bluuebunny/crossref_metadata_2025 huggingface dataset:
In vivo Gluten Ingestion in Coeliac Disease
Authors: Ciclitira P.J. , Ellis H.J.
Published: April 2003

Studies to determine the nature of the cereal component toxic to patients with coeliac disease have concentrated on wheat due to its nutritional importance. A number of in vitro studies have indicated the presence of one or more coeliac-disease-activating epitopes with the N terminus of the A gliadin molecule. In vivo challenge with three synthetic peptides subsequently indicated the toxicity of a peptide corresponding to amino acid 31–49 of A gliadin. Changes induced by this peptide included a decrease in the ratio of villous height to crypt depth, a decrease in enterocyte surface cell height and an increase in intra-epithelial lymphocyte count. There was evidence of mRNA for the pro-inflammatory cytokincs interferon γ and interleukin 2 within 2 h of the in vivo challenge. We examined electron-microscopically biopsies from patients with coeliac disease challenged with gluten to determine the subcellular sites where gliadin co-localised with T-cell receptor subunits and HLA antigens. There were differences in co-localisation patterns between treated and untreated coeliac patients. These differences and the different patterns of gliadin staining within enterocytes of coeliac patients and controls, observed by others, suggest that gliadin may be metabolised via a different immunogenic pathway in coeliac disease. This might result in an abnormal presentation to the immune system, triggering a pathogenic, rather than a tolerogenic response.
Empirical Trials in Treatment of Gastroesophageal Reflux Disease
Authors: Fass Ronnie
Published: April 2003

The assortment of diagnostic tests that are currently available for detecting gastroesophageal reflux disease (GERD) are invasive, costly and not readily available to community-based physicians. In contrast, a short course of high-dose proton pump inhibitor (PPI) as an empirical trial is an attractive alternative. This simple diagnostic test has been demonstrated to be accurate and cost-effective in patients with symptoms suggestive of GERD and those with noncardiac chest pain. Early studies in patients with extraesophageal manifestations of GERD have yielded promising results. Cost assessment of the PPI empirical trial revealed significant cost savings, mainly due to a marked decrease in utilization of invasive diagnostic tests. Thus the PPI empirical trial should be considered as the initial diagnostic step in patients with the disease spectrum of GERD.
A 2-Year Follow-Up of Behavioural and Psychological Symptoms in Alzheimer’s Disease
Authors: Haupt M. , Kurz A. , Jänner M.
Published: April 2003

Background: The aim was to examine the longitudinal occurrence and persistence of behavioural and psychological symptoms of dementia (BPSD) in Alzheimer’s disease (AD). Methods: Following 60 patients with mild to severe AD over a period of 2 years with annual evaluations, the prospective occurrence and persistence of BPSD in AD were determined by using the Behavioural Abnormalities in AD Rating scale (BEHAVE-AD). Clinical and demographic features of the AD patients were analysed for their association with course features of these symptoms. Results: All of the 60 AD patients experienced BPSD at some point during the 2-year period, particularly agitation was present in every patient within this period. 2-year persistence of BPSD in AD was frequently observed in patients with agitation and with depressiveness, with less frequency in patients with anxiety and aggressiveness, but not in patients with delusions or hallucinations. 2-year persistent aggressiveness was associated with older age and more functional impairment. More functional impairment was also related to 2-year non-persistent hallucinations. Conclusions: Counselling AD patients and their families and tailoring therapeutic strategies should take into account the different modi of BPSD in AD occurring and persisting longitudinally and interacting with functional disturbances.
The Postnatal Development of AMPA Receptor Subunits in the Basal Ganglia of the Rat
Authors: Jakowec Michael W. , Jackson-Lewis Vernice , Chen Xiaoqiong , Langston J. William , Przedborski Serge
Published: April 2003

In situ hybridization and immunohistochemistry were used to characterize the expression pattern of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors during postnatal development in the rat basal ganglia. All subunit transcripts showed some degree of developmental regulation. GluR1 and GluR2 are expressed at high levels in the neonate with reduced expression in the adult. GluR3 and GluR4 are expressed at significantly lower levels in both neonates and adults and have much more modest degrees of reduced expression in adults as compared with GluR1 and GluR2. Analysis of the flip and flop transcript isoforms indicates that GluR1 flip and flop and GluR2 flip are the predominately expressed splice variants in adults. Observed changes in the expression of the AMPA receptor transcripts indicate that there are fundamental differences in the expression of these receptor subunits in adults and neonates. This phenomenon may play a significant role in the establishment of proper synaptic circuitry within the developing basal ganglia in early postnatal life as well as contributing to differences in susceptibility to injury and disease in the aging brain.
Prenatal Exposure to Neurotoxicants Dieldrin or Lindane Alters tert-ButylbicyclophosphorothionateBinding to GABA A Receptors in Fetal Rat Brainstem
Authors: Brannen Kimberly C. , Devaud Leslie L. , Liu Jiangping , Lauder Jean M.
Published: April 2003

GABA acts as a trophic signal for cultured embryonic rat monoamine neurons by activating GABAA receptors. These effects are blocked by the organochlorine insecticide dieldrin and the classic GABAA antagonist bicuculline. Both dieldrin and another organochlorine insecticide, lindane, block the effects of GABA on the GABAA receptor by binding directly to the Cl– channel. Therefore, prenatal exposure to these chemicals could lead to disturbances in the trophic actions of GABA on monoamine neurotransmitter systems in the embryonic brain and produce alterations in GABAA receptor expression and function. Effects of daily prenatal exposure to organochlorine insecticide (dieldrin or lindane) or bicuculline from embryonic day (E)12–17 were determined in brains of E17 fetal rats using t-[35S]butyl-bicyclophosphorothionate ([35S]TBPS) binding. This radioligand was chosen because, like organochlorine insecticides, it binds directly to GABAA receptor/Cl– channels. [35S]TBPS binding was analyzed in extensively washed membranes from E17 brainstem and whole brain with the brainstem removed (‘rest of brain’) at a TBPS concentration that approximated the KD determined in [35S]TBPS saturation binding experiments performed on normal E17 rat brainstem. In utero exposure to dieldrin, lindane, or bicuculline from E12-E17 caused a significant reduction in the amount of [35S]TBPS binding in E17 brainstem compared to vehicle-injected controls, but had no significant effect on ‘rest of brain’. These data suggest that in utero exposure to organochlorine insecticides that act as GABAA antagonists negatively regulate expression of GABAA receptors in fetal brainstem. If these effects persist, they could lead to disturbances in postnatal functions of the ascending GABAergic system, possibly with behavioral consequences.
Transient Increase in Cerebellar Transcriptional Activity Precedes the Expression of GABAA Receptor α6 Subunit mRNA during Postnatal Maturation
Authors: Montpied Pascale , Yan Guan Mei , Paul Steven M. , Morrow A. Leslie
Published: April 2003

The purpose of this study was to investigate the postnatal expression of GABAA receptor α6 subunit genes in the context of cerebellar differentiation. We examined steady-state levels of GABAA receptor α1 and α6 subunit mRNAs, polyadenylated (polyA+) mRNA and β-actin mRNA in7-, 14-, 21-, 28-, 35-, 49- and 120-day-old rats. Messenger RNA expression and splicing were evaluated in parallel using Northern blot analysis and in situ hybridization histochemistry. The expression of mature GABAA receptor α6 subunit mRNA species (2.7 kb) was found 1 week after birth in cerebellar granule cells. Prior to stable expression of the mature α6 subunit gene, we detected large α6 subunit premessengers (3.8 and 3.5 kb) by Northern blot analysis. These premessenger species were detected in prenatal day (PND) 15 and neonatal rat cerebellum, when the mature α6 subunit mRNAs (2.7 kb) were not yet expressed. The maximal expression of mature α6 subunit mRNA species was observed at PND 21 when the peak level of cerebellar transcriptional activity was measured by polyA+ RNA levels. In contrast, β-actin mRNA expression was decreased at PND 21 compared to birth levels. These major transcriptional events take place during a period of about 1 week (between PND 14 and 21), immediately following the most active phase of cell division in the external granule layer and migration of granule cells to the internal granule cell layer. Comparison between the relative abundance of these genes shows that differential regulation of each gene occurs during postnatal development. The induction of GABAA receptor α6 subunit gene expression is preceded by a reduction in β-actin mRNA levels and a transient increase in total transcriptional activity. The expression of α6 subunit mRNA is maintained at the PND 21 level through adulthood, but the α1 subunit mRNA levels decrease drastically within the following week (from PND 21 to 28). These results suggest that tissue-specific expression of the GABAA receptor α6 subunit gene is correlated with a series of developmentally regulated morphologic and transcriptional events.
Activity-Regulated Phosphorylation of cAMP Response Element Binding Protein in the Developing Striatum: Implications for Patterning the Neurochemical Phenotypes of Striatal Compartments
Authors: Liu Fu-Chin , Graybiel Ann M.
Published: April 2003

A distinct feature of the striatum is that much of the expression of neurochemicals in this forebrain structure follows a compartmental (striosome/matrix) ordering. How this pattern of neurochemical compartmentation is developed and regulated is still unknown. In the present paper we propose that a key feature of this early striatal plasticity is differential control of the activation kinetics of the cAMP response element binding protein (CREB), which in turn influences striatal expression of genes containing cAMP response elements in their promoter sequences. Specifically, we propose that activity-dependent regulation of the kinetics of CREB phosphorylation, brought about early expressed protein phosphatases and protein phosphatase inhibitors in the developing striatal compartments, helps to set up and to maintain patterning of the neurochemical prototypes characteristic of striatal compartments.
Striatal Excitatory Amino Acid Receptor Subunit Expression in the D1A-Dopamine Receptor-Deficient Mouse
Authors: Ariano Marjorie A. , Drago John , Sibley David R. , Levine Michael S.
Published: April 2003

The influence of dopamine receptor deletion on the expression and distribution of striatal excitatory amino acid (EAA) receptor subunits comprising the N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) subtypes were examined in the D1A dopamine (DA) receptor-deficient mouse. EAA receptor subunit immunofluorescent staining was altered by the DA receptor genetic mutation. The NMDA-R1 subunit was used as a marker for NMDA-type receptors. The number of striatal neurons expressing this subunit decreased and there was a modest attenuation in the neuropil staining in the mutants in contrast to littermate controls. The R1 subunit for the glutamate receptor (GluR1) was used as an indicator of the AMPA receptor subtype. Immunostaining for this subunit also showed changes induced by deletion of the DA receptor subtype. In contrast to the NMDA-R1 subunit, neuropil staining for the GluR1 subunit was elevated in the mutant in comparison to littermate controls, such that the immunofluorescent reaction obscured detection of the subunit protein in striatal interneurons. The results are discussed in relation to the potential impact on functional interactions between the EAA and DA systems in the striatum.
Glucose Transporter Expression in Brain: Relationship to Cerebral Glucose Utilization
Authors: Vannucci Susan J. , Clark Rebekah R. , Koehler-Stec Ellen , Li Kang , Smith Carolyn B. , Davies Peter , Maher Fran , Simpson Ian A.
Published: April 2003

Glucose is the principle energy source for mammalian brain. Delivery of glucose from the blood to the brain requires its transport across the endothelial cells of the blood-brain barrier and across the plasma membranes of neurons and glia, which is mediated by the facilitative glucose transporter proteins. The two primary glucose transporter isoforms which function in cerebral glucose metabolism are GLUT1 and GLUT3. GLUT1 is the primary transporter in the blood-brain barrier, choroid plexus, ependyma, and glia; GLUT3 is the neuronal glucose transporter. The levels of expression of both transporters are regulated in concert with metabolic demand and regional rates of cerebral glucose utilization. We present several experimental paradigms in which alterations in energetic demand and/or substrate supply affect glucose transporter expression. These include normal cerebral development in the rat, Alzheimer’s disease, neuronal differentiation in vitro, and dehydration in the rat.
Disturbances of the Blood-Brain Barrier without Expression of Amyloid Precursor Protein- Containing Neuritic Clusters or Neuronal Loss during Late Stages of Thiamine Deficiency in Guinea Pigs
Authors: Calingasan Noel Y. , Park Larry C.H. , Gandy Samuel E. , Gibson Gary E.
Published: April 2003

Generalized oxidative deficits associated with experimental thiamine deficiency (TD) lead to selective neurodegeneration. In mouse brain, TD produces region-specific breach of the blood-brain barrier (BBB), neuronal loss and an accumulation of amyloid precursor protein (APP) in abnormal neurites. The APP-laden abnormal neurites within the damaged areas of mouse brain aggregate into neuritic clusters which strikingly resemble the neuritic component of Alzheimer amyloid plaques. However, amyloid β-peptide (Aβ) immunoreactivity has not been demonstrated in these neuritic clusters, possibly because the Aβ region of APP in mice contains three amino acid substitutions as compared with the amino acid sequence of human Aβ. In contrast, the guinea pig nucleic acid sequence is more related to the human sequence and the Aβ region is identical in sequence to that of human APP. Thus, the current studies tested whether the presence of an authentic Aβ fragment of APP (i.e., identical to that of man) might make guinea pigs more vulnerable to the development of Aβ-containing neuritic clusters following TD. During late stages of TD, BBB abnormalities, manifested by immunoglobulin G (IgG) extravasation and increased NADPH diaphorase reactivity in microvessels, occurred in brain areas known to be damaged by TD in mice. However, despite the prolonged thiamine deprivation and the advanced neurological symptoms of guinea pigs, no significant neuronal loss or altered APP/Aβ immunostaining occurred in any brain region. Microglial activation, another early marker of damage in mice, was not evident in thiamine-deficient guinea pig brain. Ferritin immunoreactivity and iron deposition in oligodendrocytes within areas of BBB abnormalities were either slightly enhanced or unchanged as compared to controls. This is the first report of brain abnormalities in the guinea pig model of dietary and pyrithiamine-induced TD. The results demonstrate species differences in the response to TD-induced damage, and further support the role of BBB and nitric oxide in the initial events in TD pathology.
Glyceraldehyde 3-Phosphate Dehydrogenase Abnormality in Metabolically Stressed Huntington Disease Fibroblasts
Authors: Cooper Arthur J.L. , Sheu Kwan-Fu Rex , Burke James R. , Strittmatter Warren J. , Blass John P.
Published: April 2003

Huntington disease (HD) fibroblasts subjected to stress exhibit an enzyme profile that is different from that exhibited by escapee (unaffected members of families with HD) or control fibroblasts. The specific activity of glyceraldehyde 3-phosphate dehydrogenase (GAPDH) in normally cultured HD fibroblasts was not different from that in control and escapee fibroblasts. However, in escapee and control fibroblasts subjected to stress by withholding fresh medium, the specific activity of GAPDH in cells harvested by trypsinization increased greatly 3 weeks after withholding medium (∼8-fold), but the increase was significantly less pronounced (∼3-fold) in the HD fibroblasts. In contrast, only small changes occurred in the specific activity of lipoamide dehydrogenase (LADH) over the same time period, and the values were not significantly different among the three groups at any time point. The specific activity of hexokinase (HK) was significantly higher in the HD fibroblasts at 1–3 weeks after withholding fresh medium than in the escapee/control fibroblasts. Finally, the total yield of fibroblasts per culture flask (as judged by protein content) was significantly greater for the stressed HD fibroblasts than for the escapee and control fibroblasts at 2 and 3 weeks after withholding medium. The present results are in accord with the hypothesis that HD is a disease associated with latent, generalized metabolic abnormalities.
Proliferation of Human Schwann Cells Induced by Neu Differentiation Factor Isoforms
Authors: Baek Sun-Yong , Kim Seung U.
Published: April 2003

Neu differentiation factor (NDF), a 44-kD polypeptide, is a member of the neuregulin family which also includes glial growth factor, heregulin and acetylcholine-receptor-inducing activity. Previous studies have demonstrated that NDF/glial growth factor/heregulin/acetylcholine-receptor-including activity are products of neurons and mediate proliferation, differentiation and gene expression in Schwann cells of experimental animals. In the present study, the efficacy of different isoforms of NDF in stimulating human Schwann cell proliferation is investigated in Schwann-cell-enriched cultures derived from fetal human dorsal root ganglia (15–20 weeks gestation). NDF isoforms examined include α1, α2, EGF-like domain α2 (EGFα2), α3, β1, EGFβ1, EGFβ, β2 and β3. For the assessment of Schwann cell proliferation, double immunostaining using antibodies specific for S-100 protein and bromodeoxyuridine was used. While treatment of Schwann cells with NDF α isoforms (α1, α2, α3 and EGFα2) had little effect on Schwann cell proliferation, NDF β isoforms (β1, β2, β3, EGFβ1 and EGFβ) induced a greatly enhanced proliferation in Schwann cells. The proliferation index in unstimulated Schwann cells was 1.3 ± 0.9%, whereas in Schwann cells treated with NDFβ isoforms the proliferation index was 21.8 ± 2.2%. The finding that the truncated β isoforms such as EGFβ1 and EGFβ retain a mitogenic activity as potent as full-length β isoform indicates that the C-terminal portion of the EGF-like domain is responsible for its receptor binding and subsequent biological activity.
Enhanced Epileptogenicity of Area Tempestas in the Immature Rat
Authors: Sperber E.F. , Velíšková J. , Benenati B. , Moshé S.L.
Published: April 2003

Age-related differences in kindling have been previously observed in terms of behavioral manifestations, seizure generalization and intensity of postictal refractory period. In the present study the development of kindling in the area tempestas (specifically the dorsal endopiriform nucleus) was examined in developing rats (15–16 days of age). Results indicate that kindling can be easily elicited from the immature area tempestas. Rats kindled from area tempestas reached the early kindling stages significantly faster, had longer afterdischarges and a greater number of severe stage 6 seizures than rats kindled from areas above the area tempestas or in the piriform cortex proper. This study indicates that the area tempestas is particularly epileptogenic in the immature rat.
Neurotrophin-3 Increases Neurite Outgrowth and Apoptosis in Explants of the Chicken Neural Plate
Authors: Li Rong , Bernd Paulette
Published: April 2003

This study examined the effect of neurotrophin-3 (NT-3) on neurite outgrowth and apoptosis of chicken neural plate explants prior to neural tube formation. In situ hybridization revealed that mRNA for the full-length (catalytic) NT-3 receptor, TrkC, was present in, and limited to, the neural plate (including the neural folds) coincident with its formation. Neural plate explants were maintained in vitro on a collagen gel under serum-free conditions in the presence or absence of exogenous NT-3 and/or an antibody to NT-3. In the absence of exogenous NT-3, explants exhibited neurite outgrowth after several days in vitro; apoptotic cells were also seen after 2 days in vitro. This does not appear to be due to endogenous NT-3, since the total number of neurites or apoptotic cells was unchanged if explants were exposed to an NT-3 antibody for the entire culture period. In the presence of exogenous NT-3, neural plate explants exhibited a dose-dependent statistically significant increase in the total number of neurites as compared to explants maintained under control conditions, as well as a statistically significant increase in apoptosis. These NT-3 effects were blocked by an NT-3 antibody. In contrast, NT-3 had no effect on the length of neurites. These findings suggest that NT-3 may play a role during early neural development in vivo.
Folate and Folate-Dependent Enzymes Associated with Rat CNS Development
Authors: Martinasevic Mariana K. , Rios Gladys R. , Miller Michael W. , Tephly Thomas R.
Published: April 2003

Folic acid and its derivatives are important mediators in growth-related cellular processes. The concentration of folate and two folate-dependent enzymes, 10-formyltetrahydrofolate synthetase (10-FTHFS) and 10-formyltetrahydrofolate dehydrogenase (10-FTHFDH), was determined in brain regions over the early period of rat development. Folate concentrations determined at birth were high in all brain regions studied. During the first 2 weeks, folate concentrations declined steadily, followed by a period of significant increase. High and invariant activity of 10-FTHFS was found throughout the period of study. Low amounts of 10-FTHFDH were seen for the first 2 weeks, but increased significantly from postnatal days 14 to 28. These changes correlated with changes determined in the concentration of folate, supporting the idea that this protein is involved with folate uptake and/or storage. Furthermore, immunohistochemical expression of 10-FTHFDH in different rat brain regions revealed glial cells as a preferential cellular location for this folate-binding protein.
Malformations of Hypothalamic Nuclei in Hyperinsulinemic Offspring of Rats with Gestational Diabetes
Authors: Plagemann Andreas , Harder Thomas , Janert Ulrich , Rake Annett , Rittel Fanny , Rohde Wolfgang , Dörner Günter
Published: April 2003

Insulin is a potent modulator of central nervous development and is suggested to influence the differentiation and maturation of hypothalamic structures involved in the regulation of body weight and metabolism. Hyperinsulinemic offspring of mothers with impaired glucose tolerance during pregnancy (gestational diabetes, GD) have an increased risk to develop overweight and diabetes mellitus during life, while the underlying pathophysiological mechanisms are still unknown. To investigate the effects of perinatal hyperinsulinism on the organization of hypothalamic regulators of body weight and metabolism, GD was induced in rats by application of streptozotocin on the day of conception (25 mg/kg, i.p.). On the 21st day of life, offspring of GD rats were overweight (p < 0.05) and hyperinsulinemic (p < 0.01). Using computer-assisted morphometric measurements, significantly decreased mean areas of neuronal nuclei and neuronal cytoplasm within the paraventricular hypothalamic nucleus (PVN; p < 0.01) and the ventromedial hypothalamic nucleus (VMN; p < 0.05) were observed in GD offspring. Analysis of topographically distinct parts revealed that these alterations particularly occurred in the parvocellular part of the PVN, as well as in the anterior, central, and dorsomedial part of the VMN. No morphometric alterations were found within the lateral hypothalamic area and the dorsomedial hypothalamic nucleus. In the arcuate hypothalamic nucleus, the mean area of neuronal cytoplasm was decreased (p < 0.05), while the number of neurons expressing tyrosine hydroxylase was clearly elevated (p < 0.002). For astrocytes, a tendency towards an increased glia/neuron ratio was observed in the periventricular hypothalamic area. These observations suggest disturbed differentiation and organization of distinct hypothalamic nuclei and subnuclei, respectively, in hyperinsulinemic offspring of GD rats, possibly leading to dysfunctions of hypothalamic regulators of body weight and metabolism which might contribute to the lifelong increased risk to develop overweight and diabetogenic disturbances.
BDNF and NGF Afford in vitro Neuroprotection against Ethanol Combined with Acute Ischemia and Chronic Hypoglycemia
Authors: Mitchell J.Jean , Paiva Michael , Walker DonW. , Heaton MarietaBarrow
Published: April 2003

Consumption of alcohol during pregnancy can result in central nervous system deficits in infants ranging from fetal alcohol effects to fetal alcohol syndrome. Changes in cerebral metabolism causing ischemic in utero conditions can also result from ethanol (EtOH). Growth factors have been shown to ameliorate ischemic damage and EtOH-induced neurotoxicity. However, using an in vitro model system of fetal alcohol effects/fetal alcohol syndrome, this study examines the neuroprotective effects of nerve growth factor, brain-derived neurotrophic factor, or glial cell line derived neurotrophic factor against EtOH treatment (0, 200, 400, 800, or 1,600 mg/dl) combined with acute ischemia (2-hour hypoxia in EtOH-containing glucose-free media) followed by chronic hypoglycemia (16-hour glucose deprivation in EtOH-containing media). 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assays assessed relative neurotoxicity. Glial cell derived neurotrophic factor was not neuroprotective. Nerve growth factor protected against ischemia/hypoglycemia combined with 0–1,600 mg/dl EtOH. Brain-derived neurotrophic factor protected against ischemia/hypoglycemia combined with 0–800 mg/dl EtOH. These studies demonstrate marked growth factor neuroprotection against a myriad of conditions encountered by developing EtOH-exposed fetuses.
Age-Dependent Retinoic Acid Regulation of Gene Expression Distinguishes the Cervical, Thoracic, Lumbar, and Sacral Spinal Cord Regions during Development
Authors: Rubin William W. , LaMantia Anthony-Samuel
Published: April 2003

We evaluated whether differences in the availability of retinoic acid (RA) establish distinct patterns of RA-dependent gene expresion in the embryonic mouse thoracic/sacral versus cervical/lumbar spinal cord regions. Exogenous RA elicits ectopic expression of an RA-activated transgene and the RA receptor beta in the dorsal thoracic and sacral cord in mice at embryonic day (E) 12.5, but not E14.5. This age-dependent regulation is cell autonomous and is not accompanied by changes in expression patterns of several retinoid receptors, binding proteins, or the SMRT nuclear corepressor. Instead, this change apparently reflects the loss of endogenous RA in the dorsal thoracic and sacral cord between E12.5 and E14.5. Thus, chronic exposure to exogenous RA between E11.5 and E13.5 restores ectopic RA-mediated gene expression. These observations suggest that the local availability of RA establishes absolute differences in gene expression that distinguish the thoracic and sacral cord from the cervical and lumbar cord during midgestation.
Ontogeny of Self-Sustaining Status epilepticus
Authors: Sankar Raman , Shin Don , Mazarati Andrey M. , Liu Hantao , Wasterlain Claude G.
Published: April 2003

Rat pups of ages of 20, 25, 30 and 35 postnatal days were subjected to the perforant-path stimulation model of status epilepticus (SE). This treatment resulted in age- and stimulus-frequency-dependent loss of inhibition in the dentate granule cell layer. Only 35% of the 20-day-old animals, but 88% of the 35-day-olds, progressed to self-sustaining status epilepticus (SSSE). Loss of inhibition as measured by 0.1-Hz paired-pulse testing and histologic damage that extended to the contralateral side, including both the hilus and some extrahippocampal limbic structures, were associated with SSSE. This model of SE differs from in vitro models of SE, in which immature animals show an increased susceptibility to epileptogenic stimuli, and provides us with a novel method to study epileptogenicity in the developing brain.
Abnormal Connections in the Malformed Cortex of Rats with Prenatal Treatment with Methylazoxymethanol May Support Hyperexcitability
Authors: Chevassus-au-Louis N. , Jorquera I. , Ben-Ari Y. , Represa A.
Published: April 2003

Prenatal treatment with methylazoxymethanol (MAM) in rats generates animals with a diffuse cortical malformation associated with hyperexcitability. These alterations are reminiscent of the cortical malformations associated with epilepsy in children. We hypothesised that one of the mechanisms supporting hyperexcitability in MAM rats could be the presence of abnormal cortical connections in the malformed cortex. Using a variety of anatomical techniques, we provide evidences for three types of such abnormal connections: (i) tangential bundles of corticocortical fibres in and below the neocortical molecular layer; (ii) partial deafferentation of neocortical heterotopias by afferent cortical fibres whatever their location; (iii) exuberant innervation of hippocampal CA3 pyramidal cells by mossy fibres that form ectopic mossy boutons on their basal dendrites. We conclude that these abnormal intrinsic cortical connections may support the propagation of paroxymal activity in the neocortex of MAM-treated rats.
Functional MRI in Children with Epilepsy
Authors: Bookheimer Susan Y. , Dapretto Mirella , Karmarkar Uma
Published: April 2003

Advances in brain mapping with functional magnetic resonance imaging (fMRI) have opened an important window into understanding how language is organized in the developing brain. Children with epilepsy, particularly those anticipating surgical intervention, may benefit from preoperative language localization with fMRI, thus minimizing the risk of incurring new deficits. Clinical applications of fMRI, however, await more information on how different linguistic skills are represented in the developing brain and how epileptic lesions impact on this organization at different stages of cognitive development. This article presents some of the current methods for brain mapping in children as well as early results using fMRI for language mapping in pediatric epilepsy.
Developmental Changes in NMDA-Induced Intrinsic Optical Signals in the Hippocampal Dentate Gyrus of Children with Medically Intractable Seizures
Authors: Isokawa Masako , Mathern Gary W.
Published: April 2003

The N-methyl-D-aspartate (NMDA) receptor is one of the ionotropic glutamate receptor subtypes and exhibits a voltage-dependent blockade of its channel function by extracellular magnesium. This magnesium block is known to be absent or weak early in development and is gradually acquired while the brain matures. Interestingly, in adult patients with temporal lobe epilepsy, the magnesium block appears to be altered allowing more current to flow at a negative membrane potential. We are interested whether a similar change might be observed in children’s hippocampi that have frequently been involved in medically intractable seizures. In the present study, we grouped the patients into 2 categories based on the degree of brain maturity: (I) children under the age of 2 (immature, n = 2) and (II) children over the age of 2 (mature, n = 6). Dentate gyri were imaged in real time for intrinsic optical signals with the use of a transmitted light in hippocampal slice preparations. Light transmittance (LT), which reflects a neuronal synaptic depolarization and a concomitant change in cell volume, was calculated. In the immature hippocampus, LT increased significantly in response to NMDA in the presence of extracellular magnesium. However, the mature hippocampi showed little response to NMDA unless magnesium ions were removed from the extracellular artificial cerebrospinal fluid. LT increase was also induced in response to α-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid (AMPA); however, there were no age-dependent differences in the AMPA induced LT increase. Differential sensitivity of the NMDA receptor to extracellular magnesium between immature and mature hippocampi suggests the probable presence of developmental regulation of magnesium block for the NMDA receptor in the human hippocampus of children with medically intractable seizures.
Prolonged Cytosolic Calcium Elevations in Growth Cones Contacting Muscle
Authors: Graf Robert A. , Kater Stanley B. , Gordon Herman
Published: April 2003

Encounters by growth cones or neurites of motor neurons with target muscle cells evoke prolonged elevations in the concentrations of neuronal cytosolic free calcium ([Ca2+]c). These calcium elevations are initiated at the point of contact and spread throughout the neuron over a period of tens of minutes. In this study, we addressed how target muscle cells initiate this unique presynaptic response. Primary questions regarding the nature of the muscle signal are whether it is diffusible and whether it must first be induced by a growth cone as part of reciprocal interaction. We addressed whether the signal was strictly target-contact dependent by fixing C2 mouse myotubes with formaldehyde, rinsing extensively and then allowing processes of chick ciliary ganglion neurons to interact with them. We observed frequent sustained elevations in [Ca2+]c in ciliary ganglion processes contacting the fixed myotubes. As a control, ciliary neurons were allowed to interact with fixed myotubes of the S27 variant line. S27 cells were isolated from the parent C2 line on the basis of a defect in glycosaminoglycan biosynthesis and previously shown to be defective in supporting synaptic vesicle localization in contacting neurites. Few elevations in [Ca2+]c were detected in encounters between ciliary processes and fixed S27 cells.In addition, neuron-neuron encounters never elicited prolonged increases in [Ca2+]c. These observations demonstrate contact dependence in the neuronal response and rule out reciprocal cellular interactions, diffusible factors or electrical activity in the muscle. The defect in carbohydrate biosynthesis in S27 cells further suggests that cell surface carbohydrates are essential to the signal on the myotube surface that triggers the presynaptic elevation in [Ca2+]c. We conclude that growth cone contact with preexisting cell surface structures on target muscle cells induces changes in presynaptic [Ca2+]c that are associated with retrograde signaling, and that proper carbohydrate biosynthesis is required for this signal.
A Mechanism for Acetylcholine Receptor Clustering Distinct from Agrin Signaling
Authors: Grow Wade A. , Ferns Michael , Gordon Herman
Published: April 2003

Acetylcholine receptors (AChRs) and other postsynaptic molecules cluster spontaneously on cultured C2 myotubes. The frequency of clustering is enhanced by neural agrin, neuraminidase, or calcium through a signaling pathway which includes tyrosine phosphorylation of a muscle-specific kinase (MuSK) and the AChR β-subunit. Vicia villosa agglutinin (VVA) lectin, previously shown to potentiate agrin-induced clustering on C2 myotubes, is shown here to also potentiate neuraminidase- and calcium-induced clustering of AChRs, while having no effect on the level of tyrosine phosphorylation of MuSK or the AChR β-subunit. We propose that VVA lectin increases the frequency of AChR clustering through a mechanism that is distinct from agrin signaling, and that may involve α-dystroglycan.
Evidence that CNS Hypomyelination Does Not Cause Death of Jimpy-msd Mutant Mice
Authors: Billings-Gagliardi Susan , Nunnari John N. , Nadon Nancy L. , Wolf Merrill K.
Published: April 2003

Mice expressing three of the proteolipid protein (Plp) mutations in the mouse (jimpy, jimpy-msd, and jimpy-4J) all have a severe deficiency of CNS myelin and oligodendrocytes (OLs), and die sometime in their 4th postnatal week. The prevailing view has been that the animals’ shortened life span and lack of myelin are causally related. Here we describe the survival of jimpy-msd males for as long as postnatal day (P) 210. Although these spontaneously occurring longer-lived jimpy-msd males show a 2- to 8-fold increase in numbers of myelinated axons in many CNS regions, this does not protect them from a later but still premature death. Investigating the cause of premature death may reveal previously undiscovered properties of the myelin genes or the cells that express them, or perhaps additional unsuspected cellular responses that contribute to the disease. This study identifies small accumulations of inflammatory cells in the brain parenchyma of jimpy-msd mice as young as P14 and as old as P60, suggesting that the pathology of the disease produced by at least this Plp mutation may be far more complex than has been previously recognized.
Quaking*Shiverer Double-Mutant Mice Survive for at Least 100 Days with No CNS Myelin
Authors: Wolf Merrill K. , Nunnari John N. , Billings-Gagliardi Susan
Published: April 2003

Mice expressing mutations that produce CNS hypomyelination often die prematurely: the more severe the hypomyelination, the shorter the life span. However, we have previously described jimpy-msd mice that survive twice as long as usual; although they acquire significantly increased amounts of myelin, they still succumb long before their unaffected littermates. This result contradicts any postulated causal relationship between extent of CNS hypomyelination and premature death of the animal. Here we have addressed this question in another way, by using an animal model that does not involve a proteolipid protein (Plp) gene mutation. We demonstrate that quaking*shiverer double-mutant mice can survive for at least 100 days without any CNS myelin whatsoever. Therefore, at least for a mouse, absence of CNS myelin is not lethal per se.
Calcium Dynamics of Neocortical Ventricular Zone Cells
Authors: Owens David F. , Flint Alexander C. , Dammerman Ryan S. , Kriegstein Arnold R.
Published: April 2003

Cell-cell signaling within the neocortical ventricular zone (VZ) has been shown to influence the proliferation of VZ precursor cells and the subsequent differentiation and fate of postmitotic neurons. Calcium (Ca2+), a ubiquitous second messenger implicated in the regulation of many aspects of development, may play a role in these signaling events. Accordingly, we have examined the spatiotemporal patterns of spontaneous intracellular free Ca2+ ([Ca2+]i) fluctuations of cells within the intact neocortical VZ. Previous observations have demonstrated that similar patterns of spontaneous [Ca2+]i increase occur in both proliferative and postmitotic cortical cells, suggesting that they may be mechanistically similar. Our results suggest that the changes in [Ca2+]i in VZ cells and cortical plate neurons are likely triggered by different mechansims, and imply that similar changes in [Ca2+]i may underlie different signaling events during distinct phases of neocortical development.
Neuronal and Astroglial Response to Pre- and Perinatal Exposure to Delta-9-Tetra- Hydrocannabinol in the Rat Substantia nigra
Authors: Suárez I. , Bodega G. , Ramos J.A. , Fernández-Ruiz J.J. , Fernández B.
Published: April 2003

The responses of neurons and astroglial cells to pre- and perinatal exposure to Δ9-tetrahydrocannabinol (Δ9-THC) were evaluated in the substantia nigra (SN) of male and female rats, at three postnatal ages (PD21, PD30 and PD70), by immunohistochemical detection of tyrosine hydroxylase (TH) in dopaminergic neurons and of glial fibrillary acidic protein (GFAP) in astrocytes. Our results showed that the effects of pre- and perinatal exposure to Δ9-THC on neuronal and astroglial immunoreactivities in the SN (compacta and reticulata) varied with sex, with male rats being more susceptible than females. Prenatal exposure to Δ9-THC decreased TH immunoreactivity in the SN of males on PD21 when compared to both their controls and Δ9-THC-exposed females of the same age. Furthermore, the TH expression decreased with age in Δ9-THC-exposed males in the SNc pars compacta, whereas it increased in controls. On the contrary, TH expression was maintained stable in the SN pars compacta of Δ9-THC-exposed females from PD21. These differences in neuronal development caused by prenatal Δ9-THC exposure were associated with significant differences in GFAP expression by astroglial cells in both sexes. On PD21, GFAP immunoreactivity decreased in the SN in Δ9-THC-exposed male rats. Although GFAP expression increased in Δ9-THC-exposed males with age, it did not reach control levels by PD70. On the contrary, significantly increased GFAP expression in the Δ9-THC-exposed females on PD21 was observed, compared to their controls and also to Δ9-THC-exposed male rats; however, the GFAP expression shown by Δ9-THC-exposed females stabilized from PD21. These Δ9-THC-induced changes in the glial development could indicate that Δ9-THC accelerated the maturation of astrocytes in female rats, whereas Δ9-THC delayed astrocytic maturation in Δ9-THC-exposed males. These findings suggest that pre- and perinatal exposure to Δ9-THC can lead to long-term effects in both neurons and glial cells.
Nitric-Oxide-Induced Inhibition of Mitochondrial Complexes following Aglycaemic Hypoxia in Neonatal Cortical Rat Brain Slices
Authors: Brooks Keith J. , Hargreaves Iain P. , Bates Timothy E.
Published: April 2003

The effect of aglycaemic hypoxia (AH) on the activity of the mitochondrial respiratory chain complexes was measured in superfused neonatal cortical brain slices. After 30 min AH, there were no significant changes in the activities of complex I, II–III and IV or citrate synthase compared to controls. Following 30 min AH and a 30-min reperfusion period (with oxygen and glucose), the activities of complex II–III and complex IV were significantly reduced (by 25 and 17%, respectively). These reductions in enzyme activity were not abrogated by removing external calcium prior to and throughout AH, but could be reversed by the presence of the nitric oxide (NO) synthase inhibitor Nω-nitro-L-arginine during these periods. These data suggest that NO or an NO-derived species is involved in the decreases in mitochondrial enzyme activities observed after AH
Brain Mitochondrial Responses to Postischemic Reperfusion: A Role for Calcium and Hydrogen Peroxide?
Authors: Sims Neil R. , Anderson Michelle F. , Hobbs Leanne M. , Powell Jason A. , Zaidan Emad
Published: April 2003

During early recirculation following global brain ischemia, mitochondria are exposed to markedly elevated Ca2+ concentrations and a short-lived production of reactive oxygen species, including hydrogen peroxide (H2O2). A brief increase in mitochondrial Ca2+ and a subsequent increase in mitochondrial glutathione content have been observed. In the present study, we have confirmed the increase in mitochondrial glutathione in a rat model of global forebrain ischemia. This change was not inhibited by treatment of the rats with FK506, contrasting with our previous finding that cyclosporin A partially blocked the increase. These results suggest that induction of the mitochondrial permeability transition may be necessary for the increase in glutathione content in these organelles. To further investigate possible mitochondrial responses during early postischemic reperfusion, mitochondria isolated from normal brain were exposed to Ca2+ and H2O2, under conditions similar to those in intact cells. Respiratory activity was substantially modified when the mitochondria were exposed to Ca2+ and H2O2 together. Two distinct and largely noninteracting mechanisms apparently accounted for the responses to these agents. The effects of Ca2+, but not H2O2, were inhibited by cyclosporin A, again implicating the permeability transition in some of the mitochondrial changes.
Immediate Reaction to Roxithromycin and Prick Test Cross-Sensitization to Erythromycin and Clarithromycin
Authors: Kruppa A. , Scharffetter-Kochanek K. , Krieg T. , Hunzelmann N.
Published: April 2003

Allergic reactions to macrolides appear to be very rare. Only a few cases of fixed drug eruption or urticaria due to the administration of erythromycin have been reported. Cross-reactions between the different macrolides have not yet been published. We report a case of a 31-year-old female patient who developed generalized urticaria and tachycardia shortly after administration of roxithromycin (Rulid®). Immediate-type hypersensitivity was confirmed by positive prick test reactions to roxithromycin and the chemically closely related macrolides erythromycin and clarithromycin.
Influence of Age, Anatomic Site and Race on Skin Roughness and Scaliness
Authors: Manuskiatti W. , Schwindt D.A. , Maibach H.I.
Published: April 2003

Background: Variations in skin roughness and scaliness between age groups, anatomic sites and race have been assumed but minimally quantified. Objective: We quantitatively investigated skin roughness, scaliness and stratum corneum hydration as a function of age, anatomic site and race (white and black). Methods: Skin roughness, scaliness and stratum corneum hydration were determined in vivo by noninvasive bioengineering and image analysis techniques in 22 female subjects grouped according to age (young and aged) and race (white and black). Results: Skin roughness, scaliness and stratum corneum hydration varied significantly in different anatomic areas and age groups. There was no racial variation in skin hydration between any anatomic site, nor significant differences in roughness and scaliness between races, except for the preauricular area. Skin roughness was significantly increased in the aged, compared to the young at the preauricle, volar forearm, lower back, thigh and lower leg. Older women demonstrated significantly more scaling at the preauricle than younger women. Stratum corneum hydration correlated with scaliness. No significant correlation between stratum corneum hydration and skin roughness was observed. Conclusion: Age and anatomic site but not race demonstrated a significant influence on skin roughness and scaliness. The desquamation index appears a good indicator of the status of stratum corneum hydration.
Trichophytic Granuloma of the Vulva
Authors: Margolis D.J. , Weinberg J.M. , Tangoren I.A. , Cheney R.T. , Johnson Jr. B.L.
Published: April 2003

Fungal infections causing deep tissue involvement are known as trichophytic granulomas. We describe an unusual case of trichophytic granuloma presenting in the vulva of a 39-year-old woman.
Aquarium Dermatitis: Cercarial Dermatitis in an Aquarist
Authors: Bastert J. , Sing A. , Wollenberg A. , Korting H.C.
Published: April 2003

A 33-year-old man presented with very itchy red papules on the back of his hands and forearms. These papules appeared about 90 min after he had cleaned his aquarium in which he kept native fish and watersnails. He had obtained the watersnails some weeks before from a nearby pond. Examination of water from the aquarium revealed cercariae. The clinical diagnosis of cercarial dermatitis was corroborated. Cercarial dermatitis has repeatedly been seen in swimmers but not in aquarists keeping fish in a home aquarium.