bluuebunny/crossref_metadata_2025 huggingface dataset:
Key Methodological Features of Randomized Controlled Trials of Alzheimer’s Disease Therapy
Authors: Burback Darren , Molnar Frank J. , St. John Phil , Man-Son-Hing Malcolm
Published: April 2003

Background: The results of clinical trials are routinely presented in terms of statistical significance, which may or may not indicate clinical significance. Analysis of the minimal clinically important difference (MCID) of cognitive scales has received little attention to date. Objectives: By reviewing the key methodological features (sample size, duration, statistical and clinical significance) of clinical trials examining the efficacy of tacrine in the treatment of Alzheimer’s disease (AD), we assessed their ability to detect clinically important changes in cognition. Design: The value for the MCID of the Mini-Mental State Examination (MMSE) was determined by surveying specialists in neurology and geriatric medicine. This value was then used to interpret the clinical significance of the results of published randomized controlled trials (RCTs) assessing the efficacy of tacrine in the treatment of AD and to retrospectively determine their optimal sample size and trial duration. Results: The mean survey MCID for the MMSE was 3.72 (95% confidence interval 3.50–3.95) points. Only 2 of 12 tacrine RCTs using the MMSE found a statistically significant difference in MMSE scores for patients taking tacrine compared with those taking placebo. These improvements were not clinically significant when compared with the survey MMSE MCID. For parallel trials of tacrine in AD, the smallest sample size and minimum trial duration required to demonstrate a clinically significant difference were calculated to be 53 subjects and 1 year, respectively. Five of the 7 parallel trials met the required sample size; however, none of them met the criteria for trial duration. Conclusions: When using the MMSE as an outcome measure, no tacrine trial reported results that were clinically significant as perceived by clinicians working with dementia patients. Application of a range of plausible MCIDs to the parallel design RCTs also demonstrated that 2 of 7 of these trials did not have sufficient sample size, and none had sufficient duration of treatment to reliably detect clinically meaningful changes in cognition. Future clinical trials in this area will need to incorporate the evolving knowledge of MCIDs in order to increase their chance of detecting clinically relevant results.
Diagnosing Dementia: Interrater Reliability Assessment and Accuracy of the NINCDS/ADRDA Criteria versus CERAD Histopathological Criteria for Alzheimer’s Disease
Authors: Hogervorst E. , Barnetson L. , Jobst K.A. , Nagy Zs. , Combrinck M. , Smith A.D.
Published: April 2003

We investigated the interrater reliability and accuracy of two independent medical doctors in using NINCDS/ADRDA criteria to classify 82 elderly subjects enrolled in OPTIMA, a longitudinal study investigating dementia. Kappa statistics revealed moderate agreement (0.5) in overall classification of dementia type, and almost perfect agreement (0.9) on the absence or presence of dementia. Combining NINCDS/ADRDA ‘possible’ and ‘probable’ Alzheimer’s disease (AD) categories produced substantial agreement (0.7). Comparison with CERAD histopathological criteria for AD showed that combining ‘possible’ and ‘probable’ AD resulted in a high sensitivity and accuracy, but a low specificity. To increase specificity, the NINCDS/ADRDA ‘probable AD’ category should be used alone. An important finding was that the accuracy of diagnoses of AD made from the case notes alone was not different from the diagnoses obtained following active involvement with participants.
Magnetic Resonance Imaging and Histopathology in Dementia, Clinically of Frontotemporal Type
Authors: Larsson Elna-Marie , Passant Ulla , Sundgren Pia C. , Englund Elisabet , Brun Arne , Lindgren Arne , Gustafson Lars
Published: April 2003

The magnetic resonance imaging (MRI) and computed tomography findings in 28 patients with the clinical diagnosis of frontotemporal dementia (FTD) were compared with the findings in a control group of 76 individuals without dementia or stroke. A pattern of frontal and temporal atrophy with predominantly frontal white matter changes was found in the FTD patients, and this was significantly different from the radiological findings in the control group. Six of the FTD patients have undergone autopsy. Histopathological evaluation showed a primary cortical degenerative disease (frontal lobe degeneration of non-Alzheimer type) in 3 of them, and primary white matter disorder, mainly frontal, of basically ischemic type (selective incomplete white matter infarction) in 3 of them. MRI could be a helpful tool to support the clinical diagnosis FTD, especially in young patients. MRI may also be helpful for the differentiation of a primary neurodegenerative from a mainly ischemic-vascular type of dementia.
Metrifonate Therapy in Alzheimer’s Disease: A Pooled Analysis of Four Randomized, Double-Blind, Placebo-Controlled Trials
Authors: Farlow M.R. , Cyrus P.A.
Published: April 2003

This retrospective analysis assessed the efficacy of metrifonate in the treatment of mild to moderate Alzheimer’s disease (AD). Those four studies meeting Food and Drug Administration guidelines for establishing the efficacy of an AD therapeutic agent were pooled for further analysis. Data were included from all patients valid for the intent-to-treat analyses (last observation carried forward). Patients received once daily placebo (n = 550), metrifonate 30–60 mg (by weight, n = 769) or 60/80 mg (by weight, n = 197). Metrifonate 60/80 mg significantly improved the cognitive abilities [AD Assessment Scale – Cognitive Subscale (ADAS-Cog), p = 0.0001; Mini Mental State Examination (MMSE), p = 0.0001], psychiatric and behavioral disturbances (Neuropsychiatric Inventory, p = 0.039; ADAS – Noncognitive Subscale, p = 0.0001), performance of instrumental and basic activities of daily living (Disability Assessment for Dementia, p = 0.0002) and global status (Clinician’s Interview-Based Impression of Change with Caregiver Input, p = 0.0001) of AD patients when compared with placebo. Metrifonate effects across these domains were dose related. Metrifonate 60/80 mg significantly improved the cognitive performance relative to both placebo and to baseline as evaluated by both the ADAS-Cog and the MMSE. Metrifonate is the first cholinesterase inhibitor consistently shown under prospective, placebo-controlled conditions to improve significantly behavior in addition to cognition, function in activities of daily living and global functional status of patients with mild to moderate AD.
People with Dementia Use Schemata to Support Episodic Memory
Authors: Rusted Jennifer , Gaskell Matthew , Watts Serena , Sheppard Linda
Published: April 2003

This paper describes two experiments which examine whether people with dementia use schemata, established knowledge stores associated with specific scenarios, to aid episodic memory. On all tests of memory, volunteers with dementia remembered less than their age-matched controls. There was evidence for an age-related decline in cognitive resources available for effortful memorising. For people with dementia, errors of commission in free recall, false recognition scores and reconstruction data were consistent with the use of shema to guide retrieval of items from memory. We conclude that retrieval support improves memory performance for both the healthy and dementing elderly. More importantly, pre-established schemata remain intact well into the course of dementia and can support recall of newly acquired episodic information.
Neuronal Migration and Differentiation in the Development of the Mouse Dorsal Cochlear Nucleus
Authors: Ivanova Anna , Yuasa Shigeki
Published: April 2003

The dorsal cochlear nucleus (DCN) of mammals displays a cortical structure containing a number of cell types organized into distinct layers. In the present study, the migratory mode of large multipolar cells and granule cells as well as the morphological differentiation of the projection neurons were investigated in the development of the mouse DCN. The classification of the DCN neurons followed that of Ryugo and Willard. The mode of neuronal migration was examined by immunohistochemical bromodeoxyuridine labeling. Large multipolar neurons originated from the primary rhombic lip and small granule cells from the secondary rhombic lip. Large multipolar neurons migrated radially from the ventricular zone into the forming DCN. Granule cells were generated later than the large multipolar neurons and migrated via the subependymal and subpial routes. Large multipolar neurons and small granule cells were thus segregated early in the DCN development and intermixed later during perinatal maturation. Projection neurons retrogradely labeled by DiI application to the contralateral inferior colliculus showed neurite extension between the pial surface and the ventricular zone during migration in the DCN primordium. The retrogradely labeled projection neurons showed a well-differentiated morphology of the large multipolar neurons as early as the late embryonic stage. The arrangement of the radial glial processes coincided with that of the migratory projection neurons. The migratory immature neurons showed close apposition with the radial glial processes, suggesting that glial scaffolds are involved in the migration and settlement of the large multipolar neurons. Thus, it is suggested that the mode of migration and settlement of large multipolar neurons and granule cells in the developing DCN is highly similar to that of Purkinje and granule cell migration in the cerebellar development, based on the findings of this study and the structural similarity between the cerebellum and DCN.
Myelin Proteolipid Protein Intron 1 Sequences Do Not Appear to Enhance Myelin Proteolipid Protein Gene Transcription
Authors: Wight Patricia A. , Dobretsova Anna
Published: April 2003

Sequences from the first intron of the mouse myelin proteolipid protein (PLP) gene were examined for their ability to modulate PLP gene expression. Glial (N20.1) or nonglial (NIH 3T3) cells were transiently transfected with constructs that contained 1.4 kb of PLP promoter sequence driving luciferase reporter gene expression, as well as various portions of PLP intron 1 DNA. Although these same PLP intron 1 fragments enhanced reporter gene expression from a heterologous basal promoter in a previous study, the results reported here demonstrate that they do not augment PLP promoter activity. Thus, the regulation of PLP cell-type-specific expression, conferred by the first intron, appears to be mediated by an enhancer-independent mechanism.
Gephyrin-Like Immunoreactivity Is a Marker for Growing Axons in the Central Nervous System of the Immature Rat
Authors: Fallah Zahra , Clowry Gavin J.
Published: April 2003

The membrane-associated protein gephyrin can form part of the glycine receptor complex at inhibitory synapses. This study provides evidence for gephyrin localisation in the developing axons of the rat brain and spinal cord, with particular reference to the corticospinal tract. Using a well-characterised monoclonal antibody (MAb 7a) gephyrin-like immunoreactivity was found expressed by growing axons, disappearing as these axons became myelinated. Immunoelectron microscopy localised the antigen to the interior of small, unmyelinated axons in the dorsal funiculus of young rats. Western blot analysis of cervical spinal cord from different post-natal ages only detected one immunoreactive band at ages when immunohistochemistry revealed gephyrin-like immunoreactivity in both the grey matter and corticospinal tract. Furthermore, the molecular weight of this band corresponded to that of gephyrin, suggesting it is present both at synapses and in axons. The known tubulin binding ability of the gephyrin may have a role in stabilisation of microtubules in growing axons.
Prevalence of Epileptic Seizures along the Wakefulness-Sleep Cycle in Adult Rats Submitted to Status epilepticus in Early Life
Authors: Ferreira Branca L.C. , Valle Angela C. , Cavalheiro Esper A. , Timo-Iaria Cesar
Published: April 2003

In 70 adult Wistar rats submitted to pilocarpine-induced status epilepticus in early life the electro-oscillograms were recorded from neocortical areas 10, 3 and 17, from CA1 and CA3 hippocampal fields and, in 10 rats, also from the ventrolateral nuclei and amygdala. Head, eye, rostrum + vibrissae, ear and forelimb movements were recorded as well. Fifty rats were subjected to 4-hour daily recording sessions and 20 to continuous 24-hour recordings. In all the rats spike-wave discharges (SWD) were found in every site from which the electro-oscillograms were recorded, and clonic seizures were also displayed by all the animals. Most seizures (83.75%, mean = 6.59 fits/h) were concentrated in nearly 9 h and 16.25% (mean = 0.77 fits/h) in the remaining 15 h. Eye movements occurred during 49.2% of the total duration of motor events, the head moved in 42.8% and the rostrum + vibrissae in 8.1% of the time, departing from normal rats. Therefore, pilocarpine-induced status epilepticus produces striking changes in the wakefulness-sleep cycle characteristics.
Electrophysiological and Morphological Analyses of Cortical Neurons Obtained from Children with Catastrophic Epilepsy: Dopamine Receptor Modulation of Glutamatergic Responses
Authors: Cepeda C. , Li Z. , Cromwell H.C. , Altemus K.L. , Crawford C.A. , Nansen E.A. , Ariano M.A. , Sibley D.R. , Peacock W.J. , Mathern G.W. , Levine M.S.
Published: April 2003

The present study examined the electrophysiological effects produced by activation of specific dopamine (DA) receptors and the distribution of DA receptor subtypes and glutamate receptor subunits [N-methyl-D-aspartate (NMDAR1) and GluR1] in cortical tissue samples obtained from children (ages 3 months to 16 years) undergoing epilepsy surgery. DA receptor activation produced differential effects depending on the receptor subtype that was activated. D1 receptor family agonists generally enhanced cortical excitability and favored the emergence of epileptogenic activity. In contrast, D2 receptor family agonists had more variable effects on cortical excitability and the expression of epileptiform discharges. Activation of D1 or D2 receptors decreased the amplitude of non-NMDA-mediated excitatory postsynaptic potentials. In contrast, DA and D1 agonists increased the amplitude of NMDA-mediated potentials. Immunohistochemical analysis showed that the DA receptor subtypes and glutamate receptor subunits examined were present in all cortical layers and areas throughout development. Whole-cell voltage clamp recordings of pyramidal neurons visualized with differential interference contrast optics and infrared videomicroscopy indicated that these neurons displayed a persistent Na+ current, followed by an outward current. DA reduced the outward current but had little effect on the persistent Na+ current. These results suggest a dual role for DA’s actions in the human cerebral cortex. Activation of D2 receptors or antagonism of D1 receptors may help control seizures in children.
Cerebral Cortical Dysplasia: Giant Neurons Show Potential for Increased Excitation and Axonal Plasticity
Authors: Kerfoot Christopher , Vinters Harry V. , Mathern Gary W.
Published: April 2003

Cerebral cortical dysplasia (CD) is a common cause of intractable childhood epilepsy. Five cases of CD were analyzed for GABAA receptor subunit β (GABAAβ), glutamate decarboxylase, AMPA receptor subunit 1 (GluR1) and subunit 2/3 (GluR2/3), and NMDA receptor 2 (NMDAR2) immunoreactivity. Antisera to the highly polysialylated neural cell adhesion molecule (PSA-NCAM) and human unc-33-like phosphoprotein 1 (hUlip 1) were used to identify neurons with ‘developmentally immature’ characteristics. Differences between CD and comparison tissue (n = 3) included: (1) prominent GABAAβ immunoreactivity of the cytoplasm of dysmorphic neurons in the subcortical white matter and cortex in 1 CD case; (2) increased immunolabeling with anti-GluR1 and GluR2/3 antisera in dysmorphic neurons compared with more normal-appearing adjacent neurons and neurons from nondysplastic cortex; (3) varying numbers of cortical dysmorphic neurons stained for NMDAR2 in all 5 CD cases, in contrast to a complete lack of cellular immunoreactivity in 2/3 of the cases of nondysplastic cortex; (4) PSA-NCAM and hUlip 1 expression (usually observed only in populations of neurons that undergo axonal growth) was observed in CD tissue, but not in normal brain tissue. In summary, dysmorphic neurons in cases of CD have increased immunoreactivity for several excitatory neurotransmitter receptor subunits, show variable immunoreactivity for GABAAβ and show expression of several proteins that are normally expressed only in immature neurons or those with the potential for synaptic plasticity.
Focal Cortical Dysplasia in Children
Authors: Hilbig Arlete , Babb Thomas L. , Najm Imad , Ying Zhong , Wyllie Elaine , Bingaman William
Published: April 2003

Cortical dysplasia (CD) is now recognized as one of the major causes of pediatric focal neocortical epilepsy, and surgical procedures have been considered early in life. However, the mechanisms involved in seizure generation and intractability in these patients are still unknown. We analyzed with immunocytochemistry for various antibodies the brain tissue from 4 children (10 months to 6 years old) with focal epilepsy due to focal CD in order to study the inhibitory and excitatory circuits in dysplastic areas. Our group had similar histopathological and clinical characteristics. In all patients we found areas of cortical disorganization with dysplastic neurons and balloon cells. We studied distributions of glial cells with glial fibrillary acidic protein (GFAP) and neurons with microtubule-associated protein 2 (MAP-2). Gliosis was present in all cases, and GFAP stained also some balloon cells. Dysplastic neurons were darkly stained by MAP-2, and we also found balloon cells weakly stained with MAP-2 in the same areas where GFAP was positive, suggesting coexpression of neuronal and glial markers in some of these cells. There was an increased expression of glutamate receptors, especially GluR2/3, but also N-methyl-D-aspartate receptors in dysplastic cortex. The inhibitory circuit does not seem to be decreased, rather we notice an increased amount of glutamate-decarboxylase-positive terminals around some of the big neurons. We discuss the possible role of these findings as mechanisms of epilepsy.
Gap Junction-Mediated Coupling in the Postnatal Anterior Subventricular Zone
Authors: Menezes João R.L. , Fróes Maira M. , Moura Neto Vivaldo , Lent Roberto
Published: April 2003

We have studied gap junctional communication in the anterior subventricular zone (SVZa) of postnatal rodents, revealed by intercellular diffusion of dyes in brain slices. Extensive intercellular dye spread was evident in the SVZa. Coupling was not uniform, being characteristically larger in the outer borders of this layer, overlapping the previously described peripheral zone of concentration of S-phase cells. Intercellular spread of the dye was unaffected by acidification, but totally blocked by high Ca2+ concentrations. In addition, application of some known uncoupling agents as carbenoxolone and halothane led to a marked reduction of dye spread in the SVZa. Our results demonstrate the presence of dye coupling mediated by gap junctions in the SVZa. Furthermore, the spatial organization of dye coupling in these slices strongly suggests the existence of cell compartments in the postnatal SVZa.
Developmental Changes in Progenitor Cell Responsiveness to Bone Morphogenetic Proteins Differentially Modulate Progressive CNS Lineage Fate
Authors: Mehler Mark F. , Mabie Peter C. , Zhu Gaofa , Gokhan Solen , Kessler John A.
Published: April 2003

Although multipotent progenitor cells capable of generating neurons, astrocytes and oligodendrocytes are present within the germinal zones of the brain throughout embryonic, postnatal and adult life, the different neural cell types are generated within discrete temporospatial developmental windows. This might suggest that multipotent progenitor cells encounter different signals during each developmental stage, thus accounting for separate waves of lineage commitment and cellular differentiation. This study demonstrates, however, that progenitor cell responses to the same class of signals, the bone morphogenetic proteins (BMPs), change during ontogeny, and that these same signals may thus initiate progenitor cell elaboration of several different lineages. BMPs promote cell death and inhibit the proliferation of early (embryonic day 13, E13) ventricular zone progenitor cells. At later embryonic (E16) stages of cerebral cortical development, BMPs exhibit a concentration-dependent dissociation of cellular actions, with either enhancement of neuronal and astroglial elaboration (at 1–10 ng/ml) or potentiation of cell death (at 100 ng/ml). Finally, during the period of perinatal cortical gliogenesis, BMPs enhance astroglial lineage elaboration. By contrast, oligodendroglial lineage elaboration is inhibited by the BMPs at all stages. Further, application of the BMP antagonist noggin to cultured progenitors promotes the generation of oligodendrocytes, indicating that endogenous BMP signaling can actively suppress oligodendrogliogenesis. These observations suggest that developmental changes in neural progenitor cell responsiveness to the BMPs may represent a novel mechanism for orchestrating context-specific cellular events such as lineage elaboration and cellular viability.
Subcellular Distribution of Pyroglutamyl-Peptidase I Activity in the Developing Rat Cerebellum
Authors: de Gandarias Juan Manuel , Gil Javier , Valdivia Asier , Larrinaga Gorka , Artola David , Casis Luis
Published: April 2003

In this work we analyzed the activity of pyroglutamyl (pGlu)-peptidase I in several subcellular fractions of the rat cerebellum during its development. The aim of this study is to determine if there is a developmental redistribution of this enzyme activity and if this fact could indicate changes in the role of the enzyme as age progresses. Results show that pGlu-peptidase I is widely distributed, but not homogeneously, in all the subcellular fractions that were studied, in both soluble and particulate forms. Significantly the distribution of the enzyme changes with development. Thus, in the soluble synaptosomal fraction, the pGlu-peptidase I activity is low until PD9 and the activity increases significantly from PD9 to PD15, when it reaches adult levels. In contrast, in the cytosolic fraction, the pGlu-peptidase I activity is high from fetal day 22 to postnatal day 6, and then decreases significantly until postnatal day 90.
Prenatal Expression of the GLUT4 Glucose Transporter in the Mouse
Authors: Vannucci Susan J. , Rutherford Tina , Wilkie Mary Beth , Simpson Ian A. , Lauder Jean M.
Published: April 2003

The GLUT4 glucose transporter is primarily expressed in skeletal muscle, heart and adipose tissue, where its expression is postnatal, coincident with the acquisition of insulin-regulated glucose transport. In muscle, contraction also regulates GLUT4 activity in the postnatal animal. Here we demonstrate that GLUT4 is expressed in the developing mouse embryo with specific tissue and spatiotemporal patterns. From embryonic day 9 (E9; E1 = day of copulation plug) to postnatal day 70 (P70), mice were analyzed for GLUT4 mRNA and protein expression by in situ hybridization, immunohistochemistry and immunoblot. Specificity was confirmed with sense riboprobe hybridization and peptide competition, respectively. At E9, GLUT4 was detected in the cranial neural folds in the outer (mantle) layer of the neuroepithelium. At E10, expression was present throughout the developing heart and was prominent in the endocardial cushions through E12. At E10–12, GLUT4 was also prominent in craniofacial mesenchyme. GLUT4 expression in cartilage and bone was evident at E12 and was maintained throughout early postnatal life. GLUT4 was apparent throughout embryonic development in the ventricular epithelium, choroid plexus and in the developing cerebellum. At birth, cardiac expression was reduced and GLUT4 was most evident in cartilage, bone and specific brain regions. In the latter, GLUT4 expression was most evident in the cerebellum, specifically in the external granular layer through P7 and in the internal granular layer thereafter. Maximal GLUT4 protein levels in the cerebellum were measured between P14 and P21 and were reduced in the adult brain. These findings suggest that GLUT4-mediated glucose transport may play important roles during development of the brain and nonneuronal tissues in the mouse embryo.
Neonatal 6-Hydroxydopamine Treatment Affects GABAA Receptor Subunit Expression in the Frontal Cortex but Not the Hippocampus of Rats during Postnatal Development
Authors: Podkletnova I. , Mäkelä R. , Korpi E.R. , Lüddens H. , Helen P. , Alho H.
Published: April 2003

The influence of neonatal administration of 6-hydroxydopamine (6-OHDA) on the maturation of GABAA receptors in the frontal cortex and hippocampus was studied using 5- to 40-day-old rats. In situ hybridization with antisense oligonucleotide probes was performed for α1, α2, α5, β2, β3 and γ2 subunit mRNAs of the GABAA receptor. We demonstrated that neonatal treatment with 6-OHDA temporarily delays the postnatal transcription of the α1 and γ2 subunits in the rat prefrontal cortex, as assessed by in situ hybridization histochemistry. The effect was selective for these subunits (the α2, α5, β2, and β3 subunit mRNAs remained unchanged) and for this region (the mRNA levels in the hippocampus were not changed). The reduction in mRNA levels at early postnatal stages (postnatal day 5, PD5, and PD10) also affected the subunit protein levels, as shown by immunohistochemistry for the α1 subunit, and the formation of GABAA receptor-associated picrotoxinin-insensitive TBPS binding sites, as shown by autoradiography. Our findings indicate that without a noradrenergic influence, the maturation of GABAergic interneurons in the frontal cortex is transiently delayed (from PD5 to PD40). However, it is possible that this transient reduction of the expression of certain GABA subunits – caused by depletion of noradrenergic innervation – cannot cause a lasting alteration to the GABAergic function in the prefrontal cortex.
Maternal High n-6 Polyunsaturated Fatty Acid Intake during Pregnancy Increases Voluntary Alcohol Intake and Hypothalamic Estrogen Receptor Alpha and Beta Levels among Female Offspring
Authors: Cabanes Anna , de Assis Sonia , Gustafsson Jan-Ake , Hilakivi-Clarke Leena
Published: April 2003

Identification of nongenetic biological factors that predispose to alcohol abuse is central to attempts to prevent alcoholism. Since an exposure to estradiol in utero increases voluntary alcohol intake in adulthood, we investigated whether an increase in pregnancy estradiol levels, caused by feeding pregnant mice a high-fat corn oil diet, also influences voluntary alcohol intake among female offspring. In addition, the effect on estrogen receptor α (ER-α) and ER-β protein levels in the brain using Western blot assay, was determined. Pregnant CD-1 mice were kept on a high n-6 polyunsaturated fatty acid (PUFA; 43% calories from corn oil) or low n-6 PUFA diet (16% calories from corn oil) throughout gestation, and switched to a Purina laboratory chow after the pups were born. When 4 months of age, the female offspring were given a choice between 5% alcohol and tap water. The offspring of high n-6 PUFA mothers voluntarily consumed more alcohol than the offspring of low n-6 PUFA mothers. ER-α and ER-β protein levels in the hypothalamus were 1.5- and 2-fold higher, respectively, in the female offspring of high n-6 PUFA mothers than in the low n-6 PUFA offspring. No significant changes in the protein levels of ER-α and ER-β were seen in the frontal brain. Our findings indicate that a maternal exposure to a high n-6 PUFA diet during pregnancy increases alcohol intake among female offspring. This behavioral change, together with previously observed increase in aggressiveness and reduction in depressive-like behavior in these offspring, may be linked to an increase in the hypothalamic ER-α and ER-β levels.
Coping with Acne vulgaris
Authors: Niemeier V. , Kupfer J. , Demmelbauer-Ebner M. , Stangier U. , Effendy I. , Gieler U.
Published: April 2003

The present study investigated how patients with acne vulgaris cope with their disease. By means of questionnaires, relations and interactions between acne and psyche were evaluated. In addition to the evaluation of a specific questionnaire for patients with chronic skin disorders (CSD), assessing psychosocial impairment by the disease, depression and social anxiety were investigated in patients with acne. The study included 50 patients with acne. The CSD showed significant correlations with Beck’s depression inventory, the interaction-anxiety questionnaire and the health locus of control scale. The CSD revealed significant differences compared to a control group of 33 patients with healthy skin. Furthermore the patients’ attitudes towards triggering factors and disease-related limitations in everyday life are presented. The results of the study demonstrate that patients with acne suffer from emotional distress and psychosocial problems caused by their disease; however, impairment is not correlated with the objective severity of acne.
Modelling the Infundibulum in Acne
Authors: Guy R. , Kealey T.
Published: April 2003

The human sebaceous-pilosebaceous infundibulum was isolated and maintained for 7 days. Infundibular viability was maintained over 7 days in this medium. The addition of 1 ng/ml interleukin 1α (IL-1α) caused hypercornification of the infundibulum similar to that seen in comedones which could be blocked by 1,000 ng/ml IL-1 receptor antagonist. However, in contrast to interferon γ1, IL-1α had no effect on the expression of intercellular adhesion molecule or human leucocyte antigen type DR in infundibular keratinocytes. The addition of 5 ng/ml epidermal growth factor or 5 ng/ml transforming growth factor α to the medium caused a disorganization of the keratinocytes of the infundibulum. We are now, therefore, able to model histologically the major infundibular changes in acne. Furthermore, we suggest that IL-1α causes the scaling seen in many inflammatory skin diseases.
Sequence-Based Diagnosis of Tyrosinase-Related Oculocutaneous Albinism: Successful Sequence Analysis of the Tyrosinase Gene from Blood Spots Dried on Filter Paper
Authors: Matsunaga J. , Dakeishi-Hara M. , Miyamura Y. , Nakamura E. , Tanita M. , Satomura K. , Tomita Y.
Published: April 2003

Background: A large number of mutations of the tyrosinase gene result in oculocutaneous albinism (OCA). Therefore, at present, sequence analysis of the tyrosinase gene has become necessary to diagnose OCA patients and their relatives. Objective: The aim of this study was to facilitate the sequence-based diagnosis of tyrosinase-related OCA by using small amounts of the patient’s blood. Methods: Blood spots dried on filter papers were used as sources of genomic DNA. The exons and flanking regions of the tyrosinase gene were amplified by polymerase chain reaction (PCR) and were directly sequenced in both directions. Results: We successfully amplified all exons of the tyrosinase gene by PCR and were able to characterize compound heterozygous mutations of R278X and +ΔC310 in the patient’s gene. Conclusion: Recent advances of PCR-related technology allowed us to use fairly limited samples of blood for sequence analysis of the tyrosinase gene.
Efficacy of Urea Therapy in Children with Ichthyosis
Authors: Küster W. , Bohnsack K. , Rippke F. , Upmeyer H.-J. , Groll S. , Traupe H.
Published: April 2003

Background: Ichthyoses are genetic disorders of keratinization which are uncomfortable due to their conspicuous scaling, itching and cosmetic problems. Especially in childhood, ichthyoses can lead to social discrimination and psychological problems. Efficient therapies are necessary which are safe and well tolerated. Objective: The aim of the study was to investigate the keratolytic and moisterurizing properties as well as the tolerance of a new urea lotion when applied to hyperkeratotic and ichthyotic skin in childhood. Methods: The study was conducted as a multicenter, randomized, placebo-controlled, double-blind, semilateral investigation. Sixty children between 1 and 16 years treated one side of the most affected extremity with Laceran 10% urea lotion for 8 weeks. On the other side the urea-free Laceran lotion base was given. On each side of the body a control area was left untreated. The investigators evaluated the global severity of ichthyotic symptoms with the help of a visual analogue scale. Results: The analysis of the global estimation of severity of ichthyosis showed improvements being stronger in the body areas treated with Laceran 10% urea lotion (from 4.8 to 2.0 points) than in the areas treated with the urea-free Laceran lotion base (from 4.8 to 2.5 points). The response rates were 65% after 4 weeks and 78% after 8 weeks for Laceran 10% urea lotion, 50% after 4 weeks and 72% after 8 weeks for the urea-free Laceran lotion base. Conclusion: It can be ascertained that Laceran 10% urea lotion has a strong positive effect on generalized ichthyotic keratinization disorders.
Itraconazole in the Treatment of Onychomycosis: A Double-Blind Comparison with Miconazole
Authors: Haneke E. , Tajerbashi M. , De Doncker P. , Heremans A.
Published: April 2003

Background: In recent years, itraconazole pulse therapy for onychomycosis has been developed [three 1-week pulses with itraconazole 400 (2 × 200) mg daily every month]. This has proved an effective and safe regimen which requires only 50% of the medication used for continuous dosing schedules. Parallel to the development of the new dosage schedule, additional studies were conducted to further document the safety and efficacy of itraconazole 200 mg once daily for 3 months to treat onychomycosis. Objective: To compare the safety of itraconazole 200 mg once daily for 3 months, with or without itraconazole 200 mg once weekly for a further 3 months, with that of miconazole cream twice daily for 6 months, in the treatment of onychomycosis. Treatment efficacy was compared as a secondary objective. Methods: In this multicenter, double-blind study, patients were randomized to receive itraconazole 200 mg once daily for 3 months followed by either itraconazole 200 mg once weekly for 3 months (ITR-ITR group, n = 599) or oral placebo once weekly for 3 months (ITR-PLAC group, n = 613), or to receive miconazole cream twice daily for 6 months (MIC-MIC group, n = 396). The primary variable was elevation of alanine aminotransferase (ALT) concentration above 50 U/l. Results: Overall incidence of elevation of ALT concentration above 50 U/l, adverse events and rate of withdrawal because of adverse events were low and similar in the three treatment groups. Efficacy was significantly greater in the ITR groups than the MIC-MIC group. Conclusion: Itraconazole and miconazole were well tolerated and had no significant effect on liver function, but itraconazole was significantly more effective.
Pustular Vasculitis of the Hands
Authors: Curcó N. , Pagerols X. , Tarroch X. , Vives P.
Published: April 2003

Pustular vasculitis of the hands has been described in 6 women, as a distinct entity limited to the dorsa of the hands similar to that seen in Sweet’s syndrome but with severe leukocytoclastic vasculitis. We describe 2 men with identical lesions and discuss this new entity.
Topical Immunotherapy of Severe Alopecia areata with Diphenylcyclopropenone: Evaluation of 68 Cases
Authors: Pericin M. , Trüeb R.M.
Published: April 2003

Background: Currently, topical immunotherapy with diphenylcyclopropenone (DCP) represents the most accepted therapeutic modality in the treatment of severe alopecia areata (AA). Objective: Efficacy, side effects and prognostic factors of DCP treatment in severe AA. Methods: Retrospective study of 68 patients with severe AA (>40% scalp hair loss), treated for at least 5 months at the Department of Dermatology, University Hospital of Zürich, between May 1989 and December 1996. Results: The overall response rate was 70.6%, complete remission was obtained in 30.9% and partial remission in 39.7%. Among the investigated prognostic factors for the outcome of DCP therapy, only the extent of AA at the time of initiation of treatment was found to be of significance. Conclusion: DCP treatment of severe AA is an effective, albeit symptomatic therapy with frequent side effects and a relatively high relapse rate. The response rate depends on the type of AA.
A Case of an Inflammatory Variant of Epidermolysis bullosa acquisita: Chronic Bullous Dermatosis Associated with Nonscarring Mucosal Blisters and Circulating IgG Anti-Type-VII-Collagen Antibody
Authors: Tokuda Y. , Amagai M. , Yaoita H. , Kawachi S. , Ito T. , Matsuyama I. , Tsuchiya S. , Saida T.
Published: April 2003

A 42-year-old man showed prominent blistering lesions of the mouth and esophagus in addition to a few bullous lesions of the skin. Direct immunofluorescence microscopy revealed distinct linear deposition of IgG and C3 at the epidermal basement membrane zone where slight deposition of IgA and IgM was also observed. In direct immunoelectron-microscopic examination, antibody was detected in the sublamina densa of the basement membrane zone. Immunoblot analysis with dermal extracts demonstrated that the patient’s serum contained circulating IgG antibodies against the 290-kD protein, which comigrated with type VII collagen. The lesions healed without any scars. The results of these studies corresponded to the laboratory findings in epidermolysis bullosa acquisita (EBA), although the clinical features were distinct from classic EBA.
Flow Cytometry Analysis of Peripheral Blood Lymphocytes from Patients with Bullous Pemphigoid
Authors: Jouen-Beades F. , Joly P. , Héron F. , Paris E. , Lauret Ph. , Tron F.
Published: April 2003

Background: Bullous pemphigoid (BP) is an autoimmune disease observed in elderly subjects in which alteration of peripheral blood lymphocyte subset repartition has been described. Objective: To evaluate peripheral blood lymphocyte subsets from BP patients and identify immunologic changes that can be assigned either to the autoimmune disease or to the ageing process. Methods: Peripheral blood lymphocytes from 24 patients with BP and 24 age- and sex-matched healthy individuals were analyzed by flow cytometry and these results were compared to those obtained from young adults. Results: This study showed: (i) the presence of T-cell lymphopenia with a decreased number of CD8+ and gdγδ T lymphocytes in BP patients compared with younger adult controls; (ii) a high dispersion of the results in the BP population; (iii) the absence of a significant difference of lymphocyte subset levels between BP patients and age- and sex-matched controls. Conclusion: This flow cytometry study suggests that the modifications of lymphocyte subpopulation values observed in BP patients are related to immunologic changes induced by age in elderly people.
HIV-Associated Eosinophilic Folliculitis and Follicular Mucinosis
Authors: Buezo G.F. , Fraga J. , Abajo P. , Ríos L. , Daudén E. , García-Díez A.
Published: April 2003

The term HIV-associated eosinophilic folliculitis (EF) designates an idiopathic dermatitis that appears in HIV-infected patients with different clinical manifestations but with a distinctive histological feature characterized by a predominantly eosinophilic infiltrate in the follicular infundibula. On the other side, follicular mucinosis (FM) is a reaction pattern in the follicular epithelium, characterized by a mucinous degeneration of the outer sheath of follicles and sebaceous glands. It has been described in association with a variety of unrelated conditions. We report 2 HIV-infected patients with a pruritic papular eruption. Histopathological study revealed the coexistence of EF and FM. To our knowledge, this is the first report that describes this association. The possible relationship between these two entities is discussed.
Genital Variant of Folliculosebaceous Cystic Hamartoma
Authors: Bolognia J.L. , Longley B.J.
Published: April 2003

Background: Clinically, folliculosebaceous cystic hamartomas (FSCH) present as skin-colored papulonodules of the face, especially the nose. This is in contrast to sebaceous trichofolliculomas which often present as depressed ostia containing terminal or vellus hairs. Observation: A 34-year-old female had a skin-colored multinodular plaque of the labia majora that demonstrated the histologic findings of an FSCH. These included an irregularly shaped central cystic structure surrounded by multiple sebaceous lobules as well as a fibrous stroma. The epithelial-lined cyst contained no hair shafts. Conclusion: A single case report of a scrotal lesion with a similar clinical appearance and histologic findings has previously been described as a genital variant of sebaceous trichofolliculoma. However, the report predated the initial description of FSCH. In our opinion, both cases represent examples of the genital variant of FSCH.
Norwegian Scabies in a Patient with Acquired Immunodeficiency Syndrome
Authors: Guggisberg D. , de Viragh P.A. , Constantin Ch. , Panizzon R.G.
Published: April 2003

We report the case of a 42-year-old man with symptomatic HIV infection (C3 CDC stage) who presented widespread hyperkeratotic skin lesions diagnosed as Norwegian scabies. The CD4 count was 87 cells/mm3. The patient has been the source of a nosocomial outbreak (20 individuals affected). He was treated successfully with combined topical treatment (permethrin 5% cream plus keratolytic agents) and oral ivermectin.
Oxidative Stress in Adamantiades-Behçet’s Disease
Authors: Freitas J.P. , Filipe P. , Yousefi A. , Emerit I. , Guerra Rodrigo F.
Published: April 2003

Background: Adamantiades-Behçet’s disease is a chronic systemic disorder associating oral and genital ulcerative lesions with ocular and cutaneous manifestations. Previous publications report increased superoxide production by neutrophils and macrophages, increases in cytokines and malondialdehyde (MDA), as well as low levels of enzymatic antioxidant defenses. Aim: We looked for another marker of oxidative stress in Adamantiades-Behçet’s disease: the presence of clastogenic factors (CF) in patients’ plasma. In addition, we determined plasma endproducts of lipid peroxidation (MDA). Patients and Methods: We studied 20 patients and 20 controls. The clastogenic activity was evaluated by means of cytogenetic methods. This test (CF test) detects circulating prooxidants, due to their clastogenic effects after exposure of lymphocyte cultures of healthy persons to plasma ultrafiltrates from patients. The clastogenic prooxidants are lipid peroxidation products and cytokines, in particular TNF-α. Lipid peroxidation was evaluated by the Yagi method. Results: The CF test was positive in 18 out of 20 patients, while it was negative in all 20 control persons. The mean increase in chromosomal breaks was 10.6 ± 3.8 in cultures exposed to patients’ plasma and 1.3 ± 2.4 for cultures receiving control plasma (p <0.001). The clastogenic effect of patients’ plasma ultrafiltrates was significantly inhibited by superoxide dismutase (EC 1.15.1.1), suggesting an important role of the superoxide radical in the clastogenic pathway. Thiobarbituric-acid-reactive substances (expressed as nanomoles MDA per milliliter) were also significantly increased in these patients: 10.6 ± 3.2 for patients and 6.6 ± 1.4 for controls (p <0.001). Conclusion: The presence of CF in the plasma of patients, indicating the presence of circulating prooxidants with chromosome-damaging effects, confirms an oxidative stress in Adamantiades-Behçet’s disease. The anticlastogenic effect of superoxide dismutase in vitro suggests the implication of the superoxide radical. MDA levels were also significantly increased in patients.
HLA Class II Allele Associations in Korean Patients with Pemphigus
Authors: Lee C.W. , Yang H.Y. , Kim S-C. , Jung J.H. , Hwang J.J.
Published: April 2003

Background: Studies at the population level have demonstrated associations between pemphigus (pemphigus vulgaris, PV, and pemphigus foliaceus, PF) and particular HLA haplotypes, which suggests that there may be a genetic predisposition for the disease. Objective/Methods: The aim of the present study was to examine the distribution/frequency pattern of HLA class II alleles (DRB1, DQA1 and DQB1) from a group of 30 Korean patients with pemphigus (15 PV and 15 PF) by PCR amplification with sequence-specific primers. Results: In PV, the frequency of DRB1*01 allele was found to be significantly high (pc = 0.0014); in PF, DRB1*01, DQA1*0302 and DQB1*0603 alleles showed positive associations with statistical significances (pc = 0.0002, 0.0007 and 0.0067, respectively), when compared with those found in Korean controls. Conclusions: In this small-sample study, findings of allelic frequencies among Korean patients with pemphigus are somewhat different from those found in other populations.
Efficacy and Safety of Short-Term Itraconazole in Tinea pedis: A Double-Blind, Randomized, Placebo-Controlled Trial
Authors: Svejgaard E. , Avnstorp C. , Wanscher B. , Nilsson J. , Heremans A.
Published: April 2003

Background: Treatment of plantar or moccasin-type tinea pedis with conventional oral antifungal agents produces poor response rates. Itraconazole is a synthetic, broad-spectrum, orally active antifungal agent with pronounced antimycotic activity. Objective: To confirm the efficacy and safety of short-term treatment with itraconazole for plantar or moccasin-type tinea pedis. Methods: The study was a double-blind, randomized, placebo-controlled, multicenter trial. Seventy-two patients with tinea pedis (plantar or moccasin-type) were treated with itraconazole (200 mg twice daily) or placebo for 1 week with an 8-week treatment-free follow-up period. Results: Thirty-six patients were randomized to each treatment group. The overall success rate (mycological cure and clinical response) at the end-point of follow-up was significantly higher in the itraconazole group than in the placebo group (53 vs. 3%; p <0.001). Mycological cure (56 vs. 8%; p <0.001) and clinical response rates (75 vs. 11%; p <0.001) were significantly higher after itraconazole treatment compared with placebo treatment. During treatment, adverse events were recorded in 7 patients in the itraconazole group and 2 patients in the placebo group. Adverse events were noted in 3 patients in the placebo group during follow-up. No serious adverse events were reported in either group. Conclusions: Short-term treatment with itraconazole was significantly more effective than placebo in tinea pedis. The safety and tolerability profile or itraconazole was comparable with placebo.
Pilomatricoma in Elderly Individuals
Authors: Behnke N. , Schulte K. , Ruzicka T. , Megahed M.
Published: April 2003

We report on 4 elderly patients aged 54–85 years with histopathologically diagnosed pilomatricoma who had been seen in our department from 1993 to 1997. Pilomatricoma is a rather uncommon neoplasm in middle-aged and old patients. It is much better known in children. Here, we clinically studied these 4 cases of pilomatricoma in elderly patients (above 50 years of age) to show the variety of clinical differential diagnosis and discuss the clinicopathological features. The results of the present study indicate that the differential diagnosis of pilomatricoma should also be considered in elderly individuals.