Ropivacaine preperitoneal wound infusion for pain relief and prevention of incisional hyperalgesia after laparoscopic colorectal surgery: a randomized, triple-arm, double-blind controlled evaluation vs intravenous lidocaine infusion, the CATCH study.

AIM: The abdominal incision for specimen extraction could trigger postoperative pain after laparoscopic colorectal resections (LCRs). Continuous wound infusion (CWI) of ropivacaine may be a valuable option for postoperative analgesia. This study was undertaken to evaluate the potential benefits of ropivacaine CWI on pain relief, metabolic stress reaction, prevention of wound hyperalgesia and residual incisional pain after LCR. A subgroup with intravenous lidocaine infusion (IVL) was added to discriminate between the peripheral and systemic effects of local anaesthetic infusions. METHOD: Patients were randomly allocated to three subgroups: CWI (0.2% ropivacaine 10 ml/h for 48 h); IVL (lidocaine 1.5% at 4 ml/h for 48 h); control group. RESULTS: In all, 95 patients were randomized (86 patients analysed). Postoperative pain intensity did not differ significantly between groups. Within the first 24 h after surgery, morphine requirement was significantly lower in the CWI group compared with the IVL group, but there was no significant difference compared with the control group (P = 0.02 and P = 0.15, respectively). The area of hyperalgesia did not differ significantly between subgroups, nor did the hyperalgesia ratio which was 1.2 cm (0.0-6.7) vs 1.9 cm (0.4-4.0) vs 2.0 cm (0.5-7.0) in the CWI, IVL and control groups respectively (P = 0.35). The number of patients reporting residual incisional pain after 3 months (3/26 vs 4/23 vs 4/23 in the CWI, IVL and control groups respectively) did not differ significantly between the groups, nor did their metabolic stress reactions. CONCLUSION: Ropivacaine CWI at the site of the abdominal incision did not provide any significant benefit either on analgesia or on the prevention of wound hyperalgesia after LCR.

Thyroid function at the third trimester of pregnancy in a Northern French population.

OBJECTIVES: During pregnancy, the production rate of thyroid hormone increases when iodine intake is sufficient. However, the appropriateness of the free thyroxin (FT4) immunoassay is questionable. We have therefore evaluated prospectively the thyroid function in pregnancy and the relevance of the FT4 immunoassay. PATIENTS AND METHODS: The thyroid function of 114 pregnant, healthy Parisian women with mild iodine deficiency was studied at the third trimester of pregnancy, 55 of whom served as their own control three months after delivery, and the results were compared to North American reference values. RESULTS: All French pregnant women showed an increase in thyroxin binding globulin (TBG) serum levels. FT4 levels decreased by about 30% at the third trimester of pregnancy, as compared to 10-15% in the American population. Moreover, the increase in total thyroxin (TT4) secretion represented only 27%, as compared to 50% in the American population. Linear regression model analysis showed a positive correlation between levels of TT4 and TBG, TT4 and FT4, as well as FT4 and free thyroxin index (FTI). CONCLUSION: The hypothyroxinemia at the third trimester of pregnancy was more prominent in the Parisian population and insufficient iodine intake could be responsible for the deficient increase in TT4. It is therefore concluded that the inability of the thyroid to establish the required equilibrium could be corrected by systematic iodine supplementation before pregnancy. Finally, the strong correlation between FT4 and FTI suggests that the quality of FT4 test immunoassay is appropriate for estimating FT4 serum levels during pregnancy.

Insulin resistance is a cause of steatosis and fibrosis progression in chronic hepatitis C.

BACKGROUND: Insulin resistance is a frequent feature of chronic hepatitis C. Whether insulin resistance could be the cause or consequence of steatosis and fibrosis is unknown. The ability of HCV genotype 3 to promote steatosis by itself provides an unique opportunity to answer this question. AIMS: The aim of the present study was to assess the relationships between insulin resistance, steatosis, and fibrosis according to genotype in 141 non-diabetic patients with biopsy proven non-cirrhotic chronic hepatitis C. METHODS: All patients had fasting serum glycaemia and insulinaemia measurements. Insulin resistance was evaluated using the homeostasis model assessment (HOMA IR) method. Liver steatosis was determined according to hepatitis C virus genotype (1 or 3). Logistic regression and multivariate regression analysis were used to identify variables independently associated with insulin resistance, fatty liver, and fibrosis. RESULTS: Although steatosis and fibrosis were more severe in genotype 3 patients, median HOMA IR was significantly higher in patients with genotype 1 related steatosis than in those with genotype 3 related steatosis (2.1 v 1; p = 0.001). Independent risk factors for steatosis were insulin resistance in genotype 1 patients (p = 0.001) and viral load in genotype 3 patients (p = 0.003). Among genotype 1 patients, independent parameters associated with insulin resistance were age (p = 0.04) and steatosis (p = 0.004). Steatosis was associated with more severe fibrosis whatever the genotype (p = 0.002). Among genotype 1 patients, although there was a significant relationship between circulating insulin level and fibrosis stage (p = 0.006), only steatosis and inflammatory score were independently associated with fibrosis. CONCLUSION: This study shows that insulin resistance is the cause rather than the consequence of steatosis and fibrosis in genotype 1 patients and that increased circulating insulin is a risk factor for fibrosis through insulin resistance induced steatosis.

Hyaluronan in horses: physiological production rate, plasma and synovial fluid concentrations in control conditions and following sodium hyaluronate administration.

REASONS FOR PERFORMING STUDY: Hyaluronic acid (HA) is an endogenous glycosaminoglycan used in the treatment of joint diseases, but medication control is required by horseracing authorities. Therefore, a medication control policy needs to be established. OBJECTIVES: To establish physiological plasma HA concentrations in post race horses, determine the HA endogenous production rate and document the disposition of HA after i.v. and intra-articular hyaluronic acid administration at recommended therapeutic doses. METHODS: Hyaluronan concentrations in plasma were determined using an ELISA specific test; concentrations in synovial fluid were determined using a radiometric binding assay. RESULTS: The overall mean plasma HA concentration in 120 post competition horses was 89 ng/ml. In a group of 6 experimental horses, synovial fluid control concentration was 328+/-112 microg/ml. After i.v. sodium hyaluronate administration (37.8 mg in toto), the terminal half-life was very short (43+/-29 mins) and after a delay of 3 h, the plasma concentration returned to control values. The endogenous HA production rate was 33-164 mg in toto per day, i.e. 1-4 times the recommended i.v. daily dose. Twenty-four hours after intra-articular administration, HA concentration was not significantly different from control values (328+/-112 microg/ml). CONCLUSIONS AND POTENTIAL RELEVANCE: Due to the rapid disappearance of HA from plasma after i.v. administration and from the joint after intra-articular administration, long-term detection needs a more appropriate approach to be developed.

Design of poly-epsilon-caprolactone nanospheres coated with bioadhesive hyaluronic acid for ocular delivery.

This study was performed to design a new ocular drug delivery system based on poly-epsilon-caprolactone (PCL) biodegradable nanospheres (NS) coated with a bioadhesive polymer, hyaluronic acid (HA), in order to combine ophthalmic prolonged action with the ease of application. The aim of this work was to investigate three strategies to attach HA on NS surface: (1) coating the core by chain entanglement with HA; (2) coating NS by HA adsorption; (3) coating NS by electrostatic interactions between negatively charged HA and a cationic surfactant (stearylamine, SA, or benzalkonium chloride, BKC). A radioimmunoassay technique, usually used for HA quantification in serum, was transposed to determine the amount of HA on the NS. The results show that HA is strongly attached on NS positively charged by cationic surfactant. This system is stable and not influenced by dilution. These results show the possibility of using cationic surfactants to obtain a HA coating by electrostatic interactions. BKC, approved for ophthalmic administration, was retained because it was more firmly anchored within the PCL matrix and the amount of HA attached was high (41.6 microg HA/mg PCL). Moreover, the yield of fixation reached 50%. Therefore, by using a simple preparation method, it was possible to obtain stable HA and intact HA-coated NS.

[Enzyme calibrators: principle and practical use]. / Le calibrage en enzymologie clinique: principe, conditions d'application et résultats.

Results of catalytic activities of enzymes are highly dependent on the measurement procedures and on local conditions. Thus, only poorly marked improvement of interlaboratory comparability of results have been observed in clinical enzymology. To solve this problem, SFBC and IFCC have proposed to use "validated enzyme calibrators". Standardised operating procedures adapted to 37 C have been developed by IFCC for the most commonly used enzymes in clinical chemistry, and will be soon published. Reference materials which have been certified with these SOPs can be used as calibrators for a set of measurement methods which exhibit the same analytical specificity. Calibrators must be commutable, a property that must be checked experimentally. It is possible to produce stable and commutable materials for the calibration of a set of methods. Interest of this approach has been demonstrated for several enzymes. Results of two studies presented here show that the comparison of results to the upper limit of reference ranges does not improve the interlaboratory comparability of results in contrast to the calibration of different methods by a common calibrator which allowed to reach an interlaboratory CV close to 4% for ALT and gammaGT.

Hyaluronidase activity in serum of patients with monoclonal gammapathy.

Hyaluronidase and hyaluronic acid, two substances thought to be strongly implicated in carcinogenesis, were assessed in the plasma of 35 patients with newly documented monoclonal gammapathy and in 25 control patients. A significant increase was found in plasma hyaluronidase activity in the patients with monoclonal gammapathy. A statistically significant positive correlation was found between hyaluronidase activity and monoclonal immunoglobulin levels in plasma. An increase in serum hyaluronidase activities may be a response to the deleterious effect of hyaluronic acid in cell migration and tumor progression. Further studies are needed to assess the value of hyaluronidase activity as a marker of tumor progression.

Randomized trial of interferon-alpha plus ursodeoxycholic acid versus interferon plus placebo in patients with chronic hepatitis C resistant to interferon.

BACKGROUND: Ursodeoxycholic acid (UDCA) could potentiate the effect of interferon (IFN) in patients with chronic hepatitis C resistant to IFN. We compared the efficacy of IFN with that of a combination of IFN and UDCA. METHODS: Patients were randomized to receive UDCA (13-15 mg/kg/day) (n = 47) or placebo (n = 44) plus interferon (3 MU three times weekly) for 6 months and were then followed up for 6 additional months. RESULTS: At entry 30% of patients had cirrhosis, and 70% had HCV genotype 1. Five and four patients withdrew from the combination and the monotherapy groups, respectively. At 6 months alanine aminotransferase (ALAT) and gamma-glutamyl transferase (GGT) activities were significantly lower (P < 0.001) in the combination group than in the monotherapy group; the differences were no longer significant at 1 year. At 6 months ALAT activities normalized in 10 and 8 patients in the combination and the monotherapy groups, respectively (P = 0.67). In 10 of them (5 in each group) HCV RNA levels became undetectable. At 1 year four versus one patient had a sustained normalization of ALAT, and in one patient the HCV RNA became negative. There was no difference in the histologic progression. In this setting, in contrast to chronic cholestasis, UDCA administration induced an increase in total serum bile acids and did not change primary bile acids. CONCLUSIONS: An IFN plus UDCA combination is more effective than IFN alone in terms of ALAT but not in terms of the virologic response. These results favor the hypothesis that UDCA has an effect on the biochemical indices of cellular injury independent of a change in primary bile acids.

Prognostic value of serum hyaluronan in patients with compensated HCV cirrhosis.

BACKGROUND/AIM: Serum hyaluronan (HA) levels increase according to the degree of liver fibrosis in patients with chronic viral hepatitis C. Patients with liver disease and markedly high serum HA levels have cirrhosis with typical signs of hepatic sinusoidal capillarization, a factor of aggravation of cirrhosis The aim of this study was to evaluate the prognostic value of serum HA for severe complications in asymptomatic patients with HCV cirrhosis. METHODS: Six hundred and sixty-eight patients with anti-HCV antibodies and increased serum alanine aminotransferase were referred to our hospital for evaluation, including liver biopsy. At entry, serum HA levels were measured in 91 patients (64 men, 27 women, 56 +/-11 years old) out of 103 who had asymptomatic, biopsy-proven cirrhosis According to the criteria of Child-Pugh, 82 were classified A and 9 B. The follow-up period was 6 to 82 months (median: 38 months), and 51 of these patients received alpha-interferon therapy during the first year. Severe complications were defined as death or liver transplantation, ascites, bleeding from esophageal varices, encephalopathy, or hepatocellular carcinoma. RESULTS: Serum HA levels at entry were higher in the cirrhotic patients in whom severe complications occurred during the follow-up period (520+/-426 microg/l vs 197+/-146 microg/l, p<0.0001). The patients with serum hyaluronan levels >350 microg/l displayed higher probabilities of occurrence of severe complications (p<0.0001). Other factors associated with the occurrence of complications or death were: serum bilirubin >18mol/l (p = 0.03), platelet count <112x10(9)/l (p= 0.02), prothrombin time <63% (p<0.0001), serum albumin <36 g/l (p=0.002), alkaline phosphatase >81 IU/l (p=0.01), and no interferon treatment (p= 0.0003). Multivariate analysis identified five independent factors predictive of severe clinical complications, namely: hyaluronan (p=0.006), prothrombin time (p=0.04), bilirubin (p=0.04), albumin (p=0.04), and no therapy (p=0.03). CONCLUSION: Serum HA level is predictive for occurrence of severe complications in HCV cirrhosis, and can be used as a prognostic marker, in addition to the parameters of the Child-Pugh score, particularly in patients with compensated cirrhosis.

[Hepatic fibrosis: physiopathology and biological diagnosis]. / Fibrose hépatique: physiopathologie et diagnostic biologique.

Hepatic fibrosis, of which cirrhosis is the most advanced stage, can result from any chronic liver disease due to any cause. Normal extracellular matrix components accumulate in the liver as a result of imbalances in their production, deposition, and breakdown. These matrix components are produced primarily by myofibroblastic hepatic cells whose main cellular source in the liver is the stellate cell (Ito cell). Histopathological examination of a liver biopsy specimen is currently the gold-standard investigation for estimating the severity of fibrosis in patients with chronic liver disease. However, the recent development of treatments with activity against the fibrosing process requires evaluation of fibrosis at closely spaced intervals and, therefore, the development of tests that do not require a liver biopsy. Advances in our understanding of the mechanisms underlying hepatic fibrogenesis have allowed to identify several substances of potential clinical usefulness. Serum assays of extracellular matrix components, their breakdown products, or enzymes involved in their metabolism have been suggested for the noninvasive evaluation of hepatic fibrosis. Clinical studies have shown that serum hyaluronate is to date the marker with the closest correlations to hepatic fibrosis and the noninvasive parameter with the highest sensitivity for cirrhosis.

[Biological examination in the diagnosis and monitoring of liver disease. Algorithms to aid the decision]. / Exploration biologique dans le diagnostic et la surveillance d'une maladie du foie. Schémas d'aide à la décision.

The goal of this article is to describe a rational step-wise strategy for using standard laboratory tests to obtain diagnostic orientation for a liver disorder; establish, support, or rule out a liver disorder; and monitor the course of treated and untreated patients with liver disorders.

Seminal androgen concentrations and residual sperm cytoplasm.

To explore a possible link between seminal androgen concentrations and residual sperm cytoplasm, which constitutes one of the cytological anomalies of the spermatozoon middle piece, testosterone (T), delta4-androstenedione, the precursor of T during testicular androgen biosynthesis and the active metabolite of T, dihydrotestosterone, were assayed in the seminal fluid of 37 patients. A statistically significant correlation was found by linear regression (r = +0.380, P = 0.020, y = 0.02x + 0.45) between seminal T concentrations and the percentage of spermatozoa with a residual cytoplasmic droplet. Given the impact on fertility of residual sperm cytoplasm, assessment of seminal T concentrations could provide useful information on the fertility status of patients.

Evidence for a deficiency of interferon response in mononuclear cells from hepatitis C viremic patients.

BACKGROUND/AIMS: The pathophysiology of chronic hepatitis C and the mechanisms of resistance to interferon alpha are poorly understood. The aim of this work was to assess the influence of HCV infection and the viral genotype on lymphocyte production of 2',5' oligo-adenylate synthetase activity and monocyte production of TNF alpha and IL1 beta. METHODS: Mononuclear cells from 50 consecutive patients were studied after 6 months of interferon treatment. Patients with persistent viremia (PCR-positive, elevated ALT, n = 39) were compared with the PCR-negative patients with normal ALT activity (n = 11) of similar age and sex ratio. RESULTS: Cells from the viremic patients showed lower basal and stimulated 2',5' oligo-adenylate synthetase activity, and a lower in vitro response capacity to human recombinant interferon. In contrast, no difference was observed in basal and stimulated TNF alpha or IL1 beta production between the two groups. In the PCR-positive patients the viral genotype had no significant influence on the response of mononuclear cells to interferon or endotoxin. CONCLUSIONS: These results show that the presence of HCV in blood is associated with an elective defect in interferon system activation, independently of the viral genotype.

[Fibronectin and hyaluronic acid in seminal fluid: relationship with sperm count and percentage of typical forms]. / Fibronectine et acide hyaluronique dans le liquide séminal: relations avec la numération spermatique et le pourcentage des formes typiques.

Two components of the extra cellular matrix, hyaluronic acid (HA) and fibronectin (Fbn), were assessed in the seminal fluids of 29 patients submitted for diagnosis of infertility. The concentrations of HA and Fbn were elevated in seminal plasma in comparison to their ranges of concentration in normal sera. No correlations were found between seminal Fbn and sperm count per ml and/or ejaculate, normal sperm cytology and multiple anomaly index (MAI). The concentrations of HA were negatively correlated with sperm count per ml (p < 0.01, r = -0.5) and ejaculate (p < 0.005, r = -0.5), and also with sperm cytology (p < 0.001, r = -0.6). A positive correlation was found between seminal concentrations of HA and MAI (p < 0.001, r = +0.7). It seems that high seminal HA concentrations were in relation with the bad results of sperm count and sperm cytology. These data suggest that spermatozoon could be implicated, in part, in the seminal HA metabolism.

Diagnostic accuracy of hyaluronan and type III procollagen amino-terminal peptide serum assays as markers of liver fibrosis in chronic viral hepatitis C evaluated by ROC curve analysis.

Diagnostic accuracy of two serum markers of liver fibrosis, hyaluronan (HA) and amino-terminal peptide of type III procollagen (P-III-P), was studied in a cohort of 326 untreated patients with chronic viral hepatitis C. Both P-III-P (RIA-gnost P-III-P, Behring Diagnostic) and HA (HA-test, Pharmacia) serum concentrations correlated with the histological grades of liver fibrosis (P < 0.001). Receiver-operating characteristic (ROC) curves showed that serum HA had greater diagnostic performance than P-III-P, both for discriminating patients with extensive liver fibrosis from those with no or mild fibrosis (area under the ROC curves: 0.864 vs 0.691, P <0.001) or for discriminating patients with cirrhosis from those without cirrhosis (area under the ROC curves: 0.924 vs 0.734, P <0.001). At cutoff values of 0.8 kU/L for serum P-III-P and 85 micrograms/L for serum HA, sensitivities were 70.0% and 64.5%, and specificities were 63.4% and 91.2%, respectively, for discriminating patients with extensive liver fibrosis from those with no or mild fibrosis. At the cutoff values of 1.0 kU/L for serum P-III-P and 110 micrograms/L for serum HA, sensitivities were 60.0% and 79.2%, and specificities were 74.0% and 89.4%, respectively, for discriminating patients with liver cirrhosis from those without cirrhosis. We conclude that, because the diagnostic accuracy of serum HA is greater than that of serum P-III-P as a marker of liver fibrosis, serum HA should be preferred when monitoring liver fibrosis in patients with chronic viral hepatitis C.

Changes in systemic gonadal and adrenal steroids in asymptomatic human immunodeficiency virus-infected men: relationship with the CD4 cell counts.

Serum sex hormone-binding globulin (SHBG), testosterone, non-SHBG-bound testosterone, androstenedione, dihydrotestosterone (DHT), dehydroepiandrosterone (DHEA), follicle-stimulating hormone (FSH), luteinizing hormone (LH) and cortisol were measured in 58 homosexual men seropositive for human immunodeficiency virus (HIV), all clinically asymptomatic (Centers for Disease Control 1993 classification stage A). The HIV patients were divided into four groups according to the CD4 lymphocyte count--group 1 (more than 500/microliters, N = 14), group 2 (between 350 and 500/microliters, N = 16), group 3 (between 200 and 349/microliters, N = 22) and group 4 (less than 200/microliters, N = 6)--and compared with 11 antibody-negative men as controls. The SHBG levels were significantly increased in groups 1, 2, 3 (p < 0.01) and 4 (p < 0.05) compared with controls, with no differences between groups of patients. Compared with controls, testosterone concentrations were significantly lower in group 4 (p < 0.05) and non-SHBG-bound testosterone levels were significantly lower in groups 1 (p < 0.05), 2 (p < 0.01), 3 (p < 0.001) and group 4 (p < 0.001); DHT and androstenedione levels were significantly lower in group 4 (p < 0.05) and DHEA levels were significantly lower in group 2, group 3 (p < 0.01) and group 4 (p < 0.05) than in controls. Cortisol levels were significantly increased in groups 1 and 4 (p < 0.05) and FSH and LH concentrations were not significantly higher in HIV-infected men than in controls. Also, the DHEA, androstenedione, non-SHBG-bound testosterone and DHT levels were correlated with CD4 cell counts, showing that hypogonadism occurs as the CD4 lymphocytes decrease.(ABSTRACT TRUNCATED AT 250 WORDS)

[Chronic viral hepatitis C. Anatomoclinical and biological correlations]. / Hépatite chronique virale C. Corrélations anatomo-cliniques et biologiques.

OBJECTIVES: The relations between the severity of histopathological lesions and epidemiological, clinical and biological data were studied in 86 patients with chronic viral hepatitis C. PATIENTS AND METHODS: None of the patients had any clinical signs of decompensated liver disease. Three groups of patients were individualized according to histopathological findings: 17 (20%) had chronic persistent hepatitis, 48 (56%) had chronic active hepatitis without cirrhosis, and 21 (24%) had cirrhosis. RESULTS: Patients with cirrhosis differed significantly from patients in the two other groups for all biological parameters. With multivariate analysis, alkaline phosphatase activity and serum hyaluronic acid were two independent parameters significantly associated with cirrhosis. A serum hyaluronic acid level above 150 micrograms/L or alkaline phosphatase activity above normal were predictive of cirrhosis with a sensitivity of 87% and a specificity of 93%. None of the parameters in this study provided a clear distinction between patients with chronic persistent and chronic active hepatitis. CONCLUSION: Determination of serum hyaluronic acid and alkaline phosphatase activity as a non invasive index of cirrhosis could be useful for diagnosis and follow-up in patients with chronic viral hepatitis C.

Serum hyaluronan as a marker of liver fibrosis in chronic viral hepatitis C: effect of alpha-interferon therapy.

BACKGROUND/AIMS: It has been suggested that increases in serum hyaluronan levels might be a marker of fibrosis in chronic viral hepatitis C. Patients receiving alpha-interferon therapy are an excellent model to determine the relationship between serum hyaluronan and liver fibrosis, since results suggest that alpha-interferon could reduce liver fibrosis. METHODS: We studied the relationship between serum hyaluronan and histopathological indices of liver fibrosis, inflammation and necrosis, before and after alpha-interferon therapy (3 MU, three times weekly for 6 months), and the effect of treatment on serum hyaluronan and on histological liver fibrosis, in 52 patients. Hyaluronan levels were measured using a radiometric assay and the liver histopathological indices were scored according to the Knodell system. RESULTS: The serum hyaluronan level correlated with the extent of liver fibrosis both before and after alpha-interferon therapy (p < 0.0001), but not with the histopathological indices of liver inflammation or necrosis. Parallel changes in serum hyaluronan and liver fibrosis occurred: serum hyaluronan levels fell significantly in patients in whom fibrosis improved (p < 0.01, n = 11), increased significantly in patients in whom fibrosis worsened (p < 0.05, n = 10), and did not change significantly in patients in whom fibrosis was unmodified (n = 31). Furthermore, fibrosis improved only when the antiviral effect of alpha-interferon was reflected by persistent normalization of serum alanine aminotransferase, although there was no correlation between serum hyaluronan levels and alanine aminotransferase activities. CONCLUSION: Serum hyaluronan thus appears to be a non-invasive index of liver fibrosis.