Heme oxygenase in liver transplantation: heme catabolism and metabolites in the search of function.
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Heme↗
Biomedical subjects
Michael Bauer
Publications and source records attributed to Michael Bauer.
Recovery of hepatocellular ATP and "pericentral apoptosis" after hemorrhage and resuscitation.
Progressive liver dysfunction contributes significantly to the development of multiple organ failure after trauma/hemorrhage. This study tested the relative impact of necrotic and apoptotic cell death in a graded model of hemorrhagic shock (mean arterial blood pressure=35+/-5 mmHg for 1, 2, or 3 h, followed by 2 h, 1 h, or no resuscitation, respectively) in rats. Prolonged periods of hemorrhagic hypotension (3 h) were paralleled by a profound decrease of hepatic ATP levels and occurrence of pericentral necrosis. Resuscitation after shorter periods of hemorrhagic hypotension resulted in restoration of tissue ATP whereas hepatocellular function as assessed by indocyanine green clearance remained depressed (49.9+/-1.6 mL/(min x kg) at baseline, 28.8+/-1.2 mL/(min x kg) after 2 h of resuscitation; P<0.05). Under these conditions, induction of caspase activity and DNA fragmentation were observed in pericentral hepatocytes that could be prevented by the radical scavenger tempol. Pretreatment with z-Val-Ala-Asp(O-methyl)-flouromethylketone prevented de novo expression of caspase-generated cytokeratin 18, DNA fragmentation, and depression of hepatocellular indocyanine green clearance. These data suggest that prolonged low flow/hypoxia induces ATP depletion and pericentral necrosis and restoration of oxygen supply and ATP levels after shorter periods of low flow ischemia propagate programmed cell death or "pericentral apoptosis."
Adenosine Triphosphate↗
Perflubron emulsion in prolonged hemorrhagic shock: influence on hepatocellular energy metabolism and oxygen-dependent gene expression.
BACKGROUND: Liver dysfunction as a result of impaired oxygen availability frequently occurs following hemorrhage and contributes to delayed mortality. Artificial oxygen carriers may improve oxygen supply to vital organs while avoiding the need for allogeneic transfusion. METHODS: Rats were subjected to hemorrhagic hypotension (mean arterial pressure = 35-40 mmHg for 120 min) and were subsequently resuscitated with (1) stored whole rat blood, (2) pentastarch, or (3) pentastarch combined with perflubron emulsion (PFE; 2.7 or 5.4 g/kg body weight), a second-generation artificial oxygen carrier. Recovery of liver adenosine triphosphate, hepatocellular injury, and expression of glutamine synthetase 1, a gene that is induced by exposure of hepatocytes to low partial pressure of oxygen, were studied at 4 h of resuscitation. RESULTS: Stored whole blood or pentastarch failed to restore liver adenosine triphosphate concentrations after prolonged shock as compared to sham controls and resulted in increased gene expression of glutamine synthetase 1. Addition of 2.7 g PFE/kg restored liver adenosine triphosphate to control, whereas 5.4 g PFE/kg resulted in adenosine triphosphate concentrations significantly above control. Improved hepatocellular oxygen supply was also confirmed by restoration of the physiologic expression pattern of glutamine synthetase 1. Serum enzyme concentrations were highest after resuscitation with stored blood, whereas addition of PFE failed to further decrease enzyme concentrations as compared to pentastarch alone. CONCLUSIONS: Resuscitation with PFE is superior to stored blood or asanguineous resuscitation with respect to restoration of hepatocellular energy metabolism. The improved hepatocellular oxygen availability is reflected in normalization of oxygen-dependent gene expression. However, improved oxygen availability failed to affect early hepatocellular injury.
Acid-Base Equilibrium↗
Expression pattern and regulation of heme oxygenase-1/heat shock protein 32 in human liver cells.
Heme oxygenase-1 (HO-1) is a stress response protein that is highly inducible under various conditions, such as oxidative or heat stress. The present study investigated expression pattern and regulation of HO-1 in human liver. Expression pattern of HO-1 immunoreactive protein was studied in liver biopsies by immunohistochemistry, revealing constitutive expression in Kupffer cells but not in hepatocytes. HO-1 was, however, inducible in hepatocytes and vascular tissue under pathological conditions, e.g. associated with fatty degeneration or liver malignancies. Regulation of HO-1 gene expression was further studied by Northern blot analysis in HepG2 cells and freshly isolated peripheral blood mononuclear cells as model systems of parenchymal and nonparenchymal liver cell populations, respectively. HO-1 mRNA was inducible in HepG2 cells and mononuclear cells by various agents inducing oxidative stress. However, HO-1 gene expression was not inducible by heat shock. Pyrrolidine dithiocarbamate, an inhibitor of nuclear factor kappaB-dependent gene expression, dose dependently decreased HO-1 mRNA transcripts in human mononuclear cells subjected to oxidative stress while slightly increasing HO-1 gene expression in HepG2 cells. In contrast, HO-1 induction upon oxidative stress was attenuated in HepG2 cells by cycloheximide and dexamethasone. Although activator protein-1 has been reported as the predominant redox-sensitive transcription factor inducing HO-1 expression in murine macrophages, nuclear factor kappaB seems to play a significant role in human mononuclear cells. Our data are consistent with a role for activator protein-1 in HO-1 induction in human HepG2 hepatoma cells. These data suggest a differential regulation of HO-1 gene expression in parenchymal and non-parenchymal human liver cells and may provide a topographic basis for the understanding of the role of the heme oxygenase/carbon monoxide pathway in human liver disease.
Blotting, Northern↗
Review: electroconvulsive therapy may be an effective short term treatment for people with depression.
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Comment↗
Lithium augmentation therapy in refractory depression: clinical evidence and neurobiological mechanisms.
OBJECTIVE: This systematic review examines the evidence and discusses the clinical relevance of lithium augmentation as a treatment strategy for refractory major depressive episodes. It also examines hypotheses on the mode of action of lithium augmentation, with a focus on serotonin (5-HT) and neuroendocrine systems, and proposes recommendations for future research. METHOD: We searched the Medline computer database and the Cochrane Library for relevant original studies published in English from January 1966 to February 2003. The key words were as follows: lithium, augmentation strategies, lithium augmentation, major depression, refractory depression, treatment-resistant depression, neuroendocrinology, and serotonin. RESULTS: Of 27 prospective clinical studies published since 1981, 10 were double-blind, placebo-controlled trials, 4 were randomized comparator trials, and 13 were open-label trials. Five of 9 acute-phase placebo-controlled trials demonstrated that lithium augmentation had substantial efficacy. In the acute-treatment trials, the average response rate in the lithium group was 45%, and in the placebo group, 18% (P < 0.001). One placebo-controlled trial showed the efficacy of lithium augmentation in the continuation-phase treatment. Summarizing the open and controlled data, approximately 50% of patients responded to lithium augmentation within 2 to 6 weeks. Animal studies offer robust evidence that lithium augmentation increases 5-HT neurotransmission, possibly by a synergistic action of lithium and the antidepressant on brain 5-HT pathways. CONCLUSIONS: Augmentation of antidepressants with lithium is the best-documented augmentation therapy in the treatment of refractory depression. Emerging data from animal studies suggest that the 5-HTergic system is involved in the augmentatory effect of lithium.
Animals↗
Prophylaxis latency and outcome in bipolar disorders.
OBJECTIVE: To analyze new and reviewed findings to evaluate relations between treatment response and latency from onset of bipolar disorder (BD) to the start of mood-stabilizer prophylaxis. METHOD: We analyzed our own new data and added findings from research reports identified by computerized searching. RESULTS: We found 11 relevant studies, involving 1485 adult patients diagnosed primarily with BD. Reported latency to prophylaxis averaged 9.6 years (SD 1.3), and follow-up in treatment averaged 5.4 years (SD 3.1). Greater illness intensity and shorter treatment latency were closely associated, resulting in a greater apparent reduction in morbidity with earlier treatment. However, this finding was not sustained after correction for pretreatment morbidity, and treatment latency did not predict morbidity during treatment. Therefore, assessments based on improvement with treatment, or without correction for pretreatment morbidity, can be misleading. CONCLUSIONS: Available evidence does not support the proposal that delayed prophylaxis may limit response to prophylactic treatment in BD and related disorders.
Anticonvulsants↗
Family and staff partnerships in long-term care. A review of the literature.
Working with the family in aged care to provide the best care possible is consistent with modern nursing philosophy, which espouses holistic care. The quality and enjoyment of the experience, however, is frequently fraught with problems and challenges for both the family and the staff involved. In residential aged care, partnerships are a complex mix of interactions among the older adult resident, the family, and the caregiving staff. To understand how family involvement in this environment can be made more meaningful, nurses need to be cognizant of how family members experience the caregiving role and how they are perceived by nursing home staff and residents. The relevant literature of the past 20 years is reviewed and key issues central to an understanding of "family care" in the nursing home from the perspective of the family, the nursing home resident, and the nursing home staff are highlighted in this article.
Aged↗
Hypothalamic-pituitary-thyroid system activity during lithium augmentation therapy in patients with unipolar major depression.
OBJECTIVE: Lithium augmentation is an established strategy in the treatment of refractory depression, but little is known about predictors of response and its mode of action. There is increasing evidence that low thyroid function indices within the normal range are associated with a poorer treatment response to antidepressants, but previous studies on the hypothalamic-pituitary-thyroid (HPT) system during lithium augmentation provide inconclusive results and have methodological limitations. This study aimed at exploring the role of thyroid function in lithium augmentation and used a prospective design that included a homogeneous sample of inpatients with unipolar major depressive disorder. METHODS: In 24 euthyroid patients with a major depressive episode who had not responded to antidepressant monotherapy of at least 4 weeks, we measured serum thyroid-stimulating hormone (TSH), total triiodothyronine (T3) and total thyroxine (T4) before (baseline) and during lithium augmentation therapy (follow-up). The time point of the endocrinological follow-up depended on the status of response, which was assessed weekly with the Hamilton Depression Rating Scale, 17-item version (HDRS17). Responders were reassessed immediately after response was determined, and non-responders after 4 weeks of lithium augmentation. RESULTS: There was a statistically significant change in thyroid system activity during lithium augmentation, with an increase of TSH levels and a decrease of peripheral T3 and T4 levels. However, there were no differences in any of the HPT hormones between responders and non-responders at baseline or at follow-up. CONCLUSIONS: The decrease of thyroid system activity during lithium treatment reflects the well-established "antithyroid" properties of lithium. However, it appears that thyroid status does not predict response to lithium augmentation in euthyroid patients before treatment.
Adult↗
Effectiveness and outcome predictors of long-term lithium prophylaxis in unipolar major depressive disorder.
OBJECTIVE: To determine the effectiveness of lithium prophylaxis in unipolar major depressive disorder (MDD) and to identify predictors of outcome including comedication. METHODS: In this long-term naturalistic study, clinical data from 55 patients with MDD (DSM-III-R) were collected prospectively in an outpatient clinic specializing in the treatment of affective disorders. OUTCOME MEASURES: Change in hospital admission rate (number and duration) during prophylaxis compared with the period before prophylaxis, Morbidity-Index during prophylaxis and time to first recurrence after initiation of lithium treatment. RESULTS: During an average follow-up period of 6.7 years, a significant decline in the number of days spent in hospital (p<0.001; 52 d/yr less; 95; CI 31-73 d) and a low Morbidity-Index (mean 0.07) was observed. Only in 6 patients did medication have to be changed because of side-effects (n=4) or a lack of efficacy (n=2). None of the independent variables we analyzed proved to be important in predicting the outcome of lithium prophylaxis. Comedication was necessary in 21 patients. The overall outcome of their prophylactic treatment, however, did not differ from the group that did not receive comedication in the symptom-free intervals. CONCLUSIONS: The results of this study, with its long observation period and the inclusion of comedication as a confounding variable, indicate that lithium is a potent prophylactic agent for unipolar MDD in a naturalistic setting. In contrast to the findings of others, age was not associated with the outcome of prophylaxis, and latency did not predict outcome. Contrary to doubts that have been raised in recent years with regard to the effectiveness of lithium in everyday clinical practice, lithium appears to be a safe and potent alternative to antidepressants.
Adult↗
Identification and characterization of single-domain thiosulfate sulfurtransferases from Arabidopsis thaliana.
Sulfurtransferases/rhodaneses (ST) are a group of enzymes widely distributed in all three phyla that catalyze the transfer of sulfur from a donor to a thiophilic acceptor substrate. All ST contain distinct structural domains, and can exist as single-domain proteins, as tandemly repeated modules in which the C-terminal domain bears the active site, or as members of multi-domain proteins. We identified several ST in Arabidopsis resembling the C-terminus of the Arabidopsis two-domain ST1 and the single-domain GlpE protein from Escherichia coli. Two of them (accession numbers BAB10422 and BAB10409) were expressed in E. coli and purified. Both proteins showed thiosulfate-specific ST enzyme activity.
Amino Acid Sequence↗
Effects of acute psychological stress on adhesion molecules, interleukins and sex hormones: implications for coronary heart disease.
RATIONALE: Subjects with high levels of daily stress suffer from an increased risk of coronary heart disease. Increased concentrations of the intercellular adhesion molecule-1 (ICAM-1) contribute to atherosclerosis. Cell adhesion molecules may be activated by psychological stress exposure, depending on their interaction with the interleukin network, sex hormones and cortisol secretion. OBJECTIVES: To assess effects of acute psychological stress on the interaction between cell adhesion molecules, interleukins, sex hormones and cortisol in healthy male subjects. METHODS: Cell adhesion molecules, interleukin-1 beta (IL-1beta), IL-2, IL-6, sex hormones and cortisol levels of 18 healthy male physicians were measured before and after an academic oral presentation and on a control day. RESULTS: The oral presentation was perceived as a stressful event and was accompanied by a significant increase in cortisol secretion in all volunteers. Soluble ICAM-1 and IL-1beta also increased in all subjects after psychological stress exposure. The stress-associated increase in IL-2 concentrations approached statistical significance and correlated negatively with luteinizing hormone plasma levels. Estradiol concentrations correlated positively with IL-6 levels. CONCLUSIONS: Subjective ratings and the increase in cortisol plasma concentrations support the validity of the chosen stress model. Acute stress exposure was followed by an increase in IL-1beta, IL-2 and soluble ICAM-1 plasma concentrations, which can contribute to coronary heart disease and immunological disorders.
Adult↗
Effects of supraphysiological doses of L-thyroxine on cognitive function in healthy individuals.
Cognitive disturbance is commonly associated with disorders of the thyroid gland, particularly hypothyroidism, and usually subsides following thyroid hormone replacement therapy. In contrast, the effects of thyroid hormones on cognitive functions in healthy individuals have rarely been studied. The goal of this open-label study was to investigate the short-term effects (duration of administration 45 days on average) of supraphysiological doses of L-thyroxine (L-T(4)) on cognitive performance in young, euthyroid, healthy subjects. Eleven subjects performed a comprehensive neuropsychological test battery, once without and once during administration of supraphysiological doses of L-T(4). There were no significant differences in any of the cognitive test results between the two test sessions. The results of this study do not support our working hypothesis that thyroid hormone can change cognitive performance in young, euthyroid, healthy individuals.
Adult↗
Selective upregulation of endothelin B receptor gene expression in severe pulmonary hypertension.
BACKGROUND: The pulmonary circulation is an important site for the production and clearance of endothelin (ET)-1, a potent vasoactive and mitogenic peptide. Increased plasma ET-1 levels are observed in pulmonary arterial hypertension (PHT) and may contribute to the regulation of pulmonary vascular resistance, as well as to proliferative changes in the pulmonary vascular bed. METHODS AND RESULTS: We prospectively assessed changes in plasma big ET-1 levels and changes in ET(A) and ET(B) receptor gene expression in 14 consecutive patients undergoing pulmonary thromboendarterectomy for thromboembolic PHT. Plasma big ET-1 levels were higher in patients with PHT (median, 2.2 pg/mL; 25th to 75th percentile, 1.5 to 3.0 pg/mL) compared with age-matched controls (median, 1.2 pg/mL; 25th to 75th percentile, 1.0 to 1.4 pg/mL; P=0.002). In addition to increased plasma big ET-1 levels, selective upregulation of ET(B) receptor mRNA transcripts and immunoreactive protein in the pulmonary artery was observed in the patients; however, ET(A) receptor gene expression was unaffected. CONCLUSIONS: These data suggest that changes in the ET signaling system in PHT caused by thromboembolic disease are not limited to an increased production of ET-1: they also affect ET receptor gene expression.
Endarterectomy↗
Bipolar disorder.
Bipolar, or manic-depressive, disorder is a frequent, severe, mostly recurrent mood disorder associated with great morbidity. The lifetime prevalence of bipolar disorder is 1.3 to 1.6%. The mortality rate of the disease is two to three times higher than that of the general population. About 10-20% of individuals with bipolar disorder take their own life, and nearly one third of patients admit to at least one suicide attempt. The clinical manifestations of the disease are exceptionally diverse. They range from mild hypomania or mild depression to severe forms of mania or depression accompanied by profound psychosis. Bipolar disorder is equally prevalent across sexes, with the exception of rapid cycling, a severe and difficult to treat variant of the disorder, which arises mostly in women. Because of the high risk of recurrence and suicide, long-term prophylactic pharmacological treatment is indicated. Lithium salts are the first choice long-term preventive treatment for bipolar disorder. They also possess well documented antisuicidal effects. Second choice prophylactic treatments are carbamazepine and valproate, although evidence of their effectiveness is weaker.
Anticonvulsants↗
Effects of supraphysiological thyroxine administration in healthy controls and patients with depressive disorders.
BACKGROUND: Thyroxine (T(4)) in supraphysiological doses has been found to be an effective supplemental treatment in open studies for refractory mood disorders. Unexpectedly, only minimal side effects have been reported. The goal of the present study was to investigate whether healthy controls and depressed patients differ in their ability to tolerate supraphysiological doses of T(4). METHODS: This was an 8-week open study to investigate side effects and levels of thyroid hormones in 13 healthy controls and to compare results with those of 13 patients with refractory depression (unipolar and bipolar) undergoing the similar procedures and T(4) dosing regimen in a previous augmentation study. RESULTS: The rate of discontinuation due to side effects was significantly higher in the control group than for the patients (38% versus 0%). The severity of the side effects in the controls increased significantly during treatment with T(4). The side effect scores of the patients were higher than those of the controls prior to T(4) treatment, but did not change significantly during the treatment period. Although the serum concentrations of thyroid hormones rose significantly in both groups, concentrations of fT(3) and fT(4) were significantly higher in the controls. CONCLUSIONS: Healthy controls and depressed patients respond significantly differently to supraphysiological T(4). Healthy controls experience higher elevations of thyroid hormones in response to supraphysiological T(4), thus inducing significantly more side effects and discontinuation. LIMITATIONS: Open-label study; groups were studied at different times; in contrast to healthy controls, depressed patients were also taking antidepressants. CLINICAL RELEVANCE: Studies provide safety and tolerability data on treatment with supraphysiological doses of T(4).
Adult↗
The influence of conformational restriction in the C-terminus of growth hormone secretagogues on their potency.
In order to obtain more potent growth hormone secretagogues, a comparison of ipamorelin and NN703 suggested the addition of a polar group at the C-terminus of NN703. A study was conducted using constrained amines for this purpose. Here, substituted 4-piperidinylamino- and 4-dimethylaminopiperidino-substituents were found to give the most active compounds. A replacement of the 4-dimethylaminopiperidino-substituent with 4-hydroxypiperidino resulted in a series of compounds, which showed in vitro activity with EC(50) values in the low nanomolar range, and favourable kinetic properties, such as 40% oral bioavailability. The most promising compound was also tested in a swine in vivo model, resulting in a growth hormone level with a C(max) of over 40 ng mL(-1).
Animals↗
Supraphysiological doses of L-thyroxine in the maintenance treatment of prophylaxis-resistant affective disorders.
This prospective open-label study examined the efficacy of adjunctive supraphysiological doses of L-thyroxine (T(4)) in the maintenance treatment of prophylaxis-resistant affective disorder. Twenty-one (16 women, 5 men) of 25 patients enrolled consecutively over an 8-year period on the basis of their status of prophylaxis resistance (defined as two or more failures to standard prophylactic trials) participated for more than four months in the study and were eligible for the intention-to-treat analysis. The mean length of adjunctive treatment with T(4) was 51.4 +/- 21.7 months. The mean T(4) dose at study end was 378.6 +/- 90.2 micro g/d. The number of episodes and hospitalizations, and the morbidity indices during the time of prophylactic T(4) treatment, were compared with those measured for the same length of time before the start of T(4) treatment (mirror-image method). On the Clinical Global Impression for Bipolar Disorder scale (CGI-BP, Change from Worst Phase of Illness), eleven subjects (52.4%) were rated as "very much improved", four (19%) as "much improved", two (9.5%) as "minimally improved" and four (19%) as "no change." The mean total number of recurrences (8.6 before T(4) treatment vs. 2.8 during T(4) treatment; p =.004), the number of hospitalizations (3.1 vs. 1.9; p =.026) and the Morbidity Index (MI(Total) = 0.71 vs. MI(Total) = 0.28; p <.001) significantly declined during T(4) treatment. Subjects with bipolar disorder (n = 13) benefited more from the T4 treatment intervention than did subjects with unipolar major depressive disorder (n = 4) and schizoaffective disorder (n = 4). In conclusion, adjunctive treatment with L-thyroxine in supraphysiological doses may be an effective strategy in the maintenance treatment of patients with prophylaxis-resistant affective disorders.
Adult↗