Biomedical subjects

N Ferrari

Publications and source records attributed to N Ferrari.

At least 19 recordsLinked to original sources

PubMed2006

The role of sex in parasite dynamics: model simulations on transmission of Heligmosomoides polygyrus in populations of yellow-necked mice, Apodemus flavicollis.

We investigated possible mechanisms that could cause sex-biased parasite transmission of the helminth Heligmosomoides polygyrus in its rodent host, Apodemus flavicollis, using a modelling approach. Two, not mutually exclusive, hypotheses were examined: that sex-biased parasite transmission is caused by differences in immunity that influence the success of free-living stages and/or is caused by sex differences in host behaviour and the dissemination of infective stages. Model simulations were compared with results from a field manipulation experiment of H. polygyrus in replicated populations of A. flavicollis. Simulations predicted the experimental field results, and both hypotheses explained the pattern observed. Transmission is male-biased if a male immune response increases fertility, hatching or survival of free-living stages. Alternatively, transmission is male-biased if their behavioural characteristics allow them to spread infective larvae in areas more frequently used by females. These results highlight that host sex is not only responsible for differences in parasite susceptibility, but may profoundly influence host-parasite interactions, resulting in a sex bias in parasite transmission.

Animals↗

PubMed2006

Multitargeted approach using antisense oligonucleotides for the treatment of asthma.

Asthma is characterized by inflammation and hyperresponsiveness related to the accumulation of inflammatory cells, particularly eosinophils, within the airways. We tested the hypothesis that a multitargeted approach is better than a single-targeted approach in a rat model of asthma. We simultaneously delivered oligonucleotides (ODNs) targeting the chemokine receptor CCR3 and the common beta chain subunit of the receptors for IL-3, IL-5, and GM-CSF at the time of ovalbumin challenge in sensitized Brown Norway rats. Fewer eosinophils were detected in bronchoalveolar lavage (BAL) of rats treated with both ODNs as compared to each ODN alone. Moreover, airway responsiveness to LTD(4) was significantly decreased at lower doses in the 2 ODN-treated groups compared to a single ODN. As ODN therapy has raised concerns of toxicity we therefore examined ODNs prepared with modified DNA bases, specifically 2'amino, 2'deoxyadenosine (DAP) in place of adenosine. In vivo, administration of individual DAP-ODN was efficacious in inhibiting airway hyperresponsiveness, whereas delivery of 2 DAP-ODNs (targeting CCR3 and common beta chain) reduced the influx not only of eosinophils but also lymphocytes and macrophages in the lungs of rats as compared to the unmodified ODNs. Blocking multiple inflammatory pathways simultaneously is more effective in preventing eosinophilia and airway hyperresponsiveness than inhibiting either pathway alone. The challenges associated with the development of a product containing two oligonucleotides in humans are discussed.

Animals↗

PubMed2005

Grapefruit juice-nifedipine interaction: possible involvement of several mechanisms.

OBJECTIVE: To develop a model based on mean residence time for better understanding the effect of grapefruit juice on the metabolism of nifedipine (NIF). MATERIAL AND METHODS: Sixteen healthy volunteers from an urban population were included. For each trial, the subjects drank water, fresh grapefruit juice or bottled grapefruit juice. Thirty minutes later, the subjects took a 10 mg capsule of NIF, orally. Plasma concentration of NIF was measured and the kinetic parameters were calculated with a non-compartmental model. RESULTS: Grapefruit juice increased the bioavailability of NIF, but did not significantly reduce the drug's metabolism as shown by the approximately constant metabolite to parent drug AUC ratio (P = 0.948). There was no significant increase in the amount of non-metabolized drug absorbed during first-pass: 0.12 and 0.16 (P = 0.470) without and with grapefruit juices respectively. There was an increase in the relative bioavailability (P = 0.039) and the apparent volume of distribution (Vdm) (P = 0.025) of dehydronifedipine with grapefruit co-administration. A second peak was also observed in the NIF plasma-concentration profile when the drug is co-administered with grapefruit juice. Therefore, the most likely explanation for the double peak phenomenon is a delay in gastric emptying (+32 min with grapefruit juice) caused by the pH of grapefruit juice. CONCLUSION: This study shows that grapefruit juice interferes with the metabolism of NIF by inhibiting NIF metabolism and slowing down the rate of gastric emptying. This study also confirms that the metabolic inhibition is not a first pass effect, but is a secondary oxidative step.

Administration, Oral↗

PubMed2004

Real-time myocardial contrast echocardiography for the detection of stress-induced myocardial ischemia. Comparison with 99mTc-sestamibi single photon emission computed tomography.

BACKGROUND: Real-time contrast echocardiography (MCE) is a new promising technique for assessing myocardial perfusion. The purpose of this study was to test whether realtime MCE can be used to detect functionally significant coronary artery stenosis in patients with known or suspected coronary artery disease. Myocardial contrast echocardiographic studies were compared with nearly simultaneous 99mTc-sestamibi single photon emission computed tomography (SPECT) as a clinical standard reference to evaluate regional myocardial perfusion defects. METHODS: Real-time MCE based on continuous infusion of Optison (8-10 ml/h) was performed in 66 patients during standard 99mTc-SPECT dipyridamole (0.56 mg/kg x 4 min) stress testing. Images were obtained in apical 4- and 2-chamber views, each divided into 6 segments. Tracer uptake and myocardial opacification were visually analyzed for each segment by two pairs of blinded observers and graded as normal, mildly reduced, severely reduced, or absent. In 792 myocardial segments, myocardial opacification by MCE was uninterpretable in 143 (18%) segments and tracer uptake by SPECT was not clearly defined in 92 (12%) segments. Interobserver variability for MCE was good with concordance rates of 83% (kappa=0.72) for rest- and 86% (kappa=0.76) for stress images. Overall concordance between MCE and SPECT was good (83%, kappa=0.63) at a segmental level. In the diagnosis of fixed and reversible defects, and of normal perfusion, concordance rates were 73, 65 and 83%, respectively. When analysis was performed at the regional level, we found comparable levels of concordance rates for LAD (83%, kappa=0.59), LCX (86%, kappa=0.64) and RCA (80%, kappa=0.68) perfusion territories. CONCLUSIONS: These findings suggest that realtime MCE is a clinically acceptable method to evaluate myocardial perfusion defects during dipyridamole stress testing.

Albumins↗

PubMed2003

Anti-angiogenesis and angioprevention: mechanisms, problems and perspectives.

The recognition that angiogenesis is a key early event in tumor progression and metastasis has led to the development of new strategies for cancer therapy. The generation of a new blood vessel network under physiological conditions is regulated by the concerted action of activators and inhibitors. Perturbation of this balance, as it occurs in solid tumor growth and metastasis, appears to be a critical point in tumorigenesis. This has led to the "angiogenic switch" hypothesis: the point at which a tumor acquires the potential to induce angiogenesis is a critical step towards malignancy. Based on experimental evidence, prevention of blood vessel development appears to be the mechanism of action of many successful chemopreventive drugs of natural or synthetic origin: a novel concept that we termed "angioprevention". The hypothesis that anti-angiogenesis is at the basis of tumor prevention also suggests that many anti-angiogenic drugs could be used for chemoprevention in higher risk populations or in early intervention. There is a growing body of experimental evidence that anti-angiogenic strategies will contribute to the future therapy of cancer, several compounds with anti-angiogenic properties are now under clinical investigation including anti-inflammatory compounds, as inflammation may play a key role in angiogenesis. We must persevere in the development of novel, powerful and safer angiogenesis inhibitors and in the use of anti-angiogenic drugs in combination with other natural or synthetic anti-cancer agents in a biological therapy strategy.

Angiogenesis Inhibitors↗

PubMed2003

Bone marrow-derived, endothelial progenitor-like cells as angiogenesis-selective gene-targeting vectors.

Human and mouse proliferation-competent, bone marrow or peripheral circulation derived endothelial progenitor-like cells (EPCs) were isolated, expanded and genetically engineered ex vivo to express the beta galactosidase (beta-gal), green fluorescence protein or thymidine kinase (TK) genes using retrovirus-mediated gene transfer. Genetically labeled EPCs were transplanted into sublethally irradiated tumor-bearing mice and were found to migrate to and incorporate into the angiogenic vasculature of growing tumors while maintaining transgene expression. Ganciclovir treatment resulted in significant tumor necrosis in animals previously administered TK-expressing EPCs with no systemic toxicity. These results demonstrate the feasibility of using genetically modified EPCs as angiogenesis-selective gene-targeting vectors and the potential of this approach to mediate non-toxic and systemic antitumor responses.

Animals↗

PubMed2002

Optimizing cerebral perfusion pressure during fiberoptic bronchoscopy in severe head injury: effect of hyperventilation.

The aim of this study was to evaluate if Hyperventilation (HV) could avoid the Intracranial Pressure (ICP) peak that occurs during Fiberoptic Bronchoscopy (FB) in severely head injured patients. A Cerebral Perfusion Pressure (CPP) > 75 mmHg was maintained in 34 patients, with a subgroup randomized to receive controlled HV during FB. Measurements were done before the procedure, during maximum ICP values and 30 minutes after FB. The HV group had minor ICP values after FB, without differences in CPP and ICP peak values.

Adult↗

PubMed2001

Inhibition of angiogenesis-driven Kaposi's sarcoma tumor growth in nude mice by oral N-acetylcysteine.

The thiol N-acetyl-L-cysteine (NAC), an analogue and precursor of reduced glutathione, has cancer chemopreventive properties attributable to its nucleophilicity, antioxidant activity, and a variety of other mechanisms. We demonstrated recently that NAC has anti-invasive, antimetastatic, and antiangiogenic effects in in vitro and in vivo test systems. In the present study, s.c. transplantation of KS-Imm cells in (CD-1)BR nude mice resulted in the local growth of Kaposi's sarcoma, a highly vascularized human tumor. The daily administration of NAC with drinking water, initiated after the tumor mass had become established and detectable, produced a sharp inhibition of tumor growth, with regression of tumors in half of the treated mice along with a markedly prolonged median survival time. The production of vascular endothelial growth factor (VEGF) and certain proliferation markers (proliferating cell nuclear antigen and Ki-67) were significantly lower in Kaposi's sarcomas from NAC-treated mice than from control mice. Treatment of KS-Imm cells with NAC in vitro resulted in a dose-dependent inhibition of chemotaxis and invasion through inhibition of gelatinase-A (matrix metalloproteinase-2, MMP-2) activity without altering MMP-2 or MMP-9 mRNA levels. NAC also significantly inhibited VEGF production but did not affect proliferation markers in vitro. Reverse transcription-PCR analysis indicated that total VEGF mRNAs were reduced by 10 mM NAC. Taken together, these findings provide evidence that NAC, the safety of which even at high doses has been established in almost 40 years of clinical use, in addition to its chemopreventive action, has a strong antiangiogenic potential that could be exploited for preventing cancer progression as well as used in cancer adjuvant therapy.

Acetylcysteine↗

PubMed2001

Therapeutic effects of viral vector-mediated antiangiogenic gene transfer in malignant ascites.

Malignant ascites is a common complication of advanced intraabdominal neoplasms for which standard treatments are suboptimal. Evidence suggests that tumor-mediated angiogenesis and enhanced vascular permeability in the peritoneal wall due to high levels of vascular endothelial growth factor play a fundamental role in the pathogenesis of malignant ascites. To explore the advantage of viral vector-mediated "targeted antiangiogenic therapy" in ascites formation, we constructed and administered adenoviral vectors encoding several different antiangiogenic proteins (angiostatin, endostatin, platelet factor 4, and a fusion protein between angiostatin and endostatin) alone or in combination intraperitoneally in mice with peritoneal carcinomatosis from breast cancer (TA3 cells) and ovarian cancer (SKOV-3 i.p. and ES-2 cell lines) to explore the potential of additive or synergistic activity. Our data demonstrated statistically significant downregulation of ascites formation, tumor growth, vascularity, and prolongation of animal survival after intraperitoneal treatment with antiangiogenic adenoviral vectors in three different ascites tumor models. Combined treatment proved to be more effective than treatment with one vector alone. Reduced ascites formation was accompanied by decreased microvascular density in the peritoneal wall and increased apoptosis of tumor cells after administration of antiangiogenic vectors in vivo. Of interest was the observation that AdPF4 caused a significant decrease in the level of VEGF secreted by tumor cells both in vitro and in TA3 ascites tumor-bearing animals in vivo. These data suggest that adenoviral vector-mediated delivery of genes encoding antiangiogenic proteins may represent a potentially new treatment modality for malignant ascites.

Adenoviridae↗

PubMed2001

Advances in management of neurosurgical trauma in different continents.

Neurotrauma is a major public health problem. The incidence varies from 67 to 317 per 100,000 and mortality rates are in the range of near 1% for minor injury, 18% for mild injury, and 48% for severe head injury. It is the main cause of death and disability in people under 40 years old. Several problems appear when outcome measurements, rehabilitation programs and treatment options are considered. In order to solve these problems a worldwide campaign is outlined. It focuses on epidemiology, prevention, education, treatment, rehabilitation, social re-insertion, and outcome measurements. The goals of such a program are to take into account realities in both developed and developing countries, to develop worldwide acceptable programs and guidelines, and to test those guidelines and programs and diminish mortality and morbidity, improving quality of life. We describe the concept of Centers of Excellence and an educational program, Advanced Brain Life Support. Such a program is a moral obligation because mortality and morbidity tend to decrease in Centers of Excellence.

Brain Injuries↗

PubMed2001

Characterization of new mutations in the coding sequence and 5'-untranslated region of the human prostacylcin synthase gene (CYP8A1).

Inheritable interindividual differences in prostacyclin production may be implicated in the pathogenesis of several human vascular diseases. Using a polymerase chain reaction/single-strand conformation polymorphism strategy, we screened for mutations in the gene encoding cytochrome P450 prostacyclin synthase (CYP8A1). DNA samples from healthy French volunteers (n = 130) of Caucasian origin were examined. Five mutations, comprising two previously reported silent mutations and three novel rare missense mutations (P38L, S118R, and R379S), were identified in the coding sequence of the gene. In the 5'-proximal region, we also found a variable number of tandem repeats (VNTR) polymorphism that consisted of four different alleles with 4-6 tandem repeats of a 9-bp unit containing a putative Spl transcriptional factor binding site. One of these (R6), a frequent allele (23.6% of alleles tested) harboring six repeats, is novel, whereas the other three are known. In vitro analysis of the effect of each VNTR allele on promoter activity of a reporter gene was performed by a transient transfection assay. Data confirmed the modulator effect of the VNTR polymorphism on reporter gene transcription. Furthermore, the data demonstrate that allele R6 has the most potent inducing effects in the A549 cell line and, after IL-6 stimulation, in human pulmonary artery endothelial cells. Overall, the data demonstrate that CYP8A1 is polymorphic in Caucasians, and that a polymorphism affecting the 5'-proximal region may result in interindividual differences in CYP8A1 transcriptional regulation in vivo. Additional factors, such as the presence of inflammatory mediators, may be required to modulate transcription of the CYP8A1 gene.

5' Untranslated Regions↗

PubMed2001

Identification of genetic variants in the human thromboxane synthase gene (CYP5A1).

Thromboxane synthase (CYP5A1) catalyzes the conversion of prostaglandin H2 to thromboxane A2, a potent mediator of platelet aggregation, vasoconstriction and bronchoconstriction. It has been implicated in the patho-physiological process of a variety of diseases, such as atherosclerosis, myocardial infarction, stroke and asthma. On the basis of the hypothesis that variations of the CYP5A1 gene may play an important role in human diseases, we performed a screening for variations in the human CYP5A1 gene sequence. We examined genomic DNA from 200 individuals, for mutations in the promoter region, the protein encoding sequences and the 3'-untranslated region of the CYP5A1. Eleven polymorphisms have been identified in the CYP5A1 gene including eight missense mutations R61H, D161E, N246S, L357V, Q417E, E450K, T451N and R466Q. This is the first report of genetic variants in the human CYP5A1 altering the protein sequence. The effect of these variants on the metabolic activity of CYP5A1 remains to be further evaluated.

Alleles↗

PubMed2001

[Acquired partial lipodystrophy. Insulin resistance, hepatic lipase activity and small and dense LDL particles].

Partial lipodystrophy (PLD) is an infrequent condition characterized by symmetric loss of subcutaneous adipose tissue in the upper or lower part of the body, although occasionally it affects only the extremities. In all cases it appears along with acantosis nigricans (AN), insulin resistance and impairment in the metabolism of lipids and carbohydrates. The case depicted pertains to a 49 year old female with no family history involving loss of adipose tissue in face and upper body. No fat in lower part of body was observed. The patient showed facial thinning at age 8, AN at 11 and gestational diabetes during her fourth pregnancy at 33. At present, the patient presents severe hyperglycemia and hyperinsulinemia with a marked insulin resistance. Type IV hyperlipoproteinemia (OMS), declined C-HDL and Apo A1 and low C-LDL but with a high proportion of small and dense LDL particles were present. Non esterified fatty acids were high. Lipoprotein lipase and hepatic lipase activities are in the lower limit and increased respectively. Fraction C3 of the complement was diminished. No mutations were observed either in codons 170, 809 and 972 of the IRS-1 receptor or in codon 276 of the adrenergic beta 2 gene.

Female↗

PubMed2000

Hyperplasia and impaired involution in the mammary gland of transgenic mice expressing human FGF4.

Fgf4, a member of the fibroblast growth factor family, is frequently amplified in a variety of human cancers, however, its expression in neoplastic tissues is rarely detectable. This makes uncertain its involvement in tumour aetiology, although several in-vitro studies link Fgf4 overexpression to malignant transformation and metastatization of culture cells. We generated a transgenic mouse model in which the whey acidic protein (WAP) promoter directs expression of human Fgf4 to mammary tissues during late pregnancy and throughout lactation, with the purpose of studying the involvement of this growth factor in mammary tumorigenesis. Expression of the transgene was specifically detected in lobular-alveolar cells of lactating mammary glands that, by histological analysis, displayed hyperplastic areas and a disorganized structure. This was accompanied by an increased number of red blood cells and expression, in alveolar epithelial cells, of the vascular endothelial growth factor, which is absent in wild type controls. The most striking effect caused by FGF4 overexpression was on the remodelling of mammary tissue at the end of lactation. Indeed, transgenic animals showed a delayed involution of the gland due to a dramatic reduction in the overall number of apoptotic cells, which are normally present in the organ after weaning. Nevertheless, none of the animals examined developed neoplastic lesions of the mammary gland even after several pregnancies and at old age. Our work represents the first in-vivo demonstration of the anti-apoptotic and angiogenic properties of FGF4.

Aging↗

PubMed2000

Down-regulation of the Diphthamide biosynthesis protein 2-like gene during retinoid-induced differentiation and apoptosis: implications against its tumor-suppressor activity.

Retinoids, synthetic and natural analogs of retinoic acid (RA) have profound effects on the proliferation and differentiation of many cell types; this accounts for their beneficial effects in the treatment of certain neoplasias. We have employed mRNA differential display to characterize genes associated with differentiation and apoptosis induced by all-trans RA in human lung cancer cells. We have identified a cDNA corresponding to the sequence of the known gene diphthamide biosynthesis protein 2-like (DPH2L). Although the function of this gene remains unknown, as it was first isolated from the critical region of deletion on chromosome 17p13.3 in human ovarian carcinoma, it has been regarded as a candidate tumor-suppressor gene. In this report, we provide evidence that DPH2L is down-regulated during differentiation or apoptosis in several cancer cell lines after treatment with all-trans RA or N-(4-hydroxyphenyl)retinamide and during cell-cycle arrest. Moreover, stable expression of DPH2L-specific anti-sense construct leads to inhibition of cell proliferation. Our results suggest that DPH2L in not a conventional tumor-suppressor gene. Instead, it may be a growth regulator and its down-regulation might be permissive for the transition from cell growth to differentiation or apoptosis. DPH2L might be a useful tool in the prognosis of neoplastic diseases.

Adenosine Diphosphate Ribose↗

PubMed2000

The alpha 3 beta 1 integrin is associated with mammary carcinoma cell metastasis, invasion, and gelatinase B (MMP-9) activity.

The alpha 3 beta 1 integrin is elevated in several types of metastatic tumor and has been associated with increased migration and invasion. Our analysis of a series of mammary carcinomas of different histotypes and their corresponding metastases demonstrated significantly increased expression of alpha 3 beta 1 in the tumor metastases. We therefore studied alpha 3 beta 1 expression of several human breast carcinoma cell lines and its association with the invasive phenotype. The MDA-MB-231 cell line expressed high levels of the beta1, alpha 2, alpha 3, alpha 5, and alpha 6 integrin subunits along with moderate levels of the alpha v beta 3 integrin. This line was highly migratory and the most invasive using a chemo-invasion assay. In contrast, the other lines tested, MDA-MB-145, MCF-7, and SK-BR-3, showed lower migratory and invasive activity and reduced alpha 3 integrin subunit expression. Metalloproteases capable of degrading collagen IV are necessary for the invasive process. RT-PCR showed that MDA-MB-231 cells expressed MMP-9, but not MMP-2, gelatinase/collagenase IV. Gelatin zymography demonstrated that invading MDA-MB-231 cells released high levels of MMP-9 gelatinase activity. A direct role for this gelatinase in MDA-MB-231 cell invasion was confirmed by inhibition of invasion using the metalloprotease inhibitor Batimastat. Treatment of MDA-MB-231 cells with a function-blocking anti-alpha 3 antibody strongly inhibited migration and invasion. This correlated with a marked reduction in MMP-9 activity produced by MDA-MB-231 cells, suggesting a role for alpha 3 beta 1 ligand binding in cell signaling and regulation of extracellular matrix degradation.

Adult↗

PubMed2000

Genotypic analysis of thiopurine S-methyltransferase in patients with Crohn's disease and severe myelosuppression during azathioprine therapy.

BACKGROUND & AIMS: Myelosuppression in patients with Crohn's disease (CD) treated with azathioprine has been attributed to low activity of thiopurine S-methyltransferase (TPMT). Allelic variants of the TPMT gene responsible for changes in the enzyme activity have been characterized. We investigated the distribution of mutant alleles associated with TPMT deficiency in patients with CD and myelosuppression during azathioprine/6-mercaptopurine therapy. METHODS: Forty-one patients with CD were included. They developed leukopenia or thrombocytopenia during azathioprine or 6-mercaptopurine treatment. Polymerase chain reaction-based methods were used to search for mutations associated with TPMT deficiency. RESULTS: Four patients (10%) had 2 mutant alleles associated with TPMT deficiency, 7 (17%) had 1 mutant allele, and 30 (73%) had no known TPMT mutation. The delay between administration of the drug and occurrence of bone marrow toxicity was less than 1.5 months in the 4 patients with 2 mutant alleles, and ranged from 1 to 18 months in patients with 1 mutant allele and from 0.5 to 87 months in patients with normal genotype. CONCLUSIONS: Twenty-seven percent of patients with CD and myelosuppression during azathioprine therapy had mutant alleles of the TPMT gene associated with enzyme deficiency. Myelosuppression is more often caused by other factors. Continued monitoring of blood cell counts remains mandatory in patients treated with azathioprine.

Adolescent↗

PubMed2000

Tissue inhibitors of metalloproteases: regulation and biological activities.

A central role in tissue invasion is played by proteases that degrade extracellular matrices; in particular specific metalloproteases (MMPs) have been frequently correlated with the invasive potential of tumor cells and with the angiogenic process. MMPs are tightly regulated by molecules controlling their activation and by specific inhibitors of MMPs, known as the Tissue Inhibitors of MetalloProteases or TIMPs. Four TIMP family members are currently known. An imbalance between MMPs and TIMPs is linked to the degradation of the extracellular matrix associated with several physiologic and pathologic events including angiogenesis, invasion and metastasis. TIMPs are not only the 'guardians' of tissue degradation, they are able to control cell proliferation and cell survival as well. Given the critical role that TIMPs play, it is vital to know how the expression of TIMPs is controlled. Here we review the major biological properties and the molecular regulation of the TIMP expression.

Amino Acid Sequence↗