bluuebunny/crossref_metadata_2025 huggingface dataset:
Modulation of schwann cell phenotype by TGF‐β1: Inhibition of P0 mRNA expression and downregulation of the low affinity NGF receptor
Authors: Mews Michaela , Meyer Michael
Published: January 2005

The phenotype of a fully differentiated, mature Schwann cell is appar‐ently largely determined by Schwann cell‐axon interactions. In vitro, elevation of intra‐cellular cAMP levels in Schwann cells induces a phenotype which resembles that of a mature, i.e., axon‐related, Schwann cell. Therefore, an important role for cAMP as a second messenger of axon‐Schwann cell interactions in vivo is assumed.

However, the effects of cAMP on Schwann cells are not restricted to induction of features of a mature phenotype. For example, elevation of intracellular cAMP levels results of also in a markedly increased synthesis of nerve growth factor (NGF) mRNA, which is barely detectable in intact sciatic nerves of adult animals. Furthermore, since cAMP induces myelin gene expression in cultured Schwann cells, additional regulatory mechanisms have to be postulated for the induction and maintenance of a mature non‐myelinating Schwann cell phenotype.

Here we show that a soluble protein “growth factor” can partially induce a non‐myelinating mature Schwann cell phenotype in vitro. Treatment with transforming growth factor β1 (TGF‐β1) results in a marked and rapid downregulation of the low affinty NGF receptor (NGFR) on cultured Schwann cells without induction of PO gene expression. In contrast, in agreement with previous studies, an increase in PO mRNA levels and a reduction in NGFR mRNA after cAMP elevation is much slower when compared with the effect of TGF‐β1, suggesting the involvement of different intracellular mechanisms. Consistent with this hypothesis, we did not observe an induction of mRNA coding for TGR‐β isoforms after cAMP elevation in cultured Schwann cells which constitutively synthesize TGF‐β1 mRNA. © 1993 Wiley‐Liss, Inc.
Transcellular retrograde labeling of radial glial cells with WGA‐HRP and diI in neonatal rat and hamster
Authors: Kageyama Glenn H. , Robertson Richard T.
Published: January 2005

Topographically distinct populations of radial glial cells in the diencephalon and mesencephalon of neonatal rats and hamsters were transcellularly labeled with wheat germ agglutinin conjugated to horseradish peroxidase (WGA‐HRP) and with the lipophilic tracer DiI. A comparison of the histological distribution of the two tracers is suggestive of two different mechanisms of transcellular labeling. Intraocular injections of WGA‐HRP resulted in the uptake of exogenously applied WGA‐HRP by retinal ganglion cells, followed by anterograde axonal transport and exocytosis within the optic target nuclei. In addition to the transneuronal labeling, which is typical of such injections, we observed the transcellular labeling of the processes and somata of radial glial cells that were topographically associated with the terminal fields of the labeled axons. Similar transcellular labeling of radial glial cells associated with the axon terminal fields of the colliculogeniculate projection to the medial geniculate nucleus was observed following injections of WGA‐HRP in the inferior colliculus. The transcellular labeling within the radial glial cells was discontinuous and somatopetally concentrated, indicating the existence of a retrograde active transport mechanism within the radial glial processes subsequent to its uptake following release of tracer from axons. This type of labeling can be referred to as transcellular retrograde glioplasmic transport. In contrast, DiI was used as a tracer through its capacity to diffuse within the plasmalemma. Topographically distinct populations of radial glial cells were transcellularly labeled following placements of DiI in the retina, inferior colliculus, or dorsal thalamus of fixed brains. The radial processes of labeled radial glial cells consistently extended into regions that also contained labeled axons. It is likely that the transcellular radial glial labeling with DiI occurred via transmembranous diffusion. These data indicate that a close structural and functional relation exists between axons and glial cells in the developing brain. © 1993 Wiley‐Liss, Inc.
Cellular expression of an HMGCR promoter‐CAT fusion gene in transgenic mouse brain: Evidence for a developmental regulation in oligodendrocytes
Authors: Duhamel‐Clerin E. , Villarroya H. , Mehtali M. , Lapie P. , Besnard F. , Gumpel M. , Lachapelle F.
Published: January 2005

The HMGCR gene encodes the 3‐hydroxy‐3‐methylglutaryl coenzyme A reductase, which is the key enzyme for cholesterol synthesis. Mice transgenic for the prokaryotic chloramphenicol acetyl transferase (CAT) reporter gene fused with a 5′ Bam H1 fragment including the promoter sequence for murine HMGCR gene have been obtained. Homozygote transgenic mice were derived from a particular line selected for similar regulation of endogenous HMGCR and the transgene expression by nutritional conditions in different tissue. In addition, high expression of the transgene was evidenced in the brain. Cellular expression of the CAT gene in the central nervous system (CNS) was investigated by immunohistochemistry (IHC). This study was performed on frozen sections of the developing and adult brain, using a rabbit anti‐CAT antiserum especially raised for that purpose. CAT expression was observed in some rare individuals in different neural cell types including Purkinje cells and astrocytes. But the most outstanding observation was the high level of CAT expression correlated with differentiated pattern of oligodendrocyte (01) distribution observed in white‐matter tracts. Double and triple labeling for CAT and stage‐specific antigens were performed on transgenic Ol‐enriched preparations and cultures. This study showed a normal sequence of differentiation in the transgenic oligodendroglial cell lineage and demonstrated a strict correlation between late differentiation and activation of the CAT gene in these cells: CAT expression started in transgenic Ols between galactocerebroside (GC)‐positive and myelin basic protein (MBP)‐positive stages and was detected in MBP‐positive cells during the myelination period. After myelination, the number of CAT‐positive Ols decreased in the adult brain. These observations demonstrate a developmental regulation of the CAT transgene in Ols during myelination in CNS and reinforce the hypothesis of endogenous synthesis as major source of cholesterol during myelination. © 1994 Wiley‐Liss, Inc.
Differences in a K current in schwann cells from normal and neurofibromatosis‐infected damselfish
Authors: Fieber Lynne A. , Schmale Michael C.
Published: January 2005

Patch clamp techniques were used to study whole cell ionic currents in Schwann cells (SC) from a tropical marine fish, the bicolor damselfish, Pomacentrus partitus. The bicolor damselfish is affected by a disease termed damselfish neurofibromatosis (DNF), being developed as an animal model of neurofibromatosis‐type 1 (NF1) in humans. NF1 affects SC, fibroblasts, and perineurial cells. The sole depolarization‐activated ionic current present in cultured SC from normal fish peripheral nerve and from neurofibromas of fish with induced or spontaneously occurring DNF was an inactivating K+ current (K current), with a strong dependence on the Nernst potential for K+. This K current activated at depolarizations to ‐40 mV and above and inactivated during a maintained test pulse (0.2‐1 s), but inactivation was significantly greater in tumored SC. Both currents were inhibited by 4‐aminopyridine (Kd  1 mM) and by dendrotoxin (15 μM) but were insensitive to extracellular tetraethyammonium (≤ 150 mM), indicating that the whole cell currents were similar pharmacologically. The currents could be distinguished on the basis of their sensitivity to depolarized holding potential, with normal cells less sensitive. Half‐inactivation of the current was ‐32 mV in normal cells and ‐38 mV in tumored cells. Inactivation curves constructed from the average normalized current for many SC were significantly different in normal and tumored cells. When the depolarized holding potential was maintained between test depolarizations, greater voltage‐dependent inactivation in tumored cells was apparent. Normal cells maintained an average of 36% of peak current at a holding voltage of −40 mV, while in tumored cells this average was 12%, a significant difference. © 1994 Wiley‐Liss, Inc.
Induction of type III‐deiodinase activity in astroglial cells by retinoids
Authors: Esfandiari Ali , Gagelin Claire , Gavaret Jean‐Michel , Pavelka Stanislav , Lennon Ana‐Maria , Pierre Michel , Courtin FrançOise
Published: January 2005

Thyroid hormones and retinoic acid (RA) are important modulators of growth, development, and differentiation. Type III deiodinase (D‐III), which catalyzes thyroid hormones degradation in the brain and in cultured astroglial cells, is induced in astroglial cells by multiple pathways, including cAMP, 12.0‐tetradecanoylphorbol‐13‐acetate (TPA), fibroblast growth factors, and thyroid hormones themselves. In the present study, the effects of retinoids on D‐III activity were examined in astroglial cells cultures in a chemically defined medium devoid of hormones and growth factors. Incubation of astroglial cells with 5 μM all‐trans‐RA caused up to 200‐fold increase in D‐III activity, which reached a plateau after 48 h. The retinoid‐induced increase in D‐III activity was concentration dependent (0.5 μM all‐trans‐RA and 9‐cis‐RA producing half‐maximal effect). Retinol was effective at physiological concentrations (1 and μM). The 48 h effects of 5 μM all‐trans‐RA and 10 nM thyroid hormones on D‐III activity were at least additive. Addition of 2 nM acidic fibroblast growth factor or 1 mM 8‐bromo‐cAMP for the last 8 h of a 48 h incubation with 5 μM all‐trans‐RA did not alter the induction by all‐trans‐RA, whereas 0.1 μM TPA in the same conditions produced an additive effect with all‐trans‐RA. All‐trans‐RA (5 μM) had little or no effect on type II deiodinase, the enzyme which catalyzes the activation of thyroxine to 3,5,3′‐triiodothyronine. The potent action of retinoids on the enzyme responsible for thyroid hormones degradation in the brain may protect the brain from the effects of 3,5,3′‐triiodothyronine in regions influenced by retinoids. © 1994 Wiley‐Liss, Inc.
Grief in old age: A review of the literature
Authors: Fasey Christopher Nigel
Published: January 2005

The literature on grief is reviewed with particular reference to old age. The characteristics of normal and abnormal grief are discussed and as far as possible a comparison between older and younger adults is made. The results are inconclusive but suggest that grief is a similar process in all adults but may be less malign in the over 65s. Whatever the differences, grief is a serious problem with a definite associated morbidity and mortality.
Religious coping and personality in later life
Authors: Koenig Harold G. , Siegler Ilene C. , Meador Keith G. , George Linda K.
Published: January 2005

A stratified random subsample of 100 older adults from long‐term participants of the Second Duke Longitudinal Study was interviewed concerning how they coped with three stressful event periods. Responses to open‐ended coping questions were categorized as religious or non‐religious in nature. Mean scores on 16 personality traits were compared between religious copers. Few differences were observed in personality scores between these groups. Compared with non‐religious copers, religious copers scored lower on factor E (less aggressive or hostile, more humble, submissive); there was also a tendency towards being higher on factor G (more responsible, conscientious, and moralistic). Over a six‐year period between wave 1 and wave 4, stability or change in personality was not related to coping style. No evidence was found for negative personality traits among older religious copers that have commonly been reported in younger religious individuals.
Kleine–Levin syndrome in a 74‐year‐old female
Authors: Brown R. , Malcolm M. T.
Published: January 2005

Kleine‐Levin syndrome characteristically occurs in young men. We describe a case in a 74‐year‐old woman suggesting that the syndrome may not be confined to a particular age group or to the male sex.
Deliberate self‐poisoning and self‐injury in older people
Authors: Hawton Keith , Fagg Joan
Published: January 2005

Patients aged 55 and over who were referred to a general hospital between 1976 and 1987 because of self‐poisoning or self‐injury were studied. The 675 individuals comprised 8.7% of suicide attempters of all ages. The mean annual rate of attempts in the 55‐64 year age group was almost double that of the 65+ age group. In the younger age group the female:male ratio of rates for the whole study period was 1.3, whereas in the older age group it was close to unity. Rates were highest in the divorced of both sexes and also high in single and widowed males. Married males had particularly low rates. Relatively few people were receiving psychiatric care at the time of their attempts. There was no evidence of any major change in rates of attempted suicide during the study period, unlike in younger people in whom rates have declined. However, there were changes in the substances used for self‐poisoning, with a very marked decline in the use of barbiturates and increasing use of non‐opiate analgesics, especially paracetamol. Repetition of attempts within one year of a first attempt during the study period occurred in nearly one in 10 cases.
Modification of the mini‐mental state examination for use in the elderly in a non‐western society. Part 1. Development of korean version of mini‐mental state examination
Authors: Park Jong‐Han , Kwon Yong Chul
Published: January 2005

The Mini‐Mental State Examination was modified for use in a non‐western elderly population and named the Korean Version of the Mini‐Mental State Examination (MMSE‐K). Study subjects were a group of normal subjects and a group of patients with functional mental disorders. Among the variables of age, sex, residence, education and diagnosis, education was the only factor found to influence total MMSE‐K scores. Among the component parts of the MMSE‐K, orientation in time, orientation in place, concentration/calculation and language function were significantly influenced by education. After adding one point to scores of orientation in time, two to scores of concentration/calculation and one to scores of language function in non‐educated individuals, differences between total scores and scores of the three items corrected lost statistical significance between the educated and non‐educated elderly groups. Cutoff points for cognitive impairment and their diagnostic validity are not presented in this article.
Total plasma 3‐methoxy‐4‐hydroxyphenylglycol (MHPG) in alzheimer patients. Comparison with depressives and normal controls
Authors: Azorin Jean M. , Michel Bernard , Chave Brigitte , Raucoules Daniel , Valli Marc , Lancon Christophe
Published: January 2005

Plasma levels of total 3‐methoxy‐4‐hydroxyphenylglycol (MHPG) were found to be significantly higher in patients with Alzheimer's disease (N = 20) than in age‐ and sex‐matched normal controls and dexamethasone‐resistant melancholic patients. Contrary to previous studies, the highest levels were not found in the most severely demented patients and this increase was not related to the duration of the illness. Although the significance of these findings remains unclear, they suggest that determination of total plasma MHPG may be useful in the differential diagnosis of Alzheimer's disease and depressive disorder.
Platelet membrane fluidity, family history, severity and age of onset in Alzheimer's disease
Authors: Eagger Sarah , Hajimohammadreza Iradj , Fletcher Keron , Levy Raymond , Brammer Michael
Published: January 2005

Platelet membrane fluidity values were assessed in three groups of subjects: (1) 15 Alzheimer's disease patients with a first‐degree family history of the disorder; (2) 16 Alzheimer's disease patients with no family history of the disorder; (3) 22 healthy control subjects. The distributions of platelet membrane fluidity changes were found to be the same in both Alzheimer disease groups, but none of the controls had raised platelet membrane fluidity

Severity of Alzheimer's disease as measured by Mini‐Mental State and Cambridge Cognitive Index scores correlated with platelet membrane fluidity values significantly for the non‐family history group but not for the family history group. There was no apparent association between raised platelet membrane fluidity and age of onset of Alzheimer's disease. There was no evidence to indicate that raised platelet membrane fluidity is a peripheral marker for familial Alzheimer's disease.
Social support in a general practice elderly sample
Authors: Lam Dominic H. , Power M. J.
Published: January 2005

In this study depressed elderly respondents were found to be more dissatisfied with their level of emotional and practical support than were non‐depressed respondents. However, unlike the findings obtained with younger populations, the depressed elderly subgroup were not found to have higher levels for the ideal amounts of support that they would like and, in fact, the majority of the elderly were satisfied with the level of social support that they received.
Computerized diagnosis from a standardized history schedule: A preliminary communication about the organic section of the HAS–AGECAT system
Authors: Dewey Michael E. , Copeland John R. M. , Lobo Antonio , Saz Pedro , Dia Jose‐Luis
Published: January 2005

This article presents the results of the application of a computerized diagnostic method (HAS–AGECAT) to a standardized psychiatric History and Aetiology Schedule (HAS) designed for use with older people. In a community sample from Zaragoza good agreement (kappa = 0.76) was obtained between HAS–AGECAT and the interviewing psychiatrist. The discrepant cases are discussed in detail.
Dementia: Questions of cost and value
Authors: Keen Justin
Published: January 2005

The importance of economic considerations in determining the quantity and quality of services for people with dementia is beyond dispute. As the pressure on the resources available for health and social care increases, the need to mount a strong case for adequate resources for dementia‐related services has become more pressing. The article reviews available evidence under three headings: the impact of dementia on national economies; its impact on individuals and their carers; and the costs and benefits of different models of service provision. It is concluded that there is evidence for the inadequacy of resources currently available; those resources could in many instances be better targeted; but there remain substantial gaps in our knowledge of the costs and benefits of different services and the likely long‐term impact of increases in the numbers of people with dementia.
Phobic disorders in the elderly: A comparison of three diagnostic systems
Authors: Lindesay James , Banerjee Sube
Published: January 2005

The case‐finding performances of three operationalized systems for identifying phobic disorder in the elderly (Geriatric Mental State (A) (GMSA)/AGECAT; DSM‐III; Phobic Disorders screen (PDS)) were compared in a sample of clients of a local authority community care service. There was considerable variation in the 1‐month prevalence rates (3.6%‐25.6%) according to the different criteria, and the concordances between various levels of case definition in the diagnostic systems demonstrated that this variation was due principally to different hierarchical diagnostic rules and severity criteria, including differing assumptions and expectations as to what constitutes a phobic disorder in old age.
Supporting everyday activities in dementia: An intervention study
Authors: Josephsson Staffan , Bäckman Lars , Borell Lena , Bernspång Birgitta , Nygård Louise , Rönnberg Lisa
Published: January 2005

The efficacy of an intervention programme designed to support performance in activities of daily living was investigated in four patients with dementia at different levels of severity of impairment. Important features of the programme included that (a) task conditions should be highly supportive, (b) the importance of episodic and semantic memory skills for successful performance should be minimized, (c) an acceptable performance level should be possible to achieve using skills that are relatively well preserved in the disease, and (d) factors related to patients' motivation and habits should be taken into account. Performance gains were evaluated using the Assessment of Motor and Process Skills instrument. Results showed intervention‐related gains in three patients. One of these patients maintained performance gains when environmental guidance (eg signs) was withdrawn, whereas the other two required environmental guidance in order to exhibit gains. The overall pattern of results suggests that this form of intervention related to everyday functioning in dementia is worthy of further empirical attention.
Age and the effects of ect
Authors: Wilkinson Andrew M. , Anderson David N. , Peters Stephen
Published: January 2005

The relationship between age and the outcome of ECT was prospectively studied in 78 patients with DSM‐III‐R major depression with melancholia or psychosis. Sixty‐eight patients were similarly evaluated for change in cognitive performance before and after treatment. Strongly positive correlations between increasing age, response to ECT and improved cognitive function were demonstrated and emphasize that ECT remains an important treatment for depression in old age, where the greatest benefits may be seen.
Delivering ‘positive care’ in nursing homes
Authors: Sixsmith Andrew , Hawley Carol , Stilwell John , Copeland John
Published: January 2005

This article describes a study of staff activity in six nursing homes for the elderly mentally ill. Three homes formed a Department of Health Special Medical Development (SMD), were highly resourced in terms of staff, and aimed to provide a good care environment and a high quality of life for the residents. The other three homes were included for comparison. The extra resources available within the SMD homes were largely used for routine care, such as resident hygiene, rather than 'positive', life ‐ enhancing care, such as social interaction and group activities. The failure to deliver positive care in line with increases in staff numbers cannot easily be explained. However, the indication is that it is not a result of substituting untrained for trained staff, but is rather related to the way staff resources are deployed.
Psychological status, life and social conditions: A study in a population of institutionalized elderly people
Authors: Bartoloni C. , Guidi L. , di Giovanni A. L. , Antico L. , Cursi F. , Pili R. , Tricerri A. , Janiri L. , Mannelli P. , Pariante C. , Menini E. , Carbonin P. , Gambassi G.
Published: January 2005

The relationship between social and life conditions on the one hand and the presence of depression on the other was analysed in a population of institutionalized elderly subjects. The influence of health status on psychological condition and the presence of endocrinological changes in hormones associated with chronic stress were investigated in depressed elderly people. One hundred and thirty‐seven elderly people (mean age 82.4 ± 7.7) were studied and 60 of them underwent a thorough psychiatric examination. The overall prevalence of depression‐not previously diagnosed in all but one patient—was 76.6%; 23.3% were severely depressed. Neither gender nor the presence of organic disease differentiated the depressed from the non‐depressed. The only two life and social variables associated with depression among the many items analysed were the length of institutionalization and the period of retirement. It was observed that a higher cortisol level in the severely depressed group showed a positive correlation between plasma (and urine) cortisol level and Hamilton Rating Scale for Depression (HRSD) score. A relationship between immunological impairment and depression in old age has been reported elsewhere; it is suggested that these findings could be partly mediated by the observed endocrinological changes.
Letters to the editor
Authors: Lester David , Pritchard Colin
Published: January 2005

Changes in the elderly suicide rates of nations from 1970 to 1980 were not associated with socioeconomic variables such as gross domestic product per capita and divorce rates, whereas changes in the total suicide rates were.
Functional and effective connectivity in neuroimaging: A synthesis
Authors: Friston Karl J.
Published: January 2005

The brain appears to adhere to two principles of functional organization; functional segregation and functional integration. The integration within and between functionally specialized areas is mediated by functional or effective connectivity. The characterization of this sort of connectivity is an important theme in many areas of neuroscience. This article presents one approach that has been used in functional imaging.

This article reviews the basic distinction between functional and effective connectivity (as the terms are used in neuroimaging) and their role in addressing several aspects of functional organization (e.g. the topography of distributed system, integration between cortical areas, time‐dependent changes in connectivity and nonlinear interactions). Emphasis is placed on the points of contact between the apparently diverse applications of these concepts and in particular the central role of eigenimages or spatial modes. Although the framework that has been developed is inherently linear, it has been extended to assess nonlinear interactions among cortical areas. ©1994 Wiley‐Liss, Inc.
Fas and TNFR1, but not cytolytic granule-dependent mechanisms, mediate clearance of murine liver adenoviral infection
Authors: Abougergi Marwan S. , Gidner Sarah J. , Spady David K. , Miller Bonnie C. , Thiele Dwain L.
Published: January 2005

After intravenous injection of replication-deficient adenovirus, hepatocytes are transduced and express high levels of adenovirus-encoded genes. However, adenovirally encoded gene expression is ablated rapidly by CD8+ T-cell–dependent mechanisms. Thus, this model is suitable for examining intrahepatic cytotoxic T lymphocyte (CTL) effector mechanisms. In the present studies, recombinant adenoviruses encoding secreted (human apolipoprotein A-I) or intracellular (β-galactosidase) gene products were infused into mice with genetic deficiencies affecting the granule exocytosis-, Fas-, or tumor necrosis factor receptor 1 (TNFR1)-mediated pathways of CTL and natural killer cell effector function; the rates of clearance of adenovirus-encoded gene products were assessed. Clearance of secreted or intracellular adenoviral gene products was not delayed in perforin-deficient mice or dipeptidyl peptidase I-deficient mice, which fail to process and activate granzyme A or granzyme B. TNFR1-deficient mice also exhibited no delay in clearance of adenoviral gene products. However, adenoviral clearance from Fas-deficient mice was delayed, and such delays were much greater in mice deficient in both TNFR1 and Fas. In contrast, chimeric mice lacking both hepatic Fas and lymphocyte perforin function exhibited no greater delay in adenoviral clearance than chimeras deficient only in hepatic Fas expression.
In conclusion,

Fas-dependent mechanisms are required for efficient clearance of virally infected hepatocytes and, in Fas-deficient animals, TNFR1-dependent mechanisms provide an alternative mechanism for hepatic adenovirus clearance. In contrast, perforin- and granule protease–dependent cytotoxicity mechanisms play no apparent role in clearance of adenovirus from the liver. (Hepatology 2005;41:97–105.)
Reconstitution of hepatitis C virus–specific T-cell–mediated immunity after liver transplantation
Authors: Weston Scott J. , Leistikow Rachel L. , Reddy Rajender K. , Torres Maria , Wertheimer Anne M. , Lewinsohn David M. , Chou Sunwen , Davey Michael P. , Corless Christopher , O'Farrelly Cliona , Nelson David R. , Rosen Hugo R.
Published: January 2005

Hepatitis C virus (HCV)-related liver failure is the leading indication for liver transplantation worldwide. After transplantation, virological recurrence is the rule, but the spectrum of histological injury is wide, ranging from the development of allograft cirrhosis within a few years to minimal hepatitis despite long-term follow-up. The immunological correlates of this variable natural history are poorly understood. Here, we studied the kinetics of the cellular immune responses, viral replication, and allograft histology in 24 patients who had undergone liver transplantation for HCV-related liver failure. Using direct

ex vivo

methodologies (

i.e
., interferon-gamma ELISPOT and major histocompatibility complex class I–peptide tetrameric complexes), we found that patients who experienced viral eradication after antiviral therapy showed restoration of HCV-specific T-cell responses, whereas patients with progressive HCV recurrence that failed to respond to therapy showed declining frequencies of these viral-specific effector cells. The cytotoxic T lymphocytes that peripherally reconstituted after transplantation were clonotypically identical to those present within the recipient explant liver, defined at the level of the T-cell receptor beta chain (one epitope/one clone). Moreover, the subset of patients who spontaneously demonstrated minimal histologic recurrence had more vigorous CD4+ T-cell responses in the first 3 months, particularly targeting nonstructural proteins. We provide evidence that T-cell responses emerge after liver transplantation, and their presence correlates with improved histological and clinical outcomes.
In conclusion,

these results may help identify patients more likely to develop severe HCV recurrence and therefore benefit from current antiviral therapy, as well as provide a rationale for the future use of novel immunotherapeutic approaches.

Supplementary material for this article can be found on the Hepatology website

(
http://interscience.wiley.com/jpages/0270-9139/suppmat/index.html
). (Hepatology 2005;41:72–81.)
Eradication of advanced hepatocellular carcinoma in rats via repeated hepatic arterial infusions of recombinant VSV
Authors: Shinozaki Katsunori , Ebert Oliver , Woo Savio L.C.
Published: January 2005

Viruses that replicate selectively in cancer cells hold considerable promise as novel therapeutic agents for the treatment of malignancy. Vesicular stomatitis virus (VSV) is a nonpathogenic RNA virus with intrinsic oncolytic specificity due to attenuated antiviral responses in many tumors. We report that repeated hepatic arterial infusion of recombinant syncytia-forming VSV vector in advanced multifocal hepatocellular carcinoma (HCC)-bearing rats at a 10-fold reduced vector dose resulted in sustained tumor-selective virus replication until the onset of high-titer neutralizing antibodies in blood. No significant elevations in serum transaminases and liver pathology were noted, indicating a lack of hepatotoxicity. Substantially improved tumor response was achieved with completely necrotic tumor nodules surrounded by mononuclear phagocytic cells, followed by fibrosis and calcification of the lesions, angiogenesis, and regeneration of normal hepatic parenchyma. Survival of tumor-bearing rats treated with repeated vector infusions was not only significantly improved over that of animals after a single injection at 10 times the vector dose (

P

= .001), but 18% of animals in the former treatment group also achieved long-term and tumor-free survival compared with 0% of animals in the latter treatment group.
In conclusion,

this treatment regimen will be very useful in the future development of VSV-mediated virotherapy as a novel therapeutic modality for patients with advanced HCC. (Hepatology 2005;41:196–203.)
The effect of antiretroviral therapy on liver disease among adults with HIV and hepatitis C coinfection
Authors: Mehta Shruti H. , Thomas David L. , Torbenson Michael , Brinkley Sherilyn , Mirel Lisa , Chaisson Richard E. , Moore Richard D. , Sulkowski Mark S.
Published: January 2005

In the era of antiretroviral therapy (ART), liver disease has emerged as an important cause of death among persons with human immunodeficiency virus (HIV)/hepatitis C virus (HCV) coinfection. The objective of this study was to estimate the burden of liver disease and evaluate determinants of liver fibrosis and necroinflammatory activity among HIV/HCV coinfected patients receiving ART. We studied 112 randomly selected and 98 referred HCV-infected patients undergoing care in the Johns Hopkins University HIV clinic. Liver disease was characterized clinically and histologically. Of the 210 individuals studied—64% of whom had received ART within 2 years of liver disease assessment—33% had no fibrosis (F0), and 26% had bridging fibrosis or cirrhosis (≥F3). The median necroinflammatory activity score was 3 (range, 0-9 of 18). ART was not associated with fibrosis; however, significantly less hepatic necroinflammatory activity was observed among persons who had received highly active antiretroviral therapy longer (

P

= .02) and more effectively (defined by HIV RNA suppression;

P

< .01). Twelve percent of individuals had previous ART-associated liver enzyme elevations (grades 3-4), but liver fibrosis was not more severe if the liver enzyme elevation resolved. On the other hand, liver fibrosis was more severe in persons with persistent liver enzyme elevations (grades 1-4).
In conclusion,

despite widespread exposure to ART and documented instances of ART-related hepatitis, we found no evidence that ART caused serious histological liver disease. Recognition of bridging fibrosis and cirrhosis in some but not most patients underscores the importance of identifying and treating liver disease in HIV/HCV coinfected persons. (Hepatology 2005;41:123–131.)
Permanently altered hippocampal structure, excitability, and inhibition after experimental status epilepticus in the rat: The “dormant basket cell” hypothesis and its possible relevance to temporal lobe epilepsy
Authors: Sloviter Robert S.
Published: January 2005

The relationship between an episode of status epilepticus, the resulting hippocampal pathology, and the subsequent development of pathophysiological changes possibly relevant to human cpilepsy was explored using the experimental epilepsy model of perforant path stimulation in the rat. Granule cell hyperexcitability and decreased feedforward and feedback inhibition were evident immediately after 24 hours of intermittent perforant path stimulation and persisted relatively unchanged for more than 1 year. All of the pathophysiological changes induced by perforant path stimulation were replicated in normal animals by a subconvulsive dose of bicuculline, suggesting that the permanent “epileptiform” abnormalities produced by sustained perforant path stimulation may be due to decreased GABA‐mediated inhibition. Granule cell pathophysiology was seen only in animals that exhibited a loss of adjacent dentate hilar mossy cells and hilar somatostatin/neuropeptide Y‐immunoreactive neurons. GABA‐immunoreactive dentate basket cells survived despite the extensive loss of adjacent hilar neurons. However, Parvalbumin immunoreactivity, present normally in a subpopulation of GABA‐immunoreactive dentate basket cells, was absent on the stimulated side. Whether this represents decreased parvalbumin synthesis in surviving basket cells or a loss of a specific subset of inhibitory cells is unclear.

Hyperexcitability and decreased paired‐pulse inhibition in response to ipsilateral perforant path stimulation were also present in the CA1 pyramidal cell layer on the previously stimulated side, despite minimal damage to CA1 pyramidal cells or interneurons. The possibility that CA1 inhibitory neurons were hypofunctional or “dormant” due to a loss of excitatory input to inhibitory cells from damaged CA3 pyramidal cells was tested by stimulating the contralateral perforant path in order to activate the same CA1 basket cells via different inputs. Contralateral stimulation evoked CA1 pyramidal cell paired‐pulse inhibition immediately in the previously stimulated hippocampus. Thus, we propose the “dormant basket cell” hypothesis, which implies that despite malfunction, inhibitory systems remain intact in “epileptic” tissue and are capable of functioning if appropriately activated.
Target cell specificity of synaptic connections in the hippocampus
Authors: Frotscher M.
Published: January 2005

A major question of neurobiological research is how precise connections between neurons are formed and maintained. In the hippocampus, afferent fiber systems are known to terminate in a laminated fashion. Previous studies have indicated that this lamination is largely due to spatiotemporal constraints during ontogenetic development. In this commentary, recent fine structural studies on the target cell specificity of the various hippocampal afferents are discussed. It becomes obvious that some afferent fibers establish synapses with all available target cells, whereas other afferents are restricted to distinct types of neurons. A high degree of neuronal specificity is found in the hippocampal and dentate axo‐axonic cells, which are restricted not only to specific types of target cells (pyramidal neurons and granule cells, respectively) but also to distinct portions of the target cell's membrane (the axon initial segment). Altogether, these data indicate that there are different levels of target cell specificity in the hippocampus. It is suggested that specific molecular interactions between pre‐ and postsynaptic elements, in addition to spatial and temporal factors, play a role in the formation and stabilization of the various synaptic connections of the hippocampal formation.
Mossy cells of the rat fascia dentata are glutamate‐immunoreactive
Authors: Soriano Eduardo , Frotscher Michael
Published: January 2005

The mossy cells represent a prominent cell type of the hilar region. Whereas the morphology of these neurons, their synaptic connections, and physiological characteristics have been described in some detail, information about their neurotransmitter is still lacking. Using immunocytochemistry in combination with Golgi impregnation, the authors demonstrate that identified mossy cells are GABA‐immunonegative but stain for glutamate. These results do not prove that these cells use glutamate as a transmitter, since glutamate is a ubiquitous metabolite. However, together with the lack of GABA staining and a recent report on asymmetric spine synapses formed by identified mossy cell axons, the present results support an excitatory nature of these neurons.
Brain temperature and hippocampal function
Authors: Andersen Per , Moser Edvard I.
Published: January 2005

Even though homeothermic animals regulate the body temperature, fluctuations up to 2–3°C may occur during physiological conditions. In many species, including the rat, a similar variation can be measured in the brain temperature. Such changes are expressed throughout the brain with a preserved gradient between the warmer basal and cooler dorsal parts. In spite of these recordable physiological changes, spatial learning is quite robust, in that it occurs at brain temperatures between 30 and 39°C. Even drastic cooling (to below 15°C) fails to affect consolidation or storage of information when the animal is tested after rewarming. The physiological temperature fluctuations have significant consequences for electrophysiological responses in the brain. Various bioelectrical signals are more sensitive during warming, axonal conduction is speeded up, and stimulus‐elicited transmitter release becomes faster and more synchronized. Action potentials have shorter rise and decay times in warm conditions, and the amplitude becomes slightly smaller. Population responses are differently affected by these changes. Dentate field potentials in response to stimulation of perforant‐path fibers appear with shorter latency in warm conditions, and the rate of rise in the field EPSP is increased. Paradoxically, the amplitude of the population spike is reduced. This is due to a combination of reduced amplitude of individual action potentials and reduced efficiency of the summation of groups of action potentials. Due to the large effects of temperature on hippocampal field potentials, it is mandatory that brain temperature changes are monitored and/or controlled whenever such responses are recorded in freely moving and anesthetized animals. © 1995 Wiley‐Liss, Inc.
Place cells recorded in the parasubiculum of freely moving rats
Authors: Taube Jeffrey S.
Published: January 2005

Previous studies have identified neurons in the hippocampus, subiculum, and entorhinal cortex which discharge as a function of the animal's location in the environment. In contrast, neurons in the postsubiculum and anterior thalamic nucleus discharge as a function of the animal's head direction in the horizontal plane, independent of its behavior and location in the environment. Because the parasubiculum (PaS) has extensive connections, either directly or indirectly, with these structures, it is centrally located to influence the neuronal activity in these areas. This study was therefore designed to determine the types of behavioral and spatial correlates in neurons from the PaS. Single unit recordings were conducted in the PaS of freely moving rats trained to retrieve food pellets thrown randomly into a cylindrical apparatus. A total of 10.3% of the cells were classified as place cells because they discharged in relation to the animal's location in the cylinder. A large percentage of cells (41.4%) were classified as theta cells. The remaining cells had nondiscernable behavioral correlates.

Quantitative analysis of the firing rate maps for the place cells showed they had higher levels of background activity and contained larger firing fields than values reported previously for hippocampal place cells. Directional analysis showed that only three out of 16 cells contained a secondary directional correlate; the firing rate for the remaining cells was not affected by the animal's directional heading within the firing field. A time shift analysis, which shifted the spike time series relative to the animal location series, was conducted to determine whether the quality of the location‐specific firing could be improved. The time shifts for three different spatial parameters were optimal when cell discharge led the animal's position. Furthermore, the optimal time shifts for two of these parameters (firing area and information content) were less than the optimal shift reported for hippocampal place cells and suggested that PaS cell discharge lagged behind hippocampal place cell activity. Rotation of the cue card with the animal out of view led to near equal rotation of the firing field when the animal was returned to the apparatus. These results indicate that a small population of cells in the PaS encode the animal's location in its environment, although the representation of space encoded by these cells is different from the type of representation encoded by hippocampal place cells. © 1995 Wiley‐Liss, Inc.
The long‐term use of psychotropic drugs: A follow‐up study in italian general practice
Authors: Fiorio R. , Bellantuono C. , Leoncini M. , Montemezzi G. , Micciolo R. , Williams P.
Published: January 2005

Four general practitioners (GPs) of Verona, a town in northern Italy of about 300,000 inhabitants, recruited in 1986 a cohort of 75 adult patients to whom they prescribed benzodiazepines or antidepressants for the “first time”. The patients, new users of psychotropic drugs, were 51 women (68 per cent) and 24 men (32 per cent). They were followed up during the 26 weeks after the first psychotropic drug prescription. At the end of the study 20 patients (26·7 per cent of the original cohort‐–“long‐term” users) were still consuming psychotropic drugs (mainly benzodiazepines with or without an antidepressant). Severity of psychiatric symptoms (only for patients over 45 years), prescriptions of an antidepressant (but only for women under 45 years) and low educational level (only in males over 45 years) were identified as factors associated with long‐term psychotropic drug consumption.
Increased anticholinergic levels, memory and judgement
Authors: Walkup J.
Published: January 2005

Clinicians who have contact with patients taking medications which produce cholinergic blockade may need to consider possible links between increased anticholinergic levels and problems in judgement. Although it appears that there has as yet been no direct experimental test of the impact of anticholinergic agents on the judgement of normals or psychiatric patients, a review is offered of two types of basic cognitive findings which strongly suggest that the risk of such a link should figure in clinical cost—benefit analysis. It is then argued that, in the absence of definitive findings, several clinical considerations suggest that the clinician should consider the possible impact of anticholinergics on judgement in his or her practice.
Study of effects of clobazam and lorazepam on memory and cognitive functions in healthy subjects
Authors: Patat A. , Klein M. J. , Surjus A. , Rostand A. , Granier J.
Published: January 2005

This was a double‐blind, placebo‐controlled crossover study in 15 healthy female volunteers. It consisted of five sessions, separated by 1 week wash‐out between sessions. The purpose of the trial was to study the potential amnesic and sedative activity of clobazam and lorazepam, and the potential antagonism between these effects under the joint influence of a high noise level and intense intermittent light stimulation (ILS), aimed at increasing the level of alertness. The study drugs were administered as a single daily oral dose. The amnesic and sedative effects were evaluated by objective measurements (digit span, Buschke selective reminding test, critical flicker fusion, reaction time, tapping, mental arithmetic test) and subjective measurements (visual analogue scale and adverse effect questionnaire) before each administration, then 1 h, 2 h, 2·5 h, 3 h, 4 h and 7 h post‐dosing. An analysis of variance according to a balanced Latin square design was performed. Clobazam, at a dosage of 10 mg, was devoided of sedative and amnesic effects; at a dosage of 30 mg it induced only moderate memory disturbances. In contrast, lorazepam, administered at doses of 1 and 3 mg, produced marked and dose‐dependent disturbances of memory, alertness and cognitive functions. The use of visual and sound stimuli, designed to increase the level of alertness, did not counteract the sedative effects induced by lorazepam.
A commentary: Measuring the health economics of depression
Authors: Eckett Simon
Published: January 2005

The perspective of a health economic analysis is vital and this is particularly true in the current debate on the economic analysis of Selective Serotonin Reuptake Inhibitors (SSRIs) and Tricyclic Antidepressants (TCAs). The perspective can be institutional, from central government, region, health commission to GP fundholder, and it can be by cost type: including drug costs alone in the analysis; other direct costs such as GPs' and counselling time; and indirect costs such as loss of earnings due to depression. Economic analysts, who focus on drug costs alone tend to favour TCAs over SSRIs. Those who cast their cost net wider tend to favour SSRIs over TCAs. Future research should concentrate on the ‘invisible costs’ that exist in the prescribing process; and on quality of life and health outcomes to establish treatment cost/successful outcome. This could form an intergral part in the development of future cost effective guidelines for depression.