Treatment of depression.
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Antidepressive Agents↗
Biomedical subjects
J W Williams
Publications and source records attributed to J W Williams.
Treatment of dysthymia and minor depression in primary care: A randomized controlled trial in older adults.
CONTEXT: Insufficient evidence exists for recommendation of specific effective treatments for older primary care patients with minor depression or dysthymia. OBJECTIVE: To compare the effectiveness of pharmacotherapy and psychotherapy in primary care settings among older persons with minor depression or dysthymia. DESIGN: Randomized, placebo-controlled trial (November 1995-August 1998). SETTING: Four geographically and clinically diverse primary care practices. PARTICIPANTS: A total of 415 primary care patients (mean age, 71 years) with minor depression (n = 204) or dysthymia (n = 211) and a Hamilton Depression Rating Scale (HDRS) score of at least 10 were randomized; 311 (74.9%) completed all study visits. INTERVENTIONS: Patients were randomly assigned to receive paroxetine (n = 137) or placebo (n = 140), starting at 10 mg/d and titrated to a maximum of 40 mg/d, or problem-solving treatment-primary care (PST-PC; n = 138). For the paroxetine and placebo groups, the 6 visits over 11 weeks included general support and symptom and adverse effects monitoring; for the PST-PC group, visits were for psychotherapy. MAIN OUTCOME MEASURES: Depressive symptoms, by the 20-item Hopkins Symptom Checklist Depression Scale (HSCL-D-20) and the HDRS; and functional status, by the Medical Outcomes Study Short-Form 36 (SF-36) physical and mental components. RESULTS: Paroxetine patients showed greater (difference in mean [SE] 11-week change in HSCL-D-20 scores, 0.21 [0. 07]; P =.004) symptom resolution than placebo patients. Patients treated with PST-PC did not show more improvement than placebo (difference in mean [SE] change in HSCL-D-20 scores, 0.11 [0.13]; P =.13), but their symptoms improved more rapidly than those of placebo patients during the latter treatment weeks (P =.01). For dysthymia, paroxetine improved mental health functioning vs placebo among patients whose baseline functioning was high (difference in mean [SE] change in SF-36 mental component scores, 5.8 [2.02]; P =. 01) or intermediate (difference in mean [SE] change in SF-36 mental component scores, 4.4 [1.74]; P =.03). Mental health functioning in dysthymia patients was not significantly improved by PST-PC compared with placebo (P>/=.12 for low-, intermediate-, and high-functioning groups). For minor depression, both paroxetine and PST-PC improved mental health functioning in patients in the lowest tertile of baseline functioning (difference vs placebo in mean [SE] change in SF-36 mental component scores, 4.7 [2.03] for those taking paroxetine; 4.7 [1.96] for the PST-PC treatment; P =.02 vs placebo). CONCLUSIONS: Paroxetine showed moderate benefit for depressive symptoms and mental health function in elderly patients with dysthymia and more severely impaired elderly patients with minor depression. The benefits of PST-PC were smaller, had slower onset, and were more subject to site differences than those of paroxetine.
Aged↗
Users' guides to the medical literature: XXIV. How to use an article on the clinical manifestations of disease. Evidence-Based Medicine Working Group.
Clinicians rely on knowledge about the clinical manifestations of disease to make clinical diagnoses. Before using research on the frequency of clinical features found in patients with a disease, clinicians should appraise the evidence for its validity, results, and applicability. For validity, 4 issues are important-how the diagnoses were verified, how the study sample relates to all patients with the disease, how the clinical findings were sought, and how the clinical findings were characterized. Ideally, investigators will verify the presence of disease in study patients using credible criteria that are independent of the clinical manifestations under study. Also, ideally the study patients will represent the full spectrum of the disease, undergo a thorough and consistent search for clinical findings, and these findings will be well characterized in nature and timing. The main results of these studies are expressed as the number and percentages of patients with each manifestation. Confidence intervals can describe the precision of these frequencies. Most clinical findings occur with only intermediate frequency, and since these frequencies are equivalent to diagnostic sensitivities, this means that the absence of a single finding is rarely powerful enough to exclude the disease. Before acting on the evidence, clinicians should consider whether it applies to their own patients and whether it has been superseded by new developments. Detailed knowledge of the clinical manifestations of disease should increase clinicians' ability to raise diagnostic hypotheses, select differential diagnoses, and verify final diagnoses. JAMA. 2000;284:869-875
Diagnosis↗
Decreasing prevalence of cigarette smoking in the middle income country of Mauritius: questionnaire survey.
OBJECTIVES: To describe changes in the prevalence of cigarette smoking in the middle income country of Mauritius from 1987 to 1998, and to relate these changes to legislative and health promotion efforts over the same period. DESIGN: Questionnaire survey. SETTING: Mauritius, an island in the Indian Ocean with a population of about 1.2 million (about 70% south Asian, 2% Chinese, and 28% Creole). PARTICIPANTS: Data were obtained from 5072 participants in 1987, 6573 in 1992, and 6281 in 1998. MAIN OUTCOME MEASURES: Prevalence of current smoking in 1987, 1992, and 1998, sales of cigarettes in Mauritius, and information on activities for control of tobacco. RESULTS: Self reported cigarette smoking has been decreasing in Mauritius since 1987, with the largest decrease between 1987 and 1992. From 1987 to 1998 smoking prevalence decreased by 23% in men and 61% in women. Smoking decreased across all age and ethnic groups and across different levels of income and education. Sales of cigarettes also decreased in line with smoking prevalence. CONCLUSIONS: The introduction of cigarette taxes, a limited health promotion programme, and the absence of massive promotional campaigns by the sole tobacco company on Mauritius have led to a striking and continued decrease in smoking prevalence and cigarette consumption on the island.
Adult↗
A systematic review of newer pharmacotherapies for depression in adults: evidence report summary.
BACKGROUND: Depressive disorders are persistent, recurring illnesses that cause great suffering for patients and their families. PURPOSE: To evaluate the benefits and adverse effects of newer pharmacotherapies and herbal treatments for depressive disorders in adults and adolescents. DATA SOURCES: English-language and non-English-language literature from 1980 to January 1998 was identified from a specialized registry of controlled trials, meta-analyses, and experts. STUDY SELECTION: Randomized trials evaluating newer antidepressants (such as serotonin reuptake inhibitors, serotonin norepinephrine reuptake inhibitors, and St. John's wort) that reported clinical outcomes were selected. DATA EXTRACTION: Two persons independently abstracted data that were then synthesized descriptively; some data were pooled by using a random-effects model. DATA SYNTHESIS: Of 315 eligible trials, most evaluated antidepressants in adults with major depression, were conducted among outpatients, and examined acute-phase treatment. Newer antidepressants were more effective than placebo for major depression (relative benefit, 1.6 [95% CI, 1.5 to 1.7]) and dysthymia (relative benefit, 1.7 [CI, 1.3 to 2.3]). They were effective among older adults and primary care patients. Efficacy did not differ among newer agents or between newer and older agents. Hypericum (St. John's wort) was more effective than placebo for mild to moderate depression (risk ratio, 1.9 [CI, 1.2 to 2.8]), but publication bias may have inflated the estimate of benefit. Newer and older antidepressants did not differ for overall discontinuation rates, but side effect profiles varied significantly. Data were insufficient for determining the efficacy of newer antidepressants for subsyndromal depression, depression with coexisting medical or psychiatric illness, or depression in adolescents. CONCLUSIONS: Newer antidepressants are clearly effective in treating depressive disorders in diverse settings. Because of similar efficacy, both newer and older antidepressants should be considered when making treatment decisions. Better information is urgently needed on the efficacy of newer antidepressants in patients with nonmajor depression and in special populations, including adolescents.
Age Factors↗
Antibiotics for acute maxillary sinusitis.
OBJECTIVES: For adults seeking care in ambulatory practices, sinusitis is the most common diagnosis treated with antibiotics. We examined whether antibiotics are indicated for acute sinusitis, and if so, which antibiotic classes are most effective. SEARCH STRATEGY: Relevant studies were identified from searches of MEDLINE and EMBASE in October 1998, contacts with pharmaceutical companies and bibliographies of included studies. SELECTION CRITERIA: Randomized trials were eligible that compared antibiotic to control or antibiotics from different classes for acute maxillary sinusitis. Additional criteria were diagnostic confirmation by radiograph or sinus aspiration, outcomes that included clinical cure or improvement and a sample size of 30 or more adults. Of 1784 potentially relevant studies, two or more reviewers identified 32 studies meeting selection criteria. DATA COLLECTION AND ANALYSIS: Data were abstracted independently by 2 persons and synthesized descriptively. Some data were analyzed quantitatively using a random effects model. Primary outcomes were a) clinical cure and b) clinical cure or improvement. Secondary outcomes were radiographic improvement, relapse rates, and dropouts due to adverse effects. MAIN RESULTS: Thirty-two trials, involving 7,330 subjects evaluated antibiotic treatment for acute maxillary sinusitis. Major comparisons were antibiotic vs. control (n=5); newer, non-penicillin antibiotic vs. penicillin class (n=10); and amoxicillin-clavulanate vs. other extended spectrum antibiotics (n=10). Most trials were conducted in otolaryngology settings. Only 5 trials described adequate allocation and concealment procedures; 10 were double-blind. Compared to control, penicillin improved clinical cures [relative risk (RR) 1.72, 95% CI 1.00 to 2.96]. Treatment with amoxicillin did not significantly improve cure rates (RR 2.06; 95% CI 0.65 to 6.53), but there was significant variability between studies. Radiographic outcomes were improved by antibiotic treatment. Comparisons between classes of antibiotics showed no significant differences: newer non-penicillins vs. penicillins (RR for cure 1.07; 95% CI 0.99 to 1.17); newer non-penicillins vs. amoxicillin-clavulanate (RR for cure 1.01, 95% CI 0.97 to 1.04). Compared to amoxicillin-clavulanate, dropouts due to adverse effects were significantly lower for cephalosporin antibiotics. Relapse rates within one month of successful therapy were 5%. REVIEWER'S CONCLUSIONS: For acute maxillary sinusitis confirmed radiographically or by aspiration, current evidence is limited but supports penicillin or amoxicillin for 7 to 14 days. Clinicians should weigh the moderate benefits of antibiotic treatment against the potential for adverse effects.
Acute Disease↗
Efficacy of newer medications for treating depression in primary care patients.
PURPOSE: Several medications have recently been introduced for the treatment of depression. We reviewed the literature to summarize their efficacy in the treatment of depression in adult patients in primary care settings. METHODS: We searched the literature published from 1980 to January 1998 using the Cochrane Collaboration Depression Anxiety and Neurosis Group's specialized registry of 8,451 clinical trials, references from trials and 46 pertinent meta-analyses, and consultation with experts. We included randomized controlled trials of at least 6 weeks' duration that measured clinical outcomes and compared one of 32 newer medications with another newer antidepressant, an older antidepressant, a placebo, or a psychosocial intervention for the treatment of depressed patients in primary care settings. The primary outcome was response rate, defined as the proportion of patients experiencing a 50% or greater improvement in depressive symptoms. RESULTS: There were 28 randomized controlled trials involving 5,940 adult primary care patients with major depression, depression requiring treatment, dysthymia, or mixed anxiety depression. Newer agents, including selective serotonin re-uptake inhibitors, serotonin norepinephrine inhibitors, reversible inhibitors of monoamine oxidase, and dopamine antagonists, were usually compared with tricyclic agents. Average response rates were 63% for newer agents, 35% for placebo, and 60% for tricyclic agents. Newer agents were significantly more effective than placebo [risk ratio = 1.6; 95% confidence interval (CI), 1.2 to 2.1), but similar to tricyclic agents (risk ratio = 1.0; 95% CI, 0.9 to 1.1). Response rates were similar in the different types of depressive disorders, except that two small trials in frail older patients showed no significant effects of newer agents compared with placebo. Dropout rates as a result of adverse effects were 8% with newer agents and 13% with tricyclic agents (P <0.05). CONCLUSIONS: In primary care settings, newer antidepressants are more effective than placebo and have similar efficacy compared with tricyclic agents in the acute treatment of depression. Dropout rates as a result of adverse effects are lower with newer compared with tricyclic agents. Future studies should compare the effectiveness of different therapies among primary care patients with less severe depression and greater medical and psychiatric comorbidity.
Antidepressive Agents, Second-Generation↗
Anti-galactose-alpha(1,3)Galactose antibody production in alpha1, 3-galactosyltransferase gene knockout mice after xeno- and allotransplantation.
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Animals↗
Efficacy of FK506, leflunomide, anti-CD4, and CTLA4IG treatments in rat to mouse pancreas xenograft transplantation.
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Abatacept↗
Anti-galactose-alpha(1,3) galactose antibody production in alpha1,3-galactosyltransferase gene knockout mice after xeno and allo transplantation.
Antibodies (Abs) that mediate the hyperacute rejection and acute vascular rejection/delayed xenograft rejection of pig organs in humans and Old World primates are predominantly directed at a single carbohydrate epitope, galactose-alpha1,3-galactose (alpha1,3Gal). The T-cell dependence of elicited anti-alpha1,3Gal Ab responses in humans and Old World primates is controversial. In this study we have characterized anti-alpha1,3Gal Ab production in mice with disrupted alpha1,3-galactosyltransferase genes (GT-Ko mice) and determined the T-cell dependence of anti-alpha1,3Gal Ab responses, following xenograft and allograft transplantation. GT-Ko mice produce natural anti-alpha1,3Gal IgM and IgG in an age-dependent manner, however, these Abs could not elicit hyperacute rejection nor affect the rate of cardiac xenograft (3-5 days) or allograft rejection (7-9 days). Transplantation of xenogeneic Lewis rats hearts elicited modest anti-alpha1,3Gal Ab, but vigorous xenoAb responses. The anti-alpha1,3Gal Ab response was restricted to the IgM and IgG3 subclass while the xenoAb response comprised IgM and all four IgG subclasses. Transplantation of allogeneic C3H hearts elicited weak anti-alpha1,3Gal Ab responses that were primarily IgM, but vigorous alloAb responses. Despite the restriction of elicited anti-alpha 1,3Gal Ab responses to the IgM and IgG3 isotypes, these responses are T-cell dependent. The ability of allografts to elicit weak anti-alpha1,3Gal but strong allo-Ab responses, can be explained by the dependence of alpha1,3Gal-specific B cells on cognate help from T cells.
Age Factors↗
Tolerance of T-independent xeno-antibody responses in the hamster-to-rat xenotransplantation model is species-restricted but not tissue-specific.
Control of early acute xenograft rejection xenoreactions in the hamster-to-Lewis rat xenotransplantation model with cyclosporine (CsA) and leflunomide subdues early T-independent xenoreactivity and uncovers a late immune response that can be controlled by CsA alone. We had attributed this acquired responsiveness to CsA to the induction of tolerance of T-independent xeno-antibody responses in the recipient and recently reported that this tolerance is species-specific. Here we have further characterized the specificity and nature of this tolerant state. Lewis rats transplanted with either hearts, skin, kidney or spleen/pancreas from Golden Syrian hamsters were treated with leflunomide (5 mg/kg/day by gavage) for 14-21 days and CsA (20 mg/kg/day by gavage) continuously from the day of transplant. Some Lewis rats received a second graft of hearts or skin from Golden Syrian hamsters (day 21-30 after first transplant), and a third heart graft from Balb/c mice (day 60 after the first transplant). Serum was harvested and the titers of xenoreactive antibodies were quantified by flow cytometry. All grafts were harvested at the end of each experiment and examined by histological and immunohistochemical methods. The combination of CsA and leflunomide was able to completely inhibit the rejection of kidney, spleen and pancreas xenografts in this hamster-to-rat xenotransplantation model. In addition, only a transient treatment with leflunomide was necessary, and long-term graft survival could subsequently be maintained by CsA alone. Histological examination of these grafts at > 80 days post-transplantation indicated minimal signs of rejection. These immediately vascularized organs induced T-independent B-cell tolerance, so that second grafts of hamster hearts and skin could be maintained with CsA alone. Under the same immunosuppressive regimen, only four out of nine Lewis rats exhibited long-term hamster skin survival, probably reflecting the increased immunogenicity of the skin compared with other vascularized grafts. Nonetheless, all rats that did not reject the hamster skin graft also did not reject the hamster heart while on CsA alone. Finally, we demonstrate that the tolerant state could be maintained for up to 30 days in the absence of xenograft. The vigorous T-independent antibody response that mediates acute xenograft rejection in the hamster-to-rat model can be tolerized by the immunosuppressive regimen of CsA and leflunomide. The lack of organ specificity for the induction of this tolerance suggests that the xenoantigens inducing tolerance may be common endothelial cell antigens. Finally, the presence of the xenograft has been previously shown to be critical for the induction of T-independent B-cell tolerance, however, the tolerant state is relatively stable and persists after the removal of the xenograft.
Animals↗
Non-depleting anti-CD4, but not anti-CD8, antibody induces long-term survival of xenogeneic and allogeneic hearts in alpha1,3-galactosyltransferase knockout (GT-Ko) mice.
The anti-galactose-alpha1,3-galactose (Gal) antibody (Ab) response following pig-to-human transplantation is vigorous and largely resistant to currently available immunosuppression. The recent generation of GT-Ko mice provides a unique opportunity to study the immunological basis of xenograft-elicited anti-Gal Ab response in vivo, and to test the efficacy of various strategies at controlling this Ab response [1]. In this study, we compared the ability of non-depleting anti-CD4 and anti-CD8 to control rejection and antibody production in GT-Ko mice following xenograft and allograft transplantation. Hearts from baby Lewis rat or C3H mice were transplanted heterotopically into GT-Ko. Non-depleting anti-CD4 (YTS177) and anti-CD8 (YTS105) Abs were used at 1 mg/mouse, and given as four doses daily from day -2 to 1 then q.o.d. till day 21. Xenograft rejection occurred at 3 to 5 days post-transplantation in untreated GT-Ko recipients, and was histologically characterized as vascular rejection. Anti-CD4, but not anti-CD8, Ab treatment prolonged xenograft survival to 68 to 74 days and inhibited anti-Gal Ab as well as xeno-Ab production. In four of the five hearts from anti-CD4 mAbs-treated GT-Ko mice, we observed classic signs of chronic rejection, namely, thickened intima in the lumen of vessels, significant IgM deposition, fibrosis and modest mononuclear cell infiltrate of Mac-1+ macrophages and scattered T cells (CD8>CD4). Xenograft rejection in untreated, as well as anti-CD4- and anti-CD8-treated, recipients was associated with increased intragraft IL-6, IFN-gamma and IL-10 mRNA. C3H allografts were rejected in 7 to 9 days by untreated GT-Ko mice and were histologically characterized as cellular rejection. Treatment with anti-CD4 and anti-CD8 mAb resulted in graft survivals of >94.8 and 11.8 days, respectively. Anti-CD4 mAb treatment resulted in a transient inhibition of alloreactive and anti-Gal Ab production. The presence of circulating alloreactive and anti-Gal Abs at >50 days post-transplant was associated with significant IgM and IgG deposition in the graft. Yet, in the anti-CD4 mAb-treated group, the allografts showed no signs of rejection at the time of sacrifice (>100 days post-transplantation). All rejected allografts had elevated levels of intragraft IL-6, IFN-gamma and IL-10 mRNA, while the long-surviving anti-CD4-treated allografts had reduced mRNA levels of these cytokines. Collectively, our studies suggest that the elicited xeno-antibody production and anti-Gal Ab production in GT-Ko mice are CD4+ T-cell dependent. The majority of xenografts succumbed to chronic rejection, while allografts survived with minimal histological change, despite elevated levels of circulating alloAbs. Thus, immunosuppression with anti-CD4 mAb therapy induces long-term survival of allografts more effectively than to xenografts.
Animals↗
Heritability of the maternal meiotic drive system linked to Om and high-resolution mapping of the Responder locus in mouse.
Matings between (C57BL/6 x DDK)F(1) females and C57BL/6 males result in a significant excess of offspring inheriting maternal DDK alleles in the central region of mouse chromosome 11 due to meiotic drive at the second meiotic division. We have shown previously that the locus subject to selection is in the vicinity of D11Mit66, a marker closely linked to the Om locus that controls the preimplantation embryo-lethal phenotype known as the "DDK syndrome." We have also shown that observation of meiotic drive in this system depends upon the genotype of the sire. Here we show that females that are heterozygous at Om retain the meiotic drive phenotype and define a 0.32-cM candidate interval for the Responder locus in this drive system. In addition, analysis of the inheritance of alleles at Om among the offspring of F(1) intercrosses indicates that the effect of the sire is determined by the sperm genotype at Om or a locus linked to Om.
Animals↗
Which antibiotics lead to higher clinical cure rates in adults with acute maxillary sinusitis?
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Acute Disease↗
The relationship of aging and dysthymia in primary care.
The authors compared symptomatic and functional characteristics between older (age > or =60; n=91) and younger (age 18-59; n=125) primary care patients with dysthymia. Three of six significantly different depression symptoms were of moderate-to-large effect size, with the older group having a lower proportion reporting the symptom. The older group had a worse physical health function score but a better mental health function score. There appears to be a core of symptoms and functional impairment that generalizes across the age span. There are also significant age differences. Growing older appears to have an impact on the nature of what it means to have dysthymia.
Adult↗
Transcriptional regulation of Fas gene expression by GA-binding protein and AP-1 in T cell antigen receptor.CD3 complex-stimulated T cells.
Fas (CD95 or APO-1), a transmembrane cell surface receptor of the tumor necrosis factor receptor family, is up-regulated in activated T lymphocytes. Our present study identified an upstream enhancer element (between nucleotide positions -862 and -682) containing a GA-binding protein (GABP) site and a low affinity activating protein-1 (AP-1)-binding site. T cell activation increased the DNA binding of GABP and AP-1 to this enhancer site. The specificity of GABP and AP-1 binding was demonstrated by competition electrophoretic mobility shift assay and supershift electrophoretic mobility shift assay with antibodies against GABP and AP-1, respectively. Mutational analysis of Fas promoter revealed that both GABP- and AP-1-binding sites were required for initiating Fas gene transcription. We further show that anti-CD3 mAb, phorbol 12-myristate 13-acetate, and phorbol 12-myristate 13-acetate/ionomycin strongly activated promoters carrying multiple copies of the Fas enhancer, and mutation of either the GABP or AP-1 binding site severely reduced transcriptional activity. Taken together, these results suggest that the transcription factors GABP and AP-1 play a critical role in the induction of Fas gene expression in T cell antigen receptor.CD3-stimulated Jurkat cells.
Base Sequence↗
In vitro and in vivo antitumor activity of a novel immunomodulatory drug, leflunomide: mechanisms of action.
Leflunomide, a novel immunomodulatory drug, has two biochemical activities: inhibition of tyrosine phosphorylation and inhibition of pyrimidine nucleotide synthesis. In the present study, we first showed that A77 1726 [N-(4-trifluoromethylphenyl-2-cyano-3-hydroxycrotoamide)], the active metabolite of leflunomide, was more effective at inhibiting the tyrosine kinase activity of platelet-derived growth factor (PDGF) receptor than that of epidermal growth factor (EGF) receptor, and had no effect on the tyrosine kinase activity of the fibroblast growth factor receptor. In the presence of exogenous uridine, A77 1726 was more effective at inhibiting the PDGF-stimulated proliferation of PDGF receptor-overexpressing C6 glioma than the EGF-stimulated proliferation of EGF receptor-overexpressing A431 cells. In vivo studies demonstrated that leflunomide treatment strongly inhibited the growth of the C6 glioma but had only a modest effect on the growth of the A431 tumor. Uridine co-administered with leflunomide did not reverse the antitumor activity of leflunomide on C6 and A431 tumors significantly. Quantitation of nucleotide levels in the tumor tissue revealed that leflunomide treatment significantly reduced pyrimidine nucleotide levels in the fast-growing C6 glioma but had no effect on the relatively slow-growing A431 tumor. Whereas uridine co-administration normalized pyrimidine nucleotide levels, it had minimal effects on the antitumor activity of leflunomide in both tumor models. Immunohistochemical analysis revealed that leflunomide treatment significantly reduced the number of proliferating cell nuclear antigen-positive cells in C6 glioma, and that uridine only partially reversed this inhibition. These results collectively suggest that the in vivo antitumor effect of leflunomide is largely independent of its inhibitory effect on pyrimidine nucleotide synthesis. The possibility that leflunomide exerts its antitumor activity by inhibition of tyrosine phosphorylation or by a yet unidentified mode of action is discussed.
3T3 Cells↗
The portosystemic shunt protects liver against ischemic reperfusion injury.
BACKGROUND: The goal of this study was to characterize the importance of splanchnic viscera in liver ischemic reperfusion injury and to enhance the tolerance of liver to warm ischemia injury with portosystemic shunt. METHODS: The hepatic blood flow of male Sprague Dawley rats was subjected to 45, 60, 120, and 150 min liver warm ischemia with or without portosystemic shunt (splenic-caval shunt). The production of tumor necrosis factor a (TNFa), nuclear factor-kappaB activation, inducible NO synthase (iNOS) expression, and apoptosis were examined. RESULTS: A total of 67% of rats with 45 min liver warm ischemia (n=6) and 100% of rats with 60 min liver warm ischemia (n=6) died within 1 day. However, all rats with 120 min (n=8) liver warm ischemia in splenic-caval shunt group survived for over 1 day, 6/8 for over 3 days, and 5/8 for over 5 days without significant histological changes of the liver. Serum tumor necrosis factor levels in liver warm ischemic rats were increased, This increase was significantly reversed after portosystemic shunt. After challenge with lipopolysaccharide (1 mg/kg, p.v.), naive rats survived for over 5 days (n=4) with the peak value of rat tumor necrosis factor (240 pg/ml) at 90 min. In contrast, all rats died within one day (n=5) with the peak value of rat tumor necrosis factor a (465 pg/ml) at 45 min after administration of lipopolysaccharide in the rats with liver warm ischemia plus splenic-caval shunt. iNOS expression and nuclear factor-kappaB activation were very strongly increased in the hepatocytes after liver warm ischemia with portosystemic shunt, compared with liver ischemia without portosytemic shunt. CONCLUSIONS: We conclude that the splanchnic viscera can contribute to liver ischemic reperfusion injury. Portosystemic shunt enhances the tolerance of liver to warm ischemia through the protective role of iNOS and nuclear factor-kappaB (NF-kappaB).
Animals↗