Hepatocyte growth factor/scatter factor facilitates migration of GN-11 immortalized LHRH neurons

The molecular cues regulating the migratory process of LHRH neurons from the olfactory placode into the brain are not well known, but gradients of chemotropic and chemorepellent factors secreted by the targets are likely to play a key role in guidance mechanisms. Hepatocyte growth factor/scatter factor (HGF/SF) is a pleiotropic cytokine inducing cell migration. It is involved in a variety of developmental processes through interaction with its receptor c-Met. Here we show that c-Met-antibody labels LHRH migrating neurons in the olfactory mesenchyme of E12 mouse and analyze the potential chemotropic effect of HGF/SF on two immortalized LHRH cell lines, GT1-7 and GN11, isolated from tumors developed in the hypothalamus and in the olfactory bulb, respectively. By RT-PCR analysis, Western blotting, and immunocytochemistry, we provide evidence for a high level of c-Met expression in GN11, but not in GT1-7, cells. In addition, HGF/SF treatment promotes specific migratory activity of GN11 cells, as demonstrated by collagen gel assay, time-lapse video microscopy, and Boyden's chamber experiments. Such promotion is inhibited by the neutralizing antibody. The data reported here represent the first direct evidence of a chemotactic effect of HGF/SF on immortalized LHRH neurons.     

DNA neosynthesis in Auerbach plexus ganglia isolated from the rat hypertrophic gut: An electrophoretic analysis

We analysed using electrophoresis the total genomic DNA extracted from isolated Auerbach plexus ganglia of the hypertrophic duodenum upstream from a partial experimental stenosis. Results indicated the presence of two extra-bands migrating below the high molecular weight DNA, suggesting that DNA amplification is the basic mechanism of the DNA neosynthesis previously observed in myenteric neurons.     

Pipecolic acid levels and transport in developing mouse brain

The regional distribution of pipecolic acid (PA) in newborn mouse brain, measured by a new sensitive high performance liquid chromatography with electrochemical detection (HPLC-EC) method, shows a two-fold difference among various areas. Diencephalon, olfactory bulb and anterior telencephalon show the highest PA levels, while the lowest PA levels are seen in mesencephalon and rhombencephalon. The pattern of regional distribution of PA is identical to the regional accumulation in brain of the newborn seen by us following i.p. injections of D,L-[3H]PA9. The highest levels of PA are seen in both brain and serum during the perinatal period of development. Pipecolic acid levels decrease in brain and serum at one day of age and reach adult values within two weeks postnatal. The brain/serum PA ratio (2.9-3.5) during the perinatal period declines gradually after birth to adult values (0.7-0.8) at 30 days. The liver and kidney follow the same pattern with higher levels of PA seen during the perinatal period; however, these levels decreased rapidly to adult levels within one week postnatal. Following injections (250 mg/kg, i.p. and s.c. in the adult and newborn, respectively), D,L-PA accumulates for up to 24 h in the newborn mouse brain. In adult, the cerebral concentration of PA increases rapidly and reaches its peak level in 5-10 min. It remains relatively constant up to 5 h and then declines slowly to 24 h. Pipecolic acid levels in serum show essentially the same pattern of accumulation between adult and newborn mice with some quantitative differences.(ABSTRACT TRUNCATED AT 250 WORDS)     

Development and aging of cholinergic synapses. I. Endogenous levels of acetylcholine and choline in developing autonomic ganglia and iris of the chick

Acetylcholine (ACh) and choline (Ch) levels were measured by means of a sensitive micromethod in developing irises, ciliary and sympathetic ganglia of the chick, starting at 5--7 days of incubation (DI) up to 1 year of age. The neurotransmitter is present in all three organs at relatively low levels (1--10 pmol) from 5 DI (iris) or 7 DI (ciliary and sympathetic ganglion). This is followed by a rapid and sustained 9-fold increase in all three tissues up to 14 DI. Thus, it appears that low levels of ACh may be sufficient for neurotransmission to occur in the primitive ciliary ganglion and iris. After hatching, total ACh levels continue to increase up to 1 year of age in the iris and ciliary ganglion and up to 3 months in the sympathetic ganglion. The increase may depend on either an increased functional demand for the neurotransmitter or an increased number of preganglionic terminals. In general Ch levels parallel closely the levels of ACh in each organ throughout development. It is concluded that ACh and Ch are present since the earliest detectable stages of development in the ganglia and iris, and their first increase seems to be correlated to the phase of innervation of the organs. The subsequent increase probably correlates to synaptogenesis. The close relationship between Ch and ACh levels indicates a regulatory role of Ch for ACh synthesis during neuronal development.     

Esophageal dischalasia: Serendipity during 99mTc thyroid scan

It is rare for a large amount of pooled radioactive saliva to be observed in the neck during a thyroid scan. Such a finding would imply abnormal salivation and/or esophageal kinesis. The case of esophageal dischalasia reported here suggests that a complete study of the esophagus is advisable when a large area or amount of radioactive saliva is observed in the neck during a thyroid scan.     

One hundred years after the discovery of Alzheimer's disease. A turning point for therapy?

Following the introduction of cholinesterase inhibitors in 1986 and a 20-yr long period of successful clinical application in mild, moderate and severe patients, the treatment of AD has turned to modify the course of pathological processes thought to comprise the disease. Several active and passive vaccines are presently under investigation for efficacy, reducing amyloid-beta in the brain of patients with mild-moderately advanced disease. Three large international immunization trials are in progress in US and Europe on mild-moderate AD patients. Among these, the most advanced trial in time is the humanized antibody trial. In addition, drugs aiming to reduce tau phosphorylation (GSK3 inhibitors) are about to enter clinical phases of development. Due to intrinsic difficulties, the developments of gamma-and beta-secretase inhibitors have not yet reached clinical stages. Only one anti-amyloid-aggregation, an aminoglycan compound, and one anti-APO-E approach with rosiglitazone are currently in clinical testing. Stem-cell therapy and gene-replacing therapy remain experimental and far from clinical application. Based on experimental evidence that NGF (nerve growth factor) treatment could provide prolonged protection of the central cholinergic system, i.c.v. infusion of NGF, with genetically modified fibroblasts or gene therapy are under current investigation. NGF treatment could probably double the clinical effect of ChEIs in time. Given the level of scientific and clinical activity it is reasonable to expect that within the next five to ten years a new therapy for AD will, by blocking disease progression, both produce long term stabilization of at least 5 years in patients with AD and prevent or delay emergence in persons at risk for AD.     

An interstitial deletion of 7.1 Mb in chromosome band 6p22.3 associated with developmental delay and dysmorphic features including heart defects, short neck, and eye abnormalities

Seven cases with an interstitial deletion of the short arm of chromosome 6 involving the 6p22 region have previously been reported. The clinical phenotype of these cases includes developmental delay, brain-, heart-, and kidney defects, eye abnormalities, short neck, craniofacial malformations, hypotonia, as well as clinodactyly or syndactyly. Here, we report a patient with a 7.1 Mb interstitial deletion of chromosome band 6p22.3, detected by genome-wide screening array CGH. The patient is a 4-year-old girl with developmental delay and dysmorphic features including eye abnormalities, short neck, and a ventricular septum defect. The deleted region at 6p22.3 in our patient overlaps with six out of the seven previously reported cases with a 6p22–24 interstitial deletion. This enabled us to further narrow down the critical region for the 6p22 deletion phenotype to 2.2 Mb. Twelve genes are mapped to the overlapping deleted region, among them the gene encoding the ataxin-1 protein, the ATXN1 gene. Mice with homozygous deletions in ATXN1 are phenotypically normal but show cognitive delay. Haploinsufficiency of ATXN1 may therefore contribute to the learning difficulties observed in the patients harboring a 6p22 deletion.     

Cholinergic receptors in human brain: effects of aging and Alzheimer disease

A general review of cholinergic receptors in human brain is presented. The paper focuses upon changes in normal aging brain and in Alzheimer disease. Studies from five different approaches are reported: 1) molecular biology; 2) receptor binding studies; 3) studies with specific neurotoxins; 4) immunocytochemistry; and 5) PET scan. These studies document profound and characteristic differences between the normal aging and the pathological Alzheimer brain with regard to cholinergic receptor localization, distribution, and function.     

Mild cognitive impairment--beyond controversies, towards a consensus: report of the International Working Group on Mild Cognitive Impairment

The First Key Symposium was held in Stockholm, Sweden, 2-5 September 2003. The aim of the symposium was to integrate clinical and epidemiological perspectives on the topic of Mild Cognitive Impairment (MCI). A multidisciplinary, international group of experts discussed the current status and future directions of MCI, with regard to clinical presentation, cognitive and functional assessment, and the role of neuroimaging, biomarkers and genetics. Agreement on new perspectives, as well as recommendations for management and future research were discussed by the international working group. The specific recommendations for the general MCI criteria include the following: (i) the person is neither normal nor demented; (ii) there is evidence of cognitive deterioration shown by either objectively measured decline over time and/or subjective report of decline by self and/or informant in conjunction with objective cognitive deficits; and (iii) activities of daily living are preserved and complex instrumental functions are either intact or minimally impaired.