Aortic valve replacement in patients age 70 years and older: early and late results

This retrospective analysis was performed to determine the early and late outcome in patients 70 years and older undergoing aortic valve replacement (AVR). From October 1994 to May 2001, 49 patients (24 men and 25 women, age 70 to 88 years [mean 74 +/- 4.6 years]) underwent primary AVR with or without concomitant procedures. Twenty-one received mechanical valves and 28 bioprostheses. Age was different between both groups: 72 +/- 2.3 years (mechanical) and 76 +/- 5.1 years (bioprosthetic) (p = 0.0005). Aortic stenosis was present in 25 patients (51%). Follow-up was 100% complete at a mean follow-up of 2.9 years (range 0.3-6.5 years). Overall hospital mortality was 4.1% (2/49). There were no postoperative complications in 24% of patients. Postoperative hospital stay or hospital survival was 27 +/- 13 days. Survival at 3 and 5 years was 89 +/- 5% and 80 +/- 7%, respectively. Three late deaths were due to noncardiac causes and 1 each had a cardiac or valve-related cause (thromboembolism). Other valve-related complications such as anticoagulant-related hemorrhage, perivalvular leak, endocarditis, prosthetic valve failure, and reoperation were not noted in any of the 49 patients. The actuarial survival curve was similar in each group of bioprosthetic versus mechanical and septuagenarians versus octogenarians. Under the selection criteria for AVR currently applied in our hospital, geriatric patients showed a satisfactory early outcome and medium-term survival benefit.     

Reverse geometrical selectivity in glucuronidation and sulfation of cis- and trans-4-hydroxytamoxifens by human liver UDP-glucuronosyltransferases and sulfotransferases

The phenolic active metabolites, cis-4-hydroxytamoxifen (cis-HO-TAM) and trans-4-hydroxytamoxifen (trans-HO-TAM), of the anti-breast-cancer drug, trans-tamoxifen (TAM), were geometrically selectively glucuronidated in the manner of cis>trans by microsomes and sulfated in the manner of trans>cis by cytosol from the liver of 10 human subjects (7 females and 3 males). There was a large individual difference in the microsomal glucuronidation of cis-HO-TAM, which correlated well with glucuronidation of 4-hydroxybiphenyl by human liver microsomes. However, there was only a slight correlation between the glucuronidation of cis-HO-TAM and trans-HO-TAM or 4-nitrophenol (NP). A small individual difference was observed for the human liver cytosolic sulfation of trans-HO-TAM, which correlated well with the sulfation of NP. Recombinant human UDP-glucuronosyltransferase (UGT)2B15 catalyzed the cis-selective glucuronidation of geometrical isomers of HO-TAM. UGTs1A1, 1A4, 1A9 and 2B7 had weak activity toward HO-TAMs with a much smaller cis-selectivity than did UGT2B15. UGTs1A3 and 1A6 had no detectable activity toward these substrates. Among the four known major sulfotransferases (SULTs) occurring in the human liver, SULT1A1 was strongly suggested to play the most important role in the hepatic cytosolic trans-selective sulfation of HO-TAM isomers. A good correlation was observed between the hepatic cytosolic sulfation of trans-HO-TAM and NP, a standard substrate for SULT1A1. SULT1E1 had slight activity toward the HO-TAMs. SULTs1A3 and 2A1 had no detectable activity toward HO-TAMs.     

Inhibitory effects of metals on ATP-induced current through P2X7 receptor in NG108-15 cells

We investigated the effects of heavy metal ions on the ATP-induced nonselective cation current through P2X7 receptor (I(NS x P2X7)) in NG108-15 cells using the whole-cell patch-clamp technique. Cu2+ inhibited the I(NS x P2X7) most potently among the metal ions investigated. Other metals such as Ni2+, Cd2+, Zn2+ and Co2+ also inhibited the I(NS x P2X7) in concentration-dependent manners. The order of potency was Cu2+ > Ni2+ > Cd2+ > Zn2+ > Co2+ with IC50 values of 16 nM, 0.79 microM, 1.2 microM, 3.0 microM and 4.6 microM, respectively. Fe3+ (10 and 100 microM) and Mn2+ (10 microM) did not affect the INS P2X7. A high concentration of Mn2+ (100 microM) slightly inhibited the I(NS x P2X7). When the concentration-response curve of ATP was obtained in the presence of 3 and 10 nM Cu2+, the maximal response but not the EC50 value appeared to be reduced, suggesting that the inhibition is not competitive. These results suggest that under physiological and toxicological conditions, metal ions, such as Cu2+, Ni2+, Cd2+, Zn2+ and Co2+, may modulate P2X7 receptor channels as inhibitors.     

Effects of anions on ATP-induced [Ca2+], increase in NG108-15 cells

We investigated the effects of anions on different P2 receptors by measuring ATP-induced increase in intracellular Ca2+ concentration ([Ca2+]i) in fura-2-loaded NG108-15 and PC12 cells. In NG108-15 cells, ATP at 100 microM and 1 mM induced a transient and a sustained [Ca2+]i increase, respectively. The former, but not the latter, was inhibited by U-73122, indicating that the former was via the P2Y2 receptor and the latter via the P2X7 receptor. When external Cl- was replaced by other anions, the [Ca2+]i increase mediated by the P2Y2 receptor was not changed, but that mediated by the P2X7 receptor varied in the order of aspartate- > methanesulfonate > Cl- > Br > or = I-. In PC12 cells, transient [Ca2+]i increases mediated by the P2Y2 and P2X2 receptors were not affected by various anions. These results suggest that modulation by anions is unique to the P2X7 receptor and does not occur in P2Y2 and P2X2 receptors. This may be because the mechanism of ATP binding to the P2X7 receptor may be different than that to other P2 receptors.     

Differential effects of bupivacaine enantiomers,ropivacaine and lidocaine on up-regulation of cell surface voltage-dependent sodium channels in adrenal chromaffin cells

In cultured bovine adrenal chromaffin cells, (+/-)-bupivacaine inhibited veratridine-induced 22Na(+) influx (IC(50) 6.8 microM). The IC(50) of (+)-bupivacaine (2.8 microM) was 6.2-, 7.4-, and 17.1-fold lower than those of (-)-bupivacaine (17.3 microM), (-)-ropivacaine (20.6 microM), and lidocaine (47.8 microM). Chronic (i.e. 3-h) treatment of cells with (+/-)-bupivacaine increased cell surface [3H]saxitoxin ([3H]STX) binding capacity by 48% (EC(50) of 233 microM; t(1/2)=7.4 h), without changing the K(d) value. Treatment for 24 h with either (+)- or (-)-bupivacaine, or (-)-ropivacaine elevated [3H]STX binding, whereas 24-h treatment with lidocaine had no effect. The rise of [3H]STX binding by (+/-)-bupivacaine was prevented by cycloheximide, an inhibitor of protein synthesis, or brefeldin A, an inhibitor of cell surface vesicular exit from the trans-Golgi network; however, (+/-)-bupivacaine did not increase Na(+) channel alpha- and beta(1)-subunit mRNA levels. In cells subjected to (+/-)-bupivacaine treatment (1 mM for 24 h) followed by 3-h washout, veratridine-induced 22Na(+) influx was enhanced, even when measured in the presence of ouabain, an inhibitor of Na(+),K(+)-ATPase. Ptychodiscus brevis toxin-3 potentiated veratridine-induced 22Na(+) influx by 2.3-fold in the (+/-)-bupivacaine-treated cells, as in non-treated cells. These results suggest that lipophilic bupivacaine enantiomers or (-)-ropivacaine acutely inhibit Na(+) channel gating, whereas its chronic treatment up-regulates cell surface expression of Na(+) channels via translational and externalization events.     

Hepatocyte growth factor protects functional and histological disorders of HgCl(2)-induced acute renal failure mice

Hepatocyte growth factor (HGF) enhances proliferation of renal epithelial cells as well as hepatocytes. HGF accelerates recovery from acute renal failure (ARF) in animal models. However, pharmacological profiles of HGF including its action mechanism has not been studied in detail. An HgCl(2)-induced ARF mouse was used in this study to evaluate the efficacy of HGF. Single administrations of recombinant human HGF or vehicle were given to ARF mice 30 min after HgCl(2) injection. Renal function was monitored by measuring serum creatinine, blood urea nitrogen and creatinine clearance. In the ARF mice, there was a deterioration of renal function biochemical parameters and histological evidence of renal damage including acute tubular necrosis of proximal tubules. These were both significantly ameliorated by a single HGF administration. The effect of HGF was noticeable in the early phase of ARF (1 day after onset) when there was no histological evidence of increased labeling indexes in renal tubular epithelial cells. Western blot analysis of the c-Met/HGF receptor showed that tyrosine phosphorylation was enhanced immediately after HGF administration indicating direct activation of renal epithelial cells. HGF prevented increase of apoptotic nuclei with DNA fragmentation in renal epithelial cells which suggests cytoprotective activity of HGF on renal epithelial cells in the ARF mice.     

Recent advances in the regulation of matrix metalloproteinase 2 activation: from basic research to clinical implication (Review)

Matrix metalloproteinases (MMPs) play an important role in degradation of extracellular matrix (ECM), which is an essential step in the cascade of metastasis. Various types of MMPs are expressed and activated in head and neck squamous cell carcinoma (HNSCC) as well as other human cancers. MMP-2 is a prominent predictor of poor prognosis. Membrane type 1-MMP (MT1-MMP) was originally identified as an activator of MMP-2. In addition to the original role, recent studies show other important functions of MT1-MMP such as degradation of type I collagen and cleavage of CD44. Tissue inhibitor of MMP-2 (TIMP-2) was identified as an inhibitor of MMP-2 and MT1-MMP. However, TIMP-2 was reported to be essential for cell-mediated activation of MMP-2, and thus the contribution of TIMP-2 to tumor invasion has remained controversial. Some studies also suggested a role of TIMP-2 as a predictor of poor prognosis. Thus, inhibition of MMP activation by TIMPs is not a suitable strategy for suppressing invasion and metastasis. Instead of TIMP-2, various MMP inhibitors (MMPI) such as BB-2516 have been investigated with regard to suppression of tumor progression and improvement of prognosis in patients with advanced cancers, which resulted in no clinical efficacy. MMPs are especially important in the early stage of cancer progression, and thus strategies for future MMPI trials should be reconsidered.     

Complete response in an elderly patient with advanced gastric scirrhous cancer treated with combined chemotherapy of TS-1 and CDDP

A 79-year-old male was diagnosed as having a scirrhous cancer of the stomach. Carcinomatous peritonitis was suspected on abdominal CT examination and the CA19-9 showed a high level of 95 U/ml. The patient was treated with combined chemotherapy of TS-1 and CDDP. TS-1 (100 mg/day) was administered for 14 days followed by 14 days rest as one course. CDDP was administered in 24-h continuous intravenous infusion on day 8. This treatment was done every 4 weeks regularly. After 5 courses, X-ray and endoscopy examinations revealed disappearance of cancerous lesions in the stomach with an improvement in the extensibility. No cancer cell were confirmed by endoscopic biopsy, nor did a CT-scan detect carcinomatous peritonitis. The CA19-9 decreased within the normal limit. Ten months after chemotherapy was started, the patient was very healthy without a recurrence of cancer. This combined chemotherapy has administered in 8 courses, and during this period no high grade toxicities (WHO grade 3 or 4) occurred. This TS-1/CDDP chemotherapy was effective for scirrhous gastric cancer and might be administered safely even for aged patients.     

Retrodental synovial cyst which disappeared after posterior C1-C2 fusion: A case report

Synovial cysts of the cervical spine are extremely rare. We describe an 8-year-old boy with atlantoaxial subluxation and hypoplasia of the dens. Magnetic resonance imaging showed a round lesion, posterior to the odontoid process. This mass was characterized by a low signal intensity on T1-weighted images, and high signal intensity on T2-weighted images. The retrodental synovial cyst disappeared after posterior atlantoaxial arthrodesis.     

Immunological evaluation of personalized peptide vaccination for patients with pancreatic cancer

The prognosis of pancreatic cancer is extremely poor, and development of new treatment modalities is needed. One such treatment could be specific immunotherapy. To evaluate safety and immunological responses, we conducted a phase I study of personalized peptide vaccination for pancreatic cancer patients (n=11). Namely, pre-vaccination peripheral blood mononuclear cells were screened for their reactivity in vitro to each of 14 or 16 peptides in HLA-A24(+) or -A2(+) patients, and only the reactive peptides (maximum: 4) were vaccinated in vivo. This regimen was generally well tolerated, although inflammatory reactions at the injection site were observed in 7 patients. Delayed-type hypersensitivity to peptides used for vaccination was observed in 7 patients. Increased cellular and humoral immune responses to at least one of peptides used for vaccination were observed in the post-vaccination PBMCs and sera from 4 of 8 patients and 4 of 10 patients tested, respectively. The 6- and 12-month survival rates for patients who received >3 vaccinations (n=10) were 80% and 20%, respectively. Due to tolerability and capability of inducing specific immunity, further development of personalized peptide-based immunotherapy for pancreatic cancer patients is warranted.