Infantile hypotonia as a presentation of Rett syndrome

Rett syndrome (RTT) is classically defined by meeting certain clinical diagnostic criteria. It affects mostly females, and one possible pathogenic mechanism was considered to involve mitochondrial function. This was based on the finding of ultrastructural alterations in the mitochondria and decreased respiratory chain enzyme activity. However, the principal etiology of RTT has since been found to be mutations in the MECP2 gene, which is located on the X chromosome. Molecular analysis has allowed the phenotype of MECP2 mutations to be broadened beyond RTT to include girls who have mild mental retardation, autism, and an Angelman syndrome phenotype, as well as males with severe encephalopathy. We present a girl with a previously described mutation in the MECP2 gene whose phenotype is of atypical RTT. She presented with hypotonia and developmental delay in infancy without a clear period of normal development. As part of her evaluation for hypotonia, a muscle biopsy and respiratory chain enzyme analysis showed a slight decrease in respiratory chain enzyme activity consistent with previous reports. This report supports broadening the phenotype of patients who should be considered for MECP2 mutation analysis to include cases of developmental delay and hypotonia without evidence of an initial period of normal development. Furthermore, it supports the hypothesis of an underlying secondary defect in energy metabolism contributing to the pathogenesis of RTT.     

Different receptors mediating the inhibitory action of exogenous ATP and endogenously released purines on guinea-pig intestinal peristalsis.

1 Adenosine 5'-triphosphate (ATP) is an enteric neurotransmitter which acts at purine receptors on intestinal nerve and muscle. This study set out to shed light on the receptor mechanisms by which exogenous and endogenous ATP influences intestinal peristalsis. 2 Peristalsis in isolated segments of the guinea-pig small intestine was triggered by a perfusion-induced rise of the intraluminal pressure. Motor changes were quantified by alterations of the peristaltic pressure threshold (PPT) at which propulsive muscle contractions were elicited. 3 ATP (>/= 3 microM) increased PPT and abolished peristalsis at concentrations of 100-300 microM. Adenosine 5'-O-2-thiodiphosphate (ADPbetaS, 3-100 microM) was more potent, whereas alpha,beta-methylene ATP (alpha,beta-meATP, 3-100 microM) was less potent, than ATP in depressing peristalsis. 4 8-Phenyltheophylline (10 microM) attenuated the anti-peristaltic effect of 10 and 30 microM ATP but not that of higher ATP concentrations. Apamin (0.5 microM) counteracted the ability of ATP, ADPbetaS and alpha,beta-meATP to enhance PPT. Suramin (300 microM) and pyridoxal phosphate-6-azophenyl-2',4'-disulphonic acid (PPADS, 150 microM) antagonized the inhibitory effect of alpha,beta-meATP on peristalsis but did not alter the effect of ATP and ADPbetaS. 5 PPADS (50-150 microM) reduced PPT by as much as 50%. This stimulant effect on peristalsis was prevented by suramin (300 microM) but left unaltered by apamin (0.5 microM) and NG-nitro-L-arginine methyl ester (300 microM). 6 These data show that exogenous and endogenous ATP inhibits intestinal peristalsis via different apamin-sensitive purinoceptor mechanisms. Exogenous ATP depresses peristalsis mostly via suramin- and PPADS-insensitive P2 receptors, whereas endogenous purines act via P2 receptors sensitive to both suramin and PPADS.     

Risk factors of gestational diabetes mellitus using results of a prospective population-based study in Iranian pregnant women

Aims

Early identification of at-risk groups is an important step in preventing gestational diabetes and its subsequent side effects. This study aimed to evaluate the risk factors of gestational diabetes based on the International Association of Diabetes and Pregnancy Study Groups criteria in Ahvaz.

Increase in gastric acid-induced afferent input to the brainstem in mice with gastritis

Acid challenge of the gastric mucosa is signaled to the brainstem. This study examined whether mild gastritis due to dextrane sulfate sodium (DSS) or iodoacetamide (IAA) enhances gastric acid-evoked input to the brainstem and whether this effect is related to gastric myeloperoxidase activity, gastric histology, gastric volume retention or cyclooxygenase stimulation. The stomach of conscious mice was challenged with NaCl (0.15 M) or HCl (0.15 and 0.25 M) administered via gastric gavage. Two hours later, activation of neurons in the nucleus tractus solitarii (NTS) was visualized by c-Fos immunocytochemistry. Gastritis was induced by DSS (molecular weight 8000; 5%) or IAA (0.1%) added to the drinking water for 7 days. Relative to NaCl, intragastric HCl increased the number of c-Fos protein-expressing cells in the NTS. Pretreatment with DSS or IAA for 1 week did not alter the c-Fos response to NaCl but significantly enhanced the response to HCl by 54 and 74%, respectively. Either pretreatment elevated gastric myeloperoxidase activity and induced histological injury of the mucosal surface. In addition, DSS caused dilation of the gastric glands and damage to the parietal cells. HCl-induced gastric volume retention was not altered by IAA but attenuated by DSS pretreatment. Indomethacin (5 mg/kg) failed to significantly alter HCl-evoked expression of c-Fos in the NTS of control, DSS-pretreated and IAA-pretreated mice. We conclude that the gastritis-evoked increase in the gastric acid-evoked c-Fos expression in the NTS is related to disruption of the gastric mucosal barrier, mucosal inflammation, mucosal acid influx and enhanced activation of the afferent stomach-NTS axis.     

ATP-binding cassette transporters P-glycoprotein and breast cancer related protein are reduced in capillary cerebral amyloid angiopathy

Alzheimer's disease (AD) is the most common form of dementia and marked by deposition of amyloid-β (Aβ) within the brain. Alterations of Aβ transporters at the neurovasculature may play a role in the disease process. We investigated the expression of ABC transporters P-glycoprotein (P-gp) and breast cancer related protein (BCRP) in non-neurologic controls, AD, and severe capillary cerebral amyloid angiopathy (capCAA) cases, which are characterized by deposition of Aβ within cerebral capillaries. Our data show that microvascular expression of P-gp and BCRP is strikingly decreased in capCAA-affected vessels but not in AD and control samples. Messenger RNA levels of P-gp, but not of BCRP, were downregulated in brain endothelial cells on exposure to oligomeric Aβ42, but not fibrillar Aβ42 or Aβ40. Coincubating Aβ42 together with clusterin, an amyloid-associated protein highly expressed in capCAA-affected vessels, strongly reduced levels of P-gp. In conclusion, accumulation of Aβ, in combination with clusterin, within and around cerebral capillaries, may further aggravate the disease process in AD by affecting P-gp expression. Loss of P-gp expression or activity may serve as a selective biomarker for ongoing capCAA.     

Alzheimer disease macrophages shuttle amyloid-beta from neurons to vessels, contributing to amyloid angiopathy

Neuronal accumulation of oligomeric amyloid-β (Αβ) is considered the proximal cause of neuronal demise in Alzheimer disease (AD) patients. Blood-borne macrophages might reduce Aβ stress to neurons by immigration into the brain and phagocytosis of Αβ. We tested migration and export across a blood-brain barrier model, and phagocytosis and clearance of Αβ by AD and normal subjects’ macrophages. Both AD and normal macrophages were inhibited in Αβ export across the blood-brain barrier due to adherence of Aβ-engorged macrophages to the endothelial layer. In comparison to normal subjects’ macrophages, AD macrophages ingested and cleared less Αβ, and underwent apoptosis upon exposure to soluble, protofibrillar, or fibrillar Αβ. Confocal microscopy of stained AD brain sections revealed oligomeric Aβ in neurons and apoptotic macrophages, which surrounded and infiltrated congophilic microvessels, and fibrillar Aβ in plaques and microvessel walls. After incubation with AD brain sections, normal subjects’ monocytes intruded into neurons and uploaded oligomeric Aβ. In conclusion, in patients with AD, macrophages appear to shuttle Aβ from neurons to vessels where their apoptosis may release fibrillar Aβ, contributing to cerebral amyloid angiopathy. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users. J. Zaghi and B. Goldenson contributed equally.     

Deletion of the acid-sensing ion channel ASIC3 prevents gastritis-induced acid hyperresponsiveness of the stomach-brainstem axis

Gastric acid challenge of the rat and mouse stomach is signalled to the brainstem as revealed by expression of c-Fos. The molecular sensors relevant to the detection of gastric mucosal acidosis are not known. Since the acid-sensing ion channels ASIC2 and ASIC3 are expressed by primary afferent neurons, we examined whether knockout of the ASIC2 or ASIC3 gene modifies afferent signalling of a gastric acid insult in the normal and inflamed stomach. The stomach of conscious mice (C57BL/6) was challenged with intragastric HCl; two hours later the activation of neurons in the nucleus tractus solitarii (NTS) of the brainstem was visualized by c-Fos immunocytochemistry. Mild gastritis was induced by addition of iodoacetamide (0.1%) to the drinking water for 7 days. Exposure of the gastric mucosa to HCl (0.25M) caused a 3-fold increase in the number of c-Fos-positive neurons in the NTS. This afferent input to the NTS remained unchanged by ASIC3 knockout, whereas ASIC2 knockout augmented the c-Fos response to gastric HCl challenge by 33% (P<0.01). Pretreatment of wild-type mice with iodoacetamide induced mild gastritis, as revealed by increased myeloperoxidase activity, and enhanced the number of NTS neurons responding to gastric HCl challenge by 41% (P<0.01). This gastric acid hyperresponsiveness was absent in ASIC3 knockout mice but fully preserved in ASIC2 knockout mice. The current data indicate that ASIC3 plays a major role in the acid hyperresponsiveness associated with experimental gastritis. In contrast, ASIC2 appears to dampen acid-evoked input from the stomach to the NTS.     

Differences in circular muscle contraction and peristaltic motor inhibition caused by tachykinin NK1 receptor agonists in the guinea-pig small intestine

The tachykinin NK1 receptor agonist substance P methyl ester (SPOME) impedes intestinal peristalsis by releasing nitric oxide (NO) from inhibitory motor neurones. Since NK1 receptor agonists differ in their receptor interaction, we set out to compare a range of NK1 receptor agonists including SPOME, septide and GR-73 632 in their effects on propulsive peristalsis and circular muscle activity in the guinea-pig isolated small intestine. SPOME (100-300 nM) inhibited peristalsis by a rise of the pressure threshold at which peristaltic waves were triggered, whereas septide and GR-73 632 (30-300 nM) interrupted peristalsis by causing circular muscle spasms. Separate experiments showed that all three NK1 receptor agonists caused contraction of the circular muscle, which was enhanced by the NO synthase inhibitor NG-nitro-L-arginine methyl ester (300 mM) and the P2X purinoceptor antagonist suramin (300 mM). In contrast, tetrodotoxin (300 nM) augmented the contractile effect of septide and GR-73 632 but not that of SPOME. It is concluded that the motor response to NK1 receptor agonists involves release of NO and adenosine triphosphate from inhibitory motor neurones. However, the NK1 receptor agonists differ in the mechanism by which they cause inhibitory transmitter release, which corresponds to differences in their antiperistaltic action.     

Rates of protein synthesis in brain and other organs

We previously found a decrease in protein synthesis in brain during development, which was much greater as measured in brain slices than in brain in vivo. In the present work such changes in brain were compared to those in other organs. With measurement of incorporation of flooding doses of [14C]valine into proteins of organs, the highest synthesis rate in the adult animal in vivo was found in liver (2.2%) followed by kidney (1.8%), spleen (1.6%), lung (1.0%), heart (0.7%), brain (0.6%) and muscle (0.5%). In immature animals the synthesis rate was highest in spleen (2.6%) followed by liver (2.4%), kidney (1.7%), lung (1.6%), brain (1.5%), heart (1.1%), and muscle (0.9%). Protein synthesis in slices from each tissue proceeded at lower rates than in vivo, especially in adults. The tissue affected the most by the preparation of the slices was muscle.