA by steroids and other growth factors, we isolated the aFGF 5' non-coding exon and its flanking region from a EMBL3 DDT1 genomic library, using a 5' non-coding exon 69 bp DDT1 aFGF cDNA probe. Clones spanning 30 kb of genomic DNA were isolated. After restriction mapping and DNA sequence analysis, the clones were shown to contain all of the 5' non-coding exon included in the cDNA and approximately 10 kb of 5' flanking region. RNase protection and primer extension assays confirmed that the 5' non-coding exon is included in the DDT1 aFGF mRNA and that a major transcription start site is approximately 136 bp upstream of the 5' non-coding splice junction of this exon. The 5' flanking region DNA was inserted into pBLCAT3 reporter gene and transfected into DDT1 cells. Chloramphenicol acetyltransferase (CAT) assays demonstrated that there are promoter elements in the -1645/-392 and -392/+131 regions of the aFGF gene in the context of DDT1 cells. NIH 3T3 cells, on the other hand, show no CAT activity with these aFGF-CAT plasmids. CAT assays also demonstrated that addition of testosterone (T) or aFGF to DDT1 cells increased CAT activity threefold. This activity was mapped to -1645 to -4 bp region of this DDT1 aFGF gene promoter.


Spot Sample Urine Specific Gravity Does Not Accurately Represent Small Decreases in Plasma Volume in Resting Healthy Males.
Urine specific gravity (USG) is often used to assess hydration status, particularly around athletic competition, but it is unknown whether high USG is indicative of plasma volume (PV) reduction (i.e., hypohydration). We tested the hypothesis that if high USG is reflective of reduced PV, subsequent fluid ingestion would increase PV. The purpose of this study was to examine 24-hour changes in USG and PV in individuals presenting with high and low spot USG. Nineteen healthy males were provided food and water over 24 hours with a total water volume of 35 ml·kg-1 body mass. Absolute PV and blood volume (BV), measured using the CO-rebreathe technique, along with USG were measured before and after a 24-hour intervention period. Based on a preintervention morning spot USG, subjects were post hoc assigned to groups according to USG (≤1.020 or >1.020; low and high USG, respectively). Despite presenting with an elevated spot USG (1.026 ± 0.004), subsequent fluid ingestion over 24 hours did not lead to changes (∆) in PV (-75 ± 234 ml) or BV (-156 ± 370 ml) in the high USG group (p > 0.05). However, a spot USG after the 24-hour intervention in this group decreased (p = 0.018) to a level indicating improved hydration status (1.017 ± 0.007). In the low USG group, there were no changes in PV (-39 ± 274 ml), BV (-82 ± 396 ml), or USG (0.003 ± 0.007) over the 24-hour fluid intervention (all p > 0.05). Despite a high preintervention USG and subsequent decrease after 24-hour fluid intake, measures of PV and BV were not indicative of this seemingly improved hydration status. This suggests that a highly concentrated spot sample USG and subsequent changes are not accurately representative of PV or BV.


Determination of the thickness of plastic sheets used in blister packaging by near infrared spectroscopy: development and validation of the method.
A near infrared (NIR) quantitative analysis method was developed for determining the thickness of PVC-based plastic sheets used as pharmaceutical packs. Samples that can be analyzed are transparent films made of polyvinyl chloride (PVC), PVC coated with polyvinylidene dichloride (PVDC) or PVC coated with Thermoelast (TE) and PVDC. The method, based on a partial least squares (PLS) algorithm, is used together with a previously developed NIR identification method to acquire simultaneously qualitative and quantitative information about the samples. Validation of the quantitative method was conducted according to the very recent European Agency for the Evaluation of Medicinal Products (EMEA) guidance on the use of NIR spectroscopy. Suggestions were made for a better statistical evaluation of the calibration model prior to validation. Validation consisted of the study of specificity, accuracy (mean recovery from the reference values was 99.56%), precision (repeatability and intermediate precision were <0.6%), linearity, quantification limit (41 microm), and robustness of the method. This demonstration of the applicability of NIR spectroscopy as a validated quality control tool for pharmaceutical packaging films will hopefully facilitate the acceptance of NIR spectroscopy in pharmaceutical laboratories.


Long-term testosterone therapy in type 2 diabetes is associated with reduced mortality without improvement in conventional cardiovascular risk factors.
To further characterize the beneficial impact of testosterone replacement therapy (TRT) on the association between mortality and hypogonadism (HG) in men with type 2 diabetes (T2DM), by determining, firstly, if changes in cardiovascular disease (CVD) risk factors after TRT play a role, secondly, whether the reduction in mortality is lost when TRT is discontinued and, finally, the presence of subgroups where benefit may be greater. We studied 857 men with T2DM, screened for the BLAST randomized controlled trial, over 3.8 years of follow-up. The men were stratified first by testosterone levels: group 1: total testosterone (TT) >12 nmol/L and free testosterone (FT) >0.25 nmol/L; Group 2: TT ≤12 nmol/L or FT ≤0.25 nmol/L. Group 2 was further stratified into those not on TRT (Group 2a) and those on TRT (Group 2b). Group 2b was further stratified by whether TRT was discontinued (Group 2b1) or not (Group 2b2). The principal outcome, mortality, was studied using Cox regression. We found that TRT was not associated with improvements in CVD risk factors. CVD risk factors (baseline and changes during follow-up) were not associated with mortality. Men in Group 1 and Group 2b were found to have lower mortality (reference: Group 2a), even with CVD risk factors included in the regression models. Mortality was lower in men in Group 2b1 (6.2%) and Group 2b2 (0%) compared with those in Group 2a (16.9%). The lower mortality associated with Group 1 and Group 2b was observed primarily in older (>64.6 years) and less overweight (≤93.8 kg) men. The benefits associated with normal testosterone levels and TRT (even after discontinuation) do not appear to be related to improvements in the CVD risk factors studied. In view of TRT having greater impact in men of lower weight, better outcomes may be achieved with concurrent TRT and weight reduction programmes.


An evaluation of the association between lockdown during the SARS-CoV-2 pandemic and prematurity at the Nice University Hospital.
To study the association between lockdown in France due to the SARS-CoV-2 pandemic and premature births at the Nice University Hospital. Data concerning neonates born at the level III maternity of the Nice University Hospital and immediately hospitalised in the neonatal reanimation unit or the neonatology department of the hospital with their mothers between the 1st of January 2017 and the 31st of December 2020, included. We did not find a significant decrease in the global number of premature births <37 weeks of gestation, in low weight at birth or a significant increase in stillbirths during lockdown compared to a period with no lockdown. The profiles of the mothers and their newborns were compared when birth occurred during lockdown vs. no lockdown. We did not find any evidence of an association between lockdown and prematurity at the Nice University Hospital. This result is in agreement with meta-analyses published in the medical literature. The possible decrease in factors of risk of prematurity during lockdown is controversial.


Rainfall preceding egg-laying - a factor of breeding success in Common Terns (Sterna hirundo).
The temporary reduction of clutch size, egg size and breeding success of the Common Tern during the breeding period of 1983 at the Lower Saxonian Wadden Sea (West Germany) was correlated with heavy rainfalls on the days preceding egg-laying (Figs. 2-4). Possible effective mechanisms and the result that the reduction of clutch size was not observed for colonies at the mainland coast are being discussed (Fig. 4).


Clinical application of endotracheal cryotherapy.
A nitrous oxide cryoprobe has been developed that may be used through the infant bronchoscope. A total of 19 discrete airway lesions have been treated in 17 patients ranging in age from 2 mo to 30 yr. Three patients with periglottic lesions have had complete eradication of these lesions without the need for tracheostomy. Six patients with subglottic stenoses have been treated, with one successful extubation and one patient approaching extubation. Five patients have been treated for distal tracheal strictures, with two successful extubations and a third pending extubation. Five patients have been treated for endotracheal granulation tissue, and 3 patients have been successfully extubated. Cryotherapy allows bloodless resection of these lesions with rapid tissue healing not accompanied by residual scarring.


Effect of monoclonal antibody drug therapy on mucosal biomarkers in airway disease: A systematic review.
Monoclonal antibody therapies have a growing role in treating refractory airway disease. The review aimed to summarize the response of respiratory mucosa to monoclonal antibody treatments in inflammatory airway conditions. We conducted a systematic review including risk of bias assessment. MEDLINE, EMBASE and PubMed from 1 January 2000 to 16 November 2019 were searched. Eligible studies assessed the immunological and histological response of airway mucosa to monoclonal antibody therapy compared with baseline or a comparison group in patients with respiratory diseases (asthma, chronic rhinosinusitis and allergic rhinitis). Any prospective interventional studies, including randomized controlled trials (RCTs) and single-arm trials, were eligible. There were 4195 articles screened, and full-text analysis produced n = 11 studies with extractable data. Nine were RCTs, and two were single-arm trials. These studies focused on asthma (n = 9 articles), chronic rhinosinusitis (n = 1) and allergic rhinitis (n = 1). Five monoclonal antibody drugs were assessed (omalizumab, mepolizumab, dupilumab, benralizumab and tralokinumab). Risk of bias was low (n = 6) or unclear (n = 3) in the RCTs and moderate in the single-arm trials. Omalizumab reduced the mucosal concentration of its target, IgE. Dupilumab reduced the concentration of one of its targets, IL-13, but not IL-4. Omalizumab, mepolizumab and benralizumab reduced tissue eosinophil cell density. Dupilumab decreased mucosal eosinophil granule proteins. Tralokinumab did not affect airway mucosa. Knowledge of the expected biological response of monoclonal antibody therapy on biomarkers in disease tissue provides an important supplement to data about clinical outcomes. An understanding of the biological effect is essential to identify likely responders, reasons for treatment failure and necessary adjustments to monoclonal antibody treatment. Further investigation into the effect of monoclonal antibody therapy on disease mucosa and more precise endotyping are required to move closer to achieving personalized medicine.


Unraveling effects of anti-aging drugs on C. elegans using liposomes.
Liposome-mediated delivery is a possible means to overcome several shortcomings with C. elegans as a model for identifying and testing drugs that retard aging. These include confounding interactions between drugs and the nematodes' bacterial food source and failure of drugs to be taken up into nematode tissues. To explore this, we have tested liposome-mediated delivery of a range of fluorescent dyes and drugs in C. elegans. Liposome encapsulation led to enhanced effects on lifespan, requiring smaller quantities of compounds, and enhanced uptake of several dyes into the gut lumen. However, one dye (Texas red) did not cross into nematode tissues, showing that liposomes cannot ensure the uptake of all compounds. Of six compounds previously reported to extend lifespan (vitamin C, N-acetylcysteine, glutathione (GSH), trimethadione, thioflavin T (ThT), and rapamycin), this effect was reproduced for the latter four in a condition-dependent manner. For GSH and ThT, antibiotics abrogated life extension, implying a bacterially mediated effect. With GSH, this was attributable to reduced early death from pharyngeal infection and associated with alterations of mitochondrial morphology in a manner suggesting a possible innate immune training effect. By contrast, ThT itself exhibited antibiotic effects. For rapamycin, significant increases in lifespan were only seen when bacterial proliferation was prevented. These results document the utility and limitations of liposome-mediated drug delivery for C. elegans. They also illustrate how nematode-bacteria interactions can determine the effects of compounds on C. elegans lifespan in a variety of ways.


Key factors associated with quality of postnatal care: a pooled analysis of 23 countries.
Progress in reducing maternal and neonatal mortality, particularly in low-income and middle-income countries (LMICs) and regions, is insufficient to achieve the Sustainable Developmental Goals by 2030. High-quality postnatal care (PNC) for mothers and neonates is crucial for mothers and babies, yet it remains the most neglected intervention on the continuum of maternal and child care. We aimed to estimate the associations between observable factors and high-quality maternal and neonatal PNC in pooled and country-specific analyses. In this cross-sectional study, we used the most recent (2015-2022) Demographic and Health Surveys from 23 countries across Africa (n = 14), Southeast Asia (n = 3), Eastern Mediterranean (n = 2), Europe (n = 2), Americas (n = 1), and Western Pacific (n = 1). Women who, within the last 5 years, were aged 15-49 years at their last live birth that had delivered a singleton child were included. We identified eleven PNC behaviours recommended by the World Health Organization (WHO) to measure PNC quality, and applied thresholds to create binary outcomes for quality maternal and neonatal PNC. 15 factors were included in our analysis to assess their association with high-quality PNC for mothers and neonates in a series of single-adjusted and mutually adjusted logistic regression models, both in pooled and country-specific analysis. We also conducted two sets of subgroup analyses for place of residence and maternal age at last birth, and two sets of supplementary analyses to test the robustness of the results. Among 172,526 women and their most recent child, 41.42% (40.93-41.91) received quality maternal PNC while 42.34% (41.86-42.83) received quality neonatal PNC. In the pooled analysis, we found that the factors showing the strongest associations with quality maternal PNC were delivery by skilled birth attendants (SBAs) (OR: 4.92; 95% CI: 4.32-5.59), four or more antenatal care (ANC) visits (OR: 1.69, 1.58-1.81), and institutional delivery (OR: 1.61; 1.46-1.78). Consistent results were found for all factors of quality newborn care (e.g., delivery by SBA: OR, 4.25; 3.75-4.81; four or more ANC visits: OR, 1.83; 1.70-1.96) except institutional delivery. The association between these leading factors and PNC quality were broadly consistent across countries. Subgroup analyses and sensitivity analyses showed generally consistent results. Our study demonstrated that institutional delivery and frequent ANC visits had the strongest positive associations with quality PNC for both mothers and neonates. Our findings highlight that improvements to the quality of maternal and neonatal PNC in the LMICs we assessed are urgently needed to achieve ambitious maternal, newborn, and child health goals. China National Natural Science Foundation.


Role of trabecular morphology in the etiology of age-related vertebral fractures.
Osteoporotic compression fractures of the spine differ from most other age-related fractures in that they usually are associated with minimal trauma and with loads no greater than those encountered during normal activities of daily living. With aging and osteoporosis, there is progressive resorption of bone, resulting in reductions in bone density, thinning of trabeculae, and loss of trabecular contiguity. These changes in trabecular bone structure are associated with losses in bone strength which are disproportionate to the reductions in bone mass alone. To explain this disproportionate loss of bone strength, the prevailing opinion is that density reductions in the vertebral centrum are accompanied by a reduction in the number of trabeculae, by preferential resorption of horizontal trabeculae, and by hypertrophy of the remaining vertical trabeculae. To evaluate this view of vertebral morphology, we performed three-dimensional stereological analysis of trabecular bone extracted from midsagittal sections of first lumbar vertebral bodies from 12 donors spanning an age of 27-81 years. We found that both the number (R2 = 0.63, P < 0.01) and thickness (R2 = 0.91, P < 0.01) of trabeculae decreased linearly with density (as expressed by bone volume fraction) whereas the spacing between the trabeculae (R2 = 0.61, P < 0.01) increased reciprocally. There were more vertical trabeculae with transverse trabeculae at all densities, and the number of vertical trabeculae changed with density at twice the rate of the number of transverse trabeculae (P < 0.001). These data do not support the prevailing view that there is preferential resorption of horizontal trabeculae or hypertrophy of the remaining vertical trabeculae.(ABSTRACT TRUNCATED AT 250 WORDS)


Carboxylesterase isoform 2 mRNA expression in peripheral blood mononuclear cells is a predictive marker of the irinotecan to SN38 activation step in colorectal cancer patients.
Irinotecan (CPT11) is a prodrug activated in humans mainly by carboxylesterase 2 (CES2) generating the SN38 metabolite responsible for the drug efficacy and toxicity. The interpatients variability in CPT11 activation step could cause unpredictable toxicity. To identify a predictive molecular marker for CPT11 activation in cancer patients, we investigated the CES2 mRNA expression in peripheral blood mononuclear cells (PBMC) and correlated it to CPT11 activation rate, toxic effects, and response. Forty-five colorectal cancer patients were treated with a CPT11-including regimen (FOLFIRI). CES2 mRNA expression in PBMC was quantified by reverse transcription-PCR in real time. Plasma concentrations of CPT11, SN38, and SN38-glucuronide were determined by high-performance liquid chromatography and the pharmacokinetic variables calculated adopting the noncompartmental model. Toxicity was evaluated by the National Cancer Institute Common Toxicity Criteria scale and response by the WHO criteria. A high interindividual variability in CES2 mRNA relative expression was observed (median, 1.45; range, 0.01-28.21). CES2 mRNA expression level was significantly associated with CPT11 activation ratio [(AUC(SN38) + AUC(SN38G))/AUC(CPT11)]. Patients with CES2 mRNA expression above the median cutoff value presented an activation ratio higher (median, 0.25; range, 0.15-0.42) than those with CES2 mRNA below the median (median, 0.20; range, 0.10-0.40; P = 0.013). This was associated with a nonsignificant trend of 1.34-fold increase of SN38 AUC in the group of patients with high CES2 mRNA expression (mean, 1.03 +/- 0.62 versus 0.77 +/- 0.32 micromol/L hour). Eight of 23 high CES2 mRNA-expressing patients (34.8%) developed grade 3 to 4 neutropenia or diarrhea compared with 2 of 22 (9.1%) in the low CES2-expressing group (P = 0.071). Our data support a predictive power of CES2 mRNA expression in PBMC for the activation rate of CPT11.


Substance P acting via the neurokinin-1 receptor regulates adverse myocardial remodeling in a rat model of hypertension.
Substance P is a sensory nerve neuropeptide located near coronary vessels in the heart. Therefore, substance P may be one of the first mediators released in the heart in response to hypertension, and can contribute to adverse myocardial remodeling via interactions with the neurokinin-1 receptor. We asked: 1) whether substance P promoted cardiac hypertrophy, including the expression of fetal genes known to be re-expressed during pathological hypertrophy; and 2) the extent to which substance P regulated collagen production and fibrosis. Spontaneously hypertensive rats (SHR) were treated with the neurokinin-1 receptor antagonist L732138 (5mg/kg/d) from 8 to 24 weeks of age. Age-matched WKY served as controls. The gene encoding substance P, TAC1, was up-regulated as blood pressure increased in SHR. Fetal gene expression by cardiomyocytes was increased in SHR and was prevented by L732138. Cardiac fibrosis also occurred in the SHR and was prevented by L732138. Endothelin-1 was up-regulated in the SHR and this was prevented by L732138. In isolated cardiac fibroblasts, substance P transiently up-regulated several genes related to cell-cell adhesion, cell-matrix adhesion, and extracellular matrix regulation, however, no changes in fibroblast function were observed. Substance P activation of the neurokinin-1 receptor induced expression of fetal genes related to pathological hypertrophy in the hypertensive heart. Additionally, activation of the neurokinin-1 receptor was critical to the development of cardiac fibrosis. Since no functional changes were induced in isolated cardiac fibroblasts by substance P, we conclude that substance P mediates fibrosis via up-regulation of endothelin-1.


Expression and regulation of a disintegrin and metalloproteinase-8 and -17 in development of rat periradicular lesion.
A disintegrin and metalloproteinases (ADAMs) are a family of transmembrane proteins that share a common domain structure. However, little is known about the possible involvement of ADAM-8 and ADAM-17 in the development of periradicular lesions. Here we demonstrated the expression of ADAM-8 and ADAM-17 in rat periradicular lesions. We induced experimentally periradicular lesions in rats. The animals were killed at 0, 2, 4, 6, and 8 weeks after pulp exposure. The left molars underwent immunofluorescence analysis for both ADAMs and for neutrophil elastase, and right molars were used for reverse transcription-polymerase chain reaction analysis of ADAM-8 and ADAM-17. The areas of these lesions were measured histometrically, and the numbers of all antigen-positive cells in the periapical portion were counted per unit area. The area of the periradicular lesions gradually expanded from 0 to 4 weeks, showing a large increase from week 2 to week 4. Both ADAM-8-positive and ADAM-17-positive cells gradually increased in number from 0 to 4 weeks and then decreased from 4 to 8 weeks. There were more ADAM-17-expressing cells than ADAM-8-expressing ones at all experimental periods except at 4 weeks. The highest expression of ADAM-8 mRNA was observed at 4 weeks, and there were significant differences between 0 and 2 weeks and between 4 and 6 weeks. The expression of ADAM-17 mRNA increased from 0 to 4 weeks and subsequently decreased from 4 to 8 weeks, with a significant difference between 4 and 6 weeks. Our results suggest that ADAM-8 and ADAM-17 may be related to the development of rat periradicular lesions.


Synchronous adenocarcinomas of the papilla major and minor.
Synchronous malignancies affecting both the major and minor papilla are rare and are usually of endocrine origin. A 60-year-old female presented with a two-week history of progressive jaundice and pruritus. Evaluation revealed features of a periampullary malignancy. A Whipple pancreaticoduodenectomy was done. There was a growth in the ampulla of Vater and another in the region of the minor duodenal papilla. On histopathology, both lesions were adenocarcinomas. Although rare, synchronous adenocarcinomas can occur in the major and minor papilla.


Identifying reference conditions and quantifying biological variability within benthic macroinvertebrate communities in perennial and non-perennial northern California streams.
Identification of minimally disturbed reference sites is a critical step in developing precise and informative ecological indicators. We tested procedures to select reference sites, and quantified natural variation (inter-site and -annual variability) among reference conditions using a macroinvertebrate data set collected from 429 mediterranean-climate stream reaches in the San Francisco Bay Area, California (USA). We determined that a landscape GIS-based stressor screen followed by a local field-based stressor screen effectively identified least-disturbed reference sites that, based on NMS ordination results, supported different biological communities than sites identified with only landscape (GIS) or local (field) stressors. An examination of least-disturbed reference sites indicated that inter-site variability was strongly associated with stream hydrology (i.e., perennial vs. non-perennial flow) and annual precipitation, which highlights the need to control for such variation when developing biological indicators through natural gradient modeling or using unique biological indicators for both non-perennial and perennial streams. Metrics were more variable among non-perennial streams, indicating that additional modeling may be needed to develop precise biological indicators for non-perennial streams. Among 192 sites sampled two to six times over the 8-year study period, the biological community showed moderate inter-annual variability, with the 100 point index of biotic integrity scores varying from 0 to 51 points (mean = 11.5). Variance components analysis indicated that inter-annual variability explained only a fraction (5-18 %) of the total variation when compared against site-level variation; thus efforts to understand causes of natural variation between sites will produce more precise and accurate biological indicators.


[Qualification concept for delegation of medical tasks to nonmedical professional groups. The "Greifswalder 3-level model"].
To manage the current demographics and the expected medical, nursing, and social care needs of the population, structural changes are needed in the German health care system. On the regional level, there is a shortage of general practitioners in Germany. In the future, the number of affected regions will likely increase. These trends require new support strategies, which include the delegation of medical tasks to nonphysician professionals of which nurses and medical assistants are the primary profession. Thus, they will expand their traditional scope of work. However, their traditional training does not qualify them to perform medical tasks responsibly and with high quality. Hence, there is a need for further development of advanced training programs. The goal is to tailor modular advanced training to the specific support needs of the patients. A recent law (GKV-Versorgungsstrukturgesetz, GKV-VStG, 1 January 2012) was passed that specifies and extends the delegation options of medical tasks beyond the restrictions defined in previous German legislation (§ 63, SGB V in 2008). In this article, we present a three-stage model for qualifying nonphysician medical professionals for defined ranges of medical tasks.


Bioelectrochemical Detoxification of Phenolic Compounds during Enzymatic Pre-Treatment of Rice Straw.
The use of lignocellulosic biomass such as rice straw can help subsidize the cost of producing value-added chemicals. However, inhibitory compounds, such as phenolics, produced during the pre-treatment of biomass, hamper the saccharification process. Laccase and electrochemical stimuli are both well known to reduce phenolic compounds. Therefore, in this study, we implemented a bioelectrochemical detoxification system (BEDS), a consolidated electrochemical and enzymatic process involving laccase, to enhance the detoxification of phenolics, and thus achieve a higher saccharification efficiency. Saccharification of pretreated rice straw using BEDS at 1.5 V showed 90% phenolic reduction (Phr), thereby resulting in a maximum saccharification yield of 85%. In addition, the specific power consumption when using BEDS (2.2 W/Kg Phr) was noted to be 24% lower than by the electrochemical process alone (2.89 W/kg Phr). To the best of our knowledge, this is the first study to implement BEDS for reduction of phenolic compounds in pretreated biomass.


A case study in applying artificial intelligence-based named entity recognition to develop an automated ophthalmic disease registry.
Advances in artificial intelligence (AI)-based named entity extraction (NER) have improved the ability to extract diagnostic entities from unstructured, narrative, free-text data in electronic health records. However, there is a lack of ready-to-use tools and workflows to encourage the use among clinicians who often lack experience and training in AI. We sought to demonstrate a case study for developing an automated registry of ophthalmic diseases accompanied by a ready-to-use low-code tool for clinicians. We extracted deidentified electronic clinical records from a single centre's adult outpatient ophthalmology clinic from November 2019 to May 2022. We used a low-code annotation software tool (Prodigy) to annotate diagnoses and train a bespoke spaCy NER model to extract diagnoses and create an ophthalmic disease registry. A total of 123,194 diagnostic entities were extracted from 33,455 clinical records. After decapitalisation and removal of non-alphanumeric characters, there were 5070 distinct extracted diagnostic entities. The NER model achieved a precision of 0.8157, recall of 0.8099, and F score of 0.8128. We presented a case study using low-code artificial intelligence-based NLP tools to produce an automated ophthalmic disease registry. The workflow created a NER model with a moderate overall ability to extract diagnoses from free-text electronic clinical records. We have produced a ready-to-use tool for clinicians to implement this low-code workflow in their institutions and encourage the uptake of artificial intelligence methods for case finding in electronic health records.


Febuxostat attenuates testosterone-induced benign prostatic hyperplasia in rats via inhibiting JAK/STAT axis.
To investigate the possible modulatory effect of febuxostat in testosterone-induced benign prostatic hyperplasia (BPH) in rats with emphasis on xanthine oxidase (XO)/Janus Kinases (JAK)/signal transducer and activator of transcription (STAT) axis. Male Wistar rats were treated with testosterone with/out febuxostat. Effect of febuxostat on BPH was assessed at the structural level by histopathology and determination of prostate weight/index. Cyclin D1 protein expression was assessed immunohistochemically and the ratio of Bax/Bcl-2 mRNA expression was determined by real time polymerase chain reaction analysis (RT-PCR). Besides, uric acid serum level was determined colorimetrically. Prostatic XO activity, as well as oxidative stress and inflammatory markers were evaluated. Additionally, western blot analysis was performed for determination of JAK-1 and phosphorylated form of STAT-3 expression in tissues. Results revealed that febuxostat inhibited the increase in prostatic weight and index compared to testosterone-treated group. Additionally, febuxostat ameliorated testosterone-induced histopathological changes, prevented the rise in cyclin D1 expression and enhanced Bax/Bcl2 ratio. Febuxostat suppressed testosterone induced- increase in XO activity in prostates and serum level of uric acid. Moreover, it regulated oxidative stress markers including; malondialdehyde (MDA), superoxide dismutase (SOD) activity and glutathione (GSH) content. Also, it inhibited the increase in prostate contents of interleukin-6 (IL-6), interleukin-1β (IL-1 β), tumor necrosis factor (TNF-α) and nuclear factor (NF-κB). Interestingly, febuxostat markedly reduced JAK-1 and subsequent phosphorylation of STAT-3 protein expression. Febuxostat ameliorates testosterone-induced BPH via suppressing XO/JAK/STAT axis. This may help to re-purpose the use of XO inhibitors.


Environmental determinants of behavioural responses to short-term stress in rats: Evidence for inhibitory effect of ambient landmarks.
Behavioural responses to stress occur in an environment-dependent manner. Complex environments require flexible behavioural coping strategies and chronic stress usually generates psychomotor inhibition. Here, we examine if short-term stress also exerts an inhibitory effect on novelty-seeking, exploratory behaviours. Rats underwent acute restraint stress or were left undisturbed, and their neuroendocrine and behavioural responses were assessed at short- and long-term time points. Animals were individually tested in the open field task (OFT) and the corridor field task (CFT) with and without a central object for free exploration and novelty seeking behaviour. Stress-related psychomotor alterations were measured by path speed, path length, number of stops and thigmotaxis in both tasks. Short-term stress activated the hypothalamic-pituitary-adrenal axis causing elevated plasma corticosterone levels. Stress also impacted psychomotor functions in terms of motivational changes (higher speed and longer path) only in the central-object variations of the OFT and CFT. Moreover, stress-induced emotional alterations were manifested by a higher number of stops and thigmotactic behaviour only in the central-object condition. These findings suggest that environmental landmarks determine the type and direction of exploratory behaviour under transient stress.


Water-energy sustainability synergies and health benefits as means to motivate potable reuse of coalbed methane-produced waters.
Management of coalbed methane (CBM)-produced water is a crucial part of the water-energy nexus, especially as CBM is projected to play a key role as a bridge fuel in major economies. In this paper, we consider one management technique, i.e., desalination of CBM-produced water to generate potable water. We discuss a confluence of geographic, sociotechnical, regulatory, and other circumstances that could make this concept viable for select coal-bearing regions. Having said that, for maximizing benefits, it is prudent to take a synergistic view targeting multiple objectives (water access, health, environmental impacts, and ease of waste management). Thus, we make design recommendations and suggest a system-evaluation framework for making sustainable decisions related to produced-to-potable water systems. For instance, a key question is whether such systems should be centralized or decentralized-and this paper highlights crucial tradeoffs that are present in both the cases.


Identification of genetic characteristics in pediatric epilepsy with focal cortical dysplasia type 2 using deep whole-exome sequencing.
Focal cortical dysplasia type 2 (FCD2) is a malformation of cortical development that constitutes a common cause of pediatric focal epilepsy. Germline or somatic variants in the mammalian target of rapamycin (mTOR) signaling pathway genes are the pathogenesis of FCD2. In this study, whole-exome deep sequencing was performed on dysplastic cortex from focal epilepsy in children to explore genetic characteristics in FCD2. Resected core lesions of FCD2 were confirmed by pathology, and peripheral blood was collected from 11 patients. Deep whole-exome sequencing (>500X) was performed on derived genomic DNA, germline, or somatic variants in brain-specific genes were analyzed and identified. In 11 patients, a heterozygous likely pathogenic germline variant of DEPDC5 was identified in one case, while somatic variants were found in four brain samples. The frequencies of the somatic variant allele were 2.52%-5.12%. Somatic variants in AKT3, TSC2, and MTOR (mTOR signaling pathway genes) were found in three samples. Besides, one somatic variant was detected in MED12 which has not been reported to associate with FCD2. Our study expanded the variant spectrum in the mTOR-GATOR pathway, and also detected a somatic variant in MED12 which was potentially associated with FCD 2.


Functional interaction between the p160 coactivator proteins and the transcriptional enhancer factor family of transcription factors.
SRC1, initially identified as a nuclear receptor coactivator, was found to interact with a member of the transcriptional enhancer factor (TEF) family of transcription factors, TEF-4. The interaction, which occurs in both intact cells and in a cell-free system, is mediated by the highly conserved basic helix-loop-helix/Per-Arnt-Sim (bHLH-PAS) domain present in the N-terminal region of SRC1. Moreover, all three members of the p160 family of nuclear receptor coactivators, SRC1, TIF2, and RAC3, are able to potentiate transcription from a TEF response element in transient transfection experiments, and this activation requires the presence of the bHLH-PAS domain. These results suggest that the p160 proteins could be bona fide coactivators of the TEF family of transcription factors.


Deuteron field-cycling relaxation spectroscopy and translational water diffusion in protein hydration shells.
The deuterated hydration shells of bovine serum (BSA) albumin, and purple membrane sheets have been studied by the aid of deuteron field-cycling relaxation spectroscopy. The deuteron Larmor frequency range was 10(3) to 10(8) Hz. The temperature and the water content has been varied. The data distinguish translational diffusion on the protein surface from macromolecular tumbling or exchange with free water. A theory well describing all dependences has been developed on this basis. All parameters have successfully been tested concerning consistency with other sources of information. The concept is considered as a major relaxation scheme determining, apart from cross-relaxation effects, the water proton relaxation in tissue.


A comparison of surgical outcome of fasciocutaneous V-Y advancement flap and Limberg transposition flap for recurrent sacrococcygeal pilonidal sinus disease.
The aim of this study was to compare the surgical outcome of fasciocutaneous V-Y advancement flap and limberg transposition flap used to treat recurrent sacrococcygeal PSD. A total of 58 patients with recurrent pilonidal sinus who underwent surgery were evaluated retrospectively between January 2008 to December 2013. Fasciocutaneous V-Y advancement flap was performed in 25 patients (Group VYF), and limberg transposition flap repair was performed in 33 patients (Group LTF). Patient demographics, operative and postoperative outcomes were recorded then retrospectively analyzed. The mean age (p = 0.69), sex ratio (p = 0.48), and concomitant diseases (p = 0.98) were not statistically different when compared the VYF with LTF groups. Mean operative time was 55 ± 19 min for the LTF group and 75 ± 25 min for the VYF group (p = 0.01). When length of hospital stay were compared, there was a significant difference between the groups (p = 0.01). Return to work was carryed out after a mean of 23 ± 1.1 days in VYF group and 16.7 ± 1.2 days in LTF group, which is significantly different (p < 0.0004). Between the groups, there was no significantly different regarding surgical complication and recurrent rate. Only one recurrence (4%) was found in VYF group. Limberg transposition flap may be use in recurrent cases of PSD, because of the lower recurrence rate and less hospital stay time, early return to work. Most important advantage of fasciocutaneous V-Y advancement flap is the ability to close larger defects in recurrent cases.


Randomized Trial of Laparoscopic Nissen Versus Anterior 180 Degree Partial Fundoplication - Late Clinical Outcomes at 15 to 20 years.
To determine very late clinical outcomes at up to 20 years follow-up from a randomized controlled trial of Nissen versus anterior 180-degree partial fundoplication. Nissen fundoplication for gastroesophageal reflux can be followed by troublesome side effects. To address this, partial fundoplications have been proposed. Previously reports from a randomized controlled trial of Nissen versus anterior 180-degree partial fundoplication at up to 10 years follow-up showed good outcomes for both procedures. One hundred seven participants were randomized to Nissen versus anterior 180-degree partial fundoplication. Fifteen to 20 year follow-up data was available for 79 (41 Nissen, 38 anterior). Outcome was assessed using a standardized questionnaire with 0 to 10 analog scores and yes/no questions to determine reflux symptoms, side-effects, and satisfaction with surgery. After anterior fundoplication heartburn (mean score 3.2 vs 1.4, P = .001) and proton pump inhibitor use (41.7% vs 17.1%, P = .023) were higher, offset by less dysphagia for solids (mean score 1.8 vs 3.3, P = .015), and better ability to belch (84.2% vs 65.9%, P = .030). Measures of overall outcome were similar for both groups (mean satisfaction score 8.4 vs 8.0, P = .444; 86.8% vs 90.2% satisfied with outcome). Six participants underwent revision after anterior fundoplication (Nissen conversion for reflux - 6), and 7 underwent revision after Nissen fundoplication (Nissen to partial fundoplication for dysphagia - 5; redo Nissen for reflux - 1; paraesophageal hernia -1). At 15 to 20 years follow-up Nissen and anterior 180-degree partial fundoplication achieved similar success, but with trade-offs between better reflux control versus more side-effects after Nissen fundoplication.


The morally disruptive future of reprogenetic enhancement technologies.
Emerging reprogenetic technologies may enable the enhancement of our offspring's genes. Beyond raising ethical questions, these biotechnologies may change some aspects of future morality. In the reproductive field, biotechnological innovations may transform moral views about reproductive choices regarding what we consider to be just or even of equal standing.


Isometric contractile function recovery following tourniquet ischemia.
The purpose of this study was to document the recovery of isometric contractile function following tourniquet ischemia. Male Wistar rats (N = 27) were subjected to unilateral hindlimb tourniquet ischemia of 0 hr (control, N = 6), 1 hr (N = 5), 2 hr (N = 5), 3 hr (N = 5) and 4 hr (N = 3). Following a 2-week recovery period, isometric force measurements were made from both gastrocnemii of each rat with the contralateral limb acting as the control side. Each muscle was analyzed for maximal twitch (Pt, N/g), maximal rate of rise of twitch tension (DP/dt, N/sec), time to peak tension (TPT, msec), half relaxation time (RT 1/2, msec), maximal tetanus (P0, N/g, at 100 Hz), and fatigue (Burke Fatigue Protocol). Pt, P0, and DP/dt were significantly different from control values (P less than 0.05) for all hours of tourniquet ischemia. A strong negative correlation (P less than 0.001) was found for twitch (R = -0.84), tetanus (R = -0.78), and maximal rate of force development (R = -0.83) with respect to increasing hours of ischemia. The recovery of isometric twitch and tetanic function following tourniquet ischemia is inversely related to the ischemic interval. This study quantified the relationship between muscle ischemia and recovery of function following a 2-week interval and stresses the functional physiological changes which occur in skeletal muscle following tourniquet ischemia.


A multicentre analysis of Nocardia pneumonia in Spain: 2010-2016.
To analyse all cases of Nocardia pneumonia occurring between 2010 and 2016 in five Spanish hospitals. This was a retrospective observational analysis of clinical and microbiological data collected from 55 cases of Nocardia pneumonia. There were one to 20 cases per hospital and six to nine cases per year. Chronic obstructive pulmonary disease, bronchiectasis, and asthma were the main predisposing underlying respiratory conditions. Thirty-four patients were receiving systemic and/or inhaled corticosteroids prior to infection, eight had neoplasia, and six had haematological malignancies. Clinical and radiological findings were common to pneumonia of other infectious aetiologies, except for the frequent presence of nodules and cavitation. Overall, the 1-year mortality was high (38.2%), and mortality was directly related to the pulmonary disease in 15 patients (27.3%). The most frequently identified species were N. cyriacigeorgica (n=21), N. abscessus (n=8), and N. farcinica (n=5). All Nocardia isolates were susceptible to linezolid and all but two were susceptible to amikacin and trimethoprim-sulfamethoxazole. Nocardia pneumonia-associated mortality remains high, probably because of the debilitated status of patients in whom this pathogen is able to cause pulmonary infection.


Digital use of standardised assessment tools for children and adolescents: can available paper-based questionnaires be used free of charge in electronic format?
Most adolescents live in low- and middle-income countries (LMIC), and about 10% of them face mental problems. The mental health provision gap in low- and middle-income countries could be addressed by evidence-based practices, however costs are implementational barriers. Digitalization can improve the accessibility of these tools and constitutes a chance for LMIC to use them more easily at a low cost. We reviewed free and brief evidence-based mental health assessment tools available for digital use to assess psychopathology across different domains in youth. For the current study, instruments from a recent review on paper-based instruments were re-used. Additionally, a systematic search was conducted to add instruments for the personality disorder domain. We searched and classified the copyright and license terms available from the internet in terms of free usage and deliverability in a digital format. In the case that this information was insufficient, we contacted the authors. In total, we evaluated 109 instruments. Of these instruments, 53 were free and digitally usable covering 11 mental health domains. However, retrieving information on copyright and license terms was very difficult. Free and digitally adaptable instruments are available, supporting the strategy of using instruments digitally to increase access. The instrument's authors support this initiative, however, the lack of copyright information and the difficulties in contacting the authors and licence holders are barriers to using this strategy in LMIC. A comprehensive, online instrument repository for clinical practice would be an appropriate next step to make the instruments more accessible and reduce implementation barriers.


Use of sodium chloride to rapidly restore polyhydroxyalkanoates production from filamentous bulking without polyhydroxyalkanoates productivity impairment.
Occurrence of filamentous bulking would lead to excess biomass washout to fail the polyhydroxyalkanoate (PHA) production process. A strategy using sodium chloride (NaCl) addition to enhance sludge settleability so that high PHA productivity could be retained was tested in two sequencing batch reactors (SBR #1 and #2) fed with different organic acid mixtures but at identical NaCl gradients (0, 5 and 10 g/L). Significant improved sludge settleability was observed at 10 g/L NaCl regardless of occurrence of filamentous bulking. The NaCl addition strategy suppressed the growth of principal filamentous bacterium, Meganema, and enriched the PHA producers (Paracoccus and Thauera) to reach enhanced PHA productivities of 0.244-0.298 g/L-1 d-1 for the present studied system.


Reduction of seclusion on a hospital-wide level: successful implementation of a less restrictive policy.
Change of treatment policy from closed to open ward settings has been shown to reduce coercive measures. The aim of the current study was to examine the effects of the change from closed to open wards on the frequency of seclusion and forced medication in a hospital-wide setting. 2-year, longitudinal observational study with 2838 inpatient cases. On a hospital-wide level, the percentage of patients with at least one seclusion was decreased significantly (χ(2)(1) = 5.8; p = .016), while there was no significant change in forced medication (χ(2)(1) = .08; p = .775). The frequency of seclusions and forced medication decreased significantly on newly opened wards, and there were no significant changes regarding seclusion on permanently closed or open wards, while the number of forced medications increased significantly on closed wards. The decrease in seclusions on newly opened wards remained statistically significant after controlling for diagnoses and severity of illness. Our results indicate that a reduction of overall seclusion can be successfully attained, and that, in particular, the frequency of seclusion and forced medication on newly opened wards was decreased significantly. These changes were not accompanied by a significant increase in seclusion on other wards. Open ward treatment was successfully implemented and was associated with a significant decrease of coercive measures in our study. It might therefore provide a good care model, strengthening the patient's right to autonomy and leading to a reduction of coercive measures.


Synergistic anti-tumor effect of 17AAG with the PI3K/mTOR inhibitor NVP-BEZ235 on human melanoma.
Drug resistance by MAPK signaling recovery or activation of alternative signaling pathways, such as PI3K/AKT/mTOR, is an important factor that limits the long-term efficacy of targeted therapies in melanoma patients. In the present study, we investigated the phospho-proteomic profile of RTKs and its correlation with downstream signaling pathways in human melanoma. We found that tyrosine kinase receptors expression correlated with the expression of pivotal downstream components of the RAS/RAF/MAPK and PI3K/AKT/mTOR pathways in melanoma cell lines and tumors. We also found high expression of HSP90 and the PI3K/AKT/mTOR pathway proteins, 4EBP1 and AKT compared with healthy tissue and this correlated with poor overall survival of melanoma patients. The combination of the HSP90 inhibitor 17AAG with the PI3K/mTOR inhibitor NVP-BEZ235 showed a synergistic activity decreasing melanoma cell growth, inducing apoptosis and targeting simultaneously the MAPK and PI3K/AKT/mTOR pathways. These results demonstrate that the combination of HSP90 and PI3K/mTOR inhibitors could be an effective therapeutic strategy that target the main survival pathways in melanoma and must be considered to overcome resistance to BRAF inhibitors in melanoma patients.


A lipase-independent pathway of lipid release and immune modulation by adipocytes.
To meet systemic metabolic needs, adipocytes release fatty acids and glycerol through the action of neutral lipases. Here, we describe a secondary pathway of lipid release from adipocytes that is independent of canonical lipolysis. We found that adipocytes release exosome-sized, lipid-filled vesicles (AdExos) that become a source of lipid for local macrophages. Adipose tissue from lean mice released ~1% of its lipid content per day via exosomes ex vivo, a rate that more than doubles in obese animals. AdExos and associated factors were sufficient to induce in vitro differentiation of bone marrow precursors into adipose tissue macrophage-like cells. Thus, AdExos are both an alternative pathway of local lipid release and a mechanism by which parenchymal cells can modulate tissue macrophage differentiation and function.


Metaanalysis of intraocular lens power calculation after laser refractive surgery in myopic eyes.
To evaluate the accuracy of intraocular lens (IOL) power calculation methods after laser refractive surgery in myopic eyes, a comprehensive literature search was carried out for retrospective case series studies with data on post-myopic laser surgery IOL power calculations published from January 2000 to May 2014. A metaanalysis of the 9 identified studies was performed using odds ratios in percentage of prediction error within ±0.5 or 1.0 diopter (D) of the target refraction. Compared with the Haigis-L method, the clinical history method, corneal bypass method, and Feiz-Mannis method were associated with lower odds of predication; the Masket method showed higher odds. The subgroup data showed significantly better performance of the Shammas no-history method with the Shammas post-LASIK formula than the Haigis-L method in predication error. The Masket method and the Shammas no-history method with the Shammas post-LASIK formula without historical data had more prediction accuracy than the Haigis-L method. The clinical history method, Feiz-Mannis method, and corneal bypass method, which required historical data, were less accurate in their predictions. No author has a financial or proprietary interest in any material or method mentioned.


Synergic chitin degradation by Streptomyces sp. SCUT-3 chitinases and their applications in chitinous waste recycling and pathogenic fungi biocontrol.
The genus Streptomyces comprises the most important chitin decomposers in soil and revealing their chitinolytic machinery is beneficial for the conversion of chitinous wastes. Streptomyces sp. SCUT-3, a chitin-hydrolyzing and a robust feather-degrading bacterium, was isolated previously. The potential chitin-degrading enzymes produced by SCUT-3 were analyzed in the present study. Among these enzymes, three chitinases were successfully expressed in Pichia pastoris at comparatively high yields of 4.8 U/mL (SsExoChi18A), 11.2 U/mL (SsExoChi18B), and 17.8 U/mL (SsEndoChi19). Conserved motifs and constructive 3D structures of these three exo- and endochitinases were also analyzed. These chitinases hydrolyzed colloidal chitin to chitin oligomers. SsExoChi18A showed apparent synergic effects with SsEndoChi19 in colloidal chitin and shrimp shell hydrolysis, with an improvement of 29.3 % and 124.9 %, respectively. Compared with SsExoChi18B and SsEndoChi19, SsExoChi18A exhibited the strongest antifungal effects against four plant pathogens by inhibiting mycelial growth and spore germination. This study provided good candidates for chitinous waste-processing enzymes and antifungal biocontrol agents. These synergic chitin-degrading enzymes of SCUT-3 are good targets for its further genetical modification to construct super chitinous waste-degrading bacteria with strong abilities to hydrolyze both protein and chitin, thereby providing a direction for the future path of the chitinous waste recycling industry.


The effect of the opting-out strategy on conditions for selection to favor the evolution of cooperation in a finite population.
We consider a Prisoner's Dilemma (PD) that is repeated with some probability 1-ρ only between cooperators as a result of an opting-out strategy adopted by all individuals. The population is made of N pairs of individuals and is updated at every time step by a birth-death event according to a Moran model. Assuming an intensity of selection of order 1/N and taking 2N2 birth-death events as unit of time, a diffusion approximation exhibiting two time scales, a fast one for pair frequencies and a slow one for cooperation (C) and defection (D) frequencies, is ascertained in the limit of a large population size. This diffusion approximation is applied to an additive PD game, cooperation by an individual incurring a cost c to the individual but providing a benefit b to the opponent. This is used to obtain the probability of ultimate fixation of C introduced as a single mutant in an all D population under selection, which can be compared to the probability under neutrality, 1/(2N), as well as the corresponding probability for a single D introduced in an all C population under selection. This gives conditions for cooperation to be favored by selection. We show that these conditions are satisfied when the benefit-to-cost ratio, b/c, exceeds some increasing function of ρ that is approximately given by (1+ρ)/(1-ρ). This condition is more stringent, however, than the condition for tit-for-tat (TFT) to be favored against always-defect (AllD) in the absence of opting-out.


In situ assays demonstrate that interferon-gamma suppresses infection-stimulated hepatic fibrin deposition by promoting fibrinolysis.
Inflammatory cytokines potently impact hemostatic pathways during infection, but the tissue-specific regulation of coagulation and fibrinolysis complicates studies of the underlying mechanisms. Here, we describe assays that quantitatively measuring prothrombinase (PTase), protein C-ase (PCase) and plasminogen activator (PA) activities in situ, thereby facilitating studies of tissue-specific hemostasis. Using these assays, we investigate the mechanisms regulating hepatic fibrin deposition during murine toxoplasmosis and the means by which interferon-gamma (IFN-gamma) suppresses infection-stimulated fibrin deposition. We demonstrate that Toxoplasma infection upregulates hepatic PTase, PCase, and PA activity. Wild type and gene-targeted IFN-gamma-deficient mice exhibit similar levels of infection-stimulated PTase activity. By contrast, IFN-gamma-deficiency is associated with increased PCase activity and reduced PA activity during infection. Parallel analyses of hepatic gene expression reveal that IFN-gamma-deficiency is associated with increased expression of thrombomodulin (TM), a key component of the PCase, increased expression of thrombin-activatable fibrinolysis inhibitor (TAFI), a PC substrate, and reduced expression of urokinase PA (u-PA). These findings suggest that IFN-gamma suppresses infection-stimulated hepatic fibrin deposition by suppressing TM-mediated activation of TAFI, thereby destabilizing fibrin deposits, and concomitantly increasing hepatic u-PA activity, thereby promoting fibrinolysis. We anticipate that further application of these in situ assays will improve our understanding of tissue-specific hemostasis, its regulation by cytokines, and its dysregulation during coagulopathy.


Behavioral treatment of Raynaud's disease.
In order to assess the efficacy of a behavioral intervention in the treatment of idiopathic Raynaud's disease, 30 female patients were trained to control their digital skin temperature using autogenic training or a combination of autogenic training and skin temperature feedback either in the laboratory or at home. All trained subjects demonstrated a significant ability to maintain digital skin temperature in the presence of a cold stress challenge and reported significant reductions in both frequency and intensity of vasospastic attacks. The addition of skin temperature feedback to autogenic training did not provide additional clinical benefit.


Stimulation of airway sensory nerves by cyclosporin A and FK506 in guinea-pig isolated bronchus.
We have investigated the contractile property of cyclosporin A and FK506 in guinea-pig isolated bronchus. Cyclosporin A (10 microM) failed to significantly attenuate the excitatory non-adrenergic non-cholinergic (eNANC) and cholinergic contractile response (per cent methacholine Emax) induced by electrical field stimulation (EFS). In contrast, eNANC responses were significantly attenuated by both the neurokinin (NK)-1 and (NK)-2 receptor antagonists, N-acetyl-L-tryptophan 3,5-bis (trifluoromethyl)-benzyl and SR48968, respectively. Cyclosporin A and FK506 caused a concentration-dependent contraction in guinea-pig isolated bronchus, which was significantly attenuated by NK-1 and NK-2 receptor antagonists. The capsaicin receptor antagonist, capsazepine (10 microM) significantly reduced the contractile response to cyclosporin A and capsaicin, but not to FK506. The N-type calcium channel blocker, omega-Conotoxin (omegaCTX: 10 nM), significantly reduced the contractile response to FK506 and the eNANC response following EFS. In contrast, omega-CTX failed to significantly reduce the contractile potency to capsaicin or cyclosporin A. In bronchial preparations desensitized by repeated application of capsaicin (1 microM), the contractile responses to both cyclosporin A (100 microM) and FK506 (100 microM), were significantly reduced. In contrast, the contractile responses to substance P and neurokinin A (10 microM) were not altered. Furthermore, repeated application of cyclosporin A (100 microM) significantly inhibited the contractile response to capsaicin (1 microM). The findings from this study would indicate that cyclosporin A and FK506 mediate contraction of guinea-pig isolated bronchus secondary to the release of neuropeptides from airway sensory nerves. However, the release of sensory neuropeptides appears to be mediated via different mechanisms for cyclosporin A and FK506, the former by stimulation of the vanilloid receptor and the latter via opening of N-type calcium channels.


Sources of dietary gluten in the first 2 years of life and associations with celiac disease autoimmunity and celiac disease in Swedish genetically predisposed children: The Environmental Determinants of Diabetes in the Young (TEDDY) study.
High gluten intake is associated with increased risk of celiac disease (CD) in children at genetic risk. We aimed to investigate if different dietary gluten sources up to age 2 y confer different risks of celiac disease autoimmunity (CDA) and CD in children at genetic risk. Three-day food records were collected at ages 6, 9, 12, 18, and 24 mo from 2088 Swedish genetically at-risk children participating in a 15-y follow-up cohort study on type 1 diabetes and CD. Screening for CD was performed with tissue transglutaminase autoantibodies (tTGA). The primary outcome was CDA, defined as persistent tTGA positivity. The secondary outcome was CD, defined as having a biopsy specimen showing Marsh score ≥ 2 or an averaged tTGA level ≥ 100 Units. Cox regression adjusted for total gluten intake estimated HRs with 95% CIs for daily intake of gluten sources. During follow-up, 487 (23.3%) children developed CDA and 242 (11.6%) developed CD. Daily intake of ≤158 g porridge at age 9 mo was associated with increased risk of CDA (HR: 1.53; 95% CI: 1.05, 2.23; P = 0.026) compared with no intake. A high daily bread intake (>18.3 g) at age 12 mo was associated with increased risk of both CDA (HR: 1.47; 95% CI: 1.05, 2.05; P = 0.023) and CD (HR: 1.79; 95% CI: 1.10, 2.91; P = 0.019) compared with no intake. At age 18 mo, milk cereal drink was associated with an increased risk of CD (HR: 1.16; 95% CI: 1.00, 1.33; P = 0.047) per 200-g/d increased intake. No association was found for other gluten sources up to age 24 mo and risk of CDA or CD. High daily intakes of bread at age 12 mo and of milk cereal drink during the second year of life are associated with increased risk of both CDA and CD in genetically at-risk children.


Profiles in altered metabolism. II--(omega -- 1)-hydroxyacid excretion in a case of episodic hypoglycemia.
A patient with recurrent severe hypoglycemia resembling Reye's syndrome was found to have large accumulations of omega -- 1 hydroxy and keto acids in serum and urine that persisted following clinical recovery. A deficiency of mitochondrial medium chain acyl CoA dehydrogenase activity is proposed on the basis of evidence obtained using gas chromatographic mass spectrometric techniques. Analytical data is presented that will allow the recognition of ths variant presenting in other patients.


Low retention of white cell fragments by polyester fiber white cell-reduction platelet filters.
There is intense interest in the potential of current white cell (WBC)-reduction filters to prevent the alloimmunization of patients by the residual donor WBCs in filtered blood components transfused to them. Little attention has been paid to the capacity of current synthetic fiber filters to remove WBC membrane fragments bearing detectable leukocyte antigens. Fluorescein isothiocyanate-conjugated monoclonal antibody to a universal WBC membrane antigen (CD45) and high-speed centrifugation coupled with ficoll-hypaque differential sedimentation were used to quantitate low-density WBC fragments in single-donor platelet components before and after filtration to determine if a polyester fiber filter retained WBC fragments. Prefiltration measurements in 25 single-donor platelet components indicated that WBC fragments increased with length of storage up to 5 days at room temperature (p < 0.0001). When fragments in eight components were measured before and after filtration, absolute values for differences were insignificant (p = 0.15). WBC fragments were poorly retained by these polyester fiber WBC-reduction filters. The antigenicity of WBC fragments could contribute to the WBC alloimmunization of some recipients of WBC-reduced blood components.


Inhibitory effect of a novel water-soluble vitamin E derivative on atherosclerosis in rabbits.
A novel vitamin E derivative that is freely soluble in water, 2-(alpha-D-glucopyranosyl)methyl-2,5,7,8-tetramethylchroman-6-ol (TMG), was evaluated for ability to inhibit development of atherosclerosis in Watanabe heritable hyperlipidemic (WHHL) rabbits or cholesterol-loaded New Zealand White rabbits. Although TMG rapidly entered the circulation blood after oral administration, the blood TMG concentration remained low, while neither TMG nor its metabolites appeared in the low-density lipoprotein (LDL) fraction. TMG did not decrease serum total cholesterol and the various lipoprotein-associated cholesterol fractions (very LDL-, or high-density lipoprotein- (HDL) cholesterol). TMG reduced the serum concentration of thiobarbituric acid-reactive substances (TBARS; an index of lipid peroxidation) in cholesterol-loaded rabbits but not WHHL rabbits. Nonetheless, TMG inhibited aortic atherosclerosis as effectively as probucol in both models. Our results indicate that TMG opposes progression of atherosclerosis not only by preventing oxidation of LDL, but also by presently unknown mechanisms. Even an antioxidant with no uptake by LDL apparently can inhibit development of atherosclerosis despite a very low serum concentration.


Nutrient use efficiency in evergreen and deciduous species from heathlands.
The nutrient (N, P) use efficiency (NUE: g g-1 nutrient), measured for the entire plant, of field populations of the evergreen shrubs Erica tetralix (in a wet heathland) and Calluna vulgaris (in a dry heathland) and the deciduous grass Molinia caerulea (both in a wet and a dry heathland) was compared. Erica and Calluna are crowded out by Molinia when nutrient availability increases. NUE was measured as the product of the mean residence time of a unit of nutrient in the population (MRT: yr) and nutrient productivity (A: annual productivity per unit of nutrient in the population, g g-1 nutrient yr-1. It was hypothesized that 1) in low-nutrient habitats selection is on features leading to a high MRT, whereas in high-nutrient habitats selection is on features leading to a high A; and that 2) due to evolutionary trade-offs plants cannot combine genotypically determined features which maximize both components of NUE.Both total productivity and litter production of the Molinia populations exceeded that of both evergreens about three-fold. Nitrogen and phosphorus resorption from senescing shoots was much lower in the evergreens compared with Molinia. In a split-root experiment no nutrient resorption from senescing roots was observed. Nutrient concentrations in the litter were equal for all species, except for litter P-concentration of Molinia at the wet site. Both Erica and Calluna had a long mean residence time of both nitrogen and phosphorus and a low nitrogen and phosphorus productivity. The Molinia populations showed a shorter mean residence time of N and P and a higher N- and P-productivity. These patterns resulted in an equal nitrogen use efficiency and an almost equal phosphorus use efficiency for the species under study. However, when only aboveground NUE was considered the Molinia populations had a much higher NUE than the evergreens.The results are consistent with the hypotheses. Thus, the low potential growth rate of species from low-nutrient habitats is probably the consequence of their nutrient conserving strategy rather than a feature on which direct selection takes place in these habitats.


Progenitors of oligodendrocytes: limiting dilution analysis in fetal rat brain culture.
In this paper, we describe the use of a combination of cell culture techniques and limiting dilution analysis to determine the number of oligodendrocyte progenitor cells and the oligodendrocyte clone size in primary dispersed cultures of 20- to 21-day-old fetal rat brain. Single-cell suspensions (1, 2, 3 x 10(6) cells/ml) were plated in either microwell or 100 mm dishes. After 22 days in culture the number of differentiated oligodendrocytes was ascertained by determining the amount of myelin basic protein by radioimmunoassay. The total amount of myelin basic protein was the same in the two types of dish, indicating that proliferation and differentiation were unaffected when oligodendrocytes were grown in microwells. The fraction (F0) of microwells containing no oligodendrocytes was determined at each cell dilution. F0 decreased exponentially with increasing total cell concentration. The linearity of the plot of ln F0 versus cell number indicates that the number of oligodendrocyte progenitor cells is limiting. From the equation describing the Poisson distribution of progenitor cells in microwells we calculate that, at the time of plating, primary cultures of fetal rat brain contain one oligodendrocyte progenitor cell per 1.3 x 10(5) brain cells, or a total population of 300-500 progenitor cells per brain. The mean oligodendrocyte clone size was determined to be approximately 825 at 22 days and close to 2000 by 35 days in culture. Therefore, each progenitor cell must undergo approximately 11 divisions, on the average, during postnatal development.


Microvascular reconstruction of facial defects in settings where resources are limited.
The surgical treatment of defects caused by noma is challenging for the surgeon and the patient. Local flaps are preferred, but sometimes, because of the nature of the disease, there is not enough local tissue available. We describe our experience of free tissue transfer in Ethiopia. Between 2008 and 2014, 34 microsurgical procedures were done over 11 missions with the charity Facing Africa, predominantly for the treatment of defects caused by noma (n=32). The mean duration of operation was 442 minutes (range 200 - 720). Six minor wound infections were treated conservatively and did not affect outcome, a return to theatre was required in 4 patients with wound infections and one with a haemorrhage; 2 flaps failed and 2 partially failed, one patient developed an oronasal fistula, and one had an infection at the donor site that required a repeat graft. In settings where resources are limited, free flaps can be used when local tissue is not available and they cause less morbidity than pedicled tissue transfer.


Recurrent molar pregnancies in a family with extensive intermarriage: report of a family and review of the literature.
Familial recurrent molar pregnancies are exceedingly rare. The genetic basis for recurrent moles is not well understood, and its association with major human lymphocytic antigen histocompatibility is debatable. The purpose of this report is to present a family with extensive intermarriage and recurrent molar pregnancies with some emphasis on the result of the human lymphocytic antigen-typing. Two sisters, both married to first-degree cousins, had three and five pathologically confirmed molar pregnancies, respectively. A second-degree cousin, also married to her first-degree cousin, is also reported to have had five consecutive moles. Chromosomal analysis and human lymphocytic antigen-typing on the two sisters and their spouses was performed. Human lymphocytic antigen-typing was compared to a cross-sectional sample of our population. This showed a high incidence of unusual human lymphocytic antigens in these family members. In families with extensive intermarriage and recurrent molar pregnancies, patients and their spouses may have unusual human lymphocytic antigen histocompatibility, which supports the possibility of a strong genetic predisposition expressed at the level of major histocompatibility class I and II gene translation.


Does anthracycline administration by infusion in children affect late cardiotoxicity?
The severity of late cardiotoxicity after anthracycline treatment for childhood cancer relates mainly to the cumulative anthracycline dose received, but all dose ranges cause some cardiac dysfunction. Anthracycline administration by infusion in order to lower peak drug concentration has been used in an attempt to reduce cardiotoxicity. Cardiac performance was assessed by echocardiography in children who were relapse-free survivors of treatment for acute lymphoblastic leukaemia (ALL). They received the same cumulative anthracycline dose (daunorubicin 180 mg/m2) either by bolus injection (UKALL X protocol, n = 40) or by infusion (UKALL XI protocol, n = 71) with a follow-up duration of 5.3 +/- 2.0 and 5.4 +/- 1.0 years respectively. On analysis, both the bolus administration and infusion groups showed similar mild impairment of cardiac performance, characterized by increased left ventricular end systolic stress and impaired left ventricular function. In conclusion, subclinical abnormality of left ventricular performance was confirmed in both groups despite the relatively modest cumulative anthracycline dose received. We were unable to demonstrate an advantage of anthracycline administration by 6-h infusion with respect to late cardiotoxicity at this dose.


Differences in apolipoproteins and low-density lipoprotein subfractions in postmenopausal women on and off estrogen therapy: results from the Framingham Offspring Study.
The use of estrogens by postmenopausal women has been associated with reduced risk of coronary artery disease (CAD) in some studies, possibly due to favorable effects of estrogens on plasma lipoproteins. In order to examine such effects, we studied 180 postmenopausal women from the Framingham Offspring Study, selected by type of menopause (natural or oophorectopic) and estrogen use. We determined fasting plasma total cholesterol, triglyceride, very-low-density lipoprotein (VLDL) cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and apolipoprotein (apo) A-l and B concentrations, as well as LDL particle size (LDL 1 to LDL 6). Apo A-l levels were significantly (P less than .005) higher, and diastolic blood pressure and glucose levels were significantly (P less than .05) lower in postmenopausal women taking estrogen regardless of type of menopause. HDL cholesterol levels were also higher in women taking oral estrogens, but differences were significant only for the oophorectomized group (P less than .02). Total cholesterol, VLDL cholesterol, and LDL cholesterol levels were significantly lower (P less than .01) in women with natural menopause who were taking estrogens than in women with natural menopause not taking this medication. No significant differences between estrogen users and nonusers were found with regard to triglyceride levels or LDL particle score, in either the natural menopause or oophorectomy groups. These data indicate that estrogen use in postmenopausal women is associated with significantly elevated plasma apo A-l levels and decreased LDL cholesterol concentrations.


Everolimus therapy is associated with reduced lipoprotein-associated phospholipase A2 (Lp-Pla2) activity and oxidative stress in heart transplant recipients.
Several studies demonstrated decreased severity and incidence of cardiac allograft vasculopathy (CAV) in heart transplant recipients receiving immunosuppressive therapy with everolimus. However, data regarding the influence of everolimus on risk factors predisposing to CAV are hitherto limited. We here systematically evaluated cardiovascular risk factors in heart transplanted patients, who underwent conversion to everolimus or were maintained on conventional therapy with calcineurin inhibitors (CNI). 50 Patients receiving everolimus and 91 patients receiving CNI in addition to mycophenolate mofetil and low-dosed steroids were included in the study. CAV risk factors were determined in plasma or urine using standard enzymatic or immunochemical methods. No significant differences were observed between both groups with regard to lipid (total, LDL- and HDL-cholesterol), metabolic (glucose, insulin), inflammatory (C-reactive protein, IL-6, myeloperoxidase) and cardiac (troponin I, NT-proBNP) risk factors. However, significantly lower activity of lipoprotein-associated phospholipase A2 (Lp-PLA2) and a negative correlation between the Lp-PLA2 activity and the everolimus concentration were observed in plasmas from everolimus-treated patients. Conversion to everolimus significantly lowered Lp-PLA2 activity in heart transplant recipients. Studies in vitro revealed reduced Lp-PLA2 expression in hepatocytes and macrophages pre-exposed to everolimus. In addition, reduced plasma markers of oxidative stress including oxidized LDL, 8-iso-prostaglandin F2α and protein carbonyls were noted in heart transplant recipients receiving everolimus therapy. Our results suggest that everolimus specifically lowers plasma activity and cellular production of Lp-PLA2 and thereby dampens oxidative stress. These effects may additionally contribute to the reduced CAV incidence observed in heart transplant recipients receiving everolimus therapy.


Grafting of phosphorylcholine functional groups on polycarbonate urethane surface for resisting platelet adhesion.
In order to improve the resistance of platelet adhesion on material surface, 2-methacryloyloxyethyl phosphorylcholine (MPC) was grafted onto polycarbonate urethane (PCU) surface via Michael reaction to create biomimetic structure. After introducing primary amine groups via coupling tris(2-aminoethyl)amine (TAEA) onto the polymer surface, the double bond of MPC reacted with the amino group to obtain MPC modified PCU. The modified surface was characterized by Fourier transform infrared (FTIR) spectroscopy and X-ray photoelectron spectroscopy (XPS). The results verified that MPC was grafted onto PCU surface by Michael reaction method. The MPC grafted PCU surface had a low water contact angle and a high water uptake. This means that the hydrophilic PC functional groups improved the surface hydrophilicity significantly. In addition, surface morphology of MPC grafted PCU film was imaged by atomic force microscope (AFM). The results showed that the grafted surface was rougher than the blank PCU surface. In addition, platelet adhesion study was evaluated by scanning electron microscopy (SEM) observation. The PCU films after treated with platelet-rich plasma demonstrated that much fewer platelets adhered to the MPC-grafted PCU surface than to the blank PCU surface. The antithrombogenicity of the MPC-grafted PCU surface was determined by the activated partial thromboplastin time (APTT). The result suggested that the MPC modified PCU may have potential application as biomaterials in blood-contacting and some subcutaneously implanted devices.


Influence of background/surrounding area on accuracy of visual color matching.
Visual shade selection is subjective and influenced by factors that might be operator-dependent or not. The objective was to evaluate influence of observer nonrelated factors (background/surrounding area, and light) and observer-related factors (gender and color competence) on shade-matching quality and to identify the most often mismatched shades in correlation with the background. Ten observers with average or superior color discrimination competence according to ISO TR 28642:2011 were asked to match 48 shade tabs of three VITA Classical shade guides, in a viewing booth under two light sources: D65 and D50. Gray, white, black, red, and light blue background/surrounding area simulated various clinical situations. The results were statistically analyzed using Kruskal-Wallis test and Mann-Whitney U test. Post hoc power analyses and sample size calculations were also conducted. The matching scores ranged between 72.7 % (using blue background) and 85.9 % (using white and black backgrounds). There was a statistically significant difference between matching scores on the five backgrounds (χ (2)(4) = 12.67, p = 0.01). When neutral gray was used as reference, Mann-Whitney U value was statistically significant only for the blue background (U = 107.00, Z = -2.52, p = 0.01). The influence of gender and lighting condition was also assessed, no statistically significance being found, but in both cases, the effect size and the achieved power were small. However, color discrimination competence did influence the results (p < 0.01). Background influenced shade matching results for tabs A3, B3, B4, and D4. Within the limitations of this study, it was concluded that 1. When it comes to the influence of the background/surround area on quality of color matching, no difference among achromatic backgrounds was recorded. Significantly worse results were recorded when the blue background was used. 2. Observers with superior color matching competence performed significantly better than the ones with average competence 3. The most frequently mismatched shade tabs were A3.5, B3, B4, and D4.


Enzymatic hydrolysis of penicillin for 6-APA production in three-liquid-phase system.
A dodecane/thermosensitive polymer/water three-liquid-phase system was introduced for enzymatic hydrolysis of penicillin G (Pen G) for 6-aminopenicillanic acid (6-APA). The enzyme was covalently attached to the terminal of PEO-PPO-PEO polymer (L63), which would be transferred into a polymer coacervate phase at high temperature above its "cloud point". 6-APA was primarily resided in the aqueous phase due to its zwitterionic nature. More than 70% phenylacetic acid (PAA) was transferred into the organic phase using trioctylmethylammonium hydroxide and trihexyl-(tetradecyl)phosphonium bis 2,4,4-trimethylpentylphosphinate ionic liquids (Cyphos IL-104) mixture at pH 5.5, while most of Pen G resided in water. As a result, high operational pH was permitted in three-liquid-phase system, which leads to higher enzymatic activity (120 IU at 40 degrees C) and stability (enzymatic half-time up to 55 h at 60 degrees C) in comparison with the value in butyl acetate/water two-phase system. On the other hand, two products in three-liquid-phase system might be automatically separated from the enzyme sphere into different phases at the same time, which facilitated the reaction equilibrium towards the product's side with 6-APA productivity of 80% at 42 degrees C, pH 5.5.