Different clinical outcomes between cerebral amyloid angiopathy-related inflammation and non-inflammatory form.

OBJECTIVE: Cerebral amyloid angiopathy-related inflammation (CAA-ri) is a rare manifestation related to CAA, thought to be more severe. We aimed to compare the clinical and radiological outcomes of CAA-ri and non-inflammatory CAA. MATERIALS AND METHODS: We retrospectively included all patients with CAA-ri from 13 French centers. We constituted a sex- and age-matched control cohort with non-inflammatory CAA and similar disease duration. Survival, autonomy and cognitive evolution were compared after logistic regression. Cerebral microbleeds (CMB), intracerebral hemorrhage, cortical superficial siderosis and hippocampal atrophy were analyzed as well as CSF biomarker profile and APOE genotype when available. Outcomes were compared using Kaplan-Meier curves and log-rank tests. RESULTS: Data from 48 CAA-ri patients including 28 already reported and 20 new patients were analyzed. Over a mean of 3.1 years, 11 patients died (22.9%) and 18 (37.5%) relapsed. CAA-ri patients were more frequently institutionalized than non-inflammatory CAA patients (30% vs 8.3%, p < 0.001); mortality rates remained similar. MMSE and modified Rankin scale scores showed greater severity in CAA-ri at last follow-up. MRI showed a higher number of CMB at baseline and last follow-up in CAA-ri (p < 0.001 and p = 0.004, respectively). CSF showed lower baseline levels of Aß42 in CAA-ri than non-inflammatory CAA (373.3 pg/ml vs 490.8 pg/ml, p = 0.05). CAA-ri patients more likely carried at least one APOE ε4 allele (76% vs 37.5%, adjusted p = 0.05) particularly as homozygous status (56% vs 6.2%, p < 0.001). INTERPRETATION: CAA-ri appears to be more severe than non-inflammatory CAA with a significant loss of autonomy and global higher amyloid burden, shown by more CMB and a distinct CSF profile. This burden may be partially promoted by ε4 allele.

Follow-up of Intracranial Aneurysms Treated by Flow Diverters: Evaluation of Parent Artery Patency Using 3D-T1 Gradient Recalled-Echo Imaging with 2-Point Dixon in Combination with 3D-TOF-MRA with Compressed Sensing.

BACKGROUND AND PURPOSE: MRA assessment of parent artery patency after flow-diverter placement is complicated by imaging artifacts produced by these devices. The purpose of this study was to assess the accuracy of liver acquisition with volume acceleration-flex technique (LAVA-Flex) MRA in combination with 3D-TOF with HyperSense MRA for the evaluation of parent vessel status after intracranial flow-diverter placement. MATERIALS AND METHODS: Fifty-six patients treated by flow diversion and followed with both DSA and 3T MRA between November 2020 and August 2021 were included. All patients were evaluated for parent artery patency using the same imaging protocol (DSA, noncontrast MRA including 3D-TOF with HyperSense and LAVA-Flex, and contrast-enhanced MRA, including time-resolved imaging of contrast kinetics MRA and delayed contrast-enhanced MRA). RESULTS: With DSA as a criterion standard to evaluate the patency of the parent vessel, noncontrast MRA had a good specificity (0.83) and positive predictive value (0.65), better than contrast-enhanced MRA (0.55 and 0.41, respectively). Both had excellent sensitivity and negative predictive value: noncontrast MRA, 0.93 and 0.97, respectively; contrast-enhanced MRA, 0.93 and 0.96, respectively. Specificity and positive predictive value tended to be lower for patients treated with additional devices than for those treated with flow diverters exclusively and for patients treated with a specific type of flow diverter. CONCLUSIONS: Noncontrast MRA can be used for noninvasive follow-up of intracranial aneurysms treated by flow diverters. The combined use of LAVA-Flex and 3D-TOF with HyperSense sequences allows monitoring the status of the parent artery and aneurysm occlusion.

Large-scale enzymatic membrane reactors for tetracycline degradation in WWTP effluents.

A mathematical model to simulate the performance of enzymatic membrane reactors was developed. It was applied to investigate the effectiveness of laccase immobilized over ceramic membranes for the degradation of tetracycline, a common antibiotic appearing as micropollutant in effluents of WWTPs. A process based on large-scale enzymatic membrane reactors in series was proposed for the treatment of the effluents from municipal, hospital and industrial wastewater treatment plants (WWTPs). The obtained results demonstrated the need for high improvements in the amount of enzyme grafted on the membranes or on enzymatic kinetics to afford the technical and economic competitiveness of the investigated designs and the possibility to be implemented within existing installations.

Effects of UP269-6, a new angiotensin II receptor antagonist, and captopril on the progression of rat diabetic nephropathy.

To estimate the effects of UP269-6, a nonpeptide angiotensin II receptor antagonist, and captopril, a converting enzyme inhibitor, on the progression of nephropathy, 77 uninephrectomized diabetic rats were maintained for 8 months with plasma glucose levels from 300 to 500 mg/dL. Systemic and renal parameters were periodically measured, and, at the time of death, a histological evaluation of renal damage was performed. Control rats (no additional treatment but insulin) showed increased blood pressure and urinary albumin levels, together with prominent alterations in the kidney (renal and glomerular hypertrophies, tubular atrophy, and 19% of sclerotic glomeruli). Captopril (50 mg/kg/day) and UP269-6 (10 mg/kg/day) reduced blood pressure and albumin excretion levels, and improved histological renal preservation (lower renal and glomerular hypertrophies, tubular atrophy, and percentage of sclerotic glomeruli: 5% and 7%, respectively). Finally, a low dose of UP269-6 (1 mg/kg/day), which induced an intermediate level of blood pressure between control and the other treated groups, produced an equivalent degree of nephroprotection. Our data demonstrate the efficacy of this new angiotensin II receptor antagonist on the progression of diabetic renal damage. These results also reinforce the role attributed to angiotensin II in the development of renal derangement in this model, as UP269-6 is devoid of agonistic effect on the kinin system.

In vitro and in vivo effects of UP 269-6, a new potent orally active nonpeptide angiotensin II receptor antagonist, on vascular smooth muscle cell proliferation.

1. The present studies were designed to measure the affinity of UP 269-6, a newly developed angiotensin AT1 receptor antagonist, for vascular AT1 receptors from normotensive and hypertensive rats and to investigate in vitro, its effects on angiotensin II (AII)-induced hyperplasia and hypertrophy of vascular smooth muscle cells (VSMC). In addition the in vivo effects of UP 269-6 on neointimal proliferation in a carotid artery balloon injury in normotensive rats were also investigated. 2. UP 269-6 selectively inhibited [125I]-Sar1-Ile8-AII binding to vascular AT1 receptors present on VSMC derived from normotensive Wistar rat and from SHR (Ki = 16.6 +/- 3.6 nM and 7.5 +/- 2.0 nM, respectively). In comparison, losartan and its metabolite, EXP 3174, inhibited [125I]-Sar1-Ile8-AII binding to vascular AT1 receptors derived from both cell models with Ki values slightly lower (losartan) and higher (EXP 3174), respectively, than that of UP 269-6. 3. AII (1 microM) induced a weak and variable hyperplastic response (4 to 32% increase in cell number) in Wistar rat VSMC after 96 h. 4. AII (1 microM) induced a time-dependent increase in cell number in VSMC from SHR. UP 269-6 inhibited concentration-dependently this effect with an IC50 value of 159 +/- 58 nM. Losartan was clearly less potent and EXP 3174 showed nearly the same inhibitory potency, compared to UP 269-6. UP 269-6 (1 microM) inhibited nearly completely the action of AII. 5. AII (500 nM) caused maximal stimulation of protein synthesis in Wistar rat VSMC (117 +/- 36%). UP 269-6, losartan and EXP 3174 totally inhibited this stimulation with IC50 values of 28 +/- 6 nM, 3504 +/- 892 nM and 21 +/- 3 nM, respectively. 6. AII (50 nM) induced maximal stimulation of protein synthesis in SHR VSMC (237 +/- 67%). UP 269-6, losartan and EXP 3174 totally inhibited this stimulation with IC50 values of 16 +/- 3 nM, 282 +/- 122 nM and 3.3 +/- 1.0 nM, respectively. 7. UP 269-6 (75 mg kg-1 day-1) administered orally in the diet for 20 days induced a 38% reduction in neointimal area and a 36% reduction in neointima/media ratio associated with the intimal thickening induced by carotid artery balloon injury. 8. In conclusion, UP 269-6 was shown to be a potent antiproliferative agent both in vitro on AII-induced hyperplasia and hypertrophy of VSMC derived from normotensive and hypertensive rats, and in vivo upon intimal thickening induced by carotid artery balloon injury in the rat.

In vivo pharmacological characterization of UP 269-6, a novel nonpeptide angiotensin II receptor antagonist.

UP 269-6, 5-methyl-7-propyl-8(-)[2'-(1H-tetrazol-5-yl)biphenyl-4- yl)methyl]-1,2,4-triazolo]1,5-c]pyrimidin-2(3H)-one is a novel nonpeptide angiotensin II receptor antagonist. In vivo studies were performed to evaluate UP 269-6 for its angiotensin II antagonistic action. In pithed rats, i.v. administration of UP 269-6 (0.03-1 mg/kg) shifted dose dependently to the right the dose-pressor response curve for angiotensin II and decreased the maximum response. The angiotensin II antagonistic effect of UP 269-6 was as potent as that of L-158,809 (5,7-dimethyl-2-ethyl-3(-)[[2'- (1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-imidazo[4,5-b]pyridine) and 10 times more potent than that of losartan. UP 269-6 antagonized the angiotensin II sympathetic-mediated tachycardiac response. UP 269-6 inhibited dose dependently the pressor response to angiotensin II with an ID50 of 4.5 micrograms/kg, i.v. in conscious normotensive dogs. Oral administration of UP 269-6 (0.1 to 30 mg/kg) resulted in a dose-dependent and long-lasting inhibition of the angiotensin II-induced pressor response in conscious normotensive rats and dogs. Compared to losartan, UP 269-6 presented a more rapid onset of action. UP 269-6 caused similar angiotensin II antagonistic effects in rats and dogs but the duration of the effect was greater in dogs than in rats. UP 269-6 did not alter the tachycardiac response to isoproterenol and the pressor response to vasopressin. UP 269-6 was demonstrated to be devoid of agonistic properties in rats and dogs. Furthermore, UP 269-6 did not induce hypotension and did not cause alteration in heart rate and ECG waveforms in dogs even at a dose 1000 times higher than the angiotensin II antagonistic effective dose. These results demonstrate that UP 269-6 is a potent and specific angiotensin II receptor antagonist and dose not possess agonistic properties.

In vitro pharmacological characterization of UP 269-6, a novel nonpeptide angiotensin II receptor antagonist.

f1p4in vitro pharmacology of UP 269-6, a novel nonpeptide angiotensin II antagonist, was examined in radioligand binding and functional isolated tissue assays. UP 269-6 bound selectively to AT1 receptors as evidenced by the inhibition of specific [125I] Sar1, Ile8-AII binding in rat adrenal membranes (IC50 = 35.8 nM) and in cultured vascular smooth muscle cells (IC50 = 23.8 nM). UP 269-6 displayed a very high selectivity for the AT1 compared to the AT2 receptor subtype (IC50 > 10,000 nM). UP 269-6 inhibited the AII-induced contraction of isolated rabbit aortic strips. The pattern of AII antagonism suggested competitive antagonism at low concentrations (10(-10), 3 x 10(-10), 10(-9) M) of UP 269-6 and insurmountable antagonism at higher concentrations (3 x 10(-9), 10(-8), 3 x 10(-8) M). Based on the calculated pA2 values, UP 269-6 (9.86 +/- 0.25) was an angiotensin II receptor antagonist as potent as L-158,809 (9.82 +/- 0.37) and much more potent than losartan (7.96 +/- 0.38). UP 269-6 was devoid of affinity (IC50 > 10,000 nM) for many other receptors, ion channels and uptake sites, demonstrating its high specificity for AII receptors. Furthermore, this compound did not affect the contractile response to KCl or phenylephrine in rabbit aorta and exhibited no effect on angiotensin converting enzyme activity. These data demonstrate that UP 269-6 is a highly potent, selective and specific AT1 receptor antagonist.

Synthesis and angiotensin II receptor antagonist activity of C-linked pyrazole derivatives.

The synthesis and pharmacological activity of new nonpeptide angiotensin II (AII) receptor antagonists are presented. These 5-O-substituted and 5-C-substituted 3-alkylpyrazole derivatives represent a new series of antagonists and have led to the discovery of compounds with potent oral antihypertensive activity in a renal artery-ligated rat model. In vitro, they displayed a high affinity for rat adrenal AII receptors. In vivo structure-activity relationship study has shown the importance of the 4-[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl moiety for oral activity and the critical role of alkyl substituents at the 1- or 2-position. In the case of oral administration, 5-C derivatives were found to be, on the whole, more potent than 5-O derivatives. UP 221-78, 5-hydroxymethyl-3-n-propyl-1-(2,2,2-trifluoroethyl)-4- [[2'-(1H-tetrazol-5-yl)biphenyl-4-]methyl]-1H-pyrazole (79), displayed equivalent antihypertensive activity to the well known antagonist Losartan at 3 mg/kg p.o. in renal artery-ligated rats, with maximal decreases in mean arterial pressure of 60 and 63 mmHg for Losartan and UP 221-78, respectively.

Synthesis and SAR studies of novel triazolopyrimidine derivatives as potent, orally active angiotensin II receptor antagonists.

The synthesis and pharmacological activity of new nonpeptide angiotensin II (AII) receptor antagonists are presented. These [1,2,4]-triazolo[1,5-c]pyrimidine and 1,2,4-triazolo[4,3-c]pyrimidine derivatives represent a new class of bicyclic antagonists that produced a potent, oral antihypertensive activity in the renal artery-ligated rat model. In vitro, they displayed a high affinity for rat adrenal AII receptors and were found to be specific for the AT1 receptor subtype. A SAR study has shown the importance of the 8-[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl for oral activity and the critical role of alkyl substituents at 5- and 7-positions. No significant differences were found between the [1,5-c] and [4,3-c]series. UP 269-6 (5-methyl-7-n-propyl-8-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl ]- [1,2,4]-triazolo[1,5-c]pyrimidin-2(3H)-one, derivative 29) was selected as the lead compound. It was shown to be a highly potent antihypertensive derivative (decrease in mean arterial pressure of 39.6 +/- 7.2 mmHg at 1 mg/kg po in renal artery-ligated rat) with a long duration of action which displayed a high affinity for adrenal AII receptors with a marked selectivity for the AT1 receptor subtype (Ki AT1 = 24 nM; Ki AT2 = 79,200 nM). This compound is currently undergoing extensive pharmacological and clinical development.

[Differences in mortality in the Dogon of Boni]. / Différences de mortalité chez les Dogon de Boni.

Mortality has been analyzed at the level of a small population of approximately 5000 persons, part of the Dogon of Mali. They are separated into four distinct groups, each composed of from three to four villages. Adjusted life tables are estimated for two periods of five years: 1977-81 and 1982-86. First these tables were calculated for the entire population and then for two of the most densely populated massifs. Mortality is very high. However, it is different in the two areas. This difference, already notable in 1977-81, increased during the period 1982-86. Possible causal factors could be linked to the presence of primary health care in the Tabi region. Although very limited, the care changed elementary rules of hygiene. Moreover, comparison between villages point to the important role of the quality and quantity of available water in relation to child mortality levels.

Cardiotonic agents. Synthesis and cardiovascular properties of novel 2-arylbenzimidazoles and azabenzimidazoles.

Novel 2-arylbenzimidazoles and azabenzimidazoles were synthesized, and their inotropic action was evaluated. Changes in left ventricular pressure, dP/dt max, were measured as an index of cardiac contractility. The structural features that impart optimal inotropic activity are presented. The most potent compounds were evaluated orally in conscious dogs with implanted Konigsberg pressure transducers. To investigate the mechanism of action, the most potent compounds were tested for their calcium-sensitizing properties and their potential for the inhibition of phosphodiesterase. Two compounds, 1 and 41, showed interesting in vitro and oral activity without side effects. They have a more potent calcium-sensitizing effect than MCI-154 and are under further investigation.

[Demographic and evolutionary dynamics of an isolate: the Dogon of Boni]. / Dynamique demographique et evolutive d'un isolat: les Dogon de Boni.

PIP: The principal results are presented of demographic and genetic studies among the Dogon of the mountains of Boni. The Dogon of Boni are a culturally homogeneous population who have retained their own identity. Their villages were hidden in the rocks and thus protected from the recurring attacks and pillagings of passing nomadic tribes. The attacks ceased after several generation, and the Dogon have spread out beyond their original settlements. The dogon 1st inhabited the area in the early 18th century, arriving in successive waves from the Mande country. The topography of a plain intersected by mountains and plateaus has resulted in division of the Dogon population into isolates. The Dogon currently live in some 15 villages. They are sedentary and practice subsistence agriculture. The climate is Sahelian and life is difficult under the best of circumstances. The persistent aggravation of the drought since the 1970s has caused growing concern and may prompt the population to resettle elsewhere. Women have 7.2 live births on average, with very high fertility rates between 20-40 years. High rates of remarriage and polygamy appear to increase fertility. The life expectancy at birth of 31-37 years depending on the year and the sex of the child is among the lowest in Mali. 40% or more of newborns die before the 5th birthday. Some 18 years of life expectancy are added once the 5th birthday is passed. Except in years of crisis resulting from drought and famine, cholera epidemics, or measles which strikes virulently every 3 or 4 years, most deaths are caused by malaria and fever or diarrhea and intestinal parasites. A health center opened in 1979 in the largest town of Tabi may have had some affect on mortality despite its precarious functioning and lack of support. The average age at 1st marriage is 18.2 for women and 23.9 for men. Almost everyone marries and successive divorces and remarriages are common. Polygamy rates vary in the different mountain areas. Only about 4% of marriages are outside the ethnic group. 84% of unions occur between persons from the same massif. Marriages within the same lineage are not the rule. Although cousin marriages appear to be preferred, the complexity of kinship networks among individuals on the same massif means that after a few generations everyone is related. Genetic studies show that each massive has been relatively autonomous. Of the 51 original settlers, only 1 or 2 hundred are reflected in the genealogies of each massif. Demographic dynamics are conditioned by cultural norms concerning choice of spouse, by limited pools of available partners, and by the hostile physical environment which limits communications.^ieng

Comparison of anticholinergic effects of cibenzoline, disopyramide, and atropine.

The anticholinergic effects of cibenzoline, disopyramide, and atropine were compared on experimental models. Using inhibition of specific binding of 3H-quinuclidinyl benzylate (3H-QNB) in rat heart and cerebral cortex, Ki values were 15.8 +/- 1.6, 12 +/- 3.5, and 0.013 +/- 0.001 microM, respectively, for heart membranes and 31.6 +/- 1.5, 7.8 +/- 1.3, and 0.006 +/- 0.001 microM, respectively, for cerebral cortex membranes. In isolated guinea pig ileum, disopyramide was about 15 times more anticholinergic than cibenzoline but about 900 times less so than atropine. In anesthetized dogs, the three drugs administered by intravenous bolus reduced bradycardia caused by vagal stimulation. The effect of cibenzoline at 7 mg/kg i.v. (double the antiarrhythmic dose) was approximately the same as that of disopyramide at 2.5 mg/kg (half the antiarrhythmic dose). The drugs were infused for 1 h at 0.17 mg/kg/h for atropine, 11.6 mg/kg/h for disopyramide, and 5.5 mg/kg/h for cibenzoline. The maximal inhibition of the vagal stimulation was 98, 95, and 52%, respectively, for the three drugs. In nonanesthetized dogs, inhibition of the vagal-tone-induced tachycardia reached 33 +/- 4, 134 +/- 20, and 206 +/- 19% for cibenzoline, disopyramide and atropine, respectively. These results show cibenzoline to exert less potent anticholinergic effects than disopyramide.

Endogamy among the Dogon of Boni, Mali.

This paper examines factors influencing endogamy in a Dogon population in Mali. Situated in Boni district, this population of about 5000 individuals is distributed over fifteen villages located on four independent massifs. This population is strongly endogamous (only 4% of all marriages are contracted with neighbouring ethnic groups), and each massif shows high endogamy. The roles of lineage, residence in the same village, and geographical distance in mating choice are examined. These different factors are successively analysed using log-linear statistical models and the results offer a more precise interpretation of endogamy in this population.

Evidence for a class 4 effect of cibenzoline "in vivo".

In anesthetized dogs, it has already been shown that cibenzoline (4 mg/kg i.v.) possesses class 1 anti-arrhythmic properties. In this work, the cardiac electrophysiologic effects of cibenzoline (1 mg/kg i.v.) were studied before and after propranolol (0.2 mg/kg i.v.) treatment. Cibenzoline caused a slight tachycardia, a reduction of conduction velocity in the His-Purkinje system and in the ventricle, but no significant effects in the atria and the atrioventricular node were detected. On the contrary, when dogs were given the beta-adrenoceptor blocking agent propranolol, cibenzoline produced major effects in the slow response structures, especially in the sinus node and the atrioventricular node (bradycardia and depression of the atrioventricular nodal conduction). No further effects were observed on the His-Purkinje system and ventricle as compared to administration of cibenzoline alone. In dogs, cibenzoline given i.v., had no effects on the slow response systems, probably because of sympathetic nervous system intervention since the class 4 effects of cibenzoline appeared after beta-adrenoceptor blockade.

Genetic origins of the Dogon population in the Arrondissement of Boni (Mali).

A study of probabilities of origin of genes was carried out on a Dogon population in Mali, spread over four massifs separated from each other by about 20 kilometers. Within each village, the founder contributions are very disparate and show that each village has a very specific origin. Therefore, the exchange of wives between massifs has not resulted in a homogenization of the population, which has remained strongly structured into four relatively independent isolates.

[p-[(Thienylcarbonyl)amino]phenoxy]propanolamines derivatives as diuretic and beta-adrenergic receptor blocking agents.

The synthesis of [[(thienylcarbonyl)amino]phenoxy]propanolamines and their beta-adrenergic blocking and diuretic activity are described. Structure-activity relationships demonstrated that ortho substitution of the phenoxy ring with an hydrogen or an ester function leads to compounds possessing both activities. Ethyl 2-[3-[(1,1-dimethylethyl) amino]-2-hydroxypropoxy]-5-[(2-thienylcarbonyl)amino]benzoate (3d) was selected as the most active compound for further investigation.

Cardiac electrophysiological effects of cibenzoline by acute and chronic administration in the anesthetized dog.

The electrophysiological effects of cibenzoline on the myocardium of the anesthetized dog were studied by the endocavitary catheter method. Plasma cibenzoline levels were measured throughout. The cibenzoline effects on the sinus rate were negligible. The corrected sinus recovery time was significantly prolonged only following chronic oral administration. Atrial refractory periods were significantly increased only at the fifth minute following acute intravenous administration and after chronic oral treatment. The intranodal conduction time (AH) and the refractory periods in atrio-ventricular node were slightly modified or not at all. On the other hand, intraventricular and His-Purkinje (HV) conduction times, ventricular refractory periods and QRS duration were strongly increased following acute or chronic administration. This would imply a principal effect on the rapid kinetics sodium entry current. Nevertheless, the very marked effect upon this current could, under the experimental conditions adopted, have masked a lesser action upon other membrane permeabilities, involved in other myocardial structures.

Effects of cibenzoline, a novel antiarrhythmic drug, on action potential and transmembrane currents in frog atrial muscle.

The mechanisms of action of cibenzoline upon the electrical activity of the cardiac membrane in vitro, were studied using frog auricular preparations. Action potentials and transmembrane currents were examined using the double sucrose gap technique. Cibenzoline 2.6 X 10(-6) M reduced the amplitude and rate of depolarization of the action potential, slightly prolonged its duration and increased the refractory period. Voltage clamp analysis revealed a notable decrease in the amplitude of sodium rapid inward current, accompanied by a decrease in the kinetics of activation and inactivation, time to peak of the current was increased, as was the inactivation time constant. Cibenzoline delayed recovery from inactivation, reactivation time constants were increased. Cibenzoline also reduced the slow kinetic current due to calcium and sodium ions. The calcium portion of this current was less affected. These data lead to the conclusion that cibenzoline has the characteristics of class I and some class IV anti-arrhythmic action, but cibenzoline is not another quinidine because it would not appear to influence outward potassium current.