Dynamics of two feline retroviruses (FIV and FeLV) within one population of cats.

We present a deterministic model of the dynamics of two microparasites simultaneously infecting a single host population. Both microparasites are feline retroviruses, namely Feline Immunodeficiency Virus (FIV) and Feline Leukaemia Virus (FeLV). The host is the domestic cat Felis catus. The model has been tested with data generated by a long-term study of several natural cat populations. Stability analysis and simulations show that, once introduced in a population, FIV spreads and is maintained, while FeLV can either disappear or persist. Moreover, introduction of both viruses into the population induces an equilibrium state for individuals of each different pathological class. The viruses never induce the extinction of the population. Furthermore, whatever the outcome for the host population (persistence of FIV only, or of both viruses), the global population size at the equilibrium state is only slightly lower than it would have been in the absence of the infections (i.e. at the carrying capacity), indicating a low impact of the viruses on the population. Finally, the impact of the diseases examined simultaneously is higher than the sum of the impact of the two diseases examined separately. This seems to be due to a higher mortality rate when both viruses infect a single individual.

Tolerance and biological activity of pentosan polysulfate after intramuscular or subcutaneous administration for ten days in human volunteers.

This study reports on the tolerance and the pharmacological activity of pentosan polysulfate (PPS) administered to healthy volunteers for 10 days. Three groups of 10 subjects received either one daily injections of 100 mg of PPS by I. M. route (group I), or two daily injection of 50 mg of PPS by I. M. or S. C. route (groups II and III, respectively). In each group two random subjects received a placebo for the 10 days; on day 0, each subject was injected by a placebo. Clinical tolerance was checked by a daily physical examination; biological tolerance was assessed comparing the results of the main biochemical and haematological constants measured before starting the treatment (day 0) and 12 or 24 h after the end of the treatment (day 11). The pharmacological activity was measured on serial samples taken before treatment and between 1 and 6 h after the drug injection on days 1, 3 and 10; the results were compared to those obtained on day 0. Clinical tolerance was good. The biological side effects concern the transaminase levels and the platelet counts. An increase above the upper normal limit was observed in 18/24 and 3/24 for alanine and aspartic transaminase respectively. The mean platelet reduction ranged between 24 and 34% according to the groups. The drug injection induced a slight Quick time (PT) prolongation, no significant alteration of factors II, VII-X, V levels and of thrombin clotting time. The activated partial thromboplastin time (APTT) was significantly prolonged and there was a weak but significant circulating anti-Xa activity.(ABSTRACT TRUNCATED AT 250 WORDS)

The thienopyridine PCR 4099 selectively inhibits ADP-induced platelet aggregation and fibrinogen binding without modifying the membrane glycoprotein IIb-IIIa complex in rat and in man.

The thienopyridines, ticlopidine and PCR 4099, inhibit ex vivo aggregation in response to ADP and other agonists. It has been shown that ticlopidine induces a functional defect in the binding of fibrinogen to its platelet membrane receptor. We have studied the effects on platelet functions of PCR 4099 in rat and in man. The aim of the study was to check the possibility of a direct modification of the fibrinogen binding site on the GP IIb-IIIa complex. Washed platelet suspensions were used for aggregation and fibrinogen binding studies. Platelet lysates were submitted to SDS-polyacrylamide gel electrophoresis, crossed immunoelectrophoresis and immunoprecipitation. We found that administration of PCR 4099 inhibited selectively and irreversibly ADP-induced aggregation. Although the effect of ADP on aggregation was blocked, PCR 4099 did not modify ADP-induced shape change. Only the effects of low concentrations of thrombin on platelet aggregation were inhibited. Fibrinogen binding was dramatically inhibited in rat and in man when platelets were stimulated with ADP and low concentrations of thrombin. At high concentration of thrombin there still remained a part of fibrinogen binding inhibition although aggregation was not impaired. Electrophoretic and immunoelectrophoretic studies showed no difference before and after treatment by PCR 4099. In particular, the GP IIb-IIIa-complex was not dissociated, its electrophoretic mobility was not changed and three monoclonal anticomplex antibodies recognized it in the same manner before and after treatment. We conclude that PCR 4099 selectively inhibits the ADP aggregation pathway and that the inhibition of fibrinogen binding is probably not due to a direct modification of the GP IIb-IIIa complex.

The thienopyridine ticlopidine selectively prevents the inhibitory effects of ADP but not of adrenaline on cAMP levels raised by stimulation of the adenylate cyclase of human platelets by PGE1.

After oral administration, ticlopidine specifically inhibits ADP-induced platelet aggregation, prolongs the bleeding time and prevents thrombosis in man. Its mechanism of action is not well known. Ticlopidine inhibits ADP-induced binding of fibrinogen to platelet glycoprotein GP IIb-IIIa but not shape change and increases deaggregation. Ticlopidine has no direct effect on the GP IIb-IIIa complex. We studied the effects of ticlopidine (500 mg/day for 8 days) in four healthy male volunteers on washed platelet aggregation induced by 5 microM ADP or thrombin (0.1 units/mL) and potentiated by 1 microM adrenaline (Adr), on basal and 1 microM PGE1-stimulated cAMP levels and on elevation of cytosolic free Ca2+ concentration ([Ca2+]i). We found that: (i) ticlopidine inhibits aggregation by ADP but not the potentiation by Adr of ADP-induced aggregation; (ii) ADP, Adr or thrombin decreases cAMP levels raised by PGE1, an effect inhibited by ticlopidine only for ADP and not for Adr or thrombin; and (iii) Ca2+ influx and Ca2+ mobilization from internal stores were not affected. These results suggested that ticlopidine or a metabolite impairs the coupling mechanism of the ADP aggregation pathway at an unknown level.

Effect of lintitript, a new CCK-A receptor antagonist, on gastric emptying of a solid-liquid meal in humans.

The role of cholecystokinin (CCK) in the regulation of gastric emptying of physiological meals containing solids and liquids in humans remains controversial. We studied the role of endogenous CCK in the emptying of a solid/liquid meal administering the new, highly specific and potent CCK-A receptor antagonist lintitript. Gastric emptying was assessed in nine healthy male volunteers using a randomized, double blind, two-period crossover design with oral lintitript (15 mg 1 h prior to meal intake) or placebo on two different days. After ingestion of a pancake (570 kcal) labelled with 500 microCi of 99mTc-sulfur colloid and 500 ml 10% dextrose containing 80 microCi. 111In-DTPA, subjects were studied in a sitting position, using a dual-headed gamma camera. Plasma CCK and pancreatic polypeptide (PP) were measured by a specific RIA. Lintitript distinctly accelerated gastric emptying of solids, while gastric emptying of liquids was not significantly altered. The lag period was shortened by 20% (P<0.05), AUC and half emptying time of solid emptying were lowered by 12% and 13%, respectively (P<0.03). Lintitript markedly increased postprandial plasma CCK release (P<0.001) while distinctly reducing postprandial PP levels (P<0.01) as compared to placebo. These data provide further evidence for a significant role of CCK in the regulation of gastric emptying of solids. The study demonstrates for the first time the marked gastrokinetic properties of the new CCK-A receptor antagonist lintitript in humans.

Phase I study of Datelliptium chloride, hydrochloride given by 24-h continuous intravenous infusion.

Datelliptium chloride, hydrochloride (SR 95 156B, NSC 626718X, DHE) was studied in a phase I trial of escalating doses given on a single 24-h continuous intravenous infusion schedule. Doses were escalated from 40 to 500 mg/m2 in 19 patients who received a total of 24 courses. Courses were repeated after a minimal interval of 3 weeks. Local venous toxicity occurred at low doses (less than or equal to 100 mg/m2) and was circumvented by the use of a central venous access for higher doses. Other clinical adverse events occurred (greater than or equal to 330 mg/m2), including moderate nausea and vomiting, mild diarrhea, dry mouth, neuropsychiatric manifestations, and fatigue. All of these side effects were reversible and none was dose-limiting. The dose-limiting toxicity was related to hepatic laboratory-test abnormalities in the form of reversible elevations of levels of serum bilirubin and liver enzymes at doses of greater than or equal to 330 mg/m2. The maximum tolerated dose for this schedule is 500 mg/m2. Hematologic toxicity was minimal and non-dose-limiting. Neither drug-related deaths nor objective complete or partial responses were observed. However, a minor response and a long-term disease stabilization were obtained.

A study of baboon hemoglobin.

Electrophoretic analysis of hemoglobin types of 409 baboons of various species, mostly from Senegal, corresponds with the findings of other authors. Baboon hemoglobin is homogeneous as a whole, but differs electrophoretically from that of other monkey species. However, a difference in the electrophoretic mobility of the nonhemoglobin fraction of Papio anubis and Papio cynocephalus suggests a possibly different amino-acid sequence. This information may be useful for the classification in doubtful cases.

Erythrocyte glucose-6-phosphate dehydrogenase in the Niokolonko (Malinke of the Niokolo) of Eastern Senegal. Identification of a slow variant with normal activity (Tacoma-like).

In a survey of blood genetic markers in the Niokolonko of Eastern Senegal, three types of G6PD variants were discovered: (1) fast variants, common Negro G6PD A +; the frequency of the Gd A + gene was 0.183; (2) deficient G6PD A--, occurring with a fairly low frequency: 0.079, and (3) some individuals were carriers of a slow moving electrophoretic variant with normal activity. After purification, the analysis of kinetic parameters showed that this enzyme was closely similar to G6PD Tacoma. We proposed to label it 'G6PD Tacoma-like'. The incidence of this mutation in the whole group studied was 0.020. G6PD Tacoma-like may be common in some African tribes.

Comparative study of haemoglobin types of two populations of eastern Senegal--Bedik and Niokholonko.

The haemoglobin types of 1487 of the East Senegal Bedik and Niokholonko populations have been studied. There are significant differences between them, the most likely explanation of which is that the populations are of different origins. The Bedik appear to be the most ancient known settlers in East Senegal: they possess only A and S haemoglobins. The Niolholonko came later, probably from Mali: they have a lower frequency of S genes but AC and AD phenotypes are also encountered among them.

[Low-dose antithymocyte globulins in kidney transplantation: results of a protocol of intermittent administration]. / Globulines antilymphocytaires à faibles doses en transplantation rénale: intérêt d'un protocole d'administration intermittente.

BACKGROUND: Despite the long history of use of antithymocyte globulins (ATG) in renal transplantation, ideal doses and duration of ATG administration based on the monitoring of T lymphocytes have yet to be defined. METHODS: Two immunosuppressive regimens based on low dose rabbit ATG (thymoglobuline, Imtix-Sangstat, Lyon-France) were assessed during the first year post-transplant: daily ATG (n = 32) where 50 mg of ATG were given every day and intermittent ATG (n = 24) where similar doses of ATG were given for the first three days and then intermittently only if CD3+T lymphocytes (measured by flow cytometry) were > 10/mm3. Both groups received steroids, azathioprine and cyclosporin A (CsA). RESULTS: ATG-induced depletion was similar for PBL and T cells in both groups: it began at day one post-transplant, was submaximal at day 3 and reached maximum intensity between days 6 and 8 from which time cell counts progressively increased. However, T cell depletion was still present at day 20. The total ATG dose per patient (361 +/- 105 vs 556 +/- 119 mg/patient) and the mean cumulative daily dose of ATG (0.60 +/- 0.17 vs 0.80 +/- 0.14 mg/kg/d) were significantly lower in the IATG group (p = 0.0001, and 0.0006 respectively). The overlap of ATG and CsA treatment was 6.7 +/- 3 vs 7.4 +/- 4.3 days (p = ns) and the mean duration of ATG therapy was 12 +/- 3 vs 11 +/- 2.5 days in the IATG and DATG groups respectively (p = ns). ATG were given in an average of one dose every 1.6 days in the IATG group compared to one dose daily in the DATG group (p = 7 x 10(-7). There was no significant difference in renal graft function, the number of acute graft rejections or ATG related side effects and complications. Despite daily immunological follow-up, there was a net saving of 920 $/patient in the cost of treatment in the intermittent ATG group. CONCLUSION: Intermittent ATG had the advantage of a reduction in the dose of ATG and in the cost of treatment while offering similar T cell depletion and effective immunosuppression. This approach could be proposed as an induction protocol, particularly for patients with poor graft function in whom CsA introduction has to be delayed.

Creatinine kinetic modelling: a simple and reliable tool for the assessment of protein nutritional status in haemodialysis patients.

While the mathematical modelling of urea kinetics is in wide use for evaluating treatment adequacy and protein nutrition in dialysis patients, the kinetics of creatinine generation in dialysis patients has been relatively unexplored. In this study creatinine kinetic modelling as a clinical tool was investigated in a group of 90 patients treated by haemodialysis (n = 20), haemodiafiltration (60), haemofiltration (7), or biofiltration (3) over a 6-36-month period. A single pool model of creatinine kinetics was employed to obtain monthly values of creatinine distribution space and creatinine appearance rate. Extrarenal creatinine degradation rate, estimated using a clearance of 0.038 l/kg/24 h as suggested by Mitch and co-workers, was added to creatinine appearance rate in urine and dialysate to calculate a corrected creatinine index (CI). Extrarenal degradation accounted for 12 +/- 2% of CI. CI was higher in males (22.4 +/- 4.5 mg/kg/24 h) than females (19.8 +/- 4.8) and decreased with age, falling off more sharply for the female group (CI = 29.9-0.185.age, R = 0.72) than the males (CI = 24.1-0.030.age, R = 0.31). CI was found to correlate strongly with protein catabolic rate determined by urea kinetic modelling (CI = 8.84 +/- 10.91.PCR). Low or reduced CI was associated in this study group with severe malnutrition status and high mortality rate. CI is suggested as a strong predictor of patient morbidity and mortality.

[Actinomycosis after renal transplantation: apropos of 1 case and review of the literature]. / Actinomycose après transplantation rénale: à propos d'une observation et revue de la littérature.

Actinomycosis is a suppurative infection usually due to a facultative anaerobic bacteria, actinomyces israelii. This rare infection has been reported in immunocompetent individuals, with buccal or pharyngeal mucosal erosions. Paradoxically, few cases have been observed after solid organ transplantation: 2 cases after lung, 1 case after heart-lung transplantation and 1 case after renal transplantation. We report on a renal transplant recipient who developed a tongue and oropharynx suppurative abscess, looking like an epithelioma. Histological examination showed granulomatous inflammation with an angiofibroblastic reaction; few colonies of actinomyces were also observed by the pathologist. This lesion disappeared easily and totally after tetracycline treatment.

Reduced sensitivity of human platelets to PAF-acether following ticlopidine intake.

We investigated in 9 patients the effect of a 7-day treatment by Ticlopidine (250 mg b.i.d.) on washed platelets activation by PAF-acether in comparison with adenosine 5'-diphosphate (ADP) and arachidonic acid (AA). Aggregations induced by ADP were totally suppressed upon drug administration. AA-induced aggregations were partly but significantly inhibited (p less than 0.05). Responses of platelets to PAF-acether before treatment differed from patient to patient. A paired Student's test and a two-way analysis of variance showed a significant inhibitory effect of Ticlopidine treatment on PAF-acether-induced aggregation. The inhibitory effect of Ticlopidine or its metabolite(s) was evidenced after platelet washing procedure, suggesting a persistent effect of this drug on platelet after administration of the drug has been stopped.

Erythropoietin-induced changes in protein nutrition: quantitative assessment by urea kinetic modeling analysis.

To evaluate objectively the effects of recombinant human erythropoietin (rHuEPO) administration on nutritional status in stable dialyzed patients, we used urea kinetic modeling (UKM) analysis and dietary protein intake evaluation by dietary assessment. Fifteen patients (9 females, 6 males; mean age 46.9 +/- 15.6 years) dialyzed for 9.4 +/- 6.3 years were studied longitudinally for 18 months, consisting of a control period (6 months) and an rHuEPO treatment period (12 months). Treatment modalities based on 3 weekly sessions were hemodialysis in 12 patients (6 cuprophane, 3 cellulose acetate and 3 highly permeable membranes), hemodiafiltration in 2 patients and postdilutional hemofiltration in 1 patient. Bicarbonate buffered dialysate was used in 9 patients and acetate in 6 patients. Urea kinetic modeling using a single-pool model was performed monthly over 1-3 cycles. rHuEPO was administered intravenously at the end of dialysis according to a two-phase protocol: (1) correction of anemia by stepwise increment of rHuEPO dose, and (2) maintenance dose to keep hemoglobin at 10-11 g/dl. rHuEPO administration corrected anemia in all patients, improving their general clinical condition. Dialysis efficacy was significantly reduced (15%) after the 3rd month of rHuEPO therapy. Clearnces were restored by increasing dialysis time and/or improving dialyzer performances, and adequacy of dialysis was maintained in all patients. During the 12 months of rHuEPO therapy, the protein catabolic rate remained stable at 1.2 g/kg/24 h in spite of an increase in appetite. At the same time, dry body weight increased significantly after 9 months, and the ratio dietary protein intake/protein catabolic rate a gross estimation of nitrogen balance, increased.(ABSTRACT TRUNCATED AT 250 WORDS)

[Recombinant human erythropoietin: 18 months of continuous use in substitution hemodialysis]. / Erythropoïétine humaine recombinante: 18 mois d'utilisation continue en hémodialyse de suppléance.

It has been shown that the regular administration of EPO permits the correction of anemia in end stage renal failure patients. We analyzed the effect of chronic administration of EPO in 13 stable, regularly-dialysed end stage renal failure patients over an 18 month period. The effects of EPO were evaluated according to standard criteria including clinical status, blood pressure control, hematology and biochemistry data, protein nutritional status and dialysis efficiency. Following a 2 week control period, EPO was administered intravenously after the dialysis session according to a 2 phase protocol. The first period (correction phase) consisted of a stepwise EPO dose increment, starting at 24 IU/kg x 3 times and doubling the dose every 14 days according to hemoglobin response in order to achieve a target hemoglobin level of 11 g/dl. In the second period (maintenance phase) EPO dose was optimized to maintain the hemoglobin level between 10 and 11 g/dl, by adjusting either the dose or the frequency of injection. Anemia was corrected in all patients within 10 weeks with EPO dose increasing from 72 to 360 IU/kg/week. The stabilisation of hemoglobin was achieved with an average EPO dose of 275 IU/kg/week (50 to 476 IU/kg/week). Concomitantly, a subjective and clinical improvement was noted in all patients. The dialysis efficacy, although remaining in an acceptable range, fell significantly by 10% over the first 3 months of treatment, remaining stable afterwards, yielding an effective urea clearance near to 120 1/week. The dietary protein intake calculated from urea kinetic modelling ranged between 1.1 and 1.2 g/kg/day.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of reuse on dialyzer efficacy.

The effect of reuse on dialyzer efficacy was examined by measuring blood compartment volume and dialyzer mass transfer coefficient (maximum dialyzer clearance) as a function of dialyzer use number. The 102 polysulfone dialyzers tested (F60 and HF80, Fresenius) were reprocessed on Renatron machines using peroxyacetic acid as the dual cleansing and sterilizing agent. Each dialyzer was used an average of 14.4 +/- 5.7SD times and was tested once (twice for 13/102 dialyzers) during a routine dialysis session at an arbitrary use number (7.6 +/- 5.3; range 1 to 24). The parameters tested were found to decrease only marginally with reuse, corresponding to a blood compartment volume loss of approximately 1% (R = 0.04) over a 5-week/15-use period and a decrease in dialyzer mass transfer coefficient of approximately 3% (R = 0.07 and 0.06) over the same period for urea and creatinine, respectively. It was concluded that the loss in dialyzer efficacy is negligible over the average use period of almost 5 weeks per dialyzer.

Recombinant human erythropoietin: 18 months' experience in hemodialysis patients.

It has been shown that the regular administration of erythropoietin (EPO) permits the correction of anemia in end-stage renal failure patients. We analyzed the effect of chronic administration of EPO in 13 stable, regularly dialyzed end-stage renal failure patients over an 18-month period. The effects of EPO were evaluated according to standard criteria including clinical status, blood pressure control, hematology and biochemistry data, protein nutritional status, and dialysis efficiency. Following a 2-week control period, EPO was administered intravenously (IV) after the dialysis session according to a two-phase protocol. The first period (correction phase) consisted of a stepwise EPO dose increment, starting at 3 x 24 IU/kg/wk and doubling the dose every 14 days according to hemoglobin response in order to achieve a target hemoglobin level of approximately 11.0 g/dL (110 g/L). In the second period (maintenance phase) EPO dose was optimized to maintain the hemoglobin level between 100 and 110 g/L (10.0 and 11.0 g/dL), by adjusting either the unit dose or the frequency of injection. Anemia was corrected in all patients within 11 weeks, with EPO dose increasing from 72 to 360 IU/kg/wk. The stabilization of hemoglobin was achieved with an average EPO dose of 275 IU/kg/wk (50 to 476 IU/kg/wk). Concomitantly, a subjective and clinical improvement was noted in all patients. The dialysis efficacy remained in an acceptable range throughout the study, falling significantly (approximately 10%) through the first 3 months of treatment to stabilize at an effective urea clearance of approximately 120 L/wk. The dietary protein intake calculated from urea kinetic modeling ranged between 1.1 and 1.2 g/kg/d.(ABSTRACT TRUNCATED AT 250 WORDS)