Whilst next generation sequencing can report point mutations in fixed tissue tumour samples reliably, the accurate determination of copy number is more challenging. The conventional Multiplex ...Ligation-dependent Probe Amplification (MLPA) assay is an effective tool for measurement of gene dosage, but is restricted to around 50 targets due to size resolution of the MLPA probes. By switching from a size-resolved format, to a sequence-resolved format we developed a scalable, high-throughput, quantitative assay. MLPA-seq is capable of detecting deletions, duplications, and amplifications in as little as 5ng of genomic DNA, including from formalin-fixed paraffin-embedded (FFPE) tumour samples. We show that this method can detect BRCA1, BRCA2, ERBB2 and CCNE1 copy number changes in DNA extracted from snap-frozen and FFPE tumour tissue, with 100% sensitivity and >99.5% specificity.
Full text
Available for:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Smoking stimulants, such as methamphetamine and "crack" cocaine, can spread infections, including hepatitis C and COVID-19, and lead to injuries, particularly when individuals share or use makeshift ...pipes. The purpose of the study was to assess the practices of people who inhale ("smoke") stimulants to guide future clinical harm reduction efforts.
Anonymous surveys were administered to participants reporting inhalation of crack cocaine and/or methamphetamine in the past 3 months. Participants were eligible if they sought services from an outreach team staffed by a municipal syringe service program (SSP) or if they were patients at a low-threshold substance use disorder treatment program, the Massachusetts General Hospital Bridge Clinic.
The survey was administered to 68 total participants, 30% of whom were recruited in the Massachusetts General Hospital Bridge Clinic and 70% through SSP outreach. Unsafe smoking practices were reported by 93% of participants. Among the 46% of participants surveyed who both smoked and injected stimulants, 61% of those participants stated that they injected instead of smoked stimulants because of lack of access to pipes. Amid COVID-19, 35% of participants adopted safer smoking practices. Most participants reported that they would be more likely to attend an SSP or health center if pipes were provided.
Inhalational practices that place participants at risk of injury and illness are common. Providing safer smoking equipment may promote health and engage individuals in care.
THE CONCISE GUIDE TO PHARMACOLOGY 2021/22 Alexander, Stephen P H; Fabbro, Doriano; Kelly, Eamonn ...
British journal of pharmacology,
10/2021, Volume:
178, Issue:
S1
Journal Article
Peer reviewed
The Concise Guide to PHARMACOLOGY 2021/22 is the fifth in this series of biennial publications. The Concise Guide provides concise overviews, mostly in tabular format, of the key properties of nearly ...1900 human drug targets with an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. Although the Concise Guide constitutes over 500 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point‐in‐time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/bph.15541. Catalytic receptors are one of the six major pharmacological targets into which the Guide is divided, with the others being: G protein‐coupled receptors, ion channels, nuclear hormone receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid‐2021, and supersedes data presented in the 2019/20, 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology (NC‐IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate.
Full text
Available for:
BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Cells require ribonucleotide reductase (RNR) activity for DNA replication. In bacteria, electrons can flow from NADPH to RNR by either a thioredoxin-reductase- or a glutathione-reductase-dependent ...route. Yeast and plants artificially lacking thioredoxin reductases exhibit a slow-growth phenotype, suggesting glutathione-reductase-dependent routes are poor at supporting DNA replication in these organisms. We have studied proliferation of thioredoxin-reductase-1 (Txnrd1)-deficient hepatocytes in mice. During development and regeneration, normal mice and mice having Txnrd1-deficient hepatocytes exhibited similar liver growth rates. Proportions of hepatocytes that immunostained for PCNA, phosphohistone H3 or incorporated BrdU were also similar, indicating livers of either genotype had similar levels of proliferative, S and M phase hepatocytes, respectively. Replication was blocked by hydroxyurea, confirming that RNR activity was required by Txnrd1-deficient hepatocytes. Regenerative thymidine incorporation was similar in normal and Txnrd1-deficient livers, further indicating that DNA synthesis was unaffected. Using genetic chimeras in which a fluorescently marked subset of hepatocytes was Txnrd1-deficient while others were not, we found that the multigenerational contributions of both hepatocyte types to development and to liver regeneration were indistinguishable. We conclude that, in mouse hepatocytes, a Txnrd1-independent route for the supply of electrons to RNR can fully support DNA replication and normal proliferative growth.
Climate change due to greenhouse gas emissions is predicted to raise the mean global temperature by 1.0-3.5°C in the next 50-100 years. The direct and indirect effects of this potential increase in ...temperature on terrestrial ecosystems and ecosystem processes are likely to be complex and highly varied in time and space. The Global Change and Terrestrial Ecosystems core project of the International Geosphere-Biosphere Programme has recently launched a Network of Ecosystem Warming Studies, the goals of which are to integrate and foster research on ecosystem-level effects of rising temperature. In this paper, we use meta-analysis to synthesize data on the response of soil respiration, net N mineralization, and aboveground plant productivity to experimental ecosystem warming at 32 research sites representing four broadly defined biomes, including high (latitude or altitude) tundra, low tundra, grassland, and forest. Warming methods included electrical heat-resistance ground cables, greenhouses, vented and unvented field chambers, overhead infrared lamps, and passive nighttime warming. Although results from individual sites showed considerable variation in response to warming, results from the meta-analysis showed that, across all sites and years, 2-9 years of experimental warming in the range 0.3-6.0°C significantly increased soil respiration rates by 20% (with a 95% confidence interval of 18-22%), net N mineralization rates by 46% (with a 95% confidence interval of 30-64%), and plant productivity by 19% (with a 95% confidence interval of 15-23%). The response of soil respiration to warming was generally larger in forested ecosystems compared to low tundra and grassland ecosystems, and the response of plant productivity was generally larger in low tundra ecosystems than in forest and grassland ecosystems. With the exception of aboveground plant productivity, which showed a greater positive response to warming in colder ecosystems, the magnitude of the response of these three processes to experimental warming was not generally significantly related to the geographic, climatic, or environmental variables evaluated in this analysis. This underscores the need to understand the relative importance of specific factors (such as temperature, moisture, site quality, vegetation type, successional status, land-use history, etc.) at different spatial and temporal scales, and suggests that we should be cautious in "scaling up" responses from the plot and site level to the landscape and biome level. Overall, ecosystem-warming experiments are shown to provide valuable insights on the response of terrestrial ecosystems to elevated temperature.
Many patients have chronic, debilitating symptoms of voiding dysfunction that are refractory to conventional medical or surgical therapies. This multicenter, prospective study evaluated the long-term ...effectiveness of sacral nerve stimulation using the implantable Medtronic InterStim therapy for urinary control in patients with otherwise intractable complaints of urinary urge incontinence, urgency-frequency, or retention. Each patient first underwent temporary, percutaneous sacral nerve test stimulation. If at least a 50% reduction in target symptoms was documented for at least 3 days, patients received a permanent Medtronic InterStim sacral nerve stimulation system that includes a surgically implanted lead and neurostimulator. Regular follow-up was conducted with outcome data. We report here on patients who have been observed from 1.5 to 3 years postimplantation. The results demonstrate that after 3 years, 59% of 41 urinary urge incontinent patients showed greater than 50% reduction in leaking episodes per day with 46% of patients being completely dry. After 2 years, 56% of the urgency-frequency patients showed greater than 50% reduction in voids per day. After 1.5 years, 70% of 42 retention patients showed greater than 50% reduction in catheter volume per catheterization. We conclude that the Medtronic InterStim therapy for urinary control system is an effective therapy with sustained clinical benefit for patients with intractable symptoms of urinary urge incontinence, urgency-frequency, or retention.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
To evaluate the long-term efficacy of sacral nerve stimulation for refractory urinary urge incontinence.
Urge incontinent patients qualified for surgical implantation of a neurostimulator system ...after trial screening with percutaneous test stimulation. Surgical implantation of the InterStim System (Medtronic Inc., Minneapolis, Minn., USA) was performed in cases where a >50% reduction in incontinence symptoms was documented during the 3- to 7-day test stimulation period. The InterStim System consists of an implantable pulse generator, a transforamenally placed quadripolar lead, and an extension that connects these two devices for unilateral stimulation of the S3 or S4 sacral nerve. Efficacy for 96 implanted patients was based on urinary symptom changes as quantified in voiding diaries collected at baseline and annually after surgical implantation.
As compared to baseline, the group of 96 implanted patients demonstrated significant reductions in urge incontinent symptoms at an average of 30.8+/-14.8 (range 12-60) months with respect to the number of urge incontinent episodes per day, severity of leaking, and the number of absorbent pads/diapers replaced per day due to incontinence (all p<0.0001, respectively). Gender, pretreatment variables, and age were not found to be relevant factors that affected these results. 11 of the 96 patients underwent device explant due to lack of efficacy, pain or bowel dysfunction. These data were conservatively included in the efficacy results. No permanent injuries associated with the devices or therapy were reported.
Sacral nerve stimulation is an effective treatment for refractory urge incontinence with sustained long-term benefit through an average of 30.8 months.
In the second C4 article, contributors examine five issues, including timely access during the hospital discharge process, access to immunosuppressive medications for life after transplant, access to ...medications used for off‐label indications, access to drugs affected by drug shortages, and the patient perspective.
Full text
Available for:
BFBNIB, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abstract
Despite many reported associations, the direct cause of neurodegeneration responsible for cognitive loss in Alzheimer’s disease and some other common dementias is not known. The normal human ...plasma protein, serum amyloid P component, a constituent of all human fibrillar amyloid deposits and present on most neurofibrillary tangles, is cytotoxic for cerebral neurones in vitro and in experimental animals in vivo. The neocortical content of serum amyloid P component was immunoassayed in 157 subjects aged 65 or more with known dementia status at death, in the large scale, population-representative, brain donor cohort of the Cognitive Function and Ageing Study, which avoids the biases inherent in studies of predefined clinico-pathological groups. The serum amyloid P component values were significantly higher in individuals with dementia, independent of serum albumin content measured as a control for plasma in the cortex samples. The odds ratio for dementia at death in the high serum amyloid P component tertile was 5.24 (95% confidence interval 1.79–15.29) and was independent of Braak tangle stages and Thal amyloid-β phases of neuropathological severity. The strong and specific association of higher brain content of serum amyloid P component with dementia, independent of neuropathology, is consistent with a pathogenetic role in dementia.
The normal blood protein, serum amyloid P component (SAP), is toxic for cerebral neurones but normally is largely excluded from the brain. Ellmerich et al. report that higher neocortical content of SAP is strongly associated with dementia at death, consistent with a pathogenetic role of SAP in neurodegeneration.
Graphical Abstract
Graphical Abstract
PDF
