Estimating cortical thickness trajectories in children across different scanners using transfer learning from normative models.

This work illustrates the use of normative models in a longitudinal neuroimaging study of children aged 6-17 years and demonstrates how such models can be used to make meaningful comparisons in longitudinal studies, even when individuals are scanned with different scanners across successive study waves. More specifically, we first estimated a large-scale reference normative model using Hierarchical Bayesian Regression from N = 42,993 individuals across the lifespan and from dozens of sites. We then transfer these models to a longitudinal developmental cohort (N = 6285) with three measurement waves acquired on two different scanners that were unseen during estimation of the reference models. We show that the use of normative models provides individual deviation scores that are independent of scanner effects and efficiently accommodate inter-site variations. Moreover, we provide empirical evidence to guide the optimization of sample size for the transfer of prior knowledge about the distribution of regional cortical thicknesses. We show that a transfer set containing as few as 25 samples per site can lead to good performance metrics on the test set. Finally, we demonstrate the clinical utility of this approach by showing that deviation scores obtained from the transferred normative models are able to detect and chart morphological heterogeneity in individuals born preterm.

Lack of referral for genetic counseling and testing in BRCA1/2 and Lynch syndromes: a nationwide study based on 240,134 consultations and 134,652 genetic tests.

Based on nationwide data from the French national cancer institute (INCa), we analyzed the evolution of cancer genetics consultations and testing over time, and the uptake of targeted tests in relatives of families with BRCA1/2 or MMR genes mutation. Genetic testing and consultations for familial high-risk individuals are exclusively funded and monitored by the INCa in France. All nationwide cancer genetics centers reported annually standardized parameters of activity from 2003 to 2011. The analysis included a total of 240,134 consultations and 134,652 genetic tests enabling to identify 32,494 mutation carriers. Referral for hereditary breast and ovarian cancer (HBOC) or colorectal cancer predisposition syndromes represented 59 % (141,639) and 23.2 % (55,698) consultations, respectively. From 2003 to 2011, we found a dramatic and steady increase of tests performed for BRCA1/2 (from 2,095 to 7,393 tests/year, P < 0.0001) but not for MMR genes (from 1,144 to 1,635/year, P = NS). The overall percentage of deleterious mutations identified in the probands tested was 13.8 and 20.9 % in HBOC and Lynch syndromes, respectively. Pooled analysis for BRCA1/2 and Lynch syndrome tests showed an inverse relationship between the percentage of mutation detected and the absolute number of tests performed over the time (overall Cochran-Armitage test for trend: P < 0.001). In families with BRCA1/2 or MMR identified mutations, there was an average number of 2.94 and 3.28 relatives performing targeted tests, respectively. This nationwide study shows a lack of referral and genetic testing in Lynch as compared to HBOC syndromes. Only a third of relatives of a proband with a predisposing mutation performed a targeted test. Enhanced information about benefit of genetic testing should be given to clinicians and patients for Lynch syndrome and relatives of a proband carrying an identified predisposing mutation.

Screening BRCA1 and BRCA2 unclassified variants for splicing mutations using reverse transcription PCR on patient RNA and an ex vivo assay based on a splicing reporter minigene.

BACKGROUND: Many unclassified variants (UV) of BRCA1 or BRCA2 may have an effect on pre-mRNA splicing. Patient blood samples suitable for RNA extraction are not always available for testing UVs at the RNA level. METHODS: Analyses of RNA from patient peripheral blood were performed, using a one-step reverse transcriptase-PCR (RT-PCR) protocol, and were compared with an ex vivo splicing assay based on PCR-amplified patient DNA inserted into a splicing reporter minigene. Using both methods 20 variants found in 17 patients were examined. RESULTS: Data from patient RNA and from the minigene assay were fully concordant, but the ex vivo splicing assay, which is monoallelic, clarified several ambiguities in the patient RNA data. Two intronic variants induced strong splicing defects: BRCA1 c.4987-5T-->A (IVS16-5T-->A) induced exon 17 skipping and BRCA2 c.316+5G-->C (IVS3+5G-->C) induced complete skipping of exon 3. Of the exonic variants, BRCA2 c.7805G-->C (p.Arg2602Thr), at the last base of exon 16, induced both exon skipping and activation of a cryptic exonic donor site, and BRCA2 c.8023A-->G (p.Ile2675Val) generated a strong donor site within exon 18. These four variants were thus classified as pathogenic, because of the total absence of a normal transcript from the corresponding allele. Variant BRCA2 c.9501+3A-->T (IVS25+3A-->T) induced incomplete skipping of exon 25, suggesting a mutation with incomplete penetrance, and BRCA2 c.8257_8259del (p.Leu2753del) modified the alternative splicing of exons 17 and 18. CONCLUSIONS: We show that functional analysis using a splicing reporter minigene is sensitive and specific, and should be used for initial screening of potential splicing defects, especially when patient RNA is not readily available.

[Malignant mesothelioma and constitutional BAP1 gene mutations]. / Mésothéliomes malins et mutations constitutionnelles du gène BAP1.

Malignant mesothelioma is a rare tumour, usually the result of asbestos exposure. Several cases of familial aggregation have been reported and recently shown to be associated with constitutional mutations of the BAP1 gene. BAP1 is a deubiquitinating enzyme implicated in several different cellular mechanisms such as the repair or differentiation of DNA. About a half of malignant mesotheliomas present a somatic, bi-allelic inactivation of BAP1, demonstrated by nuclear extinction on histochemistry. Constitutional alterations of BAP1 are extremely rare. Present in the heterozygous state they are transmitted as an autosomal dominant. They are associated with a risk of developing other tumours such as uveal and cutaneous melanomas, benign melanocytic tumours (melanocytic BAP1-mutated atypical intradermal tumour or MBAITS) and clear cell renal carcinomas. The causal link between mesothelioma and germinal mutations of BAP1 has still not been clearly identified. At present there is, in France, no consensus on recommendations for the management of patients with these mutations. This article is a synthesis of the literature on the functions of the BAP1 gene, the tumour risks related to its alteration and the follow up of patients bearing a constitutional mutation.

The contribution of germline rearrangements to the spectrum of BRCA2 mutations.

BACKGROUND: Few germline BRCA2 rearrangements have been described compared with the large number of germline rearrangements reported in the BRCA1 gene. However, some BRCA2 rearrangements have been reported in families that included at least one case of male breast cancer. OBJECTIVE: To estimate the contribution of large genomic rearrangements to the spectrum of BRCA2 defects. METHODS: Quantitative multiplex PCR of short fluorescent fragments (QMPSF) was used to screen the BRCA2 gene for germline rearrangements in highly selected families. QMPSF was previously used to detect heterozygous deletions/duplications in many genes including BRCA1 and BRCA2. RESULTS: We selected a subgroup of 194 high risk families with four or more breast cancers with an average age at diagnosis of < or = 50 years, who were recruited through 14 genetic counselling centres in France and one centre in Switzerland. BRCA2 mutations were detected in 18.6% (36 index cases) and BRCA1 mutations in 12.4% (24 index cases) of these families. Of the 134 BRCA1/2 negative index cases in this subgroup, 120 were screened for large rearrangements of BRCA2 using QMPSF. Novel and distinct BRCA2 deletions were detected in three families and their boundaries were determined. We found that genomic rearrangements represent 7.7% (95% confidence interval 0% to 16%) of the BRCA2 mutation spectrum. CONCLUSION: The molecular diagnosis of breast cancer predisposition should include screening for BRCA2 rearrangements, at least in families with a high probability of BRCA2 defects.

The Pattern of Plasma Insulin Response to Glucose in Patients with a Previous Myocardial Infarction-The Respective Effects of Age and Disease.

Plasma insulin and blood sugar variations were investigated during oral (OGTT) and intravenous (IVGTT) glucose tolerance tests in 10 patients aged 32 to 41 and 10 Patients aged 48 to 60 who had suffered a myocardial infarction at least three months previously. The results obtained in each group of patients were compared with those of ten normal subjects of corresponding age. The respective influences of age and cardio-vascular disease on the pattern of the plasma insulin and blood sugar responses to the glucose load were dissociated on the basis of analysis of variance.-Advancing age was associated with a rise in the mean blood sugar level during OGTT and a lowering of the glucose assimilation coefficient during IVGTT, but it was not accompanied by a significant change in the plasma insulin levels during either of the two tests.-Cardiovascular disease was associated with an augmentation of the mean blood sugar level during OGTT, but also with a prolonged and excessive response in plasma insulin. During IVGTT the glucose assimilation coefficient and the plasma insulin variations were not statistically different in the patients with a previous myocardial infarction and in the normal subjects.-The previous occurrence of a myocardial infarction is thus associated with a hyperinsulinism during OGTT, but not after a rapid stimulation as realized during IVGTT. The nature of the gastrointestinal factors involved in the genesis of this hyperinsulinism remains a matter of conjecture.

Efficacy of oral long-term N-acetylcysteine in chronic bronchopulmonary disease: a meta-analysis of published double-blind, placebo-controlled clinical trials.

OBJECTIVE: This meta-analysis was performed to assess the possible prophylactic benefit of prolonged treatment with oral N-acetylcysteine (NAC) in chronic bronchitis (CB) based on qualifying clinical trials. Treatment of acute exacerbations with NAC was not investigated. BACKGROUND: Prolonged treatment with oral NAC has been investigated in a number of studies of patients with CB. NAC prevented acute exacerbations and symptoms of CB in some but not all trials. METHODS: The trials included in this analysis were selected from a MEDLINE search of the period from January 1, 1980, through June 30, 1995; references in the articles retrieved in the initial search; and consultation with 2 experts. Selection was based on the following criteria: published, double-blind, placebo-controlled, chronic bronchopulmonary disease, duration of therapy > or =2 months, and data sufficient to calculate an outcome variable permitting direct comparison of studies (effect size) for both NAC and placebo groups. The primary end point was the incidence of acute exacerbations in 7 of 8 trials and clinical assessment in the other. In 7 studies, inclusion criteria were based on Medical Research Council criteria for CB, with an additional criterion in some trials. For the meta-analysis, the end points of individual trials were transformed into an effect size as a common outcome. RESULTS: Of 21 trials initially identified, 8 qualified for inclusion. References from the 8 papers and consultation with the experts produced 8 additional publications, 1 of which qualified for inclusion. NAC was administered orally at a daily dose of 400 mg (1 study), 600 mg (5 studies), or 1200 mg (1 study). One other trial used a dose of 600 mg 3 times per week. The duration of treatment was 3 months (1 study), > or =5 months (2 studies), or 6 months (7 studies). The results of this meta-analysis showed a statistically significant effect size for NAC compared with placebo. The overall value of effect size was -1.37 (95% CI, -1.5 to -1.25). Sensitivity analyses did not significantly alter these results. In a subset analysis of trials with the number of acute exacerbations as a clinical end point, a mean difference of -0.32 clinical event (95% CI, -0.50 to -0.18) was found (ie, a 23% decrease in the number of acute exacerbations compared with placebo). CONCLUSION: These findings suggest that a prolonged course of oral NAC prevents acute exacerbations of CB, thus possibly decreasing morbidity and health care costs.

Effects of cicletanine on vasoactive systems in conscious sinoaortic-denervated dogs.

The present study investigates the antihypertensive action of cicletanine, a new antihypertensive compound with diuretic properties (or placebo), on vasopressor (catecholamines, renin-aldosterone) as well as vasodepressor (prostaglandins, kallikrein-kinin) systems in conscious chronic sinoaortic denervated (SAD) dogs. Cicletanine (10 mg/kg twice a day, per os, for one month) lowered blood pressure and heart rate. The antihypertensive action does not involve an effect on sympathetic tone (since plasma catecholamine levels were unmodified) or on plasma aldosterone levels. By contrast, urinary 6 keto PGF1 or PGE2 levels and kallikrein activity were enhanced. This result indicates that the antihypertensive effect of cicletanine is associated with a stimulation of potential vasodepressor systems (such as prostaglandins or kinins).

Studies on the food and feeding habits of soil oribatei in a black pine plantation.

Food preferences and feeding behaviour of abundant species of oribatid mites in a black pine plantation have been studied by soil sectioning technique. It is suggested that Microtritia minima, Rhysotritia duplicata and Phthiracarus sp. play an important role in the mechanical breakdown of decaying litter and, by contributing to the humification process, help in the accumulation of plant nutrients. Due to poor mobility their contribution to fungal spore dissemination is insignificant. Chamobates incisus was determined to be a fungivorous species while no exact information could be obtained about the precise food of Tectocepheus velatus. Rest of the species seemed to consume large quantities of decaying litter but in view of their low populations throughout, presumably they do not contribute appreciably in the humification process.The speed of decomposition of faecal pellets seemed to be governed by the type of food ingested. The role of oribatid fauna in the litter and soil ecosystems is discussed.

Interlaboratory evaluation of three culture media for postimplantation rodent embryos.

The first aim of the study was to compare the ability of rat serum, human serum, and a mixture of human and rat serum (4:1) to support in vitro development of rodent postimplantation embryos. The comparison was made in three laboratories using rat embryos and in one laboratory using mouse embryos. Batches of sera, initial developmental stage, duration of culture, and endpoints were identical in the laboratories. The second aim of the study was to evaluate if other variables that could not be standardized would significantly influence the results of the laboratories. No reproducible difference was observed among the culture media or among the laboratories except that growth and differentiation were slower in the laboratory using mouse embryos. Further experiments are needed to exclude small differences in performance of the media.

Embryotoxicity of human sera from patients treated with isotretinoin.

Sera of 20 patients treated with 20-40 mg isotretinoin/day were tested for embryotoxicity potential. For each patient, the first sample was taken before treatment (control sample) and the second was taken 2 months after the start of treatment (treated sample). Six embryos displaying six or seven pairs of somites were cultured for 26 hr in each serum sample, when sufficient serum was available. No deaths were observed in the control sample, whereas dead embryos (6%) were observed in the treated sample. The rates of malformed embryos were 13 and 81% in the control and in the treated sample, respectively. The most frequent abnormalities affected the cephalic neural tube, the branchial bars, the yolk sac circulation and the caudal neural tube. Growth and differentiation were significantly decreased in the treated sample. The concentrations of isotretinoin and of two metabolites (trans-retinoic acid and 4-oxo-isotretinoin) were measured in 12 sera. A correlation between embryotoxicity and concentration was established for two of the chemicals. Modulation of the embryotoxicity by drug-induced changes in the serum cannot be excluded.

[Li-Fraumeni syndrome: update, new data and guidelines for clinical management]. / Le syndrome de Li-Fraumeni: mise au point, données nouvelles et recommandations pour la prise en charge.

The Li-Fraumeni syndrome (LFS) is an inherited form of cancer, affecting children and young adults, and characterized by a wide spectrum of tumors, including soft-tissue and bone sarcomas, brain tumours, adenocortical tumours and premenopausal breast cancers. In most of the families, LFS results from germline mutations of the tumor suppressor TP53 gene encoding a transcriptional factor able to regulate cell cycle and apoptosis when DNA damage occurs. Recently, germline mutations of hCHK2 encoding a kinase, regulating cell cycle via Cdc25C and TP53, were identified in affected families. The LFS working group recommendations are the following: (i) positive testing (screening for a germline TP53 mutation in a patient with a tumor) can be offered both to children and adults in the context of genetic counseling associated to psychological support, to confirm the diagnosis of LFS on a molecular basis. This will allow to offer to the patient a regular clinical review in order to avoid a delay to the diagnosis of another tumor; (ii) the 3 indications for positive testing are: a proband with a tumor belonging to the narrow LFS spectrum and developed before age 36 and, at least, first- or second-degree relative with a LFS spectrum tumor, before age 46, or a patient with multiple primary tumors, 2 of which belonging to the narrow LFS spectrum, the first being developed before 36 or a child with an adenocortical tumour; (iii) presymptomatic testing must be restricted to adults; (iv) the young age of onset of the LFS tumors the prognosis of some tumors, the impossibility to ensure an efficient early detection and the risk for mutation carriers to develop multiple primary tumors justify that prenatal diagnosis might be considered in affected families.

[Comparative study of 2 dosages of a new antihypertensive agent, cicletanine, in elderly subjects]. / Etude comparative de deux posologies d'un nouvel antihypertenseur, le ciclétanine, chez le sujet âgé.

Cicletanine chlorhydrate (C), a furopyridine derivative, is a new antihypertensive drug that acts mainly by enhancing endogenous prostacyclin release. It has been shown to induce a significant, progressive reduction in systolic and diastolic blood pressure in patients over 60 years of age at a daily dose of 150 mg in a placebo-controlled efficacy trial. As concurrent studies in adult hypertensive patients demonstrated an antihypertensive effect at even lower doses, we further compared the antihypertensive efficacy and tolerance of 50 mg vs 100 mg daily dose of C in elderly hypertensive patients in order to determine the lowest active posology. A prospective, double-blind randomized trial included 72 patients (56 female, 16 male) aged 65 years or more (mean age +/- 1 SD: 80.3 +/- 5.9 years, range 65-90) with moderate, essential hypertension, and normal-for-age renal function whose diastolic BP was greater than 95 mmHg and/or systolic BP was greater than 160 mmHg after 15 days of a single-blind placebo period. They were randomly allocated to either 50 mg (group I, 36 patients) or 100 mg (group II, 36 patients) C given in a single morning dose for 3 months with monthly surveillance. Of them, 60 achieved satisfactory BP control with C as monotherapy and completed full follow-up.(ABSTRACT TRUNCATED AT 250 WORDS)

[Antihypertensive effectiveness and tolerance of cicletanine. Results obtained with monotherapy in a large population]. / Efficacité antihypertensive et tolérance du ciclétanine. Résultats obtenus en monothérapie sur une large population.

A multicentre open study to which 229 investigators participated was carried out to demonstrate the safety of cicletanine, a new therapeutic agent, in routine clinical use. Cicletanine was administered alone for three months and normalized blood pressure (less than 160/95 mmHg) in 63 p. 100 of the 1,238 hypertensive patients who entered the study. There was a significant fall of systolic arterial pressure from 178.4 +/- 14.8 to 151.8 +/- 14.2 mmHg and a similar fall of diastolic arterial pressure from 104.0 +/- 6.7 to 86.3 +/- 6.2 mmHg. The reduction of BP values was accompanied by a significant decrease of differential BP (SBP-DBP) from 72.5 to 65.8 mmHg. The initial dosage (50 mg/day) was doubled in only one-third of the patients. The mean daily dose was 66 mg. This antihypertensive effect was paralleled by a significant and major improvement of signs (dyspnoea, oedema of the lower limbs) and symptoms (mainly dizziness, headache, visual and auditory disorders, asthenia) which existed at inclusion. A modest, but significant, reduction of heart rate from 76.7 to 73.9 beats/mn was also noted. Cicletanine produced no toxic or severe adverse events. Clinical side-effects consisted of pruritus, fatigue, headache, vertigo, lower limb oedema and gastrointestinal disorders. These effects were mild and non-specific (doubtful drug imputability); each of them occurred with an incidence ranging from 4.0 to 1.0 p. 100. They were responsible for the withdrawal of about 30 patients (2.4 p. 100). No significant alteration of biochemical or haematological values was recorded.(ABSTRACT TRUNCATED AT 250 WORDS)

[Antihypertensive effectiveness and tolerance of cicletanine. Results obtained with bitherapy]. / Efficacité antihypertensive et tolérance du ciclétanine. Résultats obtenus en bithérapie.

In a multicentre open trial involving 229 investigators, cicletanine, a new antihypertensive agent, was administered orally in doses of 50 to 100 mg/day either alone (1,238 patients) or combined with another drug (430 patients). In this second group of patients with essential hypertension whose BP had not been normalized by a beta-blocker (n = 157), a calcium inhibitor (n = 67), an angiotensin-converting enzyme inhibitor (n = 134) or an alpha-blocker (n = 7), cicletanine normalized BP (less than 160/95 mmHg) in 48.8% of the patients and significantly lowered BP values which fell from 177.7 +/- 15.9/103.3 +/- 6.3 mmHg to 157.2 +/- 17.6/88.8 +/- 8.7 mmHg. The addition of cicletanine to treatments with beta-blockers, calcium inhibitors and angiotensin-converting enzyme inhibitors normalized BP in 48%, 52% and 47% of patients respectively. A significant reduction of symptoms was noted, notably as regards headache, dizziness, palpitations, lower limb oedema, asthenia, auditory disorders and dyspnoea. The side-effects reported (headache, dizziness, gastralgia, nausea, pruritus) were minor and non-specific; they accounted for the withdrawal of only 8 patients. The only significant, though moderate, biochemical variations observed were decreases in natremia and cholesterolaemia unconfirmed by qualitative analysis. Altogether, cicletanine proved to be effective and well tolerated when administered in combination with other antihypertensive drugs belonging to three main therapeutic classes.

[Changes in the glucose tolerance parameters in non-diabetic hypertensive patients treated with cicletanine]. / Etude de l'évolution des paramètres de la tolérance glucidique chez des patients hypertendus non diabétiques traités par le ciclétanine.

The effects of cicletanine hydrochloride on glucose tolerance parameters were studied in a two-phase trial in which patients received a placebo for 2 weeks, followed by cicletanine 50 mg/day for 3 months. Ten patients with mild to moderate hypertension, who were neither obese nor diabetic and had no disorder of glucose tolerance entered the study. None of the patients was withdrawn. Glucose tolerance was evaluated by two oral glucose tolerance tests performed at 90 days' interval, each with half hourly blood glucose and insulin assays. The clinical effectiveness of the drug was assessed by monthly blood pressure measurements. No significant change in glycaemia and insulinaemia was observed. There was a significant decrease of supine SBP from 170.7 +/- 9.1 mmHg to 150.3 +/- 6.7 mmHg (p less than 0.0001) and of supine DBP from 101.3 +/- 4.1 to 80.3 +/- 7.7 mmHg (p less than 0.0001). At the end of the study, 9 of the 10 patients had normal blood pressure values. No undesirable clinical or biochemical effect was noted. thus, cicletanine, an antihypertensive drug derived from furopyridine, proved to be devoid of adverse effects on glycoregulation and clinically effective on hypertension.

[Effects of treatment with cicletanine on kidney PGE2 and PGI1 in spontaneously hypertensive rats]. / Effets du traitement par le ciclétanine sur la PGE2 et la PGI2 rénales chez les rats spontanément hypertendus.

Cicletanine is a new antihypertensive agent known for being able to stimulate prostaglandin synthesis in vivo and in endothelial cell cultures. The drug was administered to spontaneously hypertensive rats (SHP-SP) whose hypertension was enhanced by a high sodium content diet. Cicletanine prolonged the animals' survival and reduced the severity of histological renal lesions. PGE2, PGI2 and thromboxane A2 assays performed in renal tissues showed a highly significant increase of PGE2 (a prostaglandin involved in the regulation of renin synthesis) in SHR-SP rats treated with oral cicletanine in daily doses of 30 mg/kg. A less significant increase of PGI2 was found in renal tissues, whereas only slight variations in thromboxane concentrations were observed. The favourable therapeutic effect obtained with cicletanine in the treatment of hypertension may be due, at least in part, to the stimulation of PGE2 and PGI2 production in renal tissue.

[Ionic perturbations produced by a non-laminar flow in vascular smooth muscle cells in culture. Protection by cicletanine via a cyclo-oxygenase metabolite]. / Perturbations ioniques produites par un flux non laminaire dans les cellules musculaires lisses vasculaires en culture. Protection exercée par le ciclétanine via un métabolite de la cyclo-oxygénase.

The non-laminar (rather turbulent) flow, induced by cell washings was able to reversibly increase internal Na+ contents in cultured aortic smooth muscle (A10 cells). Similar changes (although to a lesser extent) were observed in cardiocytes but not in fibroblasts, erythrocytes, thymocytes or macrophages, suggesting that they are specific for excitable cells. The increased vascular sodium content had the following properties: it was inhibited by nitrendipine; it was accompanied by an increase in free cytosolic Ca2 contents; it was unable to stimulate the sodium pump and (iv) it reflected the qualitative and quantitative composition of the incubation media. These observations suggested to us that the increased vascular sodium content results from the opening of potential-dependent calcium channels with secondary internalisation of high amounts of extracellular ions. The ionic perturbations were blocked by low concentrations of cicletanine (IC50 of about 10(-9) M on intracellular sodium). Moreover, the protective effects of cicletanine were inhibited by indomethacin, suggesting that they are mediated by a cyclo-oxygenase metabolite, perhaps prostacyclin. Sodium nitroprusside, a compound able to stimulate calcium entry in the sarcoplasmic reticulum via cyclic GMP, was also able to protect vascular cells (although it acted at higher concentrations than cicletanine). Conversely, captopril and diuretic drugs such as hydrochlorothiazide, furosemide, spironolactone and acetazolamide were unable to protect vascular cells against the deleterious effects of cell washings.

[Cicletanine and the sympathetic nervous system. A study of awake sino-aortic denervated hypertensive dogs]. / Ciclétanine et système nerveux sympathique. Etude chez le chien éveillé hypertendu par dénervation sino-aortique.

The antihypertensive action of non diuretic doses of cicletanine, a new antihypertensive compound, has been studied in neurogenic hypertensive dogs. Four months after sinoaortic denervation, Fourteen dogs were randomly allocated into two parallel groups of oral treatment: cicletanine (10 mg/kg/12 h (n = 7)) or placebo (n = 7). Urinary parameters (diuresis, urinary sodium, potassium, urea and creatinine clearance), cardiovascular parameters (blood pressure (BP) and heart rate) and sympathetic tone (noradrenaline and adrenaline plasma levels) were measured before and after one month of treatment in conscious animals. Chronic treatment with cicletanine lowered BP in neurogenic hypertensive dogs (204 +/- 10/116 +/- 5 mmHg before and 159 +/- 12/86 +/- 8 mmHg after treatment) without any diuretic effect. Cicletanine failed to modify plasma noradrenaline (457 +/- 100 pg/ml versus 419 +/- 135 pg/ml) or adrenaline (213 +/- 36 pg/ml versus 166 +/- 35 pg/ml). These data confirm that cicletanine exerts antihypertensive actions which are independent of its natriuretic properties. Moreover, they suggest that the decrease in arterial blood pressure does not involve sympathetic pathways.

[Protective action of cicletanine on the vascular walls in stroke-prone spontaneously hypertensive rats]. / Etude de la protection par le ciclétanine des parois vasculaires du rat "Stroke-Prone" spontanément hypertendu.

UNLABELLED: In previous works, cicletanine has proven a protective effect on tissues in stroke-prone spontaneously hypertensive rats. The mechanism by which cicletanine lessens the tissue lesion incidence may be explained by the direct vascular effect of increased prostacyclin synthesis and by interaction with various agents mobilizing intracellular. Ca2+ ions. Histological so as to ultrastructural studies of the capillaries and small arteries were performed, specially on those of brain, kidney, heart, and choroid. Method : 36 SHR-SP/A 3N Iffa Credo rats aged 11 weeks were divided into 3 groups. Their drinking water was added with 1 p. 100 NaCl in. Group I was a control group, groups II and III were orally treated with cicletanine, respectively 100 and 150 mg/Kg. Systolic blood pressure, body weight, survival were reported. After 7 weeks of treatment the surviving rats were sacrificed. RESULTS: the control group arterioles showed endoluminal debris with intimal proliferation and a large disorganisation of the media with adventitial fibrosis. The treated groups only showed a slight oedema of the subendothelial space in ultrastructure with no intimal proliferation and no muscle coat disorganisation or proliferation. CONCLUSION: even though the decrease in blood pressure turned out to be very unimportant, the amount of lesions in vessels was striking even when treatment had been started on a already high blood pressure. The vessel walls only presented the impairments usually observed in early arterial response to hypertension. This study shows that cicletanine, due to its properties to increase PG12 synthesis and counterbalance the increase of cytosolic free Ca2+, improves the normal course of hypertensive vascular lesions in the SHR-SP.