Biomedical subjects

Toru Kubota

Publications and source records attributed to Toru Kubota.

At least 19 recordsLinked to original sources

PubMed2007

Importance of the anti-interferon capacity of Sendai virus C protein for pathogenicity in mice.

The Sendai virus (SeV) C protein blocks signal transduction of interferon (IFN), thereby counteracting the antiviral actions of IFN. Using HeLa cell lines expressing truncated or mutated SeV C proteins, we found that the C-terminal half has anti-IFN capacity, and that K(151)A, E(153)A, and R(154)A substitutions in the C protein eliminated this capacity. Here, we further created the mutant virus SeV Cm*, in which K(151)A, E(153)K, and R(157)L substitutions in the C protein were introduced without changing the amino acid sequence of overlapped P, V, and W proteins. SeV Cm* was found to lack anti-IFN capacity, as expected. While the growth rate and final yield of SeV Cm* were inferior to those of the wild-type SeV in IFN-responsive, STAT1-positive 2fTGH cells, SeV Cm* grew equivalently to the wild-type SeV in IFN-nonresponsive, STAT1-deficient U3A cells. SeV Cm* was thus shown to maintain multiplication capacity, except that it lacked anti-IFN capacity. Intranasally inoculated SeV Cm* could propagate in the lungs of STAT1(-/-) mice but was cleared from those of STAT1(+/+) mice without propagation. It was found that the anti-IFN capacity of the SeV C protein was indispensable for pathogenicity in mice. Conversely, the results show that the innate immunity contributed to elimination of SeV in early stages of infection in the absence of anti-IFN capacity.

Animals↗

PubMed2006

Blockade of NF-kappaB improves cardiac function and survival after myocardial infarction.

NF-kappaB is a key transcription factor that regulates inflammatory processes. In the present study, we tested the hypothesis that blockade of NF-kappaB ameliorates cardiac remodeling and failure after myocardial infarction (MI). Knockout mice with targeted disruption of the p50 subunit of NF-kappaB (KO) were used to block the activation of NF-kappaB. MI was induced by ligation of the left coronary artery in male KO and age-matched wild-type (WT) mice. NF-kappaB was activated in noninfarct as well as infarct myocardium in WT+MI mice, while the activity was completely abolished in KO mice. Blockade of NF-kappaB significantly reduced early ventricular rupture after MI and improved survival by ameliorating congestive heart failure. Echocardiographic and pressure measurements revealed that left ventricular fractional shortening and maximum rate of rise of left ventricular pressure were significantly increased and end-diastolic pressure was significantly decreased in KO+MI mice compared with WT+MI mice. Histological analysis demonstrated significant suppression of myocyte hypertrophy as well as interstitial fibrosis in the noninfarct myocardium of KO+MI mice. Blockade of NF-kappaB did not ameliorate expression of proinflammatory cytokines in infarct or noninfarct myocardium. In contrast, phosphorylation of c-Jun NH2-terminal kinase was almost completely abolished in KO+MI mice. The present study demonstrates that targeted disruption of the p50 subunit of NF-kappaB reduces ventricular rupture as well as improves cardiac function and survival after MI. Blockade of NF-kappaB might be a new therapeutic strategy to attenuate cardiac remodeling and failure after MI.

Animals↗

PubMed2006

Overexpression of mitochondrial peroxiredoxin-3 prevents left ventricular remodeling and failure after myocardial infarction in mice.

BACKGROUND: Mitochondrial oxidative stress and damage play major roles in the development and progression of left ventricular (LV) remodeling and failure after myocardial infarction (MI). We hypothesized that overexpression of the mitochondrial antioxidant, peroxiredoxin-3 (Prx-3), could attenuate this deleterious process. METHODS AND RESULTS: We created MI in 12- to 16-week-old, male Prx-3-transgenic mice (TG+MI, n=37) and nontransgenic wild-type mice (WT+MI, n=39) by ligating the left coronary artery. Prx-3 protein levels were 1.8 times higher in the hearts from TG than WT mice, with no significant changes in other antioxidant enzymes. At 4 weeks after MI, LV thiobarbituric acid-reactive substances in the mitochondria were significantly lower in TG+MI than in WT+MI mice (mean+/-SEM, 1.5+/-0.2 vs 2.2+/-0.2 nmol/mg protein; n=8 each, P<0.05). LV cavity dilatation and dysfunction were attenuated in TG+MI compared with WT+MI mice, with no significant differences in infarct size (56+/-1% vs 55+/-1%; n=6 each, P=NS) and aortic pressure between groups. Mean LV end-diastolic pressures and lung weights in TG+MI mice were also larger than those in WT+sham-operated mice but smaller than those in WT+MI mice. Improvement in LV function in TG+MI mice was accompanied by a decrease in myocyte hypertrophy, interstitial fibrosis, and apoptosis in the noninfarcted LV. Mitochondrial DNA copy number and complex enzyme activities were significantly decreased in WT+MI mice, and this decrease was also ameliorated in TG+MI mice. CONCLUSIONS: Overexpression of Prx-3 inhibited LV remodeling and failure after MI. Therapies designed to interfere with mitochondrial oxidative stress including the antioxidant Prx-3 might be beneficial in preventing cardiac failure.

Animals↗

PubMed2006

Targeted deletion of p53 prevents cardiac rupture after myocardial infarction in mice.

OBJECTIVE: Apoptosis may play an important role in cardiac remodeling after myocardial infarction (MI). p53 is a well-known proapoptotic factor. However, its pathophysiological significance in these conditions remains unclear. We thus examined the effects of target deletion of the p53 gene on post-MI hearts. METHODS: Anterior MI was created in male heterozygous p53-deficient (p53(+/-); n = 28) mice and sibling wild-type (p53(+/+); n = 29) mice by ligating the left coronary artery. RESULTS: By day 7, p53(+/-) mice had significantly better survival rate than p53(+/+) mice (89% vs. 69%, P < 0.05). Notably, p53(+/-) mice had a significantly lower incidence of left ventricular (LV) rupture (7% vs. 28%, P < 0.05) despite comparable infarct size (60 +/- 2% vs. 59 +/- 2%, P = NS), heart rate (488 +/- 15 vs. 489 +/- 17 bpm, P = NS), or mean arterial blood pressure (80 +/- 2 vs. 78 +/- 3 mm Hg, P = NS). The extent of infiltrating interstitial cells including macrophages into the post-MI hearts was not altered by the deletion of p53. Further, collagen deposition as well as the zymographic MMP-2 and -9 activities were comparable between p53(+/-) and p53(+/+) mice with MI. However, the p53(+/-) mice had a significantly thicker infarct wall. The number of TUNEL-positive cells in the infarct area was significantly lower in p53(+/-) mice than in p53(+/+) mice (423+/-86 vs. 1330 +/- 275/10(5) cells, P < 0.01). CONCLUSIONS: p53 is involved in cardiac rupture after MI, probably via the induction of a proapoptotic pathway. The inhibition of p53 may be a potentially useful therapeutic strategy to manage post-MI patients.

Animals↗

PubMed2006

A rat model of a repeat 70% major hepatectomy.

BACKGROUND: This study investigated the effects of a repeat 70% major hepatectomy in a rat model. MATERIALS AND METHODS: The left lateral and median lobes of the livers of 80 seven-week-old male Wistar rats were excised during primary hepatectomy, removing a total of 70% of the liver. In 40 of the rats, the regenerated right lateral lobe, comprising 70% of the remnant liver, was excised during secondary hepatectomy 7 days after the initial procedure. The survival rate, posthepatectomized regeneration ratio, and laboratory blood data were compared between the groups that had undergone initial only and repeat hepatectomies. RESULTS: All of the rats survived for at least 7 days after each procedure. The remaining liver returned to up to about 90% of its original wet weight by 5 days in both groups. The serum glutamic-pyruvic transaminase levels peaked 12 h after hepatectomy, remained at a similar level at 36 h, and had normalized by 2 days. Serum total bilirubin levels were similar in both groups. The total cell numbers after 5 days were significantly higher in the initial hepatectomy group than in the repeat hepatectomy group. CONCLUSIONS: We established a rat model in which an initial 70% major hepatectomy was followed by a repeat 70% major hepatectomy of the regenerated liver. The time taken to restore the integrity of the liver was longer in the rats that underwent repeat hepatectomy. We believe that this model will be useful for investigating the regenerative ability of the liver after a second major hepatectomy.

Alanine Transaminase↗

PubMed2006

Targeted deletion of matrix metalloproteinase 2 ameliorates myocardial remodeling in mice with chronic pressure overload.

Matrix metalloproteinases (MMPs) play an important role in the extracellular matrix remodeling. Experimental and clinical studies have demonstrated that MMP 2 and 9 are upregulated in the dilated failing hearts and involved in the development and progression of myocardial remodeling. However, little is known about the role of MMPs in mediating adverse myocardial remodeling in response to chronic pressure overload (PO). We, thus, hypothesized that selective disruption of the MMP 2 gene could ameliorate PO-induced cardiac hypertrophy and dysfunction in mice. PO hypertrophy was induced by transverse aortic constriction (TAC) in male MMP 2 knockout (KO) mice (n=10) and sibling wild-type (WT) mice (n=9). At 6 weeks, myocardial MMP 2 zymographic activity was 2.4-fold increased in WT+TAC, and this increase was not observed in KO+TAC, with no significant alterations in other MMPs (MMP 1, 3, 8, and 9) or tissue inhibitors of MMPs (1, 2, 3, and 4). TAC resulted in a significant increase in left ventricular (LV) weight and LV end-diastolic pressure (EDP) with preserved systolic function. KO+TAC mice exerted significantly lower LV weight/body weight (4.2+/-0.2 versus 5.0+/-0.2 mg/g; P<0.01), lung weight/body weight (4.9+/-0.2 versus 6.2+/-0.4 mg/g; P<0.01), and LV end-diastolic pressure (4+/-1 versus 10+/-2 mm Hg; P<0.05) than WT+TAC mice despite comparable aortic pressure. KO+TAC mice had less myocyte hypertrophy (cross-sectional area; 322+/-14 versus 392+/-14 microm2; P<0.01) and interstitial fibrosis (collagen volume fraction; 3.3+/-0.5 versus 8.2+/-1.0%; P<0.01) than WT+TAC mice. MMP 2 plays an important role in PO-induced LV hypertrophy and dysfunction. The inhibition of MMP 2 activation may, therefore, be a useful therapeutic strategy to manage hypertensive heart disease.

Animals↗

PubMed2006

Angiotensin II type 1 receptor blocker attenuates exacerbated left ventricular remodeling and failure in diabetes-associated myocardial infarction.

Diabetes mellitus adversely affects the outcomes in patients with myocardial infarction (MI), due in part to the exacerbation of left ventricular (LV) remodeling. Although angiotensin II type 1 receptor blocker (ARB) has been demonstrated to be effective in the treatment of heart failure, information about the potential benefits of ARB on advanced LV failure associated with diabetes is lacking. To induce diabetes, male mice were injected intraperitoneally with streptozotocin (200 mg/kg). At 2 weeks, anterior MI was created by ligating the left coronary artery. These animals received treatment with olmesartan (0.1 mg/kg/day; n = 50) or vehicle (n = 51) for 4 weeks. Diabetes worsened the survival and exaggerated echocardiographic LV dilatation and dysfunction in MI. Treatment of diabetic MI mice with olmesartan significantly improved the survival rate (42% versus 27%, P < 0.05) without affecting blood glucose, arterial blood pressure, or infarct size. It also attenuated LV dysfunction in diabetic MI. Likewise, olmesartan attenuated myocyte hypertrophy, interstitial fibrosis, and the number of apoptotic cells in the noninfarcted LV from diabetic MI. Post-MI LV remodeling and failure in diabetes were ameliorated by ARB, providing further evidence that angiotensin II plays a pivotal role in the exacerbated heart failure after diabetic MI.

Angiotensin II Type 1 Receptor Blockers↗

PubMed2006

Safety limit of the extent of hepatectomy for rats with moderately fatty liver: experimental study concerning living liver donor safety.

INTRODUCTION: The aim of the present study was to determine whether rats with moderately fatty liver could withstand a 90% hepatectomy, which rats with normal livers can survive. MATERIAL AND METHODS: Nine-week-old male Wistar rats were used. Normal rat chow was fed to the normal liver group, and fat-enriched rat chow was fed to the fatty liver group for 4 weeks to induce a moderately fatty liver. The authors have previously reported that this fatty liver rat model can cause fatal liver dysfunction after reduced-size-liver transplantation. A 90% and 95% hepatectomy were performed using rats of both groups to evaluate posthepatectomized liver function. RESULTS: All rats undergoing a 90% hepatectomy were still alive 30 days after the hepatectomy, but the rats that underwent a 95% hepatectomy were all dead within 4 days regardless of group. Increases in the liver remnant wet weight measured until 7 postoperative days after 90% hepatectomy were almost similar among the two groups. Alanin aminotransferase measured at 24, 48, 72, and 168 h after a 90% hepatectomy were significantly higher in the fatty liver group than in the normal liver group. Similarly, at up to 72 h postoperatively, the serum hyarulonic acids were significantly higher in the fatty liver group. CONCLUSION: A moderately fatty liver did not cause mortality in 90% hepatectomized rats. However, it caused a higher degree of hepatic parenchymal as well as sinusoidal injury.

Animals↗

PubMed2006

Genetic analyses of beta-lactamase negative ampicillin-resistant strains of Haemophilus influenzae isolated in Okinawa, Japan.

Recently, the instance of beta-lactamase-negative ampicillin (AMP)-resistant (BLNAR) strains of Haemophilus influenzae has exhibited a marked increase in Japan. Our group determined the MICs of 160 clinical isolates of H. influenzae at a university hospital in Okinawa, the southernmost part of Japan, and found that 27 strains were BLNAR, while 24 strains were beta-lactamase-producing. Among the latter, 2 strains were resistant to AMP/clavulanic acid. BLNAR strains were shown to be more resistant to cephems than non-BLNAR strains. The competitive affinity assay using biotinylated AMP for penicillin-binding protein (PBP) showed that the binding of cefotiam to PBP 3A/3B of BLNAR strain C2163 was lower than that of the AMP-susceptible strain, while bindings to other PBPs were not changed. The sequences of ftsI, the gene encoding transpeptidase domain of PBP 3A and/or PBP 3B, were determined, and it was found that sequences of the ftsI gene of BLNAR strains were heterogeneous mutations. Deduced amino acid sequence analyses of BLNAR strains showed that three residues (Asn-526, Val-547, and Asn-569) were replaced with Lys, Ile, and Ser, respectively. In addition, some BLNAR strains had an additional three residues (Met-377, Ser-385, and Leu-389) in ftsI replaced with Ile, Thr, and Phe, respectively. Furthermore, changes from Asp-350 to Asn-350 and from Ser-357 to Asn-357 were also found in most BLNAR strains. These substitutions were located around the penicillin binding sites of PBP3. Multiple substitutions in the amino acid sequence seemed to be closely related with extended resistance against beta-lactams, including third-generation cephems. Randomly amplified polymorphism DNA fingerprinting of clinical isolates of BLNAR strains showed genetic heterogeneity of the strains, suggesting that the prevalence of BLNAR in this region was a result of the emergence of multiple clones of this phenotype.

Amino Acid Sequence↗

PubMed2006

[Interferon-alpha+cisplatin+5-FU therapy for gemcitabine-refractory unresectable and recurrent pancreatic cancer].

Interferon-alpha (IFN-Alpha) + cisplatin (CDDP) + 5-FU therapy was given to 10 patients with gemcitabine (GEM)-refractory unresectable or recurrent pancreatic cancer. CDDP (35 mg/m(2)) was administered intravenously on the first day, IFN-Alpha (5x10(6)IU) subcutaneously on day 2,4 and 6 of each week, and 5-FU (175 mg/m(2)/day) continuously infused every day for 4 weeks. The 10 patients consisted of 8 men and 2 women with a mean age of 56.2 years. As the main site of progression, 5 patients had liver metastases, 1 had lung metastases, 2 had peritoneal dissemination, and 2 had local recurrence. The objective response rate was 30%, including 1 complete response. Grade 3 anorexia, neutropenia and thrombocytopenia occurred in 60%, 40% and 40%, respectively. IFN-Alpha + CDDP + 5-FU therapy is an effective treatment for GEM-refractory pancreatic cancer, but with moderate toxicity.

Aged↗

PubMed2005

Cardioprotection afforded by NF-kappaB ablation is associated with activation of Akt in mice overexpressing TNF-alpha.

When selectively overexpressed in mouse heart, TNF-alpha effects the development of a cardiomyopathy that closely mimics that seen in human failing hearts. It has been suggested that two intracellular signaling pathways, the Akt protein kinase and the NF-kappaB transcription factor, mediated TNF-alpha signaling. The present experiments assessed the effects of TNF-alpha overexpression on these two target proteins in vivo. We measured cardiac Akt kinase phosphorylation and NF-kappaB activity in mice overexpressing TNF-alpha (TNF1.6). Both basal and insulin-stimulated Akt phosphorylation were reduced by almost 70% by TNF-alpha overexpression. By contrast, NF-kappaB was robustly activated. These effects were absent when TNF-alpha receptor 1 (TNFR1) was selectively ablated. Cardiomyocyte-specific overexpression of the dominant-negative inhibitory kappaB protein transgene and subsequent inhibition of NF-kappaB activity attenuated the effects of TNF-alpha on Akt phosphorylation. NF-kappaB inhibition also significantly improved fractional shortening and diminished ventricular hypertrophy and survival without affecting infiltrative inflammation or cytokine expression. Thus, while overexpression of TNF-alpha effected a marked Akt inhibition and NF-kappaB activation in mouse hearts, inhibition of NF-kappaB offered salutary benefits mediated at least in part through activation of Akt.

Animals↗

PubMed2005

Myocardial expression of fas and recovery of left ventricular function in patients with recent-onset cardiomyopathy.

OBJECTIVES: This study aimed to evaluate the role of gene expression for predicting myocardial recovery in recent-onset cardiomyopathy. BACKGROUND: Apoptosis may limit ventricular recovery. We examined the myocardial expression of Fas, Fas ligand (FasL), tumor necrosis factor (TNF)-alpha, and TNF receptor 1 (TNFR1), and myocardial recovery in patients from the multicenter Intervention in Myocarditis and Acute Cardiomyopathy (IMAC) study. METHODS: Endomyocardial biopsy samples were obtained in 20 patients with recent-onset (<6 months) idiopathic dilated cardiomyopathy (left ventricular ejection fraction [LVEF] < or =0.40). The LVEF was assessed at baseline and at 6 and 12 months by nuclear scans. Myocardial expression was assessed by ribonuclease (RNase) protection, normalized to a constitutively active gene (glyceraldehydes 3-phosphate dehydrogenase [GAPDH]) and reported as percent GAPDH expression. The change in LVEF at 6 and 12 months was compared by tertiles of expression. RESULTS: For all patients (14 men, 6 women; age 46.5 +/- 10.7 years), the mean LVEF was 0.28 +/- 0.05 at baseline and 0.40 +/- 0.14 at six months. Patients in the highest tertile of Fas expression had minimal improvement at six months (DeltaEF = 0.03 +/- 0.05) when compared with the intermediate (DeltaEF = 0.10 +/- 0.13) and lowest tertiles (DeltaEF = 0.21 +/- 0.11, change in LVEF by tertile, p = 0.006). A similar relationship was seen with TNFR1 expression (highest tertile, DeltaEF = 0.06 +/- 0.07; lowest tertile, DeltaEF = 0.21 +/- 0.11, p = 0.02). In contrast with Fas and TNFR1, expression of TNF-alpha and FasL did not predict recovery of LV function. CONCLUSIONS: In cardiomyopathy of recent onset, increased expression of Fas and TNFR1 was associated with minimal recovery of LV function. Apoptosis limits myocardial recovery, and represents a potential target for therapeutic intervention.

Adult↗

PubMed2005

Blockade of NF-kappaB ameliorates myocardial hypertrophy in response to chronic infusion of angiotensin II.

OBJECTIVE: Nuclear factor (NF)-kappaB is a key transcription factor that regulates inflammatory processes. In the present study, we assessed the hypothesis that blockade of NF-kappaB may ameliorate ventricular hypertrophy in response to chronic infusion of angiotensin II. METHODS: Mice with targeted disruption of the p50 subunit of NF-kappaB (KO) were used to block the activation of NF-kappaB. Male KO and age-matched wild-type (WT) mice were chronically infused with angiotensin II at the rate of 0.2 (low dose) or 2 microg/kg/min (high dose) for 4 weeks. RESULTS: High- but not low-dose angiotensin II significantly increased systemic blood pressure and left ventricular weight in WT mice. In contrast, although the pressor response was slightly but significantly augmented, the hypertrophic effect of angiotensin II was significantly attenuated in KO mice. The attenuated hypertrophic responsiveness was confirmed histologically (cross-sectional area) and transcriptionally (atrial natriuretic peptide). Echocardiography revealed no evidence of cardiac dysfunction in angiotensin II-treated KO mice. Although phosphorylation of MAPKs, including ERK, JNK, or p38-MAPK, was not affected after 4 weeks of angiotensin II treatment in WT mice, phosphorylation of JNK was specifically abrogated in KO mice. Angiotensin II increased myocardial expression of proinflammatory cytokines and chemokines in WT mice, while expression of TNF-alpha and RANTES was paradoxically augmented in KO mice. CONCLUSION: Blockade of NF-kappaB activation attenuated myocardial hypertrophy without deteriorating cardiac function. NF-kappaB may play an important role in cardiac hypertrophy and remodeling besides promoting inflammation.

Angiotensin II↗

PubMed2005

Overexpression of mitochondrial transcription factor a ameliorates mitochondrial deficiencies and cardiac failure after myocardial infarction.

BACKGROUND: Mitochondrial DNA (mtDNA) copy number is decreased not only in mtDNA-mutation diseases but also in a wide variety of acquired degenerative and ischemic diseases. Mitochondrial transcription factor A (TFAM) is essential for mtDNA transcription and replication. Myocardial mtDNA copy number and TFAM expression both decreased in cardiac failure. However, the functional significance of TFAM has not been established in this disease state. METHODS AND RESULTS: We have now addressed this question by creating transgenic (Tg) mice that overexpress human TFAM gene and examined whether TFAM could protect the heart from mtDNA deficiencies and attenuate left ventricular (LV) remodeling and failure after myocardial infarction (MI) created by ligating the left coronary artery. TFAM overexpression could ameliorate the decrease in mtDNA copy number and mitochondrial complex enzyme activities in post-MI hearts. Survival rate during 4 weeks of MI was significantly higher in Tg-MI than in wild-type (WT) littermates (WT-MI), although infarct size was comparable. LV cavity dilatation and dysfunction were significantly attenuated in Tg-MI. LV end-diastolic pressure was increased in WT-MI, and it was also reduced in Tg-MI. Improvement of LV function in Tg-MI was accompanied by a decrease in myocyte hypertrophy, apoptosis, and interstitial fibrosis as well as oxidative stress in the noninfarcted LV. CONCLUSIONS: Overexpression of TFAM inhibited LV remodeling after MI. TFAM may provide a novel therapeutic strategy of cardiac failure.

Animals↗

PubMed2005

Selective disruption of MMP-2 gene exacerbates myocardial inflammation and dysfunction in mice with cytokine-induced cardiomyopathy.

Tumor necrosis factor-alpha (TNF-alpha) plays a pathophysiological role in the development and progression of heart failure. Matrix metalloproteinase (MMP)-2 is involved in extracellular matrix remodeling. Recent evidence suggests a protective role for this protease against tissue inflammation. Although MMP-2 is upregulated in the failing heart, little is known about its pathophysiological role. We thus hypothesized that ablation of the MMP-2 gene could affect cardiac remodeling and failure in TNF-alpha-induced cardiomyopathy. We crossed transgenic mice with cardiac-specific overexpression of TNF-alpha (TG) with MMP-2 knockout (KO) mice. Four groups of male and female mice were studied: wild-type (WT) with wild MMP-2 (WT/MMP(+/+)), WT with MMP-2 KO (WT/MMP(-/-)), TNF-alpha TG with wild MMP-2 (TG/MMP(+/+)), and TG with MMP-2 KO (TG/MMP(-/-)). The upregulation of MMP-2 zymographic activity in TG/MMP(+/+) mice was completely abolished in TG/MMP(-/-) mice, and other MMPs and tissue inhibitors of metalloproteinase were comparable between groups. Survival was shorter for male TG/MMP(-/-) than TG/MMP(+/+) mice. Female TG/MMP(-/-) mice were more severely affected than TG/MMP(+/+) mice with diminished cardiac function. Myocardial TNF-alpha and other proinflammatory cytokines were increased in TG/MMP(+/+) mice, and this increase was similarly observed in TG/MMP(-/-) mice. The extent of myocardial infiltrating cells including macrophages was greater in TG/MMP(-/-) than in TG/MMP(+/+) mice. Selective ablation of the MMP-2 gene reduces survival and exacerbates cardiac failure in association with the increased level of myocardial inflammation. MMP-2 may play a cardioprotective role in the pathogenesis of cytokine-induced cardiomyopathy.

Animals↗

PubMed2005

Blockade of NF-kappaB improves cardiac function and survival without affecting inflammation in TNF-alpha-induced cardiomyopathy.

OBJECTIVE: NF-kappaB, a key transcription factor that regulates inflammatory processes, has been shown to be activated in the failing human heart with enhanced expression of proinflammatory cytokines. In the present study, we assessed the hypothesis that cardiotoxic effects of proinflammatory cytokines are mediated by the activation of NF-kappaB. METHODS: Transgenic mice with cardiac-specific overexpression of TNF-alpha were used as a model of cytokine-induced cardiomyopathy. To block the activation of NF-kappaB, transgenic mice (TG/p50(+/+)) were crossed with knockout mice in which the p50 subunit of NF-kappaB was disrupted (WT/p50(-/-)). RESULTS: The electrophoretic mobility shift assay demonstrated that NF-kappaB was activated in the myocardium of TG/p50(+/+) mice, while it was completely abolished in TG/p50(-/-) mice. Male TG mice died of congestive heart failure earlier than females, where the disruption of the p50 subunit significantly improved the survival. Compared with TG/p50(+/+) mice, TG/p50(-/-) mice showed a significant reduction of ventricular dilatation and hypertrophy with preserved fractional shortening. Although the myocardial expression of proinflammatory cytokines or infiltration of inflammatory cells was not affected, increased expression and activity of MMP-9 were significantly suppressed in TG/p50(-/-) mice. CONCLUSION: Blockade of NF-kappaB activation did not ameliorate myocardial inflammation but improved cardiac function and survival in male TNF-alpha TG mice. An inhibition of NF-kappaB may be a new therapeutic strategy for cardiac remodeling and heart failure, especially when proinflammatory cytokines are activated.

Animals↗

PubMed2005

Efficacy of hepatic resection for hepatocellular carcinomas larger than 10 cm.

The objective of this study were to evaluate the efficacy of hepatic resection for large hepatocellular carcinomas (HCCs) and examine clinicopathologic factors influencing overall survival after resection of a large HCC. The pre-, intra-, and postoperative factors and long-term outcome of 26 patients with HCCs >10 cm who underwent hepatic resection (group A) were compared with the those of 143 patients with HCCs < or =10 cm (group B). Hepatic resection for large HCCs can be performed with a mortality rate of 3.8%, which was similar to the rate for group B (2.1%). The overall cumulative survival results for group A (1 year 41.0%, 3 years 29.3%, 5 years 29.3%; median survival 10.1 months) were markedly worse than those for group B (1 year 93.1%, 3 years 74.5%, 5 years 44.7%; median survival 53.4 months) (p < 0.0001). Multivariate analysis identified venous invasion as an independent risk factor of survival of patients with a large HCC. The overall cumulative survival results in patients with venous invasion (1 year 28.0%, 3 years 0%; median survival 6.4 months) were markedly worse than in patients without venous invasion (1 year 64.8%, 3.5 years 64.8%; median survival, 51.8 months) (p < 0.0066). We concluded that hepatic resection can be performed safely for HCCs >10 cm with a low mortality rate. It appears reasonable to believe that hepatic resection is the treatment of choice for large HCCs without venous invasion.

Aged↗

PubMed2005

Contrast-enhanced sonography of pancreatic carcinoma: correlations with pathological findings.

BACKGROUND: We examined contrast-enhanced harmonic gray-scale sonographic findings of pancreatic carcinoma in relation to the pathological findings in resected specimens to evaluate correlations between observations made by this modality and the pathological findings. METHODS: The pathological findings of surgical specimens obtained from 16 patients were examined in relation to the contrast-enhanced harmonic gray-scale sonography findings. Lesion vascularity was examined by contrast-enhanced harmonic gray-scale sonography from 20 to 50 s after the injection of Levovist (Schering, Berlin, Germany) (early phase), and lesion enhancement was also monitored at approximately 90 s after injection (delayed phase). RESULTS: Contrast-enhanced harmonic gray-scale sonography showed positive enhancement in 12 of the 16 lesions (peripheral tumor region alone, n = 9; entire tumor, n = 3), while the other 4 lesions showed no contrast enhancement in any region. Twelve enhanced regions (9 peripheral tumor region and 3 entire tumor regions) detected by contrast-enhanced harmonic gray-scale sonography showed: (1) mild fibrosis with inflammation, in 10 regions (83%); (2) the presence of both carcinoma cells and residual acinar cells in 8 (67%); and (3) presence of relatively large arteries in 2 (17%). In contrast, 13 non-enhanced regions (4 entire tumor regions and 9 central regions) showed: (1) severe fibrosis in 10 regions (77%); (2) necrosis in 7 (54%); and (3) mucin in 4 (31%). CONCLUSIONS: Contrast-enhanced harmonic gray-scale sonographic findings of pancreatic carcinoma are influenced by interstitial histological features associated with tumor growth.

Aged↗