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Biomedical subjects

G Merlino

Publications and source records attributed to G Merlino.

At least 91 records · Page 5Linked to original sources
PubMed1993

An epidermal growth factor receptor promoter construct selectively expresses in the thymus and spleen of transgenic mice.

To determine the range of tissues in which the human epidermal growth factor (EGF) receptor promoter is active, we created 12 independently derived lines of mice expressing a transgene consisting of human EGF receptor promoter and enhancer sequences fused to the bacterial chloramphenicol acetyltransferase (CAT) gene. Analysis for the presence of CAT activity in these transgenic mice revealed that the human EGF receptor promoter construct was consistently active in the thymus and spleen. Thymocytes separated from thymic stromal cells of EGF receptor-CAT mice demonstrated no CAT activity suggesting that expression in the thymus is confined to the thymic stroma, which consists mainly of epithelial cells. Thus, it should be possible to use the EGF receptor promoter construct described in this study to direct expression of a variety of foreign genes to the nonlymphocytic cells of the thymus and spleen so that the effect of these genes on the maturation and proliferation of thymocytes may be addressed.

Animals↗
PubMed1993

Effects of amlodipine on renal haemodynamics in mild to moderate hypertensive patients. A randomized controlled study versus placebo.

In this study the efficacy and safety of short-term amlodipine administration on renal haemodynamics were evaluated in mild to moderate hypertensive subjects. Our final goal was to evaluate whether the reduced blood pressure induced by treatment was associated with maintenance of renal function. After a run-in period with placebo, 30 hypertensive patients without cardiac or renal diseases were randomly allocated to a double-blind 4 weeks controlled study with amlodipine 10 mg once a day (15 patients) or placebo (15 patients). Renal haemodynamic measurements included effective renal plasma flow (ERPF) and glomerular filtration rate (GFR) by radionuclide study using 131I-hippuran and 99mTc, with methods described by Schlegel and Gates, respectively. In addition, effective renal blood flow [ERBF = ERPF/(1-Ht)], filtration fraction (FF = GFR/ERPF) and renal vascular resistance (RVR = MBP x 80/ERBF) were calculated. Plasma renin activity (PRA), serum aldosterone (ALD) and urinary excretion of sodium (NaU) were evaluated. At the end of amlodipine administration a significant decrease (P < 0.001) in SBP, DBP and MBP from baseline values was observed. A significant decrease (P < 0.01) in RVR and significant increases (P < 0.05) in ERPF, ERBF and in NaU were also found, without relevant changes in GFR, FF, PRA and ALD. No significant variation in clinical and renal measurements was observed in the placebo group. No relevant side effects were observed in either group. In conclusion, amlodipine was effective in lowering blood pressure in mild to moderate hypertension and exerted favourable effects on renal haemodynamics and function.

Adult↗
PubMed1993

Obesity, hypertension and atherosclerosis.

Hypertension and obesity are associated with an increased risk of clinical cardiovascular complications due to atherosclerosis. Moreover has been reported that hypertension may predispose to atheroma development. In the present review some common aspects to hypertension and atherosclerosis including smooth muscle cell proliferation, endothelial damage and intervention of growth factors have been analyzed. Additional data have to be provided to explain if the connections between hypertension and atherosclerosis could be considered two effects with one unknown cause. In addition some aspects related to obesity and atherosclerosis have been dissected. In particular we have reported our results indicating that young obese subjects without risk factors for cardiovascular disease have already several markers of cardiovascular damage i.e. atherogenetic lipid pattern, pro-thrombotic and hypofibrinolitic pattern without sign of coagulation and/or platelet in vivo activation, increased plasma endothelin and catecholamine values, rised fasting and after OGTT insulin levels. In view of this more extensively data have to be necessary to support the opinion that obesity and atherosclerosis could be two associated conditions evolving during the time to develop cardiovascular disease or events.

Adult↗
PubMed1993

Double-blind controlled study of rilmenidine versus hydrochlorothiazide in mild hypertension: clinical and renal haemodynamic evaluation.

Clinical and renal haemodynamic parameters were evaluated in 20 mild hypertensive patients after rilmenidine (RIL) administration during a one month double-blind randomised study compared with hydrochlorothiazide (HCT). At the beginning and at the end of the study, BP, heart rate and renal haemodynamic parameters were evaluated. Renal haemodynamic parameters included effective renal plasma flow (ERPF) evaluated by radionuclide study utilising 131I-Hippuran according to Schlegel's method, effective renal blood flow (ERBF = ERPF/(1-Ht)), glomerular filtration rate (GFR) by creatinine clearance, filtration fraction (FF = GFR/ERPF) and renal vascular resistances (RVR = DBP x 80/ERBF). RIL and HCT significantly (P < 0.01) reduced systolic, diastolic and mean blood pressure without relevant change in ERPF, ERBF, GFR and FF. RVR was significantly reduced both in the RIL group (P < 0.002 vs. baseline) and in the HCT group (P < 0.001 vs. baseline). No relevant side-effects were observed in either group. In conclusion, rilmenidine was effective in reducing BP in mild hypertensive patients and produced favourable effects on renal function.

Adult↗
PubMed1992

Development of liver tumors in transforming growth factor alpha transgenic mice.

We studied the development of liver tumors in male transforming growth factor alpha (TGF-alpha) transgenic mice of the CD1 strain and examined the expression of the transgene by immunohistochemistry and in situ hybridization. Livers of 4-5-week-old transgenic mice contained areas of centribobular hypertrophy with low glucose-6-phosphatase activity. These areas progressively expanded, and hypertrophy and dysplasia became generalized in livers of mice at 10-12 months of age. The expression of the transgene, determined by either immunohistochemistry or in situ hybridization, was uneven in animals that were 10 weeks old or older. The positive hepatocytes formed patches with a predominant centrilobular distribution. We studied a total of 23 liver tumors (7 hepatocellular carcinomas and 16 adenomas) obtained from 11 mice at 13-15 months of age and from one 7-month-old animal which received zinc sulfate to induce the transgene. The carcinomas were well differentiated tumors, without glucose-6-phosphatase or gamma-glutamyltranspeptidase activity, that developed from the dysplastic parenchyma and occasionally within an adenoma. In all carcinomas and in 56% of the adenomas there was overexpression of the transgene in relationship to the surrounding tissue. The majority of the tumors that overexpressed TGF-alpha were alpha-fetoprotein positive, while alpha-fetoprotein staining was not detected in tumors (all adenomas) that did not show excessive transgene expression. We conclude that TGF-alpha functions as a promoter of liver carcinogenesis through its effect as an autocrine inducer of hepatocyte proliferation. Further, the data indicate that TGF-alpha overexpression may favor tumor progression.

Animals↗
PubMed1992

Molecular and genetic analysis of liver oncogenesis in transforming growth factor alpha transgenic mice.

Overexpression of a transforming growth factor alpha (TGF-alpha) transgene induced the development of liver tumors in 69 of 93 (74%) adult male mice. To identify factors associated with oncogenesis, liver tumors from transgenic animals were characterized at the molecular level. TGF-alpha RNA transcripts were elevated in 17 of 25 (68%) liver tumors, relative to adjacent nontumorous tissue. Expression of the endogenous c-myc and insulin-like growth factor II genes was enhanced in 7 of 19 (37%) and 12 of 16 (75%) tumors, respectively. In contrast, epidermal growth factor receptor RNA levels were unchanged or reduced in all liver tumors, and mutations were not detected in either the Ha-ras or Ki-ras genes. The occurrence of liver tumors in castrated TGF-alpha transgenic mice was reduced about 7-fold, while in ovariectomized transgenic animals the incidence was increased about 6-fold. The progeny of a cross between CD1-derived TGF-alpha transgenic (MT42) and C57BL/6 mice exhibited no reduction in tumor burden (83%); however, the incidence of tumor formation in MT42 x FVB/N offspring was substantially lower (19%). We conclude that in these transgenic mice TGF-alpha promotes tumor formation and appears to play a major role in tumor progression. Moreover, other factors that may collaborate in TGF-alpha-induced hepatocarcinogenesis include c-myc, insulin-like growth factor II, sex hormones, and the genetic background upon which the transgene operates.

Animals↗
PubMed1992

Cytological changes in the pancreas of transgenic mice overexpressing transforming growth factor alpha.

Transgenic mice overexpressing human transforming growth factor alpha (TGF-alpha) predictably develop an enlarged, firm pancreas. The present study investigated the changes that occur in the different components of the pancreas in these animals. The increase in size of the pancreas may be accounted for by increased connective tissue. The added collagen is mainly type I. Thin, elongate fibroblasts are frequently bordered by a basal lamina, a relationship that is normally restricted to the perineurium. Collagen is intimately associated with epithelial cells. Fingers of connective tissue extend close to acinar lumina. Redifferentiation of acinar cells produces tubular complexes. In some cases, acinar cells take on the appearance of ductular cells. In some, there is a transition to mucin-producing cells. Intermediate forms between acinar and mucin-producing cells are present. The growth factor is localized in acinar cells and decreases with redifferentiation. The pancreas of these animals routinely displays characteristics that also are observed in diseases of the exocrine pancreas in humans, including fibrosis and redifferentiation. It is likely that the changes are the result of both direct and indirect effects of TGF-alpha, some of which may parallel altered control mechanisms in human pancreatic disease. Study of this model may provide clues to understanding the initiation of fibrosis and redifferentiation in human pancreas.

Animals↗
PubMed1992

Left ventricular function response to exercise in normotensive obese subjects: influence of degree and duration of obesity.

This study has been designed to evaluate whether duration and severity of obesity can influence left ventricular function response to exercise in obese subjects without other known cardiovascular risk factors such as hypertension, diabetes or hyperlipoproteinemia. A total of 29 obese subjects were included and they were divided, according to their body mass index and to Garrow's criteria as follows: Overweight or mildly obese subjects: body mass index from 25 to 30 kg/m2; moderately obese subjects: body mass index > 30 and < 40 kg/m2. Both obese groups were further subdivided according to their duration of obesity evaluated by accurate anamnesis in subgroup A (duration of obesity less than 120 months) and subgroup B (duration of obesity more than 120 months). Left ventricular ejection fraction was detected by blood pool gated radionuclide angiocardiography both at rest and after symptom-limited bicycle ergometer procedure. At peak exercise left ventricular ejection fraction increased significantly (p < 0.05) only in overweight subjects. Exercise produced an increase of left ventricular ejection fraction in 14 overweight and in 5 moderately obese subjects and a decrease in 2 moderately obese subjects. At peak exercise mean heart rate and mean blood pressure increased significantly (p < 0.001) in both groups. When obese subjects were subgrouped according to duration of obesity, left ventricular ejection fraction increased significantly (p < 0.05) only in overweight subjects with duration of obesity less than 120 months. Duration of obesity correlated inversely with percent change in left ventricular ejection fraction (EF) at peak exercise (delta EF) (r = -0.59; p < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

Left ventricular diastolic and systolic function in normotensive obese subjects: influence of degree and duration of obesity.

The present study was carried out to evaluate systolic and diastolic parameters in overweight and moderately obese, but otherwise healthy subjects, and in a lean control group, to determine whether degree and duration of obesity can influence left ventricular function. A total of 27 subjects, 17 overweight or with moderate obesity and 10 lean, healthy subjects were included. Patients were divided into three groups according to their body mass index (BMI) and to Garrow's criteria as follows: lean control group (BMI less than 25 kg.m-2); overweight subjects (BMI from 25 to 30 kg.m-2); moderately obese subjects (BMI greater than 30 less than 40 kg.m-2). Systolic and diastolic parameters were measured using blood pool gated radionuclide angiography. Left ventricular (LV) ejection fraction (EF), peak ejection rate (PER), time to PER (tPER), peak filling rate (PFR) and time to PFR (tPFR) were evaluated. PER and PFR values were normalized for end-diastolic volume (EDV). EF and PFR were significantly lower (P less than 0.05) both in moderately obese and in overweight subjects and tPFR was significantly (P less than 0.05) prolonged in both groups in comparison to lean controls. Only in moderately obese subjects was PER significantly (P less than 0.05) decreased and tPER significantly (P less than 0.05) prolonged in comparison to lean controls. As compared to overweight individuals, moderately obese subjects were characterized by a significant decrease (P less than 0.05) in LVEF and PER and by a significant increase (P less than 0.05) in tPER, without relevant change in PFR and in tPFR.(ABSTRACT TRUNCATED AT 250 WORDS)

Blood Pressure↗
PubMed1992

Expression of an activated Notch-related int-3 transgene interferes with cell differentiation and induces neoplastic transformation in mammary and salivary glands.

Expression of the int-3 locus is activated in mouse mammary tumors as a consequence of insertional mutagenesis by the mouse mammary tumor virus (MMTV). Integration of the MMTV provirus into the int-3 locus promotes the transcription and translation of flanking cellular int-3 sequences sharing significant homology with the intracellular domain of the neurogenic Notch gene of Drosophila, and with the yeast cell cycle regulatory genes cdc10 and SWI6. To determine the in vivo consequences of activated int-3 expression, transgenic mice were generated harboring a genomic tumor DNA fragment consisting of the MMTV LTR and the flanking cellular int-3 sequences. All six int-3 founder transgenic mice and the progeny of one established line exhibited similar dramatic phenotypic abnormalities in tissues in which the transgene was expressed. Focal and often multiple poorly differentiated mammary and salivary adenocarcinomas appeared in the majority of transgenic mice between 2 and 7 months of age. Significantly, mammary glands were arrested in development and were lactation deficient in all female int-3 mice. The salivary glands, glands of the nasal mucosa and maxillary sinus, the extraorbital lacrimal glands, and the Harderian glands of juvenile and adult transgenic mice all contained proliferating immature ductule cells and were incompletely differentiated. In addition, all male int-3 transgenic mice were sterile, apparently the result of severe hyperplasia of the epididymis. These findings demonstrate in vivo that expression of the activated Notch-related int-3 gene causes deregulation of normal developmental controls and hyperproliferation of glandular epithelia.

Adenocarcinoma↗
PubMed1992

Hypertrophic gastropathy resembling Ménétrier's disease in transgenic mice overexpressing transforming growth factor alpha in the stomach.

Transforming growth factor alpha (TGF alpha) is thought to participate in the normal and pathologic processes of numerous tissues, including the gastric mucosa. To explore its role in vivo, transgenic mice were generated overexpressing TGF alpha in the stomach. TGF alpha induced dramatic structural and functional lesions of the glandular stomach that were similar to Ménétrier's disease in humans. Transgenic mice developed severe adenomatous hyperplasia that resulted in a striking nodular thickening or hypertrophy of the gastric mucosa. Secretions obtained from affected stomachs contained no detectable gastric acid, suggesting that parietal cell function had been greatly impaired. These findings demonstrate that overproduction of TGF alpha can stimulate cellular proliferation, suppress acid secretion, and perturb organogenesis of the stomach of transgenic mice. Moreover, TGF alpha may contribute to the pathogenesis of related human hypertrophic gastropathies, such as Ménétrier's disease.

Animals↗
PubMed1991

Effect of obesity on left ventricular function studied by radionuclide angiocardiography.

Several studies have shown a significant association of obesity with cardiovascular morbidity and mortality. The present study was carried out to investigate central and systemic haemodynamics in overweight and moderate obese, but otherwise healthy subjects, and in a lean control group to determine whether obesity can influence left ventricular performance per se. In this study an attempt has been made to eliminate misleading factors, such as diabetes, lipid abnormalities and hypertension. A total of 67 subjects, 44 with overweight or moderate obesity and 23 lean healthy subjects, were included. Patients were divided into three groups according to BMI levels and Garrow's criteria as follows: lean control group (BMI less than 25 kg/m2); overweight (BMI from 25 to 30 kg/m2); moderate obese (BMI greater than 30 less than 40 kg/m2). Overweight and moderate obese subjects were further subgrouped according to duration of obesity (DO) in subgroup A (DO less than 98 months) and in subgroup B (DO greater than 98 months). Haemodynamic assessment was performed using first pass radionuclide angiocardiography. When compared with lean subjects, overweight and moderate obese subjects were characterized by a significant increase in cardiac output (CO), stroke volume (SV), end diastolic volume (EDV), end systolic volume (ESV), total blood volume (TBV) and total plasma volume (TPV) and by a significant decrease in left ventricular ejection fraction (EF); some of these changes appeared to be related to the degree of obesity. In overweight and moderate obese subjects, total peripheral resistance (TPR) was lower than in lean controls, but this difference was not significant.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1986

Reduction of EGF receptor synthesis by antisense RNA vectors.

An association has been observed between squamous cell carcinomas and elevated EGF receptor levels. The approach taken here to analyze this problem was to construct vectors which express antisense RNA for the EGF receptor. The plasmid vector used was derived from pSV2-neo, which is readily selectable. Three EGF receptor cDNA fragments, a 5'-, a middle and a 3'-region were tested for differences in efficiency as antisense RNA. The results suggest that the 5'-fragment was the most efficient.

Carcinoma, Squamous Cell↗
PubMed1985

Histogenesis of anaplastic carcinomas of the thyroid, giant cell variety: immunocytochemical investigation.

The histogenetic and differentiation characteristics of 14 cases of anaplastic carcinoma of the thyroid, giant cell variety were investigated on the basis of immunocytochemical reactivity with 5 cell markers: thyroglobulin, lactoferrin, carcinoembryonic antigen, calcitonin and chromogranin. The first 2 markers were found to be present in isolated neoplastic cells. Only 1 case was strongly and specifically positive for C cell markers and therefore interpreted as a medullary variety of anaplastic thyroid carcinoma. The patient is still alive 8 years after thyroidectomy. All the other patients died of a tumor a few months after the operation. It is suggested that while most cases of anaplastic thyroid carcinomas are probably of follicular origin, the medullary variety constitutes a rare subgroup of a separate histogenetic and prognostic significance.

Calcitonin↗
PubMedDate not supplied

General practitioners and mammographic screening uptake: influence of different modalities of general practitioner participation. Working Group.

AIMS AND BACKGROUND: To compare the impact of different modalities of general practitioner (GP) involvement, including the introduction of target payments, on the attendance rate of organized population-based screening programs for breast cancer in Italy. STUDY DESIGN: The study was conducted between 1994 and 1996 in four Italian cities where mammographic screening programs are active: Caltanissetta (CL), Firenze (FI), Modena (MO) and Torino (TO). The impact on attendance rate of different invitation strategies based on active GP involvement was tested in each center. The additional effect of economic incentives was also assessed. The incentives were proportional to the level of compliance attained by each GP and weighted by the size of his eligible patients' list. RESULTS: In the Firenze project, an invitation signed by the GP and the project co-ordinator attained a statistically significant higher participation (difference: 4.2%, chi2 = 7.42, P = 0.006). In Caltanissetta and Torino there was a significant increase of about 7% in the response rate to the postal reminder in the groups contacted by the GPs. No difference was observed in the Modena project between the two groups. CONCLUSIONS: The main contributions of GP involvement can be: "cleaning up" the invitation lists, especially when computerized archives with the mammographic history of the target population are not available; increasing the women's participation by signing the invitation letter, by counseling and active participation in the invitation phase; co-operating in the reminder phase by recalling women non responders at first invitation. The offer of target payment had a certain impact on the screening uptake, but not easily distinguishable from GP signature of the invitation letter; further studies of appropriate design should be planned. Organizational factors, such as availability of a list of non-responders, might be crucial in order to enhance the effect of the GPs' action.

Family Practice↗