bluuebunny/crossref_metadata_2025 huggingface dataset:
Selective Expression of Ser 199/202 Phosphorylated Tau in a Case of Frontotemporal Dementia
Authors: Takamatsu Junichi , Kondo Akira , Ikegami Ken , Kimura Takemi , Fujii Hideaki , Mitsuyama Yoshio , Hashizume Yoshio
Published: April 2003

We examined a 65-year-old patient with clinicopathological features that met the criteria of frontotemporal dementia (FTD), particularly frontal lobe degeneration (FLD). He came from a family with concentrated occurrence of dementia symptoms in the presenium. Neuropathological examination disclosed brain atrophy locally pronounced on the frontotemporal lobes with characteristic neuronal loss, microvacuolation and astrocytic gliosis. There were no pathological hallmarks such as senile plaques, Pick bodies (PBs), achromatic cells and neurofibrillary tangles. Precise separation of FTD from Pick disease (PD) and motor neuron disease with dementia (MNDD) has not yet been established, and they are included in one spectrum. Antibodies against paired helical filament tau protein demonstrated immunopositive cytoskeletal structures within the neurons as well as the glial cells in the brain of the present case. They were selectively stained with tau 199/202 but not tau 396, which were provided newly to recognize phosphorylation at Ser 199/202 or Ser 396 in tau, respectively. We investigated tau pathology in the present case in comparison to 8 cases with PD that were clinicopathologically confirmed. Neither tau 199/202 nor tau 396 stained the CNS structures in PD cases with few PBs, while both stained evidently those as well as PBs in PD cases associated with many PBs; so that the present case could be distinguished from PD on the basis of the immunoreactivity to site-specific phosphorylated tau. Our result suggests that FTD, especially familial FLD type might involve unique tau pathology, no matter whether FLD is a distinct entity from PD, or a variant form in the wide FTD spectrum including PD and MNDD and other related disorders.
Assessment of the Pathological Stages of Alzheimer’s Disease in Thin Paraffin Sections: A Comparative Study
Authors: Nagy Zs. , Yilmazer-Hanke D.M. , Braak H. , Braak E. , Schultz C. , Hanke J.
Published: April 2003

The staging method proposed by Braak and Braak allows the objective and reliable assessment of Alzheimer-related neurofibrillary pathology. Originally the method was designed for 100-µm thick sections. However, the use of thick sections proved to present difficulties in a routine neuropathology laboratory. In order to adapt the staging method for thin paraffin-embedded sections, we performed an inter- and intrarater study analysing the reliability of the staging method in thin sections. Statistical analysis of the data provided by six independent examiners in two rating sessions reveal kappa values of 0.6–0.8 for both the interrater and the intrarater reliability. The average rate of mistake of the examiners was rarely bigger than a half stage. We conclude that the adapted staging method in thin sections is strongly reliable and we recommend it for staging purposes in institutions where the preparation of thick sections would be difficult.
Accuracy of Clinical Operational Diagnostic Criteria for Alzheimer’s Disease in Relation to Different Pathological Diagnostic Protocols
Authors: Nagy Zs. , Esiri M.M. , Hindley N.J. , Joachim C. , Morris J.H. , King E.M.-F. , McDonald B. , Litchfield S. , Barnetson L. , Jobst K.A. , Smith A.D.
Published: April 2003

In this study we analysed the accuracy of two sets of clinical diagnostic criteria, the NINCDS/ADRDA and DSM-III-R, in relation to the currently used pathological diagnostic criteria for Alzheimer’s disease (AD), the Khachaturian criteria, the Tierney A3 criteria and the CERAD protocol. The sensitivity of the individual clinical diagnostic criteria, NINCDS/ADRDA and DSM-III-R, is poor (34–58%) irrespective of the pathological diagnostic criteria applied for the definite diagnosis of AD. The combination of the NINCDS/ADRDA ‘possible’ and ‘probable dementia of the Alzheimer type’ (DAT) categories has a high sensitivity (91–98%). However the combination resulted in very poor specificity (40–61%). Thus, none of the clinical diagnostic criteria is satisfactory. We found similar results when we analysed the predictive value of these clinical diagnostic criteria. The positive predictive value of NINCDS ‘probable DAT’ category and that of the DAT diagnosis by DSM-III-R is very high (89–100%). This makes the use of these categories suitable for research purposes. However, the negative predictive value of both diagnoses is poor (33–63%), making these criteria unsuitable for diagnostic purposes in clinical practice.
β-Amyloid Plaques: Stages in Life History or Independent Origin?
Authors: Armstrong R.A.
Published: April 2003

Several types of discrete β-amyloid (Aβ) deposit or senile plaque have been identified in the brains of individuals with Alzheimer’s disease and Down’s syndrome. The majority of these plaques can be classified into four morphological types: diffuse, primitive, classic and compact. Two hypotheses have been proposed to account for these plaques. Firstly, that the diffuse, primitive, classic and compact plaques develop in sequence and represent stages in the life history of a single plaque type. Secondly, that the different Aβ plaques develop independently and therefore, unique factors are involved in the formation of each type. To attempt to distinguish between these hypotheses, the morphology, ultrastructure, composition, and spatial distribution in the brain of the four types of plaque were compared. Although some primitive plaques may develop from diffuse plaques, the evidence suggests that a unique combination of factors is involved in the pathogenesis of each plaque type and, therefore, supports the hypothesis that the major types of Aβ plaque develop independently.
Diffusion-Weighted Magnetic Resonance Imaging in Alzheimer’s Disease
Authors: Sandson T.A. , Felician O. , Edelman R.R. , Warach S.
Published: April 2003

Diffusion-weighted imaging (DWI) is a powerful new magnetic resonance imaging technique for evaluating tissue pathophysiology in vivo. We performed DWI in three orthogonal spatial directions in 10 patients with mild to moderate Alzheimer’s disease (AD) and 11 control subjects. Average apparent diffusion coefficients (ADCavg) were calculated for gray matter regions, and anisotropy indexes were calculated for white matter regions. Global measures of atrophy and white matter hyperintensities (WMH) were obtained on T2-weighted images to control for their potential confounding effects on ADCavg and anisotropy. The measures of atrophy and WMH differed between the groups and were used as covariates in the subsequent statistical analyses. Patients with AD demonstrated diminished anisotropy in the posterior white matter (p < 0.0001) and increased ADCavg in the hippocampus (p < 0.05) when compared to the control group. Diffusion measures did not correlate with the severity of dementia. DWI provides a unique, quantitative parameter that may be sensitive to the pathophysiological and/or microstructural abnormalities that occur in AD.
Impact of the Type and Severity of Dementia on Hospitalization and Survival of the Elderly
Authors: Landi Francesco , Gambassi Giovanni , Lapane KateL. , Sgadari Antonio , Mor Vincent , Bernabei Roberto
Published: April 2003

We conducted a retrospective cohort study to examine whether patients with Alzheimer’s disease (AD) or vascular dementia (VaD) differed in the number and type of associated comorbid conditions. In addition, we evaluated the impact of the severity of cognitive impairment on hospitalization and mortality of patients in each group. We studied 161,106 patients over age 65, with any degree of cognitive impairment, residing in any of 1,573 Medicare/Medicaid-certified nursing homes of 5 states of the USA between 1992 and 1995. Patients were assessed with the federally mandated Minimum Data Set (MDS). The MDS has been cross-linked to Medicare eligibility files and to the Medicare Provider Analysis and Review database. AD patients were younger, and more likely to be female and Caucasian than VaD patients. For comparable levels of cognitive impairment, AD patients appeared to have fewer comorbid conditions, including those that were not risk factors for VaD. In addition, patients with AD had decreased morbidity and mortality relative to patients with VaD. These findings support the hypothesis that AD patients are a healthier group of demented patients.
Two-Year Treatment of Alzheimer’s Disease with Eptastigmine
Authors: Imbimbo BrunoP. , Verdelli Giulio , Martelli Paola , Marchesini Donata , and the Eptastigmine Study Group &
Published: April 2003

The effectiveness of long-term treatment of Alzheimer’s disease with cholinesterase inhibitors is a matter of controversy. We evaluated the effects of prolonged treatment with eptastigmine in 176 patients with mild to moderate Alzheimer’s disease participating in the open-label extension phase of a 25-week double-blind, placebo-controlled trial of eptastigmine. The effects of eptastigmine on cognition and daily functioning were evaluated with the cognitive portion of the Alzheimer’s Disease Assessment Scale (ADAS-Cog) and the Instrumental Activities of Daily Living (IADL) scale, respectively. Safety was monitored by physical examination, laboratory tests, vital functions and electrocardiogram measurements and by the assessment of adverse events. One hundred and fifty-three patients (87%) completed 1 year of treatment, 77 patients (44%) 18 months and 33 patients (19%) 2 years of treatment. Patients treated for 2 years showed an improvement of mean ADAS-Cog scores compared to baseline for 31 weeks and mean IADL scores remained close to baseline for 25 weeks. Cognitive and functional scores then worsened as expected in this progressive disease. After 2 years, patients deteriorated compared to baseline by 13.4 points on the ADAS-Cog and 6.1 points on IADL. Historical untreated controls with identical disease severity are expected to have an annual worsening of approximately 10.9 points on ADAS-Cog and 4.9 points on IADL. Thus patients treated with eptastigmine for 2 years had a benefit of 8.5 points on ADAS-Cog and 3.8 points on IADL. These benefits translate to about 9 months difference between eptastigmine-treated patients and untreated historical patients. The drug was generally well tolerated with 14 patients (7.9%) withdrawing due to adverse events. Adverse events, not necessarily drug-related, were recorded in 66 patients (37.5%) and were transient and generally mild in severity. This study indicates that prolonged treatment with eptastigmine is safe and produced a clinically long-term benefit in patients with Alzheimer’s disease.
Apolipoprotein E Genetic Variation and Alzheimer’s Disease
Authors: Rubinsztein David C. , Easton Douglas F.
Published: April 2003

In order to quantify the effects of apolipoprotein (apo) E on early- and late-onset, sporadic and familial Alzheimer’s disease (AD) more precisely we performed a meta-analysis of 42 case-control series published before July 1996. We excluded studies of late-onset AD with fewer than 50 cases and 50 controls. The estimated odds ratio of AD over the age of 65 years associated with the apo ε4 allele, relative to apo ε3, was 3.18 (95% CI 2.93–3.45, p < 0.00001). Apo ε4 was associated with a significantly higher relative risk of early-onset disease (<65 years) unselected for family history (OR 4.86, 95% CI 3.61–6.54, p < 0.0001), but its impact on early-onset familial disease was weaker (OR 1.48, 95% CI 1.02–2.16). The estimated odds ratio associated with the ε4/ε4 genotype, relative to the ε3/ε3 genotype, was 11.57 (95% CI 8.67–15.44) for all cases over 65 and 61.44 (95% CI 13.47–280.3) for early-onset disease unselected for family history. Apo ε2 was associated with a significantly reduced odds ratio for AD above the age of 65 (OR 0.68, 95% CI 0.58–0.80, p < 0.00001), but not in familial early-onset AD, where apo ε2 may be associated with an increased risk (OR 1.70, 95% CI 1.02–2.84). We estimate that 60% (95% CI 48–68%) of AD cases over the age of 65 years and 92% of cases below the age of 65 would be attributable to apo E and that apo E probably accounts for less than 50% of the familial aggregation of the disease.
Epidemiology of Delirium
Authors: Bucht Gösta , Gustafson Yngve , Sandberg Olov
Published: April 2003

Delirium is one of the most frequent symptoms of disease in the elderly. A large variation of incidence and prevalence data is reported probably due to different patient populations and inconsistent diagnostic criteria. In medical and surgical elderly inpatients recent studies report a prevalence rate of approximately 15% and in postoperative patients the incidence and prevalence rates vary greatly, 7–52%, depending on patient population and clinical setting. In nursing homes the prevalence is even higher and delirium is often combined with dementia. Data supports the statement that delirium is most often found in hospitalized somatically ill elderly patients. As a consequence of the rising number of elderly in hospitals we have to expect an increase in the prevalence and incidence of delirium.
Identifying and Recognizing Delirium
Authors: Johnson Jerry
Published: April 2003

Clinicians fequently under-recognize delirium. Physicians and nurses can be taught to recognize delirium by focusing on each of the components of the criteria for delirium. Teachers of physicians and nurses should emphasize the ability to recognize acuteness of onset, fluctuation of course, and attention deficits. Attention deficits in the clinical setting can be recognized by digit span testing, spelling words backwards, or assessing accessibility during the clinical interview. Attention can be scored by assigning a score from 0–10, or ranking as mild, moderate or severe, the patients ability to engage in the medical interview.
Assessment Scales in Delirium
Authors: Robertsson Barbro
Published: April 2003

In research and in clinical practice instruments assessing symptoms of delirium are of value in the diagnostic process, in the evaluation of intervention as well as in the care of patients. Different assessment instruments are needed for different purposes. Most instruments developed are screening instruments or diagnostic tools. Confusional State Evaluation (CSE) is an observer’s rating scale assessing severity of delirium. Interrater reliability and validity of the CSE have been found satisfactory. The CSE seems to be of value in following the course of delirium in elderly patients and useful for instance in evaluating effects of interventions.
Can Delirium Be Separated from Dementia?
Authors: Macdonald A.J.D.
Published: April 2003

This presentation reviews the nosological status of delirium and dementia as a prelude to a discussion of how to distinguish them, or even if they are distinguishable. It argues that committee (ICD, DSM) classification systems fossilise the meaning of the syndromes, and thereafter have a baleful effect on research. The distinction between dementia and delirium is a case in point, and it can be argued that this is much less clear than we thought. It is suggested that validation of syndromes as prognostic tools is a logical way out of the nosological swamp into which delirium and dementia research is sinking, and that cognitive improvement should be the key distinction.
Decreased Plasma Insulin-Like Growth Factor-I Level in Familial Alzheimer’s Disease Patients Carrying the Swedish APP 670/671 Mutation
Authors: Mustafa Amged , Lannfelt Lars , Lilius Lena , Islam Atiqul , Winblad Bengt , Adem Abdu
Published: April 2003

The plasma insulin-like growth factor I (IGF-I) level was determined in family members carrying the Swedish amyloid precursor protein (APP) 670/671 mutation with or without Alzheimer’s disease (AD) and in age-matched controls from the same family. Plasma growth hormone (GH) and prolactin (PRL) levels were also determined. Measurement of the plasma IGF-I level by radioimmunoassay revealed a significant reduction only in the family members with AD compared to age-matched controls. However, there was no significant difference in the levels of GH and PRL between the mutation carriers with or without AD and their respective age-matched controls. These findings indicate that the mechanism(s) regulating GH and PRL were preserved and those regulating IGF-I levels might be affected in AD patients with the Swedish APP 670/671 mutation.
Living Alone with Dementia
Authors: Ebly Erika M. , Hogan David B. , Rockwood Kenneth
Published: April 2003

This report describes a population of individuals with dementia living alone in the community. Data were collected as part of the Canadian Study of Health and Aging (CSHA). We found that one third of the subjects in the CSHA sample with a dementia residing in the community lived alone. Whether their identified informal caregiver had thought about institutionalization was an important factor in actual short-term (2-year) institutionalization and appeared to be influenced by living arrangements. Caregivers of those living alone provided less hands-on assistance, experienced less burden, and were less likely to be depressed than those living with the demented person, but were more likely to have considered institutionalization. Presumably, this was driven by concerns about safety and support. How to support the growing numbers of individuals with dementia living alone in the community will be a significant challenge.
Event-Related Potential and EEG Measures in Parkinson’s Disease without and with Dementia
Authors: Tanaka Hideaki , Koenig Thomas , Pascual-Marqui Roberto D. , Hirata Koichi , Kochi Kieko , Lehmann Dietrich
Published: April 2003

Nondemented Parkinson’s disease (PD) patients showed increased amplitude of event-related potential component P3. We recorded 18-channel spontaneous eyes-closed resting EEG and auditory oddball event-related potentials in 29 PD patients and 11 age-matched controls. Combining Mini-Mental State Examination score and oddball P3 counting performance, 15 patients were intellectually normal, 7 moderately, and 7 severely demented. P3 and N1 amplitude and latency, mean amplitude of 1,024 ms post-stimulus (separate after rare and after frequent stimuli), and resting EEG total power for 40 s were computed, and linearly regressed for age, sex, and L-dopa dosage. In nondemented PD patients, increased P3 amplitude was confirmed, but N1 amplitude and mean amplitude after rare and frequent stimuli were also increased as well as – most important – resting EEG total power. With increasing dementia, amplitude and power decreased, and P3 latency increased. Task demands cannot explain increased P3 amplitude, since similarly increased EEG total power was found during no-task resting. Prospective studies must determine whether P3 amplitude and EEG power in nondemented PD patients can serve as predictors of dementia.
Beta-Amyloid Deposition in the Temporal Lobe of Patients with Dementia with Lewy Bodies: Comparison with Non-Demented Cases and Alzheimer’s Disease
Authors: Armstrong R.A. , Cairns N.J. , Lantos P.L.
Published: April 2003

β-Amyloid (Aβ) deposition in regions of the temporal lobe in patients with dementia with Lewy bodies (DLB) was compared with elderly, non-demented (ND) cases and with Alzheimer’s disease (AD). The distribution, density and clustering patterns of diffuse, primitive and classic Aβ deposits were similar in ‘pure’ DLB and ND cases. The distribution of Aβ deposits and the densities of the diffuse and primitive deposits were similar in ‘mixed’ DLB/AD cases compared with AD. However, the density of the classic deposits was significantly lower in DLB/AD compared with AD. In addition, the primitive Aβ deposits occurred more often in small, regularly spaced clusters in the tissue and less often in a single large cluster in DLB/AD compared with ‘pure’ AD. These results suggest that pure DLB and AD are distinct disorders which can coexist in some patients. However, the Aβ pathology of DLB/AD cases is not identical to that observed in patients with AD alone.
No Evidence of Endothelial Dysfunction in Patients with Alzheimer’s Disease
Authors: McGleenon B.M. , Passmore A.P. , McAuley D.F. , Johnston G.D.
Published: April 2003

In view of accumulating evidence of vascular pathology in Alzheimer’s disease (AD), we tested the hypothesis that AD patients have impaired endothelial function. This was assessed using the technique of strain-gauge venous occlusion plethysmography, which measures forearm blood flow (FBF). Intra-arterial (brachial) infusion of acetylcholine (ACh) and sodium nitroprusside (SNP) was used to assess local endothelial dependent and independent responses, respectively. There was no difference in the basal FBF of patients and controls. ACh and SNP caused dose-related increases in FBF from baseline, but no difference was recorded between the AD and control group. This study provides no evidence of endothelial dysfunction in the systemic circulation of patients with AD.
Comprehension of Emotions: Comparison between Alzheimer Type and Vascular Type Dementias
Authors: Shimokawa Akio , Yatomi Naomi , Anamizu Sachiko , Ashikari Iyoko , Kohno Michiko , Maki Yutaka , Torii Shigeo , Isono Hiroshi , Sugai Yuuichi , Koyama Nobuyuki , Matsuno Yukiko
Published: April 2003

This study investigated the ability of recognizing emotion in dementia. Twenty-five patients with dementia of the Alzheimer type (DAT), 25 patients with vascular dementia (VD), and 12 normal control subjects were evaluated as to general cognition, visuoperception and emotion recognition. The score on the emotion recognition task significantly correlated with that of the Mini-Mental State Examination for VD patients while this was not the case for DAT patients. Moreover, VD patients performed significantly worse than DAT patients on the emotion recognition task in spite of the fact that there was no difference in the general cognitive and visuoperceptual abilities between them. The result of this study coupled with the past studies led to the hypothesis that the relationship between intellectual deficits and the deterioration in recognizing emotions differs according to type of dementia. Caregivers in nursing homes and hospitals need to take into account their patients’ intellectual deficits but also their deteriorating ability of identifying emotions.
Behavioral Differences between White Matter Lacunar Dementia and Alzheimer’s Disease: A Comparison on the Neuropsychiatric Inventory
Authors: Aharon-Peretz Judith , Kliot Dorita , Tomer Rachel
Published: April 2003

Background and Purpose: Behavioral abnormalities account for much of the morbidity of vascular dementia (VaD) and Alzheimer’s disease (AD). The goals of the study were to compare the behavioral changes in patients with VaD associated with ischemic white matter subcortical changes and lacunar infarctions (VaD-WSI) to those in patients with AD. Methods: Thirty outpatients with VaD and multiple lacunar infarctions in the periventricular white matter and 30 AD patients, matched for age and severity of dementia, were enrolled in this prospective study. The behavioral abnormalities of these patients were assessed by interviewing their caregivers with the Neuropsychiatric Inventory. Results: A similar spectrum of noncognitive behavioral changes was found in AD and WSI patients. In VaD-WSI, the severity of delusions, hallucinations, aggression, irritability, aberrant motor behavior, nighttime behavior and appetite changes was correlated with cognitive decline, whereas depression, apathy, anxiety and euphoria were unrelated to the severity of dementia. In AD, none of the behavioral changes correlated with the severity of dementia. Conclusion: Behavioral changes are frequent in VaD-WSI and are present regardless of the severity of the cognitive decline. It is therefore important to assess behavioral as well as cognitive changes at early stages of the illness, to ensure appropriate treatment.
Acetylcholinesterase Inhibition in Dementia with Lewy Bodies: Results of a Prospective Pilot Trial
Authors: Querfurth H.W. , Allam G.J. , Geffroy M.A. , Schiff H.B. , Kaplan R.F.
Published: April 2003

Objective: Dementia with Lewy bodies (DLB) is the second commonest form of dementia. The response to acetylcholinesterase inhibition (AChEI) could be greater in DLB than in Alzheimer’s disease (AD) because cholineacetyl-transferase levels are more reduced in the former. This preliminary trial seeks to compare performances in cognitive tasks before and after tacrine administration in DLB and AD subjects. Methods: Six DLB and 6 AD patients were enrolled in an open, nonrandomized, intervention trial using 80 mg/day tacrine. Patients met ADRDA or DLB consortium criteria for probable diseases. Subjects were matched for Mini Mental State Examination (MMSE) score, age and sex. Mattis Dementia Rating Scale (DRS), Controlled Oral Word Association Test (FAS) and Boston Naming tests were administered at baseline and at 6 months into treatment. Results: AD and DLB groups did not differ in initial mean total DRS scores. In the primary analysis, both groups declined during the course of treatment (–7.3 ± 4.2 and –16.8 ± 39.2 DRS points, respectively). Due to the large variability in DLB posttreatment scores, this group was divided post hoc into responders (DLBr) and nonresponders (DLBnr). The DLBr group outperformed the DLBnr group at baseline (p < 0.05) and, notably, in follow-up DRS test scores (p < 0.001). Two-way MANOVA comparing both DLB subgroups with either the entire AD cohort or similarly stratified AD subgroups showed a significant interaction (F = 7.6; p < 0.015), attributed mostly to declines in DLBnr group scores (p < 0.01). Surprisingly, on DRS memory subscale and FAS tests, there were significant improvements in DLBr scores (p < 0.02). A baseline MMSE (or DRS memory) score ≥15 predicted a positive response to tacrine in DLB. Acceleration of parkinsonism occurred in all DLB subjects. Conclusion: Results from a primary analysis of the therapeutic effect of 80 mg/day tacrine in DLB and AD were negative. However, post hoc analysis showed that mild to moderate DLB responds favorably to AChEI relative to AD through stabilization of global cognitive decline and improvements in specific cognitive areas. These results could be useful in the planning of a more definitive study.
Fate of Patients with Questionable (Very Mild) Alzheimer’s Disease: Longitudinal Profiles of Individual Subjects’ Decline
Authors: Perry Richard J. , Hodges John R.
Published: April 2003

Currently used criteria for the diagnosis of probable Alzheimer’s disease requires the presence of cognitive deficit in addition to loss of episodic memory. The recent developments in drug treatments for Alzheimer’s disease have highlighted the importance of early diagnosis and the need to characterise the cognitive profile of the earliest stages of the disease. We set out to examine the pattern of decline in terms of individual cognitive domains in non-demented subjects with clinically isolated progressive amnesia which we have termed questionable Alzheimer’s disease. Twelve subjects who fulfill criteria for a clinical diagnosis of possible Alzheimer’s disease by NINCDS-ADRDA criteria were compared to 20 age-matched controls in a longitudinal study. All subjects had MMSE scores of 24 or greater at entry to study. Individual profiles were measured by impairment in the cognitive domains of episodic memory, attention, semantic memory, visuospatial function and auditory verbal short-term (working) memory. Even after subjects were given this intensive neuropsychological battery, 8 of 12 subjects had episodic memory deficits only. Within 12 months just 3 patients were only amnesic and the other patients with pure amnesia at year 1 developed either semantic or attentional deficits. Impairment in both these cognitive domains preceded impairment in visuospatial function and auditory-verbal short-term memory. Our findings are consistent with the pattern of cognitive impairment in Alzheimer’s disease increasing in accordance with neuropathological correlates of cognitive function with amnesia linked to the initial medial temporal pathology before the pattern of spread affects critical neural substrates for attention and semantic memory. Tests of selective attention and semantic memory appear to be the most sensitive markers of decline beyond the amnestic phase of early Alzheimer’s disease.
Multinuclear NMR Spectroscopy Studies on NH4Cl-Induced Metabolic Alterations and Detoxification Processes in Primary Astrocytes and Glioma Cells
Authors: Zwingmann Claudia , Brand Annette , Richter-Landsberg Christiane , Leibfritz Dieter
Published: April 2003

Glutamine synthesis, the major pathway of ammonia detoxification, and the intracellular concentration of organic osmolytes in primary astrocytes and F98 glioma cells were investigated with multinuclear magnetic resonance spectroscopy. Acute exposure to ammonia (3 h incubation with NH4Cl) raised the concentration of glutamine and other amino acids, such as glutamate and aspartate, and decreased myo-inositol, hypotaurine, and taurine concentrations. The loss of these osmolytes was partially reversed by co-treatment with the glutamine synthetase inhibitor, methionine sulphoximine. Glutamate, the precursor of glutamine, is provided by stimulated anaplerotic flux via pyruvate carboxylase and glutamate dehydrogenase activity. Thus, the glutamine increase and myo-inositol decrease observed by in vivo magnetic resonance spectroscopy on patients with hepatic encephalopathy may be due to the disturbed osmoregulation in astrocytes caused by accumulation of glutamine and the subsequent loss of organic osmolytes.
New Insight into the Topical Management of Excessive Sebum Flow at the Skin Surface
Authors: Piérard G.E. , Ries G. , Cauwenbergh G.
Published: April 2003

The sebum flow dynamics at the skin surface results from a multistep process starting with sebocyte proliferation, intracellular lipid synthesis, cell lysis in the sebaceous duct, storage of sebum in the follicular reservoir, discharge through the follicular opening and spreading over the stratum corneum. A handful of topical products may decrease the sebum output, most of them acting at the level of the follicular reservoir function. Among them, elubiol exhibits a clinically relevant effect on oily skin.
The Sebaceous Gland and Acne – 40 Years On
Authors: Cunliffe W.J.
Published: April 2003

The purpose of this paper is to provide a review of the aetiology of acne and its treatment but more importantly to stress throughout this review the immense contributions made by Prof. J.S. Strauss in the field of sebaceous gland and acne research.
The Pilosebaceous Unit Is Part of the Skin Immune System
Authors: Böhm M. , Luger T.
Published: April 2003

It is well established that the functional state of sebaceous glands in vivo is a tightly regulated process orchestrated through the interaction of male sex hormones and functional androgen receptors expressed on sebocytes. In the last few years, however, it has become increasingly apparent that sebocytes like epidermal keratinocytes express a variety of cytokines which are implicated in inflammatory and immune responses. For example, sebocytes in vivo have been found to highly express tumor necrosis factor α (TNF-α) as determined by immunohistochemical and electron-microscopic methods. Moreover, certain neuropeptides including vascular intestinal peptide and proopiomelanocortin (POMC) peptides as well as their receptors have been localized within the pilosebaceous unit of murine and human skin. Since POMC peptides such as α-melanocyte-stimulating hormone have recently been shown to exert important immunoregulatory effects by antagonizing the function of proinflammatory cytokines (e.g. interleukin 1, interleukin 6 and TNF-α), induction of immunosuppressive cytokines (like interleukin 10), modulation of costimulatory molecule expression (e.g. B7-2) or suppression of macrophage-derived nitric oxide, complex interactions between these mediators and their target cells within the pilosebaceous gland seem to exist. The successful cultivation of sebocytes will provide a model by which the effect of these mediators can be studied in detail in order to shed light onto the various pathophysiological conditions of sebaceous glands.
Conversion of Psoriasis Patients from the Conventional Formulation of Cyclosporin A to a New Microemulsion Formulation: A Randomized, Open, Multicentre Assessment of Safety and Tolerability
Authors: Zachariae H. , Abrams B. , Bleehen S.S. , Bräutigam M. , Burrows D. , Ettelt M.J. , Fry L. , Happle R. , Haustein U.F. , Ganslandt J. , Jung E.G. , Knop J. , Kühne K.H. , Mellein B. , Mørk N.J. , Rogers S. , Schmidt A.-G. , Schopf R.E. , Sumner M. , Taube K.M. , Weidinger G. , Wurdel C. , Zahn E.
Published: April 2003

Objective: To assess the safety, tolerability and efficacy of a new cyclosporin A (CyA) microemulsion formulation, Sandimmun Neoral® (Neoral), in patients with severe psoriasis that was stable on CyA administered as Sandimmun® (SIM). Methods: In this 24-week, open, randomized, prospective, multicentre trial, 28 patients continued on the same dosage of SIM, while 30 converted to Neoral at 2.5 mg/kg/day or a dosage equivalent to their pre-conversion SIM dosage. During the study, dosages could be adjusted to maintain efficacy, because of adverse events or after disease stabilization. The maximum permitted dosage for either formulation was 5.0 mg/kg/day. Primary efficacy criteria were change in Psoriasis Area and Severity Index (PASI) from baseline and time to relapse. Results: The dosage was increased to maintain efficacy in 22 patients (Neoral 13; SIM 9) and 20 dose reductions for safety were required (Neoral 14, SIM 6). In both groups, PASI scores remained stable throughout and relapses were primarily a result of dosage reduction after disease stabilization. No significant difference was found between groups in the proportion of patients remaining relapse-free. Adverse events were recorded in 20 patients receiving Neoral and 14 receiving SIM. Most drug-related events were of mild or moderate severity and reflected the known CyA side-effect profile. Dose titration guidelines ensured that mean blood pressure and serum creatinine concentrations remained stable in both groups. Conclusions: If the guidelines for CyA use are followed and the Neoral dosage does not exceed 5 mg/kg/day, conversion of stable patients with severe psorisasis from SIM to Neoral should present no clinically relevant safety or tolerability problems and efficacy of treatment is maintained.
An Unusual Hypopigmentation in Occupational Dermatology: Presentation of a Case and Review of the Literature
Authors: Iliev D. , Elsner P.
Published: April 2003

Contact dermatitis to cooling lubricants is commonly encountered in occupational dermatology, but it rarely induces pigmentary skin changes. It is sometimes difficult to differentiate between toxic leukoderma and postinflammatory hypopigmentation when examining a depigmentation. A differential diagnosis is described in the case of a 31-year-old metal worker, spending most of his time on a computer-numerically controlled machine, who presented with cumulative irritant hand dermatitis and secondary hypopigmentation. Patch tests gave negative reactions to the European standard series, the desinfection and preservative series, the base preparation and emollient series, the metal series, the mechanical worker series as well as to the cooling lubricant itself. Atopy screening was positive for a variety of pollens. Based on biopsy findings, toxic leukoderma could be diagnosed even though none of the known melanotoxic compounds could be identified in his work environment. The patient was advised to avoid further contact with the regular composed cooling lubricant and the contact eczema improved dramatically, whereas the condition of hypopigmentation got better slowly within weeks under PUVA therapy.
Fumaric Acid Esters Suppress Peripheral CD4- and CD8-Positive Lymphocytes in Psoriasis
Authors: Höxtermann S. , Nüchel C. , Altmeyer P.
Published: April 2003

Background: For severe forms of psoriasis vulgaris, the antipsoriatic fumaric acid esters (FAE) therapy has recently gained increasing acceptance and importance. Until today, there is little knowledge about the mode of action of FAE. However, some evidence exists indicating immunosuppressive effects. Objective: The aim of this study was to examine the systemic, particularly the immunological changes in patients suffering from psoriasis treated with FAE over a long period of time, since we expect to see pharmacological effects of FAE at this point. Methods: This study is based on continuously recorded clinical data and laboratory parameters of 10 patients, who were treated over a period of 12 months with FAE. A quantitative analysis of lymphocytes and their subtypes was carried out by means of flowcytometric methods. Results: 3 months after starting treatment with FAE, a clinical effect with a remission index >95% was achieved in all 10 patients examined. This remained constant until the end of this study. Focusing on leukopenia, and particulary on lymphopenia as important parameters, these effects were found in all patients. The lymphocyte subpopulations data demonstrated extensive proportionate reductions. Within the T cell fraction a stronger suppression of CD8+ lymphocytes was observed. Conclusion: Our investigations of systemic effects of fumaric acid esters demonstrate the suppressive character of this medication. Effects of cell count reduction in leukocyte and lymphocyte numbers over the entire period of 12 months could be observed. The lymphocytic cell count number is obviously linked to the clinical effect.
Anti-Inflammatory Effect of Hamamelis Lotion in a UVB Erythema Test
Authors: Hughes-Formella B.J. , Bohnsack K. , Rippke F. , Benner G. , Rudolph M. , Tausch I. , Gassmueller J.
Published: April 2003

Background: Although Hamamelis virginiana has long been used in the traditional treatment of skin diseases, there are few controlled clinical studies defining the extent of its anti-inflammatory action. Objective:The anti-inflammatory efficacy of pH5 Eucerin aftersun lotion with 10% hamamelis distillate, the vehicle and a prior aftersun formulation were tested in 30 healthy volunteers using a modified UVB erythema test as model of inflammation. Methods: Four UVB doses ranging from 1 to 2 MED were evaluated in each subject. Test fields on the back were treated occlusively for 48 h following irradiation. Chromametry and visual scoring were used to determine the degree of erythema in the treated fields and an untreated, irradiated control field 7, 24 and 48 h after irradiation. Results: Erythema suppression ranged from approximately 20% at 7 h to 27% at 48 h in the hamamelis fields. A suppression of 11–15% was recorded in the fields treated with the other lotions. Significant differences were noted between hamamelis and these lotions. Conclusion: These data provide evidence for an anti-inflammatory action of the aftersun lotion with 10% hamamelis and support the usefulness of the UVB erythema test with multiple UV doses for the testing of nonsteroidal anti-inflammatory agents.
Granulomatous Slack Skin
Authors: van Haselen C.W. , Toonstra J. , van der Putte S.J.C. , van Dongen J.J.M. , van Hees C.L.M. , van Vloten W.A.
Published: April 2003

Purpose: Granulomatous slack skin (GSS) is a rare cutaneous disorder characterized clinically by the evolution of circumscribed erythematous lax skin masses, especially in the body folds, and histologically by a granulomatous T-cell infiltrate and loss of elastic fibers. GSS is often associated with preceding or subsequent lymphoproliferative malignancies, especially mycosis fungoides (MF) and Hodgkin’s disease (HD). No effective treatment is known yet. Whether this entity is a benign disorder, a peculiar host reaction to a malignant lymphoma, a precursor of malignant lymphoma or an indolent cutaneous T-cell lymphoma (CTCL) in itself is still a matter of debate. Patients and Methods: The results of the patients with GSS from the Netherlands are compared with the cases reported in the world literature. Results: A female patient had had GSS for 8 years without developing a secondary malignancy. In a second female patient with a histologically confirmed diagnosis of MF, GSS developed 18 years later in the axillary and inguinal folds which had previously been affected by plaque-stage MF lesions. A third male patient with a 6-year history of erythematosquamous skin disease diagnosed as CTCL developed GSS. Moreover, granuloma formation was also found in a facial basal cell carcinoma, in a cervical lymph node and the spleen. Clonal rearrangements of the T-cell receptor β genes were found in the 2 female patients; the male patient could not be tested. Conclusion: GSS is a rare clinicopathological entity. Only 34 patients have been described so far. The development of GSS within plaque MF lesions has not been reported before. Our third case developed very extensive skin lesions and showed a strong propensity to develop granulomas as compared to cases reported before. The presence of a clonal T-cell population was demonstrated in all cases tested. Our cases support the idea that GSS is a very rare and rather indolent type of CTCL. Apparently, the disease is associated with a peculiar immune response, characterized by granuloma formation and disappearance of elastic fibers resulting in the lax skin. The relationship between GSS and other preexisting or subsequent lymphoproliferative diseases (diagnosed in approximately 50% of the cases) warrants a life-long follow-up.
Pyodermitis of Genital Areas: An Atypical Manifestation of Eosinophilic Pustulosis of Childhood
Authors: Plantin P. , Mairesse H. , Milochau Ph. , Leroy J.P.
Published: April 2003

Eosinophilic pustulosis of the scalp was first described in 1984. It has also been described in other sites than the scalp. We report a case in which the lesions exclusively involved the genitals. A 4-month-old boy presented with papulopustular lesions of the genitals in the form of pyodermitis with a favourable course over several days but which subsequently recurred. A smear of a pustule revealed no signs of scabies or viral, fungal or bacterial infection. Histology showed a non-follicular eosinophilic pustulosis. This case emphasizes the ubiquitous and sometimes misleading nature of eosinophilic pustulosis and the non-follicular nature of the lesions.
Sclerotic Fibroma
Authors: Herrera Sánchez M. , Suárez Fernández R. , del Cerro Heredero M. , Rueda Gómez-Calcerrada M. , Vigaray Conde J. , Sánchez Yus E.
Published: April 2003

Sclerotic fibroma is an uncommon fibrotic neoplasm that occurs both sporadically as well as in patients affected by Cowden’s disease. We present an additional case of solitary sclerotic fibroma not associated with Cowden’s disease. Although most of the lesion was sclerotic, there was a cellular area with some multinuclear cells. We conclude that sclerotic fibroma is a mesenchymal neoplasm whose clinical and histopathologic features are not only different but opposite to those of dermatofibroma.
The in vitro and in vivo Production of a 31.5-kD Keratinolytic Subtilase from Microsporum canis and the Clinical Status in Naturally Infected Cats
Authors: Mignon B.R. , Nikkels A.F. , Piérard G.E. , Losson B.J.
Published: April 2003

Background: Microsporum-canis-infected cats, especially the asymptomatic infected ones, are mainly responsible for the zoonotic disease. The important variability of the clinical signs in cats is poorly understood. Recently, a 31.5-kD keratinolytic subtilase was found to be a putative virulence factor. Objective: To investigate the possible relationship between the clinical status of dermatophytic cats and the production of the keratinase. Methods: Seven M. canis strains isolated either from clinically affected, asymptomatic infected or mechanical carrier cats were tested for the in vitro production of the enzyme. The immunohistochemical detection of the enzyme was also assessed in skin biopsies of 4 symptomatic and 7 asymptomatic naturally infected cats. Results: All the strains produced in vitro a 31.5-kD keratinolytic subtilase. The enzyme was present in all but 1 of the infected cats. Conclusion: The production of the keratinase is not a factor directly responsible for the clinical picture seen in M. canis-infected cats.
Breast and Lung Cancers in Two Cyclosporin-A-Treated Psoriatic Women
Authors: Paquet P. , Piérard G.E.
Published: April 2003

We report malignant neoplasms of the breast and lung developed in two psoriatic patients after long-term treatment with low-dose cyclosporin A (CsA). A procarcinogen role of the drug cannot be ignored. Concern regarding the documented evidence from studies of organ transplant patients should be stressed in patients treated with low doses of CsA for chronic cutaneous inflammatory diseases.
Toxic Epidermal Necrolysis Associated with Treatment for Preterm Labor
Authors: Claessens N. , Delbeke L. , Lambert J. , Matthieu L. , Lafaire C. , van Marck E.
Published: April 2003

We report a 29-year-old pregnant woman who developed toxic epidermal necrolysis at 29 weeks of gestation after administration of ritodrine, indomethacin and betamethasone. Toxic epidermal necrolysis is an unreported side effect of this widely used combination of medications. Since toxic epidermal necrolysis is a potentially fatal disease, awareness of a possible association is warranted.
Ketoconazole Shampoo: Effect of Long-Term Use in Androgenic Alopecia
Authors: Piérard-Franchimont C. , De Doncker P. , Cauwenbergh G. , Piérard G.E.
Published: April 2003

Background: The pathogenesis of androgenic alopecia is not fully understood. A microbial-driven inflammatory reaction abutting on the hair follicles might participate in the hair status anomaly. Objective: The aim of our study was to determine if ketoconazole (KCZ) which is active against the scalp microflora and shows some intrinsic anti-inflammatory activity might improve alopecia. Method: The effect of 2% KCZ shampoo was compared to that of an unmedicated shampoo used in combination with or without 2% minoxidil therapy. Results: Hair density and size and proportion of anagen follicles were improved almost similarly by both KCZ and minoxidil regimens. The sebum casual level appeared to be decreased by KCZ. Conclusion: Comparative data suggest that there may be a significant action of KCZ upon the course of androgenic alopecia and that Malassezia spp. may play a role in the inflammatory reaction. The clinical significance of the results awaits further controlled study in a larger group of subjects.
Differential Regulation of MMP-2 and MMP-9 Gelatinases in Cultured Human Keratinocytes
Authors: Kobayashi T. , Hattori S. , Nagai Y. , Tajima S. , Nishikawa T.
Published: April 2003

Background: Among matrix metalloproteinases (MMPs), MMP-2 and MMP-9 are considered to play important roles in the tissue metabolism. Objective: To study the production of MMP-2 and MMP-9 in cultured keratinocytes. Methods: We examined the effect of cell passage number and cell differentiation on these enzymes by zymography and immunocytochemistry. Results: Both MMP-2 and MMP-9 gelatinases were detected in keratinocyte-conditioned media using zymography. The level of MMP-2 in the medium decreased after sequential passage, whereas MMP-9 was detected at a constant level. Treatment of keratinocytes with Ca2+, a potent stimulator for cell differentiation, induced secretion of MMP-9, which was confirmed immunocytochemically. Inversely, treatment with retinoic acid, which inhibits cell differentiation, increased the level of MMP-2. Conclusion: These results suggest that keratinocytes regulate their secretion of MMP-2 and MMP-9 gelatinase in distinct and independent patterns during differentiation.