[Clinical and experimental anticollagen autoimmunity].
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Biomedical subjects
Publications and source records attributed to C Fournier.
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The relations between vitamin status and immunological parameters or number of infections have been investigated in self-sufficient healthy individuals aged 60 and over. A total of 411 subjects agreed to participate, but 202 were discarded from the main statistical analysis since they could have had their immune or nutritional status modified by a recent infection, vaccination or drug consumption. Plasma concentrations of retinol, alpha-tocopherol, ascorbic acid and vitamin B6 were determined. Three indices of cellular immunity were measured: percentages of T-cell subsets, lymphoproliferative response to phytohaemaglutinin and delayed-type hypersensitivity to 7 ubiquitous antigens. A questionnaire about past infections was presented. Two results, supported by previous experimental observations, should be underlined. Vitamin B6 status was positively related to percentages of T-cell subsets: the lowest percentages of CD5 and CD4 cells were observed in the low B6 status group (50.6 and 32.6 per cent) and the highest percentages in the high B6 status group (62.0 and 41.0 per cent), with intermediate values in the medium group (57.6 and 39.5 per cent). Vitamin E status was negatively related to the number of past infections: subjects with a high alpha-tocopherol plasma concentration had fewer infections during the last 3 years (1.0) than those with a medium (2.2) or a low (2.3) concentration. In spite of these two observations, cellular immunity did not seem to be strongly related to vitamin status in the supposedly healthy population studied.
The prevention of pit and fissure caries by the use sealants has been a part of dentistry for at least the last ten years. As a result of recent studies, a certain number of characteristics relative to this technique need to be evaluated. The purpose of this article is to assist the practitioner in the use of this new material and even more so to let the practitioner understand the technical aspects related to applying sealants. A review of the literature on the efficiency of sealants and their short or long term retention rates has been done in the past and is not a component of this article. The originality of the review of literature, in this instance, rests with the fact that is will allow the reader to better understand the technique and the choice of materials when applying sealants.
A 67 year-old patient receives 5-fluorouracil for vocal chord cancer. During the perfusion, atypical angina pain occurs, accompanied with offset of ST above the baseline in standard leads and in V4 through V6. The pain subsides spontaneously in 45 minutes. These ECG alterations are followed 48 hours later by diffuse inverted T waves with lengthened QT. Cardiac ultrasonography and isotopic angiography do not show any abnormality of the left ventricular function, but myocardial tomoscintigraphy with labelled thallium show a lower hypofixation on exertion. The cardiac toxicity of 5-fluorouracil is in frequent. It is usually believed that it involves a coronary spasm, as suggested by the ECG tracing in the reported cases. The incident, which may be painful or painless, may result in a myocardial infarction or even sudden death during the perfusion. Therefore, it is advisable to discontinue the treatment as soon as an angina-type pain occurs.
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The plasma kinetics of platinum after i.v. bolus administration of cisplatin was determined for 17 patients with advanced cancer. Statistical analysis of individual values revealed a high correlation between the area under the plasma concentration-time curve (AUC) of free platinum (unbound to proteins) and the concentration of platinum bound to plasma proteins 24 h after drug administration (Cp24). A similar correlation was found between the peak plasma values of ultrafiltrable platinum (Cp0) and Cp24. When studied in the same patient, increases in free platinum AUC and Cp0 were also found to result in increased Cp24. It is suggested that a single measurement of plasma platinum concentration 24 h after i.v. infusion of cisplatin could be a simple method either of detecting patients with extreme values of AUC and Cp0 or of studying the evolution of these parameters during multiple courses of treatment, although it cannot be used to give precise values for AUC and Cp0.
A large amplitude circadian rhythm in murine tolerance for the anticancer agent, carboplatin (cyclobutane dicarboxylatoplatinum II, CBDCA) was demonstrated. Two studies were performed in a total of 266 male B6D2F1 mice standardized by LD 12:12. In the first experiment CBDCA (80 mg/kg/day) was administered intravenously (iv) daily for three consecutive days at all six circadian stages (3, 7, 11, 15, 19, or 23 hr after light onset, HALO). CBDCA dosing at 15 HALO resulted in 58% long-term survivors as compared to 0% after treatment at 3 or 23 HALO (chi 2 = 28; p less than 0.001). In the second experiment, CBDCA (72 or 80 mg/kg/day X 3 days, iv) was administered at any of three circadian stages (0, 8, or 16 HALO). Mice were killed, blood was collected, and seven tissues were obtained 5 and 10 days after the first dose, in order to determine serum urea and creatinine concentrations, leukocyte and red blood cell counts, and to evaluate histologic lesions. No renal toxicity was encountered. Bone marrow and colon mucosa were the major target tissues of CBDCA in these dosages and schedules. CBDCA dosing at 16 HALO was least toxic to the bone marrow as assessed by peripheral leukocyte count and histologic score (p from ANOVA less than 0.05). Histologically assessed lesions of the colon mucosa were less severe after CBDCA dosing at 16 HALO as compared to those at 8 HALO, and significantly so for the lowest dosage tested (p approximately 0.05). Uptake of CBDCA 24 hr after the third dose ranged from 23 micrograms/g of dry tissue in the colon to 7 micrograms/g in the duodenum. Mean tissue concentrations increased between Day 4 and Day 10 for the liver and spleen, and remained similar for the kidney. No consistent circadian dependence was found with regard to Day 4 mean Pt uptake in different tissues, whereas the lowest Day 10 Pt concentrations corresponded to CBDCA dosing at 16 HALO for all tissues investigated. Toxicity did not appear to be directly related to the total platinum concentration in these tissues.
Intradermal injection of 100 micrograms of native homologous type II collagen (CII) into DBA/1-susceptible mice induced a progressive and chronic polyarthritis. This experimental autoimmune arthritis (EAA) closely mimicked the clinical evolution of human rheumatoid arthritis (RA) except for the sex linkage. Males were highly susceptible to EAA induction even when the amount of autoantigen injected was reduced to 25 micrograms. Conversely, females remained resistant to the disease even when a booster injection of 50 micrograms was administered. With regard to age, no major difference in the incidence was observed, although younger males developed a more severe arthritis than older ones. Anti-CII autoantibodies were detected in all immunized animals, regardless of the presence or absence of joint pathology. However, in arthritic mice, the onset of the disease was associated with a predominance of IgG2a autoantibodies. Kinetic studies revealed that females as well as males exhibited early histological lesions and detectable humoral responses toward mouse CII as of the second week postimmunization. Moreover, a specific cellular autoreactivity to homologous CII occurred in different lymphoid organs with a higher intensity in females than in males. Taken together, these findings suggest that homologous CII injection induces an early subclinical arthritis that develops progressively in all immunized mice, but would be down-regulated several weeks after priming, exclusively in females.
The salivary cortisol concentration is an excellent indicator of the plasma free cortisol concentration. To establish its normal and pathological ranges, salivary cortisol concentrations were measured in 101 normal adults, 18 patients with Cushing's syndrome, and 21 patients with adrenal insufficiency. The normal subjects had a mean (+/- SEM) salivary cortisol concentration of 15.5 +/- 0.8 nmol/L (range, 10.2-27.3) at 0800 h and 3.9 +/- 0.2 nmol/L (range, 2.2-4.1) at 2000 h (n = 20). The mean value 60 min after ACTH administration in 58 normal subjects was 52.2 +/- 2.2 nmol/L (range, 23.5-99.4), and it was 1.4 +/- 1.1 nmol/L (range, 1.6-3) at 0800 h in 23 normal subjects given 1 mg dexamethasone 8 h earlier. In patients with primary or secondary adrenal insufficiency (n = 21) the mean salivary cortisol level was 7.5 +/- 0.4 nmol/L (range, 1.9-21.8) 60 min after ACTH. In patients with Cushing's syndrome (n = 7), the mean value after the 1-mg dexamethasone suppression test was 16.1 +/- 7.8 nmol/L (range, 5.8-66.8). No overlap was found between the values in the normal subjects and those in the patients during the dynamic tests. Discrepancies between salivary and total plasma cortisol were found in 8 patients with adrenal insufficiency, which may be explained by the effects of drugs such as thyroid hormones, Op'-dichlorodiphenyldichloroethane, and psychotropic agents. We conclude that salivary cortisol measurements are an excellent index of plasma free cortisol concentrations. They circumvent the physiological, pathological, and pharmacological changes due to corticosteroid-binding globulin alterations and offer a practical approach to assess pituitary-adrenal function.
Unlike amiodarone, beta-blockers have proved ineffective in the treatment of severe ventricular rhythm disorders encountered in hypertrophic myocardiopathy. We tried to evaluate the efficacy of sotalol, a betablocker with anti-arhythmic properties, like amiodarone, on the supraventricular and ventricular rhythm disorders of this disease. 13 patients (6 men and 7 women, mean age 53.5 +/- 26.5 years) were evaluated with a 48 hours electrocardiographic recording, before and 8 and 120 days after a sotalol treatment at a mean dose of 290 mg/day (160 to 640 mg). The diagnosis of hypertrophic myocardiopathy was established on standard clinical, phonomecanographic (13 cases), sonocardiographic (13 cases) and haemodynamic (9 cases) criteria. Five patients presented bursts of supraventricular tachycardia on DO. Their number decreased to 4 on D8 and to 3 to D120. Six patients presented Lown's class III or IV ventricular rhythm disorders on DO. Their number went from 2 on D8 to 4 on D120. Therefore, in this short series, sotalol has shown a non-negligible efficacy on the rhythm disorders encountered in hypertrophic myocardiopathy.
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It has long been known that the morphology of ventricular repolarization is extremely sensitive to acute or chronic myocardial anoxia. In patients with coronary disease, we are used to observe a wide variety of ST segment, T wave and sometimes U wave abnormalities. The classical description of "lesions" or "ischaemia", as well as their anatomical locations called, perhaps rather arbitrarily, "subendocardial" or "subepicardial" account for ST segment displacements and T wave inversions the patterns of which are well known to all of us. It may happen, however, that repolarization takes a frankly unusual appearance very different from the conventional images. On several occasions we were surprised to find, in a situation of acute or subacute coronary obstruction, a highly atypical and characteristically very transient repolarization pattern with considerable lengthening of QT and broad and deep inversion of T wave which, to our knowledge, have never been described in the literature. A systematic search for such unusual ECG patterns, conducted over the last 4 years in the Cardiology department of the Bicêtre Hospital on patients with ischaemic heart disease, has yielded 16 cases which are reported in the present study.
cis-Diamminedichloroplatinum (100 mg/m2) was administered to the same patients (n = 9) with advanced uterine cervical tumors, via i.v. and intraarterial (i.a.) (bilateral hypogastric arteries) routes. Measurement of plasma pharmacokinetic parameters enabled us to show up areas under the curve (AUC) of free cis-diamminedichloroplatinum versus time significantly (P less than 0.01) lower after i.a. injection (mean value, 3.9 mg.h/liter) than after i.v. injection (mean value, 5 mg.h/liter). However, the increase in intratumoral concentrations after i.a. administration was only at the limit of statistical significance (P = 0.05). Consequently, the benefit of local i.a. administration, evaluated according to the method of Collins, was small (1.2-2.3). An explanation of the phenomena observed can be given using the generalized compartmental model of Collins. We have demonstrated that the parameters of this model can be entirely calculated by taking into account both the i.v. and i.a. pharmacokinetic measurements. Calculations from experimental data of the model parameters, clearances of the body (ClB), and exchange rate between the site of administration and the rest of the body (Q) were in accordance with the physiological values. On the basis of the parameter values, it was confirmed that the low benefit of i.a. administration was due to the fast blood exchange between the injection site and the rest of the body and the probable cis-diamminedichloroplatinum binding on healthy tissues irrigated by the hypogastric artery.
An elderly patient, receiving long-term oral diltiazem at the usual dosage, presented a sudden attack of junctional bradycardia at 35 b X min-1; this was badly tolerated by the patient. The diltiazem blood level was normal. After recovery, nodal investigations were also normal. The treatment of this accident due to a calcium-blocker is stressed: the intravenous injection of a calcium salt only was sufficient, with a return to near-normal sinus function, so avoiding the necessity of pacing.
1. The effects of verapamil (120 mg orally) and a placebo on arterial pressure, heart rate, PR interval, arterial flows and diameters of the brachial and carotid arteries (pulsed Doppler technique), forearm vascular resistance, and venous diameter and compliance (cutaneous microstrain gauge and plethysmography) have been compared over a 10-hr period in six healthy volunteers during a double-blind and cross-over study. 2. Verapamil reduced diastolic blood pressure by approximately 10 mm Hg, did not affect heart rate and increased PR interval by approximately 15%. 3. Verapamil significantly increased brachial and carotid arterial blood flows by 56% (P less than 0.01) and 16% (P less than 0.05), respectively, but the diameters of these vessels were not significantly modified (+7 and +4%, respectively, NS). Forearm vascular resistance decreased by 40% (P less than 0.01), indicating that verapamil preferentially dilates small arteries. All these effects peaked at 2 h after drug intake and lasted for 6 h. 4. Verapamil increased hand dorsal vein diameter and flow by 95% (P less than 0.05) and 80% (P less than 0.05), respectively, from 2 to 4 h after drug intake but venous compliance, assessed by the venous diameter/venous flow ratio, was not significantly modified (from 0.71 to 0.69, NS), thus indicating that veins are not directly affected by this drug.
Immunisation with heterologous type II collagen (CII) induces arthritis in mice of the DBA/1 strain, which is genetically susceptible to this disease. To develop an experimental model of autoimmunity more adequate for the study of human rheumatoid arthritis (RA), DBA/1 mice were injected with 100 micrograms of native CII that had been purified from mouse xiphoid cartilage. About six weeks later the animals developed a chronic progressive polyarthritis involving the four paws but mainly confined to interphalangeal and metatarsophalangeal joints. The evolution of the disease fluctuated between remissions and exacerbations. The initial lesions assessed by clinical observations were more severe when the disease occurred early than in the case of late onset. Interestingly, the incidence of arthritis was clearly preponderant in males, and, moreover, the few female mice which developed arthritis had mild disease states with lower arthritic scores than the males. Varying levels of autoantibodies against mouse CII were found in the sera of immunised animals, regardless of the development of arthritis. These data indicate that the injection of homologous CII into mice caused a polyarthritis that is clinically closer to the human RA than the disease induced with heterologous CII and therefore will represent a useful tool for the study of the self-perpetuating mechanisms that characterise RA.
The pattern of cortisol and testosterone levels during the normal pregnancy was investigated by measuring these hormones in the same 19 healthy pregnant women at 11th to 19th, 24th to 29th and 34th to 39th week post amenorrhea. We noted the well-known increase in total plasma cortisol and testosterone, due to the elevated concentration of their transport protein, i.e., Corticosteroid Binding Globulin (CBG) and Testosterone Estradiol Binding Globulin (TeBG), consecutive to the increase in plasma oestrogens. Morning (8h) and evening salivary cortisol (20 h) values, which are a good reflect of free plasma cortisol, were found increased since the second trimester of pregnancy, with a conserved circadian cycle. 24 h urinary free cortisol was slightly increased since the first trimester, yet remaining within the normal range; in the late pregnancy it reached sometimes higher levels. "Vesperal" urinary cortisol measured on a collected urine sample between 20 h and 24 h was higher in pregnant women since the beginning of pregnancy as compared to that of non pregnant women. Levels of salivary free testosterone measured in a few patients appeared similar to that of non-pregnant controls. We also report the data obtained in two pregnant women with Cushing's syndrome due to an adrenocortical carcinoma which showed a strong elevation of urinary and salivary free cortisol while a pregnant woman with a luteoma had a lower level as compared to normal pregnant. Moreover these three patients had a marked increase in free salivary testosterone opposite to normal pregnant women.
Tumour tissue levels of platinum were determined in patients with head and neck tumours receiving carboplatin (11 patients, 400 mg/m2) and iproplatin (5 patients, 360 mg/m2). The platinum concentrations ranged from 1.1 +/- 0.4 ng Pt/mg tissue (iproplatin administration) to 1.4 +/- 0.3 ng Pt/mg tissue (carboplatin administration). These results were compared with published platinum levels after cisplatin administration. Although the administered dose of carboplatin (1.08 mmol/m2) and iproplatin (0.86 mmol/m2) was higher than the cisplatin one (0.33 mmol/m2), no significant statistical differences were observed in the resulting platinum tissue levels. The constancy of tumour platinum level after treatment with different platinum complexes could be explained, at least for carboplatin and cisplatin, by both the tumour diffusion properties and the reactivity of the drugs.