Respiratory effects of low and high doses of fentanyl in control and β-arrestin 2 deficient mice

2021 ◽  
Author(s):  
Philippe Haouzi ◽  
Marissa McCANN ◽  
Nicole TUBBS
Keyword(s):  
Excess Mortality ◽  
Breathing Control ◽  
Respiratory Effects ◽  
Ventilatory Responses ◽  
Life Threatening ◽  
Ventilatory Effects ◽  
High Doses ◽  
Deficient Mice ◽  
Very High

We have investigated the potential acute desensitizing role of the beta arrestin 2 (b-arr2) pathway on the ventilatory depression produced by levels of fentanyl ranging from analgesic to life-threatening (0.1 to 60 mg/kg IP) in control and b-arr2 deficient non-sedated mice. Fentanyl at doses of 0.1, 0.5 and 1 mg/kg IP - corresponding to the doses previously used to study the role of b-arr2 arrestin pathway - decreased ventilation, but along the V̇E/V̇CO2 relationship established in baseline conditions, which was therefore indistinguishable from animals that were immobile. Above 1.5 mg/kg, however, ventilation was depressed out of proportion of the changes in metabolism, suggesting a specific depression of the drive to breathe. The ventilatory responses were similar between the 2 groups. At high doses of fentanyl (60 mg/kg IP) one out of 20 control mice died by apnea versus 8 out of 20 b-arr2 deficient mice (P=0.008). In the surviving mice, ventilation was however identical in both groups. The ventilatory effects of fentanyl in b-arr2 deficient mice reported in the literature are primarily mediated by the "indirect" effects of sedation/hypometabolism on breathing control. There was an excess mortality at very high doses of fentanyl in the b-arr2 deficient mice, which mechanisms are still open to question, since the capacity of maintaining a rhythmic, although profoundly depressed, breathing activity remains similar in all of the surviving control and b-arr2 deficient mice.

Ventilatory responses to inspiratory threshold loading in humans

1990 ◽  
Vol 68 (6) ◽  
pp. 2511-2520 ◽  
Author(s):  
J. Yanos ◽  
A. Banner ◽  
R. Stanko ◽  
S. Gentry ◽  
K. Greenawalt
Keyword(s):  
Normal Subjects ◽  
Alveolar Ventilation ◽  
Motor Output ◽  
High Threshold ◽  
Respiratory Effects ◽  
Ventilatory Responses ◽  
Mouth Pressure ◽  
Muscular Pump ◽  
Neural Influences ◽  
Very High

Normal alveolar ventilation tends to be maintained during external mechanical loading. The precise manner by which this occurs is unclear but may involve intrinsic mechanisms related to the muscular pump, neural influences, and chemoreceptor control. Recent observations suggest that submaximal threshold loads may result in hyperventilation. In this study we explicitly examined the respiratory effects of sustained threshold loading in normal subjects. We found that sustained threshold loading resulted in hyperventilation associated with high P100's (mouth pressure 100 ms after the start of an occluded breath) and increased tidal volumes but with little effect on duty cycle or respiratory rate. In addition, this increased respiratory motor output was sustained for 30-60 s after the load was removed. At very high threshold loads, hyperventilation failed to occur, despite increased P100's. We conclude that threshold loading results in increased respiratory motor output and hyperventilation, a response that is different from that observed with either resistive or elastic loads, and that the failure to hyperventilate at the higher loads may be the result of mechanical limitation.

Very high-dose methylprednisolone for treatment of nivolumab-induced limbic encephalitis: A case report

2020 ◽  
Vol 26 (6) ◽  
pp. 1538-1543 ◽  
Author(s):  
Vincent-Thierry Taillefer ◽  
Marjorie Pigeon ◽  
Michelle Chen ◽  
Catherine Larochelle ◽  
Marie Florescu ◽  
...  
Keyword(s):  
Case Report ◽  
Limbic Encephalitis ◽  
Oral Prednisone ◽  
Neurological Impairment ◽  
Immune Checkpoint Blockade ◽  
High Dose ◽  
Life Threatening ◽  
Autoimmune Limbic Encephalitis ◽  
High Doses ◽  
Very High

Introduction Nivolumab is a programmed death 1 (PD-1) inhibitor approved by the Food and Drug Administration (FDA) for the treatment of eight different cancers including metastatic melanoma. Immune checkpoint blockade may lead to a range of neurologic immune-related adverse events (irAEs) with severity varying from mild to life-threatening, including encephalitis. Case report We describe a case of a 68-year-old man who developed alteration in mental status, physical weakness and fatigue after nine cycles of nivolumab 3 mg/kg every two weeks. These symptoms were compatible with a clinical diagnosis of autoimmune limbic encephalitis, although no specific antibodies were detected and the initial MRI was normal. Management and outcome The patient received intravenous methylprednisolone 1 g daily for 5 days, which was then converted to a maintenance dose of oral prednisone. The patient made a full clinical recovery but relapsed clinically upon steroid tapering, while hypersignal in the left mesial temporal suggestive of limbic encephalitis was observed on repeated MRI. Discussion Because of the prevailing usage of nivolumab in many cancer protocols, this case highlights the importance of rapidly recognising neurological impairment in patients treated with nivolumab and of initiating very high doses of corticosteroids.

scholarly journals Role of histone kinases as mediators of corticotropin-induced steroidogenesis*

1976 ◽  
Vol 160 (1) ◽  
pp. 1-9 ◽  
Author(s):  
W R Moyle ◽  
G J MacDonald ◽  
J E Garfink
Keyword(s):  
Cyclic Amp ◽  
Kinase Activity ◽  
Protein Kinase Activity ◽  
Dibutyryl Cyclic Amp ◽  
Cyclic Amp Accumulation ◽  
Calf Thymus ◽  
High Doses ◽  
Histone Kinase ◽  
Very High

In an attempt to determine the role of protein (histone) kinases as mediators of corticotropin-induced corticosterone formation, the ability of homogenates, prepared from adrenals treated with various doses of corticotropin to catalyse the phosphorylation of calf thymus histones was measured. Although corticotropin promoted an increase in histone kinase activity, much more of the hormone was required to induce this response than to stimulate steroidogenesis maximally. In addition, a derivative, nitrophenylsulphenyl-corticotropin, which inhibits the stimulatory effect of corticotropin on cyclic AMP accumulation, stimulated corticosterone synthesis without altering histone kinase activity. Very high doses of nitrophenylsulphenyl-corticotropin were capable of stimulating histone kinase activity. In contrast, when dibutyryl cyclic AMP was used to stimulate steroidogenesis under the same conditions, any dose of the nucleotide which increased adrenal corticosteroid content also increased histone kinase activity. Assuming that histones serve as useful substrates for measurement of total adrenal protein kinase activity, the role of protein kinases as mediators of steroidogenesis is not supported by these studies.

scholarly journals Mice deficient in IL-1beta manifest impaired contact hypersensitivity to trinitrochlorobenzone.

1996 ◽  
Vol 183 (4) ◽  
pp. 1427-1436 ◽  
Author(s):  
L P Shornick ◽  
P De Togni ◽  
S Mariathasan ◽  
J Goellner ◽  
J Strauss-Schoenberger ◽  
...  
Keyword(s):  
Essential Role ◽  
Endotoxic Shock ◽  
Embryonic Stem ◽  
Peritoneal Macrophages ◽  
Intradermal Injection ◽  
Contact Hypersensitivity ◽  
High Doses ◽  
Sensitization Phase ◽  
Deficient Mice ◽  
Very High

Mice rendered deficient in IL-1 beta by gene targeting in embryonic stem cells develop and grow normally in a protected laboratory environment. Endotoxin-stimulated peritoneal macrophages from IL-1beta-deficient mice showed normal synthesis and cellular release of IL-1alpha after treatment with 5 mM ATP demonstrating that IL-1beta is not necessary for expression and release of the IL-1alpha isoform. Mice deficient in IL-1beta showed unaltered sensitivity to endotoxic shock, with or without pretreatment with D-galactosamine. In contrast, IL-1beta-deficient mice showed defective contact hypersensitivity responses to topically applied trinitrochlorobenzene (TNCB). This defect could be overcome either by application of very high doses of sensitizing antigen, or by local intradermal injection of recombinant IL-1beta immediately before antigen application. These data demonstrate an essential role for IL-1beta in contact hypersensitivity and suggest that IL-1beta acts early during the sensitization phase of response. They suggest an important role for IL-1beta in initiation of the host of response at the epidermal barrier.

scholarly journals Outbreak of SARS-CoV-2 Lineage 20I/501Y.V1 in a Nursing Home Underlines the Crucial Role of Vaccination in Both Residents and Staff

Vaccines ◽  
2021 ◽  
Vol 9 (6) ◽  
pp. 591
Author(s):  
Andrea Orsi ◽  
Alexander Domnich ◽  
Vanessa De Pace ◽  
Valentina Ricucci ◽  
Patrizia Caligiuri ◽  
...  
Keyword(s):  
Nursing Home ◽  
Nursing Home Residents ◽  
Symptomatic Patient ◽  
Symptomatic Disease ◽  
Serological Investigation ◽  
Life Threatening ◽  
Asymptomatic Infections ◽  
Deceased Patient ◽  
Very High

Elderly residents in nursing homes are at very high risk of life-threatening COVID-19-related outcomes. In this report, an epidemiological and serological investigation of a SARS-CoV-2 outbreak in an Italian nursing home is described. Among the residents, all but one (19/20) were regularly vaccinated against SARS-CoV-2. In mid-February 2021, a non-vaccinated staff member of the nursing home was diagnosed with the SARS-CoV-2 infection. Following the outbreak investigation, a total of 70% (14/20) of residents aged 77–100 years were found positive. The phylogenetic analysis showed that the outbreak was caused by the SARS-CoV-2 variant of concern 202012/01 (the so-called “UK variant”). However, all but one positive subjects (13/14) were fully asymptomatic. The only symptomatic patient was a vaccinated 86-year-old female with a highly compromised health background and deceased approximately two weeks later. The subsequent serological investigation showed that the deceased patient was the only vaccinated subject that did not develop the anti-spike protein antibody response, therefore being likely a vaccine non-responder. Although the available mRNA SARS-CoV-2 vaccine was not able to prevent several asymptomatic infections, it was able to avert most symptomatic disease cases caused by the SARS-CoV-2 variant of concern 202012/01 in nursing home residents.

scholarly journals On assessing excess mortality in Germany during the COVID-19 pandemic

2022 ◽  
Author(s):  
Giacomo De Nicola ◽  
Göran Kauermann ◽  
Michael Höhle
Keyword(s):  
General Population ◽  
Excess Mortality ◽  
Mortality Data ◽  
Age Group ◽  
Expected Mortality ◽  
Very High ◽  
Overall Mortality

AbstractCoronavirus disease 2019 (COVID-19) is associated with a very high number of casualties in the general population. Assessing the exact magnitude of this number is a non-trivial problem, as relying only on officially reported COVID-19 associated fatalities runs the risk of incurring in several kinds of biases. One of the ways to approach the issue is to compare overall mortality during the pandemic with expected mortality computed using the observed mortality figures of previous years. In this paper, we build on existing methodology and propose two ways to compute expected as well as excess mortality, namely at the weekly and at the yearly level. Particular focus is put on the role of age, which plays a central part in both COVID-19-associated and overall mortality. We illustrate our methods by making use of age-stratified mortality data from the years 2016 to 2020 in Germany to compute age group-specific excess mortality during the COVID-19 pandemic in 2020.

Daunorubicin and Platelet Function

1981 ◽  
Vol 45 (01) ◽  
pp. 038-042 ◽  
Author(s):  
M E Pogliani ◽  
R Fantasia ◽  
G Lambertenghi-Deliliers ◽  
E Cofrancesco
Keyword(s):  
Electron Microscope ◽  
Cellular Membrane ◽  
Hemorrhagic Diathesis ◽  
Clot Retraction ◽  
Freezing And Thawing ◽  
Platelet Factor ◽  
High Doses ◽  
Very High ◽  
Platelet Functions

SummaryThe influence of Daunorubicin on some platelet functions in vitro was investigated, using different concentrations of the drug (0.01-0.02-0.04 μg/ml). Daunorubicin was shown to inhibit Collagen and Thrombin induced platelet aggregation and the intensity of inhibition depended on both drug concentration and the time of preincubation.Daunorubicin was also shown to inhibit the release reaction, the platelet prostaglandin pathway and the availability platelet factor 3; the drug at concentrations for clinical use does not damage the platelet membrane, as is the case with the freezing and thawing test, in platelet uptake of 14C-serotonin and as confirmed by the electron microscope. When very high doses (0.16 mg) of Daunorubicin are used, lysis of the platelets can be observed and this is confirmed under the electron microscope by the presence of empty platelets with fractures at the level of the cytoplasmic membrane.Finally, Daunorubicin causes irreversible inhibition of reptilase clot-retraction, even if this is less severe than with Vincristine. Working with gel-filtered platelets, it would appear that the inhibition exercised by the drug on platelet reactions is not caused through modifications in Ca++ metabolism.The authors suggest that Daunorubicin, at the dosages used clinically, induces in vitro thrombocytopathy without damaging the cellular membrane as confirmed by the electron microscope.This impairment of platelet functions could play a part in hemorrhagic diathesis observed during Daunorubicin therapy.

Collagen-Induced Platelet Aggregation: -Evidence Against the Essential Role of Platelet Adenosine Diphosphate

1979 ◽  
Vol 42 (04) ◽  
pp. 1193-1206 ◽  
Author(s):  
Barbara Nunn
Keyword(s):  
Platelet Aggregation ◽  
Time Course ◽  
Essential Role ◽  
Atp Release ◽  
Adenosine Diphosphate ◽  
Human Platelets ◽  
High Doses ◽  
Induced Aggregation

SummaryThe hypothesis that platelet ADP is responsible for collagen-induced aggregation has been re-examined. It was found that the concentration of ADP obtaining in human PRP at the onset of aggregation was not sufficient to account for that aggregation. Furthermore, the time-course of collagen-induced release in human PRP was the same as that in sheep PRP where ADP does not cause release. These findings are not consistent with claims that ADP alone perpetuates a collagen-initiated release-aggregation-release sequence. The effects of high doses of collagen, which released 4-5 μM ADP, were not inhibited by 500 pM adenosine, a concentration that greatly reduced the effect of 300 μM ADP. Collagen caused aggregation in ADP-refractory PRP and in platelet suspensions unresponsive to 1 mM ADP. Thus human platelets can aggregate in response to collagen under circumstances in which they cannot respond to ADP. Apyrase inhibited aggregation and ATP release in platelet suspensions but not in human PRP. Evidence is presented that the means currently used to examine the role of ADP in aggregation require investigation.

THE ROLE OF GRASSLAND IN MANAGEMENT

1968 ◽  
pp. 44-49
Author(s):  
B.K. Cameron
Keyword(s):  
Soil Temperature ◽  
Annual Rainfall ◽  
Silt Loam ◽  
Average Annual Rainfall ◽  
Very High ◽  
Wilting Point

THE PROPERTY to be discussed is a mixed sheep and cropping unit, situated ei ht a miles east of Ashburton and midway between the Ra aia and the Ashburton rivers. Average annual rainfall is 27 in., evenly spread, but there is very high summer evaporation and therefore frequent droughts. On average, the soil is below wilting point for 40 to 50 days each summer. Winters are cold with the soil temperature being below 48°F for about four months each year. The soil is a Lismore stony silt loam averaging 9 in. in depth over gravel.

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