904 research outputs found
M1 muscarinic allosteric modulators slow prion neurodegeneration and restore memory loss
This is the final version of the article. Available from American Society for Clinical Investigation via the DOI in this record.The current frontline symptomatic treatment for Alzheimerās disease (AD) is whole-body upregulation of cholinergic
transmission via inhibition of acetylcholinesterase. This approach leads to profound dose-related adverse effects. An
alternative strategy is to selectively target muscarinic acetylcholine receptors, particularly the M1 muscarinic acetylcholine
receptor (M1 mAChR), which was previously shown to have procognitive activity. However, developing M1 mAChRāselective orthosteric ligands has proven challenging. Here, we have shown that mouse prion disease shows many of the hallmarks
of human AD, including progressive terminal neurodegeneration and memory deficits due to a disruption of hippocampal
cholinergic innervation. The fact that we also show that muscarinic signaling is maintained in both AD and mouse prion
disease points to the latter as an excellent model for testing the efficacy of muscarinic pharmacological entities. The memory deficits we observed in mouse prion disease were completely restored by treatment with benzyl quinolone carboxylic acid (BQCA) and benzoquinazoline-12 (BQZ-12), two highly selective positive allosteric modulators (PAMs) of M1 mAChRs. Furthermore, prolonged exposure to BQCA markedly extended the lifespan of diseased mice. Thus, enhancing hippocampal muscarinic signaling using M1 mAChR PAMs restored memory loss and slowed the progression of mouse prion disease, indicating that this ligand type may have clinical benefit in diseases showing defective cholinergic transmission, such as AD.ABT, AC, and PMS received funding from a Wellcome Trust Collaborative
Award (201529/Z/16/Z). ABT, SJB, AJB, and TMH were
funded through a Medical Research Council programme leader
grant provided by the MRC Toxicology Unit. CCF, LMB, AJM, and
HES were funded by the Eli Lilly Company. JMB received funding
through a Lilly Research Award Program (LRAP) grant (Eli
Lilly). RP received funding from the Marie Curie grant āExtrabrainā
(European Commission). AC is a senior principal research
fellow and PMS a principal research fellow of the National Health
and Medical Research Council of Australia. Tissue samples were
from Randy Woltjer at the Oregon Alzheimerās Disease Center.
The Oregon Alzheimerās Disease Center is supported by NIH grant P30AG008017
Therapeutic Surgical Management of Palpable Melanoma Groin Metastases: Superficial or Combined Superficial and Deep Groin Lymph Node Dissection
Item does not contain fulltextBACKGROUND: Management of patients with clinically detectable lymph node metastasis to the groin is by ilioinguinal or combined superficial and deep groin dissection (CGD) according to most literature, but in practice superficial groin dissection (SGD) only is still performed in some centers. The aim of this study is to evaluate the experience in CGD versus SGD patients in our center. METHODS: Between 1991 and 2009, 121 therapeutic CGD and 48 SGD were performed in 169 melanoma patients with palpable groin metastases at our institute. Median follow-up was 20 and, for survivors, 45 months. RESULTS: In this heterogeneous group of patients, overall (OS) and disease-free survival, local control rates, and morbidity rates were not significantly different between CGD and SGD patients. However, CGD patients had a trend towards more chronic lymphedema. Superficial lymph node ratio, the number of positive superficial lymph nodes, and the presence of deep nodes were prognostic factors for survival. CGD patients with involved deep lymph nodes (24.8%) had estimated 5-year OS of 12% compared with 40% with no involved deep lymph nodes (p = 0.001). Preoperative computed tomography (CT) scan had high negative predictive value of 91% for detection of pelvic nodal involvement. CONCLUSIONS: This study demonstrated that survival and local control do not differ for patients with palpable groin metastases treated by CGD or SGD. Patients without pathological iliac nodes on CT might safely undergo SGD, while CGD might be reserved for patients with multiple positive nodes on SGD and/or positive deep nodes on CT scan
What is the valence of a correlated solid? The double life of delta-plutonium
Plutonium displays phase transitions with enormous volume differences among
its phases and both its Pauli like magnetic susceptibility and resistivity are
an order of magnitude larger than those of simple metals. Curium is also highly
resistive but its susceptibility is Curie-like at high temperatures and orders
antiferromagnetically at low temperatures. The anomalous properties of the late
actinides stem from the competition between the itinerancy and localization of
its f electrons, which makes the late actinides elemental strongly correlated
materials. A central problem in this field is to understand the mechanism by
which these materials resolve these conflicting tendencies. In this letter we
identify the electronic mechanisms responsible for the anomalous behaviour of
late actinides. We revisit the concept of valence using theoretical approach
that treats magnetism, Kondo screening, atomic multiplet effects, spin orbit
coupling and crystal field splitting on the same footing. Plutonium is found to
be in a rare mixed valent state, namely its ground state is a superposition of
two distinct valencies. Curium settles in a single valence magnetically ordered
state at low temperatures. The f7 atomic configuration of Curium is contrasted
with the multiple configuration manifolds present in Plutonium ground state
which we characterize by a valence histogram. The balance between the Kondo
screening and magnetism is determined by the competition between spin orbit
coupling and the strength of atomic multiplets which is in turn regulated by
the degree of itinerancy. The approach presented here, highlights the
electronic origin of the bonding anomalies in plutonium and can be applied to
predict generalized valences and the presence or absence of magnetism in other
compounds starting from first principles.Comment: 2 figures, 1 tabl
The effects of a high protein diet on indices of health and body composition ā a crossover trial in resistance-trained men
Comprehensive behavioral testing in the R6/2 mouse model of Huntington's disease shows no benefit from CoQ10 or minocycline
Previous studies of the effects of coenzyme Q10 and minocycline on mouse models of Huntington's disease have produced conflicting results regarding their efficacy in behavioral tests. Using our recently published best practices for husbandry and testing for mouse models of Huntington's disease, we report that neither coenzyme Q10 nor minocycline had significant beneficial effects on measures of motor function, general health (open field, rotarod, grip strength, rearing-climbing, body weight and survival) in the R6/2 mouse model. The higher doses of minocycline, on the contrary, reduced survival. We were thus unable to confirm the previously reported benefits for these two drugs, and we discuss potential reasons for these discrepancies, such as the effects of husbandry and nutrition
Co-designing inflammatory bowel disease (Ibd) services in Scotland : findings from a nationwide survey
Background: The Scottish Governmentās ambition is to ensure that health services are co-designed with the
communities they serve. Crohnās and Colitis UK and the Scottish Government acknowledged the need to review
and update the current IBD care model. An online survey was conducted asking IBD patients about their
experiences of the NHS care they receive. This survey was the first step of co-designing and developing a national
strategy for IBD service improvement in Scotland.
Aim: To explore IBD patientsā experiences of current services and make recommendations for future service
development.
Methods: This study was part of a wider cross-sectional on-line survey. Participants were patients with IBD across
Scotland. 777 people with IBD took part in the survey. Thematic analysis of all data was conducted independently
by two researchers.
Results: Three key themes emerged:
Quality of life: Participants highlighted the impact the disease has on quality of life and the desperate need for IBD
services to address this more holistically.
IBD clinicians and access: Participants recognised the need for more IBD nurses and gastroenterologists along with
better access to them. Those with a named IBD nurse reported to be more satisfied with their care.
An explicit IBD care pathway: Patients with IBD identified the need of making the IBD care pathway more explicit to
service users.
Conclusions: Participants expressed the need for a more holistic approach to their IBD care. This includes
integrating psychological, counselling and dietetic services into IBD care with better access to IBD clinicians and a
more explicit IBD care pathway.
Keywords: Inflammatory bowel disease, Co-designing, Qualitative study, Patient survey, Crohnās disease, Ulcerative coliti
Global constitutionalism, responsibility to protect, and extra-territorial obligations to realize the right to health: time to overcome the double standard (once again)
Individual-level socioeconomic status is associated with worse asthma morbidity in patients with asthma
<p>Abstract</p> <p>Background</p> <p>Low socioeconomic status (SES) has been linked to higher morbidity in patients with chronic diseases, but may be particularly relevant to asthma, as asthmatics of lower SES may have higher exposures to indoor (e.g., cockroaches, tobacco smoke) and outdoor (e.g., urban pollution) allergens, thus increasing risk for exacerbations.</p> <p>Methods</p> <p>This study assessed associations between adult SES (measured according to educational level) and asthma morbidity, including asthma control; asthma-related emergency health service use; asthma self-efficacy, and asthma-related quality of life, in a Canadian cohort of 781 adult asthmatics. All patients underwent a sociodemographic and medical history interview and pulmonary function testing on the day of their asthma clinic visit, and completed a battery of questionnaires (Asthma Control Questionnaire, Asthma Quality of Life Questionnaire, and Asthma Self-Efficacy Scale). General Linear Models assessed associations between SES and each morbidity measure.</p> <p>Results</p> <p>Lower SES was associated with worse asthma control (F = 11.63, p < .001), greater emergency health service use (F = 5.09, p = .024), and worse asthma self-efficacy (F = 12.04, p < .01), independent of covariates. Logistic regression analyses revealed that patients with <12 years of education were 55% more likely to report an asthma-related emergency health service visit in the last year (OR = 1.55, 95%CI = 1.05-2.27). Lower SES was not related to worse asthma-related quality of life.</p> <p>Conclusions</p> <p>Results suggest that lower SES (measured according to education level), is associated with several indices of worse asthma morbidity, particularly worse asthma control, in adult asthmatics independent of disease severity. Results are consistent with previous studies linking lower SES to worse asthma in children, and add asthma to the list of chronic diseases affected by individual-level SES.</p
Multiple Independent Genetic Factors at NOS1AP Modulate the QT Interval in a Multi-Ethnic Population
Extremes of electrocardiographic QT interval are associated with increased risk for sudden cardiac death (SCD); thus, identification and characterization of genetic variants that modulate QT interval may elucidate the underlying etiology of SCD. Previous studies have revealed an association between a common genetic variant in NOS1AP and QT interval in populations of European ancestry, but this finding has not been extended to other ethnic populations. We sought to characterize the effects of NOS1AP genetic variants on QT interval in the multi-ethnic population-based Dallas Heart Study (DHS, nā=ā3,072). The SNP most strongly associated with QT interval in previous samples of European ancestry, rs16847548, was the most strongly associated in White (Pā=ā0.005) and Black (Pā=ā3.6Ć10ā5) participants, with the same direction of effect in Hispanics (Pā=ā0.17), and further showed a significant SNP Ć sex-interaction (Pā=ā0.03). A second SNP, rs16856785, uncorrelated with rs16847548, was also associated with QT interval in Blacks (Pā=ā0.01), with qualitatively similar results in Whites and Hispanics. In a previously genotyped cohort of 14,107 White individuals drawn from the combined Atherosclerotic Risk in Communities (ARIC) and Cardiovascular Health Study (CHS) cohorts, we validated both the second locus at rs16856785 (Pā=ā7.63Ć10ā8), as well as the sex-interaction with rs16847548 (Pā=ā8.68Ć10ā6). These data extend the association of genetic variants in NOS1AP with QT interval to a Black population, with similar trends, though not statistically significant at P<0.05, in Hispanics. In addition, we identify a strong sex-interaction and the presence of a second independent site within NOS1AP associated with the QT interval. These results highlight the consistent and complex role of NOS1AP genetic variants in modulating QT interval
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