TGF-beta plasma levels in chromoblastomycosis patients during itraconazole treatment.

BACKGROUND: Chromoblastomycosis (CBM) is a dermal mycosis. The disease evolves to a chronic state, presenting a suppurative granulomatous dermatitis, combined with variable dermal fibrosis. Pathogenesis of the inflammation and tissue repair in CBM are poorly understood. AIM: To quantify Transforming Growth Factor-beta (TGF-beta) plasma levels of CBM patients during itraconazole (ITZ) treatment. METHODS: Blood plasma of 12 CBM patients was subjected to TGF-beta titration with ELISA at 0, 3, 6 and 12months of 200mg per day of ITZ therapy, and correlated with the clinical aspects. Plasma of 12 healthy individuals were used for control. RESULTS: CBM patients present high plasma levels of TGF-beta (7.016+/-1988pg/ml), decreasing after 03months (4.625+/-645pg/ml) of ITZ treatment, which correlates with a rapid clinical improvement. However, after 6 (6.566+/-777pg/ml) and 12months (6.908+/-776) of treatment, TGF-beta levels increase to almost the same levels observed before treatment, which is related to a slow clinical improvement, fungal persistence on the lesion, and fibrotic scars. CONCLUSION: TGF-beta plasma levels are high in CBM patients. Fungal destruction by ITZ correlates with TGF-beta downregulation, but tissue remodeling and fungal persistence probably raises its levels again, interfering with cellular immune responses.

Resistance of Plasmodium falciparum field isolates to in-vitro artemether and point mutations of the SERCA-type PfATPase6.

Artemisinin derivatives are an essential component of treatment against multidrug-resistant Plasmodium falciparum malaria. We aimed to investigate in-vitro resistance to artemisinin derivatives in field isolates. In-vitro susceptibility of 530 P falciparum isolates from three countries (Cambodia, French Guiana, and Senegal) with different artemisinin use was assessed with an isotopic microtest. Artemether IC50 up to 117 and 45 nmol/L was seen in French Guiana and Senegal, respectively. DNA sequencing in a subsample of 60 isolates lends support to SERCA-PfATPase6 as the target for artemisinins. The S769N PfATPase6 mutation, noted exclusively in French Guiana, was associated with raised (>30 nmol/L) artemether IC50s (p<0.0001, Mann-Whitney). All resistant isolates came from areas with uncontrolled use of artemisinin derivatives. This rise in resistance indicates the need for increased vigilance and a coordinated and rapid deployment of drug combinations.

Molecular analysis of two local falciparum malaria outbreaks on the French Guiana coast confirms the msp1 B-K1/varD genotype association with severe malaria.

BACKGROUND: Plasmodium falciparum outbreaks can occur in the coastal area of French Guiana, where the population is essentially non-immune. Two sporadic outbreaks were observed, including one with severe malaria cases. To characterize these outbreaks and verify previous observations of specific genotype characteristics in severe malaria in this area, all cases from each outbreak were studied. METHODS: P. falciparum genotypes for six genetic loci were determined by PCR amplification from peripheral blood parasites. The msp1/block2 and msp2 genotypes were determined by DNA sequencing. Microsatellite and varD genotyping was based on size polymorphism and locus-specific amplification. RESULTS: The outbreak including severe malaria cases was associated with a single genotype. The other mild malaria outbreak was due to at least five distinct genotypes. CONCLUSION: Two distinct types of outbreak occurred despite systematic and sustained deployment of malaria control measures, indicating a need for reinforced vigilance. The varD/B-K1 msp1 linkage and its association with severe malaria in this area was confirmed.

Plasmodium falciparum malaria in splenectomized patients: two case reports in French Guiana and a literature review.

Some of the immunologic mechanisms involved in malaria physiopathology remain unclear. In animals, the spleen seems to play a key role in protecting the host against malaria. However, little is known about the effect of spleen dysfunction on human malaria. We report two severe cases of Plasmodium falciparum infection with unusual clinical and parasitologic features in two splenectomized men living in French Guiana. The peripheral blood of these cases showed hyperparasitemia, with a high proportion of mature parasites and leukocytes with malaria pigment. Despite appropriate treatment and adequate absorption, hyperparasitemia persisted. Parasite clearance was delayed and one patient died. Only the patient who died had the merozoite surface protein 1 allele B-K1 and the varD gene genotype, which is considered to be a probable parasite virulence factor. These uncommon cases differ from most of those described in the literature, illustrating the complexity of the mechanisms underlying the protective function of the spleen in human malaria.

In vitro monitoring of Plasmodium falciparum drug resistance in French Guiana: a synopsis of continuous assessment from 1994 to 2005.

Implemented as one arm of the malaria control program in French Guiana in the early 1990s, our laboratory has since established in vitro profiles for parasite drug susceptibility to a panel of eight antimalarials for more than 1,000 Plasmodium falciparum isolates from infected patients. The quinine-doxycycline combination was introduced in 1995 as the first-line drug treatment against uncomplicated P. falciparum malaria, replacing chloroquine, and the first-line drug combination was changed to the artemether-lumefantrine combination in 2002. Resistance to chloroquine declined 5 years after it was dropped in 1995 as the first-line drug, but unlike similar situations in Africa, there was a rapid halt to this decline. Doxycycline susceptibility substantially decreased from 2002 to 2005, suggesting parasite selection under quinine-doxycycline drug pressure. Susceptibility to mefloquine decreased from 1997 onward. Throughout the period from 1994 to 2005, most isolates were sensitive in vitro to quinine, amodiaquine, and atovaquone. Susceptibility to amodiaquine was strongly correlated with that to chloroquine and to a lesser extent with that to mefloquine and halofantrine. Susceptibilities to mefloquine and to halofantrine were also strongly correlated. There were two alerts issued for in vitro artemether resistance in the period from 2002 to 2003 and again in 2005, both of which could be associated with the presence of an S769N polymorphism in the sarcoplasmic/endoplasmic reticulum calcium ATPase (SERCA)-type P. falciparum ATPase6 (PfATPase6) gene. Analysis of susceptibility to lumefantrine, conducted for the first time in 2005, indicates an alarming rate of elevated 50% inhibitory concentrations. In vitro monitoring of parasite drug susceptibility should be pursued to further document the consequences of specific drug policies on the local parasite population and, in particular, to establish profiles of susceptibility to individual components of drug combinations to provide early warning signs of emerging parasite resistance.

Management of chromoblastomycosis: novel perspectives.

PURPOSE OF REVIEW: Significant advances in knowledge of chromoblastomycosis and its etiologic agents have been made in the past 5 years. New explanations and approaches that could resolve persisting medical challenges for this orphan disease are reviewed here. RECENT FINDINGS: In recent years advances have been made regarding the taxonomy and ecoepidemiology of the etiologic agents, basic knowledge of the pathogenesis of the lesions, especially the fibrotic process, and the immunologic response to chromoblastomycosis. Conversely there have been no recent significant advances in knowledge of the genetic polymorphism of the wild isolates or in development of experimental models, impairing the possibility of in-depth clinicopathologic investigations. As a result medical management is dependent on the development of diagnostic and therapeutic tools developed for other fungal diseases. SUMMARY: Recent findings are applicable in laboratory and medical practice. Benefits can accrue to basic knowledge from data collected on other cutaneous diseases of parasitic or bacterial origin.