Therapeutic strategy in Paget's disease of bone.
Paget's disease of bone is a localized progressive disease, characterized by increased bone remodeling, bone hypertrophy, and abnormal bone structure, leading to pain and deformity. Disease complications involve the bones, joints, and central nervous system. Short-term treatment objectives are to alleviate or suppress bone pain; the long-term aim is for the prevention of complications caused by the slow disease progression in affected bones. The lifetime risk of complications depends on life expectancy, location, and activity index of Paget's disease. The use of potent and safe new bisphosphonates (tiludronate, pamidronate, alendronate, risedronate, and others) represents a major advance for the management of the condition: these compounds permit normalization of the biochemical indices of remodeling, and clinical doses have lasting effects without disruption to bone mineralization. Bone histomorphometry has shown that bisphosphonates can restore normal bone structure and an optimal therapeutic strategy should be defined. Symptomatic patients (or asymptomatic patients at risk) should be treated, as well as any patient requiring orthopedic surgery. The optimum strategy for preventing complications is to treat as early as possible and to halt disease progression by normalizing the biochemical markers that reflect the increased bone remodeling. There is no consensus on the threshold values for retreatment. Few studies have evaluated the long-term effects of the inhibitors of osteoclastic resorption on the risk of complications. A recent 12 year, long-term follow-up of 41 cases of Paget's disease has shown that antipagetic therapy that did not normalize biochemical markers in 71% of patients did not prevent new complications in 62% of patients. These results suggest that an optimal regimen of treatment and retreatment should target normalization of biochemical markers of bone remodeling; the new bisphosphonates make this quite feasible in most patients.


Evaluation of cancer stem cells markers expression in HCC trough real-time polymerase chain reaction.
Quantitative real-time polymerase chain reaction (qRT-PCR) flexibility, robustness and reproducibility have rapidly extended the scope of the method. Cancer stem cells are gaining increasing importance since their role in cancer initiation, treatment resistance and recurrence give rise to a wide range of potential diagnostic and therapeutic applications. The expression of several characteristic markers is proven a reliable method to assess stem-like-phenotype of cancer cells. Here, we provided a thorough protocol for the study of cancer stem cells in hepatocellular carcinoma mouse models and cell cultures using qRT-PCR.


High C-reactive protein is a strong predictor of resistance to erythropoietin in hemodialysis patients.
Inflammation is one of the major causes of resistance to erythropoietin (EPO) treatment. In the present study, the relationship between serum C-reactive protein (s-CRP) and the dose of recombinant human EPO required to maintain hemoglobin levels at approximately 12 g/dL was analyzed in 30 hemodialysis patients. The weekly EPO dose in patients with s-CRP > or = 20 mg/L was, on average, 80% higher than in patients with s-CRP less than 20 mg/L. The EPO doses and s-CRP were both inversely correlated to the levels of serum albumin and serum iron, suggesting that the principal mechanism by which inflammatory cytokines inhibit erythropoiesis is coupled to iron metabolism, ie, functional iron deficiency. Our results demonstrate the usefulness of s-CRP as a predictor of resistance to EPO treatment.


Mastitis effects on reproductive performance in dairy cattle: a review.
The reproductive performance of dairy animals is influenced by several factors, and accumulating lines of evidence indicate that mastitis is one of the determinants. Most of the published information relating mastitis with reproduction has evolved based on retrospective approach rather than controlled clinical studies. The complex nature of both mastitis and reproduction could be a limiting factor for understanding their relationship in detail. In this review, we analyzed the available retrospective studies on the effects of clinical mastitis on reproductive function and explained the possible mechanisms by which mastitis affects reproduction in dairy animals.


What we know about the relationship between autoimmune thyroid diseases and gut microbiota: a perspective on the role of probiotics on pediatric endocrinology.
Autoimmune diseases account for a cumulative overall prevalence of about 3-5% worldwide. Among them, autoimmune thyroid diseases (ATDs) are the most common and comprise two main entities: Hashimoto's thyroiditis (HT) and Graves-Basedow disease (GD). The pathogenesis of ATDs remains not fully elucidated, however the role of microbioma has been proposed. Gut microbiota exert an important influence on the intestinal barrier, nutrient metabolism and immune system development and functions. In this review, we describe on the main features of ATDs in pediatrics, focusing on the reciprocal influence between gut microbiota, thyroid hormone metabolism and thyroid autoimmunity and consider the role of probiotics and other microbiota-targeted therapies in thyroid diseases with a perspective on pediatric endocrinology. Microbiome affects both endogenous and exogenous thyroid hormone metabolism and influences the absorption of minerals important to the thyroid function, which are iodine, selenium, zinc and iron. The alteration of the gut microbiota, with the consequent modifications in the barrier function and the increased gut permeability, seems involved in the development of autoimmune and chronic inflammatory diseases, including ATDs. The supplementation with probiotics showed beneficial effects on the thyroid hormone and thyroid function because this strategy could restore the intestinal eubiosis and the good strain microorganism proliferation. Even though the evidence about the interaction between microbiota and ATDs in pediatric patients is limited, the promising results obtained in the adult population, and in other autoimmune disorders affecting children, highlight the need of for further research in the pediatric field.


Host defenses trigger salmonella's arsenal.
Salmonella survives in macrophages by using a molecular syringe to deliver proteins into the host-cell cytosol where they manipulate phagocyte physiology. Arpaia and colleagues (Arpaia et al., 2011) show that deployment of this virulence factor is triggered by the very responses that are intended to confer host resistance.


Autocrine regulation of murine B lymphocyte growth by an IgM antibody.
Culture supernatants of LPS-stimulated murine B lymphocytes are able to inhibit the growth of freshly isolated splenic B cells via an IgM antibody. The binding specificity of this IgM is not yet defined, but appears to be a B lymphocyte surface structure distinct from membrane immunoglobulin, MHC class II antigen, transferrin and Fc gamma receptors, and B220. The regulatory autoantibody allows the normal progression of early, but not late steps in the cycle of polyclonally-stimulated B lymphocytes and does not affect the increased antigen-presenting capacity of activated B cells. Therefore, this autoregulatory cycle is apparently ubiquitous and may be a major component of B lymphocyte homeostasis under physiological, as well as pathological conditions. Moreover, these findings bring into focus a possible regulating role of B lymphocytes in the humoral immune response.


Curalin supplement for patients with type 2 diabetes mellitus.
To examine the efficacy and safety of Curalin supplement in patients with type 2 diabetes. Adult patients with type 2 diabetes were randomized 1:1 to receive Curalin supplement or placebo. The primary endpoint was HbA1c decrease at 1 month. The secondary endpoint was a decrease in HbA1c by more than 0.5% and 1% and a change in 7 daily blood glucose measurements. A satisfaction questionnaire was used as an exploratory endpoint. Safety variables and adverse events were assessed. After 1 month of intervention, HbA1c was reduced by 0.94% in the Curalin arm versus 0.4% in the placebo arm (P = 0.008). 72% of Curalin patients had decreased HbA1c levels >0.5% versus 35% in the placebo arm (P < 0.05). The Treatment Satisfaction Questionnaire indicated that Curalin arm patients reported higher overall satisfaction. Curalin treatment significantly reduced HbA1c over a 1-month period and was well-tolerated.


Measurement of the lateral diffusion of human MHC class I molecules on HeLa cells by fluorescence recovery after photobleaching using a phycoerythrin probe.
The mobility of cell surface MHC class I molecules on HeLa cells was measured by fluorescence recovery after photobleaching (FRAP). The probe used for these studies was the phycobiliprotein R-phycoerythrin coupled to Fab fragments of a monoclonal antibody specific for human monomorphic MHC class I molecules. It was found that the recovery curves could be equally well fitted by either a random diffusion model with an immobile component or by an anomalous diffusion model. In the latter case, the anomalous diffusion exponent was consistent with that previously determined by single-particle tracking (SPT) experiments using the same probe (P. R. Smith, I. E. G. Morrison, K. M. Wilson, N. Fernandez, and R. J. Cherry. 1999. Biophys. J. 76:3331-3344). The FRAP experiments, however, yielded a considerably higher value of D(0), the diffusion coefficient for a time interval of 1 s. To determine whether the results were probe dependent, FRAP measurements were also performed with the same monoclonal antibody labeled with Oregon Green. These experiments gave similar results to those obtained with the phycoerythrin probe. FRAP experiments with the lipid probe 5-N-(octadecanoyl) aminofluoroscein (ODAF) bound to HeLa cells gave typical results for lipid diffusion. Overall, our observations and analysis are consistent with anomalous diffusion of MHC class I diffusion on HeLa cells, but quantitative differences between FRAP and SPT data remain to be explained.


Effect of commercial cellulases and refining on kraft pulp properties: correlations between treatment impacts and enzymatic activity components.
The importance of enzymes as biotechnological catalysts for paper industry is now recognized. In this study, five cellulase formulations were used for fibre modification. The number of PFI revolutions decreased by about 50% while achieving the same freeness value (decrease in CSF by 200 mL) with the enzymatic pretreatment. The physical properties of handsheets were modified after enzymatic pretreatment followed by PFI refining. A slight decrease in tear strength was observed with enzymes C1 and C4 at pH 7 while the most decrease in tear was observed after C2, C3, C5 treatments. C1 and C4 which had xylanase activity improved paper properties, while other enzymes had a negative impact. Therefore, the intricate balance between cellulolytic and hemicellulolytic activity is the key to optimizing biorefining and paper properties. It was also observed that C1 impact was pH dependent, which supports the importance of pH in developing an enzymatic strategy for refining energy reduction.


Alternatives to norepinephrine in septic shock: Which agents and when?
Vasopressors are the cornerstone of hemodynamic management in patients with septic shock. Norepinephrine is currently recommended as the first-line vasopressor in these patients. In addition to norepinephrine, there are many other potent vasopressors with specific properties and/or advantages that act on vessels through different pathways after activation of specific receptors; these could be of interest in patients with septic shock. Dopamine is no longer recommended in patients with septic shock because its use is associated with a higher rate of cardiac arrhythmias without any benefit in terms of mortality or organ dysfunction. Epinephrine is currently considered as a second-line vasopressor therapy, because of the higher rate of associated metabolic and cardiac adverse effects compared with norepinephrine; however, it may be considered in settings where norepinephrine is unavailable or in patients with refractory septic shock and myocardial dysfunction. Owing to its potential effects on mortality and renal function and its norepinephrine-sparing effect, vasopressin is recommended as second-line vasopressor therapy instead of norepinephrine dose escalation in patients with septic shock and persistent arterial hypotension. However, two synthetic analogs of vasopressin, namely, terlipressin and selepressin, have not yet been employed in the management of patients with septic shock, as their use is associated with a higher rate of digital ischemia. Finally, angiotensin Ⅱ also appears to be a promising vasopressor in patients with septic shock, especially in the most severe cases and/or in patients with acute kidney injury requiring renal replacement therapy. Nevertheless, due to limited evidence and concerns regarding safety (which remains unclear because of potential adverse effects related to its marked vasopressor activity), angiotensin Ⅱ is currently not recommended in patients with septic shock. Further studies are needed to better define the role of these vasopressors in the management of these patients.


Building Mexican isoscapes: Oxygen and hydrogen isotope data of meteoric water sampled across Mexico.
Oxygen and hydrogen isotope data of meteoric water samples are compiled from several States across Mexico. This dataset includes 287 oxygen and hydrogen (and deuterium excess) isotope data corresponding to meteoric water collected from the surface, groundwater wells, irrigation and observation wells, and water supply boreholes. These data facilitate the development of maps to determine the spatial distribution of water stable isotopes, also known as "isoscapes", of the Mexican territory. As such, this dataset (and the isoscapes built from it) is useful in geographic mobility studies that aim to evaluate geographic origins and residency of particular human and/or non-human individuals in antiquity and in contemporary times. Further discussion about the data and an example of an isoscape of Mexico using the meteoric water oxygen isotope data are provided in "Residential Patterns of Mexica Human Sacrifices at Mexico-Tenochtitlan and Mexico-Tlatelolco: Evidence from Phosphate Oxygen Isotopes" (Moreiras Reynaga et al., 2021). Overall, the dataset is useful in developing interpolated maps of water stable isotopes for relevant archeological, bioarchaeological, forensic, hydrogeological, and ecological research.


Involvement of N6-methyladenosine modifications of long noncoding RNAs in systemic lupus erythematosus.
LncRNAs are potential biomarkers for SLE, but the epigenetic regulatory mechanisms of N6-methyladenosine (m6A) modification in SLE remain largely unclear. In this study, we established m6A modification profile and investigated the potential roles of m6A-related lncRNAs in SLE. The m6A modification profile of SLE was established using MeRIP-seq. Four potential m6A related-lncRNAs (linc02446, linc01410, Xist, and PSMB8-AS1) were selected for validation using qRT-PCR, and their expression and association with clinical characteristics with SLE were evaluated. Overall, m6A level was lower in patients with SLE than in controls. Compared with controls, the expression of the two m6A related-lncRNAs (Xist and PSMB8-AS1) was downregulated in patients with SLE (all P < 0.05); the linc02446 was up-regulated in PBMCs of patients with SLE (Z=-2.738, P = 0.006), while it was not differentially expressed in T cells (Z=-0.387, P = 0.699). No significant alteration in linc01410 expression was observed in patients (Z=-0.940, P = 0.347). The lower expression levels of Xist and PSMB8-AS1 were associated with many clinical manifestations in patients with SLE (all P < 0.05). Additionally, mRNAs co-expressed with m6A related-lncRNAs (Xist, linc02446, and PSMB8-AS1) also participated in SLE. These results suggest that m6A methylation and m6A related-lncRNAs might be involved in the pathogenesis of SLE. Thus, our findings provide some clues on the potential function of lncRNAs that m6A modification may target in novel therapeutic or diagnostic strategies for SLE.


Impacts of triamcinolone acetonide on femoral head chondrocytic structures in lumbosacral plexus block.
Objective: To investigate impacts of triamcinolone acetonide (TRI) on femoral head chondrocytic (FHC) structures when used for lumbosacral plexus block (LPB). Methods: A total of 32 6-month-old New Zealand white rabbits were selected (averagely weighing 2.75-3.25 kg) and added TRI into nerve block solution for LPB. The rabbit were randomly divided into four groups: group A1: 2.5 ml × 2 times, group A2 2.5 ml × 4 times, group B1 5 ml × 2 times, and group B2 5 ml × 4 times; the time interval among the injection was 5 days, and the structural changes of FHC were the observed using 50/100/200 light microscope; the modified Mankin pathological scoring was also performed for the evaluation. Results: There exhibited significant microscopic changes of FHC structures between the rabbits performed LPB and the normal rabbits, among which group B2 exhibited the most serious FHC damages, and the Mankin pathological score in group B2 was much higher than those in the other three groups, and the scores of the experimental group were higher than the control group. Conclusions: The addition of TRI in LPB can damage the FHC structures, and large-dose (5 ml/once) and long-course (four times) will result in more serious injuries.


Oral administration of Parabacteroides distasonis antigens attenuates experimental murine colitis through modulation of immunity and microbiota composition.
Commensal bacteria have been shown to modulate the host mucosal immune system. Here, we report that oral treatment of BALB/c mice with components from the commensal, Parabacteroides distasonis, significantly reduces the severity of intestinal inflammation in murine models of acute and chronic colitis induced by dextran sulphate sodium (DSS). The membranous fraction of P. distasonis (mPd) prevented DSS-induced increases in several proinflammatory cytokines, increased mPd-specific serum antibodies and stabilized the intestinal microbial ecology. The anti-colitic effect of oral mPd was not observed in severe combined immunodeficient mice and probably involved induction of specific antibody responses and stabilization of the intestinal microbiota. Our results suggest that specific bacterial components derived from the commensal bacterium, P. distasonis, may be useful in the development of new therapeutic strategies for chronic inflammatory disorders such as inflammatory bowel disease.


Enhanced catabolism of low density lipoproteins in rat by lactosaminated Fab fragment. A new carrier of macromolecules to the liver.
Proteins conjugated with lactose residues exhibit enhanced hepatic uptake mediated by the galactose receptor. In this study, we demonstrate that lactosaminated Fab fragments (lac-Fab) of IgG can induce hepatic catabolism of specific antigens, especially low density lipoproteins (LDL). lac-Fab and human LDL-lac-Fab complex exhibited specific uptake in isolated rat hepatocytes. In vivo in the rat, lactosamination enhanced plasma clearance of Fab fragments 2-fold and hepatic localization 20-fold. Fab fragments retained their affinity after lactosamination. Hepatic uptake of rat 125I-IgG complexed in vitro with anti-rat lac-Fab was increased almost 5-fold, compared to rat 125I-IgG alone. Injection of rats with anti-LDL lac-Fab induced plasma clearance and hepatic uptake of tracer amounts of previously injected human 125I-LDL, which decreased 50% 10 min after injection of lac-Fab, with 30% present in the liver. Asialofetuin completely inhibited these processes. After a bolus of 6 mg of human LDL, administration of anti-LDL lac-Fab reduced the serum cholesterol of rats to basal values within 2.5 h. These findings suggest that lactosaminated Fab fragments of specific IgGs are effective reagents for inducing hepatic uptake of macromolecules through the galactose receptor. lac-Fab specific for LDL may be an effective hypocholesterolemic agent in vivo.


Protective effects of SP600125 on mice infected with H1N1 influenza A virus.
Influenza A virus (IAV) can cause high morbidity and mortality globally every year. Myriad host kinases and their related signaling pathways are involved in IAV infection, and the important role of the c-Jun N-terminal kinase signaling pathway during infection has been demonstrated. SP600125, an inhibitor of c-Jun N-terminal kinase, was found in our previous study to suppress IAV replication in vitro. In this study, we established a mouse model of H1N1 IAV infection and treated the mice with SP600125 to study its protective effect. The results showed that SP600125 treatment reduced the pulmonary inflammatory response, lung injury, and pulmonary viral load and increased the survival rate of H1N1-infected mice. Our data confirm the crucial role of c-Jun N terminal kinase in H1N1 virus replication and inflammatory responses in vivo. Hence, we speculate that SP600125 has a potential antiviral therapeutic benefit against IAV infection.


MicroRNA-373, a new regulator of protein phosphatase 6, functions as an oncogene in hepatocellular carcinoma.
MicroRNAs are a class of small noncoding RNAs that function as key regulators of gene expression at the post-transcriptional level. Recently, microRNA-373 (miR-373) has been found to function as an oncogene in testicular germ cell tumors. In our study, we found that miR-373 is upregulated in human hepatocellular carcinoma (HCC) tissues as compared with adjacent normal tissues, and promotes the proliferation of the HCC cell lines HepG2 and QGY-7703 by regulating the transition between G(1)-phase and S-phase. The gene encoding the protein phosphatase 6 catalytic subunit (PPP6C ), a negative cell cycle regulator, was identified as a direct target gene of miR-373 by use of a fluorescent reporter assay. The mRNA and protein levels of PPP6C were both inversely correlated with the miR-373 expression level. Overexpression of PPP6C abolished the regulation of cell cycle and cell growth exercised by miR-373 in HepG2 cells. These results indicate that miR-373 plays an important role in the pathogenesis of HCC, and may be a new biomarker in HCC. Our results demonstrate that miR-373 can regulate cell cycle progression by targeting PPP6C transcripts and promotes the growth activity of HCC cells in vitro. The downregulation of PPP6C by miR-373 may explain why the expression of miR-373 can promote HCC cell proliferation.


Dietary folate intake and fecundability in two preconception cohorts.
To what extent is dietary folate intake and total folate intake (dietary and supplemental intakes) associated with fecundability, the per cycle probability of conception? Preconception dietary folate intake was positively associated with fecundability in a monotonic pattern. Supplemental folic acid has been associated with improved fertility, but little is known about the relation between dietary folate and fecundability. A prospective cohort study including 9559 women trying to conceive without fertility treatment and enrolled in the period 2013-2020. We used data from two internet-based prospective cohort studies of pregnancy planners from Denmark, where folic acid fortification is not performed (SnartForældre.dk (SF); n = 3755) and North America, where the food supply is fortified with folic acid (Pregnancy Study Online (PRESTO); n = 5804). Women contributed menstrual cycles at risk until they reported conception or experienced a censoring event. We used proportional probabilities regression models to compute fecundability ratios (FRs) and 95% CI, adjusting for potential confounders. Compared with a dietary folate intake ≥400 µg/day, the adjusted FRs for women in SF were 0.92 (95% CI: 0.85-0.99) for intake 250-399 µg/day, and 0.80 (95% CI: 0.68-0.94) for intake of <250 µg/day. The corresponding FRs in PRESTO were 0.95 (95% CI: 0.89-1.01) and 0.81 (95% CI: 0.65-1.00). Compared with the highest level of total folate intake (diet folate ≥400 µg/day plus folic acid supplementation), in both cohorts fecundability was lowest among women with the lowest dietary intake <250 µg/day dietary folate and no supplementation (FR: 0.76, 95% CI: 0.59-0.98 [SF] and 0.49, 95% CI: 0.31-0.77 [PRESTO]). Further, total intake dietary folate <250 µg/day plus supplementation was associated with reduced fecundability for SF participants (FR; 0.79, 95% CI: 0.65-0.98) and for PRESTO participants (FR; 0.92, 95% CI: 0.72-1.16). It is unknown whether dietary folate and folic acid intake affect fecundability on its own or if there is an interaction with other micronutrients provided in healthy diet. Thus, the observed associations may not reflect dietary folate intake alone, but overall healthy diet. Recommendations for preconception dietary folate intake and folic acid supplementation are of importance not only to prevent neural tube defects but also to enhance fecundability. The study was supported by the National Institute of Child Health and Human Development (R01-HD086742). The authors report no competing interests. N/A.


The dynamic adaptive landscape of cetacean body size.
Adaptive landscapes are central to evolutionary theory, forming a conceptual bridge between micro- and macroevolution.1,2,3,4 Evolution by natural selection across an adaptive landscape should drive lineages toward fitness peaks, shaping the distribution of phenotypic variation within and among clades over evolutionary timescales.5 The location and breadth of these peaks in phenotypic space can also evolve,4 but whether phylogenetic comparative methods can detect such patterns has largely remained unexplored.6 Here, we characterize the global and local adaptive landscape for total body length in cetaceans (whales, dolphins, and relatives), a trait that spans an order of magnitude, across their ∼53-million-year evolutionary history. Using phylogenetic comparative methods, we analyze shifts in long-term mean body length7 and directional changes in average trait values8 for 345 living and fossil cetacean taxa. Remarkably, we find that the global macroevolutionary adaptive landscape of cetacean body length is relatively flat, with very few peak shifts occurring after cetaceans entered the oceans. Local peaks are more numerous and manifest as trends along branches linked to specific adaptations. These results contrast with previous studies using only extant taxa,9 highlighting the vital role of fossil data for understanding macroevolution.10,11,12 Our results indicate that adaptive peaks are dynamic and are associated with subzones of local adaptations, creating moving targets for species adaptation. In addition, we identify limits in our ability to detect some evolutionary patterns and processes and suggest that multiple approaches are required to characterize complex hierarchical patterns of adaptation in deep time.


Quality of life in patients with hereditary hemorrhagic telangiectasia in Norway: a population based study.
Hereditary hemorrhagic telangiectasia (HHT) is a rare, autosomal dominant disease characterized by the presence of recurrent epistaxis and small characteristic malformations of the peripheral blood vessels near the surface of the skin or mucosal linings. Arteriovenous malformations (AVM) of the lung, liver, and CNS are also known clinical findings. The purpose of this study was to examine quality of life (QoL) in patients with HHT in Norway. Sixty-six affected patients (39 women and 27 men) were included. QoL on overall-, health-related (HR-QoL), and disease-specific levels were measured with Cantril's Ladder (CL), Short Form 36 (SF-36), and a Symptom-specific QoL question in HHT patients (SFB-HHT-Q), respectively. Comparisons were made between patients and an age and gender adjusted normative sample from the Norwegian population (N = 990). Overall, the results reflected that several HHT disease-related variables were associated with reduced QoL on all three levels; overall QoL (CL), HR-QoL (SF36) as well as disease-specific QoL (SFB-HHT-Q), while demographic variables impacted HR-QoL in HHT patients. Compared to the normative sample, all subscales of SF36, but bodily pain, were significantly poorer in the HHT patients. HHT disease variables had the strongest association with QoL compared to demographic variables. The results substantiate that disease severity is associated with poorer QoL in this patients. Pain contributed independently to all levels of QoL.


Efficacy of a nitrogen-containing bisphosphonate, minodronate, in conjunction with a p38 mitogen activated protein kinase inhibitor or doxorubicin against malignant bone tumor cells.
We recently reported the sarcoma-selective antitumor effects of a newly developed nitrogen-containing bisphosphonate, minodronate (MIN), on malignant bone tumors. The aim of this study was to develop efficient combination MIN therapy in malignant bone tumors. We examined downstream molecular events of MIN in osteosarcoma and Ewing's sarcoma cells to search for a partner to combine with MIN. Furthermore, we evaluated the combined effects of MIN and clinically available Doxorubicin (DOX). We found that MIN inhibited Rap 1A prenylation, and extracellular signal-regulated kinase (ERK) or Akt phosphorylation in osteosarcoma (Saos-2) and Ewing's sarcoma (SK-ES-1) cells. Interestingly, MIN activated p38 mitogen activated protein kinase (MAPK) only in SK-ES-1 cells and a p38 MAPK inhibitor augmented MIN-induced growth inhibition in SK-ES-1 cells. Doxorubicin (DOX) exerted synergistic effects on Saos-2 and SK-ES-1 cell lines. Daily injection of MIN enhanced the growth inhibition of SK-ES-1 xenograft sarcoma treated by DOX in nude mice. These findings suggest that the inhibition of the p38 MAPK pathway may be attractive in overcoming cellular resistance against MIN. In the light of clinical settings, MIN may have a beneficial adjuvant role in the DOX treatment.


Low-dose surgical prophylaxis: Optimization of use of World Federation of Hemophilia Humanitarian Aid donated clotting factor concentrates to developing countries.
Patients with hemophilia (PWH) might need surgical interventions during the course of their lives. Such medical interventions pose hemostatic challenges and requests infusion of clotting factor concentrates (CFCs) during peri and postoperative for variable periods to prevent bleeding and until complete wound healing. Access to CFCs to PWH living in resource limited settings is usually a challenge which makes surgical interventions either risky or not practical. Recently World Federation of Hemophilia (WFH) started a humanitarian aid program to channel CFCs into resource limited countries and which allowed the possibility to perform surgical interventions for PWH in these countries. To study safety and efficacy of using lower doses of CFCs for surgical prophylaxis. Review of literature and our center experience to demonstrate safety and efficacy of low dose surgical prophylaxis using CFCs RESULTS: Several elements can help using lower doses of CFCs for surgical prophylaxis in resource limited setting. These elements include severity of hemophilia, type of surgical procedure, the use of hemostatic surgical techniques, the type of CFCs, the mode of infusion of CFCs and finally the use of adjunctive therapies CONCLUSION: Management of surgical procedures for PWH in a multidisciplinary specialized hemophilia treatment centers with proper understanding of hemostatic and surgical challenges of the procedure can allow for safe and effective use of lower doses of CFCs for surgical prophylaxis.


The association of maternal obesity and race with serum adipokines in pregnancy and postpartum: Implications for gestational weight gain and infant birth weight.
Adiponectin and leptin are hormones known to play roles in maternal metabolism during pregnancy. Levels of these hormones have been demonstrated to vary based on adiposity and race. However, there is a lack of data concerning the relationship between race and the change of adiponectin and leptin throughout pregnancy. The purpose of this study was to examine serum levels of adiponectin, leptin, and leptin-to-adiponectin ratio (LAR) throughout pregnancy and to assess their association with gestational weight gain (GWG) and infant birth weight while considering the effects of race and pre-pregnancy body mass index (BMI). Serum levels of adiponectin, leptin, gestational weight gain, and infant birth weight were measured in 80 pregnant women at early (12.4 ± 1.3 weeks gestation), mid (20.6 ± 1.3 weeks gestation), late pregnancy (29.2 ± 1.4 weeks gestation), and 7-11 weeks postpartum (8.8 ± 0.8 weeks). In women overall, serum adiponectin decreased across pregnancy and increased at postpartum (p = 0.17.) At each prenatal timepoint, both black race and obesity were associated with lower adiponectin (ps < 0.05). In women overall, serum leptin increased across pregnancy, and declined at postpartum. At every assessment, a stepwise increase in leptin was observed in relation to BMI class. Black women with obesity had markedly higher LAR in mid- and late pregnancy and postpartum than all other groups (p < 0.05). Serum leptin during pregnancy was significantly associated with total GWG in both black and white women (ps < 0.005). Neither adiponectin, leptin, nor LAR were associated with infant birth weight. Race and BMI both have significant effects on serum adiponectin, leptin, and LAR levels in pregnancy and postpartum. Notably, the combined effects of race and BMI result in markedly higher LAR among black women with obesity. Implications for racial disparities in metabolic syndrome and postpartum weight retention remain to be explicated.


Ocular toxoplasmosis, an overview focusing on clinical aspects.
Toxoplasma gondii is a widespread protozoan parasite infecting approximately one third of the world population. After proliferation of tachyzoites during the acute stage, the parasite forms tissue cysts in various anatomical sites and establishes chronic infection. Nowadays the nature of the interplay between the protozoan and its human host remains elusive. This is clearly evident in ocular toxoplasmosis, in which the parasite establishes an ambivalent relationship with the eye, manipulating the immune response and inducing variable initial lesions and further relapses. This review will focus on epidemiology and environmental, parasite and host related risk factors, clinical manifestations and laboratory findings, treatment and prophylaxis approaches in ocular toxoplasmosis. An image collection of patients referred to the Unit of Ophthalmology of Pisa's Hospital will be presented, too.


'A reservoir within a reservoir' - An unusual complication associated with a defunctioned inflatable penile prosthesis reservoir.
Inflatable penile prostheses (IPP) have been a successful method of treating men with erectile dysfunction since the early 1970s. IPP are comprised of two intracorporal cylinders, a scrotal pump and a fluid reservoir. We present a case of a retained reservoir in a sixty eight year old gentlemen presenting with a cystic abdominal mass and bothersome LUTS, 15 years after the removal of the penile components of a three-piece penile prosthesis. Percutaneous drainage of the cyst was performed, with four litres of purulent fluid evacuated. A midline laparotomy was required to remove the reservoir and drain the collection completely. Inflammatory reaction and subsequent erosion of an IPP reservoir is an infrequent but severe complication of IPP insertion, replacement or infection. Infection remains the primary indication for penile prosthesis removal and in this setting removal of the reservoir is routine. A thorough literature search has identified that in the non-infective setting, the routine removal of the original reservoir is not standard practice during three-component IPP replacement. In patients with a history of IPP presenting with new LUTS, reservoir erosion should be considered in the differential diagnosis and investigation with cystoscopy and computed tomography included early in the investigatory armament of the urologist. It is our belief that a defunctionalized reservoir serves no purpose; rather it can only cause trouble in the future. Consequently, at our institution we do not leave defunctionalized reservoirs in situ.


Blast-related mild traumatic brain injury: a Bayesian random-effects meta-analysis on the cognitive outcomes of concussion among military personnel.
Throughout their careers, many soldiers experience repeated blasts exposures from improvised explosive devices, which often involve head injury. Consequentially, blast-related mild Traumatic Brain Injury (mTBI) has become prevalent in modern conflicts, often occuring co-morbidly with psychiatric illness (e.g., post-traumatic stress disorder [PTSD]). In turn, a growing body of research has begun to explore the cognitive and psychiatric sequelae of blast-related mTBI. The current meta-analysis aimed to evaluate the chronic effects of blast-related mTBI on cognitive performance. A systematic review identified 9 studies reporting 12 samples meeting eligibility criteria. A Bayesian random-effects meta-analysis was conducted with cognitive construct and PTSD symptoms explored as moderators. The overall posterior mean effect size and Highest Density Interval (HDI) came to d = -0.12 [-0.21, -0.04], with executive function (-0.16 [-0.31, 0.00]), verbal delayed memory (-0.19 [-0.44, 0.06]) and processing speed (-0.11 [-0.26, 0.01]) presenting as the most sensitive cognitive domains to blast-related mTBI. When dividing executive function into diverse sub-constructs (i.e., working memory, inhibition, set-shifting), set-shifting presented the largest effect size (-0.33 [-0.55, -0.05]). PTSD symptoms did not predict cognitive effects sizes, β PTSD = -0.02 [-0.23, 0.20]. The results indicate a subtle, but chronic cognitive impairment following mTBI, especially in set-shifting, a relevant aspect of executive attention. These findings are consistent with past meta-analyses on multiple mTBI and correspond with past neuroimaging research on the cognitive correlates of white matter damage common in mTBI. However, all studies had cross-sectional designs, which resulted in universally low quality ratings and limited the conclusions inferable from this meta-analysis.


Health perceptions and obesity awareness of nursing students.
Obesity is a chronic disease that is a global problem. Individuals' perceptions of what health and a healthy lifestyle constitute have an important role in preventing obesity. This study aimed to determine the relationship between nursing students' health perceptions and obesity awareness. This descriptive cross-sectional study was conducted with nursing students (n = 242) between December 20, 2019 and March 20, 2020 in the XXXXX School of Health. A student information form, health perception scale, and obesity awareness scale were used to collect the data. The average total score of the obesity awareness scale was 3.14 ± 0.36, and the average total score of the health perception scale was 38.48 ± 6.65. Overall, the students perceived that health status was more associated with concepts such as chance and destiny. It is recommended that students' health perceptions be improved.


Technologies to recover nitrogen from livestock manure - A review.
Today, the livestock industry is considered to be one of the biggest emitters of ammonia in the world. The nitrogen present in livestock manure has been linked to the contamination of water bodies. Livestock manures contain a significant quantity of recoverable nitrogen. Recovering nitrogen from livestock manure can minimize negative environmental consequences. This also presents an opportunity to generate some revenue by converting the captured nitrogen to marketable nitrogenous fertilizers. Substantial research efforts have been made toward recovering nitrogen from raw as well as digested livestock manures over the last decade. Many novel technologies as well as ones that have already been implemented to recover nitrogen from municipal wastewaters have been studied for their use in the livestock sector. This paper reviews the common manure nitrogen-recovery technologies reported in the literature, summarizes their efficiencies, discusses their pros and cons, and identifies the areas for future research. Owing to their higher ammonia recovery efficiencies, relatively fewer drawbacks, lower costs, and ability to produce ammonium fertilizers, air stripping by direct aeration, thermal vacuum stripping, and gas-permeable membrane stripping appear to be the most viable choices for livestock farmers. Further studies should focus on the economic feasibility, long-term performance on the manure of varying strengths, and the quality of recovered nitrogenous products.


The use of a collar and precoating on cemented femoral stems is unnecessary and detrimental.
Evidence is presented, largely from clinical sources, that a large collar is not necessary for the transfer of load to the proximal femur in cemented total hip arthroplasty. In fact, the use of a collar may have a number of deleterious side effects that cannot be predicted from theoretical analyses. Concern is also raised over the use of precoated femoral stems.


Timing of integration into the chromosome is critical for the fitness of an integrative and conjugative element and its bacterial host.
Integrative and conjugative elements (ICEs) are major contributors to genome plasticity in bacteria. ICEs reside integrated in the chromosome of a host bacterium and are passively propagated during chromosome replication and cell division. When activated, ICEs excise from the chromosome and may be transferred through the ICE-encoded conjugation machinery into a recipient cell. Integration into the chromosome of the new host generates a stable transconjugant. Although integration into the chromosome of a new host is critical for the stable acquisition of ICEs, few studies have directly investigated the molecular events that occur in recipient cells during generation of a stable transconjugant. We found that integration of ICEBs1, an ICE of Bacillus subtilis, occurred several generations after initial transfer to a new host. Premature integration in new hosts led to cell death and hence decreased fitness of the ICE and transconjugants. Host lethality due to premature integration was caused by rolling circle replication that initiated in the integrated ICEBs1 and extended into the host chromosome, resulting in catastrophic genome instability. Our results demonstrate that the timing of integration of an ICE is linked to cessation of autonomous replication of the ICE, and that perturbing this linkage leads to a decrease in ICE and host fitness due to a loss of viability of transconjugants. Linking integration to cessation of autonomous replication appears to be a conserved regulatory scheme for mobile genetic elements that both replicate and integrate into the chromosome of their host.


Visualization and Quantification of Subcellular RNA Localization Using Single-Molecule RNA Fluorescence In Situ Hybridization.
Advancements in imaging technologies, especially approaches that allow the imaging of single RNA molecules, have opened new avenues to understand RNA regulation, from synthesis to decay with high spatial and temporal resolution. Here, we describe a protocol for single-molecule fluorescent in situ hybridization (smFISH) using three different approaches for synthesizing the fluorescent probes. The three approaches described are commercially available probes, single-molecule inexpensive FISH (smiFISH), and in-house enzymatically labeled probes. These approaches offer technical and economic flexibility to meet the specific needs of an experiment. In addition, we provide a protocol to perform automated smFISH spot detection using the software FISH-quant.


Testing software's changing features with environment-driven abstraction identification.
ions are significant domain terms that have assisted in requirements elicitation and modeling. To extend the assistance toward requirements validation, we present in this paper an automated approach to identifying the abstractions for supporting requirements-based testing. We select relevant Wikipedia pages to serve as a domain corpus that is independent from any specific software system. We further define five novel patterns based on part-of-speech tagging and dependency parsing, and frame our candidate abstractions in the form of <key, value> pairs for better testability, where the "key" helps locate "what to test", and the "value" helps guide "how to test it" by feeding in concrete data. We evaluate our approach with six software systems in two application domains: Electronic health records and Web conferencing. The results show that our abstractions are more accurate than those generated by a state-of-the-art technique. While the initial findings indicate our abstractions' capabilities of revealing bugs and matching the environmental assumptions created manually, we articulate a new way to perform requirements-based testing by focusing on a software system's changing features. Specifically, we hypothesize that the same feature would behave differently under a pair of opposing environmental conditions and assess our abstractions' applicability to this new form of feature testing.


[Standard intervention in primary lymphoma of the stomach--initial results of a prospective multicenter study].
An R0 resection seems to be a rather aggressive treatment, but can be achieved in 80% of localized gastric lymphomas and should be seen in contrast to other effective treatment modalities. For curative treatment at stage EI1-EII1, total gastrectomy with systematic lymphadenectomy (D2) seems to be necessary. Basic information about the clear diagnosis, tumor dissemination and the individual prognosis only becomes available by a standardized operation as part of multimodal therapeutic concepts.


Grasping the Ongaonga: When will New Zealand really integrate rural clinical education?
Compared to Australia, substantial rural-based clinical education in New Zealand started small and still has some way to go if it is to fulfil its potential in workforce retention and recruitment to under-served areas. The authors share some of their experiences in rural medical education and then speculate on how it could develop. They discuss the merits of a clinical school composed of a dispersed network of rural sites, which provide and coordinate rural health education.


Caregiver burden and emotional wellbeing in informal caregivers to ICU survivors-A prospective cohort study.
Informal caregivers to intensive care unit (ICU) survivors may develop post-intensive care syndrome family (PICS-F), including depression, anxiety and post-traumatic stress (PTS). Our primary aim was to investigate associations between caregiver burden in informal caregivers cohabiting with ICU survivors and patients' physical and psychological outcomes. A prospective, multicentre cohort study in four ICUs in Sweden. Adults cohabiting with ICU patients included in a previous study were eligible for inclusion. Three months post-ICU, informal caregivers received questionnaires assessing caregiver burden, health-related quality of life (HRQL) and symptoms of depression, anxiety and PTS. In parallel, patients reported their three-month physical and psychological status via validated questionnaires. The primary outcome of this study was to compare caregiver burden in informal caregivers to patients with and without adverse physical and psychological outcomes 3 months post-ICU. Secondary outcomes were correlations between caregiver burden and informal caregivers' mental HRQL. Among 62 included informal caregivers, 55 (89%) responded to the follow-up questionnaires. Caregiver burden was higher among informal caregivers to patients with an adverse outcome, compared to informal caregivers to patients without an adverse outcome, caregiver burden scale score mean (±standard deviation) 52 (11) and 41 (13) respectively (p = 0.003). There was strong negative correlation between caregiver burden and informal caregivers' mental HRQL (rs -0.74, p < 0.001). Informal caregivers to ICU survivors with adverse physical or psychological outcome experience a higher caregiver burden. A higher caregiver burden correlates with worse caregiver mental HRQL. ICU follow-up programs should consider screening and follow-up of informal caregivers for mental health problems.


Diagnosis of epileptic syndrome after a new onset seizure and its correlation at long-term follow-up: longitudinal study of 131 patients from the emergency room.
This study aims to demonstrate the reliability of the diagnosis of epilepsy after a new onset seizure, supported by a detailed anamnesis and the complementary tests accessible at the emergency room (ER), such as CT-scan and video-EEG. It was a prospective study including 131 adult patients (55% males, medium age 52.42 (±21.5)[16-98] years-old, follow-up 25.22 (±13.69)[12-31] months). In half of cases we could not identify any predisposing factor. Within the first 72 h, patients were included into an epileptic syndrome according to the ILAE 1989 classification, if possible. Thereafter, they were followed-up in the outpatient clinic of the Epilepsy Unit, where seizure recurrence was recorded and further diagnostic examinations were performed. 94.1% of patients initially diagnosed of epilepsy were confirmed as epileptics, and up to 57% of patients could be classified into a particular syndrome from the ER. Conversely, 44.6% of patients with the initial diagnosis of isolated seizure and one third of patients with non-epileptic seizures developed recurrence, switching their initial diagnosis to epilepsy. Both CT-scan and early EEG demonstrated its usefulness evaluating the risk of recurrence after a new onset seizure (Positive predictive value 78% and 88%, respectively). Epileptiform activity was a predictor of seizure recurrence (p<0.05), independently to the moment where the EEG was performed. According to our results, it is realistic to perform the diagnosis of epilepsy after a new onset seizure, although many patients still need further specific examinations, or seizure recurrence, to be diagnosed.


Characterisation of dysplastic liver nodules using low-pass DNA sequencing and detection of chromosome arm-level abnormalities in blood-derived cell-free DNA.
High-grade dysplasia carries significant risk of transformation to hepatocellular carcinoma (HCC). Despite this, at the current standard of care, all non-malignant hepatic nodules including high-grade dysplastic nodules are managed similarly. This is partly related to difficulties in distinguishing high-risk pathology in the liver. We aimed to identify chromosome arm-level somatic copy number alterations (SCNAs) that characterise the transition of liver nodules along the cirrhosis-dysplasia-carcinoma axis. We validated our findings on an independent cohort using blood-derived cell-free DNA. A repository of non-cancer DNA sequences obtained from patients with HCC (n = 389) was analysed to generate cut-off thresholds aiming to minimise false-positive SCNAs. Tissue samples representing stages from the multistep process of hepatocarcinogenesis (n = 184) were subjected to low-pass whole genome sequencing. Chromosome arm-level SCNAs were identified in liver cirrhosis, dysplastic nodules, and HCC to assess their discriminative capacity. Samples positive for 1q+ or 8q+ arm-level duplications were likely to be either HCC or high-grade dysplastic nodules as opposed to low-grade dysplastic nodules or cirrhotic tissue with an odds ratio (OR) of 35.5 (95% CI 11.5-110) and 16 (95% CI 6.4-40.2), respectively (p < 0.0001). In an independent cohort of patients recruited from Nottingham, UK, at least two out of four alterations (1q+, 4q-, 8p-, and 8q+) were detectable in blood-derived cell-free DNA of patients with HCC (n = 22) but none of the control patients with liver cirrhosis (n = 9). Arm-level SCNAs on 1q+ or 8q+ are associated with high-risk liver pathology. These can be detected using low-pass sequencing of cell-free DNA isolated from blood, which may be a future early cancer screening tool for patients with liver cirrhosis. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.


Learning to argue via apprenticeship.
We examined apprenticeship, in the form of interaction with a more capable other, as a mechanism of development of higher-order reasoning skills, specifically argumentation. Over a 1-year period, middle school students engaged in twice-weekly electronic dialogs with a sequence of different peers on a series of social issues. In one group, unbeknownst to participants, a highly capable adult substituted for peers in half of their dialogs. Beginning immediately, increasing with time, and extending to peer-only dialogs on a new topic, the quality of argumentation shown by the experimental group exceeded that of a comparison peer-only group, highlighting the power of apprenticeship as a mechanism in the development of reasoning, a demonstration of both theoretical and applied significance.


Doxorubicin Anticancer Drug Monitoring by ds-DNA-Based Electrochemical Biosensor in Clinical Samples.
In this research, glassy carbon electrode (GCE) amplified with single-wall carbon nanotubes (SWCNTs) and ds-DNA was fabricated and utilized for voltammetric sensing of doxorubicin with a low detection limit. In this technique, the reduction in guanine signal of ds-DNA in the presence of doxorubicin (DOX) was chosen as an analytical factor. The molecular docking study revealed that the doxorubicin drug interacted with DNA through intercalation mode, which was in agreement with obtained experimental results. The DOX detection performance of ds-DNA/SWCNTs/GCE was assessed at a concentration range of 1.0 nM-20.0 µM. The detection limit was found to be 0.6 nM that was comparable and even better (in many cases) than that of previous electrochemical reported sensors. In the final step, the ds-DNA/SWCNTs/GCE showed powerful ability for determination of the DOX in injection samples with acceptable recovery data.


Diterpene constituents of leaves from Juniperus brevifolia.
The dichloromethane extract from leaves of Juniperus brevifolia, through chromatographic fractionations yield six compounds: 3beta-hydroxy-abieta-8,11,13-trien-7-one, 18-hydroxy-sandaracopimara-8(14),15-dien-7-one, sandaracopimara-8(14),15-dien-18-yl formate; and the first examples of sandaracopimaranes and abieta-8,11,13-triene diterpenoids with a large aliphatic chain on C-18, abieta-8,11,13-trien-18-yl hexadecanoate, 7-oxoabieta-8,11,13-trien-18-yl hexadecanoate, sandaracopimara-8(14),15-dien-18-yl hexadecanoate. Moreover fifteen known compounds were also isolated, some of them for the first time identified on Juniperus genus. The compound abieta-8,11,13-trien-18-yl formate is reported for the first time as a natural product. All the structures were established by spectroscopic methods. 2D NMR techniques have allowed the revision of certain previously reported (13)C NMR assignments. Studies on the isolated new compounds showed those possessing a diterpenol ester of a long-chain fatty acid present lipophilicity very distinct from other diterpenoid compounds.


Identification of a second Grb2 binding site in the v-Fms tyrosine kinase.
Tyrosine autophosphorylation of the v-Fms oncogene product results in the formation of high-affinity binding sites for cellular proteins containing Src homology 2 (SH2) domains. These proteins transduce various mitogenic and morphogenic signals. As reported previously, Y696KNI in the kinase insert domain of v-Fms binds to the growth factor receptor bound protein 2 (Grb2), a stimulator of the Ras/Raf1 pathway. Here, we mapped Y921TNL within the C-terminal domain of Fms as a novel autophosphorylation site. We demonstrate that this site constitutes a second Grb2 binding site: a recombinant fusion protein (residues 904-944) containing phosphorylated Y921 bound Grb2 from FDCP-1Mac11 cell extracts significantly more efficiently than a corresponding protein (residues 617-759) containing Y696. A yeast two-hybrid system which allowed the formation of a functional Fms tyrosine kinase was employed to quantify binding of Grb2. Fms-protein containing either one of the two phosphorylation sites bound Grb2 equally well, binding was increased for proteins carrying both sites. In contrast, the simultaneous substitution of Y696 and Y921 by phenylalanines abolished Grb2 binding. Mouse NIH3T3 cells expressing the Y921F mutant Fms-protein showed a substantially higher content of fibronectin network than wild-type transformed cells and had largely lost their serum independent growth phenotype.


Patterns and metamorphic changes of serum proteins in amphibia.
1. Serum proteins in the metamorphosing larvae and adult animals ofRana temporaria, Bombina variegata, Bufo bufo andTriturus alpestris were separated by polyacrylamide gel electrophoresis. Based on various specific staining reactions the occurrence of albumin, transferrin, glycoprotein, lipoprotein and possibly haptoglobin was identified. 2. In general, the electrophoretic patterns become increasingly more complex with the progress of metamorphosis. Detailed analyses revealed the appearance of various new serum proteins both at the time of metamorphosis and during adult maturation. 3. In all three anuran species there is a rapid increase in the total serum protein concentration as metamorphosis proceeds. The albumin fraction shows the highest increasing rate, resulting in a two- to fivefold increase of the albumin/globulin ratio with the completion of metamorphosis. During postmetamorphic growth this ratio remains constant in spite of the continuous rise of the total concentration. Similar changes of the serum protein pattern have been observed in premetamorphic larvae ofR. temporaria andB. bufo treated with thyroxine. 4. T. alpestris differs from the three anurans in having a much smaller increase of the total serum protein concentration and showing no change of the albumin/globulin ratio at metamorphosis. Instead, a maximum increase of protein in the gel section of relatively slow anodal-moving globulins was observed. 5. The metabolic and molecular aspects of the changes of serum proteins during amphibian metamorphosis are discussed.


The relationship of actual height loss with health-seeking behaviors and risk factors in perimenopausal and menopausal women.
To explore whether there is a difference in the perceived height and actual height in the perimenopausal or menopausal woman and discover the difference's effect on osteoporosis health-seeking preventive behaviors and risk factor awareness. Sixty-three perimenopausal and menopausal women, aged 45-70 years, who presented at three Midwestern clinics for their annual physical exam. Data were collected with The Osteoporosis Questionnaire, which included the Osteoporosis Risk Questionnaire, Health-O-Meter height measuring stick, tape measure with inch-rule for arm span measurements, and balance scale for weight. There were a significant relationship between actual height loss and osteoporosis risk factors (r = 0.41595, p = 0.0007) and a trend for a relationship between adjusted height loss and osteoporosis risk factors (r = 0.2407, p = 0.0574). Due to the great expense of current testing for bone mass density loss, the results of this study may help clinicians more readily identify markers for increased risk of osteoporosis through simple height measurements and osteoporosis risk factor assessments during annual visits.


Hepatitis viruses and the neonate.
Great progress has been made in the last 10 years in the understanding of the various types of viral hepatitis, and new viruses, concepts, therapies, preventive measures, and control strategies have been recognized. Even more agents, vaccines, and drugs will be discovered or developed in the future, and pediatricians increasingly will be expected to provide guidance to patients and to the community on the importance and use of these new tools.


Developmental evolution: getting robust about robustness.
In the context of development, a process is robust if it can proceed normally despite the enormous capacity for perturbation inherent in all biological systems. A new mode of theoretical modeling of genetic networks holds great promise for increasing our understanding of both the quantitative mechanisms of robustness and its evolutionary impact.


Widening of the popliteal hiatus on sagittal MRI view plays a critical role in the mechanical signs of discoid lateral meniscus.
This study was undertaken to elucidate the clinical significance of widening of the popliteal hiatus on magnetic resonance imaging (MRI) after a torn discoid lateral meniscus (DLM). Included are 125 knees with meniscal disorders after arthroscopic surgery, divided according to preoperative MRI and symptoms into group A (torn DLM with mechanical symptoms,11 knees); group B (torn DLM without mechanical symptoms,41 knees); group C (asymptomatic DLM, 19 knees); and group D (medial meniscal tears, 54 knees). Popliteal hiatus width was measured on sagittal and coronal MRI. During arthroscopy, total meniscectomy or central partial meniscectomy combined repair of the remaining part was performed in group A and group B. Outcomes were evaluated with MRI, the Tegner, Lysholm Knee Scoring Scale, and visual analog scale (VAS) scores. The preoperative width of the popliteal hiatus was significantly larger in group A than in groups C and D (P < 0.05) on both views. Group A had a wider popliteal hiatus on sagittal view compared with group B (P < 0.05); group B had a wider popliteal hiatus on coronal view compared with group D (P < 0.05). The width of the popliteal hiatus on sagittal view was significantly reduced after surgery in group A (P < 0.05). In groups A and B, Lysholm and Tegner scores were improved, while VAS scores were reduced (all P < 0.05). Widening of the popliteal hiatus on MRI was correlated with torn DLM and accompanied mechanical symptoms. Arthroscopic central partial menisectomy and stabilization of the posterior part of the middle body anterior to the popliteus tendon were effective for the treatment of torn DLM. These findings may help guide appropriate treatment for torn DLM. II.


Protective effects of dietary icariin on lipopolysaccharide-induced acute oxidative stress and hepatopancreas injury in Chinese mitten crab, Eriocheir sinensis.
To investigate the effects of dietary icariin (ICA) supplementation on acute oxidative stress and hepatopancreatic injury induced by lipopolysaccharide (LPS) injection in Eriocheir sinensis, an 8-week feeding trial of crabs was conducted using 4 diets with different supplementation levels of ICA (0, 50, 100, and 200 mg/kg diet weight, respectively), and then challenged with LPS of 400 μg/kg body weight for 6 h. Results showed that 100 mg/kg ICA supplementation increased the antioxidant capacity, reduced the stress-related indicators in haemolymph, strengthen the mitochondrial membrane potential, and reduce apoptosis compared to the single LPS-treated crabs. The expressions of apoptosis-related genes and proteins were also evaluated to further understand the effects of dietary ICA pretreatment on LPS-induced cell apoptosis. As a result, dietary 100 mg/kg diet weight ICA pre-addition significantly down-regulated the expression of HSP60, HSP70, Caspase 3c, Caspase 8, Caspase 3, Caspase 9, P38, and Bax (P < 0.05), and alleviated the suppressed expression of PI3K, AKT, MEK, and Bcl-2 (P < 0.05) in crabs challenged with LPS. Overall, this research reveals that ICA supplementation of 100 mg/kg diet weight could enhance the resistance to oxidative damage and apoptosis in E. sinensis facing LPS challenge.


Using indication embeddings to represent patient health for drug safety studies.
The electronic health record is a rising resource for quantifying medical practice, discovering the adverse effects of drugs, and studying comparative effectiveness. One of the challenges of applying these methods to health care data is the high dimensionality of the health record. Methods to discover the effects of drugs in health data must account for tens of thousands of potentially relevant confounders. Our goal in this work is to reduce the dimensionality of the health data with the aim of accelerating the application of retrospective cohort studies to this data. Here, we develop indication embeddings, a way to reduce the dimensionality of health data while capturing information relevant to treatment decisions. We evaluate these embeddings using external data on drug indications. Then, we use the embeddings as a substitute for medical history to match patients and develop evaluation metrics for these matches. We demonstrate that these embeddings recover the therapeutic uses of drugs. We use embeddings as an informative representation of relationships between drugs, between health history events and drug prescriptions, and between patients at a particular time in their health history. We show that using embeddings to match cohorts improves the balance of the cohorts, even in terms of poorly measured risk factors like smoking. Unlike other embeddings inspired by word2vec, indication embeddings are specifically designed to capture the medical history leading to the prescription of a new drug. For retrospective cohort studies, our low-dimensional representation helps in finding comparator drugs and constructing comparator cohorts.


Do Reader Characteristics Affect Diagnostic Efficacy in Screening Mammography? A Systematic Review.
To examine reader characteristics associated with diagnostic efficacy in the interpretation of screening mammograms. A systematic search of the literature was conducted using databases such as Cochrane, Scopus, Medline, Embase, Web of Science, and PubMed. Search terms were combined with "AND" or "OR" and included: "Radiologist's characteristics AND performance"; "radiologist experience AND screening mammography"; "annual volume read AND diagnostic efficacy"; "screening mammography performance OR diagnostic efficacy". Studies were included if they assessed reader performance in screening mammography interpretation, breast readers, used a reference standard to assess the performance, and were published in the English language. Twenty-eight studies were reviewed. Increasing reader's age was associated with lower false positive rates. No association was found between gender and performance. Half of the studies showed no association between years of reading mammograms and performance. Most studies showed that high reading volume was more likely to be associated with increased sensitivity, cancer detection rates (CDR), lower recall rate, and lower false positive rates. Inconsistent associations were found between fellowship training in breast imaging and reader performance. Specialization in breast imaging was associated with better CDR, sensitivity, and specificity. Limited studies were available to establish the association between performance and factors such as time spent in breast imaging (n = 2), screening focus (n = 1), formal rotation in mammography (n = 1), owner of practice (n = 1), and practice type (n = 1). No individual characteristics is associated with versatility in diagnostic efficacy, albeit reading volume and specialization in breast imaging appear to be associated with with increased sensitivity and CDR without significantly affecting other performance metrics.


Human N-acetylation genotype determination with urinary caffeine metabolites.
The human acetylation genotype was determined by measuring urinary caffeine metabolites by use of a modification of a previously published HPLC method. The problem of separation of 7-methylxanthine (7X) from 1-methyluric acid (IU) in urine extracts was achieved by adding a phenyl column, in tandem with a C18 reverse-phase column, by means of a methanol:aqueous acetic acid gradient elution system. The urinary molar ratios of (AAMU)/(AAMU + 1U + 1X) and (AAMU)/(1X) were estimated in 20 subjects phenotyped with dapsone, with 100% concordance for the [AAMU]/[1X] ratio. A population study of 42 unrelated individuals exhibited trimodal distribution in acetylation capacity, consistent with the Hardy-Weinberg theory of population genetics. Definitive pedigree analysis of 16 families (75 subjects) resulted in significant similarity between the observed genotypic matings and those expected by classical Mendelian segregation. This noninvasive genotyping method promises to be useful in future investigation of the relationship between the human acetylation polymorphism and clinical disorders.


3D NiO nanoflakes/carbon fiber meshwork: Facile preparation and utilization as general platform for photocathodic bioanalysis.
Herein, we describe a customized approach for facile preparation of three-dimensional (3D) NiO nanoflakes (NFs)/carbon fiber meshwork (CFM) and its validation as a common photocathode matrix for photoelectrochemical (PEC) bioanalysis, which to our knowledge has not been reported. Specifically, 3D NiO NFs/CFM was fabricated by a sequential liquid phase deposition and annealing process, which was then characterized by scanning electron microscopy, X-ray photoelectron spectrum, UV-vis absorption spectra and N2 adsorption-desorption measurement. Sensitized by BiOI and incorporated with an alkaline phosphatase (ALP)/tyrosinase (TYR) bi-enzyme cascade system, a sensitive split-type cathodic PEC bioanalysis for the determination of ALP was achieved. This method can detect ALP concentrations down to 3 × 10-5 U L-1 with a linear response range of 0.001-10 U L-1. Moreover, this proposed system exhibited good selectivity, stability and excellent performance for real sample analysis. This research features the facile preparation of 3D NiO NFs/CFM that could acts as a universal matrix for photocathodic analysis, and is envisioned to stimulate more effort for advanced 3D photocathode for PEC bioanalysis and beyond.


Mononuclear Alkali Metal Organoperoxides Stabilized by an NNNN-Macrocycle and Short Hydrogen Bonds from ROOH Molecules.
A series of light alkali metal organoperoxides [MOOR] (M=Li, Na, K; R=tBu, CMe2 Ph) were isolated in mononuclear form, aided by the tetradentate and neutral NNNN-type macrocycle Me4 TACD (L; Me4 [12]aneN4 =1,4,7,10-tetramethyl-1,4,7,10-tetraazacyclododecane) and strong hydrogen bonds from additional ROOH molecules. The Na and K compounds are characterized by short O-H⋅⋅⋅O contacts, in the case of the Na derivative as short as 2.41 Å.


Protective effect of chlorogenic acid on the focal cerebral ischemia reperfusion rat models.
The aim of the study was to investigate the protective characteristic of chlorogenic acid, a natural glucosyl xanthone found in Lonicera Japonica on the cerebral ischemia reperfusion injury and the underlying mechanism. Focal cerebral ischemia reperfusion model was built by blocking the left middle cerebral artery in rats by using the suture-occluded method. Before operation, the corresponding drugs were given for each group once a day for 7 days. After 1 h of final administration, the model was built, after operation, reperfusion was conducted for 22 h, Before the reperfusion 10 min tail vein injection of large, medium and small dose of chlorogenic acid and then mortality was calculated, and Neurological deficit score (NDS) was conducted, and serum was collected to measure the NSE level; a 2 mm thick brain slice located at the intersection of optic nerves was collected for TTC staining, and the percentage of cerebral infarction area was calculated; brain homogenate was collected to measure the ICAM-1, VCAM-1, EPO and HIF-1α levels in brain tissue of cerebral ischemia reperfusion rat models; NGF was detected using immunohistochemical method; the morphological changes in brain tissue was observed with HE staining. All focal cerebral ischemia reperfusion rat models were duplicated successfully. Every chlorogenic acid group with different dosage can significantly reduce the mortality, NDS and cerebral infarction area of rats, and significantly increase the EPO, HIF-1α and NGF levels in brain tissue; significantly improve the pathological lesions of hippocampus and cortex in brain tissue. The results showed that chlorogenic acid could protect the focal cerebral ischemia reperfusion injury rat models by adjusting the inflammatory factor, hypoxia factor and nerve growth factor.


Regulation of diaminopimelate decarboxylase synthesis in Escherichia coli. III. Nucleotide sequence and regulation of the lysR gene.
The complete nucleotide sequence of the lysR gene, which encodes the activatory protein required for lysA expression, has been determined. Bal31 deletions and translational fusions were used to localize the promoter region and the initiator ATG of the lysR gene which encodes a 311 amino acid polypeptide. Both lysA and lysR coding sequences were found to be divergent and separated by a very short intergenic region consisting of 121 base-pairs between the postulated ATGs of the two proteins. Transfer of the whole lysR gene on a plasmid carrying a lysR-lacZ fusion shows that lysR expression is autoregulated by a factor of 7. The same binding site (73 base-pairs fragment) could be involved in both effects of the LysR product, acting simultaneously as an operator for lysR expression and an initiator for lysA expression. The genetic organization of the whole region (4127 base-pairs) is given. A strikingly symmetrical pattern is observed with the four tightly packed galR, lysA, lysR and orfX (an unidentified open reading frame) genes, in a very unusual arrangement of both divergent and convergent overlapping transcription units.


α1-Adrenergic drugs modulate differentiation and cell death of human erythroleukemia cells through non adrenergic mechanism.
Preliminary data showed that α1-adrenergic antagonists induce apoptosis and a switch towards megakaryocytic differentiation in human erythroleukemia cells. To test the hypothesis whether survival and differentiation of erythroleukemia cells are under control of α1-adrenergic signalling, we examined α1-adrenoceptor expression of erythroleukemia cells and compared the in vitro effects of α-adrenergic antagonists with those of agonists. We discovered that α1-adrenergic agonists suppress both erythroid differentiation and growth of erythroleukemia cells concomitant with lipofuscin accumulation, autophagy and necrotic cell death. α1-adrenergic agonists also inhibit the in vitro growth of physiologic hematopoietic progenitors obtained from umbilical cord blood with high selectivity for the erythroid lineage. Interestingly, the observed effects could not be related to α1-adrenoceptors, even though agonists and antagonists displayed opposing effects regarding cellular growth and differentiation of erythroleukemia cells. Our data suggest that the effects of α1-adrenergic drugs are related to a non-adrenoceptor binding site, controlling the fate of erythroid progenitor cells towards differentiation and cell death. Since the observed effects are not mediated through adrenoceptors, the physiologic relevance of our data remains unclear, so far. Nevertheless, the identification of the still unknown binding site(s) might disclose new insights into regulation of erythroid differentiation and cell death.


An Integrated Thermopile-Based Sensor with a Chopper-Stabilized Interface Circuit for Presence Detection.
This paper presents a sensor-readout circuit system suitable for presence detection. The sensor consists of a miniaturized polysilicon thermopile, realized employing MEMS micromachining by STMicroelectronics, featuring a responsivity value equal to 180 V/W, with 13 ms response time. The readout circuit is implemented in a standard 130-nm CMOS process. As the sensor output signal behaves substantially as a DC, the interface circuit employs the chopper technique in order to minimize offset and noise contributions at low frequency, achieving a measured input referred offset standard deviation equal to 1.36 μ V. Measurements show that the presented system allows successfully detecting the presence of a person in a room standing at 5.5 m from the sensor. Furthermore, the correct operation of the system with moving targets, considering people either walking or running, was also demonstrated.


Closed versus open mitral commissurotomy in pure noncalcific mitral stenosis: hemodynamic studies before and after operation.
Controversy persists regarding whether the efficacy of closed instrumental mitral commissurotomy compares well enough with that of open commissurotomy to warrant its continued use. The purpose of this study was to compare the results of operation as determined by catheterization studies in 63 patients with pure, severe, and noncalcified mitral stenosis. The patients were randomly assigned to one of two groups: thirty-two patients were operated on by the closed technique (group I) and 31 by the open technique (group II). All patients underwent left-sided and right-sided catheterization before and 4 months after operation. Preoperatively the two groups were statistically similar with regard to major clinical data and hemodynamic findings. There were no deaths at operation or systemic embolism in the two groups. The prevalence of surgically induced mitral regurgitation was similar in the two groups (12.4% versus 12.9%). Pulmonary arterial pressure and arteriolar and total pulmonary vascular resistance decreased significantly in the two groups. Pulmonary capillary wedge pressure decreased from 23.3 +/- 8.5 to 15.8 +/- 7 mm Hg in group I (p less than 0.001) and from 23.7 +/- 6 to 14 +/- 5.8 mm Hg in group II (p less than 0.001). Cardiac index increased from 2.86 +/- 0.84 to 3.14 +/- 0.78 L/min/m2 in group I, but this increase did not reach statistical significance. In group II cardiac index increased from 2.89 +/- 0.6 to 3.6 +/- 0.6 L/min/m2 (p less than 0.005). The mean and end-diastolic transmitral pressure gradients decreased significantly in the two groups, but the decrease was statistically greater in the open mitral commissurotomy group (p less than 0.001). Mitral valve area increased from 0.82 +/- 0.18 to 1.4 +/- 0.40 cm2 in group I (p less than 0.01) and from 0.84 +/- 0.15 to 2.14 +/- 0.53 cm2 in group II (p less than 0.001). The mean increase in mitral valve area was 0.61 cm2 in group I and 1.34 cm2 in group II (p less than 0.001). At exercise, in patients with resting pulmonary capillary wedge pressures of 18 mm Hg or less, cardiac index increased by 36% in group I (23 patients) and 48% in group II (24 patients), because of a smaller mitral valve area in group I (1.61 +/- 0.39 cm2) than in group II (2.45 +/- 0.65 cm2). Thus open commissurotomy improved hemodynamic values to a greater extent than closed commissurotomy at both rest and exercise.(ABSTRACT TRUNCATED AT 400 WORDS)


Septum formation, cell division, and sporulation in mutants of yeast deficient in proteinase B.
Mutants of Saccharomyces cerevisiae that carry lesions in the structural gene for proteinase B, prb1, have been isolated. Proteinase B was thought to be involved in activation of chitin synthase zymogen to allow septum formation during budding and to be involved in sporulation. The prb1 mutants are able to grow and divide and they form apparently normal septa that contain chitin. Most diploids homozygous for prb1 mutations are unable to complete sporulation.


Characteristics of HONO and its impact on O3 formation in the Seoul Metropolitan Area during the Korea-US Air Quality Study.
Photolysis of nitrous acid (HONO) is recognized as an early-morning source of OH radicals in the urban air. During the Korea-US air quality (KORUS-AQ) campaign, HONO was measured using quantum cascade - tunable infrared laser differential absorption spectrometer (QC-TILDAS) at Olympic Park in Seoul from 17 May, 2016 to 14 June, 2016. The HONO concentration was in the range of 0.07-3.46 ppbv, with an average of 0.93 ppbv. Moreover, it remained high from 00:00-05:00 LST. During this time, the mean concentration was higher during the high-O3 episodes (1.82 ppbv) than the non-episodes (1.20 ppbv). In the morning, the OH radicals that were produced from HONO photolysis were 50% higher (0.95 pptv) during the high-O3 episodes than the non-episodes. Diurnal variations in HOx and O3 concentrations were simulated by the F0AM model, which revealed a difference of ~20 ppbv in the daily maximum O3 concentrations between the high-O3 episodes and non-episodes. Furthermore, the HONO concentration increased with an increase in relative humidity (RH) up to 80%; the highest HONO was associated with the top 10% NO2 in each RH group, confirming that NO2 is one of the main precursors of HONO. At night, the conversion ratio of NO2 to HONO was estimated to be 0.88×10-2 h-1; this ratio was found to increase with an increase in RH. The Aitken mode particles (30-120 nm), which act as catalyst surfaces, exhibited a similar tendency with a conversion ratio that increased along with RH, indicating the coupling of surfaces with HONO conversion. Using an artificial neural network (ANN) model, HONO concentrations were successfully simulated with measured variables (r2 = 0.66 as an average of five models). Among these variables, NOx, aerosol surface area, and RH were found to be the main factors affecting the ambient HONO concentrations. The results reveal that RH facilitates the conversion of NO2 to HONO by constraining the availability of aerosol surfaces. This study demonstrates the coupling of HONO with the HOx-O3 cycle in the Seoul Metropolitan Area (SMA) and provides practical evidence of the heterogeneous formation of HONO by employing the ANN model.


Conservation of the c-myc coding sequence in transduced feline v-myc genes.
We have cloned the normal feline c-myc locus and determined the nucleotide sequence of all three exons. The feline c-myc gene shows close homology to other mammalian c-myc genes, particularly human c-myc. The feline and human sequences are colinear within the open reading frame for the putative c-myc product but show insertions and deletions relative to each other outside this domain. We have also analyzed a cloned FeLV provirus, CT4, which contains the host-derived myc gene. In this provirus the v-myc sequences are located at the 3' end of the pol gene, replacing pol and env sequences. Nucleotide sequence analysis of CT4 shows an open reading frame for a v-myc gene product which may be expressed without fusion to any viral protein sequences. This contrasts with another FeLV v-myc (LC), in which myc and gag sequences were found to be fused. Unlike previously identified avian v-myc genes, the feline v-myc genes contain exon 1-derived sequences, but these have been truncated or internally deleted. The FeLV CT4 v-myc sequence shows very few coding changes relative to c-myc and the FeLV LC v-myc coding sequence is unchanged relative to c-myc apart from fusion to gag. These results are discussed in relation to the mechanism of transduction and activation of myc by FeLV.


Distribution and variation of bacitracin synthetase gene sequences in laboratory stock strains of Bacillus licheniformis.
Distribution and variation of bacitracin synthetase gene (bac) sequences in 22 laboratory stock strains of Bacillus licheniformis were studied by Southern hybridization of bac gene probes from B. licheniformis ATCC 10716 to genomic PstI or HindIII restriction fragments. Eleven strains gave hybridization signals. These hybridization patterns were classed into two types. Eight strains showed similar patterns to that of ATCC 10716 and all, except one, produced bacitracin. The three strains showed fairly different hybridization patterns from that of ATCC 10716, and one (ATCC 33632) of them produced bacitracin. None of the remaining 11 strains, including ATCC 14580 (type strain), gave any hybridization signals. All strains carrying bac gene sequences were erythromycin resistant. With one exception, all strains without bac gene sequences were erythromycin sensitive. These results show that B. licheniformis strains are divided into two groups with respect to presence of bac gene sequences and erythromycin resistance.


Extended storage of platelets in an artificial medium with the platelet activation inhibitors prostaglandin E1 and theophylline.
The addition of platelet activation inhibitors to the anticoagulant and the replacement of plasma with a fortified electrolyte medium have been shown separately in previous work to improve the storage of platelets during a 2-week period. In the present study, we have combined these strategies to investigate whether a synergistic improvement could be obtained. A total of 85 concentrates was studied with 300 nM prostaglandin E1 (PGE1) and 1.9 mM theophylline added to the whole blood, platelet-rich plasma (PRP), and/or the storage medium during the preparation of platelet concentrates. In vitro markers of platelet aggregation, respiration, and cell integrity were measured over a 20-day storage period and evaluated in an analysis of variance. We found that a single-step addition of PGE1 and theophylline to the PRP prior to centrifugation was not sufficient in terms of preventing a rapid fall in pH, rise in pO2, fall in pCO2, loss of hypotonic shock response, and loss of aggregation response, compared to the addition of the inhibitors to the storage medium used to resuspend the platelet pellet. Factorial analysis showed that a reduction in the surface-to-volume ratio of the storage container further improved the maintenance of platelet respiration and, for three in vitro markers (hypotonic shock response, released lactic dehydrogenase, and surface glycoprotein Ib levels) displayed an interactive effect with the inhibitors. The addition of protease inhibitors to the formulation of PGE1 and theophylline showed further improvement in several markers. These findings demonstrate the possibility of preserving platelets for 15-20 days with the synergistic effects of activation inhibitors and an electrolyte storage medium fortified with citrate, buffers, and dextrose.(ABSTRACT TRUNCATED AT 250 WORDS)


Preparation of budesonide-loaded porous PLGA microparticles and their therapeutic efficacy in a murine asthma model.
Inhaling corticosteroids, such as budesonide (BD), is the most common treatment for asthma. However, frequent steroid administration is associated with many side effects. We hypothesized that porous microparticles containing BD could provide an effective treatment method for asthma, as the sustained delivery of corticosteroid and a reduced number of doses could be achieved using porous polymeric microparticles. Porous microparticles were prepared from poly(lactic-co-glycolic acid) (PLGA) by a water-in-oil-in-water double emulsion method with ammonium bicarbonate as the porogen. Varying the porogen concentration controlled the morphology, particle size, and pore size of the PLGA microparticles, with particle size and pore size increasing as the porogen concentration increased. The BD loading efficiency in the porous PLGA microparticles was about 60%, and BD was released from the porous microparticles in a sustained manner for 24h in vitro. Lung uptake efficiency of the porous PLGA microparticles in mice was significantly higher than that of non-porous PLGA microparticles. Budesonide-loaded porous PLGA microparticles were delivered to asthmatic mice, and the numbers of inflammatory cells in bronchoalveolar lavage (BAL) fluid and tissue sections were significantly reduced when the drug was administrated every 3days. We also found significantly reduced bronchial hyperresponsiveness of asthmatic mice after treatment with budesonide-loaded porous PLGA microparticles. This approach to controlling the porous structure of polymeric microparticles, as well as the release behavior of drugs from the microparticles, could have useful applications in the pulmonary delivery of many therapeutic drugs.


Prevalence of right ventricular dysfunction and prognostic significance in heart failure with preserved ejection fraction.
There is a paucity of data characterizing right ventricular performance in heart failure with preserved ejection fraction (HFpEF) using the gold standard of cardiovascular magnetic resonance imaging (CMR). We aimed to assess the proportion of right ventricular systolic dysfunction (RVD) in HFpEF and the relation to clinical outcomes. As part of a single-centre, prospective, observational study, 183 subjects (135 HFpEF, and 48 age- and sex-matched controls) underwent extensive characterization with CMR. transthoracic echocardiography, blood sampling and six-minute walk testing. Patients were followed for the composite endpoint of death or HF hospitalization. RVD (defined as right ventricular ejection fraction < 47%) controls was present in 19% of HFpEF. Patients with RVD presented more frequently with lower systolic blood pressure, atrial fibrillation, radiographic evidence of pulmonary congestion and raised cardiothoracic ratio and larger right ventricular volumes. During median follow-up of 1429 days, 47% (n = 64) of HFpEF subjects experienced the composite endpoint of death (n = 22) or HF hospitalization (n = 42). RVD was associated with an increased risk of composite events (Log-Rank p = 0.001). In multivariable Cox regression analysis, RVD was an independent predictor of adverse outcomes (adjusted Hazard Ratio [HR] 3.946, 95% CI 1.878-8.290, p = 0.0001) along with indexed extracellular volume (HR 1.742, CI 1.176-2.579, p = 0.006) and E/E' (HR 1.745, CI 1.230-2.477, p = 0.002). RVD as assessed by CMR is prevalent in nearly one-fifth of HFpEF patients and is independently associated with death and/or hospitalization with HF.The trial was registered retrospectively on ClinicalTrials.gov (Identifier: NCT03050593). The date of registration was February 06, 2017.


Synthesis of highly substituted acenes through rhodium-catalyzed oxidative coupling of arylboron reagents with alkynes.
The rhodium-catalyzed oxidative 1:2 coupling reactions of arylboronic acids or their esters with alkynes smoothly proceed to produce the corresponding annulated products. Of special note, highly substituted, readily soluble, and tractable anthracene and tetracene derivatives can be obtained selectively from 2-naphthyl- and 2-anthrylboron reagents, respectively.


Biological application of multi-component nanowires in hybrid devices powered by F1-ATPase motors.
In this paper, construction of hybrid device by integrating nanowires with F(1)-ATPase motors is described. The nickel nanowires and multi-segment nanowires, including gold and nickel, were fabricated by electrochemical deposition in nanoporous templates. The nickel nanowires functionalized by biotinylated peptide can be assembled directly onto F(1)-ATPase motors to act as the propellers. If the multi-component nanowires, including gold and nickel, were selectively functionalized by the thiol group modified ssDNA and the synthetic peptide, respectively, the biotinylated F(1)-ATPase motors can be attached to the biotinylated peptide on nickel segment of the nanowires. Then, the multi-component nanowires can also be used as the propellers, and one may observe the rotations of the multi-component nanowires driven by F(1)-ATPase motors. Therefore, introduction of multiple segments along the length of a nanowire can lead to a variety of multiple chemical functionalities, which can be selectively bound to cells and special biomolecules. This method provides an insight for the construction of other hybrid devices with its controlling arrangement of different biomolecule on designed nanometer scale structures.


Development of micro-solid phase extraction with titanate nanotube array modified by cetyltrimethylammonium bromide for sensitive determination of polycyclic aromatic hydrocarbons from environmental water samples.
This paper described a simple and novel analytical technique for the determination of polycyclic aromatic hydrocarbons (PAHs) in environmental water samples. A micro-solid phase extraction (μ-SPE) was developed utilizing cetyltrimethylammonium bromide modified ordered TiO(2) nanotube array. The experimental results indicated that modified TiO(2) nanotube arrays demonstrated an excellent merit on the preconcentration of PAHs, and there were excellent linear relationships between peak area and the concentration of PAHs in the range of 0.2-100 μg L(-1) and 1.0-100 μg L(-1), respectively. The detection limits of proposed method for the targeted PAHs were in the range of 0.026-0.82 μg L(-1) (S/N = 3). The real-world environmental water samples were used to validate the applicability of the proposed method and good spiked recoveries were in the range of 75.0-114%. All these results demonstrated that this new μ-SPE technique was a viable alternative to conventional enrichment techniques for the extraction and analysis of PAHs in complex samples.


Extracellular and intracellular degradation of collagen by trophoblast giant cells in acute fasted mice examined by electron microscopy.
The fine structure of trophoblast giant cells and their interaction with collagen at the antimesometrial region on the 9th day of pregnancy was examined in fed and acute fasted mice. Collagen fibrils and filamentous aggregates (disintegrating collagen fibrils) were observed in the extracellular space. Three types of intracellular vacuoles containing collagen fibrils were present: vacuole type A exhibited typical cross-banded collagen immersed in finely granular electron-translucent material; and vacuoles type B and C showed electron-opaque granular material containing, respectively, faint cross-banded collagen and narrow clear stripes often with faint periodicity. In fed animals vacuoles type B were absent and the others were less evident. Only fasted animals showed extracellular acid phosphatase activity on collagen fibrils, filamentous aggregates and confined regions of the extracellular space. Intracellular acid phosphatase activity was observed in vacuoles type B and in lysosomes. The results indicate that trophoblast giant cells are capable of breaking down extracellular collagen and also of internalizing collagen for intracellular degradation. It is likely that these events are part of the process of invasion of the uterine wall. However, in fasted mice, collagen breakdown is more pronounced, and it may therefore contribute to the provision of amino acids and other nutrients for the undernourished fetus.


Retroviruses as probes for mammalian development: allocation of cells to the somatic and germ cell lineages.
Preimplantation mouse embryos were infected with a recombinant retrovirus, which serves as a genetic marker for the progeny of an infected blastomere. Quantitative analysis of proviruses carried in mosaic animals indicated that the molarity of individual proviral bands was equal in almost all tissues. The cells that give rise to the embryo proper must therefore intermingle extensively before final tissue allocation to ensure equal contribution of founder cells to all somatic tissues. The distribution of molarities of individual proviruses suggested that somatic lineages are derived from at most eight founder cells. About half of the proviruses were present in the germ line and the somatic tissues of mosaic animals, while the remaining proviruses were found either in the germ line or in the somatic tissues, but not in both. Our results suggest that at least three cells form the germ line and are set aside prior to somatic tissue allocation.


Black hole spin-orbit misalignment in the x-ray binary MAXI J1820+070.
The observational signatures of black holes in x-ray binary systems depend on their masses, spins, accretion rate, and the misalignment angle between the black hole spin and the orbital angular momentum. We present optical polarimetric observations of the black hole x-ray binary MAXI J1820+070, from which we constrain the position angle of the binary orbital. Combining this with previous determinations of the relativistic jet orientation, which traces the black hole spin, and the inclination of the orbit, we determine a lower limit of 40° on the spin-orbit misalignment angle. The misalignment must originate from either the binary evolution or black hole formation stages. If other x-ray binaries have similarly large misalignments, these would bias measurements of black hole masses and spins from x-ray observations.


Concentration of sulbactam and ampicillin in serum and the myometrium.
Sulbactam 1g and ampicillin 2g were administered intravenously to 12 patients, and concentrations of the drugs were determined in the serum and myometrium for up to 120 minutes after infusion. The ratio of sulbactam to ampicillin was about 1:2 in the serum and myometrium. Both drugs penetrated well into the myometrium, and median concentrations of sulbactam and ampicillin were 65% and 68%, respectively, of those in the serum. Sulbactam/ampicillin was effective for perioperative prophylaxis and should be effective as therapy for pelvic infections.


Sequential pathological studies in goats infected intratracheally with Aspergillus fumigatus.
Intratracheal inoculation of goats with Aspergillus fumigatus spores resulted in the development of characteristic gross and microscopic lesions. The lesions were restricted to lungs and there was no dissemination of infection to other tissues of the body except liver in one goat 16 days after infection. The experiment was continued for 37 days. Gross changes in lungs were observed up to the 24th day post-infection. The lesions, in general, included congestion and oedema in the first 6 days followed by the development of varying greyish-white nodules in the lungs. Microscopic changes consisted of granulomatous reaction with well developed granulomas in lungs. Hyphae and conidiophores with fruiting bodies of Aspergillus fumigatus could be demonstrated in sections up to 24 days of infection. Reisolation of the fungus consistently was achieved up to 24 days. It is concluded that intratracheal inoculation of Aspergillus fumigatus spores in goats leads to pulmonary aspergillosis up to 24 days.