Plasma catecholamines and postural hypotension in familial amyloidotic polyneuropathy of the Portuguese type

Plasma adrenaline and noradrenaline levels were measured while supine and following head-up tilt to 45^°, in both normal controls and in patients with familial amyloidotic polyneuropathy of the Portuguese type. In nine patients systolic blood pressure fell by less than 15mmHg, while in seven patients it fell by more than 15mmHg. Plasma noradrenaline rose during tilt in the majority of patients, as in the controls. There was no correlation between levels of catecholamines and fall in blood pressure on head-up tilt. The data excludes widespread sympatho-neural failure as a cause for postural hypotension in familial amyloidotic polyneuropathy of the Portuguese type. The results are compatible with either segmental/patchy sympathetic denervation or dysfunction of the receptor/effector mechanisms in target organs such as the heart and blood vessels.     

Prevalence and characteristics of sleep-disordered breathing in familial dysautonomia

ObjectiveFamilial dysautonomia (FD) is an autosomal recessive disorder characterized by impaired development of sensory and afferent autonomic nerves. Untreated sleep-disordered breathing (SDB) has been reported to increase the risk of sudden unexpected death in FD. We aimed to describe the prevalence and characteristics of SDB in FD.Patients/MethodsSeventy-five patients with FD (20 adults and 55 children) underwent in-lab polysomnography, including peripheral capillary oxygen saturation (SpO₂) and end-tidal capnography (EtCO₂) measurements. A t-test and Spearman's correlation analysis were performed to evaluate the impact of age on sleep, occurrence of apneas, SpO₂ and EtCO₂ levels; and to determine the relationship between apneas and SpO₂/EtCO₂ measurements during different sleep stages.ResultsOverall, 85% of adults and 91% of pediatric patients had some degree of SDB. Obstructive sleep apneas were more severe in adults (8.5 events/h in adults vs. 3.5 events/h in children, p = 0.04), whereas central apneas were more severe (10.8 vs. 2.8 events/h, p = 0.04) and frequent (61.8% vs. 45%, p = 0.017) in children. Overall, a higher apnea–hypopnea index was associated with increased severity of hypoxia and hypoventilation, although in a significant fraction of patients (67% and 46%), hypoxemia and hypoventilation occurred independent of apneas.ConclusionMost adult and pediatric patients with FD suffer from some degree of SDB. There was a differential effect of age in the pattern of SDB observed. In some FD patients, hypoventilation and hypoxia occurred independently of apneas. Therefore, we recommend including EtCO₂ monitoring during polysomnography in all patients with FD to detect SDB.     

Electrolyte therapy for refractory seizures in familial dysautonomia

PURPOSE: Video-EEG in a family of three patients with slow development and familial dysautonomia demonstrated absence seizures associated with 3-Hz generalized spike-and-wave discharges. The seizures were refractory to antiepileptic drugs (AEDs). METHODS: Treatment was given with rice-based cereal electrolyte oral solution. RESULTS: Treatment induced seizure freedom and normalization of EEG in all three patients. Repeated video-EEG monitoring with discontinuation of AEDs and maintenance of the oral hydration therapy was associated with recurrence of epileptic activity. All three patients have remained seizure free (approximately 1 year) with a combination of topiramate and electrolytic therapy. CONCLUSIONS: Rice-based oral electrolyte hydration therapy may play a role in prevention and control of seizures in patients with familial dysautonomia.     

C-type natriuretic peptide exerts effects opposing those of atrial natriuretic peptide on anxiety-related behaviour in rats

As evidence exists that C-type natriuretic peptide (CNP) exerts effects opposing those of atrial natriuretic peptide (ANP), we studied the behavioural properties of CNP after central infusion in rats by their performance in the elevated plus maze. Doses of 0.5 μg and 5 μg i.c.v. had distinct anxiogenic properties. Our data suggest opposing effects of CNP and ANP on anxiety-related behaviour in rats, which appear to be mediated via different receptor occupation and brain regions by a corticotropin-releasing hormone (CRH)-dependent mechanism.     

Effect of atrial natriuretic peptide on DOPA potentiation in mice

The effect of rat atrial natriuretic peptide (ANP1-28) on the pargyline-DOPA potentiation test was studied following its administration into the lateral brain ventricle in mice. Thirty minutes after pargyline pretreatment, three doses of ANP (200, 500, or 1,000 ng/mouse) were administered simultaneously with DOPA and animals were then observed for 2 h. ANP in doses of 500 and 1,000 ng markedly enhanced the effect of DOPA. The maximum intensity of the effect was registered 30-45 min following administration of the peptide. The data suggest that ANP might be regarded as a dopaminergic-modulating agent in the CNS.     

Calcineurin and synaptophysin in the human spinal cord of normal individuals and patients with familial dysautonomia

Summary This report concerns the immunohistochemical demonstration of two neuronal Ca²⁺-binding proteins, calcineurin and synaptophysin, in the spinal cord of normal controls and from patients with familial dysautonomia. In controls, calcineurin immunoreactivity was highly concentrated in small nerve cells and fibers of the substantia gelatinosa. Synaptophysin immunoreactivity was normally distributed throughout the spinal cord gray matter, being highly concentrated in the substantia gelatinosa, the dorsal nucleus of Clarke and the anterior horn. In patients with familial dysautonomia, no apparent changes in calcineurin immunoreactivity were found in the substantia gelatinosa. By contrast, there was a significant depletion of synaptophysin-positive axon terminals in the substantia gelatinosa and in the dorsal nucleus of Clarke of patients with familial dysautonomia.     

Decreased density of ganglia and neurons in the myenteric plexus of familial dysautonomia patients

Background: Familial dysautonomia (FD) is a hereditary disease of the autonomic and sensory nervous system. A prominent manifestation of FD is gastrointestinal dyscoordination, which contributes to the morbidity and mortality in FD. Aim: As the myenteric plexus is an essential factor in gastrointestinal motility control, we compared its morphology in appendices of FD patients and controls. Methods: Appendices from FD patients (N=19) were obtained during surgery of fundoplication and gastrostomy; normal appendices (N=17) were obtained from patients suspected to suffer from acute appendicitis, in whom, however, the appendix was found to be normal. Specimens were stained histochemically for NADPH diaphorase (NADPH-d) and in a blinded manner examined under a light microscope for seven morphologic parameters: ganglionic density, neuronal density, ganglionic area, number of stained neurons per ganglion, nerve bundle width, ratio between nervous tissue area and total area, and neuronal area. Results: Ganglionic density was 10.13 per mm² in controls versus 5.01 per mm² in FD (p<0.05). Neuronal density was 70.12 per mm² in controls, compared with 22.09 per mm² in FD (p<0.01). The other parameters were not different between the two groups. Conclusion: Densities of myenteric ganglia and neurons of FD patients were significantly lower than in controls. This deficiency may contribute to the pathogenesis of FD gastroenteropathy.     

Atrial natriuretic peptide and arginine vasopressin secretion in schizophrenic patients

Plasma levels of arginine vasopressin (AVP) and atrial natriuretic peptide (ANP) were measured in 15 patients with schizophrenic or schizoaffective disorders and 15 healthy volunteers during oral water loading at 20 ml/kg. In the patient group, plasma AVP was secreted even when plasma osmolality was below 270 mosmol kg, although the sensitivity of AVP secretion response to osmolality was lower than in the controls. The ANP level was higher in the group of patients than in the controls. There was a negative correlation between plasma ANP and osmolality in the patients. We speculate that the volume expansion caused by inappropriate AVP secretion stimulated plasma ANP release and that the natriuresis resulting from the elevated plasma ANP level might contribute to hyponatremia.     

Founder mutation in IKBKAP gene causes vestibular impairment in familial dysautonomia

Objective

To assess vestibular function in patients with familial dysautonomia (FD), a hereditary sensory and autonomic neuropathy – caused by a mutation in the IKBKAP gene (c.2204?+?6?T > C) – and characterized by marked gait ataxia.

Localization and characterization of atrial natriuretic peptide binding sites in discrete areas of rat brain and pituitary gland by quantitative autoradiography

Atrial natriuretic peptide [rat (r) ANP6-33 or ANP99-126] binding sites were localized in discrete areas of rat brain and pituitary gland using quantitative autoradiographic techniques. High numbers of rANP6-33 binding sites were concentrated in the circumventricular organs (the organon vasculosum laminae terminalis, organon subfornicalis, and area postrema) and selected hypothalamic nuclei (the nucleus supraopticus, nucleus preopticus medianus and nucleus paraventricularis). High binding was also present in the choroid plexus and the bulbi olfactorii (laminae medullaris interna). A relatively low number of rANP6-33 binding sites was observed in other olfactory, limbic and brainstem areas (the nucleus tractus solitarii, nucleus motoris dorsalis vagii and nucleus hypoglossi), the eminentia mediana and the pituitary gland (anterior and posterior lobes). High-affinity rANP6-33 binding sites were demonstrated in the organon subfornicalis and the area postrema after incubation of consecutive sections from individual rat brains with 125I-rANP6-33 in concentrations from 20 to 400 pM. rANP6-33 binding sites were concentrated in areas associated with angiotensin II and/or vasopressin, suggesting an interaction among these peptides in the central nervous system.     

白藜芦醇对成纤维细胞分泌心钠素及脑钠素的影响

背景：白藜芦醇是从传统中药中提取的多酚类化合物，具有抑制成纤维细胞增殖作用。 目的：观察白藜芦醇对成纤维细胞分泌心钠素和脑钠素的影响，验证白藜芦醇对肌腱瘢痕成纤维细胞增殖的抑制作用。 设计、时间及地点：分组对照观察，与2007-03/12在广东医学院实验动物中心完成。 材料：雌性健康成年日本大耳白兔6只，体质量2.0~2.5 kg。白藜芦醇，中国药品生物制品鉴定所提供，纯度99%，用二甲基亚砜溶解成50 mmol/L储存液，置-20 ℃保存。 方法：采用差速贴壁法体外分离培养兔肌腱瘢痕成纤维细胞。将培养的细胞分为2组，对照组不加药物；白藜芦醇组又分为4个亚组，分别加入25，50，75，100 μmol/L白藜芦醇作用72 h。 主要观察指标：采用放免法及ELISA法检测细胞培养液中心钠素及脑钠素水平；反转录-聚合酶链反应方法检测脑钠素、心钠素mRNA表达；硝酸还原酶法测细胞培养液中一氧化氮水平；化学比色法测细胞上清液中一氧化氮合酶水平；放免法测定细胞内环磷酸鸟苷水平。 结果：白藜芦醇25~100 μmol/L作用细胞后一氧化氮、一氧化氮合酶及环磷酸鸟苷水平升高，心钠素、脑钠素水平降低，心钠素、脑钠素mRNA的表达下降，在一定范围内有明显的剂量及时间依赖性。 结论：白藜芦醇在一定浓度范围能降低培养液中心钠素及脑钠素水平，并抑制细胞中心钠素及脑钠素mRNA的表达。     

Alteration of atrial natriuretic peptide receptors in the choroid plexus of rats with induced or congenital hydrocephalus

Specific binding sites for atrial natriuretic peptide (ANP) in the choroid plexus of rats with induced or congenital hydrocephalus were examined using in vitro quantitative receptor autoradiographic methods. The number of¹²⁵I-ANP binding sites in the choroid plexus of rats with kaolin-induced hydrocephalus was significantly higher as compared to findings in the control rats, whereas no differences in the binding affinity were observed 3 days and 3 weeks after the intracisternal injection of kaolin. Conversely, rats with congenital hydrocephalus (LEW-HYR and HTX rats) had a small number of binding sites for¹²⁵I-ANP in the choroid plexus, as compared to findings in the control rats. These alterations may relate to the pathophysiology of hydrocephalus. The possibility that atrial natriuretic peptide may be involved in the regulation of cerebrospinal fluid production in the choroid plexus must be considered.     

Cortical blood flow during head-up postural change in subjects with orthostatic hypotension

Regional cerebral blood flow was measured with the 133-Xenon inhalation method in seven healthy subjects with orthostatic hypotension not due to autonomic failure (i.e. non-neurogenic clinical disorder). Measurements were performed during supine rest and during head-up tilt (70°). All subjects had a consistent drop in systolic blood pressure and the typical symptomatology of orthostatic hypotension. The results showed lower mean hemispheric blood flow during head-up tilt than during supine rest. In addition, a consistent and significant redistribution of the regional flow values was seen, with a reduction in frontal and an increase in postcentral areas. The frontal flow decrease during tilt was more marked than in subjects without orthostatic hypotension and was not related to variations in the level of p_co2 or to respiration. In contrast to the clinical symptoms of orthostatic hypotension (dizziness, nausea, visual disturbances, and in some cases syncope), the cortical blood flow reduction was, however, relatively moderate.     

The effects of postural change and exercise on renal haemodynamics in familial dysautonomia

Cardiovascular instability is a prominent manifestation of familial dysautonomia [FD] while renal insufficiency occurs in a large number of adult FD patients. To determine if there was a causative relationship, renal artery blood flow velocity using Doppler technology, was recorded and the ratio of the peak systolic velocity (point A) to the end diastolic velocity (point B) was calculated. The A/B ratio was assessed in response to change of position and exercise, and was correlated with renal function, heart rate and systemic blood pressure. Studies were performed in 54 FD patients with a mean age of 24 years ± 9.8 years, and 20 controls, with a mean age of 24.7 years ± 7.6 years.In the supine position, the mean A/B ratios were not significantly different, but FD subjects had a significantly higher mean blood pressure and heart rate than controls. When erect and post exercise, the mean A/B ratios in FD subjects were significantly higher than controls,p = 0.0004 andp = 0.0001, respectively. In contrast to controls, when FD subjects were standing erect and post exercise, mean blood pressure decreased significantly without a significant change in heart rate. When FD subjects were divided into two groups based on their creatinine clearance value, the group with the lower creatinine clearances had a significantly greater fall in diastolic pressure when they moved from the supine to the erect position. Our results indicate that noninvasive Doppler techniques are helpful in detecting changes in renal blood flow in subjects with familial dysautonomia. When the A/B ratio is used as an index of renal vascular resistance, renal perfusion decreases in FD subjects while erect and post exercise. The changes in renal haemodynamics may cause ischaemia with eventual development of renal insuffiiciency.     

损毁大鼠下丘脑室旁核后AVP和ANP的关系

目的借助立体定向技术尝试建立因下丘脑室旁核损伤引起的中枢性尿崩症动物模型.在此基础上探讨下丘脑室旁核调节水钠代谢的机制.方法SD大鼠在立体定向仪引导下,试验组向下丘脑室旁核(PVN)注射海人藻酸,以达到损毁目的;对照组则注射人工脑脊液,取血检测血管加压素(AVP)和心钠素(ANP)水平.对比分析尿量,研究PVN损伤后AVP和ANP在体内的变化.结果下丘脑PVN损毁后试验组大鼠尿量为(1.26±0.34)ml,明显多于对照组(0.78±0.16)ml;检测血浆AVP和ANP含量分别为:试验组(3.91±0.48)pg/ml、(332±27.48)pg/ml:对照组(8.05±0.78)pg/ml、(291±31.66)pg/ml.结论下丘脑PVN损毁后血浆AVP水平降低,而ANP水平反而升高,该结果可能是下丘脑损伤后机体水钠代谢紊乱的深层原因,即具体表现为肾脏排水排钠增加.