Favorable Surgical Results in 433 Elderly Patients with Papillary Thyroid Cancer

Papillary thyroid cancer (PTC) has a good prognosis among patients younger than 45 years old, but the prognosis in elder is worse and treatment strategy is not well established. We retrospectively analyzed the clinical features and outcomes of 433 patients with PTC aged 70 years or older. The patients consisted of three groups: group A (n = 327); patients receiving surgical treatment, group B (n = 51); patients with microcancer (maximal diameter, ≤ 1.0 cm) who did not undergo surgical treatment, group C (n = 55); patients in whom surgery was contraindicated due to age, high surgical risk or complication by other illnesses. In group A, the mean tumor size was 2.6 ± 1.5 cm, and 218 patients (66.7%) had pathologically confirmed lymph node metastasis; 110 patients (33.6%) had extrathyroidal invasion. The 5- and 10-year overall survival rates (OSR) in group A were 97.2% and 85%, respectively, which was significantly higher than the 5-year OSR in group C (62.6%). The 5- and 10-year disease-specific survival rates (DSSR) in group A were 98.5% and 91.3%, respectively, which was also significantly higher than the 5-year DSSR in group C (81.8%). Although the patients in group B did not receive any treatment, none of them demonstrated cause-specific death or progression of disease. Papillary thyroid cancer in elderly patients, except for microcancers, may be biologically aggressive. Thus surgery is recommended for these patients, if their general status is judged able to tolerate the stress of anesthesia and surgery.     

Clinical outcome assessment of membranous nephropathy

Appropriate treatment of idiopathic membranous nephropathy (IMN) remains a controversial issue. Whereas some authors recommend a conservative approach, based on the considerable rate of spontaneous remissions, others utilize early immunosuppressive treatment for most nephrotic patients with IMN. Our retrospective study consisted of 34 patients who presented with IMN between the period from 1987 to 2002. The patients were divided into two groups based on the type of treatment they received the immunosuppressive group comprised 18 patients who received corticosteroids with/without other immunosuppressive drugs and the supportive group comprised 16 patients who were treated with anti platelet drugs as supportive therapy. The amount of proteinuria at the base line was significantly higher in the immunosuppressive group than in the supportive group(4.7 +/- 2.9 vs. 2.7 +/- 2.7 g/24 h). At the end of the follow-up, complete remission was achieved more frequently in the immunosuppressive group than in the supportive group(9/18 vs. 3/16). This suggests that immunosuppressive treatment has the effect of decreasing proteinuria. At the end of the follow-up, 3 patients in the immunosuppressive group and 2 patients in the supportive group showed renal insufficiency (serum creatinine concentration > or = 1.5 mg/dl). Side effects besides diabetes were not seen as a result of immunosuppressive treatment. Our findings suggest that immunosuppressive treatment in IMN cases appears to be beneficial for decreasing proteinuria, but the effect on prevention of renal failure was not evident.     

Fibroblast growth factor-2 induces recovery of pulmonary blood flow in canine emphysema models

STUDY OBJECTIVES: Fibroblast growth factor (FGF)-2 is one of the most powerful angiogenic growth factors to be evaluated as an agent for the promotion of angiogenesis. The aim of this study is to investigate whether intratracheal administration of controlled-release FGF-2 microspheres restores pulmonary function in beagle dogs with emphysema. DESIGN: Randomized, controlled, experimental animal study. SUBJECTS: Eighteen Wister rats and 15 adult beagle dogs. METHODS: In the rat study, we compared the time profiles of the radioactivity remaining after intratracheal injection of 125I-labeled FGF-2, either incorporated with the controlled-release microspheres or as an aqueous solution. In the dog study, elastase-induced emphysema models were developed in 10 animals, classified into the following three groups: control group (n = 5), emphysema model with empty microspheres-treated group (FGF - group, n = 5), and emphysema model with FGF-2 containing microspheres-treated group (FGF + group, n = 5). RESULTS: In the rat study, controlled-release microspheres maintained higher whole-lung FGF-2 concentrations after intratracheal administration. In the dog study, Pa(O2) in the FGF + group was significantly higher than in the FGF - group after treatment. Pulmonary perfusion dynamic MRI revealed significant improvement in the signal intensity of damaged lung with the FGF + group. Linear intercept of the FGF + group was significantly reduced than the FGF - group. CONCLUSION: Results indicate that intratracheal administration of FGF-2 induced an increase in pulmonary blood flow in the damaged lung and led to recovery of pulmonary function. The controlled-release microsphere system increased the effectiveness of FGF-2.     

Clinical and electrophysiological characteristics of Brugada syndrome caused by a missense mutation in the S5-pore site of SCN5A

Brugada syndrome is an inherited cardiac disorder caused by mutations in the SCN5A gene encoding the cardiac sodium channel alpha-subunit, and potentially leads to ventricular fibrillation and sudden death. We report a case of a novel SCN5A mutation associated with Brugada syndrome. A 51-year-old man suffered from recurrent nocturnal syncopal attacks due to polymorphic ventricular tachycardia. His electrocardiogram showed ST-segment elevation in V1-V3 leads, but there was no evidence of structural heart disease. DNA sequence analysis of SCN5A in this patient revealed a missense mutation (R282H) in the S5-pore region of domain I. This mutational change was not present in 100 healthy Japanese controls. In the patient's family, a 36-year-old brother had died suddenly. Genetic analysis identified two other carriers of the R282H mutation, who had ST-segment elevation and slightly increased QRS widths, but they experienced no syncopal episodes or ventricular fibrillation. Electrophysiological investigation of the R282H mutant channel expressed in cultured cells showed a severe reduction in sodium current density and a mild positive shift of activation curve. R282H did not enhance intermediate inactivation. Single-channel conductance of R282H was slightly decreased compared with WT. The electrophysiological characteristics of the R282H channel are suggested to be closely related to the clinical phenotype of Brugada syndrome.     

A novel missense mutation in the SCN5A gene associated with Brugada syndrome bidirectionally affecting blocking actions of antiarrhythmic drugs

Brugada syndrome is an inherited cardiac disorder caused by mutations in the SCN5A gene encoding the cardiac sodium channel alpha subunit, which can lead ventricular fibrillation and sudden death. Inattentive use of antiarrhythmic drugs potentially triggers fatal cardiac arrhythmias through further reduction of sodium current (I(Na)). We studied the molecular mechanism underlying a case of Brugada syndrome that showed no response to a class Ic antiarrhythmic drug. Molecular genetic studies of a patient with Brugada syndrome identified a novel mutation in SCN5A, which causes substitution of serine for asparagine (N406S) in S6 of domain I (IS6). The provocation test with pilsicainide, a class Ic antiarrhythmic drug, failed to exacerbate ST-segment elevation in this case. Electrophysiological analyses of the N406S-mutant channel expressed together with the beta1 subunit in HEK293 cells showed that the voltage dependence of activation was positively shifted by 16 mV and that intermediate inactivation was enhanced. Whereas tonic block by pilsicainide was not changed in the N406S channel, use-dependent block by pilsicainide was almost completely abolished, consistent with the clinical findings of the negative provocation test. In contrast, the N406S channel showed stronger use-dependent block by quinidine than the wild-type channel. We demonstrate a novel Brugada mutation N406S, which is associated with the discordant effects on blocking actions of antiarrhythmic drugs as well as the multiple channel gating defects. We emphasis that an antiarrhythmic drug may exert unpredicted effects in patients with channel mutations.     

Single-channel properties of volume-sensitive Cl- channel in ClC-3-deficient cardiomyocytes

It is controversial whether the ClC-3 protein, which is one of the voltage-dependent chloride channel ClC family members, is a candidate for the volume-sensitive outwardly rectifying (VSOR) Cl(-) channel per se or its regulator. Here, for the first time, we examined the single-channel properties of the VSOR Cl(-) channel in ventricular myocytes isolated from ClC-3-deficient mice. The single-channel current induced by cell swelling exhibited Cl(-) selectivity, mild outward rectification, and an intermediate unitary conductance (around 38 pS). A Cl(-) channel blocker, 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid (DIDS), reversibly inhibited the outward current. These single-channel properties were identical with those in ClC-3 expressing wild-type ventricular myocytes. These results indicate that the single-channel activity of the VSOR Cl(-) channel is independent of the expression of ClC-3 proteins in mouse ventricular myocytes.     

Endothelial nitric oxide contributes to the renal protective effects of ischemic preconditioning

We determined whether endothelial nitric oxide synthase (eNOS) plays an important role in the renal protective effect of ischemic preconditioning (IP) against the ischemia/reperfusion-induced acute renal failure (ARF) by using eNOS-deficient (eNOS(-/-)) and wild-type (eNOS(+/+)) mice. Ischemic ARF was induced by occlusion of the left renal artery and vein for 45 min followed by reperfusion, 2 weeks after contralateral nephrectomy. IP, which consists of three cycles of 2-min ischemia followed by 5-min reperfusion, was performed prior to 45-min ischemia. In eNOS(+/+) mice, IP treatment markedly attenuated the ischemia/reperfusion-induced renal dysfunction and significantly improved histological renal damage such as tubular necrosis, proteinaceous casts in tubuli, and medullary congestion. Constitutive nitric oxide synthase activity in the kidney without IP was markedly decreased 6 h after reperfusion, but this decreased response was not observed in eNOS(+/+) mice with IP treatment. The improvement of renal dysfunction in eNOS(+/+) mice with IP treatment was abolished by pretreatment with N(G)-nitro-l-arginine, a nonselective NOS inhibitor, whereas aminoguanidine, an inducible NOS inhibitor, had no effect. Finally, no protective effects of IP on ischemia/reperfusion-induced renal dysfunction and histological damage were observed in eNOS(-/-) mice. These findings strongly support the view that eNOS-mediated NO production plays a pivotal role in the protective effect of IP on ischemia/reperfusion-induced ARF.