Antonella Cotoia

High mobility group B1 impairs hepatocyte regeneration in acetaminophen hepatotoxicity

BackgroundAcetaminophen (APAP) overdose induces massive hepatocyte necrosis. Necrotic tissue releases high mobility group B1 (HMGB1), and HMGB1 contributes to liver injury. Even though blockade of HMGB1 does not protect against APAP-induced acute liver injury (ALI) at 9 h time point, the later time points are not studied and the role of HMGB1 in APAP overdose is unknown, it is possible that neutralization of HMGB1 might improve hepatocyte regeneration. This study aims to test whether blockade of HMGB1 improves hepatocyte regeneration after APAP overdose.MethodsMale C57BL/6 mice were treated with a single dose of APAP (350 mg/kg). 2 hrs after APAP administration, the APAP challenged mice were randomized to receive treatment with either anti-HMGB1 antibody (400 μg per dose) or non-immune (sham) IgG every 24 hours for a total of 2 doses.Results24 hrs after APAP injection, anti-HMGB1 therapy instead of sham IgG therapy significantly improved hepatocyte regeneration microscopically; 48 hrs after APAP challenge, the sham IgG treated mice showed 14.6% hepatic necrosis; in contrast, blockade of HMGB1 significantly decreased serum transaminases (ALT and AST), markedly reduced the number of hepatic inflammatory cells infiltration and restored liver structure to nearly normal; this beneficial effect was associated with enhanced hepatic NF-κB DNA binding and increased the expression of cyclin D1, two important factors related to hepatocyte regeneration.ConclusionHMGB1 impairs hepatocyte regeneration after APAP overdose; Blockade of HMGB1 enhances liver recovery and may present a novel therapy to treat APAP overdose.

Drag-reducing hyaluronic acid increases survival in profoundly hemorrhaged rats.

We tested the hypothesis that the infusion of a small volume of a drag-reducing polymer (DRP) solution can prolong survival in rats subjected to lethal hemorrhagic shock (HS; shed 51% of estimated blood volume) in the absence of complete resuscitation with fluids or blood. In this set of experiments, we used a newly designed mixture of hyaluronic acid (molecular weight, ∼2.0 × 106 d; 0.4 mg/mL) and polyethylene oxide (molecular weight, ∼ 4 × 106 d; 0.05 mg/mL) dissolved in sterile phosphate-buffered saline. Anesthetized rats were subjected to a volume-controlled HS. During the first 20 min, blood (21.7 mL/kg) was withdrawn. During the next 40 min, additional blood (14 mL/kg) was withdrawn, and during the final 20 min, saline vehicle or saline + DRP (2.8 mL/kg) was simultaneously infused. The survival rate of the rats treated with the hyaluronic acid/polyethylene oxide was significantly higher (P < 0.01). The mean survival times for control and DRP-treated animals were 100.4 ± 9.5 vs. 154.8 ± 7.0 min (P < 0.001). MAP was higher (P < 0.005) and skin perfusion was significantly improved in the DRP-treated group after the end of the DRP infusion. These results support the use of nanomolar concentrations of DRP to prolong survival in rats after lethal HS in the absence of fluid resuscitation. The DRP formulation studied here warrants further evaluation for the amelioration of critical illness associated with profound shock when access to resuscitation fluids may not be possible or delayed.

Continuous spinal analgesia with levobupivacaine for postoperative pain management: Comparison of 0.125% versus 0.0625% in elective total knee and hip replacement: A double-blind randomized study

Background and Aims: Continuous spinal anesthesia (CSA) has not been widely used for postoperative analgesia, mainly to avoid complications from the subarachnoid injection. Recently, the introduction of low caliber CSA catheters (Spinocath®), has allowed to decrease anesthetics doses and volumes with good analgesia and reduced complications. The aim of this present study was to compare two concentrations of levobupivacaine administered through CSA for postoperative pain management after major orthopedic surgery. Secondary outcomes were adverse events associated with CSA. Material and Methods: Thirty-two patients were randomized to receive sufentanil 1 mcg/h plus levobupivacaine 0.125%-1 ml/h (Group A0.125) or 0.0625%-2 ml/h (Group B0.0625) for postoperative analgesia through CSA catheter, connected to the elastomeric pump over 48 h. The quality of analgesia was assessed based on pain intensity by Visual Analogic Scale (VAS). Sensory and motor function, hemodynamic, and respiratory parameters were recorded for 96 h after surgery, after which the catheter was removed. In addition, joint mobility was assessed, and any side effects were noted. Results: VAS score was ≤30 mm in 25 patients. Three patients in Group A0.125 and 4 in Group B0.0625 (NS), received a rescue dose of levobupivacaine. Median VAS in Group A0.125 was lower than in Group B0.0625 on T1h (8 ± 11 vs 16 ± 11; P < 0.05), and on T4h (11 ± 8 vs 18 ± 1; P < 0.05). All patients remained hemodynamically stable. There were no significant differences between groups for postoperative joints mobility. Conclusion: Levobupivacaine at a dose of 1.25 mg/h administered by CSA provides good quality analgesia independent of concentration and solution volume in patients undergoing total knee and hip replacement.

p-Hydroxyphenylpyruvate, an Intermediate of the Phe/Tyr Catabolism, Improves Mitochondrial Oxidative Metabolism under Stressing Conditions and Prolongs Survival in Rats Subjected to Profound Hemorrhagic Shock

The aim of this study was to test the effect of a small volume administration of p-hydroxyphenylpyruvate (pHPP) in a rat model of profound hemorrhagic shock and to assess a possible metabolic mechanism of action of the compound. The results obtained show that hemorrhaged rats treated with 2–4% of the estimated blood volume of pHPP survived significantly longer (p<0.001) than rats treated with vehicle. In vitro analysis on cultured EA.hy 926 cells demonstrated that pHPP improved cell growth rate and promoted cell survival under stressing conditions. Moreover, pHPP stimulated mitochondria-related respiration under ATP-synthesizing conditions and exhibited antioxidant activity toward mitochondria-generated reactive oxygen species. The compound effects reported in the in vitro and in vivo analyses were obtained in the same millimolar concentration range. These data disclose pHPP as an efficient energetic substrates-supplier to the mitochondrial respiratory chain as well as an antioxidant supporting the view that the compound warrants further evaluation as a therapeutic agent.

Effects of Tibetan Music on Neuroendocrine and Autonomic Functions in Patients Waiting for Surgery: A Randomized, Controlled Study

Background The aim of this study was to investigate the effects of listening to Tibetan music on anxiety and endocrine, autonomic, cognitive responses in patients waiting for urologic surgery. Methods Sixty patients waiting for surgery were enrolled to the study. They were randomized in music (M) and control (C) groups. The M group listened to a low-frequency Tibetan music for 30 min (T0–T30) through headphones, and the C group wore headphones with no sound. The State Trait Anxiety Inventory Questionnaire (STAI) Y-1 was administered at T0 and T30. Normalized low (LFnu) and high frequencies (HFnu) of heart rate variability, LF/HF ratio, and galvanic skin response (GRS) data were analyzed at T0, T10, T20, T30, and T35. The salivary α-amylase (sAA) samples were collected at T0, T35, and T45. Results In the M group, the STAI Y-1 score decreased at T30 versus baseline (p < 0.001), sAA levels decreased at T35 versus T0(p=0.004), and GSR remained unchanged. In the C group, the STAI Y-1 score remained unchanged, sAA level increased at T35 versus T0(p < 0.001), and GSR slightly increased at T35 versus baseline (p=0.359). LFnu was lower, and HFnu was significantly higher (T10–T30) in M versus C group. Mean LF/HF ratio slightly reduced in the M group. Conclusions Our results suggest that preoperative listening to relaxing Tibetan music might be a useful strategy to manage preoperative anxiety.

Acute abdomen as a consequence of an unusual suicide attempt: intra-abdominal injection of sulfuric acid

Caustic ingestion is a common cause of life-threatening upper gastrointestinal tract injuries. It mostly happens in children as accidental exposure, but may occur in adults as a result of suicide attempt. We present a case of an acute abdomen that occurred after a peculiar way of self-administration of sulfuric acid as a suicide attempt in an adult psychiatric male patient, already known for self-harm with caustic agents in the previous years. In a few hours, the patient developed diffuse peritonitis, pneumoperitoneum, and a rapid hemodynamic deterioration, as a consequence of ileum and sigmoid necrosis, requiring an emergency surgery with the application of a damage control strategy. The patient was then transferred to intensive care unit for hemodynamic stabilization, and definitive surgical correction of the abdominal lesions was performed after 3 days with Hartmann procedure. Thirty-nine days after hospital admission, the patient was discharged. In conclusion, to our knowledge, never has been reported in the literature a case of intra-abdominal self-administration of caustic substance causing a rapid evolution of clinical conditions and requiring the application of damage control strategy.

Circulating stem cells, HIF-1, and SDF-1 in septic abdominal surgical patients: randomized controlled study protocol

BackgroundSepsis caused by complicated intra-abdominal infection is associated with high mortality. Loss of endothelial barrier integrity, inflammation, and impaired cellular oxygen have been shown to be primary contributors to sepsis. To date, little is known regarding the pathway for the mobilization of endothelial progenitor cells (EPCs) from the bone marrow in sepsis whereas stromal-cell-derived factor 1a (SDF-1a) and hypoxia inducible factor 1 (HIF-1) seem to have a role in the EPC response to hypoxic microenvironments.The aims of the study are: (a) to determine the time course of the levels of circulating EPCs (CD133/CD34), SDF-1a, and HIF-1 in septic patients undergoing major abdominal surgery (group S), (b) to investigate the relationship between CD133/CD34, HIF-1, and SDF-1a, and (c) to investigate the relationship of these factors with the outcome of group S patients treated with standard conventional therapy alone (CT) or with the addition of extracorporeal hemoperfusion therapy (HCT).Methods/designPatients undergoing major abdominal surgery will be allocated into groups: postoperative non-septic patients in an emergency surgical ward (group C) and postoperative septic patients in an intensive care unit (group S). The latter will be randomized to receive CT alone (S1) or with HCT (S2). Healthy volunteers (group H) will be recruited at University Hospital Foggia.Peripheral blood (PB) samples will be collected preoperatively (T0), at 24 h (T1), 72 h (T2), 7 (T3), and 10 (T4) postoperative days in groups S and C, and at T0 in group H. The CD34/133 cells and HIF-1 counts will be determined by flow cytometer analysis. The concentration of SDF-1a in plasma will be calculated by enzyme-linked immunosorbent assay analysis (ELISA).DiscussionThis prospective randomized clinical trial is designed to investigate circulating stem cells, levels of HIF-1 and SDF-1a, and their interrelationship in septic postoperative abdominal surgical patients treated with CT alone or with HCT. The rationale is that an integrated understanding of the role of hypoxia-related factors and EPCs in PB of septic patients could indicate which molecular processes need to be regulated to recover the innate immunity homeostasis. Understanding the function of EPCs in sepsis may provide innovative diagnostic and therapeutic approaches to improve the prognosis of this syndrome.Trial registrationClinicalTrials.gov: NCT02589535. Registered on 28 October 2015.

Para-hydroxyphenylpyruvate inhibits the pro-inflammatory stimulation of macrophage preventing LPS-mediated nitro-oxidative unbalance and immunometabolic shift

Targeting metabolism is emerging as a promising therapeutic strategy for modulation of the immune response in human diseases. In the presented study we used the lipopolysaccharide (LPS)-mediated activation of RAW 264.7 macrophage-like cell line as a model to investigate changes in the metabolic phenotype and to test the effect of p-hydroxyphenylpyruvate (pHPP) on it. pHPP is an intermediate of the PHE/TYR catabolic pathway, selected as analogue of the ethyl pyruvate (EP), which proved to exhibit antioxidant and anti-inflammatory activities. The results obtained show that LPS-priming of RAW 264.7 cell line to the activated M1 state resulted in up-regulation of the inducible nitric oxide synthase (iNOS) expression and consequently of NO production and in release of the pro-inflammatory cytokine IL-6. All these effects were prevented dose dependently by mM concentrations of pHPP more efficiently than EP. Respirometric and metabolic flux analysis of LPS-treated RAW 264.7 cells unveiled a marked metabolic shift consisting in downregulation of the mitochondrial oxidative phosphorylation and upregulation of aerobic glycolysis respectively. The observed respiratory failure in LPS-treated cells was accompanied with inhibition of the respiratory chain complexes I and IV and enhanced production of reactive oxygen species. Inhibition of the respiratory activity was also observed following incubation of human neonatal fibroblasts (NHDF-neo) with sera from septic patients. pHPP prevented all the observed metabolic alteration caused by LPS on RAW 264.7 or by septic sera on NHDF-neo. Moreover, we provide evidence that pHPP is an efficient reductant of cytochrome c. On the basis of the presented results a working model, linking pathogen-associated molecular patterns (PAMPs)-mediated immune response to mitochondrial oxidative metabolism, is put forward along with suggestions for its therapeutic control.

Complication of General Anaesthesia in Obstetrics

The abstract is published online only. If you did not include a short abstract for the online version when you submitted the manuscript, the first paragraph or the first 10 lines of the chapter will be displayed here. If possible, please provide us with an informative abstract.

Complications of Regional Anesthesia

Obstetric anesthesia care is generally considered to be one of the higher risk areas of regional and general anesthetic techniques, although it is extremely safe and widely used. It is reassuring that serious complications related to central neuraxial block are uncommon, and they have to grapple with issues related to anatomic-physiologic changes in pregnancy and various other factors, including increasing trend of cesarean section, advanced maternal age, obesity, and other concomitant medical diseases. This chapter highlights the management and therapy of following regional anesthesia-related complications encountered during the obstetric regional anesthesia practice: cardiovascular, infective, hematologic, post-dural puncture headache, and neurologic complications.