Electrochemical sensor based on molecularly imprinted polymer film via sol-gel technology and multi-walled carbon nanotubes-chitosan functional layer for sensitive determination of quinoxaline-2-carboxylic acid.
Quinoxaline-2-carboxylic acid (QCA) is difficult to measure since only trace levels are present in commercial meat products. In this study, a rapid, sensitive and selective molecularly imprinted electrochemical sensor for QCA determination was successfully constructed by combination of a novel modified glassy carbon electrode (GCE) and differential pulse voltammetry (DPV). The GCE was fabricated via stepwise modification of multi-walled carbon nanotubes (MWNTs)-chitosan (CS) functional composite and a sol-gel molecularly imprinted polymer (MIP) film on the surface. MWNTs-CS composite was used to enhance the electron transfer rate and expand electrode surface area, and consequently amplify QCA reduction electrochemical response. The imprinted mechanism and experimental parameters affecting the performance of MIP film were discussed in detail. The resulting MIP/sol-gel/MWNTs-CS/GCE was characterized using various electrochemical methods involving cyclic voltammetry (CV), electrochemical impedance spectroscopy (EIS) and DPV. The sensor using MIP/sol-gel/MWNTs-CS/GCE as working electrode showed a linear current response to the target QCA concentration in the wide range from 2.0×10(-6) to 1.0×10(-3)molL(-1) with a low detection limit of 4.4×10(-7)molL(-1) (S/N=3). The established sensor with excellent reproductivity and stability was applied to evaluate commercial pork products. At five concentration levels, the recoveries and standard deviations were calculated as 93.5-98.6% and 1.7-3.3%, respectively, suggesting the proposed sensor is promising for the accurate quantification of QCA at trace levels in meat samples.


PDE10A Inhibition Reduces the Manifestation of Pathology in DMD Zebrafish and Represses the Genetic Modifier PITPNA.
Duchenne muscular dystrophy (DMD) is a severe genetic disorder caused by mutations in the DMD gene. Absence of dystrophin protein leads to progressive degradation of skeletal and cardiac function and leads to premature death. Over the years, zebrafish have been increasingly used for studying DMD and are a powerful tool for drug discovery and therapeutic development. In our study, a birefringence screening assay led to identification of phosphodiesterase 10A (PDE10A) inhibitors that reduced the manifestation of dystrophic muscle phenotype in dystrophin-deficient sapje-like zebrafish larvae. PDE10A has been validated as a therapeutic target by pde10a morpholino-mediated reduction in muscle pathology and improvement in locomotion, muscle, and vascular function as well as long-term survival in sapje-like larvae. PDE10A inhibition in zebrafish and DMD patient-derived myoblasts were also associated with reduction of PITPNA expression that has been previously identified as a protective genetic modifier in two exceptional dystrophin-deficient golden retriever muscular dystrophy (GRMD) dogs that escaped the dystrophic phenotype. The combination of a phenotypic assay and relevant functional assessments in the sapje-like zebrafish enhances the potential for the prospective discovery of DMD therapeutics. Indeed, our results suggest a new application for a PDE10A inhibitor as a potential DMD therapeutic to be investigated in a mouse model of DMD.


Suppression of HIV-1 replication by a combination of endonucleolytic ribozymes (RNase P and tRNnase ZL).
We examined the combinatorial action of RNase P and tRNase ZL-mediated specific inhibition of HIV-1 in cultured cells. We designed two short extra guide sequences (sEGS) that specifically recognize the tat and vifregions of HIV-1 mRNA and mediate the subsequent cleavage of hybridized mRNA by the RNase P and tRNase ZL components. We constructed an RNase P and tRNase ZL-associated vif and tat sEGS expression vector; which used the RNA-polymerase III dependent U6 promoter, as an expression cassette for EGS. Together, the RNase P and tRNase ZL-associated sEGS molecules allow more efficient suppression of HIV-1 mRNA production when separately applied. The possibilities offered by the vector to encode sEGS will provide a powerful tool for gene therapy.


Effect of azadirachtin on mortality and immune response of leaf-cutting ants.
Leaf-cutting ants are difficult pests to control because they have numerous defense strategies and are highly selective in their plant harvesting choices. The search for effective pest control methods that have minimal negative effects on the environment has been continuous. Azadirachtin, a compound extracted from the neem tree (Azadirachta indica), is a promising alternative for the control of various pests, as it is toxic to some insects but readily degrades in the environment. In this study, we evaluated the effects of azadirachtin on the mortality, through topical exposure to the compound, and immune response, by introducing an artificial antigen into leaf-cutting ants Atta sexdens and Acromyrmex subterraneus subterraneus. Azadirachtin caused death to minor and major workers of both species in a concentration-dependent manner. Topical application of the compound did not diminish the immune response of ants in a microfilament encapsulation assay. Azadirachtin showed no effect on the immune response of workers but increased worker mortality, which indicates its potential as an ant control agent.


Ocular vasodilation and angiogenesis in Potter's syndrome.
At autopsy we examined eight eyes of six infants with Potter's syndrome, an idiopathic multisystem condition with a constellation of ocular anomalies, to explore its ocular component more fully and systematically. A striking abnormality in some cases was the presence of dilated intraocular blood vessels, and these were sometimes associated with retinal and preretinal neovascularization reminiscent of the vasoproliferative stage of retrolental fibroplasia. Since oxygen therapy cannot be implicated in these cases, other causes, either genetic or environmental, must be sought. The presence of nonretinal ocular vascular anomalies, such as iris capillary dilation, peripapillary angioma formation, and vascular anomalies in nonocular tissue, point to a generalized derangement in the control of ocular angiogenesis. Our study indicated that an understanding of the pathogenesis of the vascular anomalies in Potter's syndrome is clearly relevant to other more common retinopathies that are associated with neovascularization.


Modifying effect of bradykinin on motor activity in the guinea-pig gall bladder.
1. The interaction of bradykinin and cholecystokinin preparations was investigated on the guinea-pig isolated gall bladder. Bradykinin (1-100 ng/ml) induced dose-dependent contractile effects which were considerably smaller than those produced by cholecystokinin octapeptide. Bradykinin in a low concentration (1.0 ng/ml) caused a significant increase of the contraction induced by cholecystokinin octapeptide (P less than 0.001) and natural cholecystokinin-pancreozymin (P less than 0.01), and also augmented the effects of acetylcholine on this preparation. Therefore these effects are probably not specific for cholecystokinin.


Genome-wide analysis of the MADS-box gene family in Lonicera japonica and a proposed floral organ identity model.
Lonicera japonica Thunb. is widely used in traditional Chinese medicine. Medicinal L. japonica mainly consists of dried flower buds and partially opened flowers, thus flowers are an important quality indicator. MADS-box genes encode transcription factors that regulate flower development. However, little is known about these genes in L. japonica. In this study, 48 MADS-box genes were identified in L. japonica, including 20 Type-I genes (8 Mα, 2 Mβ, and 10 Mγ) and 28 Type-II genes (26 MIKCc and 2 MIKC*). The Type-I and Type-II genes differed significantly in gene structure, conserved domains, protein structure, chromosomal distribution, phylogenesis, and expression pattern. Type-I genes had a simpler gene structure, lacked the K domain, had low protein structure conservation, were tandemly distributed on the chromosomes, had more frequent lineage-specific duplications, and were expressed at low levels. In contrast, Type-II genes had a more complex gene structure; contained conserved M, I, K, and C domains; had highly conserved protein structure; and were expressed at high levels throughout the flowering period. Eleven floral homeotic MADS-box genes that are orthologous to the proposed Arabidopsis ABCDE model of floral organ identity determination, were identified in L. japonica. By integrating expression pattern and protein interaction data for these genes, we developed a possible model for floral organ identity determination. This study genome-widely identified and characterized the MADS-box gene family in L. japonica. Eleven floral homeotic MADS-box genes were identified and a possible model for floral organ identity determination was also developed. This study contributes to our understanding of the MADS-box gene family and its possible involvement in floral organ development in L. japonica.


Microenvironmental IL-6 inhibits anti-cancer immune responses generated by cytotoxic chemotherapy.
Cytotoxic chemotherapeutics primarily function through DNA damage-induced tumor cell apoptosis, although the inflammation provoked by these agents can stimulate anti-cancer immune responses. The mechanisms that control these distinct effects and limit immunogenic responses to DNA-damage mediated cell death in vivo are currently unclear. Using a mouse model of BCR-ABL+ B-cell acute lymphoblastic leukemia, we show that chemotherapy-induced anti-cancer immunity is suppressed by the tumor microenvironment through production of the cytokine IL-6. The chemotherapeutic doxorubicin is curative in IL-6-deficient mice through the induction of CD8+ T-cell-mediated anti-cancer responses, while moderately extending lifespan in wild type tumor-bearing mice. We also show that IL-6 suppresses the effectiveness of immune-checkpoint inhibition with anti-PD-L1 blockade. Our results suggest that IL-6 is a key regulator of anti-cancer immune responses induced by genotoxic stress and that its inhibition can switch cancer cell clearance from primarily apoptotic to immunogenic, promoting and maintaining durable anti-tumor immune responses.


Administration of S-methyl-L-thiocitrulline protects against brain injuries after intracerebral hemorrhage.
Although intracerebral hemorrhage (ICH) increases the level of glutamate in the perihematomal area and cerebral spinal fluid (CSF) in the ICH acute phase, it is unclear whether elevated glutamate activates neuronal nitric oxide synthase (nNOS) in the ICH brain and whether nNOS is an important target for ICH treatment. Here, we assessed the role of the nNOS inhibitor S-methyl-l-thiocitrulline (SMTC) in the activity of NADPH-d and ICH-induced brain injuries. An autologous blood intracerebral infusion model in male rats was used. All of the rats were sacrificed 24h after ICH. ICH increased NADPH-d activity in the striatum. Administering SMTC 3h after ICH decreased the activity of NADH-d (p<0.05 vs. the ICH group). The activation of gelatinolytic enzymes in the perihematomal region of the striatum was reduced by SMTC treatment (p<0.01, vs. the ICH group). The loss of laminin- and occludin-stained vessels was significant in perihematomal regions after 24h of ICH and was significantly attenuated by the administration of SMTC (p<0.01 for laminin, p<0.05 for occluding, compared with the ICH group). Neuronal death and neurological deficits after ICH were also decreased in SMTC treatment rats (p<0.01, vs. the ICH group). The results suggest that the administration of the nNOS inhibitor SMTC after ICH protects against ICH-induced brain injuries and improves neurological function.


Self-reported prevalence and awareness of metabolic syndrome: findings from SHIELD.
This study assessed awareness of metabolic syndrome and evaluated health knowledge, attitudes and behaviours of respondents at risk. Study to Help Improve Early evaluation and management of risk factors Leading to Diabetes (SHIELD), a longitudinal US population-based survey initiated in 2004, included respondents, > or = 18 years of age, reporting a diagnosis of metabolic syndrome. Prevalence of metabolic syndrome was compared in SHIELD and National Health and Nutrition Examination Survey (NHANES) 1999-2002 survey. The proportion of SHIELD respondents who had heard of and/or understood metabolic syndrome was estimated. Respondents at high risk for metabolic syndrome were stratified into attitude-behaviour categories of 'Already Doing It', 'I Know I Should' and 'Don't Bother Me' and differences in attitudes and behaviours were evaluated with chi-square tests. Prevalence of reported metabolic syndrome was 0.6% in SHIELD screening questionnaire respondents (n = 211,097) vs. 25.9% in NHANES (n = 10,780). Less than 15% of SHIELD baseline questionnaire respondents (n = 22,001) had heard of or understood metabolic syndrome. Attitudes toward health status were more favourable in the 'Doing' group (27% reported fair/poor health) compared with those in the 'Should' (38%) and 'Don't' (54%) groups (p < 0.0001). The 'Don't' group was most likely to prefer medications to lifestyle change (13% vs. 2-4%) compared with 'Should' and 'Doing' groups (p < 0.0001). More 'Doing' respondents (79%) than 'Should' (59%) and 'Don't' (48%) respondents reported exercising regularly (p < 0.0001). The lack of knowledge about metabolic syndrome reported in SHIELD indicates limited penetration of this concept into public awareness. With behaviour categories, respondents who report healthy attitudes are more likely to embrace lifestyle changes, while respondents who do not care may be more difficult to treat.


Contribution of rare and common species to subterranean species richness patterns.
Common species contribute more to species richness patterns (SRPs) than rare species in most studies. Our aim was to test this hypothesis using a novel model system, species living exclusively in subterranean habitats. They consist of mainly rare species (small ranges), only a few of them being common (large ranges), and challenge whether rare species are less important for the development of SRPs in this environment. We separately analyzed aquatic and terrestrial species. Western Balkans in southeastern Europe. We assembled two datasets comprising 431 beetle and 145 amphipod species, representing the model groups of subterranean terrestrial and aquatic diversity, respectively. We assessed the importance of rare and common species using the stepwise reconstruction of SRPs and subsequent correlation analyses, corrected also for the cumulative information content of the subsets based on species prevalence. We applied generalized linear regression models to evaluate the importance of rare and common species in forming SRPs. Additionally, we analyzed the contribution of rare and common species in species-rich cells. Patterns of subterranean aquatic and terrestrial species richness overlapped only weakly, with aquatic species having larger ranges than terrestrial ones. Our analyses supported higher importance of common species for forming overall SRPs in both beetles and amphipods. However, in stepwise analysis corrected for information content, results were ambiguous. Common species presented a higher proportion of species than rare species in species-rich cells. We have shown that even in habitats with the domination of rare species, it is still common species that drive SRPs. This may be due to an even spatial distribution of rare species or spatial mismatch in hotspots of rare and common species. SRPs of aquatic and terrestrial subterranean organisms overlap very little, so the conservation approaches need to be habitat specific.


Long-term outcome of transplant ureterostomy in children: A National Review.
CAKUT are the most common cause of end-stage renal failure in children (Pediatr Nephrol. 24, 2009, 1719). Many children with CAKUT have poor urinary drainage which can compromise post-transplant outcome. Identifying safe ways to manage anatomical abnormalities and provide effective urinary drainage is key to transplant success. Much debate exists regarding optimum urinary diversion techniques. The definitive formation of a continent urinary diversion is always preferable but may not always be possible. We explore the role of ureterostomy formation at transplantation in a complex pediatric group. We report six pediatric patients who had ureterostomy formation at the time of transplantation at the National Paediatric Transplant Centre in Dublin, Ireland. We compared renal function and burden of urinary tract infection to a group with alternative urinary diversion procedures and a group with normal bladders over a 5-year period. There was no demonstrable difference in estimated glomerular filtration rate between the groups at 5-year follow-up. The overall burden of UTI was low and similar in frequency between the three groups. Ureterostomy formation is a safe and effective option for temporary urinary diversion in children with complex abdominal anatomy facilitating transplantation; it is, however, important to consider the implications and risk of ureterostomy for definitive surgery after transplantation.


Analysis of 13 cases of venous compromise in 178 radial forearm free flaps for intraoral reconstruction.
The purpose of this study was to analyse the causes of venous compromise and flap failure in radial forearm free flap (RFFF) surgery for intraoral reconstruction. One hundred seventy-eight RFFF reconstructions were reviewed retrospectively for intraoral defects. Of the 13 flaps with venous obstruction, 9 flaps were salvaged, and 4 were lost, with a salvage rate of 69.2%. Eleven venous occlusions occurred within the first 72h. The main reasons for venous failure were mechanical obstruction or technical errors due to inadequate pedicle length and geometry, inadequate venous drainage, compression and kinking of the vein. The main cause of failure for oropharynx reconstruction was unrecognized vascular events due to the lack of reliable monitoring for buried flap. Oozing of dusky blood from the flap margin may be directly related to venous congestion in the early postoperative period and a late indication of a change in skin colour. In conclusion, a thorough operative plan, including carefully selected drainage vein for the flap and recipient vessels, adequate pedicle length and geometry, precise surgical technique, avoidance of haematoma, and expert monitoring of buried flaps may improve the success rate of RFFF transfer in intraoral reconstruction.


Beneficial effects of methionine on myocardial hemodynamic and cellular functions in hemorrhagic shock.
Hypochlorous acid (HOCl), produced by activated polymorphonuclear (PMN) leukocytes, has been reported to depress cardiac function and contractility. Various mechanisms exist for activation of PMN leukocytes during hemorrhagic shock and reperfusion. In order to determine the role of HOCl in hemorrhagic shock and reinfusion, the authors studied the effects of shock and reinfusion on the cardiac function, contractility, blood lactate, blood gases, and creatine kinase (CK) and MB fraction of CK (MBCK) with and without methionine (quencher of HOCl) in anesthetized dogs. Dogs were divided into two groups: Group I, hemorrhagic shock (two hours) and reinfusion (two hours): Group II, hemorrhagic shock and reinfusion with methionine treatment. Cardiac index, mean arterial pressure, and index of cardiac contractility were similar in the two groups during shock. Postinfusion recovery of cardiac function and contractility was better in group II. Increases in blood lactate were similar in the two groups during shock. The rate of return of blood lactate to preshock values after reinfusion was greater in group II. The increases in serum CK and MBCK of the two groups during shock were similar but not significant. Following reinfusion the levels of these enzymes increased significantly, but the increases in group II were less. These results suggest that HOCl produced by activated PMN leukocytes may play a role in cardiac damage during hemorrhagic shock and reinfusion. Methionine may have beneficial effects in the hemodynamic and metabolic recovery and may reduce cellular damage during hemorrhage shock and reinfusion.


The adsorption and self-assembly of surfactant mixtures: How the detailed evaluation of adsorption properties provides access to the bulk behaviour.
The nature of surfactant mixing at interfaces and in bulk solution is key to understanding and optimising the diverse industrial, technological, biological and domestic applications of surfactants. The use of neutron reflectivity, NR, and small angle neutron scattering, SANS, in combination with isotopic substitution, has transformed the ability to quantify and understand the nature of surfactant mixing at the air-water interface and in self-assembled aggregates or micelles in solution. The accuracy and scope of the compositional data from NR, the application of recent developments in the pseudo phase approximation, PPA, and the availability of complementary critical micelle concentration, cmc, and micelle composition data, enables a detailed thermodynamical quantification of the mixing properties to be made. The NR data in particular, and the SANS data to a lesser extent, provides constraints on the thermodynamical analysis which reveals important properties and trends about the bulk phase which are not available from the analysis of data such as the variation in the cmc alone. The importance and impact of this approach is illustrated with an overview of a range of mixed surfactant examples from the recent literature, and which encompass mixtures with different degrees of departure from ideality.


Congenital nephrotic syndrome with prolonged renal survival without renal replacement therapy.
Infants with congenital nephrotic syndrome (CNS) develop severe nephrotic syndrome that is resistant to medical therapy, and bilateral nephrectomy is recommended toward the end of the first year of life followed by renal replacement therapy. CNS infants in New Zealand have been observed to exhibit a different course to those with the typical Finnish mutation. A database of CNS children at our center was retrospectively examined. All cases diagnosed between 1975 and 2011 were reviewed. Demographic data, clinical features, genetic mutations, treatment, and outcome were extracted from clinical records. Thirty-five patients with CNS, 23 children of Maori descent, and 12 Caucasians . Fourteen had died of either bacterial sepsis or intracranial thrombosis. Maori children had displayed a highly variable and protracted timeline to end-stage renal disease (ESRD) with median renal survival of 30 years versus 0.7 years in Caucasian patients. Mutation analysis of NPHS1 showed a founder mutation in the Maori population. Congenital nephrotic syndrome in New Zealand Maori children exhibit a different clinical course to Caucasian children and have a mutation that was first described in this ethnic group.


Ultrasound fetal thigh-calf circumferences and gestational age--independent fetal ratios in normal pregnancy.
The growth of the sonographically measured fetal thigh and fetal calf circumferences was studied during normal pregnancy. The normal range of fetal thigh and fetal calf circumferences for each week of pregnancy was determined from 20 to 41 weeks. The ratios of the ultrasonically measured fetal femur length to thigh circumference (expressed as femur length/thigh circumference X 100) and fetal tibia length to calf circumference (expressed as tibia length/calf circumference X 100) were also determined. These ratios were found to be relatively constant, with normal ranges after 20 weeks of 51.8 +/- 7.8 and 57.6 +/- 9.4 (mean +/- 2SD) respectively. The applications of these new fetal parameters in the evaluation of abnormal fetal growth patterns are discussed. It is suggested that these ratios should be used in evaluating fetal growth in high-risk patients who present late in pregnancy with unknown dates.


Responses of Scirpus triqueter, soil enzymes and microbial community during phytoremediation of pyrene contaminated soil in simulated wetland.
The aim of this study was to determine the enhancement of Scirpus triqueter in the dissipation of pyrene and the interaction of pyrene with plant, soil enzymes and microbial community. The results indicated that the dissipation ratios of pyrene in the rhizospheric and non-rhizospheric soil were 64.65 ± 3.86% and 54.49 ± 2.74%, respectively, and were higher than that in the unplanted soil (42.60 ± 0.71%) at 80 d after planting S. triqueter. The pyrene was toxic to S. triqueter, as evidenced by growth inhibition in height, diameter, shoot number and biomass during the planting period. The activities of dehydrogenase decreased significantly at the presence of pyrene in soils, and increased remarkably with the introduction of S. triqueter. It was found that the pyrene addition increased the ratios of fungal/total fatty acids and gram-positive/gram-negative, but the presence of S. triqueter decreased the ratios of gram-positive/gram-negative. A larger stress level was found in the pyrene treated soils without S. triqueter. The ratio of aerobic/anaerobic bacteria decreased with increasing pyrene concentration, but increased when S. triqueter was planted. The principal analysis of phospholipid fatty acid signatures revealed that microbial community structures in the rhizospheric and non-rhizospheric soil were similar, but different from those in the unplanted and control soil.


Physiological and metabolomic analysis of Punica granatum (L.) under drought stress.
Punica granatum has a noticeable adaptation to drought stress. The levels of the green leaf volatile trans-2-hexenal increased in response to drought stress suggesting a possible role of this compound in drought stress response in pomegranate. Punica granatum (L.) is a highly valued fruit crop for its health-promoting effects and it is mainly cultivated in semi-arid areas. Thus, understanding the response mechanisms to drought stress is of great importance. In the present research, a metabolomics analysis was performed to evaluate the effects of drought stress on volatile organic compounds extracted from the leaves of pomegranate plants grown under water shortage conditions. The time course experiment (7 days of water deprivation and 24-h recovery) consisted of three treatments (control, drought stress, and rehydration of drought-stressed plants). Plant weights were recorded and control plants were irrigated daily at pot capacity to provide the lost water. Fraction of transpirable soil water has been evaluated as indicator of soil water availability in stressed plants. The levels of proline, hydrogen peroxide and lipid peroxidation as well as of the photosynthetic parameters such as photosynthesis rate (A), stomatal conductance (g s), photosynthetic efficiency of photosystem II, and photochemical quenching were monitored after the imposition of drought stress and recovery as markers of plant stress. Constitutive carbon volatile components were analyzed in the leaf of control and drought-stressed leaves using Head Space Solid Phase Micro Extraction sampling coupled with Gas Chromatography Mass Spectrometry. A total of 12 volatile compounds were found in pomegranate leaf profiles, mainly aldehydes, alcohols, and organic acids. Among them, the trans-2-hexenal showed a significant increase in water-stressed and recovered leaves respect to the well-watered ones. These data evidence a possible role of the oxylipin pathway in the response to water stress in pomegranate plants.


Somatosensory tibial nerve evoked potentials with parasagittal tumours: a contribution to the problem of generators.
Somatosensory evoked potentials following stimulation of the median nerve at the wrist and the tibial nerve at the ankle were recorded in 5 patients with parasagittal tumours, 4 in the fronto-parietal and 1 in the frontal region. Three had intracerebral tumours and 2 parasagittal meningiomas. The extent of each lesion was determined by CT scan, showing a unilateral process involving predominantly the paracentral lobule and adjacent parts of the post- and precentral gyri ("Mantelkante') in 4 patients and a more frontal location of one meningioma affecting mainly the superior frontal gyrus. SEPs recorded from the patients with fronto-parietal tumours showed a uniform pattern with a complete absence of the wave N70 of the tibial SEP elicited by stimulating the nerve contralateral to the lesion. All other waves, including the P40-N50 complex on both sides and the median SEP, were in the normal range. In contrast, the frontal meningioma led to an only slightly altered from of the waves immediately following the initial P40-N50 complex. It is concluded that the tumour abolished the generators of the wave N70 which are apparently located in the cortical somatosensory leg area. Therefore unilateral loss of the wave N70 is indicative of parasagittal lesions. The results may give good evidence that the P40-N50 complex is generated in the thalamus or thalamo-cortical connections.


Clinical effectiveness and safety of intraoperative methadone in patients undergoing laparoscopic hysterectomy: a randomised, blinded clinical trial.
Laparoscopic hysterectomy is often carried out as day-stay surgery. Minimising postoperative pain is therefore of utmost importance to ensure timely discharge from hospital. Methadone has several desirable pharmacological features, including a long elimination half-life. Therefore, a single intraoperative dose could provide long-lasting pain relief. Patients scheduled to undergo laparoscopic hysterectomy were randomly allocated to receive methadone (0.2 mg kg-1) or morphine (0.2 mg kg-1) intraoperatively, 60 min before tracheal extubation. Primary outcomes were opioid consumption (oral morphine equivalents in milligrams) at 6 and 24 h. Secondary outcomes included pain intensity at rest and during coughing, patient satisfaction, postoperative nausea and vomiting, and adverse events up to 72 h after completion of surgery. The postoperative median opioid consumption was reduced in the methadone group compared with the morphine group at 6 h (35.5 [0-61] mg vs 48 [31-74.5] mg; P=0.01) and 24 h (42 [10-67] mg vs 54.5 [31-83] mg; P=0.03). On arrival at the PACU, pain at rest was significantly lower in patients receiving methadone (numeric rating scale: 3 [2-5] vs 5 [3-6]), whereas pain scores at rest and coughing were not significantly different throughout the rest of the observation period. No differences in other secondary outcomes were found. In this randomised, blinded, controlled trial, opioid consumption was reduced during the first 24 postoperative hours in patients receiving methadone without causing an increase in adverse events. The difference observed might be considered as small and of limited clinical relevance. NCT03908060; EudraCT no. 2018-004351-20.


Effects of tranylcypromine and pargyline on brain tryptamine.
Tranylcypromine produces behavioral excitation while pargyline produces depression. Tranylcypromine increased brain tryptophan which led to an accumulation of tryptamine. The levels of tryptamine after tranylcypromine were found to be 3 times those found after pargyline.


Small is beautiful: microRNAs and breast cancer-where are we now?
MicroRNAs are a recently discovered class of small regulatory RNAs that influence the stability and translational efficiency of target mRNAs. They have been implicated in an increasing number of biological processes, including neoplasia. Recent studies have shown an involvement for these regulatory molecules in breast cancer. For example, miRNA profiling studies have identified microRNAs that are deregulated in breast cancer. Furthermore, functional studies have uncovered their roles in breast cancer as both tumour suppressor genes (eg miR-335) and oncogenes (eg miR-21). miRNAs deregulated in breast cancer influence the translational regulation of well-established regulatory molecules, such as oestrogen receptor-alpha, which is regulated by miR-206, and novel cancer-related molecules whose functions are not yet fully understood.. Here we present an overview of our current understanding of miRNA in breast cancer.


Differential cytotoxicity of buthionine sulfoximine to "normal" and transformed human lung fibroblast cells.
Glutathione (GSH) depletion has been studied extensively as a possible means to sensitive tumor cells to radiation treatment and chemotherapy. The present study was undertaken to compare the cytotoxicity of GSH depletion in normal and transformed cells. The results showed that specific inhibition of GSH synthesis by L-buthionine sulfoximine (BSO) caused significantly higher cytotoxicity in "normal" human-lung fibroblast cells than in their transformed counterparts. This finding suggests a possibility that depletion of GSH could be more harmful to normal cells than to transformed and/or tumor cells and that the selective cytotoxicity of BSO to normal cells could limit its potential as an effective sensitizer for cancer treatment.


Can Colorectal Surgery Be Performed as an Outpatient Surgery?
The potential to discharge patients safely within the same day after colorectal surgery has developed over time with concurrent advances in concepts of enhanced recovery pathways, along with minimally invasive techniques available to surgeons. The advent of planned same-day discharges after elective colectomy is made possible by research establishing improved length of stay with minimal morbidity in patients undergoing minimally invasive surgery and especially minimally invasive surgery in the setting of an enhanced recovery after surgery (ERAS) protocol. In tracing the timeline of research and development of knowledge in this setting, the safety of outpatient colorectal surgery can be established.


The effect of retinyl palmitate added to iron-fortified maize porridge on erythrocyte incorporation of iron in African children with vitamin A deficiency.
Retinyl palmitate added to Fe-fortified maize bread has been reported to enhance Fe absorption in adult Venezuelan subjects but not in Western Europeans. It is not known to what extent these results were influenced by differences in vitamin A status of the study subjects. The objective of the present study was to evaluate the influence of retinyl palmitate added to Fe-fortified maize porridge on erythrocyte incorporation of Fe in children with vitamin A deficiency, before and after vitamin A supplementation. Erythrocyte incorporation of Fe-stable isotopes was measured 14 d after intake of maize porridge (2.0 mg Fe added as ferrous sulfate) with and without added retinyl palmitate (3.5 micromol; 3300 IU). The study was repeated 3 weeks after vitamin A supplementation (intake of a single dose of 210 micromol retinyl palmitate; 'vitamin A capsule'). Vitamin A status was evaluated by the modified relative dose-response (MRDR) technique. Retinyl palmitate added to the test meal reduced the geometric mean erythrocyte incorporation of Fe at baseline from 4.0 to 2.6 % (P=0.008, n 13; paired t test). At 3 weeks after vitamin A supplementation, geometric mean erythrocyte incorporation was 1.9 and 2.3 % respectively from the test meal with and without added retinyl palmitate (P=0.283). Mean dehydroretinol:retinol molar ratios were 0.156 and 0.125 before and after intake of the single dose of 210 micromol retinyl palmitate; 'vitamin A capsule' (P=0.15). In conclusion, retinyl palmitate added to the labelled test meals significantly decreased erythrocyte incorporation of Fe in children with vitamin A deficiency at baseline but had no statistically significant effect 3 weeks after vitamin A supplementation. The difference in response to retinyl palmitate added to Fe-fortified maize porridge on erythrocyte incorporation of Fe before and after intake of the vitamin A capsule indicates, indirectly, changes in vitamin A status not measurable by the MRDR technique. The lack of conclusive data on the effect of retinyl palmitate on Fe absorption indicates the complexity of the interactions between vitamin A status, dietary vitamin A and Fe metabolism.


CLINICAL PRACTICE GUIDELINES FOR THE PERIOPERATIVE NUTRITION, METABOLIC, AND NONSURGICAL SUPPORT OF PATIENTS UNDERGOING BARIATRIC PROCEDURES - 2019 UPDATE: COSPONSORED BY AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS/AMERICAN COLLEGE OF ENDOCRINOLOGY, THE OBESITY SOCIETY, AMERICAN SOCIETY FOR METABOLIC & BARIATRIC SURGERY, OBESITY MEDICINE ASSOCIATION, AND AMERICAN SOCIETY OF ANESTHESIOLOGISTS - EXECUTIVE SUMMARY.
Objective: The development of these updated clinical practice guidelines (CPGs) was commissioned by the American Association of Clinical Endocrinologists (AACE), The Obesity Society, American Society of Metabolic and Bariatric Surgery, Obesity Medicine Association, and American Society of Anesthesiologists Boards of Directors in adherence with the AACE 2017 protocol for standardized production of CPGs, algorithms, and checklists. Methods: Each recommendation was evaluated and updated based on new evidence from 2013 to the present and subjective factors provided by experts. Results: New or updated topics in this CPG include: contextualization in an adiposity-based chronic disease complications-centric model, nuance-based and algorithm/checklist-assisted clinical decision-making about procedure selection, novel bariatric procedures, enhanced recovery after bariatric surgery protocols, and logistical concerns (including cost factors) in the current health-care arena. There are 85 numbered recommendations that have updated supporting evidence, of which 61 are revised and 12 are new. Noting that there can be multiple recommendation statements within a single numbered recommendation, there are 31 (13%) Grade A, 42 (17%) Grade B, 72 (29%) Grade C, and 101 (41%) Grade D recommendations. There are 858 citations, of which 81 (9.4%) are evidence level (EL) 1 (highest), 562 (65.5%) are EL 2, 72 (8.4%) are EL 3, and 143 (16.7%) are EL 4 (lowest). Conclusion: Bariatric procedures remain a safe and effective intervention for higher-risk patients with obesity. Clinical decision-making should be evidence based within the context of a chronic disease. A team approach to perioperative care is mandatory, with special attention to nutritional and metabolic issues. A1C = hemoglobin A1c; AACE = American Association of Clinical Endocrinologists; ABCD = adiposity-based chronic disease; ACE = American College of Endocrinology; ADA = American Diabetes Association; AHI = Apnea-Hypopnea Index; ASA = American Society of Anesthesiologists; ASMBS = American Society of Metabolic and Bariatric Surgery; BMI = body mass index; BPD = biliopancreatic diversion; BPD/DS = biliopancreatic diversion with duodenal switch; CI = confidence interval; CPAP = continuous positive airway pressure; CPG = clinical practice guideline; CRP = C-reactive protein; CT = computed tomography; CVD = cardiovascular disease; DBCD = dysglycemia-based chronic disease; DS = duodenal switch; DVT = deep venous thrombosis; DXA = dual-energy X-ray absorptiometry; EFA = essential fatty acid; EL = evidence level; EN = enteral nutrition; ERABS = enhanced recovery after bariatric surgery; FDA = U.S. Food and Drug Administration; G4G = Guidelines for Guidelines; GERD = gastroesophageal reflux disease; GI = gastrointestinal; HCP = health-care professional(s); HTN = hypertension; ICU = intensive care unit; IGB = intragastric balloon(s); IV = intravenous; LAGB = laparoscopic adjustable gastric band; LAGBP = laparoscopic adjustable gastric banded plication; LGP = laparoscopic greater curvature (gastric) plication; LRYGB = laparoscopic Roux-en-Y gastric bypass; LSG = laparoscopic sleeve gastrectomy; MetS = metabolic syndrome; NAFLD = nonalcoholic fatty liver disease; NASH = nonalcoholic steatohepatitis; NSAID = nonsteroidal anti-inflammatory drug; OA = osteoarthritis; OAGB = one-anastomosis gastric bypass; OMA = Obesity Medicine Association; OR = odds ratio; ORC = obesity-related complication(s); OSA = obstructive sleep apnea; PE = pulmonary embolism; PN = parenteral nutrition; PRM = pulmonary recruitment maneuver; RCT = randomized controlled trial; RD = registered dietician; RDA = recommended daily allowance; RYGB = Roux-en-Y gastric bypass; SG = sleeve gastrectomy; SIBO = small intestinal bacterial overgrowth; TOS = The Obesity Society; TSH = thyroid-stimulating hormone; T1D = type 1 diabetes; T2D = type 2 diabetes; VTE = venous thromboembolism; WE = Wernicke encephalopathy; WHO = World Health Organization.


Cytotoxicity of Ro-07-0582; enhancement by hyperthermia and protection by cysteamine.
The selective cytotoxicity which Ro-07-0582 exhibits towards hypoxic cells is strongly temperature-dependent. This cytotoxicity is reduced by the radical scavenger cysteamine, suggesting that nitro radicals or nitroso intermediates are involved in cell killing by the drug. Chromosome aberrations are not induced by Ro-07-0582 even when the surviving fraction is reduced to 0-01.


A new strategy for primary structure determination of proteins: application to bovine beta-casein.
A new approach has been developed for sequencing proteins. A radioactive label is attached specifically to the C-terminus of the protein. The labelled molecule is subjected to varying proteolysis conditions. From the electrophoretic patterns (SDS-PAGE) of the hydrolysates, appropriate cleavage conditions are selected, giving labelled peptides of different lengths which are purified. The labelled peptides are sequenced in order of increasing size (from 1 to n), peptide (i) being sequenced until the N-terminal sequence of peptide (i-1) is encountered. This approach allows the determination of a complete protein sequence with a minimal number of Edman cycles. The method was successfully applied to bovine beta-casein (209 residues) which was completely resequenced with only 239 Edman cycles.


Induction of spermatogenesis and spermiation by a single injection of human chorionic gonadotropin in intact and hypophysectomized immature European eel (Anguilla anguilla L.).
Intact and hypophysectomized male silver eels (Anguilla anguilla) in fresh water received a single injection of human chorionic gonadotropin (hCG) (250 C) or solvent (0.15 M NaCl). No effect of solvent was observed. Spermatogonia proliferated in testis of hCG-treated intact or hypophysectomized eels. One month after the injection, primary and secondary spermatocytes were found. After 3 months, numerous spermatozoa were present. In hypophysectomized eels, hCG was also effective even though maturing germ cells were less numerous and spermiation was less frequent than in intact animals. Within 1 week after hCG injection, plasma levels of free and glucuroconjugated androgens (testosterone and 11-oxotestosterone) rose significantly in intact and hypophysectomized fish. The highest values were observed within 1 month, and then plasma levels decreased to pretreatment values. The most important changes were observed in the case of free 11-oxotestosterone. The long-term effects of hCG can be explained partly by the long half-life of this hormone. The effects of hypophysectomy on the response of testis to hCG caused us to think that some endogenous pituitary secretions must interfere in the intact fish so that maximal effects of hCG, especially on the induction of spermiation, are obtained.


The effect of gradient sampling schemes on diffusion metrics derived from probabilistic analysis and tract-based spatial statistics.
The purpose was to systematically evaluate the effect of diffusion gradient encoding scheme on estimated fractional anisotropy (FA), mean diffusivity (MD) and the voxel-wise probability of identifying crossing fibers in the brain. Eight healthy volunteers (mean age 26.5±1.3 years, 5 males, 3 females) were imaged using a Spin-Echo Echo-Planar-Imaging sequence acquired with two signal averages [number of signals averaged (NSA)], 127 diffusion directions, and b-values of 750 s/mm(2) and 1500 s/mm(2). The number of diffusion gradient directions (N(d)) was reduced from the original value whilst maintaining a homogeneous gradient distribution enabling direct comparison of subsampled data sets with N(d)=15, 28, 43, 84, 112 and 127. FA and MD maps were generated and analyzed using tract-based spatial statistics. Effect of N(d) on estimated FA and MD was tested with voxel-wise statistics in 13 regions of interest. The number of voxels supporting two fiber populations (NV(2)) at different N(d) values was estimated using Bayesian estimation of diffusion parameters. Low FA values decreased significantly with increasing N(d) and with increasing NSA. MD was only marginally sensitive to N(d) and NSA. NV(2) increased significantly with N(d) but not with NSA. Thus, we conclude that accurate estimation of standard diffusion metrics FA and MD is mainly dependent on the signal-to-noise ratio (SNR), whereas the ability to differentiate multiple fiber populations requires a high diffusion sampling density.


Perfect control for nonminimum-phase unstable systems defined in the multivariable continuous-time state-space framework - An inverse-based approach.
In this paper, a new perfect control law dedicated to nonminimum-phase unstable LTI MIMO systems governed in the continuous-time state-space domain is proposed. Two algorithms are investigated, one of which has turned out to be definitely accurate. Henceforth, the inverse model control-based formula can be applied to any right-invertible plants having more input than output variables. Last, not least, through the application of some generalized inverses, the perfect control procedure guarantees the structural stability behavior even for unstable systems. Thus, the notion of the nonminimum-phase property should be understood in terms of a possible achieveability covering the entire class of LTI MIMO continuous-time plants. Theoretical and practical simulation examples performed in the Matlab/Simulink environment confirm the feasibility of the newly introduced approach.


Paracrine factors of vascular endothelial cells facilitate cardiomyocyte differentiation of mouse embryonic stem cells.
For myocardial regeneration therapy, the low differentiation capability of functional cardiomyocytes sufficient to replace the damaged myocardial tissue is one of the major difficulties. Using Nkx2.5-GFP knock-in ES cells, we show a new efficient method to obtain cardiomyocytes from embryonic stem (ES) cells. The proportion of GFP-positive cells was significantly increased when ES cells were cultured with a conditioned medium from aortic endothelial cells (ECs), accompanied by upregulation of cardiac-specific genes as well as other mesodermal genes. The promotion was more prominent when EC-conditioned medium was added at an early stage of ES cell differentiation culture (Day 0-3). Inhibitors of bone morphogenic protein (BMP), cyclooxygenase (COX), and nitric oxide synthetase (NO) prevented the promotion of cardiomyogenesis by EC-conditioned medium. These results suggest that supplementation of EC-conditioned medium enables cardiomyocytes to be obtained efficiently through promotion of mesoderm induction, which is regulated by BMP, COX, and NOS.


Nickel and copper accumplation as essential elements in 10-A manganite of deep-sea manganese nodules.
MANY ferromanganese minerals have been found in marine manganese deposits. There have been terminological and intrinsic problems in accurately defining the constituents of manganese nodules(1), but 10-A manganite and delta-MnO(2) which are often compared with todorokite and birnessite seem to be the only major constituents of marine manganese nodules and crusts. [Note that birnessite is a natural species of delta-MnO(2) of four-line form, whereas marine delta-MnO(2) is two-line form, so marine and terrestrial delta-MnO(2) should not be compared directly with each other.] However, there have been few experimental studies of the mechanism of accumulation and the crystallochemistry of these elements in 10-A manganite of manganese nodules, although many experimental studies of adsorption of metals to natural and synthetic manganese and iron oxides have been made(7,8). I have now investigated the mechanism of accumulation of nickel and copper in manganese nodules by synthesising 10-A manganite and comparing the composition with that shown by microscopic and electron microprobe analyses of marine 10-A manganite.


Development and Validation of Decision Rules Models to Stratify Coronary Artery Disease, Diabetes, and Hypertension Risk in Preventive Care: Cohort Study of Returning UK Biobank Participants.
Many predictive models exist that predict risk of common cardiometabolic conditions. However, a vast majority of these models do not include genetic risk scores and do not distinguish between clinical risk requiring medical or pharmacological interventions and pre-clinical risk, where lifestyle interventions could be first-choice therapy. In this study, we developed, validated, and compared the performance of three decision rule algorithms including biomarkers, physical measurements, and genetic risk scores for incident coronary artery disease (CAD), diabetes (T2D), and hypertension against commonly used clinical risk scores in 60,782 UK Biobank participants. The rules models were tested for an association with incident CAD, T2D, and hypertension, and hazard ratios (with 95% confidence interval) were calculated from survival models. Model performance was assessed using the area under the receiver operating characteristic curve (AUROC), and Net Reclassification Index (NRI). The higher risk group in the decision rules model had a 40-, 40.9-, and 21.6-fold increased risk of CAD, T2D, and hypertension, respectively (p < 0.001 for all). Risk increased significantly between the three strata for all three conditions (p < 0.05). Based on genetic risk alone, we identified not only a high-risk group, but also a group at elevated risk for all health conditions. These decision rule models comprising blood biomarkers, physical measurements, and polygenic risk scores moderately improve commonly used clinical risk scores at identifying individuals likely to benefit from lifestyle intervention for three of the most common lifestyle-related chronic health conditions. Their utility as part of digital data or digital therapeutics platforms to support the implementation of lifestyle interventions in preventive and primary care should be further validated.


Net atrioventricular compliance can predict persistent pulmonary artery hypertension after percutaneous mitral balloon commissurotomy.
Pulmonary hypertension is a common complication of rheumatic mitral stenosis (MS). Patients with similar mitral valve (MV) areas may have different pulmonary artery pressures. Net atrioventricular compliance (Cn) was found to play an important role in the development of pulmonary hypertension. To test the value of Cn in predicting persistent pulmonary artery hypertension (PPAH) after percutaneous mitral balloon commissurotomy (PMBC). Eighty patients with severe MS, suitable for PMBC were included in the study. We excluded patients with contraindication to PMBC, atrial fibrillation, failure of PMBC, and restenosis. All patients had undergone electrocardiography, echocardiography with measurement of MV area, systolic pulmonary artery pressure (SPAP), and Cn, PMBC, and follow-up echocardiography. Patients were divided into two groups: Group I: Cn < 4.2 mL/mmHg (36 patients), Group II: Cn ≥ 4.2 mL/mmHg (44 patients). Group I patients had significantly higher SPAP, and significantly lower SPAP reduction. Sensitivity of Cn < 4.2 mL/mmHg in prediction of PPAH was 88.9%, specificity was 88.6%, and accuracy was 88.8%. Independent predictors for PPAH were baseline Cn (p = 0.0027), and Cn improvement after PMBC (p = 0.0085). There was a significant negative correlation between Cn and baseline SPAP (r = -0.349, p = 0.0015), and a significant positive correlation between Cn and percent SPAP reduction (r = 0.617, p < 0.00001). Measuring Cn can predict PPAH in MS patients after PMBC. It also may add value in evaluating MS patients undergoing PMBC and may help in predicting their prognosis.


Combining BN-PAGE and microscopy techniques to investigate pigment-protein complexes and plastid transitions in citrus fruit.
Chlorophyll and carotenoids, the most widely distributed lipophilic pigments in plants, contribute to fruit coloration during development and ripening. These pigments are assembled with pigment-protein complexes localized at plastid membrane. Pigment-protein complexes are essential for multiple cellular processes, however, their identity and composition in fruit have yet to be characterized. By using BN-PAGE technique in combination with microscopy, we studied pigment-protein complexes and plastid transformation in the purified plastids from the exocarp of citrus fruit. The discontinuous sucrose gradient centrifugation was used to isolate total plastids from kumquat fruit, and the purity of isolated plastids was assessed by microscopy observation and western blot analysis. The isolated plastids at different coloring stages were subjected to pigment autofluorescence observation, western blot, two-dimensional electrophoresis analysis and BN-PAGE assessment. Our results demonstrated that (i) chloroplasts differentiate into chromoplasts during fruit coloring, and this differentiation is accompanied with a decrease in the chlorophyll/carotenoid ratio; (ii) BN-PAGE analysis reveals the profiles of macromolecular protein complexes among different types of plastids in citrus fruit; and (iii) the degradation rate of chlorophyll-protein complexes varies during the transition from chloroplasts to chromoplasts, with the stability generally following the order of LHCII > PS II core > LHC I > PS I core. Our optimized methods for both plastid separation and BN-PAGE assessment provide an opportunity for developing a better understanding of pigment-protein complexes and plastid transitions in plant fruit. These attempts also have the potential for expanding our knowledge on the sub-cellular level synchronism of protein changes and pigment metabolism during the transition from chloroplasts to chromoplasts.


Non-Tuberculous Mycobacteria Interference with BCG-Current Controversies and Future Directions.
The global tuberculosis (TB) epidemic caused by the bacterial pathogen Mycobacterium tuberculosis (M.tb) continues unabated. The Mycobacterium bovis bacillus Calmette-Guérin (BCG) vaccination is widely utilized worldwide to protect against infection with M.tb. BCG vaccine protection against TB has had widely varying results for reasons that are not well understood. BCG vaccine interference by non-tuberculosis (NTM) mycobacterial species has been implicated as the potential cause of reduced BCG vaccine efficacy against M.tb. Ongoing efforts to develop new vaccines for TB requires a thorough understanding of the effect of NTM exposure on BCG vaccine efficacy, which may ultimately be a critical determinant of success. We reviewed the conflicting reports on whether NTM interferes with the BCG vaccine, potential explanations to help resolve the controversy, and strategies for developing better animal models. Further studies are needed to longitudinally track the effects of NTM exposure on BCG vaccine-induced host-protective anti-TB immunity.


Accuracy of intraoperative transesophageal echocardiography for estimating the severity of functional mitral regurgitation.
Although intraoperative transesophageal echocardiography (TEE) is used to guide mitral valve reconstructive procedures, the effects of hemodynamic alterations accompanying general anesthesia on mitral regurgitation (MR) are unknown. This study was performed to evaluate the effect of general anesthesia on MR jet size using TEE with color Doppler imaging in patients undergoing mitral valve surgery. Matched preoperative TEEs performed with the patient under intravenous conscious sedation, and intraoperative studies performed with the patient under general anesthesia were retrospectively reviewed in 46 patients undergoing mitral valve surgery. Patients were divided into groups based on etiology of MR, including 21 patients with myxomatous degeneration and leaflet flail, 19 patients with structurally normal leaflets and functional regurgitation due to abnormal leaflet coaptation, and 6 patients with rheumatic mitral disease. On both preoperative and intraoperative studies, regurgitation was quantified using maximal jet area and jet diameter at the vena contracta on color flow Doppler. Patients with leaflet flail and patients with functional MR had similar measures of regurgitation severity on preoperative imaging. On intraoperative imaging, regurgitant jet size was unchanged compared with preoperative studies among patients with leaflet flail (jet diameter 1.04 +/- 0.26 vs 1.10 +/- 0.28 cm, area 9.8 +/- 4.5 vs 10.1 +/- 5.2 cm2 on preoperative studies), although jet size decreased significantly in patients with functional MR (jet diameter 0.79 +/- 0.33 vs 1.10 +/- 0.29 cm [p < 0.001], area 5.7 +/- 3.5 vs 10.0 +/- 3.8 cm2 [p < 0.001] on preoperative studies). These findings were not accounted for by variation in heart rate, blood pressures, echocardiographic instrumentation, or Doppler Nyquist limit.(ABSTRACT TRUNCATED AT 250 WORDS)


MR molecular imaging and fluorescence microscopy for identification of activated tumor endothelium using a bimodal lipidic nanoparticle.
In oncological research, there is a great need for imaging techniques that specifically identify angiogenic blood vessels in tumors on the basis of differences in the expression level of biomolecular markers. In the angiogenic cascade, different cell surface receptors, including the alphavbeta3-integrin, are strongly expressed on activated endothelial cells. In the present study, we aimed to image angiogenesis by detecting the expression of alphavbeta3 in tumor bearing mice with a combination of magnetic resonance imaging (MRI) and fluorescence microscopy. To that end, we prepared MR-detectable and fluorescent liposomes, which carry approximately 700 alphavbeta3-specific RGD peptides per liposome. RGD competition experiments and RAD-conjugated liposomes were used as controls for specificity. In vivo, both RAD liposomes and RGD liposomes gave rise to signal increase on T1-weighted MR images. It was established by the use of ex vivo fluorescence microscopy that RGD liposomes and RAD liposomes accumulated in the tumor by different mechanisms. RGD liposomes were specifically associated with activated tumor endothelium, while RAD liposomes were located in the extravascular compartment. This study demonstrates that MR molecular imaging of angiogenesis is feasible by using a targeted contrast agent specific for the alphavbeta3-integrin, and that the multimodality imaging approach gave insight into the exact mechanism of accumulation in the tumor.


Surgical Patients' Hospital Experience Scores: Neighborhood Context Conceptual Framework.
Through geocoding the physical residential address included in the electronic medical record to the census tract level, we present a novel model for concomitant examination of individual patient-related and residential context-related factors that are associated with patient-reported experience scores. When assessing patient experience in the surgical setting, researchers need to examine the potential influence of neighborhood-level characteristics on patient experience-of-care ratings. We geocoded the residential address included in the electronic medical record (EMR) from a tertiary care facility to the census tract level of Orange County, CA. We then linked each individual record to the matching census tract and use hierarchical regression analyses to test the impact of distinct neighborhood conditions on patient experience. This approach allows us to estimate how each neighborhood characteristic uniquely influences Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) scores. Individuals residing in communities characterized by high levels of socioeconomic disadvantage have the highest experience ratings. Accounting for individual patient's characteristics such as age, gender, race/ethnicity, primary language spoken at home, length of stay, and average pain levels during their hospital stay, neighborhood-level characteristics such as proportions of people receiving public assistance influence the ratings of hospital experience (0.01, P < 0.05) independent of, and beyond, these individual-level factors. This manuscript is an example of how geocoding could be used to analyze surgical patient experience scores. In this analysis, we have shown that neighborhood-level characteristics influence the ratings of hospital experience independent of, and beyond, individual-level factors.


Smoking relapse one year after delivery among women who quit smoking during pregnancy.
The aim of the randomized trial was to evaluate the risk of smoking relapse one year after delivery among the women who quit smoking during pregnancy. The study was carried out in 2002 and 2003 and included the collection of data on smoking relapse within one year after delivery among 175 women who participated in the randomized smoking cessation trial and quit smoking during pregnancy. About 50% of women who quit smoking during pregnancy relapsed into that habit within 12 months postpartum. The analysis of women who quit smoking before 14 weeks of pregnancy revealed a significantly higher risk of smoking relapse after delivery for women with the higher level of smoking addiction indicated by the Fagerström test (OR = 5.0; 95% CI: 1.5-16.2). Compared to the control group, spontaneous quitters who participated in intervention activities during pregnancy showed lower risk of smoking relapse within one year after giving birth (OR = 0.3; 95% CI: 0.1-0.9). In the group of women who quit smoking after 14 weeks of gestation, the risk of smoking relapse postpartum was significantly higher for those with the higher Fagerström test score (OR = 4.8; 95% CI: 1.6-14.1). The risk of smoking relapse 12 months after delivery was lower for spontaneous quitters who participated in the intervention during pregnancy and for women who quit smoking after participation in the intervention activities than for controls (OR = 0.03; 95% CI: 0.01-0.2, OR = 0.1; 95% CI: 0.03-0.6). Women who had higher score in the Fagerström test before quitting smoking had significantly higher risk of smoking relapse within 12 months after delivery. Anti-smoking intervention during pregnancy helps women to maintain smoking abstinence after delivery.


Late onset mania as an organic syndrome: A review of case reports in the literature.
Although First Episode Mania presenting over the age of 50 is reported in several cases, there has been little systematic compilation of these case reports. We report a review of case reports on these subjects. We undertook a literature search on MEDLINE, PsychInfo and EMBASE to identify case reports of first episode of mania or hypomania presenting over the age of 50. 35 cases were identified. 29/35 (82%) had a suspected underlying organic cause. Organic causes included vascular causes, iatrogenic drug use, electrolyte imbalance, dementia and thyroid disease. Vascular risk factors were present in 17/35 cases (48%). In 10/35 (28%) of cases organic treatment contributed to successful remission of the manic episode. As evidently not all cases have been reported the main limitation is that of publication bias for this paper. Any such hypothesis generated from studying these cases would require replication in prospective longitudinal trials of this cohort of patients. This review of case reports appears to add to evidence of late onset mania having an organic basis. Whether this is a separate organic syndrome remains to be established. Our provisional findings suggest that such patients should have a thorough medical and psychiatric screening in identifying an underlying cause.


Extracellular vesicle proteomic analysis leads to the discovery of HDGF as a new factor in multiple myeloma biology.
Identifying factors secreted by multiple myeloma (MM) cells that may contribute to MM tumor biology and progression is of the utmost importance. In this study, hepatoma-derived growth factor (HDGF) was identified as a protein present in extracellular vesicles (EVs) released from human MM cell lines (HMCLs). Investigation of the role of HDGF in MM cell biology revealed lower proliferation of HMCLs following HDGF knockdown and AKT phosphorylation following the addition of exogenous HDGF. Metabolic analysis demonstrated that HDGF enhances the already high glycolytic levels of HMCLs and significantly lowers mitochondrial respiration, indicating that HDGF may play a role in myeloma cell survival and/or act in a paracrine manner on cells in the bone marrow (BM) tumor microenvironment (ME). Indeed, HDGF polarizes macrophages to an M1-like phenotype and phenotypically alters naïve CD14+ monocytes to resemble myeloid-derived suppressor cells which are functionally suppressive. In summary, HDGF is a novel factor in MM biology and may function to both maintain MM cell viability as well as modify the tumor ME.


Prediction of seizure onset in an in-vitro hippocampal slice model of epilepsy using Gaussian-based and wavelet-based artificial neural networks.
We propose that artificial neural networks (ANNs) can be used to predict seizure onsets in an in-vitro hippocampal slice model capable of generating spontaneous seizure-like events (SLEs) in their extracellular field recordings. This paper assesses the effectiveness of two ANN prediction schemes: Gaussian-based artificial neural network (GANN) and wavelet-based artificial neural network (WANN). The GANN prediction system consists of a recurrent network having Gaussian radial basis function (RBF) nonlinearities capable of extracting the estimated manifold of the system. It is able to classify the underlying dynamics of spontaneous in-vitro activities into interictal, preictal and ictal modes. It is also able to successfully predict the onsets of SLEs as early as 60 s before. Improvements can be made to the overall seizure predictor design by incorporating time-varying frequency information. Consequently, the idea of WANN is considered. The WANN design entails the assumption that frequency variations in the extracellular field recordings can be used to compute the times at which onsets of SLEs are most likely to occur in the future. Progressions of different frequency components can be captured by the ANN using appropriate frequency band adjustments via pruning, after the initial wavelet transforms. In the off-line processing comprised of 102 spontaneous SLEs generated from 14 in-vitro rat hippocampal slices, with half of them used for training and the other half for testing, the WANN is able to predict the forecoming ictal onsets as early as 2 min prior to SLEs with over 75% accuracy within a 30 s precision window.


The impact of COVID-19 on multi-month dispensing (MMD) policies for antiretroviral therapy (ART) and MMD uptake in 21 PEPFAR-supported countries: a multi-country analysis.
Increasing access to multi-month dispensing (MMD) of antiretroviral therapy (ART) supports treatment continuity and viral load suppression for people living with HIV (PLHIV) and reduces burden on health facilities. During the COVID-19 response, PEPFAR worked with ministries of health to scale up MMD and expand eligibility to new groups of PLHIV, including children and pregnant/breastfeeding women. We analysed PEPFAR program data to understand the impact of the policy changes on actual practice. We conducted a desk review in 21 PEPFAR-supported countries to identify and collect official documentation released between March and June 2020 addressing changes to MMD guidance during the COVID-19 response. MMD coverage, the proportion of all ART clients on MMD, was assessed in the calendar quarters preceding the COVID-19 response (Q4 2019, October-December 2019; and Q1, January-March 2020) and the quarters following the start of the response (Q2 2020, April-June 2020; Q3 2020, July-September, 2020; Q4 2020, October-December 2020). We used the two-proportion Z-test to test for differences in MMD coverage pre-COVID-19 (Q4 2019) and during implementation of COVID-19 policy adaptations (Q2 2020). As of June 2020, 16 of the 21 PEPFAR-supported countries analysed adapted MMD policy or promoted intensified scale-up of MMD in response to COVID-19. MMD coverage for all clients on ART grew from 49% in Q4 2019 pre-COVID-19 to 72% in Q2 2020 during COVID-19; among paediatric clients (< 15), MMD coverage increased from 27% to 51% in the same period. Adaptations to MMD policy were associated with a significantly accelerated growth in the proportion of clients on MMD (p < 0.001) for all populations, irrespective of age and dispensing interval. Access to MMD markedly expanded during the COVID-19 pandemic, supporting treatment continuity while mitigating exposure to COVID-19 at health facilities. This model is beneficial in public health emergencies and during disruptions to the healthcare system. Outside emergency contexts, expanded MMD eligibility extends client-centred care to previously excluded populations. The success in expanding MMD access during COVID-19 should motivate countries to recommend broader MMD access as a new standard of care.


NF-κB RNAi decreases the Bax/Bcl-2 ratio and inhibits TNF-α-induced apoptosis in human alveolar epithelial cells.
Apoptosis of alveolar epithelial cells (AECs) plays a key role in acute lung injury (ALI). Understanding the underlying mechanism is conducive to the treatment of ALI. The goal of this study was to determine the possible involvement of nuclear factor-κB (NF-κB)/p65 and Bax/Bcl-2 in tumor necrosis factor-α (TNF-α)-induced apoptosis in AECs. Type II AECs, A549, with or without NF-κB/p65 expression silenced by small interfering RNA (siRNA) were challenged with TNF-α. The levels of NF-κB/p65, Bcl-2 and Bax were detected by reverse transcription-polymerase chain reaction, Western blotting, and immunocytochemical staining. The apoptosis rate was measured by flow cytometry. TNF-α challenge significantly increased the transcription and translation of NF-κB/p65 and Bax genes, but significantly decreased the Bcl-2 gene level. siRNA silencing of NF-κB/p65 reversed the effect of TNF-α on NF-κB/p65, Bcl-2 and Bax, and significantly decreased the TNF-α-induced apoptosis rate of AECs, as compared to the non-silenced cells. This study indicates that NF-κB plays an important role in the process of TNF-α-induced apoptosis in AECs, via regulation of the expression of Bcl-2 and Bax.


Real-world comparative effectiveness of acalabrutinib and ibrutinib in patients with chronic lymphocytic leukemia.
Novel agents, including Bruton tyrosine kinase inhibitors (BTKis), have become the standard of care for patients with chronic lymphocytic leukemia (CLL). We conducted a real-world retrospective analysis of patients with CLL treated with acalabrutinib vs ibrutinib using the Flatiron Health database. Patients with CLL were included if they initiated acalabrutinib or ibrutinib between 1 January 2018 and 28 February 2021. The primary outcome of interest was time to treatment discontinuation (TTD). Kaplan-Meier analysis was used to estimate unweighted and weighted median TTD. A weighted Cox proportional hazards model was used to compare the TTD between cohorts. Of the 2509 patients included in the analysis, 89.6% received ibrutinib, and 14.1% received acalabrutinib. TTD was not significantly different between cohorts in the unweighted analysis. After weighting, the cohorts were balanced on all baseline characteristics except cardiovascular risk factors and baseline medications use. The median (95% confidence interval [CI]) TTD was not reached (NR; 95% CI, 25.1 to NR) for the acalabrutinib cohort and was 23.4 months (95% CI, 18.1-28.7) for the ibrutinib cohort. The discontinuation rate at 12 months was 22% for the weighted acalabrutinib cohort vs 31% for the weighted ibrutinib cohort (P = .005). After additional adjustment for prior BTKi use, the acalabrutinib cohort had a 41% lower risk of discontinuation vs ibrutinib (hazard ratio, 0.59; 95% CI, 0.43-0.81; P = .001). In the largest available study comparing BTKis, patients with CLL receiving acalabrutinib demonstrated lower rates of discontinuation and a prolonged time to discontinuation vs those receiving ibrutinib.


Hyperammonemia increases sensitivity to LPS.
Metabolic and cognitive alterations occur during hyperammonemia. Here, we report that chronic hyperammonemia also leads to increased sensitivity to LPS. Sparse-fur mice were challenged i.p. with LPS or saline control and then tested for motivation to investigate a novel juvenile over 24 h. Cytokine, ammonia, and urea concentration were quantified at the peak of sickness (2 h post injection). Chronic hyperammonemic Otc(spf-ash) mice displayed more pronounced and prolonged sickness behavior in response to LPS (P=0.02). LPS significantly (P<0.0001) increased plasma concentrations of TNFalpha, IL-1 beta, IL-6, IL-15, IL-9, IL-2, IL-1 alpha, IL-1 beta, Rantes, MIP1 alpha, MIP1 beta, MCP-1, KC, GM-CSF, G-CSF, Eotaxin, IL-13, and IL-12 in both wild type and Otc(spf-ash) mice. No significant genotype/treatment interactions (P>0.1) were detected for any cytokine. Adult Otc(spf-ash) mice (168+/-41 microM) had four times higher plasma ammonia compared to wild type mice (40 +/- 6 microM) (P=0.002). Two hours after LPS injection, plasma ammonia concentrations tended (P=0.08) to decrease in both wild type and Otc(spf-ash) mice. Learning and memory behaviors were assessed in mice under basal conditions to determine the impact of chronic hyperammonemia on cognition. Otc(spf-ash) mice performed significantly poorer in the two trial Y-maze (P=0.02) and the Morris water maze (P=0.001) than their littermate wild type controls. Taken together, these data indicate that chronic hyperammonemia results in impaired cognition and creates a state of LPS hypersensitivity.


An analysis of the mammalian ventricular action potential.
A Hodgkin-Huxley model for ventricular excitation is abstracted from electrophysiological data. A singular perturbation analysis of the 8-dimensional phase portrait of the model characterizes the role of calcium during the plateau phase of the ventricular action potential and demonstrates how the calcium refractory period prevents tetanization.


Appropriate length and position of the central venous catheter insertion via right internal jugular vein in children.
Observational study. Tertiary University Hospital. Patients, aged 6 days to 19 years, who underwent contrast enhancement computerized tomography imaging of the thorax (CT-thorax). We measured three lengths consisting of length A in axial plane at the level of the lower border of the 6th C-spine from the skin to RIJV at its mid lumen, length B and C in sagittal plane from the RIJV at the level of the lower of the 6th C-spine to the superior vena cava (SVC) at carina and from carina to SVC-right atrium junction, respectively. Lengths A plus B represented the length of CVC where the tip was expected in the SVC at carina (CVC(carina)). Lengths A plus B and C represented the length of CVC when the tip was expected in the SVC at SVC-right atrium junction (CVC(SVC-RA)). One hundred and sixty-five cases with mean age of 8.1 ± 4.7 years were reviewed. The CVC(SVC-RA) and CVC carina were significantly correlated with age and body surface area (BSA). Using multiple regression analysis, CVC(SVC-RA) (cm) was equal to 6.4 + 2.8[BSA (m2)] + 0.022[age (month)] and CVC(casina) (cm) equal to 4.9 +2.7[BSA (m2)] +0.013[age (month)] (Adjusted R-squared 0.7275, 0.7140). We recommended the appropriate CVC length via RIJV approach should be between these two calculated lengths and the CVC length in each age according to the BSA.


Transcriptome analysis of the almond moth, Cadra cautella, female abdominal tissues and identification of reproduction control genes.
The almond moth, Cadra cautella is a destructive pest of stored food commodities including dates that causes severe economic losses for the farming community worldwide. To date, no genetic information related to the molecular mechanism/strategies of its reproduction is available. Thus, transcriptome analysis of C. cautella female abdominal tissues was performed via next-generation sequencing (NGS) to recognize the genes responsible for reproduction. The NGS was performed with an Illumina Hiseq 2000 sequencer (Beijing Genomics Institute: BGI). From the transcriptome data, 9,804,804,120 nucleotides were generated and their assemblage resulted in 62,687 unigenes. The functional annotation analyses done by different databases, annotated, 27,836 unigenes in total. The transcriptome data of C. cautella female abdominal tissue was submitted to the National Center for Biotechnology Information (accession no: PRJNA484692). The transcriptome analysis yielded several genes responsible for C. cautella reproduction including six Vg gene transcripts. Among the six Vg gene transcripts, only one was highly expressed with 3234.95 FPKM value (fragments per kilobase per million mapped reads) that was much higher than that of the other five transcripts. Higher differences in the expression level of the six Vg transcripts were confirmed by running the RT-PCR using gene specific primers, where the expression was observed only in one transcript it was named as the CcVg. This is the first study to explore C. cautella reproduction control genes and it might be supportive to explore the reproduction mechanism in this pest at the molecular level. The NGS based transcriptome pool is valuable to study the functional genomics and will support to design biotech-based management strategies for C. cautella.


Investigations of the in-vitro metabolism of three opioid tetrapeptides by pancreatic and intestinal enzymes.
The metabolism of three opioid tetrapeptides, Tyr-D-Arg-Phe-Nva-NH2, Tyr-D-Arg-Phe-Phe-NH2 and Tyr-D-Ala-Phe-Phe-NH2, was investigated in the presence of pure pancreatic enzymes (trypsin, chymotrypsin, elastase, carboxypeptidase A and carboxypeptidase B), as well as in the presence of pure carboxylesterase and aminopeptidase N. The cleavage patterns of the pure pancreatic enzymes were then compared with those found in rat and human jejunal fluid. Metabolism was also studied in homogenates from different intestinal regions (duodenum, jejunum, ileum and colon) and in enterocyte cytosol from rats. The effect of various protease inhibitors was investigated in the jejunal homogenate. The parent peptides were assayed by high-performance liquid chromatography and metabolites were identified by means of liquid chromatography-mass spectrometry. Of the pure enzymes, the quickest hydrolysis of the peptides was observed for the pancreatic enzymes chymotrypsin, trypsin and carboxypeptidase A. In most cases they formed the corresponding deamidated tetrapeptides (chymotrypsin and trypsin) or tripeptides with a missing C-terminal amino acid (carboxypeptidase A). Regional differences in intestinal metabolism rates were found for all three peptides (P < 0.001), with the highest rates observed in jejunal and/or colonic homogenates. The deamidated tetrapeptides were formed both in rat intestinal homogenates and in enterocyte cytosol. Metabolism in the jejunal homogenate was markedly inhibited by some serine and combined serine and cysteine protease inhibitors. In conclusion, the C-terminal amide of these tetrapeptides did not fully stabilise them against intestinal deamidase and carboxypeptidase activities. The significant hydrolysis of the peptides by pure chymotrypsin, trypsin and carboxypeptidase A showed that lumenal pancreatic proteases might be a clear metabolic obstacle in oral delivery even for small peptides such as these tetrapeptides.


The amniotic band disruption complex: timing of amniotic rupture and variable spectra of consequent defects.
Seventy-nine patients with the amniotic band disruption complex, including 54 infants with multiple system involvement and 25 with affected limbs alone, were evaluated. No two cases of the disorder were exactly alike. Defects varied from simple digital band constrictions to major craniofacial and visceral defects; fetal death may also occur. Amniotic rupture appeared to cause injury through three basic mechanisms: (1) interruption of normal morphogenesis; (2) crowing of fetal parts; and (3) disruption of previously differentiated structure. Comparison of 35 cases in which the timing of amniotic rupture could be estimated suggests that early amniotic rupture results in multiply affected infants who are frequently aborted or stillborn, whereas later rupture results primarily in limb involvement. Our findings indicate that both the spectrum of the developmental pathology and the nature of fetal outcome are determined by the timing of amniotic rupture. Appreciation of the mechanism which explains the disparate appearances of infants with the amniotic band disruption complex will allow more acurate diagnosis and appropriate counseling with respect to the sporadic nature of the disorder.


Examining the spatial distribution of flower thrips in southern highbush blueberries by utilizing geostatistical methods.
Flower thrips (Frankliniella spp.) are one of the key pests of southern highbush blueberries (Vaccinium corymbosum L. x V. darrowii Camp), a high-value crop in Florida. Thrips' feeding and oviposition injury to flowers can result in fruit scarring that renders the fruit unmarketable. Flower thrips often form areas of high population, termed "hot spots", in blueberry plantings. The objective of this study was to model thrips spatial distribution patterns with geostatistical techniques. Semivariogram models were used to determine optimum trap spacing and two commonly used interpolation methods, inverse distance weighting (IDW) and ordinary kriging (OK), were compared for their ability to model thrips spatial patterns. The experimental design consisted of a grid of 100 white sticky traps spaced at 15.24-m and 7.61-m intervals in 2008 and 2009, respectively. Thirty additional traps were placed randomly throughout the sampling area to collect information on distances shorter than the grid spacing. The semivariogram analysis indicated that, in most cases, spacing traps at least 28.8 m apart would result in spatially independent samples. Also, the 7.61-m grid spacing captured more of the thrips spatial variability than the 15.24-m grid spacing. IDW and OK produced maps with similar accuracy in both years, which indicates that thrips spatial distribution patterns, including "hot spots," can be modeled using either interpolation method. Future studies can use this information to determine if the formation of "hot spots" can be predicted using flower density, temperature, and other environmental factors. If so, this development would allow growers to spot treat the "hot spots" rather than their entire field.


ND: YAG nomogram dosimetry scale for the bladder.
Bowel perforation and damage to surrounding organs is probably the most significant risk with the use of Nd-YAG laser in the bladder. To prevent this unwanted damage, a nomogram dosimetry scale was developed by delivering different settings of laser energy via a cystoscope to 25 female pigs. One week following treatment, exploratory laparotomy and cystectomy were performed. Microscopic analysis of the depth of laser irradiation was accomplished. From this study it was learned that, although the greater the energy delivered, the deeper the tissue damage, this is not uniform. Pulsed energy produced a deeper effect than continuous energy. The use of 30 watts of either pulsed or continuous energy for no longer than 15 seconds (450 joules) or 10 watts of either form of energy for less than 30 seconds (300 joules) did not produce bowel perforation. Other different combinations of high number of watts or pulses translated into transmural necrosis of the bladder with or without perforation and with or without bowel injury. Other factors such as density, thickness, color and temperature of tissue, type and wave length of laser and optimal focusing played a significant role in the final outcome. Useful information for human clinical use may be extrapolated from this experimental model.


Tethered Aryl Groups Increase the Activity of Anti-Proliferative Thieno[2,3-b]Pyridines by Targeting a Lipophilic Region in the Active Site of PI-PLC.
The compounds 2-amino-3-carboxamido-thieno[2,3-b]pyridines have demonstrated excellent anti-proliferative activity against human cancer cell lines, including the triple-negative breast cancer cell line MDA-MB-231. In this study, 81 novel thieno[2,3-b]pyridines were synthesised in four series to further improve their anti-proliferative activity, in particular by targeting an adjacent lipophilic pocket in the putative target enzyme phosphoinositide phospholipase C (PI-PLC). Overall, it was found that appending a propyl-aryl group at C-5 on 2-amino-3-carboxamido-thieno[2,3-b]pyridine resulted in compounds with potent biological activity, exhibiting IC50 values in the nanomolar range. The propyl linker could be an α,β-unsaturated ketone or a saturated propyl ketone, but the highest activity was obtained when allylic alcohols were the tether between thieno[2,3-b]pyridine and the appended aryl group, with compound 21r having IC50 values lower than 50 nM. Compounds with one extra carbon in the tether (i.e., a four-atom chain) were found to be considerably less active. Molecular modelling revealed this propyl tether places the newly introduced aryl ring in an untargeted lipophilic pocket within the active site of the phosphoinositide phospholipase C (PI-PLC) enzyme.


Risk factors for academic difficulties in children with myelin oligodendrocyte glycoprotein antibody-associated acute demyelinating syndromes.
To describe cognitive abilities through the evaluation of academic difficulties in children with acute demyelinating syndromes (ADS) and myelin oligodendrocyte glycoprotein (MOG) antibodies. This was an observational, retrospective study of a French paediatric cohort that included children aged 18 years and younger. Clinical, biological, and imaging data were collected and academic outcome was measured. Seventy-six children were included in the study with a mean (SD) follow-up of 4 years 7 months (6y 4mo). Median age at disease onset was 9 years 1 months (interquartile range=4y 7mo-13y 11mo; 36 females, 40 males). Thirty-six children relapsed and 20 had academic difficulties at the last follow-up. Academic difficulties, as well as deep grey matter and putaminal lesions (p=0.047 and p=0.006 respectively), were significantly more prevalent in children aged 10 years and younger (p=0.02). Using univariate binary regression analysis, we found that age at disease onset of 10 years and younger (odds ratio [OR] 3.72 [95% confidence interval {CI} 1.19-11.64]; p=0.024), acute disseminated encephalomyelitis at disease onset (OR 52.5 [95% CI 5.97-461.4]; p<0.001), and deep grey matter lesions (OR 17.33 [95% CI 3.87-77.72]; p<0.001) were associated with academic difficulties. MOG antibody-associated ADS have distinct clinical and radiological patterns that are age-dependent. Indirect cognitive evaluation through academic difficulties was prevalent in younger children and is associated with specific clinical and magnetic resonance imaging factors that need to be considered earlier on when assessing this patient population.


Rituximab as treatment of posttransplant lymphoproliferative disorder in patients who underwent small bowel/multivisceral transplantation: report of three cases.
This report describes three cases of posttransplant lymphoproliferative disorder (PTLD) in multivisceral/small bowel transplant patients treated with rituximab (anti-CD20 monoclonal antibodies). In two cases (one of which was a B-cell lymphoma) a good response to therapy was achieved. A third case (with polymorphic PTLD with low CD20 expression) developed a refractory rejection and PTLD was still documented on graftectomy. Rituximab was well tolerated, and a reduction of Epstein-Barr virus (EBV) viral load was documented by quantitive competitive-EBV polymerase chain reaction. Efficacy of therapy needs to be assessed in controlled studies.


Multilocus sequence typing of strains from the Cryptococcus gattii species complex from different continents.
Cryptococcus neoformans and Cryptococcus gattii species complexes are pathogens causing cryptococcal meningitis, a fungal infection that leads to death unless treated. Worldwide, it is estimated to kill over 180,000 individuals annually. We aim to investigate the molecular diversity of C. gattii isolates from strains isolated from 1995 to the present day from different continents. In this study, we analysed the molecular diversity by MLST and antifungal susceptibility by using the broth microdilution method according to the CLSI M27-A4 protocol of a total of 26 strains from Cryptococcus gattii species complex from both clinical and environmental sources. Genotyping showed that most of the strains (17/26; 65.4%) belonged to serotype B and were distributed between three genotypes: VGI (13/17; 76.5%), VGII (3/17; 17.6%) and VGVI (1/17; 5.9%). The serotype C strains (9/26; 34.6%) were distributed between the VGIII (1/9; 11.1%) and VGIV (8/9; 88.9%) genotypes. The 26 strains belonged to 17 different MLST subtypes, and we highlight four new MLST genotypes (ST553, 554, 555 and 556). The two environmental strains were identified as serotype B and genotype VGI, but were of ST 51 and 154. All isolates have wild-type MIC of fluconazole and flucytosine. Regarding amphotericin B, five VGI strains showed MICs to AMB equal to 1 µg/ml, and according to the ECV for these genotypes, they were considered non-wild-type strains. The current study reveals the genetic diversity and new sequence types among strains from the C. gattii complex species.


Chitosan scaffolds containing silicon dioxide and zirconia nano particles for bone tissue engineering.
A scaffold harboring the desired features such as biodegradation, biocompatibility, porous structure could serve as template for bone tissue engineering. In the present study, chitosan (CS), nano-scaled silicon dioxide (Si) and zirconia (Zr) were combined by freeze drying technique to fabricate a bio-composite scaffold. The bio-composite scaffold (CS/Si/Zr) was characterized by SEM, XRD and FT-IR studies. The scaffold possessed a porous nature with pore dimensions suitable for cell infiltration and colonization. The presence of zirconia in the CS/Si/Zr scaffold decreased swelling and increased biodegradation, protein adsorption and bio-mineralization properties. The CS/Si/Zr scaffold was also found to be non-toxic to rat osteoprogenitor cells. Thus, we suggest that CS/Si/Zr bio-composite scaffold is a potential candidate to be used for bone tissue engineering.


The Safety and Efficacy of Narrow Band Ultraviolet B Treatment in Dermatology: A Review.
Narrow-band ultraviolet B (NBUVB) phototherapy is an important treatment modality in dermatology. The most common dermatological indications for NBUVB include psoriasis, atopic dermatitis and vitiligo; however, it has been found to be an effective and well-tolerated treatment option in various other dermatoses. The efficacy of NBUVB phototherapy compares favorably with other available photo(chemo)therapy options and its efficacy is further augmented by a number of topical and systemic adjuncts. The long-term safety of NBUVB phototherapy remains to be fully elucidated; however, available data now suggest that it is safe and well-tolerated. The objective of this review was to summarize the current understanding of the safety and efficacy of NBUVB phototherapy in dermatology.


Similar semiology of epileptic and psychogenic nonepileptic seizures recorded during stereo-EEG.
We report two adolescents with refractory seizure disorders in whom both epileptic and psychogenic nonepileptic seizures (PNES) were recorded with intracerebral EEG. The ictal phenomenology of epileptic seizures (ES) and PNES, consisting of hypermotor attacks in the first patient and left-sided painful episodes in the second patient, proved remarkably similar in both cases, highlighting the difficulties which can arise with the distinction of epileptic seizures and PNES based on ictal phenomenology alone.


When Patients Talk Politics: Opportunities for Recontextualizing Ministerial Theory and Practice.
Some chaplains and pastoral caregivers may regard political conversation in a care encounter as a distraction from spiritual work or a transgression of our professional role or ethical code. Yet politics is very often an expression of values that can shape a care recipient's self-image, impact spiritual and emotional well-being, and humanize or dehumanize others. Recontextualizing political references in a care recipient's personal and social history can reveal grief beneath grievance, trauma in need of healing, and sources of meaning and strength; hence, it is possible to integrate a care recipient's politics into a spiritual assessment and plan of care. It is all the more important that we do so conscientiously at a time when care professionals are taking seriously, and sometimes wrestling with, the ethical demand for anti-racist witness and its relationship to our commitment to "meet patients where they are." In order to provide ethical and effective interventions, we must first consider our own social location insofar as it impacts relationships and use of self. This article provides a framework for doing so as well as several suggestions for clinical practice.


Effect of maternal nutritional status and infant supplementation during lactation on postpartum amenorrhea.
This paper explores the effects of maternal nutritional status and food supplementation ingested by the infant on the duration of postpartum amenorrhea. A significant negative association was found between the nutritional status of the mother during the third trimester of pregnancy and the length of postpartum amenorrhea. A negative association was also found between infant supplementation and duration of postpartum amenorrhea. Each of these associations remained significant after controlling for the other, suggesting that both factors independently affect the length of postpartum amenorrhea.


Virtual reality-based treatment for regaining upper extremity function induces cortex grey matter changes in persons with acquired brain injury.
Individuals with acquired brain injuries (ABI) are in need of neurorehabilitation and neurorepair. Virtual anatomical interactivity (VAI) presents a digital game-like format in which ABI survivors with upper limb paresis use an unaffected limb to control a standard input device and a commonplace computer mouse to control virtual limb movements and tasks in a virtual world. In a prospective cohort study, 35 ambulatory survivors of ABI (25/71% stroke, 10/29% traumatic brain injury) were enrolled. The subjects were divided into three groups: group A received VAI therapy only, group B received VAI and physical/occupational therapy (P/OT), and group C received P/OT only. Motor skills were evaluated by muscle strength (hand key pinch strength, grasp, and three-jaw chuck pinch) and active range of motion (AROM) of the shoulder, elbow, and wrist. Changes were analyzed by ANOVA, ANCOVA, and one-tailed Pearson correlation analysis. MRI data was acquired for group A, and volumetric changes in grey matter were analyzed using voxel-based morphometry (VBM) and correlated with quantified motor skills. AROM of the shoulder, elbow, and wrist improved in all three groups. VBM revealed grey matter increases in five brain areas: the tail of the hippocampus, the left caudate, the rostral cingulate zone, the depth of the central sulcus, and the visual cortex. A positive correlation between the grey matter volumes in three cortical regions (motor and premotor and supplementary motor areas) and motor test results (power and AROM) was detected. Our findings suggest that the VAI rehabilitation program significantly improved motor function and skills in the affected upper extremities of subjects with acquired brain injuries. Significant increases in grey matter volume in the motor and premotor regions of affected hemisphere and correlations of motor skills and volume in nonaffected brain regions were present, suggesting marked changes in structural brain plasticity. The trial "Limitations of motor brain activity - use of virtual reality for simulation of therapeutic interventions" has been registered under reference number ISRCTN11757651 .


D-cycloserine enhancement of fear extinction is specific to successful exposure sessions: evidence from the treatment of height phobia.
Whereas some studies have shown clear evidence for an augmentation effect of D-cycloserine (DCS) on exposure therapy for anxiety disorders, other studies have shown weak effects or no effect at all. Some preclinical data suggest that the DCS augmentation effect is moderated by the success of extinction learning. Therefore, we conducted a reanalysis of existing data to examine whether the effects of DCS on clinical outcome would vary as a function of response to the exposure session (i.e., exposure success). In a clinical trial, patients with height phobia received two sessions involving 30 minutes of virtual reality exposure therapy and were randomly assigned to a pill placebo (n = 14) or 50 mg of DCS (n = 15) immediately after each session. Mixed-effects regression analysis showed that the effects of DCS administration on clinical improvement was moderated by the level of fear experienced just before concluding exposure sessions. Patients receiving DCS exhibited significantly greater improvement in symptoms relative to patients who received placebo when fear was low at the end of the exposure. In contrast, when end fear was still elevated, patients receiving DCS improved less compared with those receiving placebo. D-cycloserine appears to enhance the benefits of exposure treatment when applied after a successful session, but it seems to have detrimental effects when administered after inadequate/unsuccessful exposure sessions.