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Biomedical subjects

G Franceschini

Publications and source records attributed to G Franceschini.

At least 127 records · Page 7Linked to original sources
PubMed1981

Relation between the HDL apoproteins and AI isoproteins in subjects with the AIMilano abnormality.

The apoprotein AIMilano (AIM) is the first described molecular abnormality of human apolipoproteins. In order to achieve a better understanding of the biochemical role of high density lipoproteins (HDL) and of their subcomponents, nine members of the AIM family were studied. Five showed the characteristic biochemical features of the AIM abnormality. All were hypertriglyceridemic; their plasma and very low density lipoprotein (VLDL) triglycerides had a significant negative correlation with the HDL cholesterol (HDL-C) levels (r = -0.961, p less than 0.01 and r = -0.939, p less than 0.05, respectively). Compositional studies of HDL in these subjects revealed a marked triglyceride (TG) enrichment, with reduced cholesterol content. HDL-C and/or phospholipid (PL) levels correlated significantly with the AIM apoprotein in HDL (r = 0.995, p less than 0.001 for HDL-C and r = 0.994, p less than 0.001 for HDL-PL) but not with the other HDL apoproteins, suggesting that only apo AIM in monomeric form, can bind lipids. Isoelectric focusing studies on the isolated AIM isoproteins from the five affected subjects revealed an isoprotein distribution markedly different from normal AI. A possible structural role for isoprotein AI1 is suggested by the strong correlation between HDL content of this isoprotein and HDL-C and HDL-PL levels (r = 0.965 and r = -0.990 respectively, both p less than 0.001). AI4 and AIM was nearly doubled, as compared to normal AI. The reported results may be of help for a better understanding of the role of the major HDL apoprotein and of its isoproteins in lipid binding and lipoprotein metabolism.

Adolescent↗
PubMed1980

A-IMilano apoprotein. Decreased high density lipoprotein cholesterol levels with significant lipoprotein modifications and without clinical atherosclerosis in an Italian family.

Significant hypertriglyceridemia with a very marked decrease of high density lipoproteins (HDL)-cholesterol levels (7-14 mg/dl) was detected in three members (father, son, and daughter) of an Italian family. The three affected individuals did not show any clinical signs of atherosclerosis, nor was the atherosclerotic disease significantly present in the family. Lipoprotein lipase and lecithin:cholesterol acyltransferase activites were normal or slightly reduced. Morphological and compositional studies of HDL in the subjects showed a significant enlargement of the lipoprotein particles (approximately 120 vs. approximately 94 A for control HDL) and a concomitant increase in the triglyceride content. Analytical isoelectric focusing of HDL apoproteins provided evidence for multiple isoproteins in the apoprotein(apo)-A-I range, with nine different bands being detected instead of the usual four bands observed in normal subjects. Two-dimensional immunoelectrophoresis against apo-A antiserum indicated a clear reduction of apo-A in the alpha electrophoretic region, with splitting of the protein "peak." The observation in otherwise clinically healthy subjects of hypertriglyceridemia, reduced HDL-cholesterol, and marked apoprotein abnormalities, without a significant incidence of atherosclerotic disease in the family suggests this is a new disease entity in the field of lipoprotein pathology, very probably related to an altered amino acid composition of the apo-A-I protein (see Weisgraber et al. 1980. J. Clin. Invest. 66: 901-907).

Adolescent↗
PubMed1980

A-Imilano apoprotein. Isolation and characterization of a cysteine-containing variant of the A-I apoprotein from human high density lipoproteins.

A recently discovered familial lipoprotein disorder is characterized by reduced plasma levels of high density lipoproteins (HDL) and elevated triglyceride levels. The clinical aspects of this disorder are presented in an accompanying article (Franceschini et al. 1980. J. Clin. Invest. 66: 892-900). The apoprotein content of the HDL isolated from these patients differed markedly from that of normal HDL in that three apoprotein bands not previously described in man were present as major protein components. As determined by sodium dodecyl sulfate (SDS) gel electrophoresis, the relative molecular weights (Mr) of these new apoprotein bands were 55,000, 35,000, and 28,000. Although the Mr 28,000 apoprotein coelectrophoresed with authentic A-I on SDS polyacrylamide gels and showed immunochemical identity with the A-I apoprotein when tested with monospecific apo-A-I antiserum, it contained two amino acid residues, cysteine and isoleucine, which were not present in the amino acid sequence of normal human apo-A-I. This variant form of the A-I apoprotein was designated the A-IMilano apoprotein and denoted A-Icys. By virtue of the presence of cysteine (2 mol/mol A-Icys), the A-Icys apoprotein was capable of forming intermolecular disulfide bonds, and dimer formation of A-Icys produced the Mr 55,000 apoprotein. The Mr 35,000 apoprotein was composed of two different subunits, A-Icys and A-II. By analogy to the apo(E--A-II) complex, which also occurs in human HDL, this mixed disulfide complex was designated as the apo(A-Icys--A-II) complex. The A-IMilano (A-Icys) is the first example of a variation in the primary sequence of a protein of plasma lipoproteins.

Adolescent↗
PubMed1978

Disposition of metformin (N,N-dimethylbiguanide) in man.

Kinetic parameters of metformin (N,N-dimethylbiguanide), an anti-diabetic reported to be associated with a lower number of episodes of lactic acidosis than phenformin, were determined in volunteers with normal renal function and in patients with different degrees of renal impairment. Drug in body fluids was measured by a highly specific and sensitive mass fragmentographic method, after the formation of a triazine derivative, obtained with heptafluorobutyric anhydride. The half-life (t 1/2) for the elimination of drug from plasma after intravenous injection in 5 normal subjects (1.52 +/- 0.3 hr) (mean +/- SD) was shorter than that reported for phenformin by a similar assay method (7 to 15 hr). The mean t 1/2 in 5 renal patients was 4.94 +/- 1.11 hr, and a correlation was observed between t 1/2 of drug from plasma and creatinine clearance. After oral administration of metformin tablets, drug recovery in urines was only 37.6%, possibly not as a consequence of low bioavailability (a similar low recovery was found after oral administration of the metformin solution used for the intravenous studies), but of binding to the intestinal wall, as shown in animal and clinical studies with metformin and other biguanides. Metformin is rapidly eliminated through active secretion by the kidney (mean renal clearance, 440.8 ml/min)--it is neither metabolized nor protein bound in plasma. The very brief plasma t 1/2 makes significant cumulation, with a standard tid regimen, unlikely. These findings may help explain the lower incidence of toxic effects, particularly lactic acidosis, than after phenformin.

Administration, Oral↗
PubMedDate not supplied

Dose-related increase of HDL-cholesterol levels after N-acetylcysteine in man.

Changes in plasma lipid-lipoprotein levels were evaluated in 10 hyperlipidemic patients during treatment with progressive doses (from 1200 mg day-1 to 3600 mg day-1) of N-acetylcysteine (NAC). Plasma total cholesterol and triglyceride levels, as well as those of lipoprotein (a) did not change to an appreciable extent, even with the highest dosage. However, the HDL-cholesterol levels showed a significant, dose-related rise, the mean absolute increase, with the highest NAC dose, being of approximately 10 mg dl-1 (16.2%). The rise of HDL-cholesterol was independent of changes in other lipid-lipoprotein parameters, suggesting a possible direct effect of NAC on the HDL system.

Acetylcysteine↗
PubMedDate not supplied

Cholesterol synthesis inhibitors do not reduce Lp(a) levels in normocholesterolemic patients.

Experimental and clinical data suggest that activation of the LDL receptors by the use of HMG CoA reductase inhibitors, in the presence of normal plasma cholesterol levels, may result in a reduction of Lp(a) concentrations. This hypothesis has been tested in an open study on seven subjects with normal cholesterolemia but marked elevations of Lp(a) levels, three of whom received pravastatin and four simvastatin at standard therapeutic doses. While the two drugs caused the expected reduction of plasma total and LDL cholesterol levels, no significant changes in Lp(a) were noted. This study contradicts a prior clinical finding and suggests that HMG CoA reductase inhibitors are unlikely to reduce plasma Lp(a) levels even in the absence of hypercholesterolemia.

Anticholesteremic Agents↗
PubMedDate not supplied

Pharmacological studies on tiadenol in type IV patients. Evidence for a mechanism of action different from other lipid-lowering drugs.

Tiadenol [bis(hydroxyethylthio) 1-10 decane], a new absorbable hypolipidemic agent differing in chemical structure from clofibrate and related compounds, was tested in hypertriglyceridemic patients, both responsive and nonresponsive to dietary treatment. Tiadenol administration was remarkably effective in inhibiting fructose induced hypertriglyceridemia in diet responsive type IV patients; it was ineffective in patients with stable, diet refractory, hypertriglyceridemia. The significant reduction of plasma triglycerides (-42%) in sensitive patients, was not accompanied in this study, by the activation of plasma lipoprotein and hepatic lipases. In a second, longer term investigation of stable type IV patients, tiadenol administration resulted in significant triglyceride decreases in the very low density lipoproteins (VLDL) (-45%), as well as in the low and high density lipoproteins (LDL and HDL) (both -25%). The cholesterol content of LDL and HDL was not modified. In VLDL a significant reduction of apoprotein E was observed (from 15.2 +/- 4.9 to 11.9 +/- 5.9% of VLDL proteins). The reported observations are consistent with a difference in the mode of action of tiadenol from that of other lipid lowering agents, particularly of the clofibrate type.

Apoproteins↗
PubMedDate not supplied

Tolerability of fibric acids. Comparative data and biochemical bases.

Fibric acids are an established class of drugs for the treatment of hyperlipoproteinaemias. Although they have been in use for 30 years or longer, some doubts remain as to their relative tolerability, both as a class and as single agents. Some side effects, e.g. lithogenicity, may be related to their mode of action, while others, e.g. the acute muscular syndrome, may be linked to the spatial conformation of the molecule. These disadvantages should, however, be weighed against the additional, potentially therapeutic properties shown by these compounds. In particular, effects on maturity onset diabetes and hyperuricaemia, as well as a very interesting fibrinolytic potential, have been described for some of them. A painstaking comparative analysis of the major literature data pertaining to the clinical toxicological profile of these agents allow to conclude that, while belonging to a chemical class, fibric acids show dramatic differences from one another, in terms of side effects and of additional pharmacodynamic activities. Moreover, in the case of lithogenicity for example, considerable differences exist between normo- and hyperlipidaemic subjects. Overall, newer molecules of more sophisticated design have a significantly improved tolerability profile vs the old clofibrate.

Animals↗
PubMedDate not supplied

Metformin improves peripheral vascular flow in nonhyperlipidemic patients with arterial disease.

The clinical activity of metformin (N,N-dimethyl biguanide), a widely used antidiabetic agent, on arterial blood flow was evaluated in 15 patients with peripheral atherosclerosis. Flow was determined by quantitative strain-gauge plethysmography; plasma lipid, lipoprotein, and apoprotein levels were repeatedly tested during the cross-over trial, comparing 6 months of drug and placebo administration. Metformin (850 mg tid) significantly increased arterial flow after a standardized ischemia (+17.3% after 3 months and +40.0% after 6 months). The increase in arterial flow was reversible after the switch to placebo was made. The drug was similarly effective, although to a lesser extent (+18.6% after 6 months), when given after the placebo. A highly significant effect of drug treatment, as well as of the sequence of administration, could be established by analysis of variance. In spite of the minimal changes of plasma lipid levels during metformin, a highly significant increase of high density lipoprotein cholesterol (+ 8.3% during the whole treatment) was demonstrated; plasma levels of isoprotein AI-1 were also raised during the metformin period. This controlled experiment confirms data from previous open studies, as well as from a longstanding clinical experience. Although the mechanism of the metformin effect cannot, at present, be defined, the reported results indicate that treatments not markedly affecting plasma lipid-lipoprotein levels may improve vascular function in selected arterial districts.

Adult↗
PubMedDate not supplied

Apolipoprotein E epsilon 4 allele in Alzheimer's disease and vascular dementia.

The frequency of the epsilon 4 allele of the apolipoprotein E (apoE) is increased in familial and sporadic late-onset Alzheimer's disease, but its prevalence in non-Alzheimer dementias in Caucasian populations is unknown. We found that the frequency of the apoE epsilon 4 allele was 0.45 in 93 Alzheimer's disease patients, 0.46 in 23 vascular dementia patients, 0.31 in 13 dementia of the frontal type patients, and 0.18 in 51 elderly controls. The association of apoE epsilon 4 allele is not unique to Alzheimer's disease, and its importance as a risk factor for the disease should be reconsidered.

Adult↗
PubMedDate not supplied

Increased apoprotein B in very low density lipoproteins of patients with peripheral vascular disease.

Lipoprotein compositional studies were carried out in 20 patients with atherosclerotic peripheral vascular disease. Twelve of these patients were normolipidemic, the other eight, hypertriglyceridemic. Ten normolipidemic and 10 hypertriglyceridemic age-matched subjects were used as controls. High density lipoprotein cholesterol levels were markedly reduced in the hypertriglyceridemic subjects, both with (35.1 +/- 5.0 mg/dl) and without (36.2 +/- 11.7 mg/dl) peripheral vascular disease, as compared to the normolipidemic patients (47.0 +/- 6.3 mg/dl) and controls (48.1 +/- 10.0 mg/dl). A decreased relative content of apo C-11 in very low density lipoproteins in the hypertriglyceridemic subjects, as compared to the normolipidemics, was detected by isoelectric focusing. Hypertriglyceridemia in patients with peripheral vascular disease shows a typical Type IV lipoprotein and apoprotein profile. Apoprotein B levels in very and low density lipoproteins were determined by electroimmunodiffusion and selective precipitation with tetramethylurea (r = 0.981 between the two methods). All the patients with peripheral vascular disease showed an increased apo B content in very low density lipoproteins vascular disease showed an increased apo B content in very low density lipoproteins (VLDL) as compared to controls (apo B cholesterol in VLDL = 0.341 +/- 0.124 for peripheral vascular disease patients and 0.236 +/- 0.086 for controls, p less than 0.001). A significant correlation between VLDL cholesterol and apo b levels was detected both in peripheral vascular disease patients and in controls; however, two distinct populations could be clearly separated (slopes of the regression lines: peripheral vascular disease patients = 0.350; controls = 0.215, p less than 0.001). The data suggest a possible discriminatory power of VLDL-apo B levels in patients with peripheral vascular disease independent from other lipoprotein and lipid parameters.

Adult↗
PubMedDate not supplied

Apolipoprotein A-IMilano. Correlation between high density lipoprotein subclass distribution and triglyceridemia.

Carriers of the apolipoprotein A-IMilano (apo A-IM) variant represent a selected group of subjects showing low levels of high density lipoprotein (HDL), variable hypertriglyceridemia, and low prevalence of atherosclerotic vascular disease. The distribution of HDL subfractions and the correlation with abnormalities in triglyceride transport were determined in these subjects. Sera from 24 apo A-IM carriers (A-IM+ and from age- and sex-matched normolipidemic controls (A-IM-) were analyzed by rate zonal ultracentrifugation. The A-IM+ subjects showed a marked decrease of HDL3 mass with reduced flotation rates and major compositional alterations; the HDL2 were nearly absent. The HDL subclasses from 10 A-IM+ subjects were resolved according to particle size by gradient gel electrophoresis (GGE). The HDL patterns detected in the carriers were unique in exhibiting a distinct peak in the (HDL3b)gge interval, undetectable in the controls. Three patterns reflecting the relative contributions of smaller (HDL3b)gge and larger (HDL3a)gge particles could be distinguished in the carriers, and these were clearly related to different triglyceride and HDL cholesterol levels in plasma. These findings in a highly selected group of subjects with generally low HDL levels and quite variable triglyceridemia confirmed the existence of relationships between alterations in triglyceride transport and abnormalities in the HDL subclass distribution, possibly reflecting the variable atherosclerotic risk in hypertriglyceridemic subjects.

Adult↗
PubMedDate not supplied

Mechanisms of HDL reduction after probucol. Changes in HDL subfractions and increased reverse cholesteryl ester transfer.

Treatment with probucol, a widely used lipid-lowering agent, is associated with a significant reduction of high density lipoprotein (HDL) cholesterol levels, but with an apparently improved removal of cholesteryl esters from tissues (e.g., from tendon xanthomas). The effects of probucol (500 mg twice daily) on HDL subfraction distribution and cholesteryl ester transfer activity were tested in 12 patients with stable type II hyperlipidemia [low density lipoprotein (LDL) cholesterol greater than 180 mg/dl] after a placebo-controlled cross-over trial. Probucol significantly lowered total cholesterol (-13.8%), LDL cholesterol (-9.1%), and HDL cholesterol (-30%). By rate zonal ultracentrifugation, a marked reduction of HDL2 cholesterol (-68%) was shown, whereas changes in HDL3 were less significant (-21%). These findings were confirmed by polyacrylamide gradient gel electrophoresis, typically showing a reduction or disappearance of HDL2b particles and the prevalence of particles in the HDL3a range. Cholesteryl ester transfer from HDL to lower density lipoproteins was significantly increased (30%) in all patients. These findings suggest that, in addition to the well-documented in vitro changes (prevention of LDL peroxidation and macrophage uptake), probucol characteristically modifies HDL particle distribution in vivo, and is associated with a significant increase of cholesteryl ester transfer activity.

Apolipoproteins↗
PubMedDate not supplied

[Axillary lymphadenectomy].

Axillary lymphadenectomy represents one of the historical hallmarks in the surgical strategy for breast cancer treatment. In recent years the role of axillary dissection is becoming matter for a renewed debate: up to date better therapeutic results together with new biologic acquisitions and progresses in early diagnosis have been influencing current indications and extension of axillary lymphadenectomy; also, cosmetic and financial considerations play a relevant role. This is the background of a large number of studies investigating the possibility of a more limited applications of axillary dissection provided that oncologic results remain unchanged. In this context sentinel node biopsy is one of the most promising lines of research. It can be stated that, as far as early stages are concerned, a trend towards more conservative resection techniques that started with the first quadrantectomies two decades ago, is now involving axillary dissection too. Possibly, in the next future, an elective axillary lymphadenectomy will not be performed any more if the presence of positive nodes will not be preliminarily ascertained. Nevertheless such conservative strategy can not be recommended to date, until the technique of sentinel node biopsy will be optimized and its results confirmed by randomized trials.

Axilla↗