Management of acetaminophen poisoning in the US and Canada: A consensus statement

IMPORTANCE: The US and Canada currently have no formal published nationwide guidelines for specialists in poison information or emergency departments for the management of acetaminophen poisoning, resulting in significant variability in management. OBJECTIVE: To develop consensus guidelines for the management of acetaminophen poisoning in the US and Canada. EVIDENCE REVIEW: Four clinical toxicology societies (America\u27s Poison Centers, American Academy of Clinical Toxicology, American College of Medical Toxicology, and Canadian Association of Poison Control Centers) selected participants (n = 21). Led by a nonvoting chairperson using a modified Delphi method, the panel created a decision framework and determined the appropriate clinical management of a patient with acetaminophen poisoning. Unique to this effort was the collection of guidelines from most poison centers in addition to systematic collection and review of the medical literature. Comments from review by external organizations were incorporated before the guideline was finalized. The project began in March 2021 and ended in March 2023. FINDINGS: The search retrieved 84 guidelines and 278 publications. The panel developed guidelines for emergency department management of single or repeated ingestion of acetaminophen. In addition, the panel addressed extended-release formulation, high-risk ingestion, coingestion of anticholinergics or opioids, age younger than 6 years, pregnancy, weight greater than 100 kg, and intravenous acetaminophen use. Differences from current US practice include defining acute ingestion as an ingestion presentation from 4 to 24 hours after overdose was initiated. A revised form of the Rumack-Matthew nomogram was developed. The term massive ingestion was replaced with the term high-risk ingestion and denoted by a specific nomogram line. Other recommendations include specific criteria for emergency department triage, laboratory evaluation and monitoring parameters, defining the role of gastrointestinal decontamination, detailed management of acetylcysteine treatment, associated adverse effects, and stopping criteria for acetylcysteine treatment, as well as criteria for consultation with a clinical toxicologist. Finally, specific treatment considerations, including acetylcysteine dosing, fomepizole administration, and considerations for extracorporeal elimination and transplant evaluation, were addressed. CONCLUSIONS AND RELEVANCE: This qualitative study provides a consensus statement on consistent evidence-based recommendations for medical, pharmacy, and nursing education and practice to optimize care of patients with acetaminophen poisoning

Caveolar disruption causes contraction of rat femoral arteries via reduced basal NO release and subsequent closure of BKCa channels

Background and Purpose. Caveolae act as signalling hubs in endothelial and smooth muscle cells. Caveolar disruption by the membrane cholesterol depleting agent methyl-β-cyclodextrin (M-β-CD) has various functional effects on arteries including (i) impairment of endothelium-dependent relaxation, and (ii) alteration of smooth muscle cell (SMC) contraction independently of the endothelium. The aim of this study was to explore the effects of M-β-CD on rat femoral arteries.Methods. Isometric force was measured in rat femoral arteries stimulated to contract with a solution containing 20 mM K+ and 200 nM Bay K 8644 (20 K/Bay K) or with one containing 80 mM K+(80 K).Results. Incubation of arteries with M-β-CD (5 mM, 60 min) increased force in response to 20 K/Bay K but not that induced by 80 K. Application of cholesterol saturated M-β-CD (Ch-MCD, 5 mM, 50 min) reversed the effects of M-β-CD. After mechanical removal of endothelial cells M-β-CD caused only a small enhancement of contractions to 20 K/Bay K. This result suggests M-β-CD acts via altering release of an endothelial-derived vasodilator or vasoconstrictor. When nitric oxide synthase was blocked by pre-incubation of arteries with L-NAME (250 µM) the contraction of arteries to 20 K/Bay K was enhanced, and this effect was abolished by pre-treatment with M-β-CD. This suggests M-β-CD is inhibiting endothelial NO release. Inhibition of large conductance voltage- and Ca2+-activated (BKCa) channels with 2 mM TEA+ or 100 nM Iberiotoxin (IbTX) enhanced 20 K/Bay K contractions. L-NAME attenuated the contractile effect of IbTX, as did endothelial removal.Conclusions. Our results suggest caveolar disruption results in decreased release of endothelial-derived nitric oxide in rat femoral artery, resulting in a reduced contribution of BKCa channels to the smooth muscle cell membrane potential, causing depolarisation and contraction

Wnt-11 expression promotes invasiveness and correlates with survival in human pancreatic ductal adeno carcinoma

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest forms of cancer, proving difficult to manage clinically. Wnt-11, a developmentally regulated gene producing a secreted protein, has been associated with various carcinomas but has not previously been studied in PDAC. The present study aimed to elucidate these aspects first in vitro and then in a clinical setting in vivo. Molecular analyses of Wnt-11 expression as well as other biomarkers involved qRT-PCR, RNA-seq and siRNA. Proliferation was measured by MTT; invasiveness was quantified by Boyden chamber (Matrigel) assay. Wnt-11 mRNA was present in three different human PDAC cell lines. Wnt-11 loss affected epithelial-mesenchymal transition and expression of neuronal and stemness biomarkers associated with metastasis. Indeed, silencing Wnt-11 in Panc-1 cells significantly inhibited their Matrigel invasiveness without affecting their proliferative activity. Consistently with the in vitro data, human biopsies of PDAC showed significantly higher Wnt-11 mRNA levels compared with matched adjacent tissues. Expression was significantly upregulated during PDAC progression (TNM stage I to II) and maintained (TNM stages III and IV). Wnt-11 is expressed in PDAC in vitro and in vivo and plays a significant role in the pathophysiology of the disease; this evidence leads to the conclusion that Wnt-11 could serve as a novel, functional biomarker PDA

Manipulating prohibitin levels provides evidence for an in vivo role in androgen regulation of prostate tumours

Current hormonal therapies for prostate cancer are effective initially, but inevitably tumours progress to an advanced, metastatic stage, often referred to as ‘androgen independent’. However, the androgen receptor (AR) signalling pathway is still key for their growth. It is speculated that tumours escape hormonal control via reduction in corepressor proteins. Manipulating such proteins is thus a potential therapeutic strategy to halt or even reverse tumour progression. We aimed to elucidate the effects of altering levels of the AR corepressor and androgen-target protein prohibitin (PHB) on prostate tumour growth. Prostate cancer cells incorporating an integrated androgen-responsive reporter gene and stably expressing vectors to inducibly overexpress or knockdown PHB were generated and used to assess effects on androgen signalling (by real time imaging) and tumour growth both in culture and in vivo. PHB overexpression inhibited AR activity and prostate-specific antigen (PSA) expression as well as androgen-dependent growth of cells, inducing rapid accumulation in G0/G1. Conversely, reduction in PHB increased AR activity, PSA expression, androgen-mediated growth and S-phase entry. In vivo, doxycycline-induced PHB regulation resulted in marked changes in AR activity, and showed significant effects upon tumour growth. Overexpression led to tumour growth arrest and protection from hormonal starvation, whereas RNAi knockdown resulted in accelerated tumour growth, even in castrated mice. This study provides proof of principle that i) reduction in PHB promotes both androgen-dependent and ‘androgen-independent’ tumour growth, and ii) altering AR activity via increasing levels or activity of corepressors is a valid therapeutic strategy for advanced prostate cancer

Studies on nitrogen fixation by groundnut at ICRISAT

Symbiotic nitrogen fixation depends on an interaction between the Rhizobium strain, host plant genome and environment. We are examining all the three components with the objective of increasing biological nitrogen fixation by groundnut........

Factors Influencing Nitrogenase Activity (Acetylene Reduction) by Root Nodules of Groundnut, Arachis hypogaea L.

Acetylene reduction assay, used to measure nitrogenase activity of legume root nodules, is influenced by environmental factors, which limit its application. The effects of some of the environmental factors on acetylene reduction by groundnut root nodules are described. The activity was nonlinear during the first hour of incubation. Assay temperature above 25 C decreased the activity. Washing the nodulated roots prior to the assay also decreased the activity. The activity was influenced by light intensity, soil moisture, and moisture content in the incubation bottle. Diurnal fluctuation with one maximum and one minimum activity period during a 24 hour cycle was observed. Nitrogenase activity was higher during the postrainy season compared to that of the rainy season. A virginia cultivar Kadiri-71 had higher nitrogenase activity than a dwarf valencia cultivar, MH 2

Overuse of non-prescription analgesics by dental clinic patients

<p>Abstract</p> <p>Background</p> <p>Many patients present to dental clinics for treatment of painful conditions. Prior to seeking treatment, many of these patients will self-medicate with non-prescription analgesics (NPA), and some will unintentionally overdose on these products. The objective of this study is to describe the use of NPA among dental patients.</p> <p>Methods</p> <p>All adult patients presenting to an urban dental clinic during a two-week period in January and February of 2001 were approached to participate in this research project. Trained research assistants using a standardized questionnaire interviewed patients. Patient demographics and the NPA usage over the 3 days preceding the office visit were recorded. We defined a supra-therapeutic dose as any dose greater than the total recommended daily dose stated on package labeling.</p> <p>Results</p> <p>We approached 194 patients and 127 participated. The mean age of participants was 35.5 years, 52% were male. Analgesic use preceding the visit was reported by 99 of 127 patients, and most (81/99) used a NPA exclusively. Fifty-four percent of NPA users were taking more than one NPA. NPA users reported using ibuprofen (37%), acetaminophen (27%), acetaminophen/aspirin combination product (8%), naproxen (8%), and aspirin (4%). Sixteen patients reported supra-therapeutic use of one or more NPA (some ingested multiple products): ibuprofen (14), acetaminophen (3), and naproxen (5).</p> <p>Conclusion</p> <p>NPA use was common in patients presenting to a dental clinic. A significant minority of patients reported excessive dosing of NPA. Ibuprofen was the most frequently misused product, followed by naproxen and acetaminophen. Though mostly aware of the potential toxicity of NPA, many patients used supra-therapeutic dosages.</p