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Gentle handling seems to elicit positive states in sheep. The study investigated whether spatial distance alters sheep responses to brushing and whether spatial distance is influenced by reactivity. Twenty Romane ewes were assessed in three sessions: in Sessions 1 and 3, one grid separated the test animal from pen mates, with no distance between them, and in Session 2 two grids separated the test animal from pen mates by a distance of about 1.7 m. Ewes had been genetically selected for low (R−) or high (R+) behavioural reactivity to social isolation. Body postures, head orientation, ear postures, closed and half-closed eyes, tail wagging and feeding behaviour, in addition to heart rate (HR) and HR variability, as the root mean square of successive differences (RMSSD), standard deviation of all normal-to-normal (NN) intervals (SDNN), RMSSD/SDNN ratio and ratio between low-frequency (LF) and high-frequency (HF) powers (LF/HF) were assessed. Data were analysed using generalized linear models and linear mixed models. Session, genetic line and phase (pre-, brushing and post-brushing) were considered fixed effects. Increased distance in Session 2 might not have influenced ewes’ responses. Fewer changes in ear postures were noted in Session 3 than 1 (P

The common practice of artificially rearing lambs from prolific meat breeds of sheep constitutes a welfare issue due to increased mortality rates and negative health issues. In this multidisciplinary study, we investigated the possible short- and mid-term advantages of artificially feeding fresh ewe's milk instead of commercial milk replacer on lambs' growth, health and welfare. Romane lambs were either separated from their mothers on D3 and fed with Lacaune ewes' milk (LAC, n = 13) or milk replacer (REP, n = 15), or they were reared by their mothers (MOT, n = 15). On D45, they were weaned, gathered in single-sex groups until the end of the study on D150. Lamb performance and biomarkers of overall health were assessed by measuring: growth, dirtiness of the perianal area, enteric pathogens in the faeces, total antioxidant status and redox status assessed by plasma reduced glutathione/oxidised glutathione ratio, and immune response after vaccination against chlamydiosis. As an exploratory approach, blood cell transcriptomic profiles were also investigated. Last, qualitative behaviour assessment (QBA) was performed as an integrated welfare criterion. Lacaune ewes' milk and REP never differed in their average daily gain but grew less than MOT lambs in the early suckling period and just after weaning. No effect was detected afterwards. On D30, LAC and REP lambs had lower total antioxidant and higher redox status than MOT lambs but did not differ among themselves. Lacaune ewes' milk and MOT had a cleaner perianal area than REP lambs on D21, while faecal pathogen infection did not vary between the treatment groups. After vaccination, LAC also had a stronger immune response on D90 compared to REP lambs. Transcriptome analysis performed on D150 showed differential gene expression, mainly in relation to inflammatory, immune and cell cycle response, between male lambs of the LAC group and those of the MOT and REP groups. Based on QBA, LAC lambs never differed from MOT lambs in their general activity and varied from REP only on D21; REP lambs were always more agitated than MOT lambs. In conclusion, artificial milk feeding impaired early growth rate, health and emotional state mainly during the milk feeding period and at weaning. Feeding artificially reared lambs with fresh ewe's milk partly mitigated some of the negative effects induced by milk replacer but without achieving the full benefit of being reared by the mother.

Recent flooding events, like Katrina (USA, 2005) or Xynthia (France, 2010), illustrate the complexity of coastal systems and the limits of traditional flood risk analysis. Among other questions, these events raised issues such as: "how to choose flooding scenarios for risk management purposes?", "how to make a society more aware and prepared for such events?" and "which level of risk is acceptable to a population?". The present paper aims at developing an inverse approach that could seek to address these three issues. The main idea of the proposed method is the inversion of the usual risk assessment steps: starting from the maximum acceptable hazard level (defined by stakeholders as the one leading to the maximum tolerable consequences) to finally obtain the return period of this threshold. Such an "inverse" approach would allow for the identification of all the offshore forcing conditions (and their occurrence probability) inducing a threat for critical assets of the territory, such information being of great importance for coastal risk management. This paper presents the first stage in developing such a procedure. It focuses on estimation (through inversion of the flooding model) of the offshore conditions leading to the acceptable hazard level, estimation of the return period of the associated combinations, and thus of the maximum acceptable hazard level. A first application for a simplified case study (based on real data), located on the French Mediterranean coast, is presented, assuming a maximum acceptable hazard level. Even if only one part of the full inverse method has been developed, we demonstrate how the inverse method can be useful in (1) estimating the probability of exceeding the maximum inundation height for identified critical assets, (2) providing critical offshore conditions for flooding in early warning systems, and (3) raising awareness of stakeholders and eventually enhance preparedness for future flooding events by allowing them to assess risk to their territory. The next challenge is to develop a framework to properly identify the acceptable hazard level, as an input to the present inverse approach.

Amylomyces rouxii is commonly found as amylolytic fungi in tapai fermentation. However, its diversity is rarely reported despite being often used for food production in Southeast Asia. This research aims to analyze the genetic diversity and the distribution pattern of A . rouxii from Ragi tapai in Java Island, Indonesia. We isolated the fungus from samples obtained from Ragi tapai producing centers in Bandung, Sumedang, Muntilan, Blora, Yogyakarta, and Bondowoso. The obtained isolates were molecularly identified based on the ribosomal regions ITS1/ITS2 and D1/D2, then analyzed for phylogenetic tree reconstruction, genetic distance, genetic variation, and haplotype networking. Six isolates showed specific morphological traits of A. rouxii . However, phylogenetic tree reconstruction on the ribosomal genes showed that the isolates were grouped into two different clades related to two species. Clade A included BDG, SMD, and MTL isolates related to A . rouxii, whereas clade B included YOG, BLR, and BDS isolates related to Mucor indicus. The genetic distances between clades for ITS1/ITS2 and D1/D2 were 0.6145 and 0.1556, respectively. In conclusion, we confirmed the genetic diversity of molds from Ragi tapai in Java Island and showed that the isolates are not only related to A. rouxii as reported before., Competing Interests: The authors declare no conflicts of interest. All the experiments were undertaken in this study comply with the country's current laws where they were performed., (© 2022 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group on behalf of the Korean Society of Mycology.)

Pemphigus vulgaris (PV) is an epidermal blistering disorder caused by antibodies directed against the desmosomal cadherin desmoglein-3 (Dsg3). The mechanism by which PV IgG disrupts adhesion is not fully understood. To address this issue, primary human keratinocytes (KCs) and patient IgG were used to define the morphological, biochemical, and functional changes triggered by PV IgG. Three phases of desmosome disassembly were distinguished. Analysis of fixed and living KCs demonstrated that PV IgG cause rapid Dsg3 internalization, which likely originates from a non-junctional pool of Dsg3. Subsequently, Dsg3 and other desmosomal components rearrange into linear arrays that run perpendicular to cell contacts. Dsg3 complexes localized at the cell surface are transported in a retrograde manner along with these arrays before being released into cytoplasmic vesicular compartments. These changes in Dsg3 distribution are followed by depletion of detergent-insoluble Dsg3 pools and by the loss of cell adhesion strength. Importantly, this process of disassembly can be prevented by expressing exogenous Dsg3, thereby driving Dsg3 biosynthesis and desmosome assembly. These data support a model in which PV IgG cause the loss of cell adhesion by altering the dynamics of Dsg3 assembly into desmosomes and the turnover of cell surface pools of Dsg3 through endocytic pathways.

Desmosomes are intercellular junctions that tether intermediate filaments to the plasma membrane. Desmogleins and desmocollins, members of the cadherin superfamily, mediate adhesion at desmosomes. Cytoplasmic components of the desmosome associate with the desmosomal cadherin tails through a series of protein interactions, which serve to recruit intermediate filaments to sites of desmosome assembly. These desmosomal plaque components include plakoglobin and the plakophilins, members of the armadillo gene family. Linkage to the cytoskeleton is mediated by the intermediate filament binding protein, desmoplakin, which associates with both plakoglobin and plakophilins. Although desmosomes are critical for maintaining stable cell-cell adhesion, emerging evidence indicates that they are also dynamic structures that contribute to cellular processes beyond that of cell adhesion. This article outlines the structure and function of the major desmosomal proteins, and explores the contributions of this protein complex to tissue architecture and morphogenesis.

Cadherins are a large family of cell-cell adhesion molecules that tether cytoskeletal networks of actin and intermediate filaments to the plasma membrane. This function of cadherins promotes tissue organization and integrity, as demonstrated by numerous disease states that are characterized by the loss of cadherin-based adhesion. However, plasticity in cell adhesion is often required in cellular processes such as tissue patterning during development and epithelial migration during wound healing. Recent work has revealed a pivotal role for various membrane trafficking pathways in regulating cellular transitions between quiescent adhesive states and more dynamic phenotypes. The regulation of cadherins by membrane trafficking is emerging as a key player in this balancing act, and studies are beginning to reveal how this process goes awry in the context of disease. This review summarizes the current understanding of how cadherins are routed and how the interface between cadherins and membrane trafficking pathways regulates cell surface adhesive potential. Particular emphasis is placed on the regulation of cadherin trafficking by catenins and the interplay between growth factor signaling pathways and cadherin endocytosis.

Pemphigus vulgaris (PV) is a life-threatening autoimmune disease characterized by oral mucosal erosions and epidermal blistering. The autoantibodies generated target the desmosomal cadherin desmoglein-3 (Dsg3). Previous studies demonstrate that upon PV IgG binding, Dsg3 is internalized and enters an endo-lysosomal pathway where it is degraded. To define the endocytic machinery involved in PV IgG-induced Dsg3 internalization, human keratinocytes were incubated with PV IgG, and various tools were used to perturb distinct endocytic pathways. The PV IgG.Dsg3 complex failed to colocalize with clathrin, and inhibitors of clathrin- and dynamin-dependent pathways had little or no effect on Dsg3 internalization. In contrast, cholesterol binding agents such as filipin and nystatin and the tyrosine kinase inhibitor genistein dramatically inhibited Dsg3 internalization. Furthermore, the Dsg3 cytoplasmic tail specified sensitivity to these inhibitors. Moreover, inhibition of Dsg3 endocytosis with genistein prevented disruption of desmosomes and loss of adhesion in the presence of PV IgG. Altogether, these results suggest that PV IgG-induced Dsg3 internalization is mediated through a clathrin- and dynamin-independent pathway and that Dsg3 endocytosis is tightly coupled to the pathogenic activity of PV IgG.

Background and Objectives: Intrathecal morphine is a widely used method for postoperative pain relief after major abdominal surgery. The aim of this randomized, double-blinded study was to compare intrathecal morphine and intravenous PCA morphine for postoperative analgesia and recovery course after major colorectal surgery in elderly patients., Methods: After written informed consent, patients >70 years of age were prospectively and randomly assigned to receive either preoperative intrathecal morphine (0.3 mg) and postoperative patient-controlled (PCA) intravenous morphine (IT morphine) or PCA alone (group control). Results are presented as mean +/- SD (95% confidence interval)., Results: Twenty-six patients successfully completed the study in each group. In the IT morphine group, rate of awakening was delayed. Pain intensity and daily intravenous morphine consumption were significantly reduced 1 and 2 days after surgery in the IT morphine group (P < .01). Mental function (assessed by Mini Mental State and Digit Symbol Substitution Test) was similar in both groups. Episodes of postoperative delirium/confusion occurred similarly in both groups. Time to ileus resolution and time to ambulation without assistance did not differ between the 2 groups. The duration of hospitalization was 8.4 +/- 1.7 (7-11) days and 7.9 +/- 2.0 (6-9.9) days for control and IT morphine, respectively (nonstatistical difference). Patients in the IT morphine group had longer time to awakening from anesthesia and experienced more sedation., Conclusions: Intrathecal morphine, as compared with intravenous PCA morphine alone, improves immediate postoperative pain and reduces parenteral morphine consumption but does not improve postoperative recovery in elderly patients after major colorectal surgery.

Human skin diseases have revealed fundamental mechanisms by which cytoskeletal proteins contribute to tissue architecture and function. In particular, the analysis of epidermal blistering disorders and the role of keratin gene mutations in these diseases has led to significant increases in our understanding of intermediate filament biology. The major cell-surface attachment site for intermediate filament networks is the desmosome, an adhesive intercellular junction prominent in the epidermis and the heart. During the past decade, substantial progress has been made in understanding the molecular basis of a variety of epidermal autoimmune diseases, skin fragility syndromes, and disorders that involve a combination of heart and skin defects caused by perturbations in desmosome structure and function. These human diseases reveal key roles for desmosomes in maintaining tissue integrity, but also suggest functions for desmosomal components in signal transduction pathways and epidermal organization.

Centrosome amplification plays a key role in the origin of chromosomal instability during cancer development and progression. In this study, breast cancer cell lines with different p53 backgrounds were used to investigate the relationship between genotoxic stress, G(1)/S cell cycle checkpoint integrity, and the development of centrosome amplification. Introduction of DNA damage in the MCF-7 cell line by treatment with hydroxyurea (HU) or daunorubicin (DR) resulted in the arrest of both G(1)/S cell cycle progression and centriole duplication. In these cells, which carry functional p53, HU treatment also led to nuclear accumulation of p53 and p21(WAF1), retinoblastoma hypophosphorylation, and downregulation of cyclin A. MCF-7 cells carrying a recombinant dominant-negative p53 mutant (vMCF-7(DNp53)) exhibited a shortened G(1) phase of the cell cycle and retained a normal centrosome phenotype. However, these cells developed amplified centrosomes following HU treatment. The MDA-MB 231 cell line, which carries mutant p53 at both alleles, showed amplified centrosomes at the outset, and developed a hyperamplified centrosome phenotype following HU treatment. In cells carrying defective p53, the development of centrosome amplification also occurred following treatment with another DNA damaging agent, DR. Taken together, these findings demonstrate that loss of p53 function alone is not sufficient to drive centrosome amplification, but plays a critical role in this process following DNA damage through abrogation of the G(1)/S cell cycle checkpoint. Furthermore, these studies have important clinical implications because they suggest that breast cancers with compromised p53 function may develop centrosome amplification and consequent chromosomal instability following treatment with genotoxic anticancer drugs.

Background: Since the first attempts at resection of Klatskin tumours, an increasingly aggressive surgical treatment has been proposed. Results obtained after examination of the specimen have shown that a significant proportion of resections were palliative. Curative resection appears to be difficult to perform selectively., Methods: This retrospective study evaluates the results of a surgically-oriented management of hilar bile duct cancers. Thirty-nine patients were operated on in the period 1982-1994. Eighteen resections were carried out, requiring liver resection in 13 cases. Pathology of the specimen showed that the resection had been curative in 14 cases. The remaining 21 patients had surgical palliation, i.e. bypass and/or stenting., Results: In the resection group, there was no death but four patients suffered severe complications. The 1- and 5-year survival rates were 67 and 47 per cent respectively, with a median survival of 26 months. In the palliation group, the mortality rate was 14 per cent and median survival was 7 months., Conclusion: In the absence of evident contraindications, surgical exploration is worthwhile as it allows detection of the cases where curative resection is possible. Curative resection often requires a major hepatectomy, but mortality and morbidity may be kept low, and it offers a real hope of cure.

We have evaluated the efficacy of new electric warming blankets, which meet the requirements of the international standard for perioperative electrical and thermal safety, in preventing intraoperative hypothermia. We studied 18 patients undergoing abdominal surgery, allocated to one of two groups: in the control group, there was no prevention of intraoperative hypothermia (n = 8) and in the electric blanket group, two electric blankets covered the legs and upper body (n = 10). Anaesthesia duration was similar in the two groups (mean 201 (SEM 11) min), as was ambient temperature (20.5 (0.1) degrees C). Core temperature decreased during operation by 1.5 (0.1) degrees C in the control group, but only by 0.3 (0.2) degree C in the electric blanket group (P < 0.01). Five patients shivered in the control group compared with one in the electric blanket group (P < 0.05). We conclude that cutaneous warming with electric blankets was an effective means of preventing intraoperative hypothermia during prolonged abdominal surgery.

Background: Hepatic vascular exclusion allows the performance of major hepatic resections with minimal intraoperative blood loss. We have previously shown that normothermic ischemia can be tolerated by a healthy liver for up to 90 minutes, and this period is increased to 4 hours if the liver is cooled to 4 degrees C using University of Wisconsin solution., Study Design: This study assessed whether these techniques could be successfully applied for patients requiring resection of a diseased liver, which is more sensitive to ischemic damage. Between July 1990 and May 1994, 12 patients (6 men, 6 women; mean age, 57.8 years) in whom the planned hepatic resection was believed to require hepatic vascular exclusion for more than 1 hour were treated with perfusion with the University of Wisconsin solution. The surgical procedures were right hepatectomy (one patient), extended right hepatectomy (seven patients), and extended left hepatectomy (four patients). The underlying hepatic disease was cirrhosis or severe fibrosis with hepatocellular carcinoma (four patients), cholestasis (due to cholangiocarcinoma and biliary stricture, one patient each), and more than 30 percent steatosis after treatment of hepatic metastases with chemotherapy (six patients). The University of Wisconsin solution that had been cooled to 4 degrees C was perfused through a cannula placed in the portal vein or the hepatic arterial branch of the segment to be resected, but with flow directed toward the liver that should be retained and effluent fluid drained through a cavotomy. Before reperfusion, the liver was rinsed with Ringer's lactate solution, which was also 4 degrees C., Results: The mean duration of hepatic ischemia was 121 minutes (range, 65 to 250 minutes), and venovenous bypass was used in three cases. The mean amount of blood transfused intraoperatively was 4.3 +/- 4 U; four cases required no transfusion. One patient died on postoperative day seven of portal vein thrombosis. The median hospital stay was 21 days (range, 12 to 56 days). Postoperative complications consisted of pneumonia (one patient), liver insufficiency (one patient, who recovered spontaneously), and subphrenic abscess (one patient). The postoperative tests of hepatic function were altered to the same degree as that seen after hepatic vascular exclusion of less than 1-hour duration in healthy livers. All patients who left the hospital were alive at 1 year., Conclusions: Cooling of the hepatic parenchyma allowed us to perform major hepatic resection in patients with diseased livers using hepatic vascular exclusion for longer than 1 hour without increased morbidity or mortality. However, because of particular difficulties due to the size or location of the lesions, the application of these new techniques should only be considered for the largest and most complex hepatic resections for which hepatic vascular exclusions longer than 1 hour are foreseen.

Background: The infusion of several liters of crystalloid solution at room temperature may significantly contribute to intraoperative hypothermia because warming fluid to core temperature requires body heat. The aim of this study was to evaluate the effect of delivering warmed intravenous (IV) fluid to the patient on preventing intraoperative hypothermia., Methods: Intraoperative core and mean skin temperatures were measured during prolonged abdominal surgery in 18 patients randomly divided into two groups according to intraoperative IV fluid management. In 9 patients (control group) all IV fluids infused were at room temperature. In the other 9 patients (group receiving warmed fluids) all IV fluids were warmed using an active IV fluid tube-warming system. In all 18 patients a warming blanket covered the skin surface available for cutaneous warming. Intraoperative changes in total body heat content (kJ) were calculated from core and mean skin temperatures., Results: At the end of surgery, core temperature was 36.7 +/- 0.2 degrees C in the group receiving warmed fluids and 35.8 +/- 0.2 degrees C in the control group (P < 0.05). The estimated reduction in heat loss provided by warming IV fluid was 217 kJ, a value very close to the theoretical value expected from thermodynamic calculation. During recovery, one patient shivered in the group receiving warmed fluids and seven in the control group (P < 0.05)., Conclusion: In conclusion, infusion of warmed fluids, combined with skin-surface warming, helps to prevent hypothermia and reduces the incidence of postoperative shivering.

Study Objective: To test the hypothesis that only one hour of preinduction skin-surface warming decreases the rate at which core hypothermia develops during the first hour of anesthesia., Design: Randomized, prospective study., Setting: Operating theater of a university hospital., Patients: 16 ASA status I and II adult patients scheduled for laparoscopic cholecystectomy under general anesthesia., Interventions: Eight patients were assigned to receive forced-air warming for one hour before induction of anesthesia (prewarmed group); the other eight patients were covered only with a wool blanket during a similar preinduction period (control group)., Measurements and Main Results: Tympanic membrane (core) and mean skin-surface temperatures were measured at 15-minutes intervals, starting one hour before induction of anesthesia. Mean skin temperature increased from 34.0 +/- 0.1 C to 37.0 +/- 0.2 degrees C in the pre-warmed group (p < 0.05), but remained unchanged at 34.7 +/- 0.3 degrees C in the control group. Core temperature during the preinduction period did not change significantly in either group. Following induction of anesthesia, core temperature decreased at a rate of 1.1 +/- 0.1 degrees C/hr in the control group, but only 0.6 +/- 0.1 degrees C/hr in the pre-warmed group (p < 0.05). After one hour of anesthesia, six of eight pre-warmed patients had core temperatures of at least 36.5 degrees C, whereas only one of the eight control patients did (p < 0.05)., Conclusions: A single hour of preoperative skin-surface warming reduced the rate at which core hypothermia developed during the first hour of anesthesia. Preoperative skin surface warming is particularly helpful during short procedures because redistribution hypothermia is otherwise difficult to treat.

The efficacy of leg skin warming in preventing hypothermia and shivering was evaluated in two separate prospective, randomized trials in patients undergoing abdominal surgery. In the first trial, 22 patients were randomized to receive no hypothermia prevention (control group) or active warming with an electric warming blanket (electric blanket group). In the second trial 33 patients were randomized to receive no hypothermia prevention (control group) or forced-air warming (Bair Hugger group) or forced-air warming with insulation of the air blanket from the environment (insulated Bair Hugger group). The core and skin temperatures were measured and changes in body heat content calculated. In the first trial, core temperature was 34.6 +/- 0.3 degrees C at the end of surgery in the control group vs 36.4 +/- 0.1 degrees C in the electric warming blanket group (P < 0.001). Shivering occurred in nine control patients and in one warmed patient (P < 0.05). In the second trial, core temperature was 35.1 +/- 0.2 degrees C at the end of surgery in the control group, 36.3 +/- 0.1 degrees C in the Bair Hugger group (P < 0.01) and 37.1 +/- 0.1 degrees C in the insulated Bair Hugger group (P < 0.01 versus control; P < 0.05 versus Bair Hugger). Shivering occurred in one patient of each warmed group and in seven of the control group (P < 0.05). Skin-surface warming limited to the legs provides sufficient heat (ranging 34 to 43 watts) to counterbalance heat losses during abdominal surgery.

A retrospective study was made of 34 patients who underwent major liver resection with a single period of vascular occlusion exceeding 60 min. The liver remnant was normal in all cases. Vascular occlusion was achieved by continuous portal triad clamping (15 patients), hepatic vascular exclusion (15) or a sequential combination of both procedures (four). Liver cooling was not used. The mean (s.e.m.) duration of continuous normothermic liver ischaemia was 73.6 (2.5) (range 60-127) min. The mean (s.e.m.) amount of blood transfused during operation was 5.3(0.8) units packed red cells. There were no deaths after surgery and the postoperative course was uneventful, or limited to asymptomatic pleural effusion, in 18 patients. Three patients suffered postoperative bleeding necessitating further surgery and one of these required reintervention for a prolonged bile leak. Four patients had transient liver failure that resolved spontaneously within 15 days. There was a 13-fold increase in serum transaminase activities and the proaccelerin level was 45 per cent that of normal on day 1 after operation. These changes were returning to normal levels within 15 days. Continuous vascular occlusion during major liver resection is a useful manoeuvre that may be performed safely on normal hepatic parenchyma for up to 90 min.

Background: Intraoperative hypothermia initially results from internal redistribution of heat facilitated by anesthesia-induced vasodilation. Preinduction skin-surface warming minimizes postinduction hypothermia in anesthetized volunteers. However, its efficacy might be reduced in surgical situations, because of multiple sources of heat loss., Methods: Intraoperative core and mean skin temperatures were measured during total hip arthroplasty in 16 patients, randomly assigned to be covered preoperatively with a warming blanket for > or = 90 min (prewarmed group) or not covered (unwarmed group)., Results: During the first hour of anesthesia, core temperature decreased more than twice as much in the unwarmed group (-0.7 +/- 0.1 degree C; mean +/- SE) than in the prewarmed patients (-0.3 +/- 0.1 degree C). At the end of surgery, core temperature was 36.3 +/- 0.1 degree C in the prewarmed group and 35.2 +/- 0.2 degree C in the unwarmed group. During recovery, seven patients obviously shivered in the unwarmed group and none in the prewarmed group., Conclusions: Preanesthetic skin-surface warming reduces the initial postinduction hypothermia in surgical patients, preventing intraoperative hypothermia and postoperative shivering even for procedures lasting 3 h or longer.

Experimental studies have shown that liver ischemia-reperfusion induces Kupffer cell activation and tumor necrosis factor-alpha (TNF alpha) release. The aim of this work was to determine whether severe hepatic ischemia and subsequent reperfusion triggers TNF alpha release in man. Serum TNF alpha was measured before and 3, 10, 30, 60, 120 min after revascularization and postoperatively at day 1 and 2 in 11 patients with orthotopic liver transplantation (group 1) and 4 patients with liver resection with vascular occlusion (group 2). In group 1, TNF alpha levels decreased during the first few minutes of reperfusion, then increased slightly to peak at 120 min (40 +/- 13 pg/ml). Primary non-function occurred in 1 patient in whom low peroperative levels of TNF alpha levels were measured. In group 2, no significant changes in TNF alpha levels were observed. These data, in a small number of patients: (a) show that hepatic ischemia-reperfusion does not result in major TNF alpha production; (b) do not support a primary pathogenic role for TNF alpha in damage after ischemia-reperfusion in humans.

The increased metabolic and respiratory demand during naloxone recovery from opioid-based anesthesia could be related to the return of thermoregulation in hypothermic patients and thus be avoided by preventing intraoperative hypothermia. In this study, we measured O2 uptake (VO2) during naloxone-induced recovery in two groups of patients to determine the effect of intraoperative heat loss on postoperative VO2 changes. In seven patients, intraoperative hypothermia was prevented (normothermic group), whereas hypothermia was allowed to develop in seven other patients (hypothermic group). Core and skin temperatures were measured throughout the study to calculate changes in body heat content. Before naloxone antagonism of fentanyl-supplemented anesthesia, core temperature (mean +/- SEM) was 36.8 +/- 0.1 degrees C in the normothermic group and 34.2 +/- 0.2 degrees C in the hypothermic group (P less than 0.001). After titrated administration of naloxone during recovery, VO2 and minute ventilation (VE) increased in the hypothermic group, by 114 +/- 37% and 97 +/- 52% respectively (P less than 0.05), with a three-fold increase in four patients. In the normothermic group, VO2 increased significantly less (25 +/- 5%), without any significant change in VE. The change in VO2 and VE was significantly greater in patients who were hypothermic. VO2 was integrated throughout the recovery period to calculate recovery energy expenditure. Recovery energy expenditure and intraoperative heat loss were highly correlated (r = 0.88; P less than 0.01). This study demonstrates that the metabolic and respiratory stresses associated with naloxone-induced recovery from opioid-based anesthesia depend on the intraoperative heat loss and can therefore be reduced by preventing intraoperative hypothermia.

Extracorporeal liver surgery has been proposed with the aim to increase the resectability rate in patients with advanced tumors. In order to avoid the inherent section of the hepatic pedicle we propose ex situ-in vivo liver surgery. The surgical procedure comprises complete mobilization and exteriorization of the liver which is rocked on the axis of the porta hepatis following section of the hepatic veins. Protection of the liver parenchyma against prolonged ischemia is obtained through cold portal perfusion (UW solution) and the use of an heat exchanger on which liver resections and vascular procedures are performed. The procedure also encompasses the use of veno-venous bypass during liver vascular exclusion. This procedure was performed in 2 patients with tumoral invasion of the 3 main hepatic veins and in 1 patient whose hemangioma was surrounding the hepatocaval confluence. Duration of hypothermic ischemia was 205, 225 and 230 minutes respectively. Postoperative course was uneventful in the 3 cases with an hospital stay of 25, 28 and 18 days. Ex situ-in vivo liver surgery allows completion of a surgical treatment in patients whose tumor appears unresectable with the use of conventional technics. This procedure may constitute an alternative to liver transplantation in highly selected cases.

Major liver resections with complex vascular reconstruction require ischemia lasting from 2 h 30 to 5 h thus exceeding hepatic tolerance to warm ischemia. We describe a new technique of "ex situ-in vivo" liver surgery with prolonged ischemia with an intact hepatic pedicle. The surgical procedure encompasses complete mobilization of the liver and inferior vena cava, inferior mesenteric and femoral to axillary vein bypass, complete vascular exclusion of the liver, cold perfusion (U. W. solution), section of the hepatic veins allowing exteriorization of the liver ("ex situ") which remains connected by the hepatic pedicle ("in vivo"). The liver is placed on a heat exchanger at 4 degrees C. This procedure was performed in three patients: one each with hepatocellular carcinoma, huge metastasis of colorectal carcinoma and a "diffuse" hemangioma. Duration of ischemia was 225, 205, and 230 min respectively. The postoperative course was uneventful in all 3 cases and patients are alive at 15, 12, and 6 months. As it improves resecability rate of liver tumors and provides radical margins of resection, this procedure may be a beneficial alternative to liver transplantation for which poor results in cancer therapy with a high rate of recurrence are mainly due to immunosuppression.

Intra-operative hemorrhage is the main surgical risk during liver resections. Nowadays hepatectomies for large or posterior liver tumors close to the hepatocaval junction can benefit from total hepatic vascular exclusion (HVE) involving portal triad exclusion and clamping of the inferior vena cava (IVC) below and above the liver. Anatomical aspects of HVE have been studied in 64 subjects by segmental occlusive phlebographies of the IVC, injection of corrosive substances into the hepatocaval network, biometry of the retrohepatic IVC and serial sections of injected livers. A total HVE should exclude the right suprarenal and phrenic veins. Clamping of the suprahepatic IVC depends on the termination of the left inferior phrenic vein. Clamping of the subhepatic IVC must be retrohepatic: the right lobe of the liver has to be mobilized to free the right border of the retrohepatic IVC into which flows the right suprarenal vein 40 +/- 20 mm above the right renal vein and under the superior right hepatic vein. Both suprahepatic and retrohepatic clamps excluding the retrohepatic portion of the IVC (46.6 +/- 13 mm) and the hepatocaval junction should come in contact behind the IVC without overlapping.

Twenty-four resections under hepatic vascular exclusion (HVE) have been performed in patients with massive liver tumors. The procedure of HVE was used to minimize blood loss and the chance of gas embolism; it included clamping of the portal triad and occlusion of the inferior vena cava above and below the liver. In 12 of these patients the HVE was associated with clamping of the abdominal aorta above the celiac axis (AoC). During the "anhepatic" phase, which lasted 24 to 65 minutes (mean 39 minutes), neither venous shunt nor refrigeration was used. When HVE was associated with AoC, the circulation to the lower part of the body was completely excluded so that the systemic circulation was reduced to a small upper compartment in which the mean arterial pressure increased by 33% while the cardiac index decreased by 40%. The diastolic pulmonary arterial pressure remained unchanged. When HVE was not associated with AoC, the body was divided into an upper vascular compartment with normal venous resistance and a lower vascular compartment with increased resistance to the venous return and increased blood volume. The cardiac index, which was distributed to these two compartments, decreased by 40% to 50% but the mean arterial pressure decreased by only 14%. The good hemodynamic tolerance to HVE without AoC that was observed in these patients confirms the efficiency of collateral venous channels in the circumstances reported. AoC appears to be unnecessary in most patients if accurate fluid volume loading has been achieved before HVE. The study of acid-base balance demonstrates the ability of the human body to correct spontaneously the acidosis that follows the release of the clamps, provided a stable hemodynamic state is maintained. Only minor disorders of coagulation, without abnormal bleeding, were observed, and no prophylactic treatment was necessary. There were no deaths during operation, but a 25% postoperative mortality rate was observed mainly related to the underlying disease and the status of the remnant liver parenchyma. Despite its apparent sophistication, HVE is a simple and safe procedure for performing otherwise hazardous liver resections for tumors of large size or that are located close to the inferior vena cava and the suprahepatic veins. Its hemodynamic and metabolic consequences appear to be moderate.

The hemodynamic effects of portal triad clamping (PTC) were studied in 48 adult patients scheduled for elective liver resection. Prior to hepatic resection the effects of a short period of PTC (3-5 min) were evaluated in all 48 patients: mean arterial pressure increased 21%, whereas pulmonary capillary wedge pressure and cardiac index decreased 10 and 17%, respectively. Systemic vascular resistance increased 48%. In 34 patients a liver resection was performed during PTC and hemodynamic measurements were repeated throughout the duration of liver ischemia, which ranged from 14 to 68 min. Hemodynamic changes occurred in the first 3 min and persisted thereafter. After releasing the clamp, hemodynamic parameters returned to initial values in 3 min. These results confirm that PTC does not induce the cardiovascular collapse in humans that it does in common laboratory animals and demonstrate that humans tolerate PTC for periods up to 1 hr.

A primary malignant tumor of the liver in a 48-year-old woman was resected by right hepatectomy extending to the medial segment of the left lobe, along with the retrohepatic inferior vena cava. The caval interruption was not followed by a venous reconstruction or an associated right nephrectomy. The favorable outcome suggests that resection of the suprarenal portion of the inferior vena cava can be considered in some exceptional cases, even if venous collateral circulation has not developed.

The intra- and early postoperative courses of 142 consecutive patients who underwent liver resections using vascular occlusions to reduce bleeding were reviewed. In 127 patients, the remnant liver parenchyma was normal, and 15 patients had liver cirrhosis. Eighty-five patients underwent major liver resections: right, extended right, or left lobectomies. Portal triad clamping (PTC) was used alone in 107 cases. Complete hepatic vascular exclusion (HVE) combining PTC and occlusion of the inferior vena cava below and above the liver was used for 35 major liver resections. These 35 patients had large or posterior liver tumors, and HVE was used to reduce the risks of massive bleeding or air embolism caused by an accidental tear of the vena cava or a hepatic vein. Duration of normothermic liver ischemia was 32.3 +/- 1.2 minutes (mean +/- SEM) and ranged from 8 to 90 minutes. Amount of blood transfusion was 5.5 +/- 0.5 (mean +/- SEM) units of packed red blood cells. There were eight operative deaths (5.6%). Overall, postoperative complications occurred in 46 patients (32%). The patients who experienced complications after surgery had received more blood transfusion than those with an uneventful postoperative course (p less than 0.001). The length of postoperative hospital stay was also correlated with the amount of blood transfused during surgery (p less than 0.001). On the other hand, there was no correlation between the durations of liver ischemia of up to 90 minutes and the lengths of postoperative hospital stay. The longest periods of ischemia were not associated with increased rates of postoperative complications, liver failures, or deaths. There was no difference in mortality or morbidity after major liver resections performed with the use of HVE as compared with major liver resections carried out with PTC alone, although the lesions were larger in the former group. It is concluded that the main priority during liver resections is to reduce operative bleeding. Vascular occlusions aim at achieving this goal and can be extended safely for up to 60 minutes.

A case of venous air embolism occurring during liver resection is reported. Diagnosis was made early from the continuous recording of pulmonary artery pressure. The aetiology was neither surgical nor an obvious disconnection of a venous line. It was caused by a blockage of the blood filter, resulting in subambient pressure between the filter and a peristaltic pump, leading to aspiration of numerous small air bubbles. The clinical course after replacement of the defective material was uneventful, except for transient postoperative pulmonary oedema.

Surgical resection is currently the only potentially curative treatment in some selected patients with colo-rectal liver metastases (LM). Unfortunately only a minority of patients are candidates for resection. Only solitary or unilobar LM that can be removed by partial liver resection, are considered to be resectable. The second condition for the resection of LM is that the primary cancer must be resected. The third condition for resection is that the patient must be able to undergo a major liver resection if it is necessary. Small metastases which do not exceed 5 cm, and appear on the surface of the liver can be removed by a simple wedge resection. If the tumor is larger than 5 cm, or if multiple unilobar nodules are discovered, a major liver resection becomes necessary. Hospital mortality does not exceed 5% in most published series. Five year survivals are very rare when histologically proven colo-rectal LM are left in place. After surgical resection of LM, five year survival rates are close to 25% and range from 18% to 52%. Surgical resection is of benefit to approximately one fourth of the patients, who survive five years or more, but three fourths of the patients have early recurrences. None of the studied criteria can predict which patients will benefit from surgical resection of LM. In order to try to reduce the rate of early recurrences adjuvant chemotherapy has been proposed. No positive data have yet been obtained.

One hundred fifty-three patients underwent hepatic resection. Hepatic venous exclusion (HVE) was utilized in 23%. Aortic clamping was used in 20% of cases with hepatic venous exclusion. The mean duration of liver ischemia was 33 minutes. HVE increases the resectability of massive posterior or hypervascular liver tumors and prevents the risk of massive bleeding or air embolism. The only counterindication is the presence of severe preexisting cardiac dysfunction.

The acid-base disorders after hepatic vascular exclusion (HVE) were studied in 30 major liver resections. HVE included portal triad clamping and occlusion of the inferior vena cava below and above the liver, without venous shunt nor cooling. Clamping of the supra-coeliac abdominal aorta (AoC) was associated with HVE in 12 patients. HVE lasted 18 to 65 min (mean 37 min). Liver ischemia and splanchnic blood pooling resulted in metabolic acidosis and hyperlactatemia. In order to prevent his acidosis, prophylactic administration of NaHCO23 was used during the first 19 cases. This induced significant metabolic alkalosis during HVE and the early postoperative period; increasing experience made us reduce the amount of NaHCO3. After the release of the clamps, Paco2 increased 25% following HVE without AoC (p less than 0.001) and 53% following HVE with AoC (p less than 0.001). In an attempt to distinguish between the effects of the metabolic acidosis and the rise of Paco2 in the fall of pH which occurred after removal of the clamps, NAaHCO3 was deliberately not given in the last 11 patients. Acidosis appeared to be greater with AoC than without and mainly related to the rise of Paco2. A fall of Paco2 to its initial value was always followed by the return of pH to the normal range. This study demonstrated the human ability to correct spontaneously the acidosis which followed HVE. The need for NaHCO3 after HVE reflected a poor hemodynamic state after major liver resection rather than a metabolic consequence of hepatic ischaemia.

Myocardial injury was studied in 104 patients undergoing coronary artery grafting without cold chemical cardioplegia using the quantity of the isoenzyme MB of the creatine kinase liberated as an indicator. This method of evaluation, which is said to permit comparison of different techniques of myocardial protection, allowed us to consider the relative importance of several factors believed to have an influence on intraoperative myocardial injury. Indices of significance were duration of symptoms before operation, presence of chronic arterial hypertension, and the type of antiangina treatment employed. Other operative factors included severity of the arterial lesions, number of anastomoses performed, and duration of extracorporeal circulation and of aortic cross-clamping.

This paper describes a new technique for the canulation of the internal jugular vein. A transsection of the neck at the level of C4 (upper border of the thyroid cartilage) (Figure 1) shows the relative position of the internal jugular vein, the carotid artery and the sternocleidomastoid muscle. The internal jugular vein at this level is more superficial than is usually imagined. A cutaneous point of entry placed at the level of the thyroid cartilage on the medial border of the sternocleidomastoid muscle would be directly above, at the zenith of the carotid artery. From that point, moving a needle externally hugging the posterior aspect of the muscle will make it possible to reach the vein while actually moving away from the carotid artery.

Serial determinations of creatine phosphokinase isoenzymes (CPK) were made during the operative period and the first postoperative week in 60 patients undergoing coronary artery bypass surgery. Electrocardiograms (ECG) and serum levels of glutamic oxaloacetic transaminase (SGOT) and lactic dehydrogenase (LDH) were also evaluated. All patients had increased CPK MB activity which first became detectable during the operative period. The CPK MB curves usually showed a peak during the first postoperative hours and then a rapid decay. Some curves, however, showed a different profile with a prolonged liberation of CPK MB. This type of curve was more frequent in patients with electrical signs of necrosis or ischemic injury. In this group, the total amount of CPK MB released was greater than that in patients with unchanged ECG tracings (p less than 0.05). A mean curve of CPK MB activity was calculated for the patients without electric and/or enzymatic signs of myocardial injury. Serum CPK MB determination is a useful technique for identifying perioperative myocardial infarction (MI) and the time sequence of its occurrence. The appearance of this isoenzyme in every patient undergoing coronary surgery is an interesting finding, and it significance needs to be clarified.

This report analyses an experience with 80 liver resections for metastatic colorectal carcinoma. Primary colorectal cancers had all been resected. Liver metastases were solitary in 44 patients, multiple in 36 patients, unilobar in 76 patients, and bilobar in 4 patients. Tumor size was less than 5 cm in 33 patients, 5-10 cm in 30 patients, and larger than 10 cm in 17 patients. There were 43 synchronous and 37 metachronous liver metastases with a delay of 2-70 months. The surgical procedures included more major liver resections (55 patients) than wedge resections (25 patients). Portal triad occlusion was used in most cases, and complete vascular exclusion of the liver was performed for resection of the larger tumors. In-hospital mortality rate was 5%. Three- and 5-year survival rates were 40.5% and 24.9%, respectively. None of the analysed criteria: size and number of liver metastases, delay after diagnosis of the primary cancer, Duke's stage, could differentiate long survivors from patients who did not benefit much from liver surgery due to early recurrence. Recurrences were observed in 51 patients during the study, two thirds occurring during the first year after liver surgery. Eight patients had resection of "secondary" metastases after a first liver resection: two patients for extrahepatic recurrences and six patients for liver recurrences. Encouraging results raise the question of how far agressive surgery for liver metastases should go.