Effects of nifedipine and indomethacin on cough induced by angiotensin-converting enzyme inhibitors: a double-blind, randomized, cross-over study.

Prostaglandins (PG) have been suggested to play a role in the genesis of cough induced by angiotensin-converting enzyme inhibitors (ACE-I) and that inhibition of PG synthesis can reduce or abolish the incidence of this side effect. Moreover, experimental and clinical data suggest that nifedipine, a dihydropyridine Ca antagonist, can inhibit PG synthesis. Therefore, we wished to determine whether nifedipine can reduce cough induced by ACE-I as compared with indomethacin, a known inhibitor of PG synthesis. Fourteen hypertensive patients who developed cough during captopril chronic therapy randomly received slow-release nifedipine 20 mg twice daily (b.i.d.), indomethacin 50 mg b.i.d., and placebo b.i.d. for 1 week in a double-blind, cross-over design. At the end of each treatment phase, cough was evaluated by a self-administered questionnaire containing an ordinal scale for daily cough intensity and frequency. Indomethacin abolished or markedly reduced cough induced by ACE-I, whereas nifedipine reduced it but to a lesser degree. These findings suggest that PG can play a role in cough caused by ACE-I, and a dihydropyridine Ca antagonist can reduce the occurrence of this side effect.     

Serum concentrations of oestradiol-17beta, progesterone, relaxin and chorionic gonadotrophin during blastocyst implantation in natural pregnancy cycle and in embryo transfer cycle in the rhesus monkey

The present study was undertaken to assess the temporal association between the profiles of serum concentrations of oestradiol-17beta, progesterone, chorionic gonadotrophin (CG) and relaxin in pregnancies established naturally, and after embryo transfer, as well as in failed pregnancies in rhesus monkeys. In naturally mated cycles (group 1) a conception rate of 75% was obtained. In group 1, the mean day of CG detection in serum was 11.5 +/- 1.9 day post-ovulation, and for relaxin, 9.0 +/- 2.5 day post-ovulation. In group 2, embryo transfer to synchronous, non-mated surrogate recipients was performed; seven embryo transfer cycles yielded three pregnancies which were allowed to continue to term and normal infants were delivered. In embryo transfer cycles the mean day of CG detection was 14.8 +/- 1.8 day post- ovulation, and for relaxin, 11.4 +/- 2.6 day post-ovulation. A delay of about 3 days was observed in the appearance in circulation of CG (P < 0.05) and also of relaxin (P < 0.05) between natural mated and embryo transfer conception cycles. Significant differences (P < 0.05 for progesterone and P < 0.03 for oestradiol) were obtained for the areas under the curves for progesterone and oestradiol between days 12 and 16 in conception cycles compared with failed pregnancies. These data provide the first observation of the normal hormonal signals associated with maternal recognition of transferred embryos during the peri- implantation period, and suggest that the use of such an experimental primate embryo transfer model may help to elucidate components of maternal and embryonic signal-response mechanisms during embryo implantation.      

Predominant and stable T cell responses to regions of myelin basic protein can be detected in individual patients with multiple sclerosis

T lymphocytes from patients with multiple sclerosis (MS) recognize multiple myelin basic protein (MBP) epitopes. This situation complicates the design of specific immunotherapies. We investigated to which extent the T cell response to MBP is heterogeneous in single subjects in terms of preferentially recognized regions of the molecule, major histocompatibility complex (MHC) restriction, and stability over time. From each of nine patients with MS, a minimum of six MBP-specific T lymphocyte lines (TLL) were assayed for the proliferative response to a panel of overlapping peptides, encompassing the whole MBP. Predominant Tcell recognitions of distinct MBP regions were present in three patients, all HLA-DR2⁺, independently of the clinical features of their disease. Tcell reactivity was preferentially directed to residues 16-38 in one patient. In this case the response was also stable over time, during different phases of the disease. Predominant reactivity to residues 86-99 was detected in the two other DR2⁺ patients. In each of the patients with other HLA-DR haplotypes (DR2^?), as well as in three DR2⁺ non-MS donors, the Tcell response to MBP appeared to be considerably more heterogeneous. The HLA restriction element varied among TLL recognizing the same MBP region, even when raised from the same individual. The genomic HLA typing, performed on the DRB1 and DRB5 genes in the DR2⁺ subjects, showed no obvious correspondence between preferential responses to regions of MBP and HLA-DR2 subtypes. In this context, a simple, new method for the genomic typing of the HLA-DRB1 gene in individuals with the HLA-DR2 serological specificity is also described. We conclude that predominant and stable T cell responses to a single MBP region can be detected in some patients with MS. In these individuals, the MHC restriction of the T cell recognition of predominant regions appears to be variable. Polymorphisms of the HLA-DR2 gene products alone do not account for the selection of the dominant MBP Tcell epitope.     

The role of size, sequence and haplotype in the stability of FRAXA and FRAXE alleles during transmission

Factors involved in the stability of trinucleotide repeats during transmission were studied in 139 families in which a full mutation, premutation or intermediate allele at either FRAXA or FRAXE was segregating. The transmission of alleles at FRAXA, FRAXE and four microsatellite loci were recorded for all individuals. Instability within the minimal and common ranges (0-40 repeats for FRAXA, 0-30 repeats for FRAXE) was extremely rare; only one example was observed, an increased in size at FRAXA from 29 to 39 repeats. Four FRAXA and three FRAXE alleles in the intermediate range (41-60) repeats for FRAXA, 31-60 for FRAXE) were unstably transmitted. Instability was more frequent for FRAXA intermediate alleles that had a tract of pure CGG greater than 37 although instability only occurred in two of 13 such transmissions: the changes observed were limited to only one or two repeats. Premutation FRAXA alleles over 100 repeats expanded to a full mutation during female transmission in 100% of cases, in agreement with other published series. There was no clear correlation between haplotype and probability of expansion of FRAXA premutations. Instability at FRAXA or FRAXE was more often observed in conjunction with a second instability at an independent locus suggesting genomic instability as a possible mechanism by which at least some FRAXA and FRAXE mutations arise.      

ST segment depression elicited by dipyridamole infusion in asymptomatic hypertensive patients

In asymptomatic patients with essential hypertension, electrocardiographic changes suggestive of myocardial ischemia can be elicited by rapid pressure lowering or by pronounced coronary arteriolar dilation. The aim of this study was to assess whether dipyridamole infusion might induce ischemic-like electrocardiographic changes in asymptomatic essential hypertensive patients and to describe the clinical and echocardiographic correlates possibly associated with this response. We therefore studied a control group of 20 normotensive individuals and a group of 28 asymptomatic patients with mild-to-moderate essential hypertension. All underwent dipyridamole-echocardiography testing (12-lead electrocardiogram and two-dimensional echocardiographic monitoring with dipyridamole infusion, 0.84 mg/kg over 10'). No patient showed transient regional dyssynergy during dipyridamole infusion. None of the normotensive and 10 of 28 of the hypertensive participants had horizontal or downsloping ST segment depression more than 0.1 mV during dipyridamole (0% versus 36%, p less than 0.01). Hypertensive patients with ("responders") (n = 10) and without ("nonresponders") (n = 18) ST segment depression showed similar values of percent fractional shortening in baseline conditions (32 +/- 5 versus 33 +/- 6, p = NS) and at peak dipyridamole infusion (45 +/- 8 versus 43 +/- 5, p = NS). The peak early to peak late velocity ratio values (evaluated from transmitral flow tracings by Doppler technique) were also similar in baseline conditions (0.86 +/- 0.14 versus 0.94 +/- 0.30, p = NS) and at peak dipyridamole (0.72 +/- 0.15 versus 0.78 +/- 0.32, p = NS).(ABSTRACT TRUNCATED AT 250 WORDS)     

Antihypertensive effect of once daily sustained release isradipine: a placebo controlled cross-over study

Summary To evaluate the magnitude and duration of the antihypertensive effect of sustained release (SRO) isradipine, 37 uncomplicated essential hypertensive patients (diastolic blood pressure 100–115 mm Hg after a one month run-in on placebo) were randomised to receive, according to a double-blind cross-over design, isradipine SRO 5 mg once daily and the corresponding placebo for 1 month. At the end of each treatment period, sitting blood pressure and heart rate were measured immediately before and every hour for 6 h after the last dose. Thirty-four patients [16 m, age 54 (7) y] completed the study.As compared to randomised placebo, isradipine SRO significantly reduced the systolic (SBP) and diastolic (DBP) blood pressure. Absolute DBP decrements versus placebo peaked 6 h after dosing (-8.8 mm Hg) and were not significantly lower (-8.2 mm Hg) at the end of the dose interval. At the same times, the absolute decrements in SBP were -9.8 mm Hg and -9.7 mm Hg, respectively.DBP was normalised in 19 patients (56%) at peak and in 17 (50%) at trough time. The trough to peak efficacy ratio in patients with peak DBP 90 mm Hg was 70%. Heart rate was slightly increased by isradipine SRO. Adverse effects monitored with a check-list occurred in 8/36 patients (22%) on isradipine SRO and in 4/35 (11%) on randomized placebo.The data suggest that isradipine SRO is an effective antihypertensive drug, with a trough to peak efficacy ratio supporting once daily administration in most mild to moderate essential hypertensives.     

The role of pancreatic venous sampling in the localization of occult insulinomas

The palpation and enucleation of occult insulinomas (less than 15 mm) can be a difficult surgical problem even with good arteriographic localization. In the authors' limited experience, confirmation of arteriographic findings by pancreatic venous sampling provided little additional localizing information. However, if arteriography is negative or equivocal, venous sampling can indicate the segment of pancreas to be "blindly" resected if the adenoma is not palpable. Venous sampling may be misleading in polyendocrine syndromes because of the frequency of multiple adenomas and variable hormone production.