Implication of non-coding PAX6 mutations in aniridia.

There is an increasing implication of non-coding regions in pathological processes of genetic origin. This is partly due to the emergence of sophisticated techniques that have transformed research into gene expression by allowing a more global understanding of the genome, both at the genomic, epigenomic and chromatin levels. Here, we implemented the analysis of PAX6, whose coding loss-of-function variants are mainly implied in aniridia, by studying its non-coding regions (untranslated regions, introns and cis-regulatory sequences). In particular, we have taken advantage of the development of high-throughput approaches to screen the upstream and downstream regulatory regions of PAX6 in 47 aniridia patients without identified mutation in the coding sequence. This was made possible through the use of custom targeted resequencing and/or CGH array to analyze the entire PAX6 locus on 11p13. We found candidate variants in 30 of the 47 patients. 9/30 correspond to the well-known described 3' deletions encompassing SIMO and other enhancer elements. In addition, we identified numerous different variants in various non-coding regions, in particular untranslated regions. Among these latter, most of them demonstrated an in vitro functional effect using a minigene strategy, and 12/21 are thus considered as causative mutations or very likely to explain the phenotypes. This new analysis strategy brings molecular diagnosis to more than 90% of our aniridia patients. This study revealed an outstanding mutation pattern in non-coding PAX6 regions confirming that PAX6 remains the major gene for aniridia.

Viral and inflammatory markers in cerebrospinal fluid of patients with HIV-1-associated neurocognitive impairment during antiretroviral treatment switch.

OBJECTIVES: The aim of the study was to evaluate HIV-1 viral load (VL) and inflammatory markers in cerebrospinal fluid (CSF) and neurocognitive performance in patients with neurocognitive impairment (NCI) while they were receiving tenofovir (TDF)/ emtricitabine (FTC)/efavirenz (EFV) and after switching to a regimen with enhanced central nervous system (CNS) penetrability. METHODS: This was a prospective, single-arm pilot study. HIV-1-infected patients with plasma viral suppression and HIV-associated NCI on a regimen including TDF/FTC/EFV were switched to abacavir (ABC)/lamivudine (3TC)/maraviroc (MVC). The Global Deficit Score (GDS) was used to score cognitive function at baseline and 48 weeks after treatment switch. Both CSF and blood samples were taken at baseline and between weeks 24 and 36 after switching. HIV-1 RNA in plasma and CSF was determined by quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR). Inflammatory biomarkers in CSF were measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: A total of 71 patients receiving TDF/FTC/EFV were screened. Twelve of them (17%) had documented NCI, lacked the human leucocyte antigen (HLA)-B*57:01 haplotype and harboured Chemokine Receptor Type-5 (CCR5)-tropic virus. Eight patients had detectable HIV-1 RNA (between 2.7 and 41.6 HIV-1 RNA copies/mL) in CSF at baseline. All participants had elevated levels of neopterin and Monocyte Chemoattractant Protein 1 (MCP-1) in CSF at baseline. Eight out of 12 patients completed their follow-up assessment after treatment switch. The GDS decreased from 0.55 to 0.4 (P = 0.085). Median HIV-1 RNA in CSF decreased from 3.49 to 2.20 (P = 0.23). Among the inflammation markers in CSF, tumour necrosis factor (TNF)-α decreased significantly from median 0.51 to 0.35 pg/mL (P = 0.027), showing a correlation with the changes in neopterin, interferon (IFN)-γ and interleukin (IL)-6. CONCLUSIONS: Most patients with NCI receiving TDF/FTC/EFV had low-level viraemia and/or increased inflammatory markers in CSF. Treatment switching to an MVC-containing regimen with better CNS penetration resulted in a trend towards improvement in neurocognitive status and reduced TNF-α concentrations in CSF.

Preliminary study: fibre content in pet rabbit diets, crude fibre versus total dietary fibre.

Fibre is an important nutrient for rabbit health, and, on commercial pet rabbit packaging, it is labelled as crude fibre (CF). In several species, it is considered that CF is not an accurate representation of the fibre content in feedstuffs. The objective of this study was to compare the CF stated on the label (CFL) with laboratory analysis of CF (CFA) and the analysed content of total dietary fibre (TDF) in different commercial pet rabbit feeds. We selected 15 commercial diets and analysed CF and TDF. A mixed model was used to evaluate differences between CFL, CFA and TDF, and linear regression was performed to study the correlation between CFL and CFA with TDF. CFA and CFL were not significantly different (p = 0.836) in the feeds studied, and both were lower than TDF (p < 0.001). The correlations between TDF and both CFA and CFL were significant (p < 0.001 and p = 0.02, respectively), but the correlation was better with CFA (R = 0.86) than with CFL (R = 0.53). As expected, TDF content was higher than CF content, an average of two times. These results suggest that the CF content in rabbit diets reported on the label is not an appropriate indicator of their total fibre content, although further work with a larger sample size is required to confirm these results.

Evaluation of the use of esterified fatty acid oils enriched in medium-chain fatty acids in weight loss diets for dogs.

Esterified fatty acid oils (EAOs) are obtained from esterification of vegetable acid oils with glycerol. These fat sources have the same fatty acid (FA) composition as their respective native oils but new chemical properties. Several studies have confirmed the potential of medium-chain fatty acids (MCFA) to reduce fat mass (FM) in humans and rodents. This study investigates the use of EAOs with different MCFA proportions on food preferences, digestibility and weight loss management in dogs. A basal diet was supplemented with 8% of three different fat sources: C0: soya bean-canola EAO, C20: soya bean-canola (80%) coconut (20%) EAO and C40: soya bean-canola (60%) coconut (40%) EAO. Food preference of these EAOs was tested using a two-pan preference test. Dogs presented a higher daily food intake of C20 and C40 compared to C0 (C20: 155 ± 18.6 g vs. C0: 17 ± 7.0 g, p < 0.001; C40: 117 ± 13.9 g vs. C0: 28 ± 10.5 g, p < 0.05 respectively). Also, the digestibility of the three experimental diets was tested. C20 and C40 showed higher ether extract, total FA and saturated FA digestibilities (p < 0.05) than C0 diet. Lastly, the three diets were investigated in a 14-week weight loss study, following 16 weeks of ad libitum feeding to induce overweight condition. Body weight (BW) reduction was lower (C0: 20.1 ± 2.32%, C20: 14.6 ± 1.43% and C40: 15.7 ± 1.23%, p < 0.05) and FM was higher (FM, 18.7 ± 3.42%, 27.9 ± 3.90% and 28.2 ± 2.88% for C0, C20 and C40, respectively, p < 0.05) for diets C20 and C40 than for C0. Feeding diets with MCFA at these inclusion levels to experimentally overweight dogs during 14 weeks do not result in faster weight loss compared to unsaturated long-chain FA.

Metformin: a cheap and well-tolerated drug that provides benefits for viral infections.

OBJECTIVES: Insulin resistance in viral infections is common. We have explored the effectiveness of metformin for alleviating insulin resistance in HIV-infected patients and assessed the relevance of the ataxia-telangiectasia mutated (ATM) rs11212617 variant in the clinical response with the rationale that metformin modulates cellular bioenergetics in an ATM-dependent process. METHODS: HIV-infected patients (n = 385) were compared with controls recruited from the general population (n = 300) with respect to the genotype distribution of the ATM rs11212617 variant and its influence on selected metabolic and inflammatory variables. We also followed up a subset of male patients with HIV and hepatitis C virus (HCV) coinfection (n = 47) who were not receiving antiviral treatment and for whom metformin was prescribed for insulin resistance, which tends to have a higher incidence and severity in coinfected patients. RESULTS: Among the HIV-infected patients, human cytomegalovirus (91.9%) and HCV (62.3%) coinfections were frequent. Selected metabolic and/or inflammatory variables were significantly altered in infected patients. Treatment with metformin in HIV and HCV coinfected patients was well tolerated and significantly increased the sensitivity of peripheral tissues to insulin. The minor allele (C) of the rs11212617 variant was associated with treatment success and may affect the course of insulin resistance in response to metformin (odds ratio 1.21; 95% confidence interval 1.07-1.39; P = 0.005). There were no differences between treated and untreated patients in viral loads or variables measuring immune defence, indicating that toxicity is unlikely. CONCLUSIONS: We provide novel data suggesting that identification of the ATM rs11212617 variant may be important in assessing the glycaemic response to metformin treatment for insulin resistance in HIV-infected patients.

Comparison of postprandial lipaemia between native and palm random esterified acid oils in two different monogastric species (dogs and broiler chickens).

It has been reported that applying a chemical reesterification process to a native fat results in a new fat source with different physicochemical properties due to their different fatty acid (FA) positional distribution within the glycerol moiety and their different proportions of mono (MAG)-, di (DAG)- and triacylglycerides (TAG). Thus, this reesterification could affect fat digestion, absorption and metabolism; and this effect could vary among species given their differences in fat metabolism. The aim of this study was to compare the effect of feeding two different random esterified acid oils (REAO), presenting different MAG, DAG and TAG proportions, with their corresponding native oil on postprandial lipaemia in broiler chickens and dogs. For this purpose, 18 dogs and 54 broiler chickens were fed a basal diet supplemented with palm native oil, palm REAO low MAG or palm REAO high MAG. The inclusion level of the oils was 10% of the diet in dogs and 6% in broiler chickens. Serum postprandial TAG concentration (mg/dl) after feeding a single meal was measured at different time points during 12 h in dogs and 3 h in chickens. Although fasting serum TAG concentration values were similar for both species (47 ± 2.4 mg/dl for dogs and 44 ± 3.0 mg/dl for broilers; p = 0.522), postprandial TAG concentrations tended to be higher in broilers than in dogs (p = 0.058). Treatment had no effect on TAG concentration at any time point in any species (p = 0.768 for dogs, p = 0.947 for broilers). However, the postprandial TAG curves were very different between species; in broiler chickens, TAG concentration returned to the fasting values 3 h after feeding while in dogs, the TAG concentration still had not returned to basal levels 12 h after feeding.

Impact of antiretroviral therapy interruption on plasma biomarkers of cardiovascular risk and lipids: 144-week final data from the STOPAR study.

OBJECTIVE: The aim of the study was to investigate changes in plasma biomarkers of cardiovascular risk and lipids in a CD4-guided antiretroviral therapy interruption study. METHODS: This was a substudy of a prospective, randomized, multicentre treatment interruption study. At months 12, 24 and 36, monocyte chemotactic protein-1 (MCP-1), soluble vascular cell adhesion molecule-1 (sVCAM-1), interleukin-6 (IL-6), interleukin-8 (IL-8), soluble CD40 ligand (sCD40L), soluble P-selectin (sP-selectin), and tissue plasminogen activator (t-PA) were measured using a multiplex cytometric bead-based assay. Total cholesterol (total-c), high-density lipoprotein cholesterol (HDL-c) and triglycerides (TG) were determined using standard methods. RESULTS: Fifty-four patients were included in the study [34 in the treatment continuation (TC) arm and 20 in the treatment interruption (TI) arm]. There were no differences at baseline between the groups, except in CD4 cell count, which was higher in the TI arm (P = 0.026), and MCP-1, which was higher in the TC arm (P = 0.039). MCP-1 and sVCAM-1 were increased relative to baseline at the three study time-points in the TI arm, with no changes in the TC arm. Soluble CD40L and sP-selectin were increased at month 36 in both arms, with a greater increase in the TI arm (P = 0.02). t-PA was increased in both arms at the three time-points. Total-c, HDL-c and low-density lipoprotein cholesterol (LDL-c) were decreased in the TI arm at the three time-points, with no changes in the total-c/HDL-c ratio. HIV viral load positively correlated with MCP-1 at months 12 and 24. Regression analysis showed a significant negative association of HDL-c with MCP-1 and sVCAM-1. CONCLUSIONS: A significant increase in cardiovascular risk biomarkers persisting over the prolonged study period was seen in the TI arm. This factor may contribute to the increased cardiovascular risk observed in previous studies.

Effects of 7-weeks competitive training period on physiological and mental condition of top level judoists.

AIM: We examined hormonal and haematological parameters and the profile of mood states (POMS) in top level judoists undertaking a 7-week competitive training period in a real contest. METHODS: Participants were 10 top level judoists belonging to the Spanish National Team. Training load was calculated by multiplying the training session intensity by the duration of the training session. The judoists competed in two official events on weeks 3 and 6 of the study. RESULTS: Urinary catecholamines increased at the end of the competitive period. Serum cortisol increased during the weeks in which judoists competed, confirming the existence of and anticipatory cortisol response to exercise; although we failed to find serum testosterone increases. Because of leukocyte values did not change, except monocytes, we speculate that the intensity of training was not sufficiently high to evoke injury to muscle tissue. Anger, tension, and fatigue increased according with training load, suggesting that the training exercise led participants into a negative psychological state. CONCLUSION: Findings indicate that during competitive periods, judoists suffer hormonal and mood changes according to training load and competitive events. Results support the usefulness of monitoring biological and psychological markers during season in order to adjust training loads and periods of recovery.

Influence of a high-protein diet on energy balance in obese cats allowed ad libitum access to food.

The influence of a high-protein [HP, 47% of metabolizable energy (ME)] diet on energy balance was evaluated in obese cats allowed ad libitum access to food. Energy intake, body weight, body composition, energy expenditure, and concentrations of hormones and metabolites associated with carbohydrate and lipid metabolism (glucose, insulin, free fatty acids, triglycerides and leptin) were measured in cats after consuming either a moderate protein (MP, 27% of ME) or HP diet for 4 months. Indirect respiration calorimetry showed that resting and total energy expenditure (kJ/day) adjusted for either body weight or lean body mass was increased in cats consuming the HP in relation to MP diets. However, voluntary energy intake also was increased in the HP treatment and, thus, there was no difference in body weight between animals consuming the two diets. Body composition measurements using deuterium oxide dilution showed that dietary protein content did not alter amounts of either lean body mass or fat mass. No significant differences (p > 0.05) were observed between the two treatment groups for blood glucose, free fatty acid or leptin concentrations, although there was a trend (p = 0.054) towards an increase of serum insulin concentrations in the cats eating the HP diet. This study showed that short-term ad libitum feeding of an HP diet did not reduce food intake or promote weight loss in obese cats. However, energy expenditure was increased in the HP diet group and it is possible that this effect of HP might help promote weight loss when energy intake is restricted.

Nonconcordance between subclinical atherosclerosis and the calculated Framingham risk score in HIV-infected patients: relationships with serum markers of oxidation and inflammation.

OBJECTIVES: HIV-infected patients show an increased cardiovascular disease (CVD) risk resulting, essentially, from metabolic disturbances related to chronic infection and antiretroviral treatments. The aims of this study were: (1) to evaluate the agreement between the CVD risk estimated using the Framingham risk score (FRS) and the observed presence of subclinical atherosclerosis in HIV-infected patients; (2) to investigate the relationships between CVD and plasma biomarkers of oxidation and inflammation. METHODS: Atherosclerosis was evaluated in 187 HIV-infected patients by measuring the carotid intima-media thickness (CIMT). CVD risk was estimated using the FRS. We also measured the circulating levels of interleukin-6, monocyte chemoattractant protein-1 (MCP-1) and oxidized low-density lipoprotein (LDL), and paraoxonase-1 activity and concentration. RESULTS: There was a weak, albeit statistically significant, agreement between FRS and CIMT (kappa=0.229, P<0.001). A high proportion of patients with an estimated low risk had subclinical atherosclerosis (n=66; 56.4%). In a multivariate analysis, the presence of subclinical atherosclerosis in this subgroup of patients was associated with age [odds ratio (OR) 1.285; 95% confidence interval (CI) 1.084-1.524; P=0.004], body mass index (OR 0.799; 95% CI 0.642-0.994; P=0.044), MCP-1 (OR 1.027; 95% CI 1.004-1.050; P=0.020) and oxidized LDL (OR 1.026; 95% CI 1.001-1.051; P=0.041). CONCLUSION: FRS underestimated the presence of subclinical atherosclerosis in HIV-infected patients. The increased CVD risk was related, in part, to the chronic oxidative stress and inflammatory status associated with this patient population.

Pitfalls in measuring high-density lipoprotein cholesterol concentrations in HIV-infected patients.

OBJECTIVES: HIV infection and its treatment are associated with dyslipidaemia and increased risk of cardiovascular disease. Accurate high-density lipoprotein (HDL) cholesterol values are necessary for the management of these abnormalities, but current methods have not been properly assessed in these patients. The aim of this study was to assess in HIV-infected patients the consistency and accuracy of a synthetic polymer/detergent homogeneous assay used to measure HDL cholesterol concentrations and to evaluate the impact of storage. METHODS: HDL cholesterol was measured using a synthetic polymer/detergent homogeneous method in samples from HIV-infected patients and healthy subjects for each of the storage regimens: baseline, after 1 week at 4 degrees C, and after 12 months at -80 degrees C. The ultracentrifugation and precipitation assays were used for comparison. RESULTS: Three out of every 20 samples from HIV-infected patients had discrepant HDL cholesterol values with respect to the ultracentrifugation method. Overestimation was associated with high C-reactive protein concentrations and underestimation with plasma gamma-globulin concentrations, an effect that was amplified by any of the storage conditions tested. CONCLUSIONS: Caution is needed when using the synthetic polymer/detergent homogeneous method for direct measurement of HDL cholesterol concentrations in HIV-infected patients. This assay is of limited use in clinical trials in which frozen samples are analysed.

High levels of dietary unsaturated fat decrease alpha-tocopherol content of whole body, liver, and plasma of chickens without variations in intestinal apparent absorption.

An experiment was designed to assess the effect of dietary unsaturated fat inclusion level on alpha-tocopherol apparent absorption and deposition in broiler chickens at 2 ages (20 and 39 d). The dietary fat was a mixture of linseed and fish oil, rich in polyunsaturated fatty acids (PUFA). The experimental treatments were the result of 4 levels of supplementation with alpha-tocopheryl acetate (0, 100, 200, and 400 mg/kg; E0, E100, E200, and E400 treatments, respectively) and 4 dietary oil inclusion levels (2, 4, 6, and 8%; O2, O4, O6, and O8 treatments respectively). Almond husk was used as an energy dilutor in the high-fat diets. Apparent absorption of total fatty acids was high in all treatments averaging 88% and was higher with high fat dietary inclusion level. alpha-Tocopheryl acetate hydrolysis and apparent absorption of alpha-tocopherol were similar in both ages and were not affected by fat inclusion level, except for a reduction of the absorption in the low-fat diet (O2) in the E100 treatment at 20 d of age. Despite this lack of differences in hydrolysis and absorption, higher-fat PUFA diets induced lower concentrations of free alpha-tocopherol in the excreta, at high alpha-tocopherol doses, suggesting an increase in the destruction of alpha-tocopherol by lipid oxidation in the gastrointestinal tract. Similarly, total and hepatic alpha-tocopherol deposition was lower in the birds fed high-PUFA diets in the E200- and E400-supplemented birds, possibly due to a destruction of vitamin E when protecting these PUFA from lipid peroxidation. alpha-Tocopherol concentration in liver and, to a lesser extent, in plasma was a useful indicator of the degree of response of this vitamin to different factors that can affect its bioavailability; however, in the present experiment, CV were too high to use liver and plasma concentrations as estimators of total body vitamin E.

Endorphin responses to stress induced by competitive swimming event.

AIM: The aim of the present study was to investigate the changes in endorphins (END) induced by swimming competitive practice. METHODS: Twenty-three males, (13 trained swimmers [experimental group] and 10 sedentary and healthy students [age-matched comparison group]) took part in this investigation. The swimmers were assessed at 3 points: basal conditions, pre- and postswimming competition (100 m freestyle), whereas subjects from the control group only undertook the basal trial. The variables analysed were anxiety level, plasma END and lactate concentrations. RESULTS: No statistical differences were observed in END basal levels between groups. An evident END response to precompetition psychological stress was observed in the experimental group, since the plasma END concentration rose from 36.3+/-2.9 pg/mL (basal conditions) to 51.8+/-3.2 pg/mL (P=0.05). The END response to the competitive effort produced a remarkable increase in its plasma concentration (128.6+/-18.1 pg/mL), showed statistical differences from precompetition (P=or<0.01) and from basal conditions (P=or<0.001). A significant rise in plasma lactate levels just at the end of the effort was found, although it did not correlate with END levels in the same situation. CONCLUSION: Swimming competition (short-term maximal type of effort) induces a psychological and physiological stress, which stimulates the secretion of END. END are secreted to counter the negative effects of competitive stress, although more research is needed to accurate the relationship between END and anxiety levels during exercise.

Stable biomembrane surfaces formed by phospholipid polymers.

Phospholipids (phosphatidylcholines) with diacetylene in each acyl chain have been deposited in Langmuir-Blodgett multilayers on a variety of substrates. Upon irradiation the diacetylene groups polymerise and link the phospholipid molecules together with a conjugated chain made up of alternating single, double and triple bonds. Advantage has been taken of this polymerisation process to increase the stability of these lipids layers and to produce stable biomembrane hydrophilic surface. These surfaces may be useful for studies of blood coagulation and protein adsorption. In addition they could also have medical application.

Influence of the dietary polyunsaturation level on chicken meat quality: lipid oxidation.

The present study was carried out to evaluate the influence of increasing amounts of dietary polyunsaturated fatty acids (PUFA) and alpha-tocopheryl acetate (alpha-TA) supplementation on lipid oxidation of raw and cooked thigh meat stored under refrigeration. One hundred ninety-two female, 1-d-old, broiler chickens were randomly distributed into 16 experimental treatments resuIting from the combination of 4 levels of dietary PUFA (15, 34, 45, and 61 g/kg) and 4 levels of supplementation with alpha-TA (0, 100, 200, and 400 mg/kg). Thiobarbituric acid reactive substance (TBARS) values in cooked meat and cooked refrigerated meat were 12- and 24-fold higher, respectively, than in raw meat. Dietary polyunsaturation and alpha-TA supplementation affected lipid oxidation more markedly in cooked meat and cooked refrigerated meat than in raw meat and raw refrigerated meat. Lipid oxidation in cooked meat showed a significant linear increase as the concentration of PUFA in raw meat increased. The oxidative stability of meat was not affected by an increase in the dietary alpha-TA level from 200 to 400 mg/kg. Nonlinear relationship between TBARS values in cooked meat and alpha-tocopherol content of raw meat showed saturation in the antioxidant effect of alpha-Toc. The equation y = x (11.88 + 63.38e(-0.007z) was calculated to predict the minimum inclusion of alpha-tocopherol to diets (z) of chickens with certain dietary PUFA content (x) to assure a certain TBARS value (y).

Effect of malabsorption on nutritional status and resting energy expenditure in HIV-infected patients.

OBJECTIVE: To assess the influence of malabsorption on nutritional status and energy expenditure in patients at different stages of HIV infection. DESIGN AND METHODS: Fifty HIV patients were classified into three groups: Group 1, HIV asymptomatic patients (n=17); Group 2, AIDS without opportunistic infection (n=16); Group 3, AIDS patients with active infection (n=17). Clinically-healthy subjects (n=19) were used as controls. Parameters measured were: anthropometry, body composition by tetrapolar bioelectrical impedance; resting energy expenditure (REE) by open-circuit indirect calorimetry; malabsoption by D-xylose absorption and triolein breath tests. RESULTS: Malabsorption (defined as abnormality of xylose and/or fat absorption test) was found in 34 (68%) of patients: 9 (53%) Group 1; 11 (69%) Group 2; 14 (82%) Group 3. Twenty-seven (54%) had sugar malabsorption and 21 (42%) fat malabsorption. A significant relationship was observed between malabsorption and weight loss. REE measured was significantly lower in malabsorptive patients than in non-malabsorptive patients and controls (6006.3+/-846.5 versus 6443.4 + 985.5 versus 6802.1+/-862.7 kJ/day, respectively; P < 0.05). The REE adjusted for fat-free mass was lower in malabsorptive than in non-malabsorptive patients and slightly higher than in controls, although the differences were not statistically significant. CONCLUSIONS: The results suggest that malabsorption is a frequent feature in HIV infection and is related to the HIV-related weight loss. Hypermetabolism is not a constant phenomenon in HIV infection since, in the presence of malabsorption, our patients show an appropriate metabolic response with a compensatory decrease in REE.

Inhibition of calcium entry induced by cularines and isocrasifoline in uterine smooth muscle.

The effects of nifedipine, papaverine and four benzylisoquinoline alkaloids (cularine, cularidine, celtisine and isocrasifoline) were studied in isolated rat uterus in order to clarify the mechanism of their relaxant action. All the compounds tested completely relaxed KCl-induced contractions and totally or partially inhibited oxytocin-induced rhythmic contractions. Only papaverine acted intracellularly, promoting relaxation of contractile responses induced by oxytocin or vanadate in a Ca(2+)-free medium. In spite of the structural relationship between papaverine and the other alkaloids, the mechanism of their relaxant action is not the same. The activities of cularine derivatives and of isocrasifoline were similar to that of nifedipine.

Hyperlipemia, fibrinolysis and arteriosclerosis.

In this work we investigated the influence of hyperlipemia on the fibrinolytic system and also attempted to determine whether vascular lesions may modify the response of plasminogen activators to hyperlipemia. The study was made on rats. Three different diets were administered to the animals, two of the diets only increased the levels of plasmatic lipids in the animals (hyperlipemic groups), but the third induced hyperlipemia and lipid infiltration in aorta (arteriosclerotic group). Fibrinolytic activity was evaluated in the plasma, on the aorta endothelial surface and in aorta wall. In the plasma, plasminogen activator (PA) activity was increased in the hyperlipemic and arteriosclerotic groups compared to control group, however, the activity of fibrinolysis inhibitors was also increased. On the endothelial surface and in the aorta wall, fibrinolytic activity was increased in the groups which received hyperlipidic diets but in the arteriosclerotic group only the endothelial surface showed a clear increase of fibrinolytic activity. A positive correlation was observed between PA activity and levels of hyperlipemia. However, no correlation has been shown between fibrinolytic activity in the aorta with cholesterol and triglyceride levels in this vascular wall.