bluuebunny/crossref_metadata_2025 huggingface dataset:
The inhibition of oligodendrocytic differentiation of O‐2A progenitors caused by basic fibroblast growth factor is overridden by astrocytes
Authors: Mayer Margot , Bögler Oliver , Noble Mark
Published: January 2005

The inhibition of differentiation of oligodendrocyte‐type‐2 astrocyte (O‐2A) progenitors into oligodendrocytes caused by basic fibroblast growth factor (bFGF) can be overcome by non‐O‐2A lineage cells present in the optic nerve and by astrocytes purified from cerebral cortices. Although purified O‐2A progenitors grown in the presence of bFGF for up to 6 days were inhibited from differentiating into oligodendrocytes, O‐2A progenitors growing in heterogeneous optic nerve cultures did not show a similar inhibition of differentiation. The factor(s) responsible for overriding the inhibitory effects of bFGF appeared to be secreted by astrocytes, as extensive generation of oligodendrocytes was seen in cultures of purified O‐2A progenitors exposed to bFGF+ medium conditioned by purified astrocytes (ACM). In addition, purified O‐2A progenitors displayed a remarkable sensitivity to bFGF, which extended at least down to concentrations of 0.03 ng/ml, a concentration of <2 × 10−12 M. At a bFGF concentration of just 0.1 ng/ml, this mitogen still promoted DNA synthesis in as many O‐2A progenitors as in cultures exposed to 1‐30 ng/ml of this growth factor, but exhibited a reduced ability to promote DNA synthesis in oligodendrocytes. In addition, although concentrations of bFGF as low as 0.03 ng/ml were a potent stimulator of DNA synthesis in O‐2A progenitors, application of this amount of bFGF no longer inhibited the differentiation of progenitors into oligodendrocytes as effectively as application of higher bFGF concentrations. Thus, the induction of DNA synthesis by bFGF can be uncoupled from the inhibition of differentiation. Our results demonstrate that exposure of O‐2A progenitors to bFGF is not necessarily associated with an inhibition of differentiation. This result may have relevance to understanding the paradox posed by the combined observations that bFGF, along with other members of the FGF family, appear to be abundantly expressed in the CNS during development, yet oligodendrocytes nonetheless are generated in vivo. In addition, the differing effects of exposure to bFGF we observed in heterogeneous optic nerve cultures vs. cultures of purified O‐2A progenitors underscore the importance of utilizing purified cell cultures to examine the direct effects of a particular factor on differentiation, in concert with the use of heterogeneous cultures to examine the complex situations which may more closely resemble the biology of the intact organism. © 1993 Wiley‐Liss, Inc.
A blood‐derived attachment factor enhances the in vitro growth of two glial cell types from adult cockroach
Authors: Howes E. A. , Armett‐Kibel C. , Smith P. J. S.
Published: January 2005

Reactive glial cells from chemically‐lesioned areas of the central nervous system (CNS) of adult cockroaches (Periplaneta americana) have been grown in vitro on a substrate of fibronectin. This paper reports the enhancement of growth that is achieved when blood cells, serum, or medium conditioned by a 2‐h incubation with blood cells are used as an alternative substrate. Glial cells rapidly grew out from connective explants to form extensive radial mats of cells linking up with those from adjacent explants on each of the blood‐derived substrates. In addition to supporting the growth of reactive glial cells, characterised by their long, thin, branching morphology, these substrates also revealed the presence of a second type of glial cell, not previously found on fibronectin. Such cells, derived from ganglionic explants, behaved in a very different way to the reactive glia, initially spreading out to form a flattened sheet of phase‐bright cells, before migrating away over the culture surface. The growth‐enhancing effects of this blood‐derived factor may play a role in the events following damage to the insect CNS, where it is known that the entry of blood cells into the lesion site is an important precursor to the rapid and structured repair seen in this system. © 1993 Wiley‐Liss, Inc.
Muscarinic acetylcholine receptor‐expression in astrocytes in the cortex of young and aged rats
Authors: van der Zee E. A. , de Jong G. I. , Strosberg A. D. , Luiten P. G. M.
Published: January 2005

The present report describes the cellular and subcellular distribution pattern of immunoreactivity to M35, a monoclonal antibody raised against purified muscarinic acetylcholine receptor protein, in astrocytes in the cerebral cortex of young and aged rats. Most M35‐positive astrocytes were localized in the superficial layers of the cortex and part of the corpus callosum. At the ultrastructural level, immunoprecipitates were localized in the Golgi complexes, but the nucleus, rough endoplasmic reticulum, mitochondria, and microfilaments were generally free of labeling. Labeling was also present associated to the cell membrane, although without the characteristic immunoreactive postsynaptic membrane thickening found in neuronal structures. In aging rats of 30‐34 months, the number of M35‐labeled astrocytes doubled, whereas the neuronal staining slightly decreased in the same region in half of the animals studied. Fluorescent double‐labeling for M35 and GFAP, an astrocytic microfilament protein, revealed that all M35‐positive glial cells express GFAP and, conversely, that almost all GFAP glial cells were M35‐immunostained. Based on the high incidence of coexpression of mAChRs and GFAP, both proteins may be functionally linked to each other. Rough semiquantitative estimates revealed that in young adult rats the GFAP/M35‐immunoreactive astrocytes made up approximately one fifth of all cortical astrocytes. An important aspect of the presently demonstrated immunoreactivity of astroglia to mAChR proteins is its labeling in situ instead of in tissue culture. This finding may further support investigation, e.g., on anatomical relations of astroglia with neuronal and vascular elements, and its reactivity in experimental conditions. © 1993 Wiley‐Liss, Inc.
Lymphokine induction of rat microglia multinucleated giant cell formation
Authors: Lee Thomas T. , Martin Fredricka C. , Merrill Jean E.
Published: January 2005

Multinucleated giant cell formation (MNGC) occurs in central nervous system AIDS. The mechanism of fusion of microglia in these cases is unknown. We investigated the ability of lymphokines to induce fusion and found that interleukin‐3 (IL‐3), interleukin‐4 (IL‐4), gamma interferon (γ‐IFN), and granulocyte‐macrophage colony stimulating factor (GM‐CSF) induced MNGC formation in cultures of rat microglia in vitro. The diacylglycerol analogue phorbol myristate acetate (PMA) also induced MNGC. Interleukin‐1 (IL‐1), interleukin‐6 (IL‐6), and tumor necrosis factor alpha (TNFα) failed to induce fusion. Preincubation of the IL‐3 treated cultures with anti‐IL‐3, anti‐leukocyte function associated antigen‐1 (LFA‐1) α‐chain (CD11a), and anti‐intercellular adhesion molecule‐1 (ICAM‐1) inhibited cell fusion. Antibody to polymorphic Class II major histocompatibility complex (MHC) determinants also inhibited MNGCs. Cell surface LFA‐1 was predominantly observed on MNGC, suggesting that LFA‐1 expression is involved in microglia fusion. We thus propose that MNGC formation of microglia result from the effects of T cell‐derived cytokines probably through the induction of cell surface adhesion molecules. © 1993 Wiley‐Liss, Inc.
Myelination by mature ovine oligodendrocytes in vivo and in vitro: Evidence that different steps in the myelination process are independently controlled
Authors: Ludwin Samuel K. , Szuchet Sara
Published: January 2005

The ability of isolated mature post‐myelination ovine oligodendrocytes to myelinate was investigated in tissue culture and in vivo. In culture, although the cells adhered preferentially to rat dorsal root ganglia (DRG) axons, sent out processes that encircled and wrapped them, proliferated, and synthesised myelin proteins (MBP), no myelination was found. This failure to find myelination occurred despite the fact that the oligodendrocytes both in the present experiments and in previous studies elaborated membranous structures that have been shown chemically and structurally to be similar to normal central nervous system myelin. These findings contrasted with those seen when neonatal rodent glial cells were added to similar DRG neuron cultures, in which myelination readily occurred. When the same adult ovine oligodendrocytes were transplanted into the brains of Shiverer mice, normal compact myelin was formed, proving that the cells were capable of myelination and suggesting that cross‐species incompatibility was probably not a major factor in the lack of myelination in vitro.

It is possible that the failure of ovine oligodendrocytes to myelinate DRG axons is due either to the relatively low number of supporting glial cells, such as astrocytes or microglia which may be necessary for satisfactory myelination, or that some other factor in the microenvironment is lacking; in any event, these results point to the complexity of oligodendrocyte‐axon interactions. It is clear that each of the events, from adherence to proliferation to wrapping and the myelin compaction may be under the control of a different signal and may operate through a distinct mechanism, even though each process is dependent on the other. The results also point to the potential usefulness of this model system for deciphering such signals and mechanisms. © 1993 Wiley‐Liss, Inc.
Axons modulate the expression of transforming growth factor‐betas in Schwann cells
Authors: Scherer Steven S. , Kamholz John , Jakowlew Sonia B.
Published: January 2005

We have investigated the expression of transforming growth factor (TGF)‐β1,‐β2, and ‐β3 in developing, degenerating, and regenerating rat peripheral nerve by immunohistochemistry and Northern blot analysis. In normal adult sciatic nerve, TGF‐β1, ‐β2, and ‐β3 are detected in the cytoplasm of Schwann cells, and the levels of TGF‐β1 and ‐β3 mRNAs are constant during post‐natal development. When sciatic nerves are transected to cause axonal degeneration and prevent axonal regeneration, the level of TGF‐β1 mRNA in the distal nerve‐stump increases markedly and remains elevated, whereas the level of TGF‐β3 mRNA falls modestly and remains depressed. When sciatic nerves are crushed to cause axonal degeneration and allow axonal regeneration, the level of TGF‐β1 mRNA initially increases as axons degenerate, and then falls as axons regenerate. TGF‐β2 mRNA was not detected in developing or lesioned sciatic nerves at any time. Cultured Schwann cells have high levels of TGF‐β1 mRNA, the amount of which is reduced by forskolin, which mimicks the effect of axonal contact. These data demonstrate that Schwann cells express TGF‐β1, ‐β2, and ‐β3, and that TGF‐β1 and ‐β3 mRNA predominate over TGF‐β2 mRNA in peripheral nerve. Axonal contact and forskolin decrease the expression of TGF‐β1 in Schwann cells. © 1993 Wiley‐Liss, Inc.
Differential activation of microglia and astrocytes in aniso‐ and isomorphic gliotic tissue
Authors: Fernaud‐Espinosa Isabel , Nieto‐Sampedro M. , Bovolenta P.
Published: January 2005

Reactive astrocytes and microglial cells are both involved in the formation of gliotic tissue. Using immunohistochemical markers, we have compared the response of both these cell types after two different kinds of damage in the brain: traumatic injury (anisomorphic gliosis) and neurotoxic induced lesion (isomorphic gliosis), in two distinct regions of the brain, the cortex and the hippocampus. We show that the time course and the relative contribution of astrocytes and microglial cells differ greatly in the two kinds of lesions. While in anisomorphic gliosis there is little activation of endogenous microglial cells independently of the brain region damaged, these cells contribute in large measure and for prolonged periods of time to the formation of isomorphic gliotic tissue. Astrocytes are quickly activated at the border of anisomorphic lesions, and after 3 days they already occupy an extensive portion of the brain parenchyma. However, after 1 month, they are found restricted to a thin strip at the lesion boundary. In contrast, after an isomorphic lesion, astrocytes become reactive around the site of neuronal cell loss but not at the site of the lesion itself. Only after 2 weeks do they totally invade the damaged region, persisting for at least 1 month. Such differences are observed independently of the brain region damaged.

These results suggest that the cellular, and therefore the molecular, composition of gliotic tissue depends on the type of insult the CNS has suffered. © 1993 Wiley‐Liss, Inc.
Native astrocytes do not migrate de novo or after local trauma
Authors: Hatton James D. , Finkelstein Jeremy P. , Sang U Hoi
Published: January 2005

While transplanted astrocytes migrate in specific patterns in therecip‐ient brains, it is not known whether native astrocytes behave similarly. The ability of normal astrocytes to migrate under non‐transplant condition was therefore explored. Native astrocytes were labelled in situ with fluorescent latex beads. These latex spheres were actively endocytosed by astrocytes in vitro, and it was therefore anticipated that these spheres would also be endocytosed by native astrocytes exposed to them. Labelling was accomplished by dissecting the pia mater away from a small region of the cerebral cortex and overlaying the area with Gelfoam containing fluorescent beads. After 2–4 h, the Gelfom was removed and the wound was cloesd. At the end of 2–4 weeks, manipulated brains were harvested for fluorescence microscopy. In this analysis, fluorescent polyspheres had been taken up by both pial fibroblasts and astrocytes at the pial‐glial margin. Labelled astrocytes [identified by glial fibrillary acidic protein (GFAP) staining] were neither hyperplastic nor hypertrophic. They were confined to the area of the original labelling site, and did not migrate either laterally across the pial margin or ventrally into the cortical layers. Knife wounding at the time of label application, either in the region of the label or distant from it, produced reactive astrocytes that were hypertrophic. These cells also did not migrate from the label site. These results suggest that astrocytes labelled by this method do not migrate in the absence of some transplant‐derived stimulus even when stimulated by local wounding. © 1993 Wiley‐Liss, Inc.
Lines of glial precursor cells immortalised with a temperature‐sensitive oncogene give rise to astrocytes and oligodendrocytes following transplantation into demyelinated lesions in the central nervous system
Authors: Trotter Jacqueline , Crang A. John , Schachner Melitta , Blakemore William F.
Published: January 2005

Immortalised lines of murine glial precursor cells expressing the neomycin resistance gene and a temperature‐sensitive mutation of the SV 40 T oncogene were established from cultures of oligodendrocytes and precursor cells infected with a replication‐incompetent, helper‐free retrovirus. At the permissive temperature (33°C), they could be continually propagated in vitro and cells were present expressing the 04 antigen specific for glial precursor cells and oligodendrocytes. At 38°C, where the expression of the T antigen is down regulated, cell division largely ceased. During early passage in vitro, limited differentiation to a more mature phenotype, as evidenced by expression of GFAP and the oligodendrocyte marker O1 was observed at both 33°C and 38°C. When transplanted into demyelinating lesions in the spinal cords of adult rats early passages of the lines yielded myelin‐forming oligodendrocytes and astrocytes. Cells from later passages of the lines although failing to synthesise myelin still associated specifically with the demyelinated axons. These experiments demonstrate the retention of physiological properties of these oncogene‐carrying glial cells when transplanted in vivo and suggest that such immortalised populations can be used for the isolation of molecules regulating glial cell function. © 1993 Wiley‐Liss, Inc.
Morphological heterogeneity of rat oligodendrocytes: Oligodendrocytes: Electron microscopic studies on serial sections
Authors: Bjartmar Carl , Hildebrand Claes , Loinder Kristina
Published: January 2005

The microanatomy of ensheathing and early myelinating rat oligodendrocytes was analyzed through electron microscopic examination of serial sections. The study included cells in the spinal cord (SC) ventral funiculus and the corpus callosum (CC), containing early myelinating, prospective large axons and late myelinating, prospective small axons, respectively. The results show that ensheathment commences fetal day (F) 19 in the SC and 12 days postnatally (P12) in the CC. By then, multipolar SC and CC oligodendrocytes provide axons with uncompacted cytoplasmic sheaths. The average number of axons ensheathed by each such cell was 7 in the SC and 13 in the CC. The mean diameter of the ensheathed axons was 0.69 μm in the SC and 0.36 μm in the CC. The formation of compact myelin had clearly been initiated at birth in the SC and at P17 in the CC. At that stage, the mean number of myelinated axons per analyzed oligodendrocyte was 3 in the SC and 15 in the CC. The mean diameter of the myelinated axons was 1.02 μm in the SC and 0.54 μm in the CC. These observations show that myelin‐related rat oligodendrocytes are morphologically heterogeneous. It also seems that this heterogeneity is related to time of onset of myelination and prospective axon diameter. Further, the data suggest that some oligodendrocytes reduce the number of sheaths initially elaborated before formation of compact myelin. © 1994 Wiley‐Liss, Inc.
Postural disturbance and psychological symptoms amongst elderly people living at home
Authors: Downton J. H. , Andrews K.
Published: January 2005

Many writers have commented on the frequency with which old people express fear of falls but this fear has not been quantified. As part of an epidemiological study of falls in the elderly living at home, 203 people over 75 years of age were questioned about falls experienced in the previous 12 months, fear of falling and symptoms of dizziness, and assessments were made of their mood, cognitive function, physical state, dependence and mobility. Fear of falling affected the same proportion of subjects as falls themselves (42.4%) and although there was an association between fear of falling and having experienced falls, a third of non‐fallers limited their activity because they were frightened of falling. Falls, fear of falling and subjective dizziness were strongly associated with anxiety and depression. Subdivision of fallers into outside and inside fallers or those who had fallen because of trips and ‘non‐trip’ fallers produced groups which differed in their physical frailty, mobility and dependence, but even the otherwise healthy and independent outside fallers and ‘trip’ fallers had high anxiety and depression scores. This may be an indication of the psychological impact of falls.
Psychotropics prescribed to the US elderly in the early and mid 1980s: Prescribing patterns of primary care practitioners, psychiatrists, and other physicians
Authors: Larson David B. , Lyons John S. , Hohmann Ann A. , Beardsley Robert S. , Hidalgo Julia
Published: January 2005

Primary care practitioners are significant providers of mental health services to older Americans. The most common mental health service provided by primary care practitioners to this segment of the population is psychotropic drugs. A USA national data base was analyzed to compare the psychotropic prescribing patterns of primary care practitioners with psychiatrists and other office‐based specialists in both the early and mid 1980s. Prescribing patterns for six different classes of psychotropics were contrasted for patients 55 years of age and older and those 15‐54. Results indicate that primary care practioners were by far the largest prescribers of psychotropics for patients 55 and over at both time periods. This pattern held for most of the individual psychotropic drug classes. In contrast to psychiatrists, primary care practitioners infrequently included a mental disorder diagnosis when they prescribed a psychotropic drug. In addition, primary care practitioners included a mental disorder diagnosis less frequently when they prescribed for the older group than when they prescribed for the younger group. These findings may be used to benefit the training of non‐psychiatrist physicians in the diagnosing and treating of mental health disorders found among older adults.
The cognitive drug research computerized assessment system for demented patients: A validation study
Authors: Simpson P. M. , Surmon D. J. , Wesnes K. A. , Wilcock G. K.
Published: January 2005

Demeneted elderly patients (N = 23, aged 60–94) and controls (N = 22, aged 52–86) performed a version of the Cognitive Drug Research computerized Assessment System comprising cognitive tasks measuring choice reaction time, vigilance, and the sensitivity and speed of digit, word and picture recognition. The demented patients showed large and highly significant impairments in the speed of choice reaction and in the sensitivity and speed of all memory tasks. Correlations between the various scores from the computerized tests and those from the Folstein Mini‐Mental State Examination, the Kendrick Battery and the Kew were high and significant, implying that the computerized tasks measure similar aspects of cognition to procedures used to assess dementia. In 16 memory clinic patients, high correlations were also found between the Stockton Rating Scale and the scores from the computerized tests, suggesting that the latter have relevance to the general behavioural condition of the patients. These findings, together with evidence of good test‐retest reliability, indicate that, for demented patients, the utility of this system to assess cognitive change should be comparable to that of previous versions used with the young and with non‐demented elderly.
The detection of psychiatric morbidity and its effects on outcome in acute elderly medical admissions
Authors: Ramsay Rosalind , Wright Penelope , Katz Anthony , Bielawska Celia , Katona Cornelius
Published: January 2005

This study examines the point prevalence of psychiatric morbidity in patients admitted to acute geriatric care, the performance of screening questionnaries in detecting psychiatric morbidity and the relationship between psychiatric morbidity and outcome (in terms of length of hospital admission and mortality) after controlling for severity of physical illness. In a sample of 119 consecutive admissions, 65 (61%) of the 106 patients assessed had dementia, while nine (10%) of the 88 assessed had a diagnosis of depression and a further 35 (40%) significant depressive symptoms, and 22 (20%) of the 106 assessed had delirium. Screening with the Mini‐Mental State Examination had 81% sensitivity and 83% specificity for dementia. The Geriatric Depression Scale (GDS) had 74% sensitivity and 72% specificity for depressive symptoms; both the GDS and General Health Questionnaire had 100% sensitivity for depressive illness. Mortality was significantly higher in the delirious (62%) than in the non‐delirious (14%,p>0.001) and in the severely demented (65%) than the mildly demented (29%) and non‐demented (15%,p>0.001) subjects. For delirium this effect was found to be independent of the severity of physical illness. Patients with severe dementia had significantly longer hospital admissions (p>0.02). No relationship was found between depression and outcome.
Modification of the mini‐mental state examination for use with the elderly in a non‐western society. Part II: Cutoff points and their diagnostic validities
Authors: Park Jong‐Han , Park Young Nam , Ko Hyo Jin
Published: January 2005

Diagnostic power of the Korean version of the Mini‐Mental State Examination (MMSE‐K) (Park and Kwon, 1990) for DSM‐III‐R dementia was studied in 406 persons aged 60 years or more from three sources. Psychiatric clinic patients (N=177) were diagnosed using standard clinical procedures, laboratory tests and psychological tests; in residential home elderly (N=128) consensus diagnoses were reached by two psychiatrists after joint interviews using the CAMDEX (Roth et al., 1988) including physical examinations but without laboratory tests; and members of psychiatric patients' families (N=101) were diagnosed after a brief psychiatric interview and assessment of activities of daily living by one psychiatrist. At the cutoff point of 24/23 of MMSE‐K score, sensitivity was 92.0% and specificity 91.5%. 23.9% of demented people and 39.3% of non‐demented obtained similar scores between 20 and 26. With the introduction of the arbitrary criteria of ‘questionable dementia’ (MMSE‐K score 21‐24) the false positive rate was reduced to 1% and the false negative rate to 3%. 74% of males with ‘questionable dementia’ scores were clinically demented while only 12% of females with the same scores were demented.
Risk factors for clinically diagnosed alzheimer's disease
Authors: Baker F. M. , Jordan Barry , Barclay Laurie , Schoenberg Bruce S.
Published: January 2005

Thirty‐six cases of patients with clinically diagnosed Alzheimer's disease (CDAD) were identified from the dementia clinic of the Burke Rehabilitation Center. Controls were identified from the rehabilitative units of the same facility. Controls were matched for age within 5 years, sex, race, marital status, status at time of surrogate interview (case alive or dead), and the absence of dementia.

Birth in an urban versus a rural environment (OR = 16), childhood in an urban versus a rural environment (OR = 9.5), and adult life in an urban versus a rural environment (OR = 16) were associated with an increased risk to develop CDAD. The daily or weekly use of beef/pork (OR = 4) and saccharin (OR = 2.25) were associated with an increased risk to develop CDAD as was the ownership of a pet rabbit (OR = 2). Further, a history of other cancers (OR = 3) in cases with CDAD was associated with an increased risk to develop CDAD. Type A personality characteristics were found to be associated with an increased risk (‘ate fast’ (OR = 3.5)), ‘not relaxed and easy‐going’ (OR = 2.25), ‘always rushed’ (OR = 2.00) to develop CDAD as was a history of depression (OR = 2). Due to the small sample size, statistically meaningful confidence intervals could not be calculated and our results must be confirmed in larger samples of case control pairs.
The depressed elderly chinese living in the community: A five‐year follow up study
Authors: Kua Ee Heok
Published: January 2005

In 1985 a random sample of 612 elderly Chinese aged 65 and over living in the community in Sigapore was interviewed using the GMS‐AGECAT package. The survey identified 35 cases and 28 subcases of depressive disorder. Five years later only 31 cases could be traced; in this subsample 10 were still depressed (32.3%), eight had recovered (25.8%), five were categorized as subcases of depression (16.1%), two were diagnosed as anxiety disorder (6.5%), one case was diagnosed as having dementia (3.2%) and five had died (16.1%). Only 25 subcases from the initial study could be traced; of these, three had developed depression (12.0%), 15 had recovered (60.0%), four remained as subcases (16.0%) and three had died (12.0%).
Application of the scaled subprofile model to functional imaging in neuropsychiatric disorders: A principal component approach to modeling brain function in disease
Authors: Alexander Gene E. , Moeller James R.
Published: January 2005

Recent advances in functional neuroimaging have presented a challenge to traditional statistical methods in characterizing the effects of neuropsychiatric illness on brain function. The most common approach for analyzing regional group differences has relied on t‐tests with significance thresholds selected to reduce the potential effect of multiple statistical tests. Regional covariance analysis offers an alternative to this threshold‐based, group difference approach by identifying the functional interactions among brain regions that can be spatially distributed throughout the brain. The Scaled Subprofile Model (SSM) is one form of regional covariance analysis that has been applied to the study of patient groups. Based on a modified principal component analysis, the SSM offers a method for modeling regionally specific patterns of brain function whose expression can be evaluated between groups and validated against clinical measures of patient disease severity and neuropsychological test scores. We review the application of the SSM, to date, in studies of the effects of neurological and psychiatric illness on brain function, including a discussion of SSM methodology and its application to the study of resting state functional neuroimaging in patient groups. SSM analyses applied to studies of Alzheimer's disease, Parkinson's disease, major depressive disorder, AIDS dementia complex, and neoplastic disease each identified functionally specific topographic effects that were associated with clinical disease severity. The results of the SSM analyses suggest that neuropsychiatric disorders may alter functional networks or systems of neural activity in ways that can be expressed as regional covariance patterns in resting functional imaging data. © 1994 Wiley‐Liss, Inc.
Regional cerebral glucose metabolism in huntington's disease: A statistical investigation
Authors: Clark Campbell M. , Kremer Barry , Hayden Michael R.
Published: January 2005

To optimize the information obtained in 18fluorodeoxyglucose (FDG) studi8es of human cerebraql metabolism, sources of metabolic variation should be identified and their relevance to clinical pathology and disease course determined. Specifically, although a definitive a priori hypothesis may be postulated in a given study, the sensitivity of a stativity of a statistical procedure for detecting differences may be compromised if the sources of variability in the dependent variable are not fully understood. The purpose of this paper is to illustrate these statements using data derived from normal subjects, patients with symptomatic Huntington's diesase, and patients at risk for Huntington's disease. With respect to positron emission tomography (PET) and FDG, a number of centers have published their findings. Although there is a general consensus that reductions in caudate metabolism are present, there is considerable debate regarding the time in the disease course such reductions occur, the best procedure for measuring such reductions, and the sensitivity of the PET/FDG methodology as a means of monitoring disease progression. The resolution of thses issues is hampered by the large variation among individuals in time of onset and severity of disease course. Because of these properties, statistical examination of regional cerebral metabolism data in Huntington's disease may provide insight into the most efective procedures for maximizing data yield. © 1994 Wiley‐Liss, Inc.
Data analysis paradigms for metabolic‐flow data: Combining neural modeling and functional neuroimaging
Authors: Horwitz Barry
Published: January 2005

Two primary data analysis techniques are used with functional neuroimaging data: the subtraction paradigm and the covariance paradigm. The first is based on the assumption that a brain region participating in a specific task should show altered neural activity (relative to a control task). The second, which is not mutually contradictory with the first, assumes that tasks are mediated by networks of interacting regions and that different tasks involve differences in the pattern of functional connections among brain regions. The neurobiological assumptions governing each paradigm and the kinds of questions each seeks to address are discussed. Illustrations of each technique using positron emission tomographic data of a blood flow study of visual processing are given. The use of neural modeling techniques for analyzing functional neuroimaging data is also discussed, with explicit reference to such systems‐level approaches as structural equation modeling. © 1994 Wiley‐Liss, Inc.
Biliary epithelial cells regulate autoreactive T cells: Implications for biliary-specific diseases
Authors: Kamihira Takashi , Shimoda Shinji , Nakamura Minoru , Yokoyama Teruhumi , Takii Yasushi , Kawano Akira , Handa Mizuki , Ishibashi Hiromi , Gershwin Eric M. , Harada Mine
Published: January 2005

The biliary epithelial cell (BEC) is the target for several human immune mediated liver diseases, including primary biliary cirrhosis, but it is not always clear whether the BEC functions as an accessory cell or an antigen presenting cell, although it is well documented that BECs express high levels of human leukocyte antigen Class II, intercellular adhesion molecule-1, and lymphocyte function–associated antigen-3. To examine this issue, we established autoreactive T-cell clones from human leukocyte antigen–DR53 patients with primary biliary cirrhosis and characterized BEC function as a function of the ability of BECs to regulate T-cell activation. We report herein that BEC-mediated T-cell activation occurs partially via programmed death 1 ligands in a cell-contact–dependent manner. Further, such activation occurs via prostaglandin E2 production in a cell-contact–independent fashion. Moreover, the production of prostaglandin E2 was partially controlled by interleukin-1β and tumor necrosis factor α.
In conclusion,

the regulatory activities of BECs are important for the maintenance of peripheral immune tolerance. Further, modulation of BEC function may be used for therapeutic modulation. (Hepatology 2005;41:151–159.)
Elevated prevalence of hepatitis C infection in users of United States veterans medical centers
Authors: Dominitz Jason A. , Boyko Edward J. , Koepsell Thomas D. , Heagerty Patrick J. , Maynard Charles , Sporleder Jennifer L.
Published: January 2005

Several studies suggest veterans have a higher prevalence of hepatitis C virus infection than nonveterans, possibly because of military exposures. The purpose of this study was to estimate the prevalence of anti–hepatitis C antibody and evaluate factors associated with infection among users of Department of Veterans Affairs medical centers. Using a two-staged cluster sample, 1,288 of 3,863 randomly selected veterans completed a survey and underwent home-based phlebotomy for serological testing. Administrative and clinical data were used to correct the prevalence estimate for nonparticipation. The prevalence of anti–hepatitis C antibody among serology participants was 4.0% (95% CI, 2.6%-5.5%). The estimated prevalence in the population of Veterans Affairs medical center users was 5.4% (95% CI, 3.3%-7.5%) after correction for sociodemographic and clinical differences between participants and nonparticipants. Significant predictors of seropositivity included demographic factors, period of military service (

e.g.
, Vietnam era), prior diagnoses, health care use, and lifestyle factors. At least one traditional risk factor (transfusion or intravenous drug use) was reported by 30.2% of all subjects. Among those testing positive for hepatitis C antibody, 78% either had a transfusion or had used injection drugs. Adjusting for injection drug use and nonparticipation, seropositivity was associated with tattoos and incarceration. Military-related exposures were not found to be associated with infection in the adjusted analysis.
In conclusion,

the prevalence of hepatitis C in these subjects exceeds the estimate from the general US population by more than 2-fold, likely reflecting more exposure to traditional risk factors among these veterans. (Hepatology 2005;41:88–96.)
Quantitative isolation of α1AT mutant Z protein polymers from human and mouse livers and the effect of heat
Authors: An Jae-Koo , Blomenkamp Keith , Lindblad Douglas , Teckman Jeffrey H.
Published: January 2005

Alpha-1-antitrypsin (α1AT) deficiency in its most common form is caused by homozygosity for the α1AT mutant Z gene. This gene encodes a mutant Z secretory protein, primarily synthesized in the liver, that assumes an abnormal conformation and accumulates within hepatocytes causing liver cell injury. Studies have shown that mutant α1ATZ protein molecules form unique protein polymers. These Z protein polymers have been hypothesized to play a critical role in the pathophysiology of liver injury in this disease, although a lack of quantitative methods to isolate the polymers from whole liver has hampered further analysis. In this study, we demonstrate a quantitative α1ATZ polymer isolation technique from whole liver and show that the hepatocellular periodic acid-Schiff–positive globular inclusions that are the histopathological hallmark of this disease are composed almost entirely of the polymerized α1ATZ protein. Furthermore, we examine the previously proposed but untested hypothesis that induction of α1ATZ polymerization by the heat of physiological fever is part of the mechanism of hepatic α1ATZ protein accumulation. The results, however, show that fever-range temperature elevations have no detectable effect on steady-state levels of intrahepatic Z protein polymer in a model

in vivo

system.
In conclusion,

methods to separate insoluble protein aggregates from liver can be used for quantitative isolation of α1ATZ protein polymers, and the effect of heat from physiological fever may be different

in vivo

compared with

in vitro

systems. (Hepatology 2005;41:160–167.)
Local circuit synaptic interactions between CA1 pyramidal cells and interneurons in the kainate‐lesioned hyperexcitable hippocampus
Authors: Nakajima S. , Franck J. E. , Bilkey D. , Schwartzkroin P. A.
Published: January 2005

Following kainate (KA)‐induced lesions of subfield CA3–a lesion relevant to human temporal lobe epilepsy–remaining pyramidal cells in CA1 display synchronous hyperexcitability associated with a loss of synaptic inhibition. Despite this loss, inhibitory interneurons in CA1 remain viable, and the density and function of GABAergic receptors on the CA1 pyramidal cells are maintained at approximately normal levels.

To further evaluate inhibition in this system, the authors examined interactions between pyramidal cells and inhibitory interneurons in paired intracellular recordings. Recordings were carried out in rat hippocampal slices 2–4 weeks following bilateral intraventricular KA injections. The frequency of synaptic interactions between CA1 basket cells and pyramidal cells was lower in hyperexcitable slices than in controls; both synapses in the recurrent inhibitory circuit appeared to be involved. No recurrent excitatory interactions were seen between pyramidal cell pairs in lesioned or normal slices.

The weakened interconnections between pyramidal cells and interneurons are consistent with the decreased inhibition previously found in the model. Unexpectedly, strong stimulation, which may directly activate local inhibitory circuitry, was effective in reducing hyperexcitability in KA‐lesioned slices. These data suggest that development of recurrent excitatory connections among CA1 hippocampal pyramidal cells contribute little to tissue excitability, and support the hypothesis that a functional uncoupling between inhibitory interneurons and CA1 pyramidal cells is responsible for the seizure‐like activity typical of KA‐lesioned hippocampus. The data are also consistent with the hypothesis that in the KA model, the structural circuitry needed for inhibition in CA1 is maintained, and can be functionally activated by appropriate stimuli.
Long‐term enhancement of CA1 synaptic transmission is due to increased quantal size, not quantal content
Authors: Foster T. C. , McNaughton B. L.
Published: January 2005

Quantal components of Schaffer collateral synaptic transmission recorded intracellularly from CA1 pyramidal cells were examined using 2 methods: simultaneous recordings of CA3‐CA1 cell‐pairs, and minimal electrical stimulation in stratum radiatum. Quantal parameters estimated by the method of failures and by a computer algorithm that optimized parameter estimates using deconvolution of background noise were highly correlated. EPSP‐amplitude histograms of CA3‐CA1 cell pairs (N = 10) and minimal electrical stimulation (N = 33) could be adequately described either by Poisson or binomial statistics, or by both, and exhibited similar estimates of unit quantal size (q) and mean quantal content (m). Paired‐pulse stimulation with 50 msec between stimuli resulted in an expected facilitation in the EPSP amplitude and increase in m during the second response, as estimated by noise deconvolution, by the decrease in apparent failures, and by a decrease in the coefficient of variation of the EPSP. Tetanization of the Schaffer collaterals that induced long‐term enhancement (LTE/LTP) of the population response was associated with an average increase in q for minimal‐stimulation responses, with no significant change in any estimate of m. Taken together, these data indicate that, under the present experimental conditions, LTE is expressed as an increase in quantal size, rather than an increase in the number of quanta released per presynaptic impulse. Although this is not definitive evidence for a postsynaptic mechanism, these findings do further restrict the classes of possible presynaptic mechanisms that may be proposed to account for LTE expression.
Hippocampal mossy fibers and swimming navigation in mice: Correlations with size and left‐right asymmetries
Authors: Bernasconi‐Guastalla Sonja , Wolfer David P. , Lipp Hans‐Peter
Published: January 2005

Individual differences in the extent of the infrapyramidal mossy fiber porjection (IIP‐MF) correlate with performance in tasks sensitive to hippocampal lesions, notably two‐way avoidance, radial maze learning, and swimming navigation. Previous studies of swimming navigation suggested that the capacity of reversal learning and measures of directionality might also be related to asymmetries in the distribution of the IIP‐MF. In order to verify these findings, the authors crossed the Collins High‐ and Low‐lateralized mice (known to differ in mossy fiber morphology and brain asymmetries) and obtained a F2‐generation characterized by strong individual differences in these traits. Twenty‐three (13 females, 10 males) mice were tested during 3 days for acquisition of swimming navigation (16 trials) toward a central platform, and during two days (12 trials) for their capacity of reversal learning toward a shifted platform. Morphometry of Timm‐stained hippocampi revealed several, partially independent correlations: Larger IIP‐MF projections were associated with prolonged crossing over the former platform position during the entire reversal learning; larger IIP‐MF projections on the left were correlated with more precise crossing of the former platform position during the first 45 seconds of reversal learning; both extent and asymmetry of IIP‐MF correlated positively with overnight improvement of reversal learning; the size of the entire mossy fiber projection (CA4, suprapyramidal and IIP‐MF) correlated positively with the time spent in the platform quadrant and measures of initial orientation during acquisition of the task; and the mice showed an ipsilateral turning bias (spin) toward the side with the larger mossy fiber projection. The authors conclude that an intact hippocampus mediates differential processes underlying swimming navigation, and that left and right subfields may have differential functions.
Electrophysiological effects of mu‐selective opioids on hilar neurons in the hippocampus in vivo
Authors: Mayer Joseph H. , Henriksen Steven J.
Published: January 2005

Although mu‐selective opioids have been shown to produce dramatic effects on neurons within the CA1 and dentate regions of the rat hippocampus, little is known regarding their effects on neurons within the hilus, a region of potential importance in several disease states. We studied the neurophysiologic responses of hilar neurons recorded extracellularly to electrophoretic [D‐Ala2, NMe‐Phe4, Gly‐ol]‐enkephalin (DAMGO) and systemic morphine (MS) in anesthetized rats. We found that hilar cells could be readily divided into two categories, based on their pattern of spontaneous activity and response to perforant path stimulation. Cells that discharged in a bursting‐type pattern formed a homogeneous group electrophysiologically. The response of these cells to opioids was dependent on route of administration, with the spontaneous activity of all cells tested increasing following electrophoretically administered DAMGO, and remaining unchanged in response to systemic MS. Cells that discharged in a non‐bursting pattern showed some electrophysiologic variation, as well as some differential response to opioids. However, the spontaneous activity in the majority of non‐bursting cells increased following electrophoretic administration of DAMGO. In these cells, MS produced similar, although usually less dramatic, effects. Comparison with intracellular data suggests that the bursting cells in our study correlate most closely with hilar “mossy cells,” while the non‐bursting action potentials were recorded from other cells, primarily putative interneurons. We conclude that mu‐selective opioids produce excitation of mossy cells, probably through an indirect mechanism, with the primary site of action occurring on cells in the granule cell layer. This regional excitation may help to mediate the effects of locally administered mu‐selective opioids within the dentate gyrus. © 1995 Wiley‐Liss, Inc.
Similarities vs. differences in place learning and circadian activity in rats after fimbria‐fornix section or ibotenate removal of hippocampal cells
Authors: Whishaw Ian Q. , Jarrard Leonard E.
Published: January 2005

Damage to either the fimbria‐fornix or to the hippocampus can produce a deficit in spatial behavior and change in locomotor activity but the extent to which the two kinds of damage are comparable is not known. Here we contrasted the effects of cathodal sections of the fimbria‐fornix with ibotenic acid lesions of the cells of the hippocampus (Ammon's horn and the dentate gyrus) on place learning in a swimming pool and on circadian activity. Rats in both ablation groups were impaired relative to control rats in learning a single place response but they did acquire the response as measured by swim latencies, errors, and by enhanced searching on probe trials. They were also more active than the control group on the test of activity. Nevertheless, the fimbria‐fornix group was initially more impaired on learning and was more active than the hippocampal group. Analysis of the strategies used in learning indicated that the lesion groups were very similar to each other but different from the control group especially in that at asymptotic performance, rats in both lesion groups made rather tight loops as they swam toward the platform. This strategy likely contributed to the greater proportion of time they spent swimming in the correct quadrant on the subsequent probe trial. These findings confirm that rats with fimbria‐fornix or hippocampal damage display impairments in place learning and are hyperactive but also show that there are lesion differences. The results are discussed with respect to the relative effectiveness of the lesions and the possibility that fibers in the fimbria‐fornix may mediate some functions that are not attributable to the hippocampus. © 1995 Wiley‐Liss, Inc.