This study aimed to comprehensively assess the metabolic, mitochondrial, and inflammatory effects of first-line efavirenz, emtricitabine, and tenofovir disoproxil fumarate (EFV/FTC/TDF) single-tablet regimen (STR) relative to untreated asymptomatic HIV infection. To this end, we analyzed 29 people with HIV (PWH) treated for at least one year with this regimen vs. 33 antiretroviral-naïve PWH. Excellent therapeutic activity was accompanied by significant alterations in metabolic parameters. The treatment group showed increased plasmatic levels of glucose, total cholesterol and its fractions (LDL and HDL), triglycerides, and hepatic enzymes (GGT, ALP); conversely, bilirubin levels (total and indirect fraction) decreased in the treated cohort. Mitochondrial performance was preserved overall and treatment administration even promoted the recovery of mitochondrial DNA (mtDNA) content depleted by the virus, although this was not accompanied by the recovery in some of their encoded proteins (since cytochrome c oxidase II was significantly decreased). Inflammatory profile (TNFα, IL-6), ameliorated after treatment in accordance with viral reduction and the recovery of TNFα levels correlated to mtDNA cell restoration. Thus, although this regimen causes subclinical metabolic alterations, its antiviral and anti-inflammatory properties may be associated with partial improvement in mitochondrial function.

Carbon monoxide (CO) is a colorless and odorless gas that is a leading cause of environmental poisoning in the USA with substantial mortality and morbidity. The mechanism of CO poisoning is complex and includes hypoxia, inflammation, and leukocyte sequestration in brain microvessel segments leading to increased reactive oxygen species. Another important pathway is the effects of CO on the mitochondria, specifically at cytochrome c oxidase, also known as Complex IV (CIV). One of the glaring gaps is the lack of rigorous experimental models that may recapitulate survivors of acute CO poisoning in the early phase. The primary objective of this preliminary study is to use our advanced swine platform of acute CO poisoning to develop a clinically relevant survivor model to perform behavioral assessment and MRI imaging that will allow future development of biomarkers and therapeutics.

Four swine (10 kg) were divided into two groups: control (n = 2) and CO (n = 2). The CO group received CO at 2000 ppm for over 120 min followed by 30 min of re-oxygenation at room air for one swine and 150 min followed by 30 min of re-oxygenation for another swine. The two swine in the sham group received room air for 150 min. Cerebral microdialysis was performed to obtain semi real-time measurements of cerebral metabolic status. Following exposures, all surviving animals were observed for a 24-h period with neurobehavioral assessment and imaging. At the end of the 24-h period, fresh brain tissue (cortical and hippocampal) was immediately harvested to measure mitochondrial respiration.

While a preliminary ongoing study, animals in the CO group showed alterations in cerebral metabolism and cellular function in the acute exposure phase with possible sustained mitochondrial changes 24 h after the CO exposure ended.

This preliminary research further establishes a large animal swine model investigating survivors of CO poisoning to measure translational metrics relevant to clinical medicine that includes a basic neurobehavioral assessment and post exposure cellular measures.

The liver is affected by two of the most common groups of malignant tumours: primary liver tumours and liver metastases from colorectal carcinoma. Liver metastases are significantly more common than primary liver cancer and long-term survival rates reported for patients after radical surgical treatment is approximately 50%. However, R0 resection (resection for cure) is not feasible in the majority of patients. Cryotherapy is performed with the use of an image-guided cryoprobe which delivers liquid nitrogen or argon gas to the tumour tissue. The subsequent process of freezing is associated with formation of ice crystals, which directly damage exposed tissue, including cancer cells.

To assess the beneficial and harmful effects of cryotherapy compared with no intervention, other ablation methods, or systemic treatments in people with liver metastases.

We searched The Cochrane Hepato-Biliary Group Controlled Trials Register, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE Ovid, Embase Ovid, and six other databases up to June 2018.

Randomised clinical trials assessing beneficial and harmful effects of cryotherapy and its comparators for liver metastases, irrespective of the location of the primary tumour.

We used standard methodological procedures expected by Cochrane. We extracted information on participant characteristics, interventions, study outcomes, and data on the outcomes important for our review, as well as information on the design and methodology of the trials. Two review authors independently assessed risk of bias in each study. One review author performed data extraction and a second review author checked entries.

We found no randomised clinical trials comparing cryotherapy versus no intervention or versus systemic treatments; however, we identified one randomised clinical trial comparing cryotherapy with conventional surgery. The trial was conducted in Ukraine. The trial included 123 participants with solitary, or multiple unilobar or bilobar liver metastases; 63 participants received cryotherapy and 60 received conventional surgery. There were 36 women and 87 men. The primary sites for the metastases were colon and rectum (66.6%), stomach (7.3%), breast (6.5%), skin (4.9%), ovaries (4.1%), uterus (3.3%), kidney (3.3%), intestines (1.6%), pancreas (1.6%), and unknown (0.8%). The trial was not reported sufficiently enough to assess the risk of bias of the randomisation process, allocation concealment, or presence of blinding. It was also not possible to assess incomplete outcome data and selective outcome reporting bias. The certainty of evidence was low because of risk of bias and imprecision.The participants were followed for up to 10 years (minimum five months). The trial reported that the mortality at 10 years was 81% (51/63) in the cryotherapy group and 92% (55/60) in the conventional surgery group. The calculated by us relative risk (RR) with 95% Confidence Interval (CI) was: RR 0.88, 95% CI 0.77 to 1.02. We judged the evidence as low-certainty evidence. Regarding adverse events and complications, separately and in total, our calculation showed no evidence of a difference in recurrence of the malignancy in the liver: 86% (54/63) of the participants in the cryotherapy group and 95% (57/60) of the participants in the conventional surgery group developed a new malignancy (RR 0.90, 95% CI 0.80 to 1.01; low-certainty evidence). The frequency of reported complications was similar between the cryotherapy group and the conventional surgery group, except for postoperative pain. Both insignificant and pronounced pain were reported to be more common in the cryotherapy group while intense pain was reported to be more common in the conventional surgery group. However, the authors did not report whether there was any evidence of a difference. There were no intervention-related mortality or bile leakages.We identified no evidence for health-related quality of life, cancer mortality, or time to progression of liver metastases. The study reported tumour response in terms of the carcinoembryonic antigen level in 69% of participants, and reported results in the form of a graph for 30% of participants. The carcinoembryonic antigen level was lower in the cryotherapy group, and decreased to normal values faster in comparison with the control group (P < 0.05).

the trial did not provide information on funding.

The evidence for the effectiveness of cryotherapy versus conventional surgery in people with liver metastases is of low certainty. We are uncertain about our estimate and cannot determine whether cryotherapy compared with conventional surgery is beneficial or harmful. We found no evidence for the benefits or harms of cryotherapy compared with no intervention, or versus systemic treatments.

The treatment strategy for jaundiced patients with hilar cholangiocarcinoma (HC) is not well established. In this study, we evaluate the feasibility of our perioperative protocol for jaundiced patients with HC.

Twenty patients with HC who underwent hepatic resection at our institute were enrolled, and patients were divided into icteric(n=6) and normal(n=14) group. As a perioperative protocol, Oral administration of Inchinkoto(ICKT), steroid and nafamostat mesilate were introduced. The evaluation of functional future remnant liver(FRL) by asiaroscintigraphy, and postoperative outcomes were retrospectively compared.

Indocyanine green dye retention rate at 15 minutes was higher, and LHL15 values was lower in icteric group. However, in the functional evaluation of FRL, which was the sum of GSA uptake of the future FRL, there was no significant difference of LHL15 values of the remnant liver functional reserve between the two groups. As results, according to the difference of liver function, serum AST level was not different between two groups. The number of patients with postoperative morbidity in the two groups was comparable.

Even in HC patients with icteric liver, accurate assessment of liver functional reserve and effective perioperative treatment may attribute to successful hepatectomy and favorable post-operative outcomes. J. Med. Invest. 65:37-42, February, 2018.

Posthepatectomy complications have markedly decreased with advances in techniques and management; however, surgical risk to patients with injured livers is still not negligible. We evaluated several preoperative parameters of functional liver reserve tests in patients with various liver diseases as predictors of posthepatectomy complications. A comprehensive evaluation of preoperative liver functions is necessary for the prediction of the risk of posthepatectomy complications.

Over a 10-y period, we examined 442 patients who underwent hepatectomy for liver and biliary diseases. The patients' background liver diseases included chronic viral liver diseases in 211 patients, obstructive jaundice in 29 patients, and normal liver in 202 patients. Hepatectomy-related postoperative complications (i.e., long-term ascites, intra-abdominal infection, and hepatic failure) occurred in 115 (26%) patients. A multivariate logistic analysis was performed to detect the predictive parameters, and a multivariate linear regression analysis was performed to derive a predictive formula for complications.

A univariate analysis identified 15 significant parameters associated with hepatectomy-related complications, and eight parameters (i.e., presence of chronic hepatic injury, clearance index by technetium-99 m galactosyl human serum albumin liver scintigraphy of ≥ 0.60, total bilirubin level of >1 mg/dL, serum hyaluronic acid level of ≥ 75 ng/mL, major hepatectomy, blood loss of ≥ 950 mL, operating time of ≥ 500 min, and combined resection of another organ or major vessel) were independent predictive factors identified in the multivariate analysis. Clearance index by technetium-99 m galactosyl human serum albumin liver, bilirubin level, hyaluronic acid level, and major hepatectomy were the parameters included in the predictive formula.

In the present study, we present a comprehensive formula based on the predictive parameters for hepatic complications for prospective assessment to avoid posthepatectomy morbidity.

Interleukin-8 (IL-8) is a neutrophil chemotactic factor, which is associated with some inflammatory diseases and various types of surgical stress. The aim of this study was to investigate whether the early postoperative serum IL-8 level may potentially be a new indicator of a surgical stress in patients undergoing a hepatic resection.

The serum IL-8 levels were measured in 37 patients who underwent a hepatectomy. The serum IL-8 levels were serially measured using an enzyme-linked immunosorbent assay both before and after a hepatic resection. In addition, the correlation between the postoperative IL-8 value and several clinical variables were examined.

The mean level of IL-8 significantly increased immediately after the operation (P < 0.01 vs before the operation) and decreased on the first postoperative day (POD 1, P < 0.05 vs after the operation). The early postoperative IL-8 levels positively correlated with the length of the procedure (r = 0.383; P < 0.05), the estimated blood loss (r = 0.483; P < 0.01) and the serum bilirubin level on POD 1 (r = 0.390; P < 0.05), and inversely correlated with the white blood cell counts (r = -0.388; P < 0.05) and lymphocyte counts on POD 1 (r = -0.424; P < 0.05). In a comparison of the postoperative IL-8 levels with the surgical factors, there was a significant difference in the extension of the resection (P < 0.05) and in blood transfusion. The patients with a fever of more than 38 degrees C showed higher levels of IL-8 immediately after the operation than those without fever (P < 0.01).

The early postoperative serum IL-8 level was found to correlate with the degree of the severity of surgery in patients undergoing a hepatic resection, and it is also considered to be a new indicator of surgical stress and liver injury.

Extensive experimental studies and a few clinical series have shown that ischemic preconditioning (IPC) attenuates oxidative ischemia/reperfusion (I/R) injuries in liver resections performed under inflow vascular control. Selective hepatic vascular exclusion (SHVE) employed during hepatectomies completely deprives the liver of blood flow, as it entails simultaneous clamping of the portal triad and the main hepatic veins. The aim of the present study was to identify whether IPC can also protect hepatocytes during liver resections performed under SHVE.

Patients undergoing major liver resection were randomly assigned to have either only SHVE (control group, n = 43) or SHVE combined with IPC--10 min of ischemia followed by 15 min of reperfusion before SHVE was applied (IPC group, n = 41).

The two groups were comparable with regard to age, liver resection volume, blood loss and transfusions, warm ischemic time, and total operative time. In liver remnant biopsies obtained 60 min post-reperfusion, IPC patients had significantly fewer cells stained positive by TUNEL compared to controls (19% +/- 8% versus 45% +/- 12%; p < 0.05). Also IPC patients had attenuated hepatocyte necrosis, systemic inflammatory response, and oxidative stress as manifested by lower postoperative peak values of aspartate transaminase, interleukin-6, interleukin-8, and malondialdehyde compared to controls. Morbidity was similar for the two groups, as were duration of intensive care unit stay and extent of total hospital stay.

In major hepatectomies performed under SHVE, ischemic preconditioning appears to attenuate apoptotic response of the liver remnant, possibly through alteration of inflammatory and oxidative pathways.

Tumour necrosis factor-alpha (TNF-alpha) plays a key role in causing ischaemia/reperfusion (I/R) injury. I/R also causes activation of xanthine oxidase and dehydrogenase (XDH + XO) system that, via generated free radicals, causes organ damage. We investigated the effect of ischaemia, reperfusion and non-ischaemic prolonged perfusion (NIP) on TNF-alpha and XDH + XO production in an isolated perfused rat liver model.

Rat livers underwent 150 min NIP (control group) or two hours of ischaemia followed by reperfusion (I/R group). TNF-alpha (TNF-alpha mRNA and protein level), XDH + XO production and bile secretion were determined in tissue and effluent at baseline, at 120 min of ischaemia, after 30 min of reperfusion (I/R group) and after 120 and 150 min of prolonged perfusion (control).

Unexpectedly, neither ischaemia nor reperfusion had any effect on TNF-alpha production. TNF-alpha in effluent was 11 +/- 4.8 pg mL(-1) at baseline, 7 +/- 3.2 pg mL(-1) at the end of ischaemia, and 13 +/- 5.3 pg mL(-1) after 30 min of reperfusion. NIP, however, caused a significant increase of TNF-alpha synthesis and release. TNF-alpha effluent level after 120 and 150 min of perfusion was 392 +/- 78.7 pg mL(-1) and 408 +/- 64.3 pg mL(-1), respectively. TNF-alpha mRNA in tissue was also significantly elevated compared to baseline levels (1.31 +/- 0.2 P < 0.001 and 1.38 P < 0.002, respectively). Decrease of liver function (expressed by bile secretion) during I/R and NIP was accompanied by significant XDH + XO elevation.

This is the first evidence that NIP, and not I/R, is the decisive trigger for TNF-alpha production. This study leads to a better understanding of pathogenesis of liver I/R and perfusion damage.

Recent studies have shown that hyperbaric oxygen therapy (HBOT) reduces neutrophil endothelial adherence in venules and also blocks the progressive arteriolar vasoconstriction associated with ischemia-reperfusion (I-R) injury in the extremities and the brain. In order to elucidate the effects of HBOT after I-R in digestive organs, particularly in the liver, we evaluated the following: 1) the relationship between timing of HBOT and tissue damage; and 2) HBOT's effects on neutrophil sequestration. Using a hepatic I-R (45 minute) model in male rats, survival rate, liver tissue damage, and neutrophil accumulation within the sinusoids in the HBOT-treated group (Group H) were compared to those in the nontreated group (Group C). For the HBOT-treated group, HBOT was administered as 100% oxygen, at 2.5 atm absolute, for 60 minutes. When HBOT was given 30 minute after I-R, the survival rate was much better in Group H than in Group C. HBOT performed within 3 hours of I-R markedly suppressed increases in the malondialdehyde level in tissues of the liver and lessened the congestion in the sinusoids. In addition, HBOT just after I-R caused decreased number of cells stained by the naphthol AS-D chloroacetate esterase infiltrating into the sinusoids. HBOT 3 hours after reperfusion, however, showed no clear effects upon neutrophil sequestration compared to Group C. These results indicate that HBOT performed within 3 hours of I-R alleviates hepatic dysfunction and improves the survival rate after I-R. Herein, we propose 1 possible mechanism for these beneficial effects: early HBOT given before neutrophil-mediated injury phase may suppress the accumulation of neutrophils after I-R. In conclusion, we believe that the present study should lead to an improved understanding of HBOT's potential role in hepatic surgery.

Experimental findings have demonstrated a beneficial role of retrograde blood flow from hepatic veins that takes place during the Pringle maneuver in liver resections. The cytoprotective effect of hepatovenous back-perfusion has not been evaluated in humans. A randomized prospective study was designed to compare the response of liver cells to ischemic-reperfusion injury during the application of two different ischemic procedures: inflow versus inflow plus outflow vascular occlusion of the liver.

Forty patients were randomly allocated to undergo liver resection using the continuous Pringle maneuver (n = 20) or inflow plus outflow vascular occlusion of the liver by selective hepatic vascular exclusion (n = 20). Liver function was assessed on postoperative days 1 to 6. Response of liver cells to I/R injury was evaluated by measuring interleukins IL-6 and IL-8 at 3, 12, 24, and 48 hours after reperfusion. Oxidative stress was assessed by measuring malondialdehyde levels.

Both groups were comparable regarding ischemic time, operative time, and extent of liver resection. Patients in whom retrograde blood flow to the liver took place during the Pringle maneuver showed better liver function postoperatively and less severe hepatic I/R injuries compared with those undergoing liver resection using both inflow and outflow vascular occlusion. Oxidative stress was significantly lower in the Pringle maneuver group compared with the inflow plus outflow vascular occlusion group (mean [+/- SD] malondialdehyde 8 +/- 2.1 micromol/L in the Pringle group versus 14.7 +/- 1.8 micromol/L in the selective hepatic vascular exclusion group 30 min after reperfusion, p < 0.01).

Back perfusion via hepatic veins contributes to attenuation of I/R damage during the Pringle maneuver and should be preferred if possible during liver resection.

A new concept of surgical stress has been proposed that consists of both aggressiveness of operation and systemic reactions to an operation.

We have investigated a possible modulation of such systemic reactions to operation and have demonstrated the following 3 points: (1) coagulation and fibrinolytic systems are independently activated during hepatectomy and such activation can be modulated by protease inhibitors such as nafamostat mesilate and antithrombin III; (2) elevated thromboxane A2 during hepatectomy is characterized in the prostanoid system, the elevation of thromboxane A2 is inhibited by thromboxane A2 synthetase inhibitor, and postoperative liver injury is reduced; (3) cytokine response induced by hepatectomy is modulated by preoperative administration of methylprednisolone, leading to possible prevention of bacterial translocation. Therefore, modulating systemic reactions to hepatectomy may be important for successful minimally invasive hepatectomy. Another important option for minimally invasive hepatectomy is the use of operative procedures such as laparoscope or thoracoscope. We have investigated the usefulness of a laparoscopic hepatectomy from the standpoints of early and long-term outcome after hepatectomy. Laparoscopic hepatectomy, which is a difficult and dangerous procedure, can be a feasible option and can result in better short-term outcome and a similar long-term outcome after hepatectomy when compared with conventional open hepatectomy. Therefore, the laparoscopic approach is also a viable option for minimally invasive hepatectomy.

Modulation of systemic reactions to the operation itself and laparoscopic hepatectomy may be new strategies for performing minimally invasive hepatectomy.