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L Cordier

Publications and source records attributed to L Cordier.

17 recordsLinked to original sources
PubMed2006

Antiretroviral treatment and age-related comorbidities in a cohort of older HIV-infected patients.

BACKGROUND: The availability of several therapeutic regimens has transformed HIV infection from a life-threatening disease into a chronic condition. Older patients (>50 years old) with HIV infection constitute a new treatment challenge in terms of the cumulative effects of ageing and antiretroviral therapy (ART). METHODS: The immunovirological effects and metabolic interactions of 48 weeks of ART in older patients followed up in three Infectious Diseases Units in Milan, Italy since 1994 were compared with those in younger controls aged 25-35 years. RESULTS: The 159 older patients and 118 controls enrolled in the study were comparable for HIV stage, baseline CD4 cell count and viral load but differed for mode of HIV transmission, comorbid conditions and related chronic treatments. Mean viral load decreased after 48 weeks of treatment by 2.6 log(10) HIV RNA copies/mL and CD4 count increased by 137.5 cells/microL in older patients, and similar values for immunovirological effects were obtained in the young controls. The relative risk (RR) of an abnormal test in older patients was 7.33 [95% confidence interval (CI) 4.36-12.36] for glucose, 1.73 (95% CI 1.45-2.07) for total cholesterol, 1.56 (95% CI 1.22-2.0) for high-density lipoprotein cholesterol, 1.26 (95% CI 1.02-1.56) for triglycerides, 6.48 (95% CI 4.36-9.66) for serum creatinine, and 0.45 (95% CI 0.35-0.58) for ALT. Moderate/severe liver and renal toxicities were recorded in the older patients but not in the controls. The tolerability of ART did not differ between the older patients and the controls. Thirty-nine new cardiovascular, endocrine-metabolic and neuralgic disorders (24.52 per 100 person-years) were diagnosed in the older patients and four (3.39 per 100 person-years) in the controls (P<0.0001). CONCLUSIONS: Diseases induced by, or related to, the toxic effects of antiretrovirals interact with age-specific health profiles, raising new questions and challenges. Comparative epidemiological studies, research studies addressing specific questions and surveillance are needed to answer the questions that arise in clinical monitoring.

Adult↗
PubMed2001

Muscle-specific promoters may be necessary for adeno-associated virus-mediated gene transfer in the treatment of muscular dystrophies.

Recombinant adeno-associated virus (rAAV) vectors allow efficient gene transfer and expression in the muscle; therefore, rAAVs represent a potential gene therapy vector for muscular dystrophies. For further investigations, we used a mouse muscular dystrophy model (gsg(-/-) mice) gamma-sarcoglycan, a subunit of the dystrophin-glycoprotein complex, is missing. gsg(-/-) mice develop progressive dystrophy representative of a severe human phenotype disease. We previously showed high levels and stable expression of gamma-sarcoglycan in myofibers after direct muscle injection into gsg(-/-) mice of a recombinant AAV vector (AAV.dMCK.gSG) carrying the gamma-sarcoglycan cDNA driven by a muscle-specific promoter (truncated version of muscle creatine kinase). Here, we show that when gamma-sarcoglycan expression is driven by the ubiquitous cytomegalovirus (CMV) promoter (AAV.CMV.gSG), lower levels of transgene expression are observed and are associated with a humoral response to gamma-sarcoglycan. When using an rAAV vector, expressing the highly immunogenic product gamma-galactosidase under the CMV promoter (AAV.CMV.LacZ), we measured a strong cellular and humoral immune response to the transgene after intramuscular injection into gsg(-/-) mice. This study suggests that restriction of transgene expression to the muscle is an important criterion for the treatment of muscular dystrophies and will aid in the design of protocols for gene therapy.

Animals↗
PubMed2000

Rescue of skeletal muscles of gamma-sarcoglycan-deficient mice with adeno-associated virus-mediated gene transfer.

In humans, a subset of cases of Limb-girdle muscular dystrophy (LGMD) arise from mutations in the genes encoding one of the sarcoglycan (alpha, beta, gamma, or delta) subunits of the dystrophin-glycoprotein complex. While adeno-associated virus (AAV) is a potential gene therapy vector for these dystrophies, it is unclear if AAV can be used if a diseased muscle is undergoing rapid degeneration and necrosis. The skeletal muscles of mice lacking gamma-sarcoglycan (gsg-/- mice) differ from the animal models that have been evaluated to date in that the severity of the skeletal muscle pathology is much greater and more representative of that of humans with muscular dystrophy. Following direct muscle injection of a recombinant AAV [in which human gamma-sarcoglycan expression is driven by a truncated muscle creatine kinase (MCK) promoter/enhancer], we observed significant numbers of muscle fibers expressing gamma-sarcoglycan and an overall improvement of the histologic pattern of dystrophy. However, these results could be achieved only if injections into the muscle were prior to the development of significant fibrosis in the muscle. The results presented in this report show promise for AAV gene therapy for LGMD, but underscore the need for intervention early in the time course of the disease process.

Age Factors↗
PubMed2000

Differential requirement for individual sarcoglycans and dystrophin in the assembly and function of the dystrophin-glycoprotein complex.

Sarcoglycan is a multimeric, integral membrane glycoprotein complex that associates with dystrophin. Mutations in individual sarcoglycan subunits have been identified in inherited forms of muscular dystrophy. To evaluate the contributions of sarcoglycan and dystrophin to muscle membrane stability and muscular dystrophy, we compared muscle lacking specific sarcoglycans or dystrophin. Here we report that mice lacking (delta)-sarcoglycan developed muscular dystrophy and cardiomyopathy similar to mice lacking (gamma)-sarcoglycan. However, unlike muscle lacking (gamma)-sarcoglycan, (delta)-sarcoglycan-deficient muscle was sensitive to eccentric contraction-induced disruption of the plasma membrane. In the absence of (delta)-sarcoglycan, (alpha)-, (beta)- and (gamma)-sarcoglycan were undetectable, while dystrophin was expressed at normal levels. In contrast, without (gamma)-sarcoglycan, reduced levels of (alpha)-, (beta)- and (delta)-sarcoglycan were expressed, glycosylated and formed a complex with each other. Thus, the elimination of (gamma)- and (delta)-sarcoglycan had different molecular consequences for the assembly and function of the dystrophin-glycoprotein complex. Furthermore, these molecular differences were associated with different mechanical consequences for the muscle plasma membrane. Through this in vivo analysis, a model for sarcoglycan assembly is proposed.

Animals↗
PubMed1999

Muscle degeneration without mechanical injury in sarcoglycan deficiency.

In humans, mutations in the genes encoding components of the dystrophin-glycoprotein complex cause muscular dystrophy. Specifically, primary mutations in the genes encoding alpha-, beta-, gamma-, and delta-sarcoglycan have been identified in humans with limb-girdle muscular dystrophy. Mice lacking gamma-sarcoglycan develop progressive muscular dystrophy similar to human muscular dystrophy. Without gamma-sarcoglycan, beta- and delta-sarcoglycan are unstable at the muscle membrane and alpha-sarcoglycan is severely reduced. The expression and localization of dystrophin, dystroglycan, and laminin-alpha2, a mechanical link between the actin cytoskeleton and the extracellular matrix, appears unaffected by the loss of sarcoglycan. We assessed the functional integrity of this mechanical link and found that isolated muscles lacking gamma-sarcoglycan showed normal resistance to mechanical strain induced by eccentric muscle contraction. Sarcoglycan-deficient muscles also showed normal peak isometric and tetanic force generation. Furthermore, there was no evidence for contraction-induced injury in mice lacking gamma-sarcoglycan that were subjected to an extended, rigorous exercise regimen. These data demonstrate that mechanical weakness and contraction-induced muscle injury are not required for muscle degeneration and the dystrophic process. Thus, a nonmechanical mechanism, perhaps involving some unknown signaling function, likely is responsible for muscular dystrophy where sarcoglycan is deficient.

Age Factors↗
PubMed1999

Plasmodium berghei development in irradiated sporozoite-immunized C57BL6 mice.

The C57BL6 strain of mice is highly susceptible to Plasmodium berghei sporozoite infections and consequently requires repeated immunizations with irradiated sporozoites to obtain protective immunity. After a live sporozoite challenge in the immunized hosts, hepatic-stage parasites found in the liver after 48 h are of different sizes--small schizonts corresponding to blocked forms (derived from irradiated sporozoites), and schizonts of intermediate size (derived from live sporozoites). Large schizonts corresponding to mature hepatic forms are found only in unimmunized but challenged C57BL6 mice. Using monoclonal and polyclonal antibodies directed to liver-stage parasites, different patterns of binding reactivity to the above forms are observed. More than 20% of the irradiated sporozoites transform into blocked forms after immunization and persist in the liver. Upon sporozoite challenge in such immunized animals the rate of transformation of sporozoites into hepatic parasites is less than 2%. These observations shed light on the fate of live sporozoite development in irradiated sporozoite-immunized C57BL6 mice.

Animals↗
PubMed1999

Aminoglycoside antibiotics restore dystrophin function to skeletal muscles of mdx mice.

Duchenne muscular dystrophy (DMD) is caused by mutations in the dystrophin gene, leading to the absence of the dystrophin protein in striated muscle. A significant number of these mutations are premature stop codons. On the basis of the observation that aminoglycoside treatment can suppress stop codons in cultured cells, we tested the effect of gentamicin on cultured muscle cells from the mdx mouse - an animal model for DMD that possesses a premature stop codon in the dystrophin gene. Exposure of mdx myotubes to gentamicin led to the expression and localization of dystrophin to the cell membrane. We then evaluated the effects of differing dosages of gentamicin on expression and functional protection of the muscles of mdx mice. We identified a treatment regimen that resulted in the presence of dystrophin in the cell membrane in all striated muscles examined and that provided functional protection against muscular injury. To our knowledge, our results are the first to demonstrate that aminoglycosides can suppress stop codons not only in vitro but also in vivo. Furthermore, these results raise the possibility of a novel treatment regimen for muscular dystrophy and other diseases caused by premature stop codon mutations. This treatment could prove effective in up to 15% of patients with DMD.

Animals↗
PubMed1999

[Evaluation of esophageal motility disorders triggered by ingestion of solids in the case of non-obstructive dysphagia].

UNLABELLED: The aim of this study was to define the normal manometric pattern of esophageal motility in response to food ingestion and to evaluate the contribution of esophageal manometry in the management of patients complaining of functional dysphagia. PATIENTS AND METHODS: Twenty-one healthy volunteers and 25 consecutive patients complaining of functional dysphagia with normal conventional esophageal manometry were included in this prospective study. An event marker was used to study the relationship between dysphagia and motility events. RESULTS: Twenty-two out of 25 patients (88%) reported dysphagia during esophageal manometry with food ingestion, while none complained of dysphagia during conventional esophageal manometry. Significantly, food ingestion induced in healthy volunteers and in patients: an increase in the amplitude and duration of esophageal body peristaltic contractions, and a decrease in their propagation speed; an increase in the basal pressure and a decrease in the relaxation percentage of the lower esophageal sphincter during deglutition. The percentage of solid swallows with one or several of the 7 abnormal motility patterns studied prospectively was significantly higher among patients (53.7%) than among healthy volunteers (4.3%) (P < 0.0001); it was also significantly higher among patients during swallows with dysphagia (70.1%) than without dysphagia (33.6%) (P < 0.0001). CONCLUSION: Esophageal manometry with food ingestion is an effective means of defining abnormal motility patterns and their relationship with dysphagia during functional dysphagia.

Adult↗
PubMed1997

IL-2 gene delivery within an established murine tumor causes its regression without proliferation of preexisting antitumor-specific CTL.

Regression of P815 tumors established on naive syngeneic mice can be obtained by the intratumoral injection of a single dose of an adenoviral vector expressing the IL-2 gene (Ad.IL2). Injection triggers local IL-2 production for at least 10 days. We measured a number of immunologic parameters in situ following intratumoral Ad.IL2 treatment. We also analyzed the situation of regression obtained upon challenge with P815 cells of mice previously immunized against the tumor and compared both systems. While IFN-gamma messenger RNA expression was found to be elevated in both situations of tumor regression, the level of infiltration by tumor-specific CTL was different. A small amount of tumor-specific CD8+ T cells were present in growing, untreated tumors. Such cells are found in much larger numbers in tumors rejected upon challenge, consistent with a CTL-mediated rejection. In contrast, they were found not to proliferate following Ad.IL2 injection. The latter caused an increased infiltration of a polyclonal, presumably nonspecific, T cell population. These results suggest that the initial regression of established P815 tumors following Ad.IL2 treatment in vivo is mostly due to nonspecific effectors.

Animals↗
PubMed1996

Strategies for cancer gene therapy using adenoviral vectors.

Modification of tumor cells using gene transfer either to enhance host immunity or to act directly on tumor cells is being intensively studied in animal models. Remarkable results have yielded to approved clinical protocols in the treatment of cancer patients using this approach. Several methods of gene delivery have been developed. This article is particularly devoted to the interest of the use of adenoviral vectors in the different strategies of cancer gene therapy.

Adenoviridae↗
PubMed1996

LacZ gene transfer into tumor cells abrogates tumorigenicity and protects mice against the development of further tumors.

Numerous studies have shown that the expression of immuno-stimulatory genes in tumor cells can result in the development of antitumoral immunity resulting in the rejection of the tumor cells. We show here that the simple integration and expression of the lacZ gene in the highly tumorigenic murine mastocytoma cell line P815 strongly reduces the cell's tumorigenicity. All the animals having rejected P815-lacZ challenges develop a long-lasting immunity against unmodified P815 cells with all of the animals rejecting further challenges with tumorigenic doses of P815 cells. However, this protective immunity conferred by P815-lacZ, directed against both the nuclearly expressed lacZ and surface tumor antigens, is not sufficient to act as curative immunity. In this immunogenic tumor model the expression of the lacZ antigen is more efficient than the irradiation of the cells to induce a strong immune response and an antitumoral state of vaccination in syngeneic animals.

Animals↗
PubMed1995

Ciprofloxacin and long-term prevention of spontaneous bacterial peritonitis: results of a prospective controlled trial.

The aim of this prospective double-blind study was to evaluate the value of long-term antibiotic prophylaxis using ciprofloxacin for the prevention of spontaneous bacterial peritonitis (SBP) in 60 cirrhotic patients with low ascitic fluid protein levels (< 15 g/L). The patients were assigned to two groups: group I (n = 28) ciprofloxacin 750 mg per os once a week for 6 months, group II (n = 32) placebo. The two groups were similar for clinical and laboratory characteristics. Twelve patients developed an intercurrent disorder, and 10 patients died during the trial. There were no adverse effects in the treated group. There was a significant decrease in the incidence of SBP (3.6 vs. 22%) (P < .05) and duration of hospitalization (9.3 +/- 4.5 vs. 17.6 +/- 6.2 days) (P < .05) in the treated group as compared with the placebo group. The bacteriological study showed no acquired resistance to ciprofloxacin after 6 months' treatment. These results suggest that long-term preventive antibiotic prophylaxis based on the weekly administration of 750 mg of ciprofloxacin is effective in the prevention of SBP in cirrhotic patients.

Adult↗
PubMed1995

Complete recovery of mice from a pre-established tumor by direct intratumoral delivery of an adenovirus vector harboring the murine IL-2 gene.

Direct introduction of exogenous genes into pre-existent tumors could provide an effective therapeutic approach for treatment of localized tumors. In this report we show that direct intratumoral delivery in animals of a replication-deficient adenovirus vector harboring the murine interleukin (IL)-2 gene (AD-mIL2) causes complete disappearance of P815 murine mastocytoma tumors in up to 75% of cases. Histological analysis of treated tumors revealed the presence of several zones of necrosis and the infiltration of macrophages and T cells. Moreover, the successfully treated animals develop a long lasting state of immunity during which further challenges with the tumor cells are rejected. To our knowledge this is the first successful in vivo treatment of an established tumor using adenoviral gene therapy methods.

Adenoviruses, Human↗
PubMed1993

Adenoviral interleukin-2 gene transfer into P815 tumor cells abrogates tumorigenicity and induces antitumoral immunity in mice.

The murine mastocytoma cell line P815 was used as a model to evaluate the effect on its tumorigenic capacity following interleukin-2 (IL-2) gene transfer into the tumor cells using a replication-defective adenovirus vector. The data show that P815 cells infected in vitro with this recombinant adenovirus secreted significant amounts of functional IL-2 as tested on CTL-L2 cells. Furthermore, when injected into syngeneic DBA/2 mice, the tumorigenic phenotype is lost in up to 80% of the animals. The rejection of the infected cells was host dependent, because co-injection at the same site or concomitant injection at the opposite side of the animal with a tumorigenic dose of noninfected P815 cells did not lead to tumor development in 50-70% of the mice. Moreover, protected animals developed a long-lasting state of immunization against the P815 tumor cells and their splenocytes were able to transfer the immunity to syngeneic naive recipients.

Adenoviridae↗