Relationships between transepidermal water loss, cutaneous microcirculatory function and autonomic nervous activity.

OBJECTIVE: Several studies have shown that a deterioration of skin properties, an impaired cutaneous microcirculatory function and an imbalance of autonomic nervous activity are observed in smokers and in patients with diabetes mellitus or Raynaud's phenomenon. These observations suggest that skin properties are associated with cutaneous microcirculatory function and autonomic nervous activity in pathological conditions. However, there is no published evidence to support the concept that these two functions have any relationship with skin properties even in healthy subjects. To investigate the hypothesis that these properties are related, we conducted a survey of healthy adult subjects to investigate the relationships between cutaneous microcirculatory function and autonomic nervous activity and skin properties. METHODS: The hydration of the stratum corneum and transepidermal water loss (TEWL) were investigated as skin properties, and the responsiveness of skin blood flow (SkBF) to local warming was examined as an index of cutaneous microcirculatory function in 19 healthy adult male subjects. Electrocardiograms were monitored for 24 h and heart rate variability was analysed considering low-frequency power (LF: 0.04-0.15 Hz), high-frequency power (HF: 0.15-0.40 Hz) and a ratio of low- to high-frequency power (LF/HF) as indices of autonomic nervous activity; HF is an index of parasympathetic activity, whereas LF/HF is an index of sympathovagal balance. The relationships between those indices were then analysed. RESULTS: A moderate negative correlation was found between TEWL and the relative maximum rate of increases in the responsiveness of SkBF on local warming. A moderate positive and a moderate negative correlation were observed between TEWL and LF/HF or HF, respectively. Moreover, a moderate negative and a moderate positive correlation were shown between the responsiveness of SkBF and LF/HF or HF, respectively. The hydration of the stratum corneum showed no correlations with any indices of microcirculation or autonomic nervous activity. CONCLUSION: These results indicate that skin barrier function, cutaneous microcirculatory function and autonomic nervous activity are mutually associated in healthy adults.

[Surgical treatment for Pancoast tumors--significance of surgical approach and induction chemoradiotherapy].

We analyzed 46 patients with Pancoast tumor who underwent surgical resection. Anterior approach was employed for 16 patients and hook approach for 30 patients. Twenty-one patients received preoperative treatment; chemotherapy for 1 patient, radiotherapy for 11 patients, and chemoradiotherapy for 9 patients. Complete resection was achieved in 59% (27/46) of patients. The overall 5-year survival rate was 10.9%. Five-year survival was significantly higher in the patients received complete resection than the patients received incomplete resection (18.5 vs 0%, p=0.0016). The complete resection rate has improved in recent cases, and one of the reasons seems to be the adoption of preoperative chemoradiotherapy. But postoperative complications occurred more frequently in patients who received induction therapy than the others. Optimal selection of surgical approach and induction chemoradiotherapy for Pancoast tumors appear to provide improved complete resection rate and long term survival.

[Evaluation of tracheobronchoplasty for lung cancer].

Tracheobronchoplasty has become one of the standard procedures for lung cancer. In this study, we examined the incidence of complications and survival of tracheobronchoplasty and compared with these of pneumonectomy. In 119 patients underwent tracheobronchoplasty, bronchopleural fistula occurred in 6 (5.0%) and anastomotic stenosis occurred in 5 (4.2%). Five-year survival rate of 119 patients underwent tracheobronchoplasty was 47.3%, and the median survival time was 49.3 months. We compared the sleeve or wedge lobectomy and pneumonectomy, the incidence of complications and 30-days death were similar, but the rate of in-hospital death and the prognosis of the sleeve or wedge lobectomy were better than these of pneumonectomy. So to preserve a respiratory function, we should use a bronchoplastic procedures to avoid pneumonectomy.

[A study of high-resolution computed tomography (HRCT) findings of resected small pulmonary nodules 2 cm or less in diameter with reference to the malignant nature].

To identify the characteristics of peripheral small lung mass lesions on high-resolution computed tomography (HRCT) and discriminate between malignant and benign, 223 mass lesions 2 cm or less resected surgically were evaluated about following points. 1) Density : 90.7% of lesions with mixed solid and ground-glass opacity (GGO) components were adenocarcinomas. Pure GGO lesions without scale-down between several months were all adenocarcinomas or atypical adenomatous hyperplasia (AAH). Thereby, patients with these findings are good candidates for surgical resection. 2) Spicular or pleural indentation :75.2% (88 of 117 cases) of adenocarcinomas and all squamous cell carcinomas (18 cases) showed these findings, but 26.6% (41 of 154 cases) of positive cases were benign lesion (non-specific inflammation, mycobacterisis, and so on). Accordingly, they are not peculiar to malignancy. 3) Satellite lesion : all lesions with this one showed benign, therefore it was thought that this finding could exclude malignant lesion. Thus, recognition of certain characteristics at HRCT can be helpful in discrimination between small malignant mass and benign mass.

[Assessment of surgery for stage IV non-small cell lung cancer].

We assessed the survival of surgery for stage IV non-small cell lung cancer. Forty-two patients were operated on lung cancer for stage IV from 1986 to 2005. Overall median survival time (MST) was 12.3 months and 5-year survival rate was 9.8%. There was significant difference in survival between pulmonary metastasis (pm2) and other sites metastasis (p<0.05). In pm2 patients there was significant difference between ipsilateral metastasis and contralateral metastasis (MST 21.9 months, 2-year survival rate 48.6%, 5-year survival rate 21.6% and MST 12.3 months, 2-year survival rate 0%) [p<0.05], and between complete resection and incomplete resection (MST 36 months, 2-year survival rate 64.8%, 5-year survival rate 28.8% and MST 12.3 months, 2-year survival rate 0%) [p<0.01]. In patients with brain metastasis, surgery of brain metastasis was better prognosis than radiation therapy (MST 12.5 months, 3-year survival rate 33.3% and MST 8.3 months, 2-year survival rate 0%) [NS].

[The effect of multimodality induction therapy for locally advanced non-small cell lung cancer].

In this study we analyzed induction therapy for locally advanced non-small cell lung cancer. Eligible patients had mediastinoscopic proven N2 disease and T4 with mediastinal involvement. From January 1997 to May 2005, 56 patients entered the study. They received 2 cycle chemotherapy (platinums based 2 or 3 drugs), in 32 patients with concurrent radiotherapy followed by surgery. Response rates were 57.1%. Fifty-one patients underwent surgery. A radical resection was possible in 39 patients. Complication occurred in 14 patients (27.5%). Overall 5-year survival was 27.5%. In N2 disease, there was no statistically significant difference in survival between the induction group and the historical group. In T4 disease, overall 5-year survival was 30.2% for the induction group and 5.2% for historical group. There was significant difference in survival between the groups (p < 0.05).

Expression of the cdc25B gene as a prognosis marker in non-small cell lung cancer.

There is an evidence to suggest that cdc25B phosphatase is an oncogenic. We hypothesized that cdc25B gene may be expressed in tumors of patients with non-small cell lung cancer (NSCLC) and affect their clinical outcome. Expression of cdc25B messenger RNA was evaluated by reverse transcription polymerase chain reaction in 55 non-small cell lung carcinomas and adjacent histological normal lung samples using LightCycler. The data was analyzed in reference to clinicopathological data and survival data. There was no difference of cdc25B expression level between the NSCLC tissue and normal lung tissue. There was no relationship between cdc25B gene expression and age, gender, N or T-status and clinical stage. However, the NSCLC patients with high cdc25B expression had significantly poor survival than the patients with low cdc25B expression (P=0.0173). Thus we suggest that cdc25B may predict poor survival.

Effect of phorbol ester and calcium ionophore on human thymocytes.

Positive selection of immature thymocytes is a developmental process in which TCR ligation with low avidity induces generation of mature T cells. In mouse thymocytes, CD4(+)8(+) double-positive (DP) cells which were treated with a proper combination of calcium ionophore ionomycin and phorbol 12-myristate 13-acetate (PMA) have been reported to differentiate into CD4 single positive cells. However, in human thymocytes the effects of PMA and ionomycin have remained unclear. Here we report that DP cells that were treated with PMA and ionomycin up-regulated bcl-2 and down-regulated CD1 expression. However, CD3 expression remained low. This treatment induced prolonged CD4 down-regulation in DP cells which was an effect also seen in mature peripheral blood T cells. PMA/ionomycin-treated DP cells showed high cell proliferation and resistance to dexamethasone-induced apoptosis. These results indicate that PKC activation and calcium elevation may be part of the biochemical signals that induce positive selection of human DP cells and the system described in this paper may be a useful model to study the signals involved in the selection of human thymocytes.

Sugar-pendant diamines.

A set of 1,3-propanediamine derivatives connected to carbohydrates (5) has been prepared in four steps from peracetylated sugar and 1,3-dibromo-2-propanol in 60-73% yields. D-Glucose, D-mannose, D-galactose, D-xylose, D-ribose, and maltose are utilized as sugar molecules in this work. The diamine moiety was connected to the C1 carbon of the glycopyranose ring via an O-glycoside bond. All of the anomeric configurations and sugar puckering conformations, except in the D-maltose derivative, were determined by X-ray crystallography of the diazido or dibromo precursors. While glycosidation of peracetylated galactopyranose with 1,3-dibromo-2-propanol in the presence of boron trifluoride afforded both anomers, the neighboring group participation of the 2-acetoxy group yielded a single anomer for the other substrates. This method has been used to synthesize a library of sugar-pendant diamines including an OH-protected derivative (6), and an N,N'-diisopropyl-substituted derivative (7). A similar series of reactions using 2,3-dibromo-1-propanol gave ethylenediamine-type derivatives (11), and bis(bromomethyl)bis(hydroxymethyl)methane (12) gave bisglucose-pendant derivatives (16).

Evaluation of new TNM lung cancer classification.

OBJECTIVE: A new staging system for lung cancer was proposed by the Union Internationale Contre le Cancer in 1997, with Stages I and II subdivided and T3N0M0 assigned as stage IIB. We studied the usefulness of this new classification. METHODS: Subjects were 753 patients with non-small-cell lung cancer undergoing pulmonary resection and follow-up data were retrospectively reviewed. RESULTS: A significant difference was seen between stage IA and IB survival--70.4% vs 52%. No significant difference was seen between survival for T3N0M0, T1N1M0 and T2N1M0--35.3%, 42.3%, and 43.8%--at 5 years. We found, however, that the prognosis for T3N2M0 tumors--6.5% 5-year survival--is too poor to be grouped with other N2 diseases having a better prognosis--23.9% 5-year survival. Significant differences were also seen in the survival of T3N0 or T3N1 patients by organ and diseases involving the rib, diaphragm, or mediastinum may be classified as T4. CONCLUSION: The new staging system predicts patient outcome fairly well and the modification is well grounded. It appears, however, to be appropriate to subdivide T3 tumors by invaded organs and T3N2M0 disease may be better classified as stage IIIB. The classification of pulmonary metastasis appears to require further improvement.

Effects of NKH477 on endothelin-1-induced renal responses in anaesthetized dogs.

1. Intrarenal arterial infusion of a direct adenylate cyclase activator (NKH477; 300 ng/kg per min) increased renal blood flow, urine flow rate and urinary sodium excretion in anaesthetized dogs. 2. Intrarenal arterial infusion of endothelin (ET)-1 (2 ng/kg per min) reduced basal values of these parameters and glomerular filtration rate, which were recovered by the addition of NKH477 during ET-1 infusion. 3. These results demonstrate that NKH477 can counteract ET-1-induced antinatriuresis, mainly by restoring glomerular filtration.

Effects of NKH477 on renal nerve stimulation-induced responses in anesthetized dogs.

We evaluated the effects of an adenylate cyclase activator, N, N-dimetyl-beta-alanine[3R-(3alpha,4alphabeta,5beta+ ++,6beta,6aalpha, 10alpha,10abeta,10balpha)]-5(acetyloxy)-3-eth enyldodecahydro-10, 10b-dihydroxy-3,4a,7,7,10a-pentamethyl-1-oxo-1H-naphtho[2, 1-b]pyran-6-yl ester hydrochloride (NKH477), on neural control of renal functions in anesthetized dogs. Renal nerve stimulation (2 Hz) increased renal norepinephrine efflux and reduced renal blood flow, glomerular filtration rate, urine flow rate, urinary Na(+) excretion and fractional Na(+) excretion. Intrarenal arterial infusion of NKH477 (300 ng/kg/min) suppressed the stimulation-induced reductions in renal blood flow and glomerular filtration rate and attenuated the reductions in urine flow rate and urinary Na(+) excretion but not the changes in renal norepinephrine efflux and fractional Na(+) excretion. Infusion of NKH477 did not affect the urinary responses induced by renal nerve stimulation at a lower frequency (0.5-1 Hz) which had little influence on renal blood flow and glomerular filtration rate. The present results demonstrate that NKH477 inhibits renal vasoconstriction and hypofiltration but not the enhanced tubular Na(+) reabsorption during activation of the renal sympathetic nervous system.

Effects of NKH477 on renal functions and cyclic AMP production in anesthetized dogs.

The present study was undertaken to evaluate the effects of an adenylate cyclase activator N,N-dimethyl-beta-alanine[3R-(3alpha, 4alphabeta, 5beta, 6beta, 6aalpha, 10alpha, 10abeta, 10balpha)]-5(acetyloxy)-3-ethenyldodecahydro-10, 10b-dihydroxy-3, 4a, 7, 7, 10a-pentamethyl-1-oxo-1H-naphtho [2,1-b] pyran-6-yl ester hydrochloride (NKH477) on renal functions and cyclic AMP production in the dog kidney. The intrarenal arterial infusion of NKH477 (30, 100 and 300 ng kg(-1) min(-1)) increased renal blood flow, glomerular filtration rate, urine flow rate, urinary Na+ and cyclic AMP excretion, fractional Na+ excretion and arterial and renal venous plasma cyclic AMP concentrations in a dose-dependent manner. The intrarenal arterial infusion of rolipram (0.3 microg kg(-1) min(-1)), a cyclic AMP-specific phosphodiesterase inhibitor, also caused the same renal responses as NKH477. The increasing effects of NKH477 on renal blood flow, fractional Na+ excretion and renal venous plasma cyclic AMP concentration were facilitated in the presence of rolipram. NKH477 reduced glomerular filtration rate and filtration fraction in the presence of rolipram. The increasing effects of NKH477 on urine flow rate and urinary Na+ excretion were not affected by rolipram. The present results suggest that NKH477 increases glomerular filtration and suppresses tubular sodium reabsorption through activation of cyclic AMP production, and thereby induces natriuresis. The results also demonstrate that renal cyclic AMP level during the activation of adenylate cyclase is regulated by phosphodiesterase IV in both the vascular and tubular sites.

Effects of rolipram and cilostamide on renal functions and cyclic AMP release in anesthetized dogs.

The present study was undertaken to examine whether phosphodiesterases III and IV regulate renal cAMP level and whether inhibition of these enzymes influences renal functions in anesthetized dogs. The intrarenal arterial infusion of rolipram (0.1, 0.3, and 1 microgram/kg/min), a selective phosphodiesterase IV inhibitor, increased renal blood flow, glomerular filtration rate, urine flow rate, and urinary Na+ excretion with elevating arterial and renal venous plasma cAMP concentrations and urinary cAMP excretion. However, cilostamide (0.1, 0.3, and 1 microgram/kg/min), a selective phosphodiesterase III inhibitor, did not affect the values of these parameters. Indomethacin (3 mg/kg i.v. bolus and 1 mg/kg/min i.v. infusion), a cyclooxygenase inhibitor, reduced the basal arterial and renal venous plasma cAMP concentrations and blunted the rolipram-induced elevation of cAMP concentrations and urinary cAMP excretion. The effects of rolipram on renal hemodynamics and urine formation were attenuated in the presence of indomethacin. These results suggest that in the dog kidney in vivo, 1) phosphodiesterase IV, but not phosphodiesterase III, participates in degradation of cAMP and 2) the inhibition of phosphodiesterase IV enhances glomerular filtration and urinary Na+ excretion, the responses of which depend in part on indomethacin-susceptible (prostaglandin-mediated, probably) control of basal cAMP level.

Effects of sodium nitroprusside on renal functions and NO-cGMP production in anesthetized dogs.

Although the renal nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) system plays an important role in maintaining urinary sodium and water excretion, effects of an authentic NO donor sodium nitroprusside (SNP) on urine formation have been controversial. In this study, we examined whether SNP increases renal NO release and cGMP production and induces natriuresis in the denervated kidney of anesthetized dogs. The intrarenal arterial infusion of SNP at 10, 30, and 100 ng/kg/min did not affect renal function or NO-cGMP production. The higher dose of SNP (1,000 ng/kg/min) reduced systemic blood pressure and urine flow rate. The antidiuresis was observed also in the contralateral control kidney, the degree of which was larger than that observed in the ipsilateral SNP-infused kidney. During the SNP infusion, reductions in urinary Na+ excretion, fractional Na+ excretion, and urinary nitrite + nitrate excretion occurred in the control kidney but not in the SNP-infused kidney. Urinary cGMP excretion and renal venous plasma cGMP concentration were significantly increased during the SNP infusion in the SNP-infused kidney but not in the control kidney. These renal effects of SNP were similar to those obtained by intrarenal arterial infusion of a specific NO donor, NOC 7 (300 ng/kg/min). These results suggest that SNP can produce nitric oxide and increase cGMP levels in the kidney and suppress sodium reabsorption, but the natriuretic property of SNP may be masked by its counteracting effects including the systemic hypotension in anesthetized dogs.

Inhibitory effect of TRK-530 on inflammatory cytokines in bone marrow of rats with adjuvant arthritis.

TRK-530 is a novel synthetic bisphosphonate compound which exhibits inhibitory activity in the rat adjuvant arthritis (AA) model. We found that, during AA development, the concentrations of cytokine-induced neutrophil chemoattractant-1 (CINC-1) and tumor necrosis factor alpha (TNF-alpha) in the bone marrow increased, and that administration of TRK-530 decreased the concentrations of these cytokines. The suppression of these concentration increases paralleled the inhibition of paw edema. Paw edema inhibition by TRK-530 in rat AA may be the result of decreasing CINC-1 and TNF-alpha concentrations.

Inhibitory effects of TRK-530 on rat adjuvant arthritis.

TRK-530 is a novel bisphosphonate derivative. We examined the anti-inflammatory effects of TRK-530 on adjuvant arthritis (AA) rats. When TRK-530 at a dose of 2.5 mg/kg was administered for 2 weeks to AA rats, it inhibited destructive changes in arthritic joints such as paw edema, bone loss and joint degeneration. TRK-530 also inhibited splenomegaly and suppressed the increase in serum sialic acid which is measured as a systemic parameter of inflammation. To clarify the inhibitory mechanism of TRK-530, interleukin-1 (IL-1)-like activities of resident peritoneal macrophages in AA rats given TRK-530 were compared with those of control rats. We found that TRK-530 inhibited IL-1-like activity induced by bacterial lipopolysaccharide 6 weeks after administration when the IL-1-like activities of control rats were still at high levels. These findings suggest that TRK-530 exerts anti-inflammatory activities in AA rats.

Cyclosporin A and FK-506 inhibit development of superantigen-potentiated collagen-induced arthritis in mice.

1. Staphylococcal enterotoxine B (SEB; superantigen) accelerated the onset of arthritis in mice preimmunized with type II collagen (SEB-potentiated collagen-induced arthritis). Cyclosporin A and FK-506 inhibited the induction and development of clinical signs and histopathological changes of SEB-potentiated collagen-induced arthritis in mice. 2. Simultaneously, both cyclosporin A and FK-506 inhibited the development of humoral and cellular immunity to type II collagen. 3. The expression of IL-2 receptor (CD25) by SEB on splenocyte T cells from collagen-preimmunized mice was inhibited by both agents in ex vivo experimentation.

TRK-530 inhibits accumulation of superoxide anions derived from human polymorphonuclear leukocytes and bone resorption induced by activated osteoclasts.

TRK-530, a newly synthesized bisphosphonate, was assessed for its effects on the accumulation of superoxide anions derived from human formyl-methionyl-leucyl-phenylalanine-stimulated polymorphonuclear leukocytes (PMN), and for its effects on bone resorption using a pit formation assay. TRK-530 concentration-dependently inhibited superoxide accumulation derived from PMN and osteoclast pit formation stimulated by 1,25-dihydroxyvitamin D3. Incadronate and risedronate had a strong inhibitory effect on pit formation, but no antioxidative activity. These data suggest that the anti-bone resorption activities of TRK-530 are possibly unrelated to its antioxidant properties. However, it is difficult to conclude at present which mechanisms play the most important role in the anti-bone resorption activities of TRK-530.