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Biomedical subjects

G Chiesa

Publications and source records attributed to G Chiesa.

At least 19 recordsLinked to original sources
PubMed2006

Effects of chronic treatment with statins and fenofibrate on rat skeletal muscle: a biochemical, histological and electrophysiological study.

BACKGROUND AND PURPOSE: Skeletal muscle injury by hypolipidemic drugs is not fully understood. An extensive analysis of the effect of chronic treatment with fluvastatin (5 mgkg(-1) and 20 mgkg(-1)), atorvastatin (10 mgkg(-1)) and fenofibrate (60 mgkg(-1)) on rat skeletal muscle was undertaken. EXPERIMENTAL APPROACH: Myoglobinemia as sign of muscle damage was measured by enzymatic assay. Histological and immunohistochemical techniques were used to estimate muscle integrity and the presence of aquaporin-4, a protein controlling water homeostasis. Electrophysiological evaluation of muscle Cl(-) conductance (gCl) and mechanical threshold (MT) for contraction, index of intracellular calcium homeostasis, was performed by the two-intracellular microelectrodes technique. KEY RESULTS: Fluvastatin (20 mgkg(-1)) increased myoglobinemia. The lower dose of fluvastatin did not modify myoglobinemia, but reduced urinary electrolytes, suggesting direct effects on renal function. Atorvastatin also increased myoglobinemia, with slight effects on urinary parameters. No treatment caused any histological damage to muscle or modification in the number of fibres expressing aquaporin-4. Either fluvastatin (at both doses) or atorvastatin reduced sarcolemma gCl and changed MT. Both statins produced slight effects on total cholesterol, suggesting that the observed modifications occur independently of HMGCoA-reductase inhibition. Fenofibrate increased myoglobinemia and decreased muscle gCl, whereas it did not change the MT, suggesting a different mechanism of action from the statins. CONCLUSIONS AND IMPLICATIONS: This study identifies muscle gCl and MT as early targets of drugs action that may contribute to milder symptoms of myotoxicity, such as muscle cramps, while the increase of myoglobinemia is a later phenomenon.

Action Potentials↗
PubMed2004

Evaluation of a soft atherosclerotic lesion in the rabbit aorta by an invasive IVUS method versus a non-invasive MRI technology.

The intravascular ultrasound (IVUS) modality has rapidly gained acceptance for the measurement of arterial plaque thickness and for anatomical characterization. In view, however, of the growing interest in the direct assessment of plaque size after therapeutic modalities directly reducing plaque burden, a non-invasive method such as magnetic resonance imaging (MRI) may be of help for repeated evaluations. The two methods were compared directly on a focal plaque developed at the abdominal aortic level by a combination of local electric lesion followed by a hypercholesterolemic diet. The plaque was fully characterized histopathologically at intervals up to 120 days from lesion induction, and maximal plaque formation was detected at 90 days from electrical injury. Plaques could be well assessed by IVUS at each time point analyzed and data correlated very well to histopathologic findings (r = 0.969, P = 0.0014). The MRI technology provided reliable determinations only at 90 days after lesion induction, i.e. at maximal plaque formation, with excellent correspondence to IVUS determinations (r = 0.989, P = 0.0111). Altogether these findings indicate that the non-invasive MRI technology, when applied to the analysis of arterial plaques of adequate size, can be used successfully for plaque determination, with results comparable to the invasive IVUS technique.

Analysis of Variance↗
PubMed2001

Development of a lipid-rich, soft plaque in rabbits, monitored by histology and intravascular ultrasound.

Lipid rich, soft plaques in the clinic are a common forerunner to occlusive thrombus formation, even with modest arterial stenosis. Animal models of atherosclerosis, obtained by various methods, do not generally allow direct in vivo evaluation of the lesion and, furthermore, cannot be examined more than once. The aim of the study was the generation of a rabbit model of atherosclerosis, with morphological characteristics similar to human lipid-rich, soft atheromatous plaques, and the evaluation of the reliability of intravascular ultrasound (IVUS) technology in the study of the development of atherosclerotic lesions in this model. Briefly, New Zealand white rabbits undergo perivascular electrical injury at both common carotid arteries, together with a 1.5% cholesterol diet for up to 90 days. The lesioned arterial segments show progressive changes, from diffuse cellular mortality, to macrophage infiltration in the media, up to the final migration of macrophages to the neointima, resulting in bulky, eccentric, macrophage and lipid-rich lesions. At IVUS, the produced lesions clearly resemble those described as 'soft plaques' in the clinical setting, with minimal calcification and reduced echo-reflectivity versus the adventitial layer. Quantitative and morphometric analysis of plaques shows a significant correlation between histological and IVUS measurements at each time point. In conclusion, vascular injury in the common carotids of rabbits generates atherosclerotic lipid-rich, soft plaques, that can be properly assessed by the IVUS methodology. The easy accessibility of the arterial lesion allows serial IVUS investigations and the direct evaluation of a number of locally or generally delivered therapeutic agents.

Analysis of Variance↗
PubMed2001

Leukotriene D4-induced activation of smooth-muscle cells from human bronchi is partly Ca2+-independent.

Cysteine-containing leukotrienes (cysteinyl-LTs) are potent bronchoconstrictors and play a key role in asthma. We found that histamine and LTD4 markedly constrict strips of human bronchi (HB) with similar efficacy. However, in human airway smooth-muscle (HASM) cells, LTD4, at variance with histamine, elicited only a small, transient change in intracellular calcium ion concentration. HASM cells express both Ca2+-dependent and -independent isoforms of protein kinase C (PKC) (i.e., PKC-alpha and PKC-alpha ). Western blot analysis showed that PKC-alpha is activated by histamine and, to a lesser extent, by LTD4, whereas only LTD4 translocates PKC-alpha. This translocation was specifically inhibited by the LTD4 antagonist pobilukast. Phorbol-dibutyrate ester (PDBu) (a PKC activator) contracted HB strips to the same extent in the presence as in the absence of extra- and intracellular Ca2+. In the absence of Ca2+, LTD4 contracted HB strips to the same extent as did PDBu, suggesting the involvement of a Ca2+-independent PKC in LTD4-mediated signal transduction. PDBu-induced desensitization and the PKC inhibitor H7 abolished the slow and sustained LTD4-triggered contraction of HB strips in the absence of Ca2+, although H7 did not greatly affect the response in the presence of the ion. Thus, in human airways, we identified a novel LTD4 transduction mechanism linked to bronchial smooth-muscle contraction, which is partly independent of Ca2+ and involves the activation of PKC-alpha.

Bronchi↗
PubMed2000

Liposome-delivered angiostatin strongly inhibits tumor growth and metastatization in a transgenic model of spontaneous breast cancer.

The possibility to inhibit tumor growth by interfering with the formation of new vessels, which most neoplasias depend on, has recently raised considerable interest. An angiogenic switch, in which proliferating cells acquire the ability to direct new vessel formation, is thought to be an early step in the natural history of solid tumors. Using a transgenic model of breast cancer, which shows many similarities to its human counterpart, including ability to metastasize, we targeted angiostatin production to an early stage of tumor formation. Liposome-delivered angiostatin considerably delayed primary tumor growth and, more importantly, inhibited the appearance of lung metastases. These findings can be relevant to the design of therapeutic intervention in humans.

Angiostatins↗
PubMed2000

Effect of endogenous and exogenous prostaglandin E(2) on interleukin-1 beta-induced cyclooxygenase-2 expression in human airway smooth-muscle cells.

We studied the effect of endogenous and exogenous prostaglandin E(2) (PGE(2)), a metabolite of arachidonic acid through the cyclooxygenase (COX) pathway, on interleukin (IL)-1 beta-induced COX-2 expression, using primary cultures of human bronchial smooth-muscle cells (HBSMC). Treatment with exogenous PGE(2) resulted in enhanced expression of IL-1 beta-induced COX-2 protein and messenger RNA (mRNA) as compared with the effect of the cytokine per se. Inhibition of PGE(2) production with a nonselective COX inhibitor (flurbiprofen, 10 microM) resulted in a significant reduction in IL-1 beta- induced COX-2 expression, supporting a role of endogenous COX metabolites in the modulation of COX-2 expression. None of the experimental conditions used in the study affected the expression of constitutive cyclooxygenase (COX-1). Treatment with cycloheximide to inhibit translation, and with dexamethasone or actinomycin D to inhibit transcription, linked the effect of PGE(2) to the transcriptional level of COX-2 mRNA rather than to a potential effect on protein and/or mRNA stabilization. PGE(2) increased adenylate cyclase activity in a concentration dependent manner, and forskolin, a direct activator of adenylate cyclase, caused a marked increase in IL-1 beta-dependent COX-2, suggesting the existence of a causal relationship between the two events. The same results were observed with salbutamol, a bronchodilator that acts by increasing cyclic adenosine monophosphate. The effect of PGE(2) on COX-2 expression may contribute to the hypothesized antiinflammatory role of PGE(2) in human airways, providing a self-amplifying loop leading to increased biosynthesis of PGE(2) during an inflammatory event.

Adenylyl Cyclases↗
PubMed1999

Improvement of pulmonary function after lobectomy for non-small cell lung cancer in emphysematous patients.

OBJECTIVE: Pulmonary emphysema is frequently associated with lung cancer and, because of the impaired pulmonary function involved, it may contraindicate surgical treatment. However, improvement of pulmonary function has been observed after surgical resection in patients with advanced emphysema. The aim of this study was to evaluate whether pulmonary emphysema, as assessed by pulmonary function tests and radiological evaluation, can influence postoperative respiratory function after lobectomy for non-small cell lung cancer (NSCLC). METHODS: Respiratory function was evaluated before and after lobectomy for NSCLC. Radiological evaluation of emphysema was performed on chest X-ray and CT scan. Patients that had undergone chemo- or radiotherapy or had segmental or lobar atelectasis were excluded from the study. RESULTS: Thirty-five patients entered the study. A decrease in static lung volumes was observed after surgery. Total lung capacity (TLC) decreased from 6.58+/-0.92 to 5.46+/-0.77 l; functional residual capacity (FRC) from 3.70+/-0.88 to 2.96+/-0.73 1 and residual volume (RV) from 2.93+/-0.78 to 2.2+/-0.53 l. However, in a subgroup of 10 patients (Group 1), dynamic volumes after surgery were unchanged or slightly increased (forced vital capacity (FVC) from 3.23+/-0.65 to 3.3+/-0.68 l; forced expiratory volume in 1 s (FEV1) from 2.14+/-0.51 to 2.25+/-0.54 l), and airway resistances (sRaw) decreased from 15.58+/-5.18 to 11.42+/-5.25 cm H2O/s. Preoperative data showed that these patients had a greater obstruction, with FEV1 changing from 69+/-12.42 to 72.70+/-13.72% of predicted, as compared with a change from 87+/-12.7 to 72.08+/-13.10% in the other group of 25 patients (Group 2). Correlation analysis reached statistical significance between FEV1% variation (deltaFEV1%) and preoperative FEV1 and FVC% (r = -0.49, P = 0.002 and r = -0.5, P = 0.001, respectively) and between delta (FEV1)% and radiological scores for 3-level CT (r = 0.39, P = 0.04) and the sum of chest X-ray, single and 3-level CT scores (r = 0.49, P = 0.01). CONCLUSIONS: Pulmonary function may remain unchanged or even increase after lobectomy in patients with a pronounced emphysematous component of airway obstruction. The identification of preoperative parameters that identify this group of patients could extend the indications for the treatment of lung cancer in patients with pulmonary emphysema.

Aged↗
PubMed1999

Increased cholesterol efflux potential of sera from ApoA-IMilano carriers and transgenic mice.

The ability of HDL to remove cholesterol from peripheral cells and drive it to the liver for excretion is believed to explain most of the strong inverse correlation between plasma HDL cholesterol levels and coronary heart disease. Carriers of the ApoA-IMilano (A-IM) mutant have a severe hypoalphalipoproteinemia but are not at increased risk for premature of coronary heart disease. To explain this apparent paradox, we compared the capacity of serum from A-IM and control subjects to extract cholesterol from Fu5AH cells. Because the A-IM carriers are all heterozygotes for the mutation, we also compared the cholesterol efflux capacity of serum from transgenic mice expressing A-IM or wild-type ApoA-I (A-IWT), in the absence of murine ApoA-I. In the whole series of human or mouse sera, cholesterol efflux was significantly correlated with several HDL-related parameters; after adjustment for concomitant variables, the only parameter that remained significantly correlated with cholesterol efflux was the serum ApoA-I concentration (r2=0.85 in humans and 0.84 in mice). The same was true when samples from control subjects, A-IM carriers, A-IWT or A-IM mice were analyzed separately. Cholesterol efflux to sera from the A-IM carriers was only reduced slightly compared with control sera (25.0+/-4.2% versus 30.4+/-3.3%), although there was a large reduction (-45%) in the serum ApoA-I concentration in the former. Cholesterol efflux was also lower to sera from A-IM than A-IWT mice (15.6+/-3.8% versus 30. 1+/-7.1%), but less than expected from the 70% reduction in serum ApoA-I concentration. A relative efflux potential of serum was calculated in each group as the slope of the regression line fitting cholesterol efflux to ApoA-I concentrations. Therefore, the relative efflux potential reflects the relative efficiency of ApoA-I in determining cell cholesterol efflux. The relative efflux potential of mouse and human sera was in the following order: A-IM mice>A-IM carriers>A-IWT mice=control subjects, suggesting a gene-dosage effect of the A-IM mutation on the efficiency of serum to extract cholesterol from cells. The high efficiency of A-IM-containing HDL for cell cholesterol uptake would result in an improved reverse cholesterol transport in the A-IM carriers, possibly explaining the low susceptibility to atherosclerosis development.

Adult↗
PubMed1999

Transgenic mice expressing a human apolipoprotein[a] allele.

The most important determinant of plasma levels of Lp[a] are sequence differences at the highly polymorphic apolipoprotein[a] (apo[a]) locus. To define the sequences that mediate the regulation of apo[a] expression, we cloned a 370 kb DNA fragment that included a 130 kb apo[a] gene, and 40 kb 5'- and 200 kb 3'-flanking region from an individual with high plasma levels of Lp[a] using a YAC vector. This genomic clone was used to generate transgenic mice. In the YAC-apo[a] transgenic mouse, apo[a] was only expressed in the liver, as it is in humans. The mean serum level of apo[a] in 4-week-old YAC-apo[a] transgenic mice was 20 mg/dl. In the female mice the levels of apo[a] varied over a 1.5-fold range during the 4-day estrus cycle and the levels correlated directly with serum progesterone levels. The serum levels of apo[a] decreased to almost undetectable level in male mice after puberty and this decrease was reversed by castration. Ingestion of a high-fat diet resulted in a approximately 100-fold fall in hepatic apo[a] mRNA levels and >60-fold decrease in serum apo[a] levels. To delimit the control elements that mediate tissue-specific and sex hormone-responsive apo[a] transcription, we derived a reporter YAC in which 40 kb of 5' flanking sequences from the cloned apo[a] allele were linked to a luciferase reporter gene. Analysis of four independent transgenic lines revealed no hepatic luciferase expression, suggesting that important cis -acting elements located outside the apo[a] 5'-flanking region are necessary for in vivo expression of apo[a].

Alleles↗
PubMed1998

Elevated triglycerides and low HDL cholesterol in transgenic mice expressing human apolipoprotein A-I(Milano).

In general, plasma concentrations of high density lipoproteins (HDL) are inversely related to the incidence of coronary artery disease. One exception to this trend is individuals with apolipoprotein A-I(Milano) (apo A-IM), a molecular variant of apo A-I, which results in very low plasma apo A-I and HDL-cholesterol levels. Despite these low levels, and other lipoprotein defects, individuals with this mutation have no increased risk for cardiovascular disease. As a first step in proving why apo A-IM carriers appear to be protected from the pro-atherogenic effect of a low HDL, transgenic mice expressing apo A-IM were generated. Mice expressing either wild-type human apo A-I or apo A-IM, together with human apo A-II, were crossed into mice lacking murine apo A-I. Apo A-IM/A-II mice had lower cholesterol and HDL plasma levels compared to apo A-I/A-II mice. Moreover, as in human carriers, apo A-IM mice were characterized by elevated triglyceride plasma levels and by the presence of a population of very small HDL particles. These results indicate that the expression of apo A-IM in a mouse model reproduces the major lipid/lipoprotein abnormalities observed in human carriers. Thus, apo A-IM transgenic mice appear to be a suitable model in which to assess whether the mutation has an anti-atherogenic effect.

Animals↗
PubMed1998

Human apolipoproteins A-I and A-II in cell cholesterol efflux: studies with transgenic mice.

The first step in reverse cholesterol transport is the movement of cholesterol out of cells onto lipoprotein acceptors in the interstitial fluid. The contribution of specific lipoprotein components to this process remains to be established. In this study, the role of human apolipoproteins (apo) A-I and A-II in the efflux of cellular cholesterol was investigated in transgenic mouse models in which the expression of murine apoA-I was abolished due to gene targeting (A-IKO). Serum from A-IKO mice and from mice expressing human apoA-I and/or human apoA-II was incubated with [3H]cholesterol-labeled Fu5AH rat hepatoma cells for 4 hours at 37 degrees C. The cholesterol efflux to the serum of A-IKO mice was markedly lower than that to the serum of mice transgenic for human apoA-I (5.0 +/- 1.5% versus 25.0 +/- 4.0%). Expression of human apoA-II alone did not modify the cholesterol efflux capacity of A-IKO mouse serum. Cholesterol efflux to serum of mice expressing human apoA-II together with human apoA-I was significantly lower than that to human apoA-I mouse serum (20.0 +/- 2.3% versus 25.0 +/- 4.0%). Regression analysis of cholesterol efflux versus the lipid/apolipoprotein concentrations of mouse serum suggested that 3 independent factors contribute to determine the cholesterol efflux potential of serum: the apolipoprotein composition of HDL, the serum concentration of HDL phospholipids, and the presence of a small fraction of particles containing apoA-I.

Animals↗
PubMed1997

A transgenic mouse model for the detection of cellular stress induced by toxic inorganic compounds.

Transgenic mice for genotoxicity testing have been developed, although no such models have been produced for the evaluation of toxic, nongenotoxic chemical compounds. We have developed a transgenic mouse model for the analysis of toxic inorganic compounds. We engineered a mouse lineage with the human growth hormone (hGH) gene under the control of the human hsp70 promoter, in which a plasma-detectable hGH response can be elicited by exposure to heat shock. In primary cell cultures from these mice, hGH release was observed following treatment with several toxic inorganics. Transgenic mice injected intraperitoneally with sodium arsenite, cadmium chloride, copper sulphate, or methylmercurium chloride showed significant hGH levels in plasma.

Animals↗
PubMed1997

Imaging of bronchial carcinoid tumors associated to Cushing syndrome with 111In-Octreoscan scintigraphy and immunoscintigraphy with anti-chromogranin monoclonal antibodies. Report of two cases.

Bronchial carcinoid tumors are neuroendocrine neoplasms capable of expressing somatostatin receptors and of secreting neuromediators such as ACTH and chromogranins. Radiologic appearance is usually non-specific and has to be distinguished from benign pulmonary nodules and other malignant diseases. Standard radiological techniques have limited accuracy in the evaluation of such lesions. Radioisotopic imaging techniques may increase the specificity of diagnostic assessment. The role of immunoscintigraphy with anti-chromogranin A and B monoclonal antibodies (MoAbs) and of 111In-Octreoscan scintigraphy is evaluated in two cases of bronchial carcinoid tumors associated to Cushing syndrome.

Adolescent↗
PubMed1997

High density lipoprotein particle size restriction in apolipoprotein A-I(Milano) transgenic mice.

Human carriers of apolipoprotein A-I(Milano) (Arg173 --> Cys substitution in apolipoprotein A-I) are characterized by an HDL deficiency in which small, dense HDL accumulate in plasma. Because affected individuals are heterozygous for this mutation, the full impact of apolipoprotein A-I(Milano) (apoA-I(Milano)) on HDL-cholesterol metabolism is unknown. In this study, apoA-I(Milano) transgenic mice were used to evaluate the extent of apoA-I(Milano) dimerization and HDL particle size restriction in the absence of wild-type apoA-I. Murine apoA-I knockout mice were utilized to express apoA-I(Milano) and human apoA-II in the presence of wild-type, human apoA-I (apoA-IMilano/A-Iwt/A-II) and in its absence (apoA-IMilano/A-II). Plasma HDL-cholesterol concentrations were similar (30 mg/dl) in both lines of apoA-I(Milano) transgenic mice. In the apoA-IMilano/A-Iwt/A-II phenotype, 14% of the apoA-I(Milano) formed homodimers and 33% formed heterodimers with apoA-II. ApoA-I(Milano) homodimers increased by 71% in the apoA-IMilano/A-II transgenics and was associated with an abundance of small, 7.6-nm HDL3-sized particles compared to the 9.5, 8.3, and 7.6-nm-sized particles in apoA-IMilano/A-Iwt/A-II mice. The unesterified cholesterol/cholesteryl ester mole ratio of HDL was elevated by 45% in apoA-IMilano/A-Iwt/A-II mice and by 90% in apoA-IMilano/A-II transgenics compared to wild-type (human apoA-I/A-II). Both apoA-I(Milano) transgenics possessed normal levels of plasma LCAT activity, but endogenous cholesterol esterification rates were reduced by 50% compared to controls. Thus, HDL particle size restriction was not the result of impaired LCAT activation; rather, dimerization of apoA-I(Milano) limited the esterification of cholesterol on endogenous HDL. In the absence of wild-type apoA-I, the more extensive dimerization of apoA-I(Milano) severely limited cholesteryl ester accumulation on plasma HDL accounting for the abundance of small, 7.6-nm HDL3 particles in apoA-IMilano/A-II mice.

Animals↗
PubMed1995

[Blood preservation in thoracic surgery: feasibility and limitations].

The transfusion of homologous blood carries risks associated with reactions to transfusion and the transmission of diseases. Minimizing surgery-related blood use is therefore of utmost importance. However, the application of blood-saving methods in surgery is restricted by a number of factors. Thoracic surgery poses particular problems in this regard due to the type of diseases treated, patients' general status and the use of neoadjuvant chemotherapy protocols. The aim of this study was to analyse the feasibility of a blood conservation program for thoracic surgery. A detailed analysis of blood-sparing techniques was carried out and the factors influencing blood consumption were evaluated in the preoperative, intraoperative and postoperative periods. Although pre-operative autologus blood donation is an extremely important factor, its effect is limited in thoracic surgery since only a few patients are suitable candidates for such a procedure. Our personal experience confirms the difficulty of applying a blood sparing program to thoracic surgery. Nevertheless the risks associated to transfusions, especially those related to the use of homologous blood, can be reduced by optimizing existing blood sparing techniques or developing new hemostatic agents.

Blood Group Incompatibility↗
PubMed1994

Intrapleural administration of interleukin-2 and LAK cells in locally advanced non-small-cell lung cancer. A case report.

AIMS AND BACKGROUND: The systemic administration of recombinant interleukin-2 (rIL-2) and lymphokine-activated killer (LAK) cells is ineffective in non-small-cell lung cancer (NSCLC). However, there is some evidence that their intrapleural administration could be effective, since it increases the concentrations of the cytokine and the effector cells in the tumor area, thereby obtaining greater antitumor activity. STUDY DESIGN: We report the case of a patient affected by a locally advanced lung adenocarcinoma with pleural effusion (T4 N0 M0-stage IIIb) treated with repetitive courses consisting of a priming continuous i.v. infusion (48 h) of rIL-2 (18 MIU/m2/day) intraplural administration of LAK cells (3-9 x 10(9)/day), in a single daily bolus, for 3 consecutive days and concomitant administration of rIL-2 (1.8-7.2 x 10(6) IU/day), for 5 days. RESULTS: We observed early disappearance of neoplastic cells in the pleural effusion, progressive decrease until disappearance of the pleural effusion, cavitation of the primary lesion during the treatment, and its stabilization for 9 months until progression. Radiologic changes were accompanied by a marked eosinophilia (up to 50 x 10(9)/L), and the intrapleural route of administration of rIL-2 induced a relevant increase in eosinophil count in peripheral blood. Immunologic changes in lymphocyte subpopulation phenotypes were also observed. The performance status of the patient improved, and she was still alive and eupnoic 25 months from the diagnosis and 23 months from the start of treatment. CONCLUSIONS: This case suggests a therapeutic role for intrapleural rIL-2, and we believe that the relationship among intrapleural administration of rIL-2 and LAK cells, the development of peripheral eosinophilia, and clinical response should be further investigated.

Carcinoma, Non-Small-Cell Lung↗