Prunella vulgaris has been used therapeutically for inflammation-related conditions for centuries, but systematic studies of its anti-inflammatory activity are lacking and no specific active ...components have been identified. In this study, water and ethanol extracts of four P. vulgaris accessions were applied to RAW 264.7 mouse macrophages, and the ethanol extracts significantly inhibited lipopolysaccharide (LPS)-stimulated prostaglandin E2 (PGE2) and nitric oxide (NO) production at 30 μg/mL without affecting cell viability. Extracts from different accessions of P. vulgaris were screened for anti-inflammatory activity to identify accessions with the greatest activity. The inhibition of PGE2 and NO production by selected extracts was dose-dependent, with significant effects seen at concentrations as low as 10 μg/mL. Fractionation of ethanol extracts from the active accession, Ames 27664, suggested fractions 3 and 5 as possible major contributors to the overall activity. Rosmarinic acid (RA) content in P. vulgaris was found to independently inhibit inflammatory response, but it only partially explained the extracts’ activity. LPS-induced cyclooxygenase-2 (COX-2) and nitric oxide synthase (iNOS) protein expression were both attenuated by P. vulgaris ethanol extracts, whereas RA inhibited only COX-2 expression.
Prior research has demonstrated that chronic tic disorders (CTD) are associated with functional impairment across several domains. However, methodological limitations, such as data acquired by ...parental report, datasets aggregated across child and adult samples, and small treatment-seeking samples, curtail interpretation. The current study explored the functional impact of tics among youth in a large, “virtual” community sample. An Internet-based survey was completed by families with children who had CTD. The sample included 740 parents and 232 of their children (ages 10–17 years). The survey assessed impact across five functional domains: physical, social, familial, academic, and psychological. Health-related quality of life and perceptions of discrimination resulting from tics were also assessed. Results suggest that (1) youth with CTD experience mild to moderate functional impairment, (2) impairment is generally positively correlated with tic severity, (3) children with CTD plus one or more co-occurring psychiatric conditions tend to have greater functional impairment, and (4) a notable portion of youth with CTD experience discrimination due to tics. Implications and limitations of these findings are discussed.
BACKGROUND
Knowledge of blood utilization can assist clinicians in directing patient blood management (PBM) initiatives and can facilitate demand planning by blood services. We describe a national ...study of red blood cell (RBC) utilization in England and North Wales in 2014.
STUDY DESIGN AND METHODS
All hospitals that are supplied with blood components by NHS Blood and Transplant (NHSBT) were asked to provide data on the age and sex of all recipients of transfusions of RBCs, and the clinical indication for every unit transfused, for two separate weeks in 2014. Clinical indication categories were derived from those used in previous studies in an English region. Completeness of data collection was checked against NHSBT issue and wastage data.
RESULTS
Data on 46,111 RBC units were collected, representing 73% of all RBCs issued by NHSBT during the weeks surveyed. A total of 67% of RBC units were transfused for a medical indication, with 27 and 6% being transfused for surgical and obstetric/gynecologic indications, respectively. For comparison, figures from a study in the North of England in 2009, on which this national study was based, showed that 64% of RBCs were transfused to medical patients. All but 20 units could be ascribed to a broad clinical heading, for example, “gastrointestinal bleeding.”
CONCLUSION
Our findings confirm the previous regional finding that the percentage of RBC units that are transfused to surgical patients in England and North Wales is now much lower than for medical patients and suggest that PBM initiatives should now focus on medical patients.
Rwanda 20 years on: investing in life Binagwaho, Agnes, Dr; Farmer, Paul E, MD; Nsanzimana, Sabin, MD ...
The Lancet (British edition),
07/2014, Letnik:
384, Številka:
9940
Journal Article
Recenzirano
Odprti dostop
Summary Two decades ago, the genocide against the Tutsis in Rwanda led to the deaths of 1 million people, and the displacement of millions more. Injury and trauma were followed by the effects of a ...devastated health system and economy. In the years that followed, a new course set by a new government set into motion equity-oriented national policies focusing on social cohesion and people-centred development. Premature mortality rates have fallen precipitously in recent years, and life expectancy has doubled since the mid-1990s. Here we reflect on the lessons learned in rebuilding Rwanda's health sector during the past two decades, as the country now prepares itself to take on new challenges in health-care delivery.
Charcot-Marie-Tooth (CMT) disease is the most common inherited neuromuscular disorder, affecting 1 in 2,500 individuals. Mitochondrial DNA (mtDNA) mutations are not generally considered within the ...differential diagnosis of patients with uncomplicated inherited neuropathy, despite the essential requirement of ATP for axonal function. We identified the mtDNA mutation m.9185T>C in MT-ATP6, encoding the ATP6 subunit of the mitochondrial ATP synthase (OXPHOS complex V), at homoplasmic levels in a family with mitochondrial disease in whom a severe motor axonal neuropathy was a striking feature. This led us to hypothesize that mutations in the 2 mtDNA complex V subunit encoding genes, MT-ATP6 and MT-ATP8, might be an unrecognized cause of isolated axonal CMT and distal hereditary motor neuropathy (dHMN).
A total of 442 probands with CMT type 2 (CMT2) (270) and dHMN (172) were screened for MT-ATP6/8 mutations after exclusion of mutations in known CMT2/dHMN genes. Mutation load was quantified using restriction endonuclease analysis. Blue-native gel electrophoresis (BN-PAGE) was performed to analyze the effects of m.9185T>C on complex V structure and function.
Three further probands with CMT2 harbored the m.9185T>C mutation. Some relatives had been classified as having dHMN. Patients could be separated into 4 groups according to their mutant m.9185T>C levels. BN-PAGE demonstrated both impaired assembly and reduced activity of the complex V holoenzyme.
We have shown that m.9185T>C in MT-ATP6 causes CMT2 in 1.1% of genetically undefined cases. This has important implications for diagnosis and genetic counseling. Recognition that mutations in MT-ATP6 cause CMT2 enhances current understanding of the pathogenic basis of axonal neuropathy.
To compare the efficacy and safety of edoxaban vs warfarin in high-risk subgroups.
ENGAGE AF-TIMI 48 was a multicenter randomized, double-blind, controlled trial in 21,105 patients with atrial ...fibrillation (AF) within 12 months and CHADS2 score >2 randomized to higher-dose edoxaban regimen (HDER) 60 mg/reduced 30 mg, lower-dose edoxaban regimen (LDER) 30 mg/reduced 15 mg, or warfarin, and followed for 2.8 years (median). The primary outcome for this analysis was the net clinical outcome (NCO), a composite of stroke/systemic embolism events, major bleeding, or death. Multivariable risk-stratification analysis was used to categorize patients by the number of high-risk features.
The annualized NCO rates in the warfarin arm were highest in patients with malignancy (19.2%), increased fall risk (14.0%), and very-low body weight (13.5%). The NCO rates increased with the numbers of high-risk factors in the warfarin arm: 4.5%, 7.2%, 9.9% and 14.6% in patients with 0 to 1, 2, 3, and >4 risk factors, respectively (Ptrend <0.001). Versus warfarin, HDER was associated with significant reductions of NCO in most of the subgroups: elderly, patients with moderate renal dysfunction, prior stroke/TIA, of Asian race, very-low body weight, concomitant single antiplatelet therapy, and VKA-naïve. With more high-risk features (0->4+), the absolute risk reductions favoring edoxaban over warfarin increased: 0.3%->2.0% for HDER; 0.4%->3.4% for LDER vs warfarin (P = .065 and P < .001, respectively).
While underuse of anticoagulation in high-risk patients with AF remains common, substitution of effective and safer alternatives to warfarin, such as edoxaban, represents an opportunity to improve clinical outcomes.
Objective: The purpose of this study was to investigate characteristics associated with farm equipment and horse and buggy roadway crashes in relation to person, incident, and injury characteristics ...to identify appropriate points for injury incident prevention.
Methods: Information on crashes occurring on public roads during the years 2010-2013 was obtained from the Pennsylvania Department of Transportation (PennDOT) and analyzed.
Results: There were 344 farm equipment and 246 horse and buggy crashes during the 4-year study period. These crashes involved 666 and 504 vehicles and 780 and 838 people, respectively. In incidents with farm equipment, the non-farm equipment drivers had an almost 2 times greater injury risk than farm equipment operators. Horse and buggy crashes were almost 3 times more injurious to the horse and buggy drivers than the drivers of the other vehicles.
Conclusions: The average crash rate for farm equipment was 198.4 crashes per 100,000 farm population and for horse and buggy the crash rate was calculated as 89.4 crashes per 100,000 Amish population per year. This study suggests that road safety and public health programs should focus not only on farm equipment operators and horse and buggy drivers but on other motorists sharing the roadway with them.
Metastatic melanoma is an aggressive disease, despite recent improvements in therapy. Eradicating all melanoma cells even in drug-sensitive tumors is unsuccessful in patients because a subset of ...cells can transition to a slow-cycling state, rendering them resistant to most targeted therapy. It is still unclear what pathways define these subpopulations and promote this resistant phenotype. In the current study, we show that Wnt5A, a non-canonical Wnt ligand that drives a metastatic, therapy-resistant phenotype, stabilizes the half-life of p53 and uses p53 to initiate a slow-cycling state following stress (DNA damage, targeted therapy, and aging). Inhibiting p53 blocks the slow-cycling phenotype and sensitizes melanoma cells to BRAF/MEK inhibition. In vivo, this can be accomplished with a single dose of p53 inhibitor at the commencement of BRAF/MEK inhibitor therapy. These data suggest that taking the paradoxical approach of inhibiting rather than activating wild-type p53 may sensitize previously resistant metastatic melanoma cells to therapy.
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•Wnt5A increases the half-life of wild-type p53 to promote a slow-cycling phenotype•Multiple types of stress increase Wnt5A and p53 expression in metastatic melanoma•Inhibiting p53 sensitizes melanoma cells to BRAF/MEK inhibitor therapy
Cancer cells adopt multiple ways to evade therapy, including adopting a slow-cycling phenotype to resist drugs that target rapidly proliferating cells. Webster et al. show by circumventing this slow-cycling state through inhibition of p53, cells can be sensitized to targeted therapies that affect proliferation pathways such as the MAPK pathway.
Human leukemic stem cells, like other cancer stem cells, are hypothesized to be rare, capable of incomplete differentiation, and restricted to a phenotype associated with early hematopoietic ...progenitors or stem cells. However, recent work in other types of tumors has challenged the cancer stem cell model. Using a robust model of xenotransplantation based on NOD/SCID/IL2Rγc-deficient mice, we confirmed that human leukemic stem cells, functionally defined by us as SCID leukemia-initiating cells (SL-ICs), are rare in acute myelogenous leukemia (AML). In contrast to previous results, SL-ICs were found among cells expressing lineage markers (i.e., among Lin+ cells), CD38, or CD45RA, all markers associated with normal committed progenitors. Remarkably, each engrafting fraction consistently recapitulated the original phenotypic diversity of the primary AML specimen and contained self-renewing leukemic stem cells, as demonstrated by secondary transplants. While SL-ICs were enriched in the Lin-CD38- fraction compared with the other fractions analyzed, SL-ICs in this fraction represented only one-third of all SL-ICs present in the unfractionated specimen. These results indicate that human AML stem cells are rare and enriched but not restricted to the phenotype associated with normal primitive hematopoietic cells. These results suggest a plasticity of the cancer stem cell phenotype that we believe has not been previously described.
A rapidly expanding catalog of neurogenetic disorders has encouraged a diagnostic shift towards early clinical whole exome sequencing (WES). Adult primary mitochondrial diseases (PMDs) frequently ...exhibit neurological manifestations that overlap with other nervous system disorders. However, mitochondrial DNA (mtDNA) is not routinely analyzed in standard clinical WES bioinformatic pipelines. We reanalyzed 11,424 exomes, enriched with neurological diseases, for pathogenic mtDNA variants. Twenty‐four different mtDNA mutations were detected in 64 exomes, 11 of which were considered disease causing based on the associated clinical phenotypes. These findings highlight the diagnostic uplifts gained by analyzing mtDNA from WES data in neurological diseases. ANN NEUROL 2021;89:1240–1247
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