Exposure to HIV-protease inhibitors selects for increased expression of P-glycoprotein (ABCB1) in Kaposi's sarcoma cells.

BACKGROUND: Given that HIV-protease inhibitors (HIV-PIs) are substrates/inhibitors of the multidrug transporter ABCB1, can induce ABCB1 expression, and are used in combination with doxorubicin for AIDS-Kaposi's Sarcoma (KS) treatment, the role that ABCB1 plays in mediating multidrug resistance (MDR) in a fully transformed KS cell line (SLK) was explored. METHODS: The KS cells were exposed to both acute and chronic treatments of physiological concentrations of different HIV-PIs (indinavir, nelfinavir, atazanavir, ritonavir, or lopinavir), alone or together with doxorubicin. The ABCB1 mRNA and protein expression levels were then assessed by qRT-PCR and western blotting, flow cytometry, and immunofluorescence. RESULTS: Chronic treatment of SLK cells with one of the five HIV-PIs alone or together resulted in increased resistance to doxorubicin. Co-treatment with one of the HIV-PIs in combination with doxorubicin resulted in a synergistic increase in resistance to doxorubicin, and the degree of resistance was found to correlate with the expression of ABCB1. The SLK cells were also revealed to be cross-resistant to the structurally unrelated drug paclitaxel. CONCLUSION: These studies suggest that ABCB1 is primarily responsible for mediating MDR in SLK cells selected with either HIV-PIs alone or in combination with doxorubicin. Therefore, the roles that ABCB1 and drug cocktails play in mediating MDR in KS in vivo should be evaluated.

Isolated spleen metastatic involvement from a colorectal adenocarcinoma complicated with a gastrosplenic fistula. A case report and literature review.

We present the case of a 66-year-old man with a moderately differentiated adenocarcinoma of the left colon and isolated spleen metastases, complicated with a gastrosplenic fistula. The patient underwent a palliative segmental resection of the primitive colic tumour, as no curative treatment could be offered in view of the spleen involvement. Adjuvant chemotherapy was started. After a few chemotherapy treatments, he developed a gastrosplenic fistula which required the resection of the spleen and the greater gastric curvature together. This fistula was, among other things, responsible for bad breath that immediately disappeared postoperatively. At the end of the chemotherapy course, all carcinologic features had also disappeared.

Valved central venous catheter connected to subcutaneous port: A multicenter phase IV study based on a cohort of 50 oncology patients.

PURPOSE: Since technical aspects and clinical features of central venous valved catheters are far from being completely understood, a multinational group of investigators has decided to assess a new distally-valved catheter connected to a port, in the clinical setting of oncology patients undergoing chemotherapy, in an attempt to verify its safety and viability, while also investigating its practical features. METHODS: Our project was structured as a phase IV multicenter study. Hospitalized adults (ages 18-80 years) who had solid tumors and were candidate for intravenous chemotherapy met the criteria to enter the study. One single type of port was used (made of titanium, plastic and silicone) connected to a silicone, distally valved catheter (as manufactured by B. Braun Aesculap). A case report form was provided for each treated case; all relevant data regarding implantation and follow-up were entered into the form, mailed to a coordinating center (G. Chevillon, B. Braun Medical, France) and stored in a software database for statistical analysis. RESULTS: 50 patients (from 6 participating centers) were included in this study. No major complications occurred at insertion. The most frequent clinical problem during follow-up was inability to draw blood samples (9% during the first chemotherapy cycle; 8% after the second cycle); blood obtained from the device was defined 'unsuitable for hematology test' in 9% of the cases at first chemotherapy cycle and in 23% of the cases after the second cycle. No catheter obstruction occurred. CONCLUSION: The distally valved catheter port tested in this study was reliable, safe and practical for long-term treatment of an oncology patients' population undergoing chemotherapy. As most other reports and clinical trials dealing with other types of distally valved catheters pointed out, inability to draw viable blood samples (so called withdrawal occlusion) is a major concern in their clinical use. Mechanisms underlying this technical problem are still unclear.

Assessment of neurotoxicity following repeated cremophor/ethanol injections in rats.

As the mixture cremophor/ethanol is known to have side-effects affecting the peripheral nervous system, we have assessed its behavioural and morphological neurotoxicity after repeated intraperitoneal injections in male Sprague Dawley rats. Clinical status of the animals was good throughout the experiment and no motor deficits were observed. Nevertheless, sensory testing demonstrated an hyperalgesia and an allodynia to mechanical stimuli, associated to peripheral axon degeneration.

The effects of diet, ad Libitum feeding, and moderate and severe dietary restriction on body weight, survival, clinical pathology parameters, and cause of death in control Sprague-Dawley rats.

A 2-year study was conducted in Sprague-Dawley rats to compare the effects of ad libitum (AL) feeding and dietary restriction (DR) on body weight, survival, cause of death, and clinical pathology parameters. Three groups of 120 rats/sex each received the following daily rations of a maintenance rodent diet: ad libitum (AL group); 75% of adult AL food consumption (25% DR group); and 45% of adult AL food consumption (55% DR group). Among the 3 groups, there were generally no differences in relative (food intake per gram of body weight) food consumption. Compared to the AL group, decreased body weight gain occurred in DR groups and was associated with an increase in survival proportional to the DR rate. The main cause of death was pituitary adenomas in all groups. Decreases in total leukocyte, segmented neutrophil, lymphocyte, and platelet counts occurred in the 55% DR group. In serum biochemistry, there were decreases in total protein, albumin, total and HDL cholesterol, and total calcium, and increases in alkaline phosphatase activities and chloride in 55% DR females, as well as decreases in triglycerides in the 55% DR group and in 25% DR females. Results of urinalyses showed decreases in urine volume and protein, and increases in urinary pH in both DR groups. In conclusion, a DR rate of approximately 25% appears to be appropriate for Sprague-Dawley rats in toxicity and carcinogenicity assays to improve survival without impairing growth and routine clinical pathology parameters.

Description of a short-term Taxol-induced nociceptive neuropathy in rats.

This work describes a new animal model of neuropathic pain produced by the single intraperitoneal administration of Taxol (32 mg/kg) to male Sprague-Dawley rats. During the course of the experiment, the clinical status of the rats remained satisfactory and motor function was not altered. A number of classical behavioural tests of nociception as well as histological and electrophysiological investigations were performed. Taxol administration produced an important and rapidly developing mechanical hyperalgesia, a thermal hypoalgesia but no mechanical or thermal allodynia. Degenerative changes were observed in the sciatic nerve, the nerve fibres in the paw subcutaneous tissue and in the lumbar spinal cord. When Taxol or vehicle (a mix of Cremophor and ethanol) were repeatedly injected once a week for 5 weeks, similar nociceptive disorders were observed in addition to a decrease in peripheral nerve conduction velocity. The selective dysfunction of high-diameter myelinated fibres observed after one single administration of Taxol (32 mg/kg) may be attributable to paclitaxel-induced neuropathy, however other mechanisms causing neurochemical dysfunction must also be involved.

[Implantation of autologous chondrocytes for cartilagenous lesions in young patients. A study of 24 cases]. / Implantation de chondrocytes autologues pour lésions cartilagineuses du sujet jeune. Etude de 24 cas.

STUDY AIM: The aim of this study was to describe the treatment of symptomatic knee cartilage defects on young active patients by autologous chondrocyte implantation and to report preliminary results in 24 patients. PATIENTS AND METHODS: Since April 1996, 24 selected patients underwent 25 implantations in five military hospitals. There were 19 men and five women (all of them practicing sports); mean age was 27. Lesions were localized on left (n = 13) and right (n = 12) aligned and stabilized knees. There were 12 isolated cartilage defects (eight OCD and four posttraumatic) and 13 associated with ligament lesions (n = 8) or multiple and severe lesions (n = 3 indication of salvage). Mean surface of cartilage defects was 6 cm2. Mean preoperative evolution was 11 months and stage was grade IV (Outerbridge) for all. The first step was arthroscopy for classification and biopsy. The second one was implantation after a 3-week delay (for the ex vivo culture) through arthrotomy, under a periosteal flap taken from tibia and sutured on the edges of the prepared defect. Weight bearing was allowed after the 6th week; MRI was performed at 6, 12, 18, 24 months. The follow up was evaluated with three scales: Lysholm 2, Tegner Activity, Cincinnati Knee Rating System. RESULTS: Postoperative complications included: algodystrophy (n = 2) and phlebitis (n = 1). Four patients were revised at 6 months, seven between 6 and 12 months, 11 after. The longest follow-up was 26 months. Results were poor in one patient (salvage). For the others, pain and swelling decreased after 6 months and disappeared after 12 months. CONCLUSION: Autologous chondrocyte implantation used in this senes and in a large international ongoing series seems to be the only procedure allowing a true long-term regeneration of cartilage defects. Some questions remain, on the biological level in relation with the use of some growth factors and the risk of chromosomic abnormalities, and on the economical level because of the high cost of this technique.

Lipidosis induced in the dog gallbladder by a direct 5-lipoxygenase inhibitor.

The direct 5-lipoxygenase inhibitor L-739,010 was administered at a dose of 60 mg/kg/day per os to beagle dogs for 15 days. Histopathological examination of gallbladders from treated dogs showed epithelial vacuolation and submucosal infiltration by foamy macrophages that were positive for lipids in Sudan Black-and/or Oil Red O-stained sections. Scanning electron microscopic examination of gallbladder mucosa showed thickening of epithelial folds and multifocal epithelial membrane disruptions. Transmission electron microscopy confirmed these findings and showed mucosal epithelial cell lipid droplet accumulation and submucosal infiltration of macrophages filled with lipid droplets, myelin figures, heterophagosomes, and cholesterol clefts. These changes resembled those reportedly seen in the human gallbladder with cholesterolosis and/or chronic cholecystitis.

Spontaneous retinal changes in Sprague Dawley rats.

Routine ophthalmological examination of over 6,000 untreated Crl:CD(SD)BR rats up to 2 years old, used in toxicologic studies from 1989 to 1992, has provided information on spontaneous retinal changes and their incidence with age. Focal linear retinopathy and coloboma were the most common findings; retinal hemorrhage, saccular aneurysm of the retinal vessels, retinal fold, absence of optic disk and retinal vascularization, and myelination of optic nerve fibers were also observed. Such accumulated data in untreated animals are of prime necessity in assessing possible drug- and chemical-induced effects on the eye after either systemic or local exposure.

[Changes in the peroneal flap and its use in reconstructive surgery of the lower limb. Apropos of an experience of 10 cases]. / Variations sur le thème lambeau péronier et ses applications en chirurgie reconstructrice du membre inférieur. A propos d'une expérience de dix cas.

A peroneal fasciocutaneous flap supplied by the peroneal septocutaneous vessels and raised from the lateral side of the lower leg was reported by Yoshimura in 1983. This flap which can be used as a proximally or distally pedicled or free flap is very useful for leg skin coverage. This flap has a great potential for skin cover and composite reconstruction of the lower limb due to its multiple structural facets (cutaneo-aponevrotic or composite flap), its possible extensions to other vascular territories and the variable geometry of its mode of transfer. 8 reconstructions have been performed. Their indications are described: 4 proximally pedicled flaps (3 with the fibula), 4 reverse-flow island flaps (1 with Soleus and Peroneus longus muscles). The authors stress the importance of preoperative assessment of the feasibility of a given flap which may be limited by post-traumatic, surgical or anatomic modifications. In particular, the uppermost septocutaneous artery which corresponds inconstantly to the "circumflex peroneal artery" can only be visualized by preoperative arteriography. This artery supplies a proximal peroneal flap which can be used as an island or a free flap. We have used this new variety as a free flap in 2 cases and were satisfied with the results. These various clinical applications without any significant complication or flap failure confirm the biological performance and the safe procedure of peroneal flaps.

Inhibition of the transport of rabies virus in the central nervous system.

The effect of colchicine, an inhibitor of axonal transport, on the spread of rabies virus in the central nervous system was investigated using Wistar rats. Colchicine was inoculated into the striatum at various times before and after inoculation of rabies virus into the same site. Rats were killed at various times after viral inoculation and the spread of rabies virus was monitored by rabies immunofluorescence of selected areas of brain. The most effective inhibitory effect was obtained by colchicine treatment applied two days before virus inoculation. Under these conditions, no fluorescent foci could be detected until day 3 post-infection whereas control rats exhibited infected cells as soon as two days post-infection. This inhibitory effect is reversible and the general consequence seems to be a delay in the rate of viral spread. However, five days after the virus challenge, some major brain areas were still partially preserved from infection (striatum, frontal cortex, pyriform cortex). Ten days after colchicine treatment, the microtubules have recovered their capacity to transport the virus. At the onset of paralysis, the general pattern of infection in brain sections from colchicine-treated rats was not significantly different from that of control rats. This inhibitory effect on the transport of rabies virus can be prolonged by administration of additional colchicine.

Collagen and lipid biosynthesis in a case of epitheliogenesis imperfecta in cattle.

An analysis of the dermis and a study of collagen and lipid biosynthesis by fibroblast cultures were carried out in one case of epitheliogenesis imperfecta in a new born calf. This was found to be not only an epidermal disease with fissures and blisters within basal cells on the basement membrane but also a metabolic disease affecting the dermal fibroblasts. These fibroblasts showed a significant decrease in collagen biosynthesis with an increase in the percentage of type III collagen and also a decrease in the biosynthesis of lipids, especially glycerides and cholesterol.

Experimental trichinellosis in horses: biological and parasitological evaluation.

Three groups of three horses each were, respectively, infected with 5000, 20,000 and 50,000 larvae of Trichinella spiralis. The strain used was isolated from a human biopsy during horsemeat-related outbreaks of trichinellosis in France. Transient muscular disorders were only observed in two of the horses infected with 50,000 larvae but none of the horses had fever. A significant increase in blood eosinophils was noticed in 5 horses. Serum LDH, aldolase and CPK peaked at the fifth week post-infection. Specific IgG assayed by indirect immunofluorescence and ELISA, appeared 2-5 weeks post-infection and disappeared between 16 and 40 weeks. The distribution of T. spiralis larvae was maximal in the tongue, masseters and diaphragm, but a large decrease in the number of larvae recovered from the muscles was noticed among the horses slaughtered at the beginning and end of the experiment. In muscular histological sections, larvae were observed in an intramyofibrillar position and were surrounded by a mild to severe inflammatory reaction.

[Properties of an orthopoxvirus strain isolated from camels in Niger]. / Propriétés d'une souche d'orthopoxvirus isolée des dromadaires du Niger.

The VD47 viral strain, isolated from camels (Camelus dromedarius) in Niger possesses camelpoxvirus morphology and characteristic properties: heat sensitive, ether resistant, chloroform and IDU sensitive, with ceiling-temperature 38.5 degrees C. It induces formation of syncytial and retracted cell foci with hemadsorption test positive. No pathogen for mice and very mildly for rabbits, this virus is neutralizable by anti-vaccine serum. The question of camelpoxvirus and camelparapoxvirus pathogenicity for human is discussed by the authors.

Knobbed spermatozoa in two Normande bulls.

Two unrelated yearling Normande bulls in a bull stud had 26 and 18% knobbed spermatozoa as well as other major sperm abnormalities. One of the bulls was eliminated from the bull stud because of poor semen quality and growth performance. The other bull was maintained for additional semen evaluation, during which time the mean percentage of major sperm abnormalities decreased, indicating amelioration of a transient testicular degeneration.

[Study on the immunosuppressive effect of virulent and vaccine strains of hemorrhagic enteritis of turkey]. / Etude de l'effet immunodépresseur de souches virulente ou vaccinale de l'entérite hémorragiquede la dinde.

The immunosuppression caused by virulent and vaccine strains of haemorrhagic enteritis administered in turkey, is assessed, by their influence on the serological response to Newcastle disease vaccination. The histological modifications of lymphoid organs after haemorrhagic enteritis vaccination are also studied. It is concluded that the vaccine virus has an immunosuppressive effect comparable to those of the virulent virus, but the duration of this effect is very short with some variations depending on genetic breed of turkey.

Axonal transport of rabies virus in the central nervous system of the rat.

Stereotaxic inoculation of rabies virus into specific nuclei in the central nervous system has been used for the investigation of the central neural transport mechanisms of viral information. The infection was monitored by specific fluorescence and peroxidase studies and the titration of viral infectivity in dissected brain areas. Twenty-four hours after inoculation into the striatum, cortex, or substantia nigra, infected neurons were detected only in cells from areas and nuclei which were related to the site of inoculation. The distribution of infected neurons showed that retrograde axoplasmic flow plays a determining role in the transport of rabies virus 24 hours after delivery of virus to specific target nuclei. Local destruction of neurons by kainic acid at the site of viral inoculation did not prevent the uptake and subsequent retrograde axonal transport of virus. There was an overall correlation between the major neural connections of the inoculated areas (e.g. the striatum) and the infected areas 24 hours later (e.g. the substantia nigra).

Isolation, characterisation and preliminary cross-protection studies with a new pathogenic avian infectious bronchitis virus (strain PL-84084).

Virological 1 examination of a severe infectious bronchitis (IB)-like field case in laying hens, led to the isolation of a coronavirus antigenically different from Massachusetts, Connecticut and four Dutch IB variant strains. The virulence of the isolate for the fowl, and its dual tropism for the respiratory and genital tracts were demonstrated. In preliminary cross-protection studies Commercial vaccines did not protect against challenge with this isolate. These points and the possible economic significance of the virus are discussed.