Six deaths linked to misuse of buprenorphine-benzodiazepine combinations.
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Benzodiazepines↗
Biomedical subjects
G Petit
Publications and source records attributed to G Petit.
[Misuse of buprenorphine-benzodiazepines combination: 6 deaths].
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Adult↗
Immune response to the filaria Litomosoides sigmodontis in susceptible and resistant mice.
Comparisons were made between the immune responses evoked during the course of chronic and patient infections of Litomosoides sigmodontis in susceptible BALB/c mice and non-patent infections in resistant B10.D2 mice. Early antigen specific responses of spleen cells were weak in both mouse strains. However, by day 58 post infection a strong Th2 response, as determined by production of IL-4, IL-5 and IL-10, was observed in BALB/c mice but not in B10.D2 mice. Antibody responses seemed to appear sooner in B10.D2 than in BALB/c mice, and these differentially recognised two antigens of 15 kD and 80 kD.
Animals↗
Early reduction of the challenge recovery rate following immunization with irradiated infective larvae in a filaria mouse system.
The filaria Litomosoides sigmodontis, which develops a patent infection in BALB/c mice, was used to determine the fate of a challenge inoculum following immunization of mice with irradiation attenuated infective larvae (3 subcutaneous inoculations at weekly intervals with 25 L3 irradiated at 60 krad, and challenge with 25 L3 two weeks after the final immunization). The adult worm burden of vaccinated mice was reduced to 50% of that of controls although the pattern of larval migration and microfilaraemia were not affected. Necropsies showed that the increased killing of the filariae of the challenge inoculum occurred at the L3 stage within the first 2 days of challenge. This result draws attention on the protective mechanisms operating very early and probably in the subcutaneous region.
Animals↗
Ivermectin and moxidectin in two filarial systems: resistance of Monanema martini; inhibition of Litomosoides sigmodontis insemination.
Effects of ivermectin and moxidectin were compared on two filarial species: Monanema martini which presents dermal microfilariae and induces Onchocerca-like lesions in its natural murid host Lemniscomys striatus, and Litomosoides sigmodontis (= L. carinii). M. martini microfilariae showed an unusual resistance to ivermectin, in vitro and in vivo; moxidectin was no more efficient. However, the two drugs used at high concentrations deeply altered the uterine embryogenesis, but had no lethal effect on adult filariae. L. sigmodontis blood microfilariae showed a great susceptibility to moxidectin, similar to that previously described for ivermectin. The two drugs also induced a long term effect because they inhibited the insemination of the female filariae. This result reinforces the observations made by other authors on the human parasite, Onchocerca volvulus.
Animals↗
Rapid delineation of closely-related filarial parasites using genetic markers in spacer rDNA.
Two closely-related species of filarial parasite, Litomosoides galizai and L. sigmodontis, were characterised using a polymerase chain reaction-linked restriction fragment length polymorphism (PCR-RFLP) technique. The rDNA region spanning the first and second internal transcribed spacers as well as the 5.8S gene (ITS+) was amplified by PCR from each of the species using conserved primers to the 18S and 28S ribosomal genes, digested separately with a range of restriction endonucleases and the fragments separated by agarose gel electrophoresis. PCR-RFLP of ITS+ using endonucleases Alu I, Cfo I, Dra I, Rsa I and Vsp I produced characteristic patterns for each species. No variation in RFLP patterns was detected among different DNA sample preparations or the sexes of each species. The present study demonstrates that the ITS+ provides genetic markers for the differentiation of L. galizai from L sigmodontis and suggests that internal transcribed spacer rDNA may provide species markers for other filarioid nematodes. Such markers have implications for diagnosis and for studying the biology, pathogenesis and systematics of filarial parasites.
Animals↗
The fate of the filaria Litomosoides sigmodontis in susceptible and naturally resistant mice.
The fate of Litomosoides sigmodontis was compared in susceptible BALB/c and resistant B10D2 mice, presenting the same major histocompatibility complex (H-2d), with an attempt to dissociate the different elements of the life cycle in order, later, to dissociate the different mechanisms involved. Each female mouse was inoculated once with a small dose of infective larvae (25 L3) or a large dose (100 or 200 L3). In total, 92 BALB/c and 49 B10D2 were studied. Necropsies were performed up to D85 following infection with 25 larvae. The early fate was similar in B10D2 and BALB/c mice; particularly the recovery rate of worms was almost identical during the first month p.i. and represented a quarter of the inoculated larvae. Resistance in B10D2 mice appeared progressively, as judged by retardation of growth and of the fourth moulting, the presence of very small sterile female worms and male worms with abnormal left spicule, and a high frequency of live filariae coated with inflammatory cells and encapsulated dead worms. The L. sigmodontis life span in B10D2 was about half that in BALB/c. Necropsies were carried out up to D20 following infection with 100-200 L3. The recovery rate was increased in BALB/c. Growth was retarded earlier in B10D2 mice, this crowding effect already apparent at D10; this may indicate a role for metabolic factors. The pattern of the life cycle in both mouse strains confirms recent conclusions on Onchocercinae: the recovery rate is established as soon as the second day during "phase 1 of massive destruction", then it is stable during "phase 2 of insignificant mortality". During phase 1, the infective larvae are immediately destroyed in the subcutaneous tissue if they are not able to escape the inflammatory process by penetrating in local lymphatic vessels. By contrast, phase 2, which is longer than the duration of the third larval stage, indicates there is no mortality linked to the third moulting, at least following a single inoculation.
Animals↗
[Left ventricular thrombosis complicating systemic lupus erythematosus].
The authors report an isolated pediculated thrombus in the left ventricle of a young 14 year old girl with systemic lupus erythematosus with antiphospholipid antibodies without any other cardiovascular abnormality, especially ventricular wall motion abnormalities. After surgical ablation of the thrombus, the patient was followed up to avoid recurrence. This type of cardiac lesion (ventricular thrombosis without underlying myocardial disease) is exceptionally rare. Echocardiographic follow-up after surgical ablation showed no recurrence of thrombosis after four years.
Adolescent↗
An unusual death by zipeprol overdose.
Capillary gas chromatography coupled to mass spectrometry was employed to quantify zipeprol in biological fluids and tissues in a death attributed to oral zipeprol ingestion. The blood concentration of zipeprol was 6.69 mg/l. Hair analysis clearly indicated chronic drug abuse, with a concentration of 33.1 ng/mg. Results are discussed in the light of the existing literature.
Adult↗
Larval biology of six filariae of the sub-family Onchocercinae in a vertebrate host.
The development of six filariae of the sub-family Onchocercinae-Litomosoides sigmodontis, Acanthocheilonema viteae, Molinema dessetae, Monanema martini, Brugia malayi, B. pahangi-was compared in rodents, following a single inoculation of a low or high dose of infective larvae. Analysis was done with 105 rodents dissected and 53 rodents fixed for histopathology. The percentage of larvae which developed corresponded to the proportion of those which were able to penetrate into the sub-cutaneous lymphatic vessels; this percentage was determined during the first day (phase 1) and was characteristic of the filaria-host pair, and independent of the number of larvae inoculated. It could remain stable for a long time, more than eight months with M. martini (phase 2); the phenomena of regulation appeared later (phase 3). The larvae migrated through the lymphatic system, which represents a medium less protected and thus less aggressive than the blood system. The coelomic cavities, almost devoid of inflammatory cells, represented an ultimate shelter, as well as the joint-cavities (colonized by some Dirofilariinae). Localizations in the cardio-pulmonary blood system were accidental and occurred when, during the migrations, some larvae penetrated into the thoracic channel and arrived in the superior vena cava, then the right ventricle and the pulmonary arteries (the biology of Dirofilaria immitis resulted in a secondary adaptation); such accidents may occur with adult filariae, especially, after drug treatment. One may expect similar events in human filariasis. These "occult" filariae, more frequent than it is usually thought, influence the immunological status and the pathology.
Animals↗
Monanema martini in its murid hosts: microfiladermia related to infective larvae and adult filariae.
The microfiladermia of Monanema martini was studied in two natural murid hosts, Lemniscomys striatus and Arvicanthis niloticus, with 137 and 39 rodents respectively inoculated once, twice or several times. Microfilarial densities (mf/mm2) were measured at the ear pinna every three months. Almost all the rodents developed a microfiladermia. When L. striatus rodents were inoculated once with 30, 80, or 400 infective larvae, microfiladermia increased (peaks of 108, 148, 174 mf/mm2 respectively, at six to nine months p.i.); this fits with the fact that, in this filaria-host pair, the number of adult filariae is proportional to the number of inoculated larvae, and remains at a constant level for more than eight months. Nevertheless microfiladermia was limited, especially during the peak, showing the complexity of its regulatory mechanisms. Several low doses over one year, resulting in 145 L3, increased the microfiladermia at the same level than one dose of 400 larvae; the recovery rate of the larvae was reduced but the total number of filariae recovered was increased. A. niloticus, from which the filarial strain originates, showed a much lower microfiladermia than L. striatus (7 mf/mm2 with 80 larvae, at six months p.i.). This was due to a smaller recovery rate of the infective larvae in this host and, overall, to a reduced fertility of the female worms and a shorter lifetime of adult filariae. However, repeated inoculations increased the microfiladermia (32 mf/mm2), due to the constant presence of small numbers of young filariae producing microfilariae. It is to be noted that the two biological systems presented by M. martini in L. striatus and A. niloticus correspond to the two types of ocular pathology described in a recent opthalmological study, chorioretinal atrophy and keratitis respectively.
Animals↗
Is disease progression the major factor in morphine 'tolerance' in cancer pain treatment?
To assess the contribution of pharmacological tolerance to increasing doses of morphine, 29 cancer patients requiring oral morphine to treat pain were studied by two teams working independently. The first team assessed physical impairment, pain intensity and pain treatment. The second team assessed depressive disorders (DSM III criteria), emotional and behavioural depressive patterns (Retardation Depressive Scale, Polydimensional Mood Scale). All patients were seen at the initiation of morphine therapy and followed to the first morphine dose modification. Evaluations were carried out in out-patient clinics except staging investigations which were undertaken at the beginning and at the end of the study. Our results showed that (1) in 24 of the 25 patients for whom morphine doses were increased, progressive disease was recorded; (2) in 4 patients, morphine doses were not increased and in these patients their disease was stable or in remission; and (3) changes in depressed mood were not correlated with pain intensity. These data strongly suggest that, instead of pharmacological tolerance, the main factor resulting in increasing oral morphine requirement in cancer pain management is pain increase due to disease progression.
Adult↗
Effect of ivermectin on two filaria-vector pairs. Brugia malayi-Aedes aegypti; Litomosoides sigmodontis-Bdellonyssus bacoti.
The effect of ivermectin was studied on two filaria-vector pairs, Brugia malayi-Aedes aegypti and Litomosoides sigmodontis-Bdellonyssus bacoti. The rodent hosts, respectively Mastomys coucha and Meriones unguiculatus, were treated with ivermectin doses of 0.05 mg/kg, or 0.2 mg/kg or 2 mg/kg. Batches of vectors were fed on rodents, infected or not, treated or not, from H7 to D43 post-ivermectin. Vector survival was observed and dissections were performed to study the filarial development. It appears that ivermectin has no systemic effect on vectors, or very little. The drug acts on transmission because it affects the microfilariae. Transmission of L. sigmodontis is blocked because microfilariae are eliminated from the blood. Transmission of B. malayi is blocked although microfilaremia remains present at a low level. Two particular features are observed: microfilariae are hyper-ingested, but they do not cross the stomach wall (in contrast, they cross at a high rate in the control batch of Aedes, due to the "stomach wall limitation"). These events might be explained by a muscular passivity of the microfilariae treated with ivermectin. Transmission of the two filarioid species is restored normally about D25-40 post ivermectin because a new population of microfilariae has appeared. These ivermectin experiments emphasize the diversity and complexity of two important phases of the filarial cycle in the vector: the ingestion of microfilariae and the passage through the stomach wall.
Aedes↗
Ophthalmological study of the lesions induced by the filarial worm with dermal microfilariae, Monanema martini, in its murid hosts.
The filaria Monanema martini with skin-dwelling microfilariae induces in its natural murid hosts lesions similar to those in human onchocerciasis. This was demonstrated by histo-pathological studies but it appeared useful to evaluate the model by a clinical investigation. An ophthalmological analysis was performed on the two species of hosts, inoculated by one, two, or multiple doses of larvae, and with infections of at least one year duration. A total of 140 eyes was examined (anterior and posterior segments). We established a system for enumerating the different types and severities of lesions. We prepared a file for each eye and attempted to quantify our observations. The significant lesions were different in the two host species. In Arvicanthis niloticus, in which motile microfilariae were seen in the anterior segment, punctate keratitis was predominant. In Lemniscomys striatus, the posterior segment showed complete chorioretinal atrophy, similar to the final stage of onchocercal chorioretinitis in humans. M. martini represents in its natural hosts two complementary models for the study of the pathogenesis and treatment of human onchocerciasis.
Animals↗
Maturation of the filaria Litomosoides sigmodontis in BALB/c mice; comparative susceptibility of nine other inbred strains.
When inoculated subcutaneously, the infective larvae of L. sigmodontis undergo complete development and produce a patent microfilaraemia in mice of the BALB background (BALB/c, BALB/K and BALB/B, with respectively the H-2d, H-2k et H-2b haplotypes). The most susceptible strain is BALB/c with all mice harbouring adult filariae and 47% of mice presenting with a patent microfilaraemia. Mice with the B10 background (B10, B10Br and B10D2, with respectively the H-2b, H-2k et H-2d haplotypes) are almost completely resistant to infection. Adult filariae were recovered from all mice of the CBA/Ca, CBA/HN, C3H/HeN, DBA/2N strains. However, the site and structural development of the parasite varied in each strain. Absence of microfilaraemia is associated with absent or abnormal spicules, reduced number of female filariae and small size of female filariae. These results show that the Major Histocompatibility Complex only modulates the developmental pattern of filariae within the limits imposed by background genes. Male CBA/HN and C3H/HeN were more susceptible to infection than female mice. Inverse phenomenon was observed with strains BALB/c; and, no host sex effect was seen in DBA/D2N.
Animals↗
The filaria Litomosoides galizai in mites; microfilarial distribution in the host and regulation of the transmission.
The mites, Bdellonyssus bacoti, are engorged on rodents having 800 to 60,000 microfilarie/10 mm3 blood. Quantitation of L. galizai larval development shows that an additional blood meal improves development and that high microfilaremiae do not result in a proportional increase in the number of infective larvae. The first important stage of transmission regulation occurs during ingestion of microfilariae: the numbers of ingested microfilariae are lower than expected in cases of high microfilaremia. This phenomenon cannot be ascribed to the mite vector that engorges a constant blood meal whatever the level of microfilaremia. Contrarily, one finds that microfilarial density in the small peripheral blood vessels (blood drawn from incision of the dorsal skin) increases less than in large blood vessels (retro-orbital sinus). A similar observation was reported by Dickerson et al. (1989) working with Wuchereria bancrofti. We assume that in both cases, the high microfilaremiae cause the small blood vessles accessible to the vector to become saturated with parasites. Although regulation during engorging is not the sole factor to monitor the infection in B. bacoti (another one operates during larval development of L. galizai), demonstrating its existence seems to us fundamental: it points out the concept that sub-ingestion, as well as over-ingestion, shows the inequalities of microfilarial densities in the host which seem to be dependent on mechanical factors such as the diameter of blood vessles and the size of microfilariae.
Animals↗
Prevalence of HIV infection among patients with leprosy in African countries and Yemen.
Screening for human immunodeficiency viruses types 1 and 2 (HIV-1 and HIV-2) antibodies was carried out in the serum of 1,245 leprous patients and 5,731 controls selected in nine different centers from the Congo, Ivory Coast, Senegal, and Yemen Arab Republic. In Yemen, all sera were negative. In the Congo, the seropositivity among patients and controls was, respectively, 3.8 and 5.2%; in Senegal, it was 1.3 and 0.6%; and in the Ivory Coast 4.8 and 3.9%. Differences were not statistically significant, even considering lepromatous or tuberculoid forms (3.6% and 3.7%, respectively). HIV-2 antibodies were only detected in subjects from the Ivory Coast and Senegal. Using appropriate criteria for seropositivity (confirmation by Western blot, reactivity to HIV envelope glycoproteins) and a large selection of patients (several countries with several centers), it appears that leprosy (and specially the lepromatous form) is not a factor for HIV infection.
Adolescent↗
[Litomosoides, parasites of rodents; taxonomic consequences].
A redescription of the type specimens of the three following species is given: L carinii (Travassos, 1919) from Sciurus sp. in Brazil. L, sigmodontis Chandler, 1931 from Sigmodon hispidus and L. scotti Forrester et Kinsella. 1977 from Oryzomys palustris in North America. A description of two brazilian species is also given: L. galizai n. sp. from (Ecomys trinitatus tapajinus and L. kohnae n. sp. from Nectomys squamipes. The conclusions are: The type species of the genus Litomosoides: L. sigmodontis, and L.carinii are two distinct species. As a result, the filaria which is widely used in drug trials has to be reinstated sigmodontis and not curinii. With the exception of the two parasite species of Geomyid rodents, which show affinities with the genus Litomosa, the species of Litomosoides may be devided into two groups, principally based on the morphology of the spicules: the sigmodontis group, with 13 species; the carinii group, with 8 species. Each group includes parasites of Chiuroptera, Marsupials and Rodents. The two new species (L. galizai and L. kohnae) belong to the group sigmodontis; they are characterised by the shape of the buccal capsule, the size of the spicules, the structure of the female body-wall and the microeilaria.
Animals↗