When laughter arrests speech: fMRI-based evidence.

Who has not experienced that sensation of losing the power of speech owing to an involuntary bout of laughter? An investigation of this phenomenon affords an insight into the neuronal processes that underlie laughter. In our functional magnetic resonance imaging study, participants were made to laugh by tickling in a first condition; in a second one they were requested to produce vocal utterances under the provocation of laughter by tickling. This investigation reveals increased neuronal activity in the sensorimotor cortex, the anterior cingulate gyrus, the insula, the nucleus accumbens, the hypothalamus and the periaqueductal grey for both conditions, thereby replicating the results of previous studies on ticklish laughter. However, further analysis indicates the activity in the emotion-associated regions to be lower when tickling is accompanied by voluntary vocalization. Here, a typical pattern of activation is identified, including the primary sensory cortex, a ventral area of the anterior insula and the ventral tegmental field, to which belongs to the nucleus ambiguus, namely, the common effector organ for voluntary and involuntary vocalizations. During the conflictual voluntary-vocalization versus laughter experience, the laughter-triggering network appears to rely heavily on a sensory and a deep interoceptive analysis, as well as on motor effectors in the brainstem. This article is part of the theme issue 'Cracking the laugh code: laughter through the lens of biology, psychology and neuroscience'.

[Primary hyperparathyroidism]. / Hyperparathyroïdie primitive.

For the past 40 years, primary hyperparathyroidism has been recognized as a common endocrine disease which is, most often, "non-symptomatic", without the occurrence of nephrolithiasis or osteitis fibrosa cystica. Our knowledge in the pathophysiology has increased largely and diagnosis of primary hyperparathyroidism is usually easy. The only radical treatment is surgery and the surgical indications have been codified by several consensus conferences. For patients who do not undergo surgery, prolonged medical monitoring is needed.

Is it Possible to Differentiate between Angiotensin II Type 1 (AT1) Receptor Blockers in Normotensive Volunteers?

Variability of blood pressure responses to inhibition of the renin-angiotensin system is influenced by factors inherent in the patient, such as renin status, and by drug-specific factors, such as pharmacokinetics. The pharmacokinetic-pharmacodynamic interactions of two doses of candesartan cilexetil, which is an ester prodrug of the insurmountable angiotensin II type 1 (AT 1 ) receptor blocker candesartan, were compared with those of the standard dose of losartan in normotensive volunteers whose renin status was controlled by mild sodium depletion. In a double-blind, placebo-controlled crossover study, the effects of single oral doses of candesartan cilexetil, 8 mg and 16 mg, and losartan, 50 mg, were compared for 24 h in 16 healthy individuals pretreated with a single 40-mg dose of furosemide. Mean blood pressure was recorded by repeated measurements using the oscillometric method. In addition, measurements were made of plasma active renin, angiotensin I and angiotensin II, and plasma levels of candesartan and EXP-3174, the active metabolites of candesartan cilexetil and losartan, respectively, were determined by high-performance liquid chromatography and correlated to pharmacodynamic changes. The large interindividual variability of EXP-3174 levels in subjects who received losartan revealed a significant correlation between active renin and peak drug levels ( r = 0.77, n = 16, p < 0.01). Such a correlation was not found within either group of individuals who received candesartan cilexetil, because of lower interindividual pharmacokinetic variability. A dose-response relationship was found between plasma renin and candesartan when both doses of candesartan cilexetil were analysed. The pharmacodynamic effects of a single oral dose of candesartan cilexetil, 16 mg, were superior to those of candesartan cilexetil, 8 mg, and losartan, 50 mg (see Table). This conclusion has been confirmed by the results of a parallel-group, dose-determination study performed in hypertensive patients. The less variable pharmacokinetic-pharmacodynamic interaction for candesartan cilexetil than for losartan could account for the smooth 24-h reduction in blood-pressure found in patients treated with candesartan cilexetil. These results suggest not only that AT 1 -receptor antagonists can be differentiated, but that they will not be equally useful in clinical practice where, in contrast to clinical research, clear evidence is more difficult to obtain because of variability in renin status.

Effect of angiotensin-converting enzyme inhibition on plasma, urine, and tissue concentrations of hemoregulatory peptide acetyl-Ser-Asp-Lys-Pro in rats.

The hemoregulatory peptide Acetyl-Ser-Asp-Lys-Pro (AcSDKP) has been reported to accumulate in plasma and urine after the oral administration of angiotensin-converting enzyme (ACE) inhibitors in humans. It is unknown whether such an accumulation also occurs in tissues. We administered captopril (3, 10, or 30 mg/kg) orally for 2 weeks to Wistar rats. In a second experiment, captopril (10 mg/kg) was administered for 9 days and was followed by a 1-h i.v. infusion of either AcSDKP (0.1 or 2 mg/kg) or saline on day 9. Captopril alone dose-dependently increased plasma AcSDKP by a factor of 3 to 5 and urine AcSDKP by a factor of 3. It slightly increased renal and pulmonary AcSDKP concentrations but did not affect AcSDKP concentrations in bone marrow and spleen. The combination of AcSDKP (2 mg/kg) and captopril gave very high AcSDKP concentrations in plasma and urine and increases in AcSDKP concentration by factors of 27 in kidney, 5.5 in lung, and 6.9 in the extracellular fraction of bone marrow. In contrast, no change was observed in the AcSDKP concentration in spleen and in the intracellular fraction of bone marrow. In conclusion, during chronic ACE inhibition in rats, AcSDKP levels slightly increased in organs with high ACE contents. No such increase occurred in hematopoietic organs. AcSDKP had to be combined with captopril to significantly increase its concentration in tissues other than the spleen. The possibility of pharmacologically increasing AcSDKP levels in the extracellular fraction of bone marrow may be of value for protecting hematopoietic cells from the toxicity of cancer chemotherapy.

High plasma level of N-acetyl-seryl-aspartyl-lysyl-proline: a new marker of chronic angiotensin-converting enzyme inhibition.

The acute administration of the angiotensin-converting enzyme (ACE) inhibitor captopril to healthy subjects transiently increases 5.5-fold the plasma levels of a natural stem-cell regulator, N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP). The aim of this study was to measure plasma Ac-SDKP levels during chronic treatment with all types of ACE inhibitors and to assess its relevance as a marker of ACE inhibition. Plasma levels of Ac-SDKP were blindly determined in age- and sex-matched hypertensive patients either treated (ACEI group, n=27) or not (non-ACEI group, n=23) with an ACE inhibitor for more than 1 month. Geometric mean [range] of plasma Ac-SDKP levels were significantly higher in the ACEI group (3.78 [1.48 to 14.5] pmol/mL) than in the non-ACEI group, with no overlap between the groups (0.75 [0.36 to 1.22] pmol/mL, P<.0001). The measurement of Ac-SDKP in plasma discriminated all the patients of the ACEI group, whereas the simultaneous determination of either in vitro (using hippuryl-histidine-leucine as substrate) or in vivo (angiotensin II/angiotensin I ratio) ACE activity failed to identify nine and five cases, respectively. We conclude that Ac-SDKP accumulates in plasma during chronic ACE inhibitor treatment. The long-term consequences of Ac-SDKP accumulation are unknown. The reliability of plasma Ac-SDKP measurement makes it the best marker of chronic ACE inhibition, which can help to verify patients' compliance to ACE inhibitor treatment.