bluuebunny/crossref_metadata_2025 huggingface dataset:
The Progression of Alzheimer’s Disease from Limbic Regions to the Neocortex: Clinical, Radiological and Pathological Relationships
Authors: Nagy Zs. , Hindley N.J. , Braak H. , Braak E. , Yilmazer-Hanke D.M. , Schultz C. , Barnetson L. , King E.M.-F. , Jobst K.A. , Smith A.D.
Published: April 2003

Alzheimer’s disease (AD) is characterised by the gradual accumulation of neurofibrillary pathology in selected regions of the brain. Earlier studies indicate that the accumulation of neurofibrillary tangles is associated both with decline in patient’s cognitive performance as well as with medial temporal lobe atrophy on CT scans. There are also indications that progression through the pathological stages of AD is associated with decline in cognitive functions. The results of this study indicate that progression of disease, especially beyond the boundaries of the limbic regions, is associated with marked decline in the cognitive performance of patients suffering from AD. However the clinical manifestations of early pathological stages are not so well defined. We also found that the atrophy of the medial temporal lobe on CT scans is related to the progression of pathology. Atrophy is most apparent when the disease reaches its isocortical stages and is not marked in the limbic stages of the disease. The additive effect of pathologies co-existing with AD is apparent in reduced cognitive scores, while the atrophy of limbic structures, as measured on CT scans, seems to be mainly attributable to AD-related pathology.
Agraphia in Alzheimer’s Disease
Authors: Croisile Bernard
Published: April 2003

Writing disorders are an early manifestation of Alzheimer’s disease (AD), often more severe than language difficulties. AD patients produce shorter and less informative written descriptions of a complex picture than controls. These abbreviated texts also include many intrusions, semantic substitutions, and misspellings. Syntactic difficulties are characterized by a reduction of subordinate clauses rather than by the occurrence of grammatical errors. Lexical spelling is systematically more impaired and affected earlier than phonological spelling. With disease progression, the deficits of central writing processes extend to graphic difficulties and alteration of handwriting spatial organization. In the context of a semiotic hierarchy, an inverse relationship is suggested between writing acquisition during childhood and subsequent writing degradation in AD. The writing disturbance in AD is evidently related to a disruption in the anatomicofunctional cerebral network designed for writing processes, mainly in the parietal regions.
Validity of Different Linguistic Versions of the Alzheimer’s Disease Assessment Scale in an International Multicentre Alzheimer’s Disease Trial
Authors: Inzitari D. , Rossi R. , Lamassa M. , Mugnai S. , Carlucci G. , Bianchi C. , Amaducci L.
Published: April 2003

Owing to the involvement of Italian Centres in a multicentre, German-Italian therapeutical trial with Alzheimer’s dementia patients, to be assessed with the Alzheimer’s Disease Assessment Scale (ADAS), it was decided that the Italian centres would use an Italian version of the scale, derived from that used by the German centres. However, the lists of words for exploring verbal memory are not merely translated from the German version, but are composed of selective Italian words chosen according to linguistic criteria. This Italian version was validated following the same procedure adopted for validating the German version. We submitted this Italian version to an interrater reliability, test-retest reliability, concurrent validity, internal consistency and sensitivity evaluation, using demented patients. Based on the results of these tests this Italian version of the ADAS proved valid and reliable. Moreover, the results were strikingly comparable to those from the validation of the German version. Our work supports the validity, reliability and transnational comparability of national versions of the ADAS constructed following definite linguistic criteria.
Impact of Delirium on Professionals
Authors: Hallberg Ingalill Rahm
Published: April 2003

There is a paucity of empirical research on the impact of delirium on professionals’ reactions, interpretations or attitudes to people in a delirious state. This is striking because it stands to reason that it is demanding to take care of a person who is desorientated, perhaps agitated and who may hallucinate and/or act in a manner that calls for interventions involving the use of force or actions that oppose the will of the patient. Apart from some recent intervention studies, there is also little empirical research focusing on the care of delirious patients. Because of the lack of research, deductions will be made from research findings in other areas as well as research findings focusing on the views of patients about what it was like to have been confused, which they narrated afterwards.
A Quantitative and Immunohistochemical Study on Apolipoprotein E in Brain Tissue in Alzheimer’s Disease
Authors: Hesse Camilla , Bogdanovic Nenad , Davidsson Pia , Blennow Kaj
Published: April 2003

Apoliprotein E (ApoE) has been implicated in the pathogenesis of Alzheimer’s disease (AD). Antibodies to ApoE label senile plaques (SP), and an interaction between ApoE and β-amyloid has been found in in vitro studies. Further, an increased frequency of the ApoE ε4 allele in AD has been reported in numerous papers. However, the pathogenetic mechanism of ApoE in AD is not known. We studied ApoE in brain tissue (hippocampus, cerebellum, frontal and temporal cortex) from patients with AD and age-matched control subjects, using both quantitative Western blotting and immunohistochemistry. In AD, a reduction of ApoE was found in the hippocampus (50% of the control value) and in the frontal cortex (52% of the control value), while no significant changes in ApoE levels were found in the temporal cortex or in the cerebellum. Also by immunohistochemistry, ApoE staining was generally decreased in AD brains, both in the neuropil and in the neuronal cellular compartments. Within the AD group, there was no significant correlation between the ApoE level and SP or neurofibrillary tangle (NFT) counts, either in the hippocampus (r = –0.14 and r = 0.55, respectively), or in the frontal cortex (r = –0.03 and r = 0.01, respectively). There were no significant differences in duration, severity of dementia, SP or NFT counts, or ApoE levels between AD patients with different numbers of ApoE ε4 alleles. After experimental brain damage in animals, marked increases in ApoE are found, probably as part of lipid recycling in neuronal and synaptic remodelling and regeneration. One may speculate whether the decrease in ApoE may suggest a disturbance in the ApoE system in AD that is unrelated to ApoE isoforms, β-amyloid deposition and NFT formation.
Alpha-1-Antichymotrypsin Gene Polymorphism and Risk for Sporadic Alzheimer’s Disease in a German Population
Authors: Schwab Sibylle G. , Bagli Metin , Papassotiropoulos Andreas , Jessen Frank , Maier Wolfgang , Rao Marie Luise , Heun Reinhard
Published: April 2003

The A allele of a common A-T polymorphism in the signal peptide of α1-antichymotrypsin gene (ACT) has been reported to contribute a two- to threefold increased risk to Alzheimer’s disease (AD) patients who carry the apolipoprotein E ε4 (APOE ε4) genotype. Since the ACT expression in AD brains is enhanced in particular in areas that develop amyloid plaques, the ACT polymorphism is considered to be a good candidate gene. We have analyzed this polymorphism in 102 AD patients and 191 matched controls, all originating from Western Germany. No statistically significant differences in allele frequencies and in genotype distribution of ACT could be shown between AD patients and controls. When we analyzed the polymorphism in APOE ε4 carriers, no overrepresentation in our AD group could be shown for the ACT*AA genotype carriers.
Plasma Homocysteine Is a Sensitive Marker for Tissue Deficiency of Both Cobalamines and Folates in a Psychogeriatric Population
Authors: Nilsson Karin , Gustafson Lars , Hultberg Björn
Published: April 2003

The concentration of blood folates was decreased and the concentration of plasma homocysteine was increased in a psychogeriatric population, whereas the concentrations of methylmalonic acid or serum cobalamins were not changed compared with healthy subjects. The highest frequency of abnormal values was shown by plasma homocysteine concentration, which was increased in 88 of 168 patients. In 29 of these 88 patients increased concentration of plasma homocysteine could possibly be attributed to tissue cobalamin deficiency. One patient had only a lowered concentration of blood folate. Thirteen patients had elevated concentrations of serum creatinine which could explain increased plasma homocysteine concentration. Even if the remaining patients (n = 45) had normal vitamin levels in circulation, the increased plasma homocysteine concentration in most cases must be attributed to tissue deficiency of cobalamins and/or folates. Thus, many patients with increased plasma homocysteine concentrations need further vitamin supplementation despite their normal vitamin levels in serum and blood.
Dementia with Leukoaraiosis: Clinical Differentiation by Temporoparietal Hypometabolism on 18FDG-PET Imaging
Authors: Mendez Mario F. , Ottowitz William , Brown Charles V. , Cummings Jeffrey L. , Perryman Kent M. , Mandelkern Mark A.
Published: April 2003

Patients with dementia and leukoaraiosis may have either Alzheimer’s disease (AD) with cerebrovascular changes or a form of vascular dementia (VaD). The presence or absence of the characteristic AD pattern of bilateral temporoparietal hypometabolism on 18FDG-PET was used to differentiate 30 patients with progressive dementia and severe leukoaraiosis. Compared to 18 patients with the typical AD pattern (group I), the remaining 12 (group II) had better recognition memory, and greater difficulty with sustained attention and serial reversals. Better recognition memory, confluent periventricular leukoaraiosis, and poorer sustained attention distinguished all group II patients from group I. Dementia patients with severe leukoaraiosis and bilateral temporoparietal hypometabolism may have predominant AD; those who lack this pattern and have confluent leukoaraiosis may have a greater contribution from VaD.
Acute versus Chronic Pain Experience in Alzheimer’s Disease
Authors: Scherder Erik J.A. , Bouma Anke
Published: April 2003

The low use of analgesics in patients with Alzheimer’s disease (AD), compared to nondemented elderly persons, is generally explained by (1) a lower prevalence of painful conditions in the former group and (2) undertreatment of pain due to a decrease in communicative abilities in AD. However, considering the neuropathology in limbic areas in this disorder, a decline in pain affect may also explain this phenomenon. In the present study, a newly developed questionnaire was applied to 20 elderly persons without dementia, 20 patients in an early stage and 20 patients in a midstage of AD. The questionnaire includes 10 pairs of painful situations, each pair consisting of an acute and a chronic affective painful situation. It was hypothesized that, compared to controls, AD patients during the course of the disease would report to suffer increasingly more from an acute than from a chronic, affective painful situation. The results support our hypothesis. Limitations of the present study are discussed.
A 6-Month, Double-Blind, Placebo-Controlled Trial of Eptastigmine in Alzheimer’s Disease
Authors: Imbimbo Bruno P. , Troetel William M. , Martelli Paola , Lucchelli Federica
Published: April 2003

Objectives: To evaluate the efficacy and safety of eptastigmine as a treatment for patients with mild-to-moderate Alzheimer’s disease (AD). Patients and Methods: The study was designed as a randomized, double-blind, placebo-controlled, parallel-group study. It was performed in 26 Italian and American geriatric and neurological centers. The study group comprised 349 outpatients with a diagnosis of probable AD according to the criteria of the National Institute of Neurological and Communicative Disorders and Stroke and the AD and Related Disorders Association. Patients were assigned to one of the three study groups: placebo (n = 119), eptastigmine 10 mg t.i.d. (n = 115) or eptastigmine 12 mg t.i.d. (n = 115) for 25 weeks. The AD Assessment Cognitive Subscale (ADAS-Cog) and the Clinical Dementia Rating Scale-Sum of the Boxes (CDR-SB) were the primary outcome measures for efficacy. Results: The two doses of eptastigmine produced similar results and are presented together. Percentages of patients completing double-blind treatment were 82 and 87% in the placebo and eptastigmine groups, respectively. At the end of treatment, the intentto-treat analysis on 342 patients showed a statistically significant effect of eptastigmine compared to placebo on both ADAS-Cog (p = 0.047) and CDR-SB (p = 0.010). Patients on eptastigmine performed significantly better than placebo-treated patients also on the Mini-Mental State Examination (p < 0.001). The drug was well tolerated with 5% of patients withdrawing due to adverse events versus 3% on placebo. Adverse events were recorded in 46% of the patients on placebo compared to 52% of the patients taking eptastigmine. Cholinergic side effects (nausea, vomiting, diarrhea and abdominal pain) were reported with similar frequency in the eptastigmine and placebo-treated patients. Conclusion: Eptastigmine doses up to 12 mg t.i.d. for 25 weeks are well tolerated. The drug positively affects cognitive performance and global function of patients with mild-to-moderate AD.
Determinants of Quantitative Spectral Electroencephalography in Early Alzheimer’s Disease: Cognitive Function, Regional Cerebral Blood Flow, and Computed Tomography
Authors: Claus J.J. , Ongerboer de Visser B.W. , Bour L.J. , Walstra G.J.M. , Hijdra A. , Verbeeten Jr. B. , van Royen E.A. , Kwa V.I.H. , van Gool W.A.
Published: April 2003

Electroencephalography (EEG) bands may have different clinical or physiological correlates at initial diagnosis of Alzheimer’s disease (AD). We studied 163 consecutive patients with probable (n = 105) and possible (n = 58) AD with measurements of cognitive function (CAMCOG), regional cerebral blood flow (rCBF) with single photon emission computed tomography using technetium-99m-labeled hexamethylpropylene amine oxime, and computed tomography (CT). Lower CAMCOG scores were significantly and most strongly associated with lower parieto-occipital and fronto-central alpha power. In a separate analysis of cognitive domains, disturbances in language, praxis, attention, and abstraction were also significantly and most consistently related to decrease in alpha power. Presence of cortical atrophy as measured on CT showed some statistically significant relations with EEG bands, but these associations were not consistent. Lower temporal and parietal rCBF were significantly related to lower parieto-occipital alpha activity. Presence of leukoaraiosis was significantly associated with lower beta values, but also with higher absolute theta and delta activity. The results suggest that alpha on EEG is most closely linked to cognitive function and rCBF, while beta and theta activity more likely reflect lower cortical or subcortical changes. Our study thus provides evidence that the EEG bands reflect differential pathophysiologic changes in AD.
Association between Changes in Adrenal Secretion and Cerebral Morphometric Correlates in Normal Aging and Senile Dementia
Authors: Magri F. , Terenzi F. , Ricciardi T. , Fioravanti M. , Solerte S.B. , Stabile M. , Balza G. , Gandini C. , Villa M. , Ferrari E.
Published: April 2003

The circadian organization of adrenal secretion was studied in 23 healthy elderly subjects, 23 elderly demented patients and 10 healthy young subjects, in order to investigate the relationships between the hypothalamic-pituitary-adrenal axis and some cerebral morphometric parameters. The cerebral morphometric analysis was performed in some subjects of the three groups by MRI. A significant increase in cortisol levels during evening and nighttime was found in both groups of the aged subjects. In elderly subjects, particularly if demented, the mean serum dehydroepiandrosterone sulfate (DHEAs) levels throughout the 24-hour cycle were significantly lower than in young controls. A significant reduction of the hippocampal and temporal volume and an enlargement of the lateral ventricles were found in aged subjects, these changes being significantly related to subjects’ age. Moreover, the hippocampal volume was positively correlated with the circadian mesor of DHEAs (i.e., the circadian rhythm adjusted mean) and with the cortisol nocturnal increase. Our data may suggest the existence of a link between the selective impairment of cortisol secretion and DHEAs levels, and the progression of hippocampal degeneration.
Alzheimer Disease and Vascular Dementia: Relationships with Fasting Glucose and Insulin Levels
Authors: Carantoni M. , Zuliani G. , Munari M.R. , D’Elia K. , Palmieri E. , Fellin R.
Published: April 2003

Cerebrovascular disease and Alzheimer disease are the leading causes of dementia in elderly subjects. In spite of it, relatively little is known about the pathogenesis and risk factors for dementia. We evaluated fasting plasma glucose and insulin, albumin, lipids, Lp(a) and uric acid levels in nondiabetic patients of both sexes affected by vascular dementia (VD) and senile dementia of the Alzheimer type (SDAT) as well as in a control group of age-matched nondemented subjects. Following a covariance analysis by gender, body mass index, albumin levels and prevalence of arterial hypertension, total and LDL cholesterol as well as HDL cholesterol levels were not significantly different among the three groups. Fasting glucose (p < 0.001 and p < 0.005, respectively) and insulin levels (p < 0.05 for both differences) were higher in patients with VD and SDAT than in control subjects. Our data show that nondiabetic patients with VD or SDAT have higher fasting glucose and insulin levels than healthy control subjects. These metabolic characteristics were not influenced by differences in gender, adiposity, nutritional status, lipids or presence of arterial hypertension.
Intrathecal Release of Nitric Oxide in Alzheimer’s Disease and Vascular Dementia
Authors: Tarkowski E. , Ringqvist Å. , Blennow K. , Wallin A. , Wennmalm Å.
Published: April 2003

A growing body of evidence points out the potential role of inflammatory mechanisms in the pathophysiology of brain damage in dementia. We have recently demonstrated that patients with Alzheimer’s disease (AD) and vascular dementia (VaD) display an intrathecal production of proinflammatory cytokines. TNF-α, one of these cytokines, leads to the production of nitric oxide (NO), a potent inflammatory mediator, by induction of inducible NO synthase. The aim of the present study was to investigate the intrathecal levels of nitrate, one of the main metabolites of NO, and to relate its levels to the degree of intellectual impairment, in patients with AD and VaD. Twenty patients with early AD and 26 patients with VaD were analyzed with respect to cerebrospinal fluid levels of nitrate by gas chromatography/mass spectrometry. Interestingly, in patients with AD but not VaD, the intrathecal levels of nitrate were significantly and inversely correlated (r = –0.68, p = 0.002) to the degree of intellectual impairment. Our study demonstrates an inverse correlation between the intrathecal levels of nitrate and the degree of cognitive impairment in patients with AD, suggesting a neuroprotective effect of NO in AD.
Quantification and Characterisation of Fluctuating Cognition in Dementia with Lewy Bodies and Alzheimer’s Disease
Authors: Walker M.P. , Ayre G.A. , Perry E.K. , Wesnes K. , McKeith I.G. , Tovee M. , Edwardson J.A. , Ballard C.G.
Published: April 2003

Fluctuating cognition (FC) is a common and important symptom in dementia, particularly dementia with Lewy bodies (DLB), although it has not been empirically quantified or characterised. Forty subjects (15 DLB, 15 AD, 10 elderly controls) were evaluated using a clinical FC severity scale, as well as receiving measures of variability in attentional performance and slow EEG rhythms across 90 s, 1 h and 1 week. DLB patients had significantly more severe FC and more severe variability in attentional and slow electrocortical measures than either AD patients or normal controls in all time frames. Attentional and EEG variability also correlated significantly with independent clinical ratings of FC. Clinical quantification and measures of attention and EEG variability can therefore make an important and standardised contribution to the assessment of FC in dementia, facilitating future treatment studies with important implications for the potential causative mechanisms and differential diagnosis.
Early Patterning of Prelimbic Cortical Axons to the Striatal Patch Compartment in the Neonatal Mouse
Authors: Nisenbaum Laura K. , Webster Sarah M. , Chang Sarah L. , McQueeney Kelly D. , LoTurco Joseph J.
Published: April 2003

The striatum receives excitatory input from virtually the entire cerebral cortex. In the adult, this input is segregated into two functionally distinct compartments of the striatum, the patch (striosome) and matrix regions. This study determined whether the patterning of corticostriatal afferents from the prelimbic cortex to the striatal patch compartment develops during the early period of collateral formation or instead at the time of peak synaptogenesis. Initial formation of corticostriatal axon collaterals was observed by embryonic day (E) 19. Quantification of corticostriatal collaterals revealed a significant increase in the number and complexity of collateral branches at postnatal day 6 as compared to E19. Concomitant with the increase in collateral branching, a heterogeneous pattern of collateralization consisting of parallel rows of corticostriatal collaterals was observed in the medial striatum. In addition to the rows, clusters of corticostriatal axons occurred more laterally. These clusters colocalized with patches of dense tyrosine hydroxylase-positive fibers, a marker for the striatal patch compartment in the neonatal mouse. Together, these data indicate that corticostriatal patterning occurs during the period of early axon collateralization resulting in a segregation of corticostriatal axon collaterals from the prelimbic cortex to the striatal patch compartment.
Physiological and Molecular Properties of AMPA/Kainate Receptors Expressed by Striatal Medium Spiny Neurons
Authors: Stefani Alessandro , Chen Quan , Flores-Hernandez Jorge , Jiao Yun , Reiner Anton , Surmeier D. James
Published: April 2003

The mechanisms by which glutamate shapes the activity of striatal medium spiny neurons are of fundamental importance to our understanding of normative and pathological striatal physiology. Non-N-Methyl-D-aspartate (non-NMDA) glutamate receptor expression and function were studied in medium spiny neurons with a combination of single cell RT-PCR, immunocytochemistry and whole-cell voltage-clamp techniques. Reverse transcription polymerase chain reaction analysis found that GluR2 mRNA appeared to be the most abundant and widely distributed AMPA receptor mRNA. GluR1 was also commonly detected. However, GluR3 mRNA was preferentially expressed by neurons coexpressing substance P and enkephalin and GluR4 mRNA was not detected in identified medium spiny neurons. All neuronal classes appeared to express GluR5 or GluR6 and/or GluR7 mRNA in addition to kainate (KA) subunit mRNA. Immunocytochemical studies confirmed the mRNA distributions and also revealed that GluR1 protein was largely restricted to dendritic spines. Although the mRNA and protein for both α-amino-3-hydroxy-5-methyl-ioxyzole-4-proprionic acid (AMPA) and KA class subunits was detected, the physiological response to glutamatergic ligands and the benzothiadizine cyclothiazide was characteristic of AMPA, not KA receptors. The AMPA receptor antagonist GYKI 52466 blocked the response to AMPA and all but a small transient component of the response to KA. The current-voltage relationship of the AMPA-evoked currents was relatively linear but Ca2+ fluorometry revealed that substantial changes in intracellular Ca2+ concentration accompanied exposure to either agonist. These results argue that somatodendritic non-NMDA glutamate receptors in medium spiny neurons are primarily GluR2-containing receptors of the AMPA class but that activation of these receptors as a group nevertheless results in a significant Ca2+ influx.
Studies of the Source of Glucose in the Extracellular Compartment of the Rat Brain
Authors: Fillenz M. , Lowry J.P.
Published: April 2003

Rats were implanted in the striatum with a glucose biosensor glued to a dialysis probe. Changes in extracellular glucose concentration in response to either neuronal stimulation or 3-min periods of hypoxia and hyperoxia were compared when the dialysis probe was perfused with either artificial cerebrospinal fluid (aCSF) alone or aCSF with the addition of the β-adrenoceptor antagonist propranolol. Propranolol had no effect on basal levels of glucose or the changes in glucose produced by hypoxia and hyperoxia, which are attributed to changes in the utilization of glucose. Following neuronal activation there is an initial reduction followed by a delayed, prolonged increase in glucose which is suppressed by propranolol. The results suggest that propranolol has no effect on glucose utilization, but blocks the delivery of glucose from astrocytes.
Putative Significance of Shifts in Acetyl-CoA Compartmentalization in Nerve Terminals for Disturbances of Cholinergic Transmission in Brain
Authors: Szutowicz A. , Tomaszewicz M. , Bielarczyk H. , Jankowska A.
Published: April 2003

Acetylcholine and acetyl-CoA metabolism in nerve terminals isolated from rat brain were found to be affected by several neurotoxic and neuroprotective agents, such as aluminium, nitric oxide, β-hydroxybutyrate, verapamil and thiamine deficiency. The changes evoked by these factors in Ca2+-dependent acetylcholine release were highly significantly correlated (r = 0.98) with changes in concentration of synaptoplasmic acetyl-CoA. On the other hand, in the same experimental conditions, no correlation was found between rates of pyruvate oxidation, intramitochondrial acetyl-CoA levels and different pools of releasable acetylcholine. These data indicate that disturbances in the availability of acetyl-CoA in the cytoplasm of nerve terminals may be a key factor in the pathogenesis of several cholinergic encephalopathies.
Prenatal Availability of Choline Alters the Development of Acetylcholinesterase in the Rat Hippocampus
Authors: Cermak Jennifer M. , Blusztajn Jan Krzysztof , Meck Warren H. , Williams Christina L. , Fitzgerald Claudia M. , Rosene Douglas L. , Loy Rebekah
Published: April 2003

Choline (Ch) supplementation during embryonic days (ED) 12–17 enhances spatial and temporal memory in adult and aged rats, whereas prenatal Ch deficiency impairs attention performance and accelerates age-related declines in temporal processing. To characterize the neurochemical and neuroanatomical mechanisms that may mediate these behavioral effects in rats, we studied the development [postnatal days (PD) 1, 3, 7, 17, 27, 35, 90, and 26 months postnatally] of acetylcholinesterase (AChE) activity in hippocampus, neocortex and striatum as a function of prenatal Ch availability. We further measured the density of AChE-positive laminae (PD27 and PD90) and interneurons (PD20) in the hippocampus as a function of prenatal Ch availability. During ED11-ED17 pregnant Sprague-Dawley rats received a Ch-deficient, control or Ch-supplemented diet (average Ch intake 0, 1.3 and 4.6 mmol/kg/day, respectively). Prenatal Ch deficiency increased hippocampal AChE activity as compared to control animals in both males and females from the 2nd to 5th week postnatally. Moreover, prenatal Ch supplementation reduced hippocampal AChE activity as compared to control animals over the same developmental period. There was no effect of prenatal Ch status on either cortical or striatal AChE activity at any age measured, and by PD90 the effect of Ch on hippocampal AChE was no longer observed. In order to localize the early changes in hippocampal AChE activity anatomically, frozen coronal brain sections (PD20, PD27, PD90) were stained histochemically for AChE. Consistent with biochemical results, the AChE staining intensity was reduced in PD27 hippocampal laminae in the Ch-supplemented group and increased in the Ch-deficient group compared to control animals. There was no effect of the diet on hippocampal AChE staining intensity on PD90. In addition, the prenatal Ch availability was found to alter the size and density of AChE-positive PD20 interneurons. These results show that prenatal Ch availability has long-term consequences on the development of the hippocampal cholinergic system.
Monoclonal Antibody against a Neuronal Antigen Impairs Formation of the Axon Scaffold in Grasshopper Central Nervous System
Authors: von Bernhardi Rommy , Carpenter Ellen M.
Published: April 2003

The pathway a growing axon follows is determined by a number of cues, including differential adhesion to surface molecules on axons and the matrix of the fascicles along which they grow. We have characterized the differential expression of an extracellular antigen and the effects of a monoclonal antibody against this molecule on the development of the grasshopper central nervous system (CNS). The 5C1 monoclonal antibody was generated against ganglion chains of grasshopper embryos; it labels cell bodies of newly differentiated neurons and their axons as they extend. Electron microscopy of embryos at 42% of development reveals that 5C1 labels neuronal filopodia, axons and somata, and areas of glial membrane in apposition to neurite fascicles. After 70% of development, labeling is lost from axon bundles, but remains on cell bodies. 5C1 also cross-reacts with an epitope expressed in Drosophila CNS during embryonic development. Enzymatic digestion suggests that the antigen recognized by the antibody is likely to be a glycolipid. In embryos exposed to 5C1 during early stages of development of the CNS, at the time when the first axons begin to extend, the formation of axon pathways is blocked or greatly delayed. Our results suggest that the 5C1 antigen participates in the formation of the axon scaffold and may play a functional role in the initiation and maintenance of axon outgrowth during early development of the CNS.
Developmental Regulation of the Distribution of Aromatase- and Estrogen-Receptor- mRNA-Expressing Cells in the Zebra Finch Brain
Authors: Jacobs Erin C. , Arnold Arthur P. , Campagnoni Anthony T.
Published: April 2003

Strong evidence exists for the masculinizing effects of estrogen on the neural network that controls song learning and behavior in zebra finches. However, the mechanisms by which estrogen acts to influence the development of this circuitry are not well understood. In this study, we used in situ hybridization to detect the distribution of cells expressing mRNAs for AROM and ERα at postnatal days 5–25 (P5–25). Our findings revealed developmental regulation of both mRNAs in the neostriatum, archistriatum, hippocampus, diencephalon and midbrain. Within the vocal control circuitry, cells expressing ERα mRNA were found in the medial HVC (P10–25), archistriatum lateral to the RA (Ad; P25), in the ICo (P5–25), and along the fiber tract containing efferents from the RA. High levels of AROM mRNA were found in the neostriatum, including both the lateral and mMAN and along their projections to the RA and HVC, respectively, (P5–25), in the archistriatum (P18–25) and around RA (P18). Codistribution of the two mRNAs occurred along the border of the HVC suggesting that in this region, local synthesis of estrogen may be acting through its nuclear receptor to regulate gene transcription. Taken together, our findings show that the neural circuitry controlling song may be exposed to the effects of estrogen during early postnatal development. However, in most of the song control regions, these mRNAs were not expressed together either temporally or spatially, indicating that AROM may have a role in the development of the song system independent of ERα.
Expression of the EGF Receptor Family Members ErbB2, ErbB3, and ErbB4 in Germinal Zones of the Developing Brain and in Neurosphere Cultures Containing CNS Stem Cells
Authors: Kornblum Harley I. , Yanni Daniel S. , Easterday Mathew C. , Seroogy Kim B.
Published: April 2003

The epidermal growth factor receptor family consists of four related tyrosine kinases: the epidermal growth factor receptor (EGF-R or ErbB), ErbB2, ErbB3, and ErbB4. These receptors are capable of extensive cross-activation upon the binding of their ligands – the EGF family of peptides for EGF-R and the neuregulins for ErbB3 and ErbB4. Since EGF-R is expressed by proliferating cells in the central nervous system (CNS), including multipotent CNS stem cells, we examined the expression of ErbB2, ErbB3 and ErbB4 in the germinal epithelia of the developing rat brain using in situ hybridization. ErbB2 and ErbB4 mRNAs were widely distributed within the germinal zones as early as E12. However, as development proceeded, ErbB2 mRNA was mainly present within the layers of cells immediately adjacent to the ventricular surface – the ventricular zone, while ErbB4 mRNA was predominantly expressed by subventricular zone cells, in the regions where these specialized germinal epithelia were present. ErbB3 mRNA distribution within germinal epithelia was more restricted, primarily confined to the diencephalon and rostral midbrain. Cultured neurospheres, which contain CNS stem cells, expressed ErbB2, ErbB4 and, to a lesser extent, ErbB3 protein as demonstrated by Western blot analysis. This expression declined during following differentiation. Heregulin-β1, a neuregulin, had no effect on the proliferative capacity of neurospheres. Overall, our results indicate that ErbB2, ErbB3 and ErbB4 may play important and distinct roles in the genesis of the CNS. However, our in vitro data do not support a role for neuregulins in proliferation, per se, of CNS stem cells.
Musashi1: An Evolutionally Conserved Marker for CNS Progenitor Cells Including Neural Stem Cells
Authors: Kaneko Y. , Sakakibara S. , Imai T. , Suzuki A. , Nakamura Y. , Sawamoto K. , Ogawa Y. , Toyama Y. , Miyata T. , Okano H.
Published: April 2003

In situ detection of neural progenitor cells including stem-like cells is essential for studying the basic mechanisms of the generation of cellular diversity in the CNS, upon which therapeutic treatments for CNS injuries, degenerative diseases, and brain tumors may be based. We have generated rat monoclonal antibodies (Mab 14H1 and 14B8) that recognize an RNA-binding protein Musashi1, but not a Musashi1-related protein, Musashi2. The amino acid sequences at the epitope sites of these anti-Musashi1 Mabs are remarkably conserved among the human, mouse, and Xenopus proteins. Spatiotemporal patterns of Musashi1 immunoreactivity in the developing and/or adult CNS tissues of frogs, birds, rodents, and humans indicated that our anti-Musashi1 Mabs reacted with undifferentiated, proliferative cells in the CNS of all the vertebrates tested. Double or triple immunostaining of embryonic mouse brain cells in monolayer cultures demonstrated strong Musashi1 expression in Nestin(+)/RC2(+) cells. The relative number of Musashi1(+)/Nestin(+)/RC2(+) cells increased fivefold when embryonic forebrain cells were cultured to form ‘neurospheres’ in which stem-like cells are known to be enriched through their self-renewing mode of growth. Nestin(+)/RC2(–) cells, which included Tα1-GFP(+) neuronal progenitor cells and GLAST(+) astroglial precursor cells, were also Musashi1(+), as were GFAP(+) astrocytes. Young neurons showed a trace of Musashi1 expression. Cells committed to the oligodendroglial lineage were Musashi(–). Musashi1 was localized to the perikarya of CNS stem-like cells and non-oligodendroglial progenitor cells without shifting to cell processes or endfeet, and is therefore advantageous for identifying each cell and counting cells in situ.
Oral Contraceptives and Cyproterone Acetate in Female Acne Treatment
Authors: Beylot C. , Doutre M.S. , Beylot-Barry M.
Published: April 2003

The sebaceous gland is a target of androgens, and hormonal influences play an important role in the multifactorial pathogenesis of acne. In both men and women, acne may be related to an excessive hypersensitivity of the sebaceous end organ to androgens. However, in women, the ovarian and adrenal production and the plasma transport of androgens may be implicated, particularly in late-onset or persistent acne or with associated hirsutism. Many reports have shown that females with acne frequently have abnormal levels of circulating androgens. Hormonal treatment is not usually the first line in female acne. But in relation to the possibilities, particularly the tetracyclines, this may be a choice when one prescribes a pill like Dianette® to a young woman presenting a mild acne and who requests contraception. However, antiandrogen treatment is sometimes mandatory, especially in resistant acne in adult women and/or in female acne which is resistant or relapsing rapidly after treatment with Roaccutane® and which is often related to hyperandrogenism. Finally, in severe prepubertal acne, the possible cause is an adrenal enzymatic block of which the only treatment is hormonal.
Why and When the Treatment of Acne Fails
Authors: Katsambas A.D.
Published: April 2003

The majority of acne patients show a good response to the proper acne treatment. However, a small percentage not exceeding 10–15% do not respond as satisfactorily as expected. The main reason for the treatment failure is the poor patient compliance. In order to improve the patient compliance the strategy for the treatment of acne has to be carefully planned and includes the following: discussion before treatment; give clear instructions; explain the rhythm of improvement; explain the role of cosmetics; explain the role of sunbathing; explain the expected side effects. It has to be emphasized that all acne cases can be adequately controlled if the relationship between doctor and patient has been built on trust and confidence, maximizing the patient compliance.
Monitoring of Isotretinoin Therapy by Measuring the Plasma Levels of Isotretinoin and 4-Oxo-Isotretinoin
Authors: Almond-Roesler B. , Blume-Peytavi U. , Bisson S. , Krahn M. , Rohloff E. , Orfanos C.E.
Published: April 2003

Background: Isotretinoin for oral therapy in severe acne conglobata and acne nodulocystica represents a significant achievement; however, the drug exerts several mucocutaneous and systemic adverse effects, besides its teratogenic potency. Objective: The aim of this study was to investigate the plasma levels of isotretinoin and of 4-oxo-isotretinoin over long-term treatment of severe acne and to assess any correlation with the given dose, the clinical improvement and the occurrence of side effects. Methods: Forty-one patients with severe acne and acne-related disorders were studied under long-term oral intake of isotretinoin. Therapeutic effects and side effects were evaluated prior, during and at the end of therapy. The plasma levels of isotretinoin and of its major metabolite 4-oxoisotretinoin were measured by reversed-phase HPLC and were correlated with the administered oral dose and the number and frequency of side effects. Results: Dose-dependent plasma levels of isotretinoin and its metabolite were observed. At a mean dosage of 0.75–1.0 mg/kg/day, 404 ± 142 ng/ml were measured, whereas the plasma levels of 4-oxo-isotretinoin were 1–2 × higher. The plasma levels correlated well with the orally administered dose of isotretinoin and the observed mucocutaneous side effects. Conclusion: The study demonstrates that measuring of the plasma levels may be a helpful tool to monitor the individual therapeutic dose regimen in patients with severe acne in order to minimize undesired side effects and to control oral intake.
The Organ-Maintained Human Sebaceous Gland
Authors: Guy R. , Kealey T.
Published: April 2003

In the absence of epidermal growth factor (EGF) and phenol red in the maintenance medium, human sebaceous glands apparently retain in vivo rates of cell division and lipogenesis over 7 days and also retain in situ morphology. This is reversible on the re-addition of 10 ng/ml EGF and 10 mg/ml phenol red. The addition of 600 pM 17β-oestradiol results in a significant fall in the rate of lipogenesis over 7 days’ maintenance, without affecting the rate of cell division. This effect is apparently due to abnormal differentiation of newly formed sebocytes. Neither 1 nM testosterone nor 1 nM dihydrotestosterone has any effect on rates of cell division or lipogenesis over 7 days. 1 μM 13-cis-retinoic acid causes a significant reduction in the rate of lipogenesis over 7 days.
Propionibacterium acnes Colonization in Acne and Nonacne
Authors: Leyden J.J. , McGinley K.J. , Vowels B.
Published: April 2003

Propionibacterium acnes is a member of the resident bacterial flora and resides in sebaceous follicles. Age-related and body-dependent quantitative differences exist, indicating the role of sebum as an important ecological factor for P. acnes. Acne patients demonstrate marked increases in this organism which generates inflammation through a variety of mechanisms.
Inflammatory Acne Represents Hypersensitivity to Propionibacterium acnes
Authors: Webster G.F.
Published: April 2003

Hypersensitivity to P. acnes may account for the great variation in acne severity. Alternative explanations such as hyperandrogenism fail to account for disease severity in large numbers of patients.
Clinical Aspects of Acne
Authors: R. Shalita Alan
Published: April 2003

Acne vulgaris may present in a wide variety of clinical forms depending on the type, number and severity of the predominant lesion. Thus there may be mild, moderate or severe comedonal or inflammatory acne, the latter with many subtypes. Furthermore, the number and extent of the lesions do not necessarily predict the response to therapy, and patients may also be catergorized as therapeutically responsive or therapeutically refractory. Finally, there may be alterations in the clinical manifestations and therapeutic response depending on the distribution of the lesions, age of the patient and provoking or complicating factors.
Eccrine Syringofibroadenoma: Report of a Case and Analysis of Cytokeratin Expression
Authors: Takeda H. , Mitsuhashi Y. , Yoshikawa K. , Katagata Y. , Kondo S.
Published: April 2003

Eccrine syringofibroadenoma (ESFA) is a rare disorder which shows differentiation toward the eccrine sweat apparatus. There is a controversy concerning the pathogenesis and precise differentiation of this tumor. We report a case of ESFA and its differentiation pattern by an analysis of cytokeratin expression. Using paraffin-embedded materials, histopathological and immunohistochemical studies were performed. Staining patterns of the luminal, peripheral, and inner cells of the tumor strands closely matched or mimicked those of the luminal, outer and intermediate cells of the normal eccrine dermal duct, respectively. The case of ESFA reported revealed a pattern of differentiation suggestive of an eccrine duct origin.
Polythelia within Becker’s Naevus
Authors: Urbani C.E. , Betti R.
Published: April 2003

We report a case of accessory mammary tissue of type 2a (or polythelia) entirely localized within a Becker’s naevus of mixed type in a 32-year-old Caucasian woman. Polythelia was congenital in origin while Becker’s naevus appeared during puberty. Renal ultrasonographic studies, laboratory examinations and other instrumental investigations were either normal or negative. Although the association of accessory mammary tissue with Becker’s naevus has previously been reported – also in the form of mammorenal and acromammorenal syndromes – this is the first case characterized by an anatomic overlap between the two anomalies. It may be the expression of a common disturbance acting early in embryogenesis in the specific developmental fields involved.
Exfoliative Cheilitis: A Case Report and Review of the Literature
Authors: Taniguchi S. , Kono T.
Published: April 2003

We examined a 16-year-old male with persistent crusting of the lips. Biopsy showed parakeratosis, which is a normal feature, and a mild inflammatory infiltrate without fungal infection. These findings are compatible with a diagnosis of exfoliative cheilitis. Medication with antidepressants was helpful. To date, the condition has been reported under various names: factitious cheilitis, localized crusting as an artifact, factitious lip crusting, and exfoliative cheilitis, because some cases are thought to be factitious. We suggest to call this condition ‘factitious type’ or ‘idiopathic type’ of exfoliative cheilitis, respectively, independent of the presence of a psychiatric problem.
A Female Patient with the Rothmund-Thomson Syndrome Associated with Anhidrosis and Severe Infections of the Respiratory Tract
Authors: Snels D.G.C.T.M. , Bouwes Bavinck J.N. , Muller H. , Vermeer B.J.
Published: April 2003

The Rothmund-Thomson syndrome is a rare syndrome which is believed to be inherited in an autosomal pattern. Poikiloderma of the face and extremities is a characteristic feature. Besides this, less common aspects have been reported like alopecia, cataracts, short stature, musculoskeletal/bone defects or small hands, hypogonadism, abnormal teeth, dysplastic nails, anhidrosis and a high incidence of cutaneous and non-cutaneous malignancies. We present a patient with the Rothmund-Thomson syndrome together with anhidrosis and multiple infections of the upper and lower respiratory tract. Investigation of immunological function revealed a low total number of T lymphocytes with a slightly depressed reactivity. Immunoglobulins were markedly increased.
Interaction between Terbinafine and Warfarin
Authors: Gupta A.K. , Ross G.S.
Published: April 2003

A 71-year-old woman presented with gastrointestinal bleeding. She had been stabilized on warfarin for the previous few months. Terbinafine had been started 32 days prior to this episode for the treatment of onychomycosis. The patient had been on cimetidine for the previous 2 years and on other medications for the last 10 years. At the time of admission for the gastrointestinal bleeding, the coagulation indices were all above the therapeutic range. Endoscopy of the gastrointestinal tract exhibited diffuse intestinal ‘oozing’ consistent with coagulopathy as the cause of bleeding. Terbinafine may have had an effect on the metabolism of warfarin since both are metabolized through the liver and cimetidine can reduce terbinafine clearance by 33% resulting in higher concentrations of the antifungal agent. Our experience suggests that caution should be exercised when prescribing terbinafine to a patient receiving warfarin.
Superantigen Production by Staphylococcus aureus in Psoriasis
Authors: Sayama K. , Midorikawa K. , Hanakawa Y. , Sugai M. , Hashimoto K.
Published: April 2003

Background: Activation of T cells is believed to play a critical role in the pathogenesis of psoriasis. Recently, it has been proposed that psoriasis is a T-cell-mediated autoimmune reaction triggered by bacterial superantigen. Objective: We investigated whether patients with chronic plaque psoriasis bear superantigen-producing Staphylococcus aureus on the skin or the throat. Methods: S. aureus producing exfoliative toxin, staphylococcal enterotoxin B or toxic shock syndrome toxin 1 was isolated from the skin and throat of 100 psoriasis patients using Western blot analysis and polymerase chain reaction. Results: Only 5, 4 and 9 patients had super-antigen producing S. aureus identified on lesional skin, nonlesional skin and throat, respectively. The vast majority of patients did not bear superantigen-producing S. aureus. Conclusion: We believe that superantigens are not essential in sustaining disease activity but may, instead, be exacerbating or triggering factors for some psoriasis patients.