Investigating locations of recurrences with MRI after CRS-HIPEC for colorectal peritoneal metastases.

PURPOSE: Patients with colorectal peritoneal metastases (PM) treated with cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) are at high risk of recurrent disease. Understanding where and why recurrences occur is the first step in finding solutions to reduce recurrence rates. Although diffusion-weighted (DW) MRI is not routinely used in the follow-up of CRC patients, it has a clear advantage over CT in detecting the location and spread of (recurrent) PM. This study aimed to identify common locations of recurrence in CRC patients after CRS-HIPEC with MRI. METHOD: This was a single-centre retrospective study of patients with recurrent PM after CRS-HIPEC performed between January 2016 and August 2020. Patients were eligible for inclusion if they had both an MRI preoperatively (MRI1) and at the time of recurrent disease (MRI2). Two abdominal radiologists reviewed in consensus and categorized recurrences according to their location on MRI2 and in correlation with previous disease location on prior imaging (MRI1) and the surgical report of the CRS-HIPEC. RESULTS: Thirty patients were included, with a median surgical PCI of 7 (range 3-21) at the time of primary CRS-HIPEC. In total, 68 recurrent metastases were detected on MRI2, of which 14 were extra-peritoneal. Of the remaining 54 PM, 42 (78%) occurred where the peritoneum was damaged due to earlier resections or other surgical procedures (e.g. inserted surgical abdominal drains). Most recurrent metastases were found in the mesentery, lower abdomen/pelvis and abdominal wall (87%). CONCLUSIONS: Most recurrent PMs appeared in the mesentery, lower abdomen/pelvis and abdominal wall, especially where the peritoneum was previously damaged.

Next-generation muscle-directed gene therapy by in silico vector design.

There is an urgent need to develop the next-generation vectors for gene therapy of muscle disorders, given the relatively modest advances in clinical trials. These vectors should express substantially higher levels of the therapeutic transgene, enabling the use of lower and safer vector doses. In the current study, we identify potent muscle-specific transcriptional cis-regulatory modules (CRMs), containing clusters of transcription factor binding sites, using a genome-wide data-mining strategy. These novel muscle-specific CRMs result in a substantial increase in muscle-specific gene transcription (up to 400-fold) when delivered using adeno-associated viral vectors in mice. Significantly higher and sustained human micro-dystrophin and follistatin expression levels are attained than when conventional promoters are used. This results in robust phenotypic correction in dystrophic mice, without triggering apoptosis or evoking an immune response. This multidisciplinary approach has potentially broad implications for augmenting the efficacy and safety of muscle-directed gene therapy.

Alteration of cardiac progenitor cell potency in GRMD dogs.

Among the animal models of Duchenne muscular dystrophy (DMD), the Golden Retriever muscular dystrophy (GRMD) dog is considered the best model in terms of size and pathological onset of the disease. As in human patients presenting with DMD or Becker muscular dystrophies (BMD), the GRMD is related to a spontaneous X-linked mutation of dystrophin and is characterized by myocardial lesions. In this respect, GRMD is a useful model to explore cardiac pathogenesis and for the development of therapeutic protocols. To investigate whether cardiac progenitor cells (CPCs) isolated from healthy and GRMD dogs may differentiate into myocardial cell types and to test the feasibility of cell therapy for cardiomyopathies in a preclinical model of DMD, CPCs were isolated from cardiac biopsies of healthy and GRMD dogs. Gene profile analysis revealed an active cardiac transcription network in both healthy and GRMD CPCs. However, GRMD CPCs showed impaired self-renewal and cardiac differentiation. Population doubling and telomerase analyses highlighted earlier senescence and proliferation impairment in progenitors isolated from GRMD cardiac biopsies. Immunofluorescence analysis revealed that only wt CPCs showed efficient although not terminal cardiac differentiation, consistent with the upregulation of cardiac-specific proteins and microRNAs. Thus, the pathological condition adversely influences the cardiomyogenic differentiation potential of cardiac progenitors. Using PiggyBac transposon technology we marked CPCs for nuclear dsRed expression, providing a stable nonviral gene marking method for in vivo tracing of CPCs. Xenotransplantation experiments in neonatal immunodeficient mice revealed a valuable contribution of CPCs to cardiomyogenesis with homing differences between wt and dystrophic progenitors. These results suggest that cardiac degeneration in dystrophinopathies may account for the progressive exhaustion of local cardiac progenitors and shed light on cardiac stemness in physiological and pathological conditions. Furthermore, we provide essential information that canine CPCs may be used to alleviate cardiac involvement in a large preclinical model of DMD.

New insights into the role of age and carcinoembryonic antigen in the prognosis of colorectal cancer.

The aim of this study was to verify through relative survival (an estimate of cancer-specific survival) the true prognostic factors of colorectal cancer. The study involved 506 patients who underwent locally radical resection. All the clinical, histological and laboratory parameters were prognostically analysed for both overall and relative survival. This latter was calculated from the expected survival of the general population with identical age, sex and calendar years of observation. Univariate and multivariate analyses were applied to the proportional hazards model. Liver metastases, age, lymph node involvement and depth of bowel wall involvement were independent prognosticators of both overall and relative survival, whereas carcinoembryonic antigen (CEA) was predictive only of relative survival. Increasing age was unfavourably related to overall survival, but mildly protective with regard to relative survival. Three out of the five prognostic factors identified are the cornerstones of the current staging systems, and were confirmed as adequate by the analysis of relative survival. The results regarding age explain the conflicting findings so far obtained from studies considering overall survival only and advise against the adoption of absolute age limits in therapeutic protocols. Moreover, the prechemotherapy CEA level showed a high clinical value.

Challenges in the treatment of gastrointestinal tumours.

In the last 20 years there have been many breakthroughs in the treatment of gastrointestinal tumours. In this review we have considered the three most important subgroups of gastrointestinal tumours (colorectal, gastric and pancreatic cancer), focusing on the state-of-the-art treatments.

Haemodynamic effects of propranolol, octreotide and their combination during fasting and post-prandial splanchnic hyperaemia in patients with cirrhosis.

BACKGROUND/AIMS: This double-blind study was designed to evaluate the haemodynamic effect of two drugs, propranolol and octreotide, and their combination in patients with cirrhosis. METHODS: Fifteen patients with cirrhosis were randomly assigned to two groups receiving either octreotide subcutaneously at 100 microg ('octreotide' group, n = 9) or propranolol orally at 40 mg followed by a subcutaneous dose of octreotide (100 microg) after 1 h ('propranolol + octreotide' group, n = 6); then, after 30 min, a standard meal was administered to both groups. The hepatic vein pressure gradient by hepatic vein catheterization, portal and superior mesenteric artery blood flow velocity, superior mesenteric artery pulsatility index by the echo-Doppler duplex system were recorded at baseline, 1 h after propranolol in the 'propranolol + octreotide' group, and in both groups 30 min after octreotide and 30 min after meal. RESULTS: At fast, propranolol was more active in decreasing portal pressure (from 16 +/- 2.2 to 12.7 +/- 3.8 mmHg, -20%, P < 0.05) as compared to octreotide (from 18.6 +/- 4.8 to 16.6 +/- 4.3 mmHg, -11%, P < 0.05). Conversely, octreotide was more active on the mean blood flow velocity of superior mesenteric artery (from 22.8 +/- 5 to 19 +/- 4.5 cm/ s, -17%; P< 0.05). Octreotide administration in patients receiving beta-blockers showed, also, a trend to increase the mesenteric vascular resistances (pulsatility index from 3.14 +/- 0.69 to 3.68 +/- 1.29, +17%, not significant (NS)) which had not been affected by previous treatment with propranolol. After the meal, a reduction of the expected hyperaemic response occurred in both groups. CONCLUSIONS: The combined acute haemodynamic effect of this association suggests the possible combination of these two drugs in critical situations, such as variceal bleeding in patients receiving beta-blockers. The simultaneous use of echo-Doppler and hepatic vein catheterization permitted us a more complete analysis of the acute haemodynamic events.

Nitrogen metabolite repression in Hansenda polymorpha: the nmrl-l mutation.

In Hansenula polymorpha, the expression of the nitrate assimilation metabolism is subjected to re-pression-derepression mechanisms triggered by reduced nitrogen compounds such as ammonium. To further our knowledge on the genetics of these regulatory mechanisms, a screening strategy for the isolation of mutants exhibiting nitrate reductase activities in the presence of reduced nitrogen compounds was set up. This strategy makes use of a nitrate+ methylamine mutant to isolate suppressors of its characteristic phenotype--the inability to grow on a nitrate plus methylamine medium. A total of 21 regulatory mutants were isolated with this strategy and grouped into five complementation classes. One of these mutants harbours the recessive mutation nmr1-1, which determines the derepression of the nitrate assimilation metabolism in media containing nitrate plus a repressing nitrogen source (ammonium, methylamine, glutamate, urea or aspartate). Therefore, nitrate reductase activities are detected in the presence of reduced nitrogen sources, as long as nitrate is also in the medium. Our data indicate that the processes of repression-derepression and induction are controlled by elements which are distinct. Furthermore, they indicate that Nmrlp is involved in repressing circuits which control not only the nitrate-utilisation pathway, but also other pathways which are necessary for the utilisation of nitrogen sources alternative to ammonium. Of considerable interest is the fact that our nmr1-1 mutant is derepressed in glutamate but not in glutamine. Since the phenotype of this mutant seems to exclude a glutamine synthetase defect, we suggest that glutamate (or a derivative of this compound) might be involved in signalling nitrogen metabolite repression in H. polymorpha. Thus, in H. polymorpha, a glutamine-dependent circuit may co-exist with a glutamine-independent circuit.

Mutations affecting the expression of the MOX gene encoding peroxisomal methanol oxidase in Hansenula polymorpha.

In this study, aimed at identifying genetic factors acting positively upon the MOX gene, we report the isolation and characterisation of several methanol utilisation-defective (Mut-) mutants of Hansenula polymorpha. These fall into 12 complementation groups, eight of which show significant reductions in alcohol (methanol) oxidase activity in methanol. Three of these groups, identifying the MUT3, MUT5 and MUT10 loci, exhibit extremely low levels of MOX promoter activity, not only in methanol medium, but also during growth in glycerol or methylamine. We suggest that these loci play a significant role in the derepression of the MOX gene expression. One of these genes (MUT10) also seems to be involved in the utilisation of carbon sources other than methanol, and it is apparent that the same gene plays some role in the biogenesis or in the enlargement of the peroxisome. Three other genes (MUT7, MUT8 and MUT9) appear to be involved in peroxisome biogenesis, whereas most other mutants harbour lesions that leave the peroxisome biogenesis and proliferation unaffected.

A regulatory mutant of Hansenula polymorpha exhibiting methanol utilization metabolism and peroxisome proliferation in glucose.

Mutant LGM-128 of Hansenula polymorpha harbors the recessive mutation glr2-1 which confers a complex pleiotropic phenotype, the major feature of which is the metabolically unnecessary induction of methanol utilization metabolism (C1 metabolism) during growth on glucose, whether or not methanol is in the medium. Therefore, in this mutant, peroxisomes are formed and proliferate upon cultivation in glucose-containing media. In these media, LGM-128 shows induction levels of C1 metabolism that are similar to those observed in methanol-containing media. This indicates that GLR2 controls the repression-derepression process stimulated by glucose and that the induction process triggered by methanol plays only a minor role in activating C1 metabolism. Cultivating LGM-128 in methanol and then transferring it to glucose media revealed that active degradative processes occur, leading to the disappearance of C1 metabolism. This observation suggests that, although stimulated by glucose, the two processes are controlled by elements which are, at least in part, distinct. Finally, glr2-1 does not affect ethanol repression, suggesting that in H. polymorpha the two repressing circuits are separated.

Plasma levels of the molecular markers of coagulation and fibrinolysis in patients with peripheral arterial disease.

In 103 patients with peripheral arterial disease (PAD) of the lower limbs, coagulation and fibrinolytic parameters were evaluated to identify hemostatic abnormalities characteristic of this patient population. PAD was defined as clinically stable Leriche stage 2 (based on clinical history, peripheral pulses, ankle-arm index, and treadmill test) for at least 3 months, walking distance > 100 m, and no other major illnesses, rest pain, or trophic lesions. Defibrotide, a polydeoxyribonucleotide derivative with vascular effects, was administered to the patients as part of a multicenter trial. The PAD patients exhibited a prothrombotic state as evidenced by high D-dimer in all but 24% of the patients (average 797 +/- 802 vs. 163 +/- 54 ng/mL normal population; p < 0.001) and high thrombin-antithrombin III complex (TAT) levels (10.2 +/- 8.9 vs. 2.5 + 1.5 ng/mL; p < 0.001) with low to normal levels of protein C (86 +/- 25 vs. 102 +/- 18%; p < 0.01) and plasminogen activator inhibitor-1 (PAI-1) antigen (5.9 +/- 4.5 vs. 1.3 + 0.7 ng/mL; p < 0.001) were elevated in 79% of the patients. These results suggest that there is ongoing thrombosis in the majority of PAD patients. Differences from normal controls were observed for t-PA, PAI-1, protein C, and protein S; however, it is not certain that the thrombosis in patients with PAD is due to these factors.

Insulin resistance and myocardial hypertrophy in the attenuated reduction in mean arterial pressure after a glucose load in hypertensive patients.

Although long recognized, the vasodilator effect of insulin has been relatively neglected over the last few years. Recent reports have focused on the sympathetic and antinatriuretic actions of this hormone. In the first part of the present study we characterized the reduction in blood pressure after a glucose load in hypertensive patients with and without insulin resistance. Fourteen hypertensive Caucasian patients and ten Caucasian controls were submitted to a standard oral glucose tolerance test (OGTT) and intravenous insulin tolerance test (15-min ITT). In the hypertensive patients with insulin resistance the reduction in mean arterial pressure (MAP) after a glucose load was blunted (6.7 +/- 1.7% (N = 5)) when compared to insulin-sensitive (12.9 +/- 1.1% (N = 9)) and normal subjects (10.1 +/- 0.8%). In the second part of the study we investigated whether hypertensive patients with myocardial hypertrophy were more insulin resistant than hypertensive individuals with a normal cardiac mass. The glucose disappearance rate (Kitt) was lower in hypertensive patients with myocardial hypertrophy (6.0 +/- 1.0 (N = 6)) when compared to hypertensive patients without myocardial hypertrophy (8.2 +/- 1.0%/min (N = 8)), suggesting an association between this organomegaly and insulin resistance. In conclusion, our results suggested that 1) insulin resistance, rather than hyperinsulinemia, acts as a risk factor for the development of hypertension, because of insulin's inability to decrease MAP in this situation, and 2) there is an association between left ventricular hypertrophy and insulin resistance in hypertensive patients.

Insulin resistance and myocardial hypertrophy in the attenuated reduction in mean arterial pressure after a glucose load in hypertensive patients

Although long recognized, the vasodilator effect of insulin has been relatively neglected over the last few years. Recent reports have focused on the sympathetic and antinatriuretic actions of this hormone. In the first part of the present study we characterized the reduction in blood pressure after a glucose load in hypertensive patients with and without insulin resistance. fourteen hypertensive Caucasian patients and ten Caucasian controls were submitted to a standard oral glucose tolerance test (OGTT) and intravenous insulin tolerance test (15-min ITT). In the hypertensive patients with insulin resistance the reduction in mean arterial presure (MAP) after a glucose load was blunted (6.7 ñ 1.7 per cent (N = 5)) when compared to insulin-sensitive (12.9 ñ 1.1 per cent (N = 9)) and normal subjects (10.1 ñ 0.8 per cent). IN the second part of the study we investigated whether hypertensive patients with myocardial hypertrophy were more insulin resistant than hypertensive individuals with a normal cardiac mass. The glucose disappearance rate (Kitt) was lower in hypertensive patients with myocardial myocardial hypertensive patients with myocardial hypertrophy (6.0 ñ 1.0 (N = 6)) when compared to hypertensive patients without myocardial hypertrophy (8.2 ñ 1.0 per cent/min (N = 8)), suggesting an association between this organomegaly and insulin resistance. In conclusion, our results suggested that 1) insulin resistance, rather than hyperinsulinemia, acts as a risk factor for the development of hypertension, because of insulin's inability to decrease MAP in this situation, and 2) there is an association between left ventricular hypertrophy and insulin resistance in hypertensive patients

Expression of the FOX1 gene of Saccharomyces cerevisiae is regulated by carbon source, but not by the known glucose repression genes.

We have investigated the regulation of expression of the FOX1 gene of Saccharomyces cerevisiae which encodes acyl-CoA oxidase, the first enzyme in the peroxisomal beta oxidation of fatty acids. We have found that the FOX1 steady state mRNA level is repressed by glucose, partially induced by ethanol (but not by raffinose) and fully induced by oleic acid as a carbon source. Glucose repression was observed even if cultures were grown to stationary phase; however, if the glucose supply was limited initially then partial induction of FOX1 mRNA occurred upon growth to high cell density. A variety of mutants are known to affect the glucose repression of many genes, including the FOX3 gene which encodes the thiolase activity in peroxisomal beta oxidation. However, upon examination none of these mutants showed de-repression of FOX1 expression. Similarly we investigated the role of two inducers of genes encoding peroxisomal enzymes (namely SNF1 and ADR1). No evidence was found to suggest that either of these plays a significant role in the induction of FOX1 mRNA levels. These observations indicate that the regulation of FOX1 is under the control of as yet unidentified genes involved in catabolite repression and suggest that the regulatory circuit influencing acyl CoA oxidase activity, and hence beta oxidation and peroxisome function, is significantly different than that which might have been assumed from other studies.

Octreotide blunts postprandial splanchnic hyperemia in cirrhotic patients: a double-blind randomized echo-Doppler study.

The effect of octreotide, a long-acting synthetic analog of somatostatin, on fasting and postprandial splanchnic hemodynamics was investigated in cirrhotic patients. Splanchnic hemodynamics were assessed using an echo-Doppler duplex system in a prospective, double-blind, placebo-controlled, crossover study performed on 2 separate days, 1 week apart, in 30 cirrhotic patients. Measurements of portal vein (PV) cross-sectional area (PV-A) and mean velocity (PV-V), and of superior mesenteric artery (SMA) mean velocity (SMA-V) and pulsatility index (SMA-PI) (an index of vascular resistance) were performed at baseline, 30 minutes after octreotide (200 micrograms subcutaneously) or placebo administration, and 30 and 60 minutes after the ingestion of a liquid meal. In the fasted state, octreotide induced a significant decrease in PV-V (-7%) and in SMA-V (-10%) and an increase in PI (+16%). On the day of placebo administration, meal ingestion induced a significant increase in PV-V (+21%) and in SMA-V (+43%) and a decrease in PI (-21%). In contrast, meal ingestion on octreotide day induced significantly smaller increases in PV-V (+10%) and in SMA-V (+18%) and a significantly smaller decrease in PI (-10%). Octreotide, although producing a mild reduction in PV-V and SMA-V in the fasted state, markedly blunts postprandial splanchnic hyperemia in cirrhotic patients.

Comparison between the effect of L-propionylcarnitine, L-acetylcarnitine and nitroglycerin in chronic peripheral arterial disease: a haemodynamic double blind echo-Doppler study.

The haemodynamic effects on the peripheral vascular bed of L-acetylcarnitine, L-propionylcarnitine, and nitroglycerin were tested by echo-Doppler in a double blind cross-over study. Eleven male patients suffering from peripheral arterial obliterative disease (PAOD) in the second stage of Fontaine's classification, and 11 matched control subjects were enrolled in the study. Each subject received one of three different treatments on each day of the study in a different order following a random assignment. The treatments were either 30 mg x kg of L-acetylcarnitine (LAC) or 30 mg x kg of L-propionylcarnitine (LPC) or nitroglycerin (NTG) 1.25 mg given as a single i.v. bolus injected over 3 min. Echo-Doppler measurements of blood flow velocity, and cross-sectional area of the femoral artery were performed at baseline and 10, 20, and 30 min after injection of the drugs. Pulsatility Index (an index derived from the blood flow velocity and related to vascular resistance: PI = Vmax - Vmin/Vmean) was also obtained each time. Results were analysed using a Student's t-test for paired data. L-acetylcarnitine and L-propionylcarnitine showed no haemodynamic effects in either group of subjects (controls and PAOD patients) whether blood flow or vascular resistance was considered. There were haemodynamic changes (a decrease in blood flow velocity and an increase in arterial systemic resistance) only after NTG administration. The changes were more evident in controls than in PAOD patients. Femoral artery cross-sectional area showed no statistically significant effect as regards treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

[Echo-color Doppler in the study of portal hypertension]. / Eco color-Doppler nello studio dell'ipertensione portale.

Color-Doppler US is currently an extremely valuable tool in the study of abdominal circulation, cirrhosis of liver and its complications, different kinds of portal hypertension, vascular/avascular liver malformations and, finally, in the evaluation of liver transplants. Moreover, its use in experimental studies has yielded good results. Even spontaneous porto-systemic shunts can be demonstrated in most cases (up to 88%). Color-Doppler allows partial obstructions to be demonstrated and permits qualitative and quantitative dynamic evaluations the presence/absence of flow, vascular masses--e.g., mean velocity measurement and blood flow assessment. The interobserver variability of the method was calculated with a double-blind study carried out by our laboratory team cooperating with a study group from the University of Yale, USA. The study evidenced how color-Doppler US cannot be used to follow the single patient unless the variations to measure are higher than variability itself. Color-Doppler limitations depend on the subjectivity of the results and on its difficult application to obese patients or to those with severe intestinal meteorism.

Echo-Doppler evaluation of acute flow changes in portal hypertensive patients: flow velocity as a reliable parameter.

In order to evaluate the behavior of the portal vein cross-sectional area during changes in portal flow, two groups of subjects were analyzed in two blinded cross-over studies using echo-Doppler flowmetry. The first group (I) consisted of 21 patients with cirrhosis and 16 controls. They received a standardized meal which is known to increase portal flow. The second group (II) consisted of 31 patients with cirrhosis who received a dose of propranolol which is known to decrease portal flow. In Group I, 30 min after the meal, the portal vein blood velocity increased by 35 +/- 6% (p less than 0.01) in cirrhotic patients and by 55 +/- 5% (p less than 0.01), in normal subjects. The portal vein cross-sectional area increased significantly in normal subjects (22 +/- 2%, p less than 0.01) but not in cirrhotic patients (4 +/- 2%, n.s.). In Group II, 2 h after propranolol, there was a significant decrease in portal blood velocity (-14 +/- 2%), whereas the portal vein cross-sectional area did not show any significant changes. These data demonstrate that, in portal hypersensitive patients, the portal area measured by echo-Doppler flowmetry can be assumed to be constant and hence its calculation to estimate changes in portal blood flow can be omitted. Therefore, the use of blood velocity alone is suggested to monitor acute changes in flow in portal hypertension using Doppler flowmetry. The elimination of the portal vein cross-sectional area measurement simplifies the quantitative calculation of portal hemodynamics and increases the reliability of the technique by avoiding a source of error.

Superiority of L-propionylcarnitine vs L-carnitine in improving walking capacity in patients with peripheral vascular disease: an acute, intravenous, double-blind, cross-over study.

The effects of L-propionylcarnitine on walking capacity were assessed in a group of patients with peripheral vascular disease. In 12 patients, 300 mg of L-propionylcarnitine, given intravenously as a single bolus did not affect walking capacity, while 600 mg increased both initial claudication distance from the placebo value of 179 +/- 114 to 245 +/- 129 m (P less than 0.05), and maximal walking distance from 245 +/- 124 to 349 +/- 155 m (P less than 0.05). Once the efficacious dose of L-propionylcarnitine was assessed, its effect was compared to that of an equimolar dose of L-carnitine (500 mg i.v.) according to a double-blind, double-dummy, cross-over design. In 14 patients, both treatments improved walking capacity; however, the analysis of variance showed that the increase in maximal walking distance with L-propionylcarnitine was greater than that with L-carnitine (P less than 0.05). Finally, in seven additional patients, the effects of L-propionylcarnitine and L-carnitine on the haemodynamics of the affected limb were assessed by an ultrasonic duplex system. Results indicated that both drugs did not affect the blood velocity and the blood flow rate in the ischaemic leg, thus suggesting that the beneficial effect on walking capacity was dependent on a metabolic effect. In conclusion, L-propionylcarnitine improves walking capacity in patients with peripheral vascular disease, probably acting through a metabolic mechanism. On a molar basis, this beneficial effect is greater than that observed with L-carnitine and, thus, the findings of the present study may have clinical relevance in terms of treatment cost and patient compliance.

Acute systemic and splanchnic haemodynamic effects of L-carnitine in patients with cirrhosis.

L-carnitine (L-C) is a naturally occurring substance in mammalian tissues that has recently been proposed as a therapeutic agent in hepatic encephalopathy and liver steatosis. L-C also produces some acute, non-metabolic, haemodynamic effects that have not previously been studied in patients with cirrhosis. Therefore, the authors evaluated the acute effect of i.v. administration of L-C (30 mg/kg) on systemic and splanchnic haemodynamics in ten patients (L-C group) with chronic liver disease (Child-Pugh's class A: 4, B: 3, C: 3 patients) and a control group composed of ten patients with similar clinical characteristics (Child-Pugh's class A: 5, B: 2, C: 3 patients) who received placebo. Heart rate, cardiac index and pulmonary arterial pressure (measured by right heart catheterization) decreased slightly but significantly in the L-C group and the changes observed in stroke volume were highly correlated to the Pugh's score. Moreover, the hepatic venous pressure gradient (measured by hepatic vein catheterization) decreased significantly in the L-C group, whereas no changes occurred in the placebo group. The overall response to L-C was contradictory to that previously observed in animals and humans with normal liver function, and the extent seemed to depend on the severity of liver disease. The effect of the drug on cardiac index, heart rate and hepatic venous gradient could possibly be beneficial for patients with hyperdynamic circulatory condition and portal hypertension.