Effect of different anaesthetic techniques on gene expression profiles in patients who underwent hip arthroplasty.

OBJECTIVES: To investigate the modulation of genes whose expression level is indicative of stress and toxicity following exposure to three anaesthesia techniques, general anaesthesia (GA), regional anaesthesia (RA), or integrated anaesthesia (IA). METHODS: Patients scheduled for hip arthroplasty receiving GA, RA and IA were enrolled at Rizzoli Orthopaedic Institute of Bologna, Italy and the expression of genes involved in toxicology were evaluated in peripheral blood mononuclear cells (PBMCs) collected before (T0), immediately after surgery (T1), and on the third day (T2) after surgery in association with biochemical parameters. RESULTS: All three anaesthesia methods proved safe and reliable in terms of pain relief and patient recovery. Gene ontology analysis revealed that GA and mainly IA were associated with deregulation of DNA repair system and stress-responsive genes, which was observed even after 3-days from anaesthesia. Conversely, RA was not associated with substantial changes in gene expression. CONCLUSIONS: Based on the gene expression analysis, RA technique showed the smallest toxicological effect in hip arthroplasty. TRIAL REGISTRATION: ClinicalTrials.gov number NCT03585647.

Treatment of recent onset low back pain with periradicular injections of meloxicam: a randomized, double blind, placebo controlled cross-over study.

BACKGROUND: Low back pain (LBP) is a common and costly illness. This randomized, double-blind, placebo-controlled, cross-over study tested the hypothesis that periradicular injections of meloxicam would reduce LBP and improve physical activity compared to a saline injection at 3 months follow-up. METHODS: After IRB approval, 80 consenting patients suffering LBP of <6 months duration were randomly assigned to the control (C-group, N.=40, receiving 10 mL of saline) or the meloxicam (M-group, N.=40, receiving 10 mg in 10 mL saline). If the pain Numeric Rating Score (NRS) at 24 hours remained >50% of the pretreatment score, the patient was crossed-over to the other group. A successful treatment was NRS<3 at 3 months follow-up. Secondary outcome measures which were assessed included work-absence, physical-assistance, physical-activities limitations and pain-related insomnia. RESULTS: The baseline NRS was 9.3 (95% CI: 8.9-9.7) in the C-group and 9.2 (95% CI: 8.8-9.6) in the M-group. At the 24 hours follow-up after the initial treatment, the mean NRS was 6.3 (95% CI: 5.4-7.2) in the C-group vs. 3.5 (95% CI: 2.6-4.4) in the M-group (P<0.05). The number of cross-over cases was significantly higher in the C-group (N.=31, 77.5% vs. N.=5, 12.5%, P<0.001). At the 3 months follow-up, 66 patients (35+31) were allocated in the M-group and 54 (82%) reported NRS Score <3, while only 14 (9+5) patients remained in the C-group and eight patients had NRS<3. CONCLUSIONS: Periradicular injection of meloxicam is an effective analgesic treatment for acute/subacute LBP. This novel use of meloxicam also leads to an improvement in the level of physical activity at the 3-month follow-up.

Mechanism underlying the effect of long-term exposure to low dose of pesticides on DNA integrity.

Pesticides, including herbicides, insecticides and fungicides, are widely used in intensive agriculture. Recently, the long-term effects of pesticide exposure were found to be associated with many diseases. In this study, we evaluated the long-term effect of low-level exposure to a mixture of pesticides on DNA damage response (DDR) in relation to individual detoxifying variability. A residential population chronically exposed to pesticides was enrolled, biological/environmental pesticide levels; paroxonase 1 (PON-1) activity and 192 Q/R polymorphism and DDR were evaluated at three different periods of pesticide exposure. OGG1-dependent DNA repair activity was decreased in relation to pesticide exposure. The increase of DNA lesions and pesticide levels in the intensive pesticide-spraying period was independent on PON-1 activity. Next, human bronchial epithelial and neuronal cells were used as a model for in vitro evaluation of the mechanistic effect of pesticides. Pesticides induced mitochondrial dysfunction leading to ROS formation. ROS from mitochondria induced DNA damage, which in turn induced OGG1-dependent DNA repair activity through 8-oxoguanine DNA glycosylase 1 (OGG1) expression and activation. Even though OGG1 was overexpressed, an inhibition of its activity, associated with DNA lesion accumulation, was found at prolonged pesticide-exposure. A post-translational regulation of OGG1 by pesticide may be postulated. Taken together, long-term exposure to low-levels of pesticides affects DDR resulting in accumulation of DNA lesions that eventually may lead to cancer or neurological disorders.

Continuous wound infusion and local infiltration analgesia for postoperative pain and rehabilitation after total hip arthroplasty.

BACKGROUND: Total hip arthroplasty is one of the most common procedures in orthopedic surgery. We hypothesized that local infiltration of analgesia and continuous wound infusion of anesthetics in the first 72 hours after surgery could provide more effective postoperative analgesia with better rehabilitation. METHODS: A double-blind, randomized, controlled study was conducted with 96 patients who underwent total hip arthroplasty. The patients were randomized to receive either a local infiltration analgesia and continuous wound infusion of anesthetics or a local infiltration analgesia and continuous wound infusion of saline solution. The patients in both groups received subarachnoid anesthesia and a local infiltration analgesia. A multihole catheter was placed next to the implant and connected to an electronic pump containing a 300-mL solution of 0.2% levobupivacaine (experimental group) or saline (control group). RESULTS: A total of 96 consecutive patients were enrolled and randomized. Of these, 48 patients received local infiltration analgesia and continuous wound infusion of local anesthetics, and the remainder received local infiltration analgesia and continuous wound infusion of saline solution. The analysis showed a significant main effect of treatment on the postoperative incident of pain (Ftreat(1,93)=22.62, P=0.000) and on resting pain during the post-surgery follow-up (Ftreat(1,93)=15.62, P=0.0002). The pain scores during the rehabilitation period were significantly less in the experimental group. Analgesic consumption was less in the experimental group. CONCLUSIONS: The addition of continuous wound infusion of anesthetics to local infiltration analgesia provided an extended analgesic effect associated with good rehabilitation performance.

Transversus Abdominis Plane Block in the Management of Acute Postoperative Pain Syndrome after Caesarean Section: A Randomized Controlled Clinical Trial.

BACKGROUND: The international literature is unclear regarding the analgesic efficacy of the transversus abdominis plane block (TAPB) after a Caesarean section (CS). OBJECTIVES: The aim of this study was to determine whether a correctly performed ultrasound-guided TAPB (USG-TAPB) could provide better control of acute postoperative pain during the first 72 hours after CS and if it could provide a faster postoperative recovery. STUDY DESIGN: A double-blind, randomized, controlled clinical trial on pregnant women who underwent CS. SETTING: Pain clinic and Anesthesia and Intensive Care Unit in an academic hospital. METHODS: A double-blind, randomized, controlled study was conducted with 96 patients who underwent CS. The patients in both groups received subarachnoid anesthesia (SAB) with 13 mg of 0.5% isobaric levobupivacaine. The patients were randomized so that some received USG-TAPB with local anesthetic, and the remainder received USG-TAPB with saline. The patients' demographic information and data regarding anesthesia, hemodynamic changes, side effects, acute rest and incident postoperative pain, painkiller consumption, recovery time of bowel function, and the time of hospital discharge were recorded. RESULTS: Our data reinforce the assumption that if TAP block is performed correctly and is part of a multimodal analgesic scheme, effective pain control is possible both for somatic and visceral acute pain. Furthermore, the need for painkillers is reduced, and their related side effects are moderate, yielding a positive benefit/cost ratio. LIMITATIONS: USG-TAPB provides good analgesia for acute postoperative somatic pain, but opiates were still needed for the management of visceral acute postoperative pain. CONCLUSIONS: These results could confirm the assumption that the correct performance of an USG-TAPB as part of a multimodal analgesic treatment could represent a viable alternative to common analgesic procedures performed for acute postoperative pain control after a CS.Key words: Bowel function, Caesarian section, incident pain, local anesthetics, multimodal analgesic treatment, postoperative recovery, rest pain, ultrasound-guided TAP block.

Organic honey supplementation reverses pesticide-induced genotoxicity by modulating DNA damage response.

SCOPE: Glyphosate (GLY) and organophosphorus insecticides such as chlorpyrifos (CPF) may cause DNA damage and cancer in exposed individuals through mitochondrial dysfunction. Polyphenols ubiquitously present in fruits and vegetables, have been viewed as antioxidant molecules, but also influence mitochondrial homeostasis. Here, honey containing polyphenol compounds was evaluated for its potential protective effect on pesticide-induced genotoxicity. METHODS AND RESULTS: Honey extracts from four floral organic sources were evaluated for their polyphenol content, antioxidant activity, and potential protective effects on pesticide-related mitochondrial destabilization, reactive oxygen and nitrogen species formation, and DNA damage response in human bronchial epithelial and neuronal cells. The protective effect of honey was, then evaluated in a residential population chronically exposed to pesticides. The four honey types showed a different polyphenol profile associated with a different antioxidant power. The pesticide-induced mitochondrial dysfunction parallels ROS formation from mitochondria (mtROS) and consequent DNA damage. Honey extracts efficiently inhibited pesticide-induced mtROS formation, and reduced DNA damage by upregulation of DNA repair through NFR2. Honey supplementation enhanced DNA repair activity in a residential population chronically exposed to pesticides, which resulted in a marked reduction of pesticide-induced DNA lesions. CONCLUSION: These results provide new insight regarding the effect of honey containing polyphenols on pesticide-induced DNA damage response.

Italian Registry of Complications associated with Regional Anesthesia (RICALOR). An incidence analysis from a prospective clinical survey.

BACKGROUND: Regional anesthesia (RA) is associated with many advantages, but side effects also occur. Several registries were developed to investigate such complications in many countries, which produced conflicting results. In consideration of the ongoing evolution and improvements in RA, and its widespread diffusion in Italy in the last decade (with increasing experience by anesthesiologists), a reappraisal of the incidence and the characteristics of major complications are useful to improve patient's safety. METHODS: A web-based prospective registry was developed in Italy with: 1) quarterly report of total anesthetic acts and RA procedures performed; and 2) voluntary registration of complications on dedicated forms. We evaluated incidence of complications, describing their characteristics and outcomes. RESULTS: Participants (N.=17 hospitals) registered 117,182 procedures, including 63,692 with RA (54.3%, both as primary anesthetic technique and for postoperative analgesia). A total of 34,147 neuraxial blocks (4954 epidurals/CSE, 29,193 subarachnoid blocks) and 29,545 peripheral (single shot and continuous) blocks were registered. Total incidence of complication was 4.6/10.000; incidence was 4.1/10,000 for central blocks and 5.1/10,000 for peripheral blocks, long-term neurologic deficit (at 6 months) was observed after an epidural abscess, while other complications did not lead to any long-term adverse outcomes. No hemorrhagic events or other infections have occurred. Incidence of major complications was 0.07/1000, while minor complications presented in 0.38/1000 cases. CONCLUSIONS: We confirmed RA as generally safe, but monitoring and diagnosis, together with further research efforts, are needed to improve patients' care and clarify potential risk factors.

Treatment of chronic cervicobrachial pain with periradicular injection of meloxicam.

BACKGROUND: Cervicobrachial pain (CBP) is often resistant to conventional oral analgesics. We hypothesized that the periradicular injection of meloxicam would produce a significant reduction in their intractable CBP. The secondary objective was to assess the impact of the treatment on functional recovery. METHODS: 48 patients with persistent CBP (>3 months of duration) despite multimodal analgesic therapy received 1-3 periradicular injections of meloxicam, 5-20 mg, at the dermatomal level(s) corresponding to their pain symptoms. Pain level (0=none to 10=severe), rescue analgesics, and functional activity were recorded at baseline and for 90d after the last injection. The injection was repeated if the pain score remained >3 or paresthesia persisted. RESULTS: The mean pain score was reduced from a baseline of 8.9 (±1) to 1.7 (±2.2) at 90 days after the last meloxicam injection. Following meloxicam treatment(s), only 13% of the patients required oral analgesic rescue medication. All patients increased their functional activity level. CONCLUSIONS: Cervical periradicular injection of meloxicam reduced CBP by 81% at 90-day follow-up and also improved functional recovery.

Combined circulating epigenetic markers to improve mesothelin performance in the diagnosis of malignant mesothelioma.

OBJECTIVES: Malignant mesothelioma (MM) is a highly aggressive tumor with poor prognosis. A major challenge is the development and application of early and highly reliable diagnostic marker(s). Serum biomarkers, such as 'soluble mesothelin-related proteins' (SMRPs), is the most studied and frequently used in MM. However, the low sensitivity of SMRPs for early MM limits its value; therefore, additional biomarkers are required. In this study, two epigenetically regulated markers in MM (microRNA-126, miR-126, and methylated thrombomodulin promoter, Met-TM) were combined with SMRPs and evaluated as a potential strategy to detect MM at an early stage. MATERIALS AND METHODS: A total of 188 subjects, including 45 MM patients, 99 asbestos-exposed subjects, and 44 healthy controls were prospectively enrolled, serum samples collected, and serum levels of SMRPs, miR-126 and Met-TM evaluated. Logistic regression analysis was performed to evaluate the diagnostic value of the three biomarkers. Using this approach, the performance of the '3-biomarker classifier' was tested by calculating the overall probability score of the MM and control samples, respectively, and the ROC curve was generated. RESULTS AND CONCLUSION: The combination of the three biomarkers was the best predictor to differentiate MM patients from asbestos-exposed subjects and healthy controls. The accuracy and cancer specificity was confirmed in a second validation cohort and lung cancer population. We propose that the combination of the two epigenetic biomarkers with SMRPs as a diagnosis for early MM overcomes the limitations of using SMRPs alone.

Can neural blocks prevent phantom limb pain?

Phantom limb syndrome (PLS) is a syndrome including stump pain, phantom limb pain and not-painful phantom sensations, which involves a large part of amputee patients and often has devastating effects on their quality of life. The efficacy of standard therapies is very poor. Nerve blocks have been investigated for the treatment and prevention of PLS. Epidural and peripheral blocks limited to the first three postamputation days can only reduce acute pain but cannot prevent the later development of PLS. Recent studies have shown that ambulatory prolonged peripheral nerve block (up to 30 days postamputation) may represent a new possible option to treat phantom pain and prevent the development of PLS and chronic pain.

Alpha-tocopheryl succinate inhibits autophagic survival of prostate cancer cells induced by vitamin K3 and ascorbate to trigger cell death.

BACKGROUND: The redox-silent vitamin E analog α-tocopheryl succinate (α-TOS) was found to synergistically cooperate with vitamin K3 (VK3) plus ascorbic acid (AA) in the induction of cancer cell-selective apoptosis via a caspase-independent pathway. Here we investigated the molecular mechanism(s) underlying cell death induced in prostate cancer cells by α-TOS, VK3 and AA, and the potential use of targeted drug combination in the treatment of prostate cancer. METHODOLOGY/PRINCIPAL FINDINGS: The generation of ROS, cellular response to oxidative stress, and autophagy were investigated in PC3 prostate cancer cells by using drugs at sub-toxic doses. We evaluated whether PARP1-mediated apoptosis-inducing factor (AIF) release plays a role in apoptosis induced by the combination of the agents. Next, the effect of the combination of α-TOS, VK3 and AA on tumor growth was examined in nude mice. VK3 plus AA induced early ROS formation associated with induction of autophagy in response to oxidative stress, which was reduced by α-TOS, preventing the formation of autophagosomes. α-TOS induced mitochondrial destabilization leading to the release of AIF. Translocation of AIF from mitochondria to the nucleus, a result of the combinatorial treatment, was mediated by PARP1 activation. The inhibition of AIF as well as of PARP1 efficiently attenuated apoptosis triggered by the drug combination. Using a mouse model of prostate cancer, the combination of α-TOS, VK3 and AA was more efficient in tumor suppression than when the drugs were given separately, without deleterious side effects. CONCLUSIONS/SIGNIFICANCE: α-TOS, a mitochondria-targeting apoptotic agent, switches at sub-apoptotic doses from autophagy-dependent survival of cancer cells to their demise by promoting the induction of apoptosis. Given the grim prognosis for cancer patients, this finding is of potential clinical relevance.

Effect of ascorbic acid-rich diet on in vivo-induced oxidative stress.

Using hyperbaric oxygen (HBO) therapy as an in vivo oxidation model, we investigated the effect of a diet enriched in ascorbic acid (AA) on HBO-induced oxidative stress. Volunteers (n 46) were allocated to the AA-rich diet group or the control group. Blood samples were collected at the basal time, after the 1-week diet before and immediately after the HBO treatment, and 1 week after the HBO treatment. AA level, total antioxidant status (TAS), hydroperoxides (HP), lymphocyte DNA oxidation and DNA repair capacity were assessed. The expression of genes involved in oxidative stress was evaluated in lymphocytes and the protein activity of the modulated genes was determined in the plasma. The AA level and the antioxidant status of plasma were increased by AA-rich food consumption. HBO exposure did not affect the AA levels or TAS, but induced HP formation in the control group. The lymphocytes isolated from dietary-supplemented subjects were resistant to ex vivo DNA oxidation, showing an increased DNA repair capacity compared with controls. A difference in gene expression pattern was observed between the groups. AA-rich foods provide dual protection against oxidative stress, enhancing plasma antioxidant levels and stimulating genes involved in cell detoxification.