Abstract BACKGROUND Local drug delivery systems (LDDSs) applied during neurosurgery offer a means of overcoming poor blood brain barrier (BBB) permeability and have been extensively investigated for ...the treatment of adult gliomas. To the best of our knowledge, they have not been investigated for the treatment of paediatric cerebellar tumours, including medulloblastoma group 3 (MB3) and atypical teratoid/rhabdoid tumours (ATRT), both of which are associated with poor prognoses. METHODS We prepared and characterised an injectable and biodegradable poly(ethyleneglycol)-poly(caprolactone)-poly(ethyleneglycol) (PECE) hydrogel, which has been investigated broadly throughout the literature with an array of therapeutic agents against numerous cancer types. Here, we loaded the PECE hydrogel with chemotherapeutics previously identified as being effective against primary MB3 and ATRT in vitro, but which do not cross the BBB in vivo, namely CHIR99021, ribavirin and PG545. Biocompatibility and cytotoxicity of drug loaded hydrogels was assessed in vitro. LDDSs safety and efficacy was evaluated using patient derived MB3 and ATRT intracranial xenograft resection models. RESULTS The hydrogel was both biocompatible and effected cytotoxicity following drug release. In vivo efficacy experiments against MB3 indicated a comparable median survival in treatment arms receiving radiotherapy or CHIR99021 and PG545 loaded LDDS. However, combined radiotherapy and LDDS conferred a significant survival enhancement including long-term survivors. Against ATRT, the median survival of arms receiving radiotherapy was comparable to that of the CHIR99021 and ribavirin loaded LDDS, with long-term survivors observed only in the latter arm. CONCLUSIONS The application of LDDSs against cerebellar brain tumours offers a promising novel therapeutic alternative. For MB3, the combination of radiotherapy and a LDDS significantly enhances survival compared to radiotherapy alone. For ATRT, the comparable survival of the LDDS and radiotherapy alone is encouraging and indicates the possibility of circumventing radiation-induced adverse effects for young children impacted by this disease.
CART peptides Kuhar, Michael J; Adams, Larry D; Hunter, Richard G ...
Regulatory Peptides,
05/2000, Volume:
89, Issue:
1
Book Review, Conference Proceeding, Journal Article
Peer reviewed
CART peptides are among the newest putative peptide neurotransmitter/cotransmitters. They show no significant homology to any other peptide, and they are thought to have a role in reward and ...reinforcement, feeding, development, sensory processing, stress and endocrine control.
Purpose:
To investigate in an in vitro model the ability of different covered and uncovered stents to resist displacement/migration of a fenestrated stent-graft.
Methods:
Three different types (2 ...covered, 1 bare) of commonly used 7-mm balloon-expandable stainless steel stents (Jostent, Advanta V12, and Palmaz Genesis) were investigated in a testing rig consisting of 2 overlapping tubes with 2 sets of 7-mm holes representing bilateral renal artery fenestrations and ostia. The rig was attached to a tensile tester via pneumatic clamps. The stents were deployed without flaring to 7 mm through the overlapping holes. The rig was moved apart at a constant rate of 12 mm/min up to a maximum displacement of 6 mm; force versus displacement values were recorded while stent deformation was observed. Tests were repeated at least 6 times for each stent type at room temperature. The median force required to cause a 25%, 50%, or 75% reduction in cross-sectional area of the bilateral “renal artery” stents was determined.
Results:
The median force (interquartile range) required to cause a 50% reduction in cross-sectional area of identical bilateral “renal artery” stents securing fenestrations was 25.1 N (8.1) for a covered Jostent, 9.3 N (0.9) for a covered Advanta V12 stent, and 7.5 N (0.7) for a bare Palmaz Genesis stent. The differences were statistically significant (p<0.01) between stents at each of the 3 levels of cross-sectional area reduction.
Conclusion:
There is a significant difference in the ability of different commercial “non-dedicated” stents to withstand a crushing force when deployed within endograft fenestrations, which has important implications for clinical practice.
Increases in extreme weather events from climate change are likely to hinder forage crop production. Cropping system diversification may be a strategy for improving productivity and enhancing yield ...stability of forage production systems in the face of climate change, yet farmers are often constrained by their operations as to what strategies they can readily adopt. Moreover, the type of diversity necessary to provide desired outcomes and the potential tradeoffs from such outcomes are largely unknown. We compared three strategies to increase cropping system diversity via intercropping in winter annuals, summer annuals, and perennials in a three-year forage crop experiment conducted in New York, New Hampshire, and Vermont, USA. For each crop type, three diversification strategies, (1) cultivar diversity (Intraspecific), (2) crop species diversity (Interspecific), and (3) both cultivar and species diversities (Intra+Inter), were compared against a control of a single cultivar of a single species (Baseline). Measured responses included yield, weed biomass, forage nutritive value, and yield stability. Across all crop types, yields in Interspecific and Intra+Inter treatments were 15% and 14% greater than the Baseline treatment, respectively. Species diversity had the greatest effect on performance in perennials, which we partially attribute to temporal diversity indicated by differences in biomass composition across harvests within a season. Perennial diversity treatments that contained species diversity had lower weed biomass, lower crude protein, and greater fiber content than the Baseline or Intraspecific treatments. Stability analysis of yields across growing conditions showed that perennial crop yields were consistently greater in the Inter and Intra+Inter treatments than the Baseline treatment. In the summer annuals, yields of the Intra+Inter treatment were greater than yields of the Baseline treatment in sub-optimal environments (20th percentile of the environmental index), whereas, in winter annuals yields in the Intra+Inter treatment were greater than yields of the Baseline treatment in optimal environments (80th percentile of the environmental index). Across crops, strategies of species diversity had a greater impact on responses than cultivar diversity and no additional benefits were detected in strategies that also incorporated cultivar diversity. Benefits of mixtures could be further enhanced by selecting specific traits that maximize both functional and response diversity. Future research should aim to develop guidelines for species and trait compatibility in mixtures and appropriate seeding rates to optimize performance.
Display omitted
•Cultivar and species diversity were added to a monoculture control in annuals and perennials.•Adding crop species diversity improved yields and sometimes yield stability.•Adding cultivar diversity had little effect on yield, weed production, or nutritive value.•Composition of grass-legume perennial mixtures showed temporal diversity.•Mixtures can be constructed more precisely based on traits and seeding rates.
Despite its relevance for quality care initiatives, the field of psychiatry has little scientific knowledge regarding the course of current major depression when primary care patients with the ...disorder remain undetected. Using statewide telephone screening, we identified and followed 98 adults with current major depression who made one or more visits to a primary care physician during the 6 months following baseline. Thirty-two percent of primary care patients with current major depression remained undetected for up to 1 year. Almost half of undetected patients developed suicidal ideation. Less than one-third of undetected patients made a visit during the month they reported their worst symptoms. Fifty-three percent of undetected patients reported five or more current symptoms at 1 year follow-up. Primary care patients with undetected major depression report persistently poor outcomes. Comparison of outcomes with detected patients suggests that quality improvement efforts directed at improving detection without improving management of detected patients may not improve outcomes.
A functional analysis indicated that chronic eye poking exhibited by a woman with profound mental retardation persisted in the absence of social contingencies. We initiated a procedure in which a ...therapist delivered a punisher (mild reprimand) contingent on eye poking in the presence, but not the absence, of a neutral stimulus (wristbands). Subsequently, eye poking was suppressed when the participant wore the wristbands in novel environments without the reprimand contingency.
The activity of nitric oxide synthase (NOS) was assayed in enterocytes isolated from human duodenal biopsies to determine its role in celiac disease. Patients were categorized into groups with ...irritable bowel syndrome, iron-deficiency anemia, B(12)/folate deficiency, and treated and untreated celiac disease. Enterocytes isolated from all groups showed 1400W-inhibitable Ca2+-independent NOS activity with a pH level and temperature optimum of 9.4 and 37 degrees C, respectively. Western blotting showed that enterocytes expressed the inducible NOS protein and proteins with nitrated tyrosine residues, the latter being indicative of nitric oxide-driven peroxynitrite and/or free-radical damage. Endothelial NOS was seen only in the lamina propria. Patients with celiac disease had higher NOS activity than other patient groups. Treatment of the condition led to a fall in activity. Enzyme-linked immunosorbent assay demonstrated cGMP production by the enterocyte fraction, but cGMP levels did not correlate with NOS activity. These results suggest that inducible NOS is constitutively expressed in human duodenal enterocytes, is increased in patients with untreated celiac disease, and is partially corrected when such patients are treated. We found no evidence to support a role for nitric oxide in the formation of cGMP within the small intestine. Furthermore, we were unable to demonstrate a role for peroxynitrite/free radical damage in the pathophysiology of celiac disease.
Zika virus (ZIKV) has caused significant disease, with widespread cases of neurological pathology and congenital neurologic defects. Rapid vaccine development has led to a number of candidates ...capable of eliciting potent ZIKV-neutralizing antibodies (reviewed in refs.
). Despite advances in vaccine development, it remains unclear how ZIKV vaccination affects immune responses in humans with prior flavivirus immunity. Here we show that a single-dose immunization of ZIKV purified inactivated vaccine (ZPIV)
in a dengue virus (DENV)-experienced human elicited potent cross-neutralizing antibodies to both ZIKV and DENV. Using a unique ZIKV virion-based sorting strategy, we isolated and characterized multiple antibodies, including one termed MZ4, which targets a novel site of vulnerability centered on the Envelope (E) domain I/III linker region and protects mice from viremia and viral dissemination following ZIKV or DENV-2 challenge. These data demonstrate that Zika vaccination in a DENV-experienced individual can boost pre-existing flavivirus immunity and elicit protective responses against both ZIKV and DENV. ZPIV vaccination in Puerto Rican individuals with prior flavivirus experience yielded similar cross-neutralizing potency after a single vaccination, highlighting the potential benefit of ZIKV vaccination in flavivirus-endemic areas.
The effectiveness of a parenting curriculum designed for parents who exhibit risk factors for child maltreatment was evaluated. Six skills were taught during a 5-week series of 3-hour classes that ...met 1 day per week. A written quiz containing questions corresponding to skills taught in each class was administered to participants before the series of classes, following each class session, and after completion of the course. Repeated administration of the quiz permitted an analysis of skill acquisition. A role-play assessment was conducted prior to and following the series of classes. Results demonstrate an improvement in the participants'ability to recognize correct answers in a multiple-choice format and demonstrate the behavioral skills taught in class within a role-play context.
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