bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of repeated cocaine on medial prefrontal cortical GABAB receptor modulation of neurotransmission in the mesocorticolimbic dopamine system
Authors: Jayaram Prathiba , Steketee Jeffery D.
Published: July 2004

Increased excitatory output from medial prefrontal cortex is an important component in the development of cocaine sensitization. Activation of GABAergic systems in the prefrontal cortex can decrease glutamatergic activity. A recent study suggested that sensitization might be associated with a decrease in GABAB receptor responsiveness in the medial prefrontal cortex. Therefore, the present study examined whether repeated exposure to cocaine‐modified neurochemical changes in the mesocorticolimbic dopamine system induced by infusion of baclofen into the medial prefrontal cortex. In vivo microdialysis studies were conducted to monitor dopamine, glutamate and GABA levels in the medial prefrontal cortex and glutamate levels in the ipsilateral nucleus accumbens and ventral tegmental area during the infusion of baclofen into medial prefrontal cortex. Baclofen minimally affected glutamate levels in the medial prefrontal cortex, nucleus accumbens or ventral tegmental area of control animals, but dose‐dependently increased glutamate levels in each of these regions in animals sensitized to cocaine. This effect was not the result of changes in GABAB receptor‐mediated modulation of dopamine or GABA in the medial prefrontal cortex. The data suggest that alterations in GABAB receptor modulation of medial prefrontal cortical excitatory output may play an important role in the development of sensitization to cocaine.
Aging, gender and APOE isotype modulate metabolism of Alzheimer's Aβ peptides and F2‐isoprostanes in the absence of detectable amyloid deposits
Authors: Yao Jun , Petanceska Suzana S. , Montine Thomas J. , Holtzman David M. , Schmidt Stephen D. , Parker Carolyn A. , Callahan Michael J. , Lipinski William J. , Bisgaier Charles L. , Turner Brian A. , Nixon Ralph A. , Martins Ralph N. , Ouimet Charles , Smith Jonathan D. , Davies Peter , Laska Eugene , Ehrlich Michelle E. , Walker Lary C. , Mathews Paul M. , Gandy Sam
Published: July 2004

Aging and apolipoprotein E (APOE) isoform are among the most consistent risks for the development of Alzheimer's disease (AD). Metabolic factors that modulate risk have been elusive, though oxidative reactions and their by‐products have been implicated in human AD and in transgenic mice with overt histological amyloidosis. We investigated the relationship between the levels of endogenous murine amyloid β (Aβ) peptides and the levels of a marker of oxidation in mice that never develop histological amyloidosis [i.e. APOE knockout (KO) mice with or without transgenic human APOEɛ3 or human APOEɛ4 alleles]. Aging‐, gender‐, and APOE‐genotype‐dependent changes were observed for endogenous mouse brain Aβ40 and Aβ42 peptides. Levels of the oxidized lipid F2‐isoprostane (F2‐isoPs) in the brains of the same animals as those used for the Aβ analyses revealed aging‐ and gender‐dependent changes in APOE KO and in human APOEɛ4 transgenic KO mice. Human APOEɛ3 transgenic KO mice did not exhibit aging‐ or gender‐dependent increases in F2‐isoPs. In general, the changes in the levels of brain F2‐isoPs in mice according to age, gender, and APOE genotype mirrored the changes in brain Aβ levels, which, in turn, paralleled known trends in the risk for human AD. These data indicate that there exists an aging‐dependent, APOE‐genotype‐sensitive rise in murine brain Aβ levels despite the apparent inability of the peptide to form histologically detectable amyloid. Human APOEɛ3, but not human APOEɛ4, can apparently prevent the aging‐dependent rise in murine brain Aβ levels, consistent with the relative risk for AD associated with these genotypes. The fidelity of the brain Aβ/F2‐isoP relationship across multiple relevant variables supports the hypothesis that oxidized lipids play a role in AD pathogenesis, as has been suggested by recent evidence that F2‐isoPs can stimulate Aβ generation and aggregation.
Distribution of CNT2 and ENT1 transcripts in rat brain: selective decrease of CNT2 mRNA in the cerebral cortex of sleep‐deprived rats
Authors: Guillén‐Gómez Elena , Calbet Marta , Casado Javier , De Lecea Luís , Soriano Eduardo , Pastor‐Anglada Marçal , Burgaya Ferran
Published: July 2004

Nucleoside transport processes regulate the levels of adenosine available to modulate neurotransmission, vascular tone and other physiological events. However, although equilibrative transporter transcripts or proteins have been mapped in the central nervous system of rats and humans, little is known about the presence and distribution of the complete family of nucleoside transporters in brain. In this study, we analysed the distribution of the transcript encoding the high affinity adenosine‐preferring concentrative transporter CNT2 in the rat central nervous system and compared it with that of the equilibrative transporter ENT1. Furthermore, we evaluated the changes in expression of these two transporters in a situation of increased extracellular levels of adenosine, such as sleep deprivation. CNT2 mRNA was widespread in rat brain, although most prevalent in the amygdala, the hippocampus, specific neocortical regions and the cerebellum. The distribution of CNT2 mRNA only partially overlapped that of ENT1. Most of the cells labelled were neurones. Total sleep deprivation dramatically diminished the amounts of CNT2 mRNA, whereas ENT1 mRNA remained unchanged. This specific decrease in CNT2 transcript suggests a new physiological role for the transporter in the modulation of extracellular adenosine levels and the sleep/wakefulness cycle.
Phosphorylation of Ser19 increases both Ser40 phosphorylation and enzyme activity of tyrosine hydroxylase in intact cells
Authors: Bobrovskaya Larisa , Dunkley Peter R. , Dickson Phillip W.
Published: July 2004

We have previously shown that the phosphorylation of Ser19 in tyrosine hydroxylase can increase the rate of phosphorylation of Ser40 in tyrosine hydroxylase threefold in vitro. In this report we investigated the role of Ser19 on Ser40 phosphorylation in intact cells. Treatment of bovine chromaffin cells with anisomycin produced a twofold increase in Ser19 phosphorylation with no increase in Ser31 phosphorylation and only a small increase in Ser40 phosphorylation. Treatment of bovine chromaffin cells with forskolin produced a fourfold increase in Ser40 phosphorylation but no significant increase in either Ser19 or Ser31 phosphorylation. When chromaffin cells were first treated with anisomycin, the level of Ser40 phosphorylation after treatment by forskolin was 76% greater than the level of Ser40 phosphorylation in cells treated with forskolin alone. This potentiation of Ser40 phosphorylation by anisomycin could be completely blocked by the p38 MAP (mitogen‐activated protein) kinase inhibitor SB 203580. The potentiation of Ser40 phosphorylation by anisomycin was not due to an increase in Ser40 kinase activity. Anisomycin treatment of chromaffin cells potentiated the forskolin‐induced increase in tyrosine hydroxylase activity by 50%. This potentiation of activity was also blocked by SB 203580. These data provide the first evidence that the phosphorylation of Ser19 can potentiate the phosphorylation of Ser40 and subsequent activation of tyrosine hydroxylase in intact cells.
Lack of mitochondrial nitric oxide production in the mouse brain
Authors: Lacza Zsombor , Horn Thomas F. W. , Snipes James A. , Zhang Jie , Roychowdhury Sanjoy , Horváth Eszter M. , Figueroa Jorge P. , Kollai Márk , Szabó Csaba , Busija David W.
Published: July 2004

Based on our initial finding that the nitric oxide (NO) sensitive fluorochrome diaminofluorescein (DAF) was localized to mitochondria in cultured primary neurons, we investigated whether brain mitochondria produce NO through a mitochondrial NO synthase (mtNOS) enzyme. Isolated brain mitochondria were loaded with DAF and subjected to flow cytometry analysis. Neither the application of NOS inhibitors nor the genetic disruption of either NOS gene diminished the DAF‐fluorescence. However, peroxynitrite scavengers reduced the mitochondrial DAF fluorescence, indicating that the DAF signal is not specific to NO. Chemiluminescence detection in the head space gas and a Clark‐type NO‐sensitive electrode in the solution failed to detect NO release in brain mitochondria. NOS activity in mitochondria was only 1% of the whole brain NOS activity level, which may be attributed to extramitochondrial contamination. Extensive immunoblotting and immunoprecipitation experiments failed to show the presence of endothelial, neuronal, or inducible NOS in mouse brain mitochondria using a variety of primary antibodies. Arginine, calmodulin or 2,5‐ADP affinity purification protocols successfully concentrated eNOS and nNOS from full brain tissue but failed to show any signal in mitochondria. We conclude that mouse brain mitochondria do not contain NOS isoforms, nor do they produce NO through a NOS‐dependent mechanism.
Cross‐linking of glycine receptor transmembrane segments two and three alters coupling of ligand binding with channel opening
Authors: Lobo Ingrid A. , Trudell James R. , Harris R. Adron
Published: July 2004

Contact points between transmembrane segments (TMs) two and three of the glycine receptor are undefined and may play an important role in channel gating. We tested whether two amino acids in TM2 (S267) and TM3 (A288), known to be critical for alcohol and volatile anesthetic action, could cross‐link by mutating both to cysteines and expressing the receptors in Xenopus laevis oocytes. In contrast with the wild‐type receptor and single cysteine mutants, the S267C/A288C double mutant displayed unusual responses, including a tonic leak activity that was closed by strychnine and a run‐down of the response upon repeated applications of glycine. We hypothesized that these characteristics were due to cross‐linking of the two cysteines on opposing faces of these adjacent, alpha helical TMs. This would alter the movement of these two regions required for normal gating. To test this hypothesis, we used dithiothreitol to reduce the putative S267C–A288C disulfide bond. Reduction abolished the leak current and provided normal responses to glycine. Subsequent application of the cross‐linking agent mercuric chloride caused the initial characteristics to return. These data demonstrate that S267 and A288 are near‐neighbors and provide insight towards the location and role of the TM2–TM3 interface in ligand‐gated ion channels.
Effects of post‐injury hypothermia and nerve growth factor infusion on antioxidant enzyme activity in the rat: implications for clinical therapies
Authors: DeKosky Steven T. , Abrahamson Eric E. , Taffe Kevin M. , Dixon C. Edward , Kochanek Patrick M. , Ikonomovic Milos D.
Published: July 2004

The pathological sequelae of traumatic brain injury (TBI) include increased oxidative stress due to the production of reactive oxygen species (ROS). Regulation of ROS levels following TBI is determined primarily by antioxidant enzyme activity that in turn can be influenced by nerve growth factor (NGF). Hypothermia is one of the current therapies designed to combat the deleterious effects of TBI. However, it has been shown to suppress post‐trauma increases in NGF levels in rat brain. The present study sought to determine whether post‐injury hypothermia also impairs the antioxidant response to injury, and if such an effect could be reversed by infusion of exogenous NGF. We employed a lateral controlled cortical impact injury model in rat, followed by moderate hypothermia treatment with supplemental intracerebroventricular infusion of NGF or vehicle. The time course of changes in post‐injury/intervention levels of NGF and activity of three major enzymes responsible for ROS scavenging, catalase (CAT), glutathione peroxidase (GPx) and superoxide dismutase (SOD), was determined in the hippocampus. Relative to levels in injured, normothermic animals, hypothermia treatment not only suppressed NGF levels, but also attenuated CAT and GPx activity, and increased SOD activity. Infusion of NGF in injured, hypothermia‐treated animals was ineffective in restoring hippocampal antioxidant enzymes activity to levels produced after injury under normothermic conditions, although it was able to increase septal cholinergic (choline acetyltransferase) enzyme activity. These results have implications for clinical treatment of TBI, demonstrating that moderate hypothermia suppresses NGF and the antioxidant response after TBI; the latter cannot be countered by exogenous NGF administration.
Hierarchies of evidence and hierarchies of education: reflections on a multiprofessional education initiative
Authors: Page Susie , Meerabeau Liz
Published: July 2004

The concept of a hierarchy of evidence is an established part of the discourse of evidence‐based health care. In the drive to incorporate research findings into all aspects of health and social care practice, value judgements about the quality of the evidence available are commonplace, with research findings obtained via particular research approaches often being given more scientific credence than those obtained by using alternative methods. This hierarchy of evidence mirrors the existence of a well‐documented professional hierarchy within the healthcare workplace, with medicine as the dominant occupational group. Academic arguments for a broader appreciation of research evidence have been made in the literature for a number of years and have achieved considerable success. Equally, medical dominance in the workplace has been addressed on various levels, one approach being the rise in multiprofessional education initiatives. This article draws on the experience of facilitating multiprofessional groups undertaking a research appraisal skills programme within National Health Service‐based ‘classroom’ settings. The continuing existence of both medical dominance in the healthcare arena and a belief in a hierarchy of evidence was apparent from the courses. In addition, what might be called a hierarchy of educational backgrounds, presented some complex dynamics within the teaching situation and raised a number of hitherto seemingly unaddressed questions for the group facilitator.
Hepatitis B virus‐specific T cell response in chronic hepatitis B patients treated with lamivudine and interferon‐α
Authors: Pontesilli Oscar , Van Nunen Andeltje B. , Van Riel Debby , Carotenuto Patrizia , Niesters Hubert G. , Uytdehaag Fons G. , De Man Robert A. , Osterhaus Albert D.
Published: July 2004

Abstract: Aims: The goal of the present study was to assess the impact combination antiviral therapy has on immune responses in chronic hepatitis B.

Materials and methods: T cell responses were studied in 16 chronically hepatitis B virus (HBV)‐infected patients treated with sequential, partially overlapping, lamivudine‐interferon (IFN)‐α combination therapy.

Results: HBcAg‐specific lymphoproliferative response (LPR) was transiently detected in four of five patients who achieved virus suppression (HBV DNA <104 genome equivalents/ml) at end of dual therapy, and then reverted to pre‐treatment viral load after therapy discontinuation. In contrast, no significant HBcAg‐specific LPR was detected in 8 patients who did not attain profound HBV suppression, as well as in three patients who experienced no HBV DNA rebound after therapy discontinuation.

Conclusions: This pilot study suggests that restored viral replication after pharmacological suppression drives the immune response to HBV in chronically infected patients. Further characterization of the adaptive immunity and its regulatory mechanisms at time of therapy discontinuation appears therefore necessary in controlled trials.
Increased levels of tissue inhibitor of metalloproteinase‐1 in human hepatocellular carcinoma
Authors: Matsumoto Eiji , Nakatsukasa Harushige , Nouso Kazuhiro , Kobayashi Yoshiyuki , Nakamura Shinichiro , Suzuki Mayumi , Takuma Yoshitaka , Tanaka Hironori , Fujikawa Tatsuya , Shiratori Yasushi
Published: July 2004

Abstract:  Background: Invasion and metastasis of hepatocellular carcinoma (HCC) are regulated by matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs). However, the role of TIMPs in these processes is not clear.

Aim: To examine the potential involvement of TIMP‐1 in HCC and the association between TIMP‐1 and clinical outcome of patients with HCC.

Methods: The study included 91 patients who underwent surgical removal of HCC. TIMP‐1 concentrations in the supernatant of tissue homogenates of HCC and non‐neoplastic liver were measured by enzyme immunoassay. The relationships between TIMP‐1 concentration and various clinicopathological features and recurrence of HCC after surgical operation were examined.

Results: The mean level of TIMP‐1 in HCC (486±610 ng/mg protein, ±SD) was significantly higher than in the non‐neoplastic liver (75±69, P<0.0001). The median level of TIMP‐1 in poorly differentiated HCCs (701 ng/mg protein) was significantly higher than in well‐ (80) and moderately (172) differentiated HCCs (P=0.0047 and P=0.0082, respectively). TIMP‐1 level in liver cirrhosis was higher than in chronic hepatitis (P=0.0015). TIMP‐1 levels in HCC did not influence the recurrence rate of HCC.

Conclusions: TIMP‐1 concentration in HCC was higher than in non‐neoplastic liver and correlated with the differentiation grade of HCCs. However, tissue TIMP‐1 concentration does not seem to be an important determinant of HCC recurrence.
Diagnostic and therapeutic implications of bile duct injury in autoimmune hepatitis
Authors: Czaja Albert J. , Muratori Paolo , Muratori Luigi , Carpenter Herschel A. , Bianchi Francesco B.
Published: July 2004

Abstract: Background: Bile duct injury is not a feature of classical autoimmune hepatitis (AIH), but it has been described in variant forms of the disease.

Aims: Our goals were to assess the similarity of AIH with bile duct injury to classical disease and to evaluate the possibility of concurrent primary biliary cirrhosis (PBC).

Methods: Fifteen patients with bile duct injury were compared with 151 patients with classical AIH. Patterns of nuclear immunofluorescence and the frequency and nature of autoantibodies associated with AIH and PBC were determined.

Results: Patients with bile duct injury had the same nuclear‐staining patterns, frequency and nature of autoantibodies, and genetic risk factors as the comparison group. Features specific for PBC, including the multiple nuclear dot pattern of immunofluorescence and antibodies to the M2 antigens, Sp100 and nuclear pore complex antigen, gp210, did not distinguish them from classical disease. Remission and treatment failure occurred with similar frequencies in both groups.

Conclusions: Patients with AIH and bile duct injury lack features of PBC, and they respond as well to corticosteroid therapy as patients with classical disease. Background bile duct changes should not alter the diagnosis or treatment of AIH.
The role of heat shock protein 27 expression in hepatocellular carcinoma in Japan: special reference to the difference between hepatitis B and C
Authors: Harimoto Norifumi , Shimada Mitsuo , Aishima Shin‐ichi , Kitagawa Dai , Itoh Shinji , Tsujita Eiji , Maehara Shin‐ichiro , Taketomi Akinobu , Tanaka Shinji , Shirabe Ken , Maehara Yoshihiko
Published: July 2004

Abstract:  Background: A recent report showed that heat shock protein (HSP)‐27 expression was related to histological grade and survival of patients with hepatocellular carcinoma (HCC).

Aims: The aim of this study was to examine the effect of expression of HSP‐27 on clinicopathological variables in Japanese patients with HCC.

Methods: An immunohistochemical study for HSP‐27 was performed on 60 HCC cases using a monoclonal anti‐HSP‐27 antibody. We divided 60 patients into two groups, patients with a low expression of HSP‐27 (n=34) and those with a high expression of HSP‐27 (n=26). Forty patients tested positive for the hepatitis C virus (HCV) antibody and 20 tested positive for the hepatitis B surface antigen.

Results: There appeared to be no relationship between HSP expression and clinicopathologic factors and no differences were observed between the high expression group and the low expression group. In the hepatitis B virus (HBV) group (n=20), HSP‐27 expression correlated significantly with prognosis, disease‐free survival (DFS) and overall survival. High expression was significantly associated with poor prognosis in the HBV group. In contrast, patients with a high expression tended to have a good prognosis in the HCV group (n=40): DFS and overall survival.

Conclusions: This study showed the possibility that HSP‐27 plays different roles in HBV‐ and HCV‐associated HCCs.
Nitric oxide synthase 1 is partly compensating for nitric oxide synthase 3 deficiency in nitric oxide synthase 3 knock‐out mice and is elevated in murine and human cirrhosis
Authors: Biecker Erwin , Neef Markus , Sägesser Hans , Shaw Sidney , Koshy Abraham , Reichen Jürg
Published: July 2004

Abstract:  Background: The role of endothelial nitric oxide synthase 3 (NOS‐3) in the hyperdynamic circulation associated with cirrhosis is established but not that of the neuronal (NOS‐1) isoform. We therefore investigated aortic NOS‐1 levels in NOS‐3 knock‐out (KO) and wildtype (WT) mice and in hepatic arteries of patients.

Methods: Mice rendered cirrhotic by bile duct ligation (BDL) were compared with sham‐operated controls. Hepatic arteries of cirrhotic patients were collected during liver transplantation; donor vessels served as controls. mRNA levels were quantified by real‐time PCR, protein levels by Western blotting and NO production by Nω‐nitro‐l‐arginine methyl ester inhibitable arginine–citrulline assay.

Results: Aortae of NOS‐3 KO mice exhibited higher NOS‐1mRNA (5.6‐fold, P<0.004) and protein levels (8.8‐fold) compared with WT. NO production in aortae of NOS‐3 KO mice was 52% compared with WT (P=0.002). BDL increased NOS‐1 mRNA (2.4‐fold, P=0.01) and protein (7.1‐fold) levels in aortae of WT, but no further in the NOS‐3 KO mice. Hepatic artery NOS‐1 mRNA levels in cirrhotic patients were markedly increased compared with controls (24.5‐fold, P=0.0007).

Conclusions: Increased NOS‐1 mRNA and protein levels and partially maintained in vitro NO‐production in aortae of NOS‐3 KO mice suggest that NOS‐1 may partially compensate for NOS‐3 deficiency. BDL‐induced increase in aortic NOS‐1 mRNA and protein levels hint that not only NOS‐3, but also NOS‐1 may be involved in the regulation of systemic hyperdynamic circulation and portal hypertension. Upregulation of NOS‐1 mRNA levels in hepatic arteries of portal hypertensive patients suggests possible clinical significance for these experimental findings.
Hepatic hydrothorax – pathophysiology, diagnosis and treatment – review of the literature
Authors: Gur Chamutal , Ilan Yaron , Shibolet Oren
Published: July 2004

Abstract: Hepatic hydrothorax is defined as the accumulation of significant pleural effusion in a cirrhotic patient without primary pulmonary or cardiac disease. Hydrothorax is uncommon occurring in up to 4–6% of all patients with cirrhosis and up to 10% in patients with decompensated cirrhosis. Although ascites is usually present, hydrothorax can occur in the absence of ascites. Patients with hepatic hydrothorax usually have advanced liver disease with portal hypertension and most of them will require liver transplantation. Over the last few years, new insights into the pathogenesis of this entity have lead to improved treatment modalities such as portosystemic shunts (TIPS) and video‐assisted thoracoscopy for closure of diaphragmatic defects. These modalities may be of help as a bridge to transplantation. The aim of this review is to describe recent developments in the pathogenesis, diagnosis and treatment of hepatic hydrothorax.
Analysis of the functional integrity of cryopreserved human liver cells including xenografting in immunodeficient mice to address suitability for clinical applications
Authors: Cho Jae‐Jin , Joseph Brigid , Sappal Baljit Singh , Giri Ranjit K. , Wang Richard , Ludlow John W. , Furth Mark E. , Susick Robert , Gupta Sanjeev
Published: July 2004

Abstract: Background: The availability of well‐characterized human liver cell populations that can be frozen and thawed will be critical for cell therapy. We addressed whether human hepatocytes can recover after cryopreservation and engraft in immunodeficient mice.

Methods: We isolated cells from discarded human livers and studied the properties of cryopreserved cells. The viability of thawed cells was established with multiple in vitro assays, including analysis of liver gene expression, ureagenesis, cytochrome P450 activity, and growth factor‐induced cell proliferation. The fate of transplanted cells was analysed in immunodeficient NOD‐SCID mice.

Results: After thawing, the viability of human hepatocytes exceeded 60%. Cells attached to culture dishes, proliferated following growth factor stimulation and exhibited liver‐specific functions. After transplantation in NOD‐SCID mice, cells engrafted in the peritoneal cavity, a heterologous site, as well as the liver itself, retained hepatic function and proliferated in response to liver injury. Transplanted hepatocytes were integrated in the liver parenchyma. Occasionally, transplanted cells were integrated in bile ducts.

Conclusions: Cryopreserved human liver cell showed the ability to retain functional integrity and to reconstitute both hepatic and biliary lineages in mice. These studies offer suitable paradigms aimed at characterizing liver cells prior to transplantation in people.
Inhibition of tumor necrosis factor‐induced apoptosis in transgenic mouse liver expressing creatine kinase
Authors: Hatano Etsuro , Tanaka Akira , Kanazawa Akiyoshi , Tsuyuki Shigeru , Tsunekawa Shoji , Iwata Shingo , Takahashi Rei , Chance Britton , Yamaoka Yoshio
Published: July 2004

Abstract: Background: The mitochondrion acts as a pivotal decision center in many types of apoptotic responses. To clarify the effects of the enhanced mitochondrial function on tumor necrosis factorα (TNFα)‐induced apoptosis, we studied hepatic injuries in transgenic mice whose livers express creatine kinase (CK).

Methods: Mice fed a diet containing 10% creatine, came to accumulate phosphocreatine and to enhance hepatic ATP levels and mitochondrial oxidative phosphorylation activities. TNFα‐mediated hepatic apoptosis in normally fed and Cr‐feeding CK transgenic mice were assessed.

Results: TNFα and actinomycin D cause severe liver failure in normally fed transgenic mice, and in the wild‐type mice. In contrast, no significant elevations in transaminase levels after injection were observed in Cr feeding transgenic mice. The disruption of the mitochondrial transmembrane potential at 2 h after TNFα injection, prior to ATP depletion, activation of caspase 3 like protease, and DNA fragmentation at 4–6 h after injection, were observed in normally fed transgenic mice. These were fully suppressed in Cr feeding transgenic mice. However, anti‐Fas antibody‐induced apoptosis was not inhibited in both groups.

Conclusions: The results indicate that TNFα‐induced apoptosis was inhibited in CK transgenic mice livers by maintaining mitochondrial function.
Constructing Realities: An Art of Lenses
Authors: HOFFMAN LYNN
Published: July 2004

In this essay I attempt to map the dimensions of my own move away from a cybernetic‐biologic analogy for “family‐systems” therapy. Central to this shift has been social construction theory augmented by two other lenses: a second‐order view, and a sensitivity to gender. These conceptual tools have helped me to distance myself from my previous therapeutic stance and to envision a very different model, one that is less strategic and instrumental, and more collaborative and unconcealed.
Mind‐Body Problems in Family Therapy: Contrasting First‐ and Second‐Order Cybernetics Approaches
Authors: GRIFFITH JAMES L. , GRIFFITH MELISSA ELLIOTT , SLOVIK LOIS S.
Published: July 2004

Using detailed case examples, we contrast first‐ and second‐order cybernetics approaches to family problems involving somatic symptoms in a family member. A second‐order cybernetics approach views the reality of the problem as linguistically shaped by those interacting around it, including the therapist and observing team members. This co‐constructed reality, the story of the problem, inadvertently contributes to the problem's endurance by narrowing the choice of more effective solutions. In our approach, the therapist elicits from each person his or her story about the illness in the family. The therapist then facilitates a therapeutic conversation that provides a context for new linguistic distinctions to be drawn, including the way mind and body may interact to generate the symptoms. Shifts in beliefs and behaviors follow, and more innovative solutions to the problem can then emerge. Unlike the approach in our previously published work based upon ecosystemic patterns as “system diagnoses,” this approach uses only descriptions and explanations of the problem as are collaboratively constructed within this therapeutic conversation.
Focal Family Therapy: Theory and Practice
Authors: Levene Judith E. , Newman Frances , Jeffries J. Joel
Published: July 2004

During the past 30 years, the prescription of neuroleptic medication has made a major impact on the treatment of symptoms in patients with schizophrenia. Nonetheless, for many patients, symptom remission and social functioning remain less than optimal. Consequently, clinicians have employed a combined approach of drugs, psychosocial therapies, and psychiatric rehabilitation to treat the range of deficits presented by individuals suffering with this illness. In this article, we describe Focal Family Therapy, a model of family therapy developed for working with families and patients who are struggling with schizophrenia. Using the example of a particular case, we illustrate the following: (a) the identification and formulation of the Focal Issue; (b) the targeting of behavior and attitudes that will constitute the Focal Change; and (c) the techniques of Focal Family Therapy.
The Effect of Being Reared with an Alcoholic Half‐Sibling: A Classic Study Reanalyzed
Authors: COOK WILLIAM L. , GOETHE JOHN W.
Published: July 2004

Data from an early study of alcoholism among half‐siblings of alcoholic probands (17) was reanalyzed using log‐linear analysis. The original study, which used chi‐square analysis, identified genetic factors but found no environmental effects that contributed to the prediction of alcoholism. Log‐linear analysis, however, reveals that being reared with a proband is associated with a reduced incidence of alcoholism in half‐siblings. The results do not disconfirm the presence of genetic factors, but they do indicate that family dynamics make an independent and statistically significant contribution to the development of alcoholism not heretofore demonstrated. Similarities between these results and the results from studies of identical twins are discussed.
Convergent and Discriminant Validity of FACES‐III: Family Adaptability and Cohesion
Authors: EDMAN SALLY O. , COLE DAVID A. , HOWARD GEORGE S.
Published: July 2004

Research on earlier versions of the Family Adaptability and Cohesion Evaluation Scales (FACES) has ostensibly shown that the scales lack discriminant and convergent validity (23). However, these studies have defined convergence as agreement between family members or as agreement between family members and family therapists. Such definitions confound real differences between respondents' perceptions of the family with the notion of convergent validity. In the current study, we take a different approach to construct validity. Multiple measures of family adaptability, cohesion, and talkativeness were administered to two family members (insiders) and two significant others (outsiders). The two insiders' responses were averaged together, as were the two outsiders' responses. Using confirmatory factor analysis, we demonstrated that family adaptability, cohesion, and talkativeness are distinct traits, and that the different sources of information about these traits, including FACES‐III (24), have convergent validity.
Further Thoughts on Second‐Order Family Therapy — This Time It's Personal
Authors: ATKINSON BRENT J. , HEATH ANTHONY W.
Published: July 2004

A series of articles has recently appeared in which implications of second‐order cybernetics for the practice of family therapy have been discussed. In this article, we attempt to advance the discussion by addressing ideas that we think have not been adequately emphasized thus far. Specifically proposed are ideas about conditions that might facilitate the emergence of consciously pragmatic strategy informed by the kind of systemic wisdom that delicately balances natural systems without the benefit of human planning. It is argued that a shift in the personal habits of knowing and acting that typically organize individual human experience is required. After attempting to specify what this shift might involve, implications of these ideas for the practice of family therapy and for human action in general are discussed.
Advancing a Family Perspective in Health Research: Models and Methods
Authors: FISHER LAWRENCE , TERRY HOWARD E. , RANSOM DONALD C.
Published: July 2004

In this essay we review and respond to four problems that have impeded the application of family theory to health research: the difficulty in translating family concepts to empirical health research; the confusion and uncertainty in measuring “wholes” and “parts” of a family in a single health project; the apparent conflict between circular‐causal and linear perspectives in model building; and the putative, implicit “violation” of a family perspective by the employment of certain data management and design strategies. We argue that current, complex conceptualizations of the family have to be matched with equally complex research designs and methods, and that techniques are available to reach these goals. We distinguish between theoretical models and research methods, and review several strategies, design issues, and alternatives for data analysis. Throughout, we point to 1) the need to maintain consistency among theory, construct, and indicator, 2) the employment of multidimensional family assessment in health research, and 3) the use of readily available but infrequently used methods and procedures for appreciating the richness of multivariate family data.
Can Communication Deviance Be Measured in a Family Problem‐Solving Interaction?
Authors: VELLIGAN DAWN I. , GOLDSTEIN MICHAEL J. , NUECHTERLEIN KEITH H. , MIKLOWITZ DAVID J. , RANLETT GREGORY
Published: July 2004

Communication deviance (CD) refers to confusing and fragmented communication that prevents family members from attaining a shared focus of attention and meaning. Levels of communication deviance based on individual parental projective test protocols — Thematic Apperception Test (TAT) and Rorschach — have repeatedly been found to be higher in parents of schizophrenic offspring than in parents of normal or nonpsychotic offspring. CD has also been measured in family transactions in which parents and their offspring interact with one another around a projective test stimulus, the Consensus Rorschach. There have been relatively few attempts to measure specific CD codes in familial interaction that is not initiated around an ambiguous visual stimulus. The present article examines the reliability and construct validity of an interactional measure (ICD) obtained from family transactions in which parents and patients are working toward the solution of a salient family problem. ICD from this family problem‐solving task was compared to more traditional measures of CD from parental TAT protocols in a sample of 59 parents of 37 recent‐onset schizophrenic patients. Results indicated that CD could be reliably measured in an interactive setting not initiated around a projective test stimulus, and provided evidence for the construct validity of ICD.
The Therapeutic Use of Self in Constructionist/Systemic Therapy
Authors: REAL TERRY
Published: July 2004

The introduction of a constructivist orientation to family therapy has promoted a reconceptualization of the therapeutic use of self. The multiply‐engaged therapist is seen as positioned within rather than as acting upon a system. Such a therapist facilitates change through participation in, and active engagement with, each system member's perceptions and experience. Multiple engagement synthesizes the “instrumental” and “noninstrumental” perspectives through use of the idea of systemic influence, or systemic positioning. Multiple engagement stresses the relational perspective over the extremes of either pure interventionism or pure facilitation. Five specific therapeutic stances are introduced and are clinically illustrated; taken together, these stances articulate one model for a constructivist family therapy.
A Test of the Olson Circumplex Model: Examining Its Curvilinear Assumption and the Presence of Extreme Types
Authors: ANDERSON STEPHEN A. , GAVAZZI STEPHEN M.
Published: July 2004

The debate over the usefulness of different family models continues. Recent attention has been paid to comparisons between the Olson Circumplex Model and the Beavers Systems Model. The present study seeks to contribute evidence that bears directly upon one of the most fundamental points of controversy surrounding the Olson model—the linear versus curvilinear nature of the cohesion and adaptability dimensions. A further contribution is an examination of the actual occurrence of the Circumplex Model's extreme types in a clinical population.
Intergenerational Effects of the Holocaust: Patterns of Engagement in the Mother‐Daughter Relationship
Authors: HALIK VICKI , ROSENTHAL DOREEN A. , PATTISON PHILIPPA E.
Published: July 2004

The present study explored the quality of engagement between mothers and adult daughters. Daughters of Holocaust survivors, European immigrants, and nonimmigrants were compared on mothers'protectiveness and care during their daughters' first 16 years, and on daughters' individuation from the family of origin. The survivor group perceived themselves as less individuated from both their parents than the other two groups. However, daughters in the three groups reported feeling equally intimate with their parents. There were no significant group differences found on intergenerational intimidation or competing loyalties. There was a tendency for mothers in the survivor group to be perceived as more indulgently protective. These findings suggest that the relationship between survivor mothers and their daughters may be characterized by a lower degree of individuation, though not at the cost of intimacy.
From Universe to Multiverses—and Back Again
Authors: TJERSLAND ODD ARNE
Published: July 2004

A number of concepts and ideas from constructivist and second‐order cybernetic family therapy literature are presented and their implications for therapy are examined. I was inspired by and, in this article, refer to videotapes of consultations and therapy sessions shown at an international conference on constructivism and family therapy in Sulitjelma, Norway, June 1988, and to written material from the Tromsø group Andersen and Anna M. Flå), the Milan team (Luigi Boscolo and Gianfranco Cecchin), and the Galveston team (Harlene Anderson and Harold Goolishian). The article also represents an attempt to use constructivist concepts and ideas in a reflection on the author's own professional development as a psychologist and family therapist.
A Universe of Stories
Authors: PARRY ALAN
Published: July 2004

The complete adoption of a narrative paradigm for therapy is proposed and its implications and possibilities spelled out, especially for life in a post‐modern world that lacks any objective frame of reference. In the post‐modern sensibility, the story is set free to perform as simply a story that allows for re‐invention as the story‐teller finds a voice rooted in the person's own experience and in the connection of her story to those of others, and to larger stories of culture and humanity. The realization that we are all characters in each other's stories as well as our own reminds us that our stories only go forward as we act in ways that also forward the stories of others. A hermeneutics for such therapy validates and questions all points of view so that they do not harden into stories that are assumed to be objectively true.
Evaluating FACES III and the Circumplex Model: 2,440 Families
Authors: GREEN ROBERT G. , HARRIS ROBERT N. , FORTE JAMES A. , ROBINSON MARGARET
Published: July 2004

Previous evaluations of the Circumplex Model's curvilinear hypothesis using FACES instruments have yielded conflicting results. A review of the different research procedures and samples used in those investigations revealed that none of the studies had samples large and/or heterogenous enough to test the curvilinear hypothesis adequately. The present study evaluates the curvilinear hypothesis of family functioning and the concurrent validity of FACES III with a sample of optimal size (N = 2,440 families) and diversity. The lack of support for the curvilinear hypothesis in this “greenhouse” sample is explained by different findings for the two FACES III subscales. There was no relationship between the study's measures of well‐being and the adaptability subscale and a linear relationship between these measures and the cohesion subscale. Implications of these findings for the continuing use of the FACES III and for the Circumplex Model of Marital and Family Systems are discussed.
COMMENTARY: THREE‐DIMENSIONAL (3‐D) CIRCUMPLEX MODEL AND REVISED SCORING OF FACES III
Authors: Olson David H.
Published: July 2004

This commentary on FACES III research by Green and colleagues (see preceding article) provides a useful format for introducing the three‐dimensional (3‐D) Circumplex Model and the revised scoring of FACES III. This article describes how the 3‐D Circumplex Model will improve the model conceptually, methodologically, and clinically. Expanding the Circumplex into a 3‐D model offers the opportunity to integrate second‐order change into the model.
Adolescent Adjustment to Parental Divorce: An Investigation from the Perspective of Basic Dimensions of Structural Family Therapy Theory
Authors: ABELSOHN DAVID , SAAYMAN GRAHAM S.
Published: July 2004

This study, conducted within the framework of concepts of structural family therapy, examined the relationship of four family‐based, clinical dimensions to the adjustment of 45 adolescents during the first 18 months of parental separation. There were two samples of mother‐custody families: an Aided group that applied for treatment, and an Unaided group of paid volunteers. The inclusion of this variable addressed a major methodological deficit of previous studies. There was a significant association between perceived postseparation family structure and adolescent adjustment, demonstrating that individual adolescent adjustment is contingent on structural features of the contemporary postseparation family. Further, Aided families were perceived as more chaotic, disengaged, and enmeshed than Unaided families, while Aided adolescents were characterized by more behavior problems than Unaided adolescents. This suggests that divorce, as an unscheduled transition, might be within the realm of adaptation for many families and adolescents and is not necessarily “disastrous.”
The Family's Conception of Accountability and Competence: A New Approach to the Conceptualization and Assessment of Family Stress
Authors: REISS DAVID , OLIVERI MARY ELLEN
Published: July 2004

Clinicians and researchers have a strong interest in understanding how families respond to stress. Often, they begin their analyses by attempts to estimate the seriousness or magnitude of the stressful events impinging on the families they observe. Until now, they have relied on two strategies. First, they attempt to develop objective or external indicators of the magnitude of the stress of the events. The problem here is that the family's own perceptions and experiences are not properly weighted. The second strategy depends heavily or exclusively on the family's perceptions of the events. However, these perceptions are often a product of the family's efforts to cope with the stress since the organization and perception of meaning in events is a fundamental part of family coping. Thus, this approach cannot disentangle the stress inherent in the events from the family's efforts to cope with it. This article explores a third alternative. The social community in which the family lives often provides a coherent frame of meanings for most events. It not only defines the magnitude of the event but it also defines how accountable the family is for producing the event in the first place. A method for assessing these community frameworks is presented. Initial results suggest that there is not only a coherent community framework attributing magnitude and family accountability to a large number of stressful events impinging the family but, also, that these community attributions are embedded in a community concept of family development.
Lie to Me No More: Believable Stories and Marital Affairs
Authors: SMITH THOMAS EDWARD
Published: July 2004

This case study illustrates the dilemmas of systemic practice when the presenting problem is relational infidelity (marital affairs). After several months of treatment with a structural therapist, the couple and therapist were at an impasse because of arguments over the husband's alleged sexual encounter 3 years previously. The introduction of a consultant and a story‐based therapy allowed the couple to reconcile their marital difficulties. The article ends with a discussion of the implications of systemic paradigms and personal morality.
The Discourses of Intimacy: Adding A Social Constructionist and Feminist View
Authors: WEINGARTEN KATHY
Published: July 2004

Though most people desire intimacy in their primary relationships, it is more elusive than not. I argue that people's assumptions about intimacy interfere with their creation of it. Using a social constructionist and feminist perspective, two prevailing discourses of intimacy that shape our ideas about intimacy are identified and critiqued. Both tend to direct attention away from an assessment of particular interactions to a global assessment of the capacity of an individual or a relationship to provide intimacy. An alternative is proposed in which intimacy is conceptualized as built up from single intimate or non‐intimate interactions that can produce a variety of experiences, including connection and domination. My critique of the two discourses of intimacy rests fundamentally on the belief that they obscure crucial distinctions that a discourse of intimacy as meaning‐making would reveal, in particular, that there are politics nestled in the heart of intimacy.
Outcomes of Systemic/Strategic Team Consultation:
Authors: GREEN ROBERT‐JAY , HERGET MARY
Published: July 2004

This is the third in a series of reports on a small‐sample study of systemic/strategic team consultations. It sheds new light on aspects of the therapeutic alliance in Milan‐informed therapy. Ratings of the end‐of‐session interventions and ratings of the therapist's relationship skills (warmth, active structuring) significantly predicted client improvement at 1‐month and 3‐year followups. These results dispute the Milan team's idea that an intervention's effects are unpredictable. Also, our findings challenge the way some teams have adopted an impersonal, emotionally unresponsive style under the guise of “neutrality.” In view of this and other recent studies, we conclude that systemic/strategic therapists should devote more attention to collaborative and affective qualities of the therapeutic alliance.