Stressful life events are important contributors to relapse in recovering cocaine addicts, but the mechanisms by which they influence motivational systems are poorly understood. Studies suggest that ...stress may "set the stage" for relapse by increasing the sensitivity of brain reward circuits to drug-associated stimuli. We examined the effects of stress and corticosterone on behavioral and neurochemical responses of rats to a cocaine prime after cocaine self-administration and extinction. Exposure of rats to acute electric footshock stress did not by itself reinstate drug-seeking behavior but potentiated reinstatement in response to a subthreshold dose of cocaine. This effect of stress was not observed in adrenalectomized animals, and was reproduced in nonstressed animals by administration of corticosterone at a dose that reproduced stress-induced plasma levels. Pretreatment with the glucocorticoid receptor antagonist RU38486 did not block the corticosterone effect. Corticosterone potentiated cocaine-induced increases in extracellular dopamine in the nucleus accumbens (NAc), and pharmacological blockade of NAc dopamine receptors blocked corticosterone-induced potentiation of reinstatement. Intra-accumbens administration of corticosterone reproduced the behavioral effects of stress and systemic corticosterone. Corticosterone treatment acutely decreased NAc dopamine clearance measured by fast-scan cyclic voltammetry, suggesting that inhibition of uptake₂-mediated dopamine clearance may underlie corticosterone effects. Consistent with this hypothesis, intra-accumbens administration of the uptake₂ inhibitor normetanephrine potentiated cocaine-induced reinstatement. Expression of organic cation transporter 3, a corticosterone-sensitive uptake₂ transporter, was detected on NAc neurons. These findings reveal a novel mechanism by which stress hormones can rapidly regulate dopamine signaling and contribute to the impact of stress on drug intake.
Silymarin prevents liver disease in many experimental rodent models, and is the most popular botanical medicine consumed by patients with hepatitis C. Silibinin is a major component of silymarin, ...consisting of the flavonolignans silybin A and silybin B, which are insoluble in aqueous solution. A chemically modified and soluble version of silibinin, SIL, has been shown to potently reduce hepatitis C virus (HCV) RNA levels in vivo when administered intravenously. Silymarin and silibinin inhibit HCV infection in cell culture by targeting multiple steps in the virus lifecycle. We tested the hepatoprotective profiles of SIL and silibinin in assays that measure antiviral and anti-inflammatory functions. Both mixtures inhibited fusion of HCV pseudoparticles (HCVpp) with fluorescent liposomes in a dose-dependent fashion. SIL inhibited 5 clinical genotype 1b isolates of NS5B RNA dependent RNA polymerase (RdRp) activity better than silibinin, with IC50 values of 40-85 µM. The enhanced activity of SIL may have been in part due to inhibition of NS5B binding to RNA templates. However, inhibition of the RdRps by both mixtures plateaued at 43-73%, suggesting that the products are poor overall inhibitors of RdRp. Silibinin did not inhibit HCV replication in subgenomic genotype 1b or 2a replicon cell lines, but it did inhibit JFH-1 infection. In contrast, SIL inhibited 1b but not 2a subgenomic replicons and also inhibited JFH-1 infection. Both mixtures inhibited production of progeny virus particles. Silibinin but not SIL inhibited NF-κB- and IFN-B-dependent transcription in Huh7 cells. However, both mixtures inhibited T cell proliferation to similar degrees. These data underscore the differences and similarities between the intravenous and oral formulations of silibinin, which could influence the clinical effects of this mixture on patients with chronic liver diseases.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Summary
Background
B‐type CpG oligodeoxynucleotides (ODN) is currently used in clinical trials because of its prolonged half–life, which is due to its phosphorothioate backbone. A‐type CpG ODN is a ...stronger inducer of IFN but has an unstable phosphodiester backbone that has so far prohibited its clinical use. However, upon association with virus‐like particles (VLP) consisting of the bacteriophage Qβ coat protein, A‐type CpG ODN can be stabilized and can become an efficient adjuvant in mice. Therefore, the phase I/IIa study presented represents the first test of A‐type CpGs in humans.
Objective
To test the safety, tolerability and clinical efficacy of QbG10 as an adjuvant for subcutaneous immunotherapy with a house dust mite (HDM) allergen extract in allergic patients.
Methods
A single centre, open‐label phase I/IIa study evaluated the safety, tolerability and clinical efficacy of QbG10 as an adjuvant to immunotherapy with a subcutaneous HMD allergen extract in 20 patients suffering from HDM allergy. Twenty‐one patients were enrolled between March and July 2005. Individual immunotherapy lasted 10 weeks. Clinical end‐points included questionnaires, conjunctival provocation, skin prick tests and the measurement of allergen‐specific IgG and IgE.
Results
QbG10 was well tolerated. Almost complete tolerance to the allergen was observed in conjunctival provocation testing after treatment with QbG10, and symptoms of rhinitis and allergic asthma were significantly reduced. Within 10 weeks of therapy, patients were nearly symptom‐free and this amelioration lasted for at least 38 weeks post‐treatment. Following injections of QbG10 and HDM allergen extract, allergen‐specific IgG increased, while there was a transient increase in allergen‐specific IgE titres. Skin reactivity to HDM was reduced.
Conclusion
The subcutaneous application of HDM allergen, together with A‐type CpG ODN packaged into VLP, was safe. All patients achieved practically complete alleviation of allergy symptoms after 10 weeks of immunotherapy. This promising clinical outcome calls for larger placebo‐controlled phase II studies.
Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer with precursor B-cell ALL (pB-ALL) accounting for ~ 85% of the cases. Childhood pB-ALL development is influenced by genetic ...susceptibility and host immune responses. The role of the intestinal microbiome in leukemogenesis is gaining increasing attention since Vicente-Dueñas’ seminal work demonstrated that the gut microbiome is distinct in mice genetically predisposed to ALL and that the alteration of this microbiome by antibiotics is able to trigger pB-ALL in
Pax5
heterozygous mice in the absence of infectious stimuli. In this review we provide an overview on novel insights on the role of the microbiome in normal and preleukemic hematopoiesis, inflammation, the effect of dysbiosis on hematopoietic stem cells and the emerging importance of the innate immune responses in the conversion from preleukemic to leukemic state in childhood ALL. Since antibiotics, which represent one of the most widely used medical interventions, alter the gut microbial composition and can cause a state of dysbiosis, this raises exciting epidemiological questions regarding the implications for antibiotic use in early life, especially in infants with a a preleukemic “first hit”. Sheading light through a rigorous study on this piece of the puzzle may have broad implications for clinical practice.
Congenital mesoblastic nephroma (CMN) is a rare pediatric renal tumor with low malignant potential that most commonly occurs early in infancy. Treatment strategies are based on the few published CMN ...series, while a significant number of CMN patients have been described in case reports. The aim of this narrative review was to create an up‐to‐date overview of the literature. Complete surgical removal is curative in most cases. The risk of treatment‐related mortality (both surgery‐ and chemotherapy‐related) is relatively high in the first weeks of life, indicating that these young patients deserve special attention with respect to timing and type of treatment.
Objective
To prospectively assess the evolution of postoperative MRI findings in asymptomatic patients after total hip arthroplasty (THA) over 24 months (mo).
Methods
This prospective cohort study ...included 9 asymptomatic patients (56.7 ± 15.0 years) after THA. Metal artifact–reduced 1.5-T MRI was performed at 3, 6, 12, and 24 mo after surgery. The femoral stem and acetabular cup were assessed by two readers for bone marrow edema (BME), periprosthetic bone resorption, and periosteal edema in addition to periarticular soft tissue edema and joint effusion.
Results
BME was common around the femoral stem in all Gruen zones after 3 mo (range: 50–100%) and 6 mo (range: 33–100%) and in the acetabulum in DeLee and Charnley zone II after 3 mo (100%) and 6 mo (33%). BME decreased substantially after 12 mo (range: 0–78%) and 24 mo (range: 0–50%), may however persist in particular in Gruen zones 1 + 7. Periosteal edema along the stem was common 3 mo postoperatively (range: 63–75%) and rare after 24 mo: 13% only in Gruen zones 2 and 5. Twelve months and 24 mo postoperatively, periprosthetic bone resorption was occasionally present around the femoral stem (range: 11–33% and 13–38%, respectively). Soft tissue edema occurred exclusively along the surgical access route after 3 mo (100%) and 6 mo (89%) and never at 12 mo or 24 mo (0%).
Conclusion
Around the femoral stem, BME (33–100%) and periosteal edema (0–75%) are common until 6 mo after THA, decreasing substantially in the following period, may however persist up to 24 mo (BME: 0–50%; periosteal edema: 0–13%) in few non-adjoining Gruen zones. Soft tissue edema along the surgical access route should have disappeared 12 mo after surgery.
Echinacea preparations, which are used for the prevention and treatment of upper respiratory infections, account for 10% of the dietary supplement market in the U.S., with sales totaling more than ...$100 million annually. In an attempt to shed light on Echinacea's mechanism of action, we evaluated the effects of a 75% ethanolic root extract of Echinacea purpurea, prepared in accord with industry methods, on cytokine and chemokine production from RAW 264.7 macrophage-like cells. We found that the extract displayed dual activities; the extract could itself stimulate production of the cytokine TNF-α, and also suppress production of TNF-α in response to stimulation with exogenous LPS. Liquid:liquid partitioning followed by normal-phase flash chromatography resulted in separation of the stimulatory and inhibitory activities into different fractions, confirming the complex nature of this extract. We also studied the role of alkylamides in the suppressive activity of this E. purpurea extract. Our fractionation method concentrated the alkylamides into a single fraction, which suppressed production of TNF-α, CCL3, and CCL5; however fractions that did not contain detectable alkylamides also displayed similar suppressive effects. Alkylamides, therefore, likely contribute to the suppressive activity of the extract but are not solely responsible for that activity. From the fractions without detectable alkylamides, we purified xanthienopyran, a compound not previously known to be a constituent of the Echinacea genus. Xanthienopyran suppressed production of TNF-α suggesting that it may contribute to the suppressive activity of the crude ethanolic extract. Finally, we show that ethanolic extracts prepared from E. purpurea plants grown under sterile conditions and from sterilized seeds, do not contain LPS and do not stimulate macrophage production of TNF-α, supporting the hypothesis that the macrophage-stimulating activity in E. purpurea extracts can originate from endophytic bacteria. Together, our findings indicate that ethanolic E. purpurea extracts contain multiple constituents that differentially regulate cytokine production by macrophages.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Central nervous system (CNS) and non-CNS embryonal tumors occur principally in children and are rarely seen in adults. The incidence rates for rare entities such as atypical teratoid/rhabdoid tumors ...(AT/RT) or primitive neuroectodermal tumors in the CNS are rarely published. Incidence rates for certain subgroups, such as hepatoblastomas, have been increasing in some countries.
Data of 8337 embryonal tumors, registered in children (0-14 years) between 1991 and 2012 (for AT/RT 2000-2012) in the population-based German Childhood Cancer Registry with complete national coverage were analyzed for incidence rates, time trends, and survival.
For most entities, the incidence rates were the highest for children <1 year. An important exception was medulloblastomas, which occurred mainly in 1- to 9-year-olds. Neuroblastomas and ganglioneuroblastomas as well as Wilms tumors (nephroblastomas) had the highest age standardized incidence rates (13.7 and 9.4 per million, respectively). A statistically significant increasing trend for hepatoblastomas (annual average percent change 4.6%) was detected. The survival probabilities varied between the diagnostic groups: primitive neuroectodermal tumors and AT/RT had the lowest and retinoblastomas the highest. The survival was dependent on the age at diagnosis, the most extreme examples being neuroblastomas, for which the survival probability declined steeply for children ≥1 year and medulloblastomas, for which the highest survival was seen for 10- to 14-year-olds.
This study presents a comprehensive overview of pediatric embryonal tumors from a well-established, complete nationwide cancer registry. Significant increasing trend for hepatoblastomas was detected for the first time in Europe.
Brown ring patch of cool-season turfgrass, caused by Waitea circinata Warcup & Talbot, was first reported in Japan on creeping bentgrass (Agrostis palustris Huds.) in 2005 (Toda et al. 2005) and in ...the United States on annual bluegrass (Poa annua L.) in 2007 (de la Cerda et al. 2007). In April 2015, a rapid decline was observed on a stand of perennial ryegrass (Lolium perenne cv. Soprano, 1G Squared, and Apr2116) that had been overseeded on a bermudagrass stand at a baseball field in Stillwater, OK. Symptomatic leaf tissue was surface sterilized for 1 min in a 0.8% sodium hypochlorite solution, rinsed with sterile water, and plated onto potato dextrose agar (PDA). A Rhizoctonia-like fungus was consistently isolated and suspected to be the causal pathogen. After 3 days at 25degreesC white, cottony growth formed in culture, which turned orange to brown as the culture aged. Spherical sclerotia of irregular diameters were present in the 7-day-old culture that followed the same color development as mycelia. Colony and sclerotia morphology were consistent with previous descriptions of W. circinata. (de la Cerda et al. 2007; Toda et al. 2005). DNA was extracted and the internal transcribed spacer region (ITS) of the ribosomal RNA gene was amplified using primer pair ITS4/ITS5 and sequenced (White et al. 1990). Amplified fragments matched with 100% similarity to published ITS sequences (GenBank Accession Nos. HM807352, HQ166071, and FJ55889). A pathogenicity test was conducted on 3-week-old perennial ryegrass seedlings of the same cultivar blend on which the disease was initially observed. This blend was grown in 10-cm-diameter pots containing commercial planting mix (Sun Gro Horticulture, Bellevue, WA). One 4-mm-diameter plug was removed from the margin of a 4-day-old colony growing on PDA and placed on wet leaves. Five replicate pots of each inoculated and noninoculated ryegrass seedlings were kept in a moist chamber at 22degreesC. Within 4 to 5 days, inoculated leaves exhibited slight chlorosis, and water soaked lesions with white aerial mycelium were present. Koch's postulates were fulfilled as mycelia were recovered from diseased lesions, and confirmed by amplification and sequencing of the same ITS region. This demonstrates that W. circinata is present in Oklahoma and in the southern Midwest of the United States. To our knowledge this is the first report of W. circinata infecting perennial ryegrass in this region. Given that it has not been reported in this region, turfgrass managers may not be correctly identifying this disease.
Survival for subgroups of patients with Wilms tumor (WT), such as those who suffer from relapse, is disappointing. Some patients' treatment plans include high-dose chemotherapy (HDT) with autologous ...hematopoietic cell transplantation (aHCT), although proof for its benefit is lacking. To increase the level of evidence regarding children with WT receiving aHCT as consolidation of first or second remission (after first relapse), we extracted relevant data from the European Blood and Marrow Transplantation Registry concerning 69 patients. Different HDT regimens were administered, mostly either melphalan-containing (n = 34) or thiotepa-containing (n = 14). For the whole population, 5-year overall survival (OS) and event-free survival (EFS) probabilities were 0.67 (±0.06) and 0.63 (±0.06), respectively (median observation time 7.8 years); for children transplanted in first remission, OS and EFS were 0.69 (±0.09) and 0.72 (±0.08). In univariate analysis, male gender and relapse in multiple sites were associated with lower OS probabilities. The use of a given pretransplant regimen (i.e. melphalan alone versus regimens with multiple drugs) did not seem to influence EFS/OS probability after aHCT, but significantly influenced platelet engraftment (more delayed with thiotepa). We here provide further data to improve the basis for future evidence-based clinical decision-making when using HDT and aHCT in relapsed/refractory WT.
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