Pain management after elective craniotomy: A systematic review with procedure-specific postoperative pain management (PROSPECT) recommendations.

BACKGROUND Pain after craniotomy can be intense and its management is often suboptimal. OBJECTIVES We aimed to evaluate the available literature and develop recommendations for optimal pain management after craniotomy. DESIGN A systematic review using procedure-specific postoperative pain management (PROSPECT) methodology was undertaken. DATA SOURCES Randomised controlled trials and systematic reviews published in English from 1 January 2010 to 30 June 2021 assessing pain after craniotomy using analgesic, anaesthetic or surgical interventions were identified from MEDLINE, Embase and Cochrane Databases. ELIGIBILITY CRITERIA Each randomised controlled trial (RCT) and systematic review was critically evaluated and included only if met the PROSPECT requirements. Included studies were evaluated for clinically relevant differences in pain scores, use of nonopioid analgesics, such as paracetamol and NSAIDs, and current clinical relevance. RESULTS Out of 126 eligible studies identified, 53 RCTs and seven systematic review or meta-analyses met the inclusion criteria. Pre-operative and intra-operative interventions that improved postoperative pain were paracetamol, NSAIDs, intravenous dexmedetomidine infusion, regional analgesia techniques, including incision-site infiltration, scalp nerve block and acupuncture. Limited evidence was found for flupirtine, intra-operative magnesium sulphate infusion, intra-operative lidocaine infusion, infiltration adjuvants (hyaluronidase, dexamethasone and α-adrenergic agonist added to local anaesthetic solution). No evidence was found for metamizole, postoperative subcutaneous sumatriptan, pre-operative oral vitamin D, bilateral maxillary block or superficial cervical plexus block. CONCLUSIONS The analgesic regimen for craniotomy should include paracetamol, NSAIDs, intravenous dexmedetomidine infusion and a regional analgesic technique (either incision-site infiltration or scalp nerve block), with opioids as rescue analgesics. Further RCTs are required to confirm the influence of the recommended analgesic regimen on postoperative pain relief

Marburg hemorrhagic fever in Durba and Watsa, Democratic Republic of the Congo: clinical documentation, features of illness, and treatment

The objective of the present study was to describe day of onset and duration of symptoms of Marburg hemorrhagic fever (MHF), to summarize the treatments applied, and to assess the quality of clinical documentation. Surveillance and clinical records of 77 patients with MHF cases were reviewed. Initial symptoms included fever, headache, general pain, nausea, vomiting, and anorexia (median day of onset, day 1-2), followed by hemorrhagic manifestations (day 5-8+), and terminal symptoms included confusion, agitation, coma, anuria, and shock. Treatment in isolation wards was acceptable, but the quality of clinical documentation was unsatisfactory. Improved clinical documentation is necessary for a basic evaluation of supportive treatment

Glycogen synthase kinase-3 mediates acetaminophen-induced apoptosis in human hepatoma cells

ABSTRACT The mild analgesic drug acetaminophen (AAP) induces severe hepatic injury when taken at excessive doses. Recent evidence shows that the initial form of damage is through apoptosis, but this fails to go to completion and degenerates into necrosis. The aim of this study was to elucidate the mechanism through which AAP induces apoptosis using human HuH7 hepatoma cells as an in vitro model system to investigate the initial phase of AAP-induced hepatic injury. AAP-induced apoptosis in HuH7 cells as evidenced by chromatin condensation was preceded by the translocation of Bax to mitochondria and the cytoplasmic release of the proapoptotic factors cytochrome c and Smac/DIABLO. A concomitant loss of mitochondrial membrane potential occurred. Activation of the mitochondrial pathway of apoptosis led to the activation of execution caspases-3 and -7. AAP-induced apoptosis and cell death was blocked by inhibitors of caspases but not by inhibitors of calpains, cathepsins, and serine proteases. Apoptosis was unaffected by inhibitors of the mitochondrial permeability transition pore and by inhibitors of Jun NH 2 -terminal kinases, p38 mitogen-activated protein kinase, or mitogen-activated protein kinase kinase 1/2. However, pharmacological inhibition of glycogen synthase kinase-3 (GSK-3) delayed and decreased the extent of AAP-induced apoptosis. In comparison, endoplasmic reticulum stress-induced but not prooxidant-induced apoptosis of HuH7 cells was sensitive to GSK-3 inhibition. It is concluded that AAP-induced apoptosis involves the mitochondrial pathway of apoptosis that is mediated by GSK-3 and most likely initiated through an endoplasmic reticulum stress response. The mild analgesic acetaminophen (paracetamol, AAP) remains the commonest cause of acute liver failure in the United States and other parts of the world as a result of accidental or deliberate overdose Many of the histochemical and biochemical features of the late stages of AAP toxicity, particularly after high doses, support the conclusion that AAP induces hepatocellular necrosi

Glycogen synthase kinase-3 mediates acetaminophen-induced apoptosis in human hepatoma cells

Abstract: 232 Introduction: 61

Ebola haemorrhagic fever outbreak in Masindi District, Uganda: outbreak description and lessons learned

ABSTRACT

Risk Factors for Marburg Hemorrhagic Fever, Democratic Republic of the Congo

We conducted two antibody surveys to assess risk factors for Marburg hemorrhagic fever in an area of confirmed Marburg virus transmission in the Democratic Republic of the Congo. Questionnaires were administered and serum samples tested for Marburg-specific antibodies by enzyme-linked immunosorbent assay. Fifteen (2%) of 912 participants in a general village cross-sectional antibody survey were positive for Marburg immunoglobulin G antibody. Thirteen (87%) of these 15 were men who worked in the local gold mines. Working as a miner (odds ratio [OR] 13.9, 95% confidence interval [CI] 3.1 to 62.1) and receiving injections (OR 7.4, 95% CI 1.6 to 33.2) were associated with a positive antibody result. All 103 participants in a targeted antibody survey of healthcare workers were antibody negative. Primary transmission of Marburg virus to humans likely occurred via exposure to a still unidentified reservoir in the local mines. Secondary transmission appears to be less common with Marburg virus than with Ebola virus, the other known filovirus

Bone Marrow Stromal Cells Modulate Mouse ENT1 Activity and Protect Leukemia Cells from Cytarabine Induced Apoptosis

BACKGROUND: Despite a high response rate to chemotherapy, the majority of patients with acute myeloid leukemia (AML) are destined to relapse due to residual disease in the bone marrow (BM). The tumor microenvironment is increasingly being recognized as a critical factor in mediating cancer cell survival and drug resistance. In this study, we propose to identify mechanisms involved in the chemoprotection conferred by the BM stroma to leukemia cells. METHODS: Using a leukemia mouse model and a human leukemia cell line, we studied the interaction of leukemia cells with the BM microenvironment. We evaluated in vivo and in vitro leukemia cell chemoprotection to different cytotoxic agents mediated by the BM stroma. Leukemia cell apoptosis was assessed by flow cytometry and western blotting. The activity of the equilibrative nucleoside transporter 1 (ENT1), responsible for cytarabine cell incorporation, was investigated by measuring transport and intracellular accumulation of (3)H-adenosine. RESULTS: Leukemia cell mobilization from the bone marrow into peripheral blood in vivo using a CXCR4 inhibitor induced chemo-sensitization of leukemia cells to cytarabine, which translated into a prolonged survival advantage in our mouse leukemia model. In vitro, the BM stromal cells secreted a soluble factor that mediated significant chemoprotection to leukemia cells from cytarabine induced apoptosis. Furthermore, the BM stromal cell supernatant induced a 50% reduction of the ENT1 activity in leukemia cells, reducing the incorporation of cytarabine. No protection was observed when radiation or other cytotoxic agents such as etoposide, cisplatin and 5-fluorouracil were used. CONCLUSION: The BM stroma secretes a soluble factor that significantly protects leukemia cells from cytarabine-induced apoptosis and blocks ENT1 activity. Strategies that modify the chemo-protective effects mediated by the BM microenvironment may enhance the benefit of conventional chemotherapy for patients with AML

Mechanisms of drug-induced apoptosis in liver cells : relevance to in vivo hepatotoxicity

EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Mechanisms of Drug-Induced Apoptosis in Liver Cells: Relevance to in vivo Hepatotoxicity.

In response to a cytotoxic insult, a cell can die by necrosis or by apoptosis. Therefore, the overall objective of this investigation was to identify the mechanisms of drug-induced liver cell apoptosis in vitro to help with the discovery of novel markers of apoptosis that could be used for predicting hepatocyte apoptosis in vivo. In this investigation, the capability of drugs to induce apoptosis in liver cells was investigated using two cellular models, namely primary mouse hepatocytes and the hepatoma cell line, HuH7. This study was performed using three model compounds, paracetamol, thapsigargin and duroquinone. The hepatotoxin, paracetamol, is a widely used analgesic drug, can induce fatal liver injury through a combination of apoptosis and necrosis, when taken in large doses. Our work has previously shown that apoptosis plays an essential role in paracetamol-induced hepatic injury since inhibiting apoptosis, prevents the development of acute liver failure. The endoplasmic reticulum (ER) stress inducer, thapsigargin, acts by selectively inhibiting the ER Ca2+ -ATPase, which pumps calcium against a concentration gradient into the ER. Both paracetamol and thapsigargin caused marked cytotoxicity in HuH7 cells as evidenced by chromatin condensation and DNA fragmentation. Similarly, the redox-cycler, duroquinone, caused cell death in the HuH7 cells and primary hepatocytes by both the induction of apoptotic and necrotic cell death. All three compounds caused the activation of executioner caspases-3 and -7 and also the cleavage of caspase-3 cellular substrates including fodrin and cytokeratin 18. Furthermore, the pan-caspase inhibitor benzyloxycarbonyl-Val-Ala-DL-Asp-fluoromethylketone (Z-VAD-fmk) protected from paracetamol and thapsigargin-induced cytotoxicity. However, Z-VAD-fmk did not afford protection from duroquinone-induced cell death by oxidative stress in the HuH7 cells. Non-caspase proteases including calpains, cathepsins, serine proteases and the proteasome were not involved in cell death by these compounds. The manifestation of apoptosis was preceded by a loss of mitochondrial membrane potential and the release of cytochrome c and Smac/DIABLO. However, the inhibitors of the membrane permeability transition pore (PTP) cyclosporine A and bongkrekic acid failed to prevent apoptosis. In contrast, the Bcl-2 pro-apoptotic protein Bax, was found to translocate to the mitochondria to allow the release of cytochrome c in the HuH7 cells treated with paracetamol, thapsigargin and duroquinone. It was postulated that as a result of the metabolic activation of paracetamol and the concomitant production of reactive oxygen species (ROS), a cellular stress response was induced in HuH7 cells. To investigate the role of this stress response in the initiation of apoptosis by paracetamol and also thapsigargin and duroquinone, stress-activated protein kinases including c-Jun N-terminal kinase (JNK) and p38 and also MEK1/2 and glycogen synthase kinase-3 (GSK-3) were investigated. Although JNK was shown to be activated, the pharmacological inhibition of JNK, p38 and MEK did not afford protection from cell death by these compounds in the HuH7 cells. However, the inhibition of pro-apoptotic GSK-3 protected significantly from paracetamol and thapsigargin-induced cell death by apoptosis