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Biomedical subjects

M Franco

Publications and source records attributed to M Franco.

At least 73 records · Page 4Linked to original sources
PubMed2000

alpha(4)beta(7) independent pathway for CD8(+) T cell-mediated intestinal immunity to rotavirus.

Rotavirus (RV), which replicates exclusively in cells of the small intestine, is the most important cause of severe diarrhea in young children worldwide. Using a mouse model, we show that expression of the intestinal homing integrin alpha(4)ss(7) is not essential for CD8(+) T cells to migrate to the intestine or provide immunity to RV. Mice deficient in ss7 expression (ss7(-/-)) and unable to express alpha(4)ss(7) integrin were found to clear RV as quickly as wild-type (wt) animals. Depletion of CD8(+) T cells in ss7(-/-) animals prolonged viral shedding, and transfer of immune ss7(-/-) CD8(+) T cells into chronically infected Rag-2-deficient mice resolved RV infection as efficiently as wt CD8(+) T cells. Paradoxically, alpha(4)ss(7)(hi) memory CD8(+) T cells purified from wt mice that had been orally immunized cleared RV more efficiently than alpha(4)ss(7)(low) CD8(+) T cells. We explained this apparent contradiction by demonstrating that expression of alpha(4)ss(7) on effector CD8(+) T cells depends upon the site of initial antigen exposure: oral immunization generates RV-specific CD8(+) T cells primarily of an alpha(4)ss(7)(hi) phenotype, but subcutaneous immunization yields both alpha(4)ss(7)(hi) and alpha(4)ss(7)(low) immune CD8(+) T cells with anti-RV effector capabilities. Thus, alpha(4)ss(7) facilitates normal intestinal immune trafficking to the gut, but it is not required for effective CD8(+) T cell immunity.

Adoptive Transfer↗
PubMed2000

[Heart failure caused by severe systolic ventricular dysfunction of hypertensive origin. Long-term clinical and functional course].

AIMS: The aims of our study were to evaluate survival and evolution of functional class and ventricular function in patients with severe congestive heart failure due to dilated cardiomyopathy. METHODS: Inclusion criteria were: class III or IV heart failure, dilated left ventricle with ejection fraction < 40%, history of poor controlled hypertension, and exclusion of other etiologies for heart failure. We studied 17 patients with these features; mean age was 64 +/- 7 years and 70% were male. They were followed up during a mean period of 3.3 +/- 1 years (2 to 6; median 3 years). RESULTS: Baseline left ventricular ejection fraction was 30 +/- 5% (20 to 40); 35% of patients were in functional class III and 65% in class IV; 100% of patients received ACE inhibitors and diuretics, 53% betablockers, and 35% calcium-antagonists. Survival was 100%. Left ventricular ejection fraction increased from 30 +/- 5% to 44 +/- 11% at one year, to 50 +/- 11% at 3 years and 51 +/- 10% at the end of follow-up (p < 0.001). This improvement was mainly due to a reduction in systolic left ventricular diameter (from 51 +/- 4 mm to 42 +/- 11 mm, p < 0.01), since diastolic diameter did not significantly changed (63 +/- 4 to 59 +/- 11 mm). CONCLUSIONS: The evolution of severe systolic left ventricular dysfunction due to arterial hypertension is favourable at long-term, with null mortality and clinical ejection fraction and functional improvement. Nevertheless, the persistence of left ventricular dilatation suggests that myocardial damage caused by chronic pressure overload does not disappear.

Aged↗
PubMed2000

[Aortic valve replacement with pulmonary autograft (the Ross procedure) in adult and pediatric patients].

Aortic valve replacement with pulmonary autograft was first performed by Donald Ross in 1967. Initially, the procedure was not widely accepted, by Cardiologists and Cardiac surgeons fundamentally due to its complexity and demanding surgical technique, and because innumerous series two cardiac valves were at risk. The results published in the last 10-15 years established the pulmonary autograft as one of the best methods of aortic valve replacement, especially in pediatric patients and young adults. In the present article, we reviewed present indications and contraindications, and our clinical experience with 26 patients (pediatrics and adults). Analysis of the first 22 the patients with a minimum of 6 months of follow-up (180-620 days) was performed. Follow-up is complete (100%). Mean age was 31.4 +/- 12.6 years. Five patients were pediatrics (<= 14 years). Three patients (11%) with previous percutaneous procedures and 4 patients (14%) with previous surgical procedures. There was no early or late mortality. In the last follow-up, 19 of 22 (86.36%) had no autograft insufficiency (>= grade 1), and in one patient it was moderate (grade 2). The 2 remaining patients developed severe autograft insufficiency (grade 4) and were reoperated on, with satisfactory postoperative outcome. Mean maximal gradient was 7.85 +/- 5 mmHg at 18 months (3-29). Patients with preoperative aortic stenosis showed a significant reduction in myocardial mass index (208.7 +/- 32 a 95.8 +/- 28.8 g/m2) at 18 months. In these patients, septal and posterior wall thickness decreased significantly, in the first month. Two pediatric patients have developed transpulmonar gradient > 50 mmHg. One of them underwent successful stent implantation. We have not observed significant homograft insufficiency in any of our patients. All our patients remain asymptomatic (functional class I) without medical treatment. We have not observed either thromboembolic or haemorrhagic episodes, nor endocarditis. No patient is receiving anticoagulants. Clinical and echocardiographic mid term results in pulmonary autograft and homograft in our series, are excellent after the Ross procedure.

Adult↗
PubMed2000

Clues to the presence of pathogenic fungi in certain environments.

The presence of various pathogenic fungi in rather unsuspected hosts and environments has always attracted the attention of the scientific community. Reports on the putative role of animals in fungal infections of humans bear important consequences on public health as well as on the understanding of fungal ecology. Fungi are ubiquitous in nature and their great capacity for adaptation allows them to survive and indeed, to thrive, in plants, trees and other natural substrata. Nonetheless, we are just beginning to learn the significance that these diverse fungal habitats have on the increasing number of immunosuppressed individuals. The accidental or permanent presence of fungi in animals, plants, soils and watercourses should not be taken too lightly because they constitute the source where potential pathogens will be contracted. If those fungal habitats that carry the largest risks of exposure could be defined, if seasonal variations in the production of infectious propagules could be determined, and if their mode of transmission were to be assessed, it would be possible to develop protective measures in order to avoid human infection. Additionally, unsuspected avenues for the exploration of fungal survival strategies would be opened, thus enhancing our capacity to react properly to their advancing limits. This paper explores several ecological connections between human pathogenic fungi and certain animals, trees, waterways and degraded organic materials. The occurrence of such connections in highly endemic areas will hopefully furnish more precise clues to fungal habitats and allow the design of control programs aimed at avoiding human infection.

Animals↗
PubMed1999

Novel 2-phenylimidazo[1,2-a]pyridine derivatives as potent and selective ligands for peripheral benzodiazepine receptors: synthesis, binding affinity, and in vivo studies.

The substituent effects at positions 6 and 8 (compounds 17-31) as well as at the amide nitrogen (compounds 32-40) of a series of 2-phenylimidazo[1,2-a]pyridineacetamides were evaluated at both central (CBR) and peripheral (PBR) benzodiazepine receptors. The structure-activity relationship studies detailed herein indicate the key structural features required for high affinity and selectivity for PBR. Substitution on the imidazopyridine nucleus at position 8 with lipophilic substituents and the presence of one chlorine atom at the para position of the phenyl ring at C(2) are crucial features for high binding affinity and selectivity toward PBR. A small subset of active ligands (i.e., 17, 20, 26, 34, and 35) were evaluated in vitro in Xenopus oocytes expressing cloned human GABA(A) receptors for their effects at CBR and in vivo for their ability to stimulate the synthesis of neurosteroids such as pregnenolone, progesterone, allopregnanolone, and allotetrahydrodeoxycorticosterone (THDOC). Compounds 17, 20, 26, and 34 markedly increased the levels of neuroactive steroids in plasma and cerebral cortex, unlike compound 35.

Animals↗
PubMed1999

Effect of simvastatin treatment on the electronegative low-density lipoprotein present in patients with heterozygous familial hypercholesterolemia.

Most described modifications of low-density lipoprotein (LDL) cholesterol share an increase in its negative electric charge; in fact, an electronegative form of LDL can be identified and isolated from plasma. Although the exact nature of the chemical modification of electronegative LDL is still controversial, its toxicity on endothelial cells has been demonstrated. Statins have protective effects against cardiovascular disease that are independent of their lipid-lowering action and which could be due, at least in part, to the prevention of LDL modification. We evaluated the effect of 6 months of simvastatin therapy (40 mg/day) on electronegative LDL proportion and LDL susceptibility to in vitro induced oxidation in 21 patients with heterozygous familial hypercholesterolemia (FH). Eleven normolipemic subjects were analyzed as a control group. Total cholesterol as well as LDL and very low density lipoprotein cholesterol, triglycerides, and apoprotein B decreased 30% after the first month of therapy, with no further decreases thereafter. LDL susceptibility to oxidation was similar in FH patients and controls and did not change throughout the treatment. Electronegative LDL proportion was 35.1 +/- 9.9% in FH patients and 9.1 +/- 2.4% in control subjects (p <0.0001) but, in contrast to total LDL cholesterol and the rest of lipid parameters, it decreased to 28.6 +/- 9.1% in the third month and to 21.2 +/- 7.7% in the sixth month of therapy. The decrease in these cytotoxic particles may be a relevant mechanism by which simvastatin protects against cardiovascular disease.

Adult↗
PubMed1999

Physicochemical characterization and in vivo properties of Zolpidem in solid dispersions with polyethylene glycol 4000 and 6000.

Solid dispersions and physical mixtures of Zolpidem in polyethylene glycol 4000 (PEG 4000) and 6000 (PEG 6000) were prepared with the aim to increase its aqueous solubility. These PEG based formulations of the drug were characterized in solid state by FT-IR spectroscopy, X-ray powder diffraction, and differential scanning calorimetry. By these physical determinations no drug-polymer interactions were evidenced. Both solubility and dissolution rate of the drug in these formulations were increased. Each individual dissolution profile of PEG based formulation fitted Baker-Lonsdale and first order kinetic models. Finally, significant differences in ataxic induction time were observed between Zolpidem orally administered as suspension of drug alone and as solid dispersion or physical mixture. These formulations, indeed, showed almost two- to three-fold longer ataxic induction times suggesting that, in the presence of PEG, the intestinal membrane permeability is probably the rate-limiting factor of the absorption process.

Animals↗
PubMed1999

Reactivation and persistence of human herpesvirus-8 infection in B cells and monocytes by Th-1 cytokines increased in Kaposi's sarcoma.

Patients with Kaposi's sarcoma (KS) have a human herpesvirus-8 (HHV-8) load higher than patients without KS and present a CD8(+) T-cell activation with production of Th1-type cytokines both in tissues and peripheral blood mononuclear cells (PBMC). Because in tissues of KS patients detection of inflammatory cytokines (IC) can precede detection of HHV-8 DNA and because signs of immunoactivation and/or dysregulation can precede KS development, we investigated the effect of IC on HHV-8 infection. To achieve this goal, PBMC and purified cell populations from 45 patients with KS and 45 patients at risk of KS were analyzed for HHV-8 DNA and/or gene expression and for cell survival, growth, and phenotype before or after culture with or without the IC increased in KS. The results indicate that PBMC that are polymerase chain reaction (PCR)-positive at day 0 generally loose the virus upon culture. However, the presence of IC maintains HHV-8 DNA load in cultured cells. In addition, IC increase viral load to detectable levels in PBMC from serologically positive patients that were PCR-negative before culture. gamma Interferon is sufficient for these effects, whereas tumor necrosis factor and interleukin-6 have little or no activity. The increase of HHV-8 DNA by IC is observed after short-term (7 days) or long-term (28 days) culture of the cells and occurs in one or both of the two circulating cell types that are infected in vivo: B cells and monocytes. In both cases it is associated with lytic gene expression, suggesting that virus reactivation is one of the most likely mechanisms for the effect of IC on virus load. However, IC have also effects on the cells target of HHV-8 infection, because they increase B-cell survival and induce the growth and differentiation of monocytes into KS-like spindle cells with markers of endothelial macrophages. Because cells with markers of endothelial macrophages are present in blood and lesions from KS patients and are infected by HHV-8, these data may explain the high HHV-8 load associated with KS development and suggest that infected monocytes may carry the virus to tissues, transmit the infection, or differentiate in loco in spindle cells with endothelial macrophage markers.

Acquired Immunodeficiency Syndrome↗
PubMed1999

EFA6, a sec7 domain-containing exchange factor for ARF6, coordinates membrane recycling and actin cytoskeleton organization.

We have identified a human cDNA encoding a novel protein, exchange factor for ARF6 (EFA6), which contains Sec7 and pleckstrin homology domains. EFA6 promotes efficient guanine nucleotide exchange on ARF6 and is distinct from the ARNO family of ARF1 exchange factors. The protein localizes to a dense matrix on the cytoplasmic face of plasma membrane invaginations, induced on its expression. We show that EFA6 regulates endosomal membrane recycling and promotes the redistribution of transferrin receptors to the cell surface. Furthermore, expression of EFA6 induces actin-based membrane ruffles that are inhibited by co-expression of dominant-inhibitory mutant forms of ARF6 or Rac1. Our results demonstrate that by catalyzing nucleotide exchange on ARF6 at the plasma membrane and by regulating Rac1 activation, EFA6 coordinates endocytosis with cytoskeletal rearrangements.

ADP-Ribosylation Factor 1↗
PubMed1999

[Aortic valve replacement with a pulmonary autograft (the Ross operation) in adult and pediatric patients. A preliminary study].

INTRODUCTION AND OBJECTIVES: Aortic valve replacement with the patients own pulmonary autograft (the Ross procedure) is by now, the best surgical method for the replacement of the diseased aortic valve in certain groups of patients, this is particularly true for young adults and children or neonates with complex left ventricular outflow tract obstructions. The procedure was described by Donald Ross in 1967, and many years have passed. So in view of the accumulated experience the indications have extended to a wide group of patients which include children, neonates and young adults with formal contraindications for anticoagulation. In this publication we present our experience and our preliminary results in a group of fifteen patients which include adult and pediatric. MATERIAL AND METHODS: In six patients the etiology of lesion was congenital and in the remainder nine the valve had an acquired lesion. Two patients had an open heart procedure before this operation both of them to relieve an obstruction to the left ventricular outflow tract. In this group of patients the Ross procedure was carried out inserting the pulmonary autograft in the aortic position as a total root which was always reconstructed with cryopreserved pulmonary homograft, the mean homograft diameter was 26.1 +/- 4 mm (19-35). RESULTS: In all patients a transesophageal echocardiogram was performed in the operating room and postoperative, 1 or 2 months later. Only in one patient a mild aortic regurgitation was detected, no significant transaortic or transpulmonary gradients were detected postoperative. One patient was reoperated for bleeding in the postoperative course, there was no hospital mortality in our group and all the patients had an uneventful postoperative period. In the short term follow-up (41-155 days). All the patients are free of anticoagulant therapy, all them are in New York Heart Association Functional Class I. CONCLUSIONS: The patients presented in this publication which include adult and pediatric, are the first group of patients operated in our country with some excellent preliminary results. We hope that this procedure will become popular and that other surgical groups will adopt it as another surgical tool to replace a diseased aortic valve.

Adolescent↗
PubMed1999

2-Phenyl-imidazo[1,2-a]pyridine derivatives as ligands for peripheral benzodiazepine receptors: stimulation of neurosteroid synthesis and anticonflict action in rats.

Selective activation of peripheral benzodiazepine receptors (PBRs) in adrenal cells and brain oligodendrocytes promotes steroidogenesis. Three 2-phenyl-imidazo[1,2-a]pyridine derivatives (CB 34, CB 50 and CB 54) have now been investigated with regard to their selectivity for PBRs and their ability to stimulate central and peripheral steroidogenesis in rats. The three CB compounds (10(-10)-10(-4) M) potently inhibited the binding of the PBR ligand [3H]-PK 11195 to brain and ovary membranes in vitro, without substantially affecting [3H]-flunitrazepam binding to central benzodiazepine receptors. These compounds (10(-7)-10(-4) M) also had little or no marked effects on GABA-evoked Cl- currents in voltage-clamped Xenopus oocytes expressing human alpha1beta2gamma2S GABA(A) receptors. In addition, they failed to affect ligands binding to GABA(B), D1/D2 dopamine, muscarinic acetylcholine, N-methyl-D-aspartic acid and opiate receptors. Intraperitoneal administration of CB compounds (3-50 mg kg(-1)) induced a dose-dependent increase in the concentrations of neuroactive steroids in plasma and brain. The brain concentrations of pregnenolone, progesterone, allopregnanolone and allotetrahydrodeoxycorticosterone (THDOC) showed maximal increases in 96+/-3, 126+/-14, 110+/-12 and 70+/-13% above control, respectively, 30 to 60 min after injection of CB 34 (25 mg kg(-1)). CB 34 also increased the brain concentrations of neuroactive steroids in adrenalectomized-orchiectomized rats, although to a lesser extent than in sham-operated animals, suggesting that CB compounds stimulate brain steroidogenesis independently of their effects on peripheral tissues. The increase in brain and plasma neurosteroid content induced by CB 34 was associated with a marked anticonflict effect in the Vogel test. Our results indicate that the three CB compounds tested are specific and potent agonists at peripheral benzodiazepine receptors, and that they stimulate steroidogenesis in both the brain and periphery.

Adrenalectomy↗
PubMed1999

Nephrotic syndrome as a clinical manifestation of graft-versus-host disease (GVHD) in a marrow transplant recipient after cyclosporine withdrawal.

GVHD is one of the most frequent complications of BMT and recently nephrotic syndrome (NS) has been described as a manifestation of chronic GVHD. Here, we present an AA patient who developed NS 1 year after BMT when cyclosporine was stopped. Renal biopsy showed focal sclerosis associated with membranous deposits. He also had other clinical manifestations of chronic GVHD: sicca-like syndrome and colestasis. After 15 days of CsA therapy, he experienced a remarkable improvement in the NS and GVHD as a whole. We comment on immunological mechanisms that could be involved in the pathogenesis of this manifestation.

Adult↗
PubMed1999

The effect of non-antihypertensive doses of angiotensin converting enzyme inhibitor on myocardial necrosis and hypertrophy in young rats with renovascular hypertension.

In renovascular hypertensive rats, low doses of angiotensin converting enzyme (ACE) inhibitors have been found to prevent myocardial hypertrophy independent of blood pressure level. This finding would suggest humoral rather than mechanical control of myocyte growth. The aim of this study was to examine the effect of nonantihypertensive doses of ACE inhibitor on myocardial hypertrophy and necrosis in hypertensive rats. Renovascular hypertension (RHT) was induced in four-week-old Wistar rats. Twenty-eight animals were treated for four weeks with three doses of ramipril (0.01, 0.1 or 1. 0 mg/kg/day, which are unable to lower blood pressure. Fourteen animals were not treated (RHT group). A sham operated, age/sex-matched group was used as control (n = 10). Myocardial histology was analysed in 3 microm thick sections of the ventricle stained with either haematoxylin-eosin, reticulin silver stain or Masson's trichrome. There was a significant correlation between systolic blood pressure and left ventricular to body weight ratio in both sets of animals: untreated plus controls and ramipril-treated rats. ACE inhibition prevented myocyte and perivascular necrosis and fibrosis in a dose-dependent manner. We conclude that myocardial hypertrophy in rats with renovascular hypertension is directly related to arterial pressure, and that this relationship is not affected by nonantihypertensive doses of ACE inhibitor. Myocardial necrosis/fibrosis and coronary artery damage induced by angiotensin II are prevented by ACE inhibitor in a dose-dependent manner, despite the presence of arterial hypertension.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1999

Alpha interferon inhibits human herpesvirus 8 (HHV-8) reactivation in primary effusion lymphoma cells and reduces HHV-8 load in cultured peripheral blood mononuclear cells.

Infection by human herpesvirus 8 (HHV-8) is associated with the development of Kaposi's sarcoma (KS). Since regression of KS can be achieved by treatment of the patients with alpha interferon (IFN-alpha), we analyzed the effects of IFN-alpha or anti-IFN-alpha antibodies (Ab) on HHV-8 latently infected primary effusion lymphoma-derived cell lines (BCBL-1 and BC-1) and on peripheral blood mononuclear cells (PBMC) from patients with all forms of KS and from at-risk subjects. IFN-alpha inhibited in a dose-dependent manner the amplification of HHV-8 DNA in BCBL-1 cells induced to lytic infection with tetradecanoyl phorbol acetate (TPA). This effect was associated with the inhibition of the expression of HHV-8 nut-1 and kaposin genes that are induced early and several hours, respectively, after TPA treatment. In addition, IFN-alpha inhibited virus production and/or release from BCBL-1 cells. Inhibition of nut-1 and kaposin genes by IFN-alpha was also observed in BC-1 cells induced with n-butyrate. Conversely, the addition of anti-IFN-alpha Ab to TPA-induced BCBL-1 cells resulted in a larger number of mature enveloped particles and in a more extensive cytopathic effect due to the neutralization of the endogenous IFN produced by these cells. IFN was also produced by cultured PBMC from HHV-8-infected individuals, and this was associated with a loss of viral DNA during culture. However, the addition of anti-IFN-alpha Ab or anti-type I IFN receptor Ab promoted the maintenance of HHV-8 DNA in these cells that was associated with the detection of the latency-associated kaposin RNA. Finally, the addition of IFN-alpha reduced the HHV-8 load in PBMC. Thus, IFN-alpha appears to have inhibitory effects on HHV-8 persistent infection of PBMC. These results suggest that, in addition to inhibiting the expression of angiogenic factors that are key to KS development, IFN-alpha may induce KS regression by reducing the HHV-8 load and/or inhibiting virus reactivation.

Genes, Viral↗
PubMed1999

Adenosine regulates renal nitric oxide production in hypothyroid rats.

In the hypothyroid kidney, exogenous adenosine (ADO) produces vasodilation and restores renal function to near-normal values. This study evaluates whether this response is mediated by nitric oxide synthesis stimulated by adenosine. GFR and urinary excretion of NO2-/NO3- (UNO2-/NO3-) were measured in normal (NL) and hypothyroid (HTX) rats under basal conditions and during infusion of: intra-aortic ADO, intravenously, 1,3-dipropyl-8p-sulfophenylxanthine (DPSPX), 8-cyclopentyl-1,3-dipropyl xanthine (DPCPX), N(omega)-nitro-L-arginine methylester (L-NAME) + ADO, L-NAME + PSPX, L-NAME + DPCPX, and intrarenal (IR) ADO or DPCPX + IR ADO. Intra-aortic ADO induced a fall in GFR and increased UNO2-/NO3- slightly in NL rats; in HTX rats, both GFR and UNO2-/NO3- increased significantly. DPSPX and DPCPX increased UNO2-/NO3- excretion in NL animals with minor changes in GFR; the blockers increased both GFR and UNO2-/ NO3- in HTX rats. L-NAME completely blocked the increase in NO2-/NO3- induced by ADO, DPSPX, and DPCPX. The intrarenal infusion of ADO at 1, 10, and 35 nmol/kg per min progressively decreased GFR with a slight increase in UNO2-/ NO3- in NL rats; in the HTX, GFR increased with the highest dose and UNO2-/NO3- progressively increased. DPCPX prevented the fall in GFR induced by intrarenal ADO in NL rats, with no further changes in UNO2-/NO3-; in HTX rats, intrarenal ADO under A1 blockade further increased GFR and UNO2-/NO3-. Arterial and venous ADO concentrations were lower in the HTX rats. In the HTX kidney, NO production was stimulated by ADO, most likely through activation of A2 or A3 receptors, whereas A1 receptors had an inhibitory effect. Thus, ADO receptors are involved in the regulation of kidney function in pathophysiologic conditions.

Adenosine↗