Comparative population genomics in animals uncovers the determinants of genetic diversity.

Genetic diversity is the amount of variation observed between DNA sequences from distinct individuals of a given species. This pivotal concept of population genetics has implications for species health, domestication, management and conservation. Levels of genetic diversity seem to vary greatly in natural populations and species, but the determinants of this variation, and particularly the relative influences of species biology and ecology versus population history, are still largely mysterious. Here we show that the diversity of a species is predictable, and is determined in the first place by its ecological strategy. We investigated the genome-wide diversity of 76 non-model animal species by sequencing the transcriptome of two to ten individuals in each species. The distribution of genetic diversity between species revealed no detectable influence of geographic range or invasive status but was accurately predicted by key species traits related to parental investment: long-lived or low-fecundity species with brooding ability were genetically less diverse than short-lived or highly fecund ones. Our analysis demonstrates the influence of long-term life-history strategies on species response to short-term environmental perturbations, a result with immediate implications for conservation policies.

Population genomics of eusocial insects: the costs of a vertebrate-like effective population size.

The evolution of reproductive division of labour and social life in social insects has lead to the emergence of several life-history traits and adaptations typical of larger organisms: social insect colonies can reach masses of several kilograms, they start reproducing only when they are several years old, and can live for decades. These features and the monopolization of reproduction by only one or few individuals in a colony should affect molecular evolution by reducing the effective population size. We tested this prediction by analysing genome-wide patterns of coding sequence polymorphism and divergence in eusocial vs. noneusocial insects based on newly generated RNA-seq data. We report very low amounts of genetic polymorphism and an elevated ratio of nonsynonymous to synonymous changes ­ a marker of the effective population size ­ in four distinct species of eusocial insects, which were more similar to vertebrates than to solitary insects regarding molecular evolutionary processes. Moreover, the ratio of nonsynonymous to synonymous substitutions was positively correlated with the level of social complexity across ant species. These results are fully consistent with the hypothesis of a reduced effective population size and an increased genetic load in eusocial insects, indicating that the evolution of social life has important consequences at both the genomic and population levels.

Discovery of parvovirus-related sequences in an unexpected broad range of animals.

Our knowledge of the genetic diversity and host ranges of viruses is fragmentary. This is particularly true for the Parvoviridae family. Genetic diversity studies of single stranded DNA viruses within this family have been largely focused on arthropod- and vertebrate-infecting species that cause diseases of humans and our domesticated animals: a focus that has biased our perception of parvovirus diversity. While metagenomics approaches could help rectify this bias, so too could transcriptomics studies. Large amounts of transcriptomic data are available for a diverse array of animal species and whenever this data has inadvertently been gathered from virus-infected individuals, it could contain detectable viral transcripts. We therefore performed a systematic search for parvovirus-related sequences (PRSs) within publicly available transcript, genome and protein databases and eleven new transcriptome datasets. This revealed 463 PRSs in the transcript databases of 118 animals. At least 41 of these PRSs are likely integrated within animal genomes in that they were also found within genomic sequence databases. Besides illuminating the ubiquity of parvoviruses, the number of parvoviral sequences discovered within public databases revealed numerous previously unknown parvovirus-host combinations; particularly in invertebrates. Our findings suggest that the host-ranges of extant parvoviruses might span the entire animal kingdom.

Putative neurotransmitters in three experimental filariasis models.

Some putative neurotransmitters in three experimental filariasis models were investigated by a new relevant chromatographic method, sensitive and specific. No catecholaminergic compounds have been detected, but serotonin was found in Dipetalonema vitae. However, further investigations revealed very high levels of gamma amino butyric acid (GABA) in the macro-filariae. These data allow us to foresee new fields in filariasis therapeutics.

Microtopography of Nippostrongylus brasiliensis (Nematoda: Heligmosomatidae): free-living larval stages.

Microtopographic features of the various growth stages of the three free-living larval stages of the rat hookworm Nippostrongylus brasiliensis (Nematoda) were surveyed by scanning electron microscopy. These worms have a rounded anterior end and an elongated tail. Cuticular annulations were observed along the body, which also bore two ribbon-like lateral alae. Two rings of six lip-like lappets were observed around the triradiate oral opening in all larval stages. The cephalic space contained two lateral amphidial pits. The excretory pore in the third anterior part was observed in a ventral view of the larvae. No deirids were observed. The anus with a crescent-shape opening was located posteriorly. Phasmidial apertures, only observed in the third-stage larvae, opened on the lateral alae in the tail region.

Microtopography of Nippostrongylus brasiliensis (Nematoda: Heligmosomatidae): parasitic larval stages and adults.

Specimens of the rat hookworm, Nippostrongylus brasiliensis (Nematoda) were recovered from lungs (third- and fourth-stage larvae) and intestine (fourth-stage larvae and adults). The following features were studied in the different stages by scanning electron microscopy: cephalic structures, especially sense organs, synlophe, cervical region, and caudal part. The main differences between the third and fourth stages concerned the lip-like structures around the oral aperture, the appearance of the cephalic space with the presence of a cephalic cap in fourth-stage larvae, the pattern of longitudinal ridges, and sexual differentiation. Pore-like papillae, not seen in third-stage larvae, developed in later stages. Deirids were observed only in adults, and phasmids were poorly discerned. Some of these morphological features, such as the cephalic sense organ apertures and cuticle pores and micropores, can be observed only by scanning electron microscopy. The possible functions of these different structures and their relationship with the behavior of the worms during their life cycle are discussed.

Unloaded polyisobutylcyanoacrylate nanoparticles: efficiency against bloodstream trypanosomes.

The potential use of polyisobutylcyanoacrylate nanoparticles in antiparasitic chemotherapy is described. The nanoparticles on their own proved to have trypanocidal activity against Trypanosoma brucei brucei in-vitro but not against Trichomonas vaginalis or Entamoeba histolytica. The trypanocidal activity was partly confirmed in-vivo with T. brucei-infected mice.

In-vitro evaluation of filaricidal activity of GABA and 1,3-dipalmitoyl-2-(4-aminobutyryl)glycerol HCl: a diglyceride prodrug.

A diglyceride ester of gamma-aminobutyric acid (GABA) has been synthesized and its filaricidal activity compared with GABA, and progabide in-vitro, on infective larvae and microfilariae of Molinema dessetae, a rodent filaria. GABA induced paralysis in infective larvae but was inactive on microfilariae. There were interactions between the culture medium and GABA. The ester drug at 0.1 mmol L-1 (1,3-dipalmitoyl-2-(4-aminobutyryl)glycerol HCl) was as active as progabide on infective larvae and hundredfold more potent than GABA. Its microfilaricidal activity at 1 mmol L-1 was lower than that progabide at 0.1 mmol L-1 but a delayed effect was observed. The data confirm filariae sensitivity to GABA derivatives.

Study of lymphotropic targeting and macrofilaricidal activity of a melphalan prodrug on the Molinema dessetae model.

This study deals with the design of a new macrofilaricidal drug derived from melphalan and having a lymphotropism to avoid the hepatic first pass effect and enhance bioavailability after oral administration. Melphalan was linked to a ligand leading to a prodrug called 1,3-dp-melphalan which has structural analogy to triglycerides. The Molinema dessetae/Proechimys oris model was used for antiparasitic evaluation. Melphalan was macrofilaricidal in vitro against Molinema dessetae at 1mM, inactive in vivo after an oral single dose at 164 mumol/kg while the prodrug 1,3-dp-melphalan was active against adult worms after a single dose at 82 mumol/kg. After an oral administration of the prodrug to rats, the maximum concentration and the cumulated quantities of melphalan in lymph were about 45-fold higher than those observed with the free drug under the same conditions. Moreover, the plasma concentration of melphalan was 2-fold higher than those observed after the administration of the free drug. These results are in favor of lymphotropic targeting as a novel approach to develop new orally active macrofilaricides.

Synthesis and anthelminthic evaluation of 2-amidino-1,3,4-oxa and 1,3,4-thiadiazoles, structurally related to tetramisole.

N-(1,3,4-thiadiazol-2-yl) 1a-1k and N-(1,3,4-oxadiazol-2-yl-) amidines 2a-2g, N-(1,3-thiazol-2-yl) 3a, 3b and N-(1,3-benzothiazol-2-yl-)amidines 4a, 4b were synthesized and tested as anthelminthics, in vitro, against a free nematode (Rhabditis pseudoelongata), against infecting larvae of an intestinal parasite of rats (Nippostrongylus brasiliensis) and against infecting larvae of a filaria (Molinema dessetae).

Synthesis and nematocidal activity of arylmercaptovinyltetrahydropyrimidines.

A set of mercaptovinyl tetrahydropyrimidines was synthesized in good yields by lithiation of 1,2-dimethyltetrahydropyrimidine with n-butyl lithium in tetrahydrofurane, followed by condensation with aromatic thioesters. Against three nematode genera, anthelminthic screening shows little activity; 2b and 2d were the most potent against Molinema dessetae.

Synthesis of some 4-oxo-delta 2-thiazolin-2-ylhydrazones as potential antiprotozoal agents.

Several 4-oxo-delta 2-thiazolin-2-ylhydrazone derivatives 6 (6-1 - 6-19) derived from the cyclization reaction between the thiosemicarbazones 5 and homologous alpha-chloroacids were prepared. Only compound 6-2 was found to be active against Entamoeba histolytica and Trichomonas vaginalis.

[Experimental filariasis in Proechimys oris by Dipetalonema dessetae: 4. Effect of parasitism on protein and tissue binding of diethylcarbamazine]. / Filariose expérimentale du Proechimys oris par Dipetalonema dessetae: 4. Influence du parasitisme sur la fixation protéique et tissulaire de la diethylcarbamazine.

Several groups of control and filaria-infected Rodents were treated by radio-labelled diethylcarbamazine in order to study the effect of parasitism on the protein binding and tissue distribution of the drug. These studies were performed using equilibrium dialysis, chromatography and autoradiography. The plasmatic protein concentrations were lower in the group of infected Rodents, due to a decrease of albumin. The binding rate depended on the electrophoretic fractions, but remained low and unaffected by parasitism. The radioactivity of DEC and its metabolites appeared very quickly in the tissues, particularly in infected Rodents. This was due to the fact that the already rapid intestinal absorption and diffusion were enhanced by filariasis.

[Experimental filariasis in Proechimys oris by Dipetalonema dessetae. 5. Effect of parasitism on metabolism of diethylcarbamazine]. / Filariose expérimentale du Proechimys oris par Dipetalonema dessetae: 5. Effet du parasitisme sur le métabolisme de la diéthylcarbamazine.

The metabolism of diethylcarbamazine (DEC) in healthy and filaria-infected Proechimys oris Rodents was investigated. DEC and 14C labelled DEC were orally administrated (100 mg/kg). The drug was quickly and intensively metabolised. About 90% of the dose administered was eliminated in the urine within 24 hours. Monodeethylation was the major pathway. The major urinary metabolites were ethylcarbamazine and its N-oxide. Traces of N methylpiperazine 2,5 dione and their N-oxide were also found. Elimination was faster in filarial than in healthy animals, but metabolites were the same.

Experimental filariasis of Dipetalonema dessetae in Proechimys oris: 3. Effects of parasitism on the pharmacokinetics of diethylcarbamazine.

The pharmacokinetic parameters of diethylcarbamazine were compared in the plasma and peritoneal fluid of 5 non-infected rodents. In the filarial animals, the absorption rate constant and the elimination rate constant were significantly increased. The peak plasma concentration was twofold higher in the infested rodents than the control animals, and this may account for the rapid action of diethylcarbamazine on blood-circulating microfilariae. The area under the curve was unchanged. Total clearance is slightly increased in filarial rodents. These data are explained by an important reduction of renal clearance combined with a moderate increase of extra renal clearance. High levels of diethylcarbamazine in peritoneal fluid, resulting from the excellent diffusion of the drug in filarial animals explains the activity on adult worms. But the parasitism does not affect the mechanism of distribution of the drug between plasma and peritoneal liquid.

Activity of albendazole-ivermectin combination and other filaricidal drugs against infective larvae, preadult, microfilariae and adult worms of Molinema dessetae in the rodent Proechimys oris.

The efficacy of albendazole-ivermectin combination was tested an adult and developing stages of Molinema dessetae in the rodent Proechimys oris. Albendazole and ivermectin, both given alone, suramin and diethylcarbamazine were used as reference compounds. The drug combination (albendazole at 10 mg/kg/ day x 5 days and Ivermectin at 0.04 mg/kg/day x 5 days) was effective against infective larvae and preadult worms, and substantially reduced the number of live adult worms. The known filaricidal agents, diethylcarbamazine (400 mg/kg twice daily x 5 days), ivermectin (0.2 mg/kg/day x 5 days), and suramin (40 mg/kg/day x 5 days), as well as albendazole (50 mg/kg/day x 5 days) were active on infective larvae, preadult worms, microfilariae and adult worms. All drugs had the same level of efficacity on infective larvae. Albendazole had the highest efficacy against adult and preadult worms and diethylcarbamazine was the most active on microfilariae. Although the drug combination was not as effective against preadult and adult worms as albendazole alone, the results indicate that albendazole-ivermectin combination at a low dose had prophylactic effect and suggest a possible macrofilaricidal activity.

[Fluctuations of serotonin and its metabolites in the lung and intestinal mucosa in the rat infected with Nippostrongylus brasiliensis]. / Fluctuations de la sérotonine et de ses métabolites au niveau du poumon et du mucus intestinal chez le rat infesté par Nippostrongylus brasiliensis.

The influence of parasitism on host biogenic amine levels was investigated in Nippostrongylus brasiliensis infected rats. Amine levels were estimated in tissues surrounding Nematods in their biological environment: the lung and intestinal mucus. D0 being the day of infestation, tissues were obtained at 24, 30 and 45 hrs, and every day between D4 and D14 (when the rat was completely deparasited by the self-cure phenomenon). Biogenic amines belonging to the serotoninergic pathway were quantified by HPLC with electrochemical detection. In the lungs and mucus, parasitism resulted in an important decrease in serotonine (5-HT) and 5-hydroxyindolacetic acid (5-HIAA) levels, as opposed to the immediate 5-HT precursor, the 5-hydroxy-tryptophane (5-HTP). Host response to parasitism is translated by serotoninergic pathway levels. This leads to two hypotheses: 5-HT turn-over may be accelerated, but the inhibition of 5-HT synthetic enzyme, 5-hydroxytryptophane hydroxylase, by the parasite present in the host seems more probable.

[Leponex: experience of the hospital pharmacist]. / Leponex: l'expérience du pharmacien hospitalier.

Clozapine's monitoring, with a co-responsibility between psychiatrists and pharmacists, is very efficient for the prevention of neutropenia's side effects. This intensive drug safety has lowered the cases of agranulocytosis in France to a 0.5% prevalence. However the cost of clozapine led to a strict estimation for health expenditures. Our study, performed in a university department of psychiatry in Sainte-Anne Hospital (Paris), has included 14 patients treated with clozapine for at least 12 months and has displayed a decrease of 10% in their annual global cost, comparing with the same group of patients treated by classical neuroleptics during the preceding year. This global cost includes the treatment, the blood monitoring and the cost of different hospital or community cares. Quality of life, in the clozapine group, was much improved, as illustrated by the shortened full time hospitalization which was followed at an earlier stage by community care and earlier social readaptation.

[Leponex: experience of the hospital pharmacist]. / Leponex: l'expérience du pharmacien hospitalier.

Clozapine's monitoring, with a co-responsibility between psychiatrists and pharmacists, was very efficient for the prevention of neutropenia's side effects. This intensive drug safety has lowered the agranulocytosis' cases in France to a 0.5% prevalence. However the cost of clozapine led to a strict estimation for Health expenditures. Our study, trained in an university department of psychiatry in Sainte-Anne Hospital (Paris), has included 14 patients treated with clozapine during at least 12 months and has displayed a decrease of 10% in their annual global cost, comparing to the same group of patients treated by classical neuroleptics during the preceding year. This global cost includes the treatment, the blood monitoring and the cost of different hospital or community cares. Quality of life, in clozapine group, was much improved as illustrated by lowing full time hospitalization relayed earlier by community care and precocious social readaptation.

[Chemotherapy in Alzheimer's disease. Retrospective study in a specialized hospital center]. / Chimiothérapie dans la maladie d'Alzheimer. Etude rétrospective dans un Centre Hospitalier Spécialisé.

In this study, our aim was to analyse the prescriptions of drugs used to improve Alzheimer's disease at CHS Paul Guiraud. This study was carried out a posteriori on 16 hospitalized patients. We have seen that for our patients there is no general rule, nor therapeutic scheme but the choice of treatment is carried out according to the professional experience of the physician. The treatment therefore is composed of symptomatic drugs alone or associated with etiologic drugs. Eleven anxiolytic or hypnotic drugs were prescribed. Alimemazine is the most prescribed in the sixteen cases. The preferential use of this drug can be explained by its presentation in the form of drops. In two cases, behavioural improvements were noted, in two other cases, we noted accentuation of dementia. Meprobamate used in seven cases of the sixteen, was never used alone. We find neuroleptics in fifteen of the sixteen cases studied: In seven cases they were administered from the beginning of the hospitalisation; for the others they were introduced later during a phase of agitation or delirium. On the whole, they were effective on aggressive agitation, in particular thioridazine. Eight of the patients, were treated with halopéridol. In two cases, the behaviour disorders were not stopped; in four cases, there was a worsening of dementia. We noted depression in 6 cases from the beginning of hospitalization, and two cases during hospitalization. The anti-depressive drugs besides their main effect, reduce also anxiety. In two cases, we observed an aggravation of disorientation and confusion following of the prescription of amitryptiline and mianserine.(ABSTRACT TRUNCATED AT 250 WORDS)