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L Gradoni

Publications and source records attributed to L Gradoni.

At least 19 recordsLinked to original sources
PubMed2000

Nitric oxide inhibits cruzipain, the major papain-like cysteine proteinase from Trypanosoma cruzi.

Nitric oxide (NO) is a pluripotent regulatory molecule showing, among others, an antiparasitic activity. Moreover, NO inhibits cysteine proteinase action by nitrosylating the Cys catalytic residue. In the present study, the inhibitory effect of the substrate N-alpha-benzyloxycarbonyl-L-phenylalanyl-L-arginine-(7-amino-4-methyl coumarin) and of NO on the catalytic activity of cruzipain, the major papain-like cysteine proteinase from Trypanosoma cruzi (the hemoflagellate protozoan parasite which causes the American trypanosomiasis), is reported. In particular, NO-donors S-nitroso-glutathione (GSNO), (+/-)-(E)-4-ethyl-2-[(E)-hydroxyimino]-5-nitro-3-hexenamide (NOR-3), 3-morpholinosydnonimine (SIN-1), S-nitroso-acetyl-penicillamine (SNAP), and sodium nitroprusside (SNP) dose-dependently inhibited cruzipain, this effect being likely attributable to the S-nitrosylation of the Cys25 catalytic residue. These results were analyzed in parallel with those concerning the inhibitory effect of the substrate and of NO on the catalytic activity of falcipain, the cruzipain-homologous cysteine proteinase from Plasmodium falciparum. The modulation of the cruzipain and falcipain activity by NO may be relevant in developing new strategies against T. cruzi and P. falciparum in human host. As a whole, the NO-mediated S-nitrosylation of pathogenic viral, bacterial, fungal, and parasitic cysteine proteinases may represent a general mechanism of antimicrobial and antiparasitic host defences.

Animals↗
PubMed2000

Nitric oxide inhibits falcipain, the Plasmodium falciparum trophozoite cysteine protease.

Nitric oxide (NO) is a pluripotent regulatory molecule possessing, among others, an antiparasitic activity. In the present study, the inhibitory effect of NO on the catalytic activity of falcipain, the papain-like cysteine protease involved in Plasmodium falciparum trophozoite hemoglobin degradation, is reported. In particular, NO donors S-nitrosoglutathione (GSNO), (+/-)-(E)-p6ethyl-2-[(E)-hydroxyimino]-5-nitro-3-hexenami de (NOR-3), 3-morpholinosydnonimine (SIN-1), and sodium nitroprusside (SNP) inhibit dose-dependently the falcipain activity present in the P. falciparum trophozoite extract, this effect likely attributable to S-nitrosylation of the Cys25 catalytic residue. The results represent a new insight into the modulation mechanism of falcipain activity, thereby being relevant in developing new strategies for inhibition of the P. falciparum life cycle.

Animals↗
PubMed1999

Early suppression of lymphoproliferative response in dogs with natural infection by Leishmania infantum.

Dogs are the domestic reservoirs of zoonotic visceral leishmaniasis caused by Leishmania infantum. Early detection of canine infections evolving to clinically patent disease may be important to leishmaniasis control. In this study we firstly investigated the peripheral blood mononuclear cell (PBMC) response to leishmanial antigens and to polyclonal activators concanavalin A, phytohemagglutinin and pokeweed mitogen, of mixed-breed dogs with natural L. infantum infection, either in presymptomatic or in patent disease condition, compared to healthy animals. Leishmania antigens did not induce a clear proliferative response in any of the animals examined. Furthermore, mitogen-induced lymphocyte proliferation was found strongly reduced not only in symptomatic, but also in presymptomatic dogs suggesting that the cell-mediated immunity is suppressed in progressive canine leishmaniasis. To test this finding, naive Beagle dogs were exposed to natural L. infantum infection in a highly endemic area of southern Italy. Two to 10 months after exposure all dogs were found to be infected by Leishmania, and on month 2 of exposure they all showed a significant reduction in PBMC activation by mitogens. Our results indicate that suppression of the lymphoproliferative response is a common occurrence in dogs already at the beginning of an established leishmanial infection.

Animals↗
PubMed1998

Diffuse necrotic hepatic lesions due to visceral leishmaniasis in AIDS.

A rare case of an AIDS patient who developed scattered necrotic involvement of the liver caused by Leishmania infantum is described. Of interest, marked splenomegaly, hypergammaglobulinemia and serum anti-Leishmania antibodies were absent and an incomplete response to therapy was observed. Diagnosis of visceral leishmaniasis (VL) was achieved by the demonstration of numerous amastigotes in both hepatocytes and macrophages on liver biopsy. Hepatic necrotic lesions, which when extensive could lead to acute hepatic failure, possibly reflect an atypical manifestation of liver involvement caused by L. infantum and depend on the immunological impairment which characterizes AIDS patients, thus preventing the formation of granulomas. Our observation confirms that VL can manifest atypical aspects in HIV-positive patients depending on the degree of the immunodeficiency. The frequency and severity of this pathology accounts for the need to list VL among AIDS-defining conditions.

AIDS-Related Opportunistic Infections↗
PubMed1998

Comparative efficacy of meglumine antimoniate and aminosidine sulphate, alone or in combination, in canine leishmaniasis.

Thirty-two domestic dogs naturally infected with Leishmania infantum and showing viscero-cutaneous signs of canine leishmaniasis were treated with aminosidine sulphate (11 dogs) meglumine antimoniate (10 dogs) or with a combination of the two drugs (11 dogs) for 21 consecutive days. Clinical and laboratory assessments, made on day 21 and at 2, 4 and 6 months after initiation of treatment, showed that the drug combination gave the best score in terms of clinical efficacy, incidences of early clinical relapse, any clinical relapse or apparent parasitological cure, and reduction in parasite densities in bone-marrow and lymphnode aspirates (even though a lower dose of antimonial was used in the combination than for antimonial monotherapy). For each of the above parameters, however, the higher efficacy of the drug combination was not statistically significant, probably because of the large variations caused by using naturally infected animals of various ages and breeds.

Animals↗
PubMed1998

A cloned antigen (recombinant K39) of Leishmania chagasi diagnostic for visceral leishmaniasis in human immunodeficiency virus type 1 patients and a prognostic indicator for monitoring patients undergoing drug therapy.

Serologic assays using crude antigens for the diagnosis of visceral leishmaniasis in human immunodeficiency virus type 1 (HIV)-seropositive patients have been shown to lack sensitivity and specificity, particularly in AIDS patients. Antibodies to a cloned antigen, recombinant (r) K39, of Leishmania chagasi are specific for members of the Leishmania donovani complex and have been shown to indicate active disease in immunocompetent persons. This study demonstrated that antibodies to rK39 were also detectable in HIV-seropositive patients coinfected with Leishmania infantum. Furthermore, the rK39 ELISA was more sensitive than an IFA for detecting L. infantum infections in patients with AIDS. In addition, antibody titers to rK39 in HIV-negative patients infected with L. infantum or L. chagasi declined during treatment with meglumine antimoniate or liposomal amphotericin B. In contrast, most patients who clinically relapsed showed increased antibody titers to rK39. These data demonstrate the diagnostic and prognostic utility of rK39 in detecting active visceral leishmaniasis.

AIDS-Related Opportunistic Infections↗
PubMed1997

A retrospective clinical study of canine leishmaniasis in 150 dogs naturally infected by Leishmania infantum.

The clinical and laboratory findings observed in 150 dogs naturally infected by Leishmania infantum, from a large endemic area of southern Italy, are described. There was a gradual onset of clinical signs and the course of the disease was progressive in almost all the cases. The majority of the dogs were mongrels (43.3 per cent), male (64.7 per cent), of medium size (50.6 per cent), three to seven years old (64.7 per cent), and living outdoors (60 per cent). They showed generalised (56.7 per cent) or symmetrical (32 per cent) lymphadenomegaly; the mucous membranes of 87 of the dogs (58 per cent) were pale and moderate or severe splenomegaly was diagnosed in 80 dogs (53.3 per cent); weight loss was observed in 32 per cent of the animals. Skin abnormalities were very common, and included dry exfoliative dermatitis (56 per cent), ulcers (40 per cent) periorbital alopecia ('lunettes') (18 per cent), diffuse alopecia (14 per cent) and onychogryphosis (24 per cent). Ocular signs were observed in 24 dogs (16 per cent) including 16 cases of keratoconjunctivitis (three with keratoconjunctivitis sicca), six cases of moderate uveitis and two cases of panophthalmitis. The acute form of the disease was diagnosed in only six dogs and was characterised by fever and generalised lymphadenomegaly, and by the absence of skin lesions. Another six dogs had severe renal failure without systemic clinical signs of leishmaniasis. The most important laboratory findings were a severe or moderate increase in gammaglobulins, hypoalbuminaemia, hyperproteinemia and anaemia. Cultures or cytology tests for L infantum parasites were positive in 134 of the dogs. Following the standard procedures developed for human lymph node and bone marrow cytology tests, the leishmania density in the dogs varied from 1+ to 2+. Leishmania antibody titres were high (> 1:160) in almost all the dogs. Immunological tests for autoantibodies were positive in 25 of 53 dogs tested in the antinuclear antibody (ANA) test, in 15 of 43 dogs tested in the latex test and in five of 24 dogs tested in the Coombs test.

Animals↗
PubMed1997

Treatment of visceral leishmaniasis in children with liposomal amphotericin B.

We used liposomal amphotericin B as first-choice treatment of visceral leishmaniasis in 106 immunocompetent children who acquired the infection in a temperate region of southern Europe (Italy) where Leishmania infantum visceral leishmaniasis is endemic. The aim of the study was to identify the minimum total dose of liposomal amphotericin B needed to cure the infection in children and reduce the period of hospitalization. We conclude that the optimal regimen in immunocompetent children with L. infantum visceral leishmaniasis to be a total dose of 18 mg/kg of liposomal amphotericin B (3 mg/kg per day for 5 days, followed by 3 mg/kg administered as an outpatient regimen on day 10).

Adolescent↗
PubMed1997

Epidemiologic surveillance of visceral leishmaniasis in Sicily, Italy.

Visceral leishmaniasis (VL) is endemic in Sicily. Although it is a notifiable disease, there is evidence that the actual number of cases is higher than that reported. In 1987, a regional reference center for active surveillance of VL was established and it recorded a total of 284 cases through 1995, a mean of 31.5 cases/year and about four-fold more than previously reported. Of the 284 cases, 150 (53%) were children (< or = 14 years of age), and of the 134 adults, 39 (29%) were coinfected with human immunodeficiency virus (HIV). The commonest viscerotropic zymodeme of Leishmania infantum, MON 1, was identified in 40 (93%) of 43 HIV-negative and eight (57%) of 14 HIV-positive patients. Among 280 patients evaluated (i.e., all HIV-negative and 35 of 39 HIV-positive subjects), 254 (91%) were treated with meglumine antimoniate alone or in combination with other drugs; 23 (8%) received allopurinol or amphotericin B, either conventional or in liposomal form; and three terminally ill patients were not treated. Among the 245 HIV-negative patients, 236 (96%) were successfully cured, while nine (4%) (seven adults) died during the course of antimonial treatment. None of the 35 HIV-positive patients was definitively cured, although mortality was apparently associated with other opportunistic infections.

Adolescent↗
PubMed1996

Visceral leishmaniasis in HIV infected patients: treatment with high dose liposomal amphotericin B (AmBisome).

Visceral leishmaniasis (VL) in patients coinfected with human immunodeficiency virus (HIV) is often atypical, and characteristically relapses after treatment. We treated 10 HIV infected patients (9 men) with parasitologically confirmed VL with liposomal amphotericin B ("AmBisome': L-AMB) at a dose of 4 mg/kg/day on days 1, 2, 3, 4, 5, 10, 17, 24, 31, and 38. Patients were hospitalized for the first 5 days, and were monitored during, and 1 week and 1, 3 and 6 months after, L-AMB therapy. There were no serious adverse events, and L-AMB was well tolerated. 9/10 patients completed therapy, one patient defaulted at day 24. Clinical improvement was seen in all nine patients and the bone marrow aspirate was cleared of visible/culturable parasites in 8/9 patients. During follow-up, one patient defaulted. The seven remaining patients relapsed at 2, 3, 3, 5, 5, 6 and 7 months. Re-treatment with a variety of antileishmanial drugs was unsatisfactory. The time from first diagnosis of VL to death in six patients was 5-40 months (mean 18.8 months). Only one patient remained alive 26 months after treatment. L-AMB is safe and provides a good initial clinical response. Intermittent dosing enables a short period of hospitalization. However, relapse is probably inevitable.

AIDS-Related Opportunistic Infections↗
PubMed1996

Short-course treatment of visceral leishmaniasis with liposomal amphotericin B (AmBisome).

We evaluated liposomal amphotericin B (AmBisome; Vestar, San Dimas, CA) administered to 88 immunocompetent patients (56 children) with visceral leishmaniasis (VL) caused by Leishmania infantum. Thirteen patients received 4 mg/kg on days 1-5 and 10 (total dose, 24 mg/kg), and all were cured; 42 received 3 mg/kg on days 1-5 and 10 (18 mg/kg), and 41 were cured; 32 received 3 mg/kg on days 1-4 and 10 (15 mg/kg), and 29 were cured (amastigotes were not cleared from 1 child, and 2 relapsed). One adult was cured with a total dose of 12mg/kg. The four children who were not cured received 3 mg/kg for 10 days; none had further relapses. There were no significant adverse events. For VL due to L. infantum, we recommended a total dose of AmBisome of > or = 20 mg/kg, given in > or = 5 doses of 3-4 mg/kg over > or = 10 days.

Adolescent↗
PubMed1996

Epidemiological surveillance of leishmaniasis in HIV-1-infected individuals in Italy.

OBJECTIVE: To actively detect leishmaniasis in HIV-1-infected individuals in Italy, to describe the epidemiological features of the disease in these patients, and to compare them with epidemiological features of leishmaniasis in HIV-negative patients. DESIGN: Retrospective and prospective surveillance study. PATIENTS: Italian patients with HIV-1 infection and leishmaniasis diagnosed between 1985 and 1994. RESULTS: We recorded 116 leishmaniasis cases (115 visceral leishmaniasis), of which 94 (81%) were diagnosed over the last 4 years. Seventy-eight patients (67%) fulfilled the 1993 Centers for Disease Control and Prevention AIDS criteria. Leishmaniasis was passively reported in only 18% of cases. Leishmania incidence estimated among approximately 2700 AIDS patients living in leishmaniasis endemic areas averaged 1.6%, with a maximum of 4.9% in Sicily. These rates were up to 500-fold higher than among HIV-negative individuals living in the same areas, and were similar to those of ubiquitous opportunistic agents indicative of AIDS condition. Data from two major endemic regions indicated that overlap of HIV-1 and Leishmania infections has focal characteristics. The occurrence of small case clusters would suggest occasional modes of Leishmania transmission different from the insect vector. The isoenzyme characterization of 38 Leishmania stocks showed a zymodeme spectrum qualitatively and quantitatively different from that of the parasitic agent of visceral leishmaniasis in HIV-negative adults. CONCLUSIONS: Active surveillance provided reliable evaluation on the occurrence of HIV-Leishmania coinfections in Italy, although it was limited to hospital-based cases in this study due to general under-reporting of cases. Biological and epidemiological spectrum of the disease suggests that visceral leishmaniasis should be included among AIDS-defining pathologies.

Acquired Immunodeficiency Syndrome↗
PubMed1996

[Eco-epidemiological study of Phlebotomus perniciosus in foci of visceral leishmaniasis in Campania].

An entomological survey was carried out during the sandfly season (June-October) of 1993 in three of the main visceral leishmaniasis (VL) foci of the Campania region of Italy. During the period 1989-1993, 39 VL cases were recorded in the three foci: 19 in Maddaloni, 14 in Ercolano and 6 in Ischia. For each focus, collecting stations representative of sandfly habitats (domestic, peri-domestic and sylvatic) located in urban, peri-urban and rural areas were selected for the sandfly investigation. Three monthly captures by means of sticky traps (20 x 20 cm) were carried out in each station. A total of 2,773 sandfly specimens were caught and identified as belonging to 4 species: Phlebotomus perniciosus (66.2%). P. mascittii (0.4%). P. papatasi (0.2%) and Sergentomyia minuta (33.2%). P. perniciosus, the proven vector of VL in Italy, showed the highest prevalence in all foci studied, Maddaloni (61.0%). Ercolano (62.5%) and Ischia (88.2%); the absolute density of the species (number of specimens/m2 of sticky trap) was not so high in all areas and habitats sampled, the values observed being between 0.14 and 22.05/m2. The relationship between the eco-epidemiological aspects and the distribution of P. perniciosus in the foci investigated is discussed.

Animal Diseases↗
PubMed1995

Heterogeneity among zymodemes of Leishmania infantum from HIV-positive patients with visceral leishmaniasis in south Italy.

Eleven zymodemes of Leishmania infantum were identified among 38 parasite stocks isolated from Italian HIV-positive patients with visceral leishmaniasis (VL). Only one zymodeme is a common agent of Mediterranean VL in HIV-negative individuals, five zymodemes usually cause simple, self-resolving cutaneous leishmaniasis (CL), and five belong to unique genotypes which have not been previously reported from either VL or CL cases in immunocompetent individuals. This last group of parasites showed reassortment patterns within electromorphs frequently observed in dermotropic L. infantum zymodemes. The highest zymodeme heterogeneity was found in south Italy (Sicily), with six zymodemes identified among 12 HIV-positive patients surveyed.

Animals↗
PubMed1995

Induction of interleukin 1 alpha in murine macrophages infected in vitro with different species and strains of Leishmania.

It is now generally agreed that several cytokines released by immunocompetent cells such as macrophages play a crucial role in the outcome of infections caused by protozoa belonging to the genus Leishmania. In particular, tumor necrosis factor (TNF) induction during the course of cutaneous leishmaniasis has been related to resistance to L. major infection in mice. However, the role played by interleukin 1 (IL-1) in the host response to leishmaniasis has yet to be completely elucidated. The aim of this work was to study whether different species and strains of Leishmania could induce IL-1 alpha in murine macrophages in vitro. Resident peritoneal macrophages of BALB/c and C3H/HeN mice were infected with L. donovani, L. major, or different strains of L. infantum. It was found that L. donovani did not induce IL-1 alpha in macrophages from either mice strain. Infection with L. major or with three out of six strains of L. infantum induced consistent amounts of IL-1 alpha, but only in macrophages from genetically resistant C3H/HeN mice. No relationship was found between the rate of infection of macrophages and the amount of IL-1 alpha detected in the supernatants of infected macrophages. Data obtained confirm that the release of IL-1 alpha by murine macrophages infected in vitro with Leishmania is influenced by the genetic background of the cells as well as by the parasite species.

Animals↗
PubMed1995

Activity of liposomal amphotericin B (AmBisome) in dogs naturally infected with Leishmania infantum.

Thirteen dogs naturally infected with Leishmania infantum showing viscero-cutaneous signs of disease were treated with different dosages of liposomal amphotericin B (AmBisome). The animals were followed clinically and parasitologically over a period of eight months. Dogs which received three to five administrations of AmBisome 3-3.3 mg/kg showed rapid clinical improvement, with regression of lymphadenomegaly and splenomegaly, and cure of skin lesions. The clinical response was similar to that obtained with 14-21 doses of conventional antileishmanial drugs. However, follow-up lymph node aspirates remained positive for Leishmania in all dogs except one, which was treated with the total dose of AmBisome 15 mg/kg. The failure in parasitological cure may be due to inadequate drug targeting to parasitized cells, or to T-cell immune depression characteristic of patent cases of canine leishmaniasis, or to both.

Amphotericin B↗