Water extract of gromwell (Lithospermum erythrorhizon) enhances migration of human keratinocytes and dermal fibroblasts with increased lipid synthesis in an in vitro wound scratch model.

BACKGROUND: Although organic extracts of gromwell (Lithospermum erythrorhizon) have been shown to promote wound healing, the wound healing effects of water extracts of gromwell (WG) that are commonly used in traditional remedies have not been elucidated. OBJECTIVE: We investigated whether WG promotes the migration and/or proliferation of cultured human keratinocytes (CHK) or dermal fibroblasts in parallel with increases in lipid synthesis during in vitro wound healing. METHODS: CHK or fibroblasts were treated with 1-1,000 µg/ml WG for up to 48 h following scratch wound formation. Cell migration was assessed by measuring coverage (in percent) from the wound margin, while cell proliferation and lipid synthesis were determined by [(3)H]thymidine incorporation into DNA fractions, and [(3)H]palmitate or [(3)H]serine incorporation into lipid fractions, respectively. RESULTS: Low-dose WG (1 µg/ml) enhanced the wound coverage for both CHK and fibroblasts at 24 h, while cell proliferation was not altered in either cell types. Synthesis of both total lipids and individual lipid classes, including phospholipids, sphingolipids and neutral lipids, were found to be increased at 24 h in CHK treated with 1 µg/ml WG; in similarly treated fibroblasts, only the syntheses of sphingolipids (such as ceramides and glucosylceramides), but not other lipid species, were significantly increased. In contrast, a higher dose of WG (10-1,000 µg/ml) did not enhance wound coverage, and 100 µg/ml WG neither altered cell proliferation nor lipid synthesis in both CHK and fibroblasts. CONCLUSION: Low-dose WG (1 µg/ml) enhances the migration of both CHK and fibroblasts with increased lipid synthesis in an in vitro wound scratch model.

Effects of socioeconomic factors and cancer survivors' worries on their quality of life (QOL) in Japan.

Effects of socioeconomic factors and cancer survivors' worries on their quality of life (QOL) were investigated. In 2002, Japanese national survey was performed to assess distress among cancer patients using a semi-structured questionnaire (http://www.scchr.jp/yorozu/pdf/taiken_koe_eng.pdf). We investigated relationships between patients' distress and their QOL measured by European Organization for Research and Treatment of Cancer Core Questionnaire (EORTC QLQ-C30) and Functional Assessment of Chronic Illness Therapy--12-item Spiritual Well-Being Scale (FACIT-Sp), using a covariance structure analysis and multivariate regression analysis. A total of 130 outpatients (male: 42%; average age: 59 years; performance status rating 0-2:89%; breast/lung/gastrointestinal cancer: 38/22/21%) answered the questionnaires. A covariance structure analysis extracted latent variables, which were named socioeconomic distress and cancer worries, using a model that sufficiently represented the observed data (Goodness of fit index = 0.833). Regression analysis demonstrated that higher family income significantly correlated with better Global health status/QOL (p = 0.003) but that losing a job negatively correlated with all of the scales on functioning in the QLQ-C30 (p < 0.05) and spiritual well-being (p < 0.05). Patients' QOL was also affected by physical worries and spiritual issues in terms of emotional, cognitive, and social functioning. In conclusion, cancer survivors' QOL was doubly affected by socioeconomic distress and cancer worries. In the former, lower family income and losing employment by experiencing cancer had a negative impact on patients' QOL. As to the latter, physical worries and spiritual issues also affected patients' QOL.

Ebselen decreases ozone-induced pulmonary inflammation in rats.

We studied the effects of ebselen on rat lung inflammatory responses against ozone exposure. Rats were treated with ebselen every 12 h from 1 h before a single 4-h exposure to 2 ppm ozone. Treatment with ebselen (10 mg/kg) significantly decreased pulmonary inflammation as indicated by the albumin concentration and the number of neutrophils in the bronchoalveolar lavage fluid 18 h after the ozone exposure. Although treatment with ebselen did not alter the macrophage expression of inducible nitric oxide synthase after the ozone exposure, it did markedly inhibit the nitration reaction of tyrosine residues, suggesting that ebselen scavenges peroxynitrite during ozone-induced pulmonary inflammation. Treatment with ebselen also enhanced the pulmonary expression of both copper, zinc, and manganous superoxide dismutases at the same time point. These enzymes may also contribute to a decrease in the formation of peroxynitrite by lowering the concentration of superoxide. Thus, ebselen represents a useful compound for protecting against certain acute lung injuries by modulating the oxidant-related inflammatory process.

Local antithrombotic therapy using a novel porous balloon catheter.

The efficacy of local treatment of thrombosis with low-dose antithrombotic drugs (heparin: 30 U/kg, or argatroban: 0.02 mg/kg) was investigated using a novel porous balloon catheter. This novel balloon catheter can deliver drug into arterial walls without causing vascular trauma. Thrombus formation was significantly inhibited in balloon-injured and locally-treated iliac arteries compared with control balloon-injured arteries in 12 dogs. In the systemic high-dose delivery group (ten times as high as the low dose), thrombus formation in injured arteries was significantly less than that of controls in 7 dogs. Low-dose systemic delivery was not effective at inhibiting this thrombus formation. Thus, local treatment with an antithrombotic drug using this novel porous balloon catheter can prevent thrombosis without influencing systemic coagulability.

Molecular cloning and characterization of Ca2+-dependent inducible nitric oxide synthase from guinea-pig lung.

We have isolated a full-length cDNA for an inducible nitric oxide synthase (iNOS) from guinea-pig lung. The cDNA has a 3447 bp open reading frame encoding 1149 amino acid residues. The deduced amino acid sequence is approx. 80% identical with iNOS of human epithelial cells and murine macrophages. Consensus recognition sites for cofactors are highly conserved. COS cell lysate transfected with the guinea-pig iNOS shows significant levels of nitric oxide synthase (NOS) activity, and this is inhibited by 79% by chelation of Ca2+ ions. The NOS activity is restored in a concentration-dependent manner by increasing the free Ca2+ level. The NOS activity is also inhibited by trifluoperazine, a calmodulin antagonist, which suggests that the Ca2+ dependence is due to Ca2+-dependent calmodulin binding to the enzyme. Northern blot analysis reveals that the cloned iNOS mRNA is expressed in the lung and the colon in normal guinea pigs. Stimulation in vivo by lipopolysaccharide induces the expression of iNOS in the kidney, the spleen and the colon, but in the lung the same stimulation decreases its expression. These results suggest that the cloned guinea-pig iNOS is distinct in characteristics and expression from previously described iNOS forms.

Advanced nasopharyngeal carcinoma treated with chemotherapy and radiotherapy: distant metastasis and local recurrence.

One hundred and twenty-nine patients with NPC treated at the Department of Radiology, Chiba University Hospital and Keio University Hospital from 1980 through 1993 were selected for this study. Forty-four patients received cisplatin (CDDP)- or carboplatin-based chemotherapy, and 58 patients received adriamycin (ADM)- and/or 5-FU-based chemotherapy. The remaining 27 patients were treated with radiotherapy alone. The median radiation dose to the nasopharyngeal region was 64 Gy, and to the initially involved cervical node, 60 Gy. The 5 year survival rates for the CDDP, the ADM/5-FU and the radiation alone groups were 61%, 47% and 42%, respectively. The cumulative incidences of local control in the CDDP, the ADM/5-FU and the radiation alone groups were 77%, 49% and 53% respectively. The CDDP group achieved the significantly better local control (CDDP vs ADM: p=0.001). The overall incidence of distant metastases was 54% in the CDDP group. On the other hand, it was 24% in the ADM/5-FU group and 22% in the radiation alone group (CDDP vs ADM: p=0.048). While the locoregional control rate was significantly better in the CDDP given group, more distant metastases were seen in this group.

Structural and biochemical basis for the UVB-induced alterations in epidermal barrier function.

Ultraviolet light (UVR) induces a myriad of cutaneous changes, including delayed disruption of the permeability barrier with higher doses. To investigate the basis for the UVB-induced barrier alteration, we assessed the epidermal lamellar body secretory system at various time points before and after barrier disruption with a single high dose of UVB (7.5 MED) to murine epidermis. Morphological data were correlated with changes in epidermal proliferation and lipid synthesis, indicative of lamellar body generation. Twenty-four hours following UVB, the stratum corneum (SC) is normal, but a layer of abnormal, vacuolated, and lamellar body (LB)-deficient cells is present, immediately beneath the stratum granulosum (SG)/SC interface. Immediately subjacent to this band of damaged cells, normal keratinocytes that contain intact LBs are present. By 72 h, concomitant with the appearance of a barrier abnormality, extensively damaged cells persist at the SC/SG interface, and abnormal lamellar membrane structures appear in the lower SC. Upper stratum spinosum (SS) and lower SG cells appear normal, with increased numbers of LBs. A barrier abnormality is still present at 96 h, in association with membrane abnormalities in the lower SC interstices, but up to four normal appearing, subjacent SG cell layers are present. By 120 h, accelerated LB formation and precocious LB extrusion occur throughout the thickened SG; normal lamellar membranes are present in the lower SC; and barrier recovery is almost complete. Whereas, epidermal synthesis of the major barrier lipid species (i.e., cholesterol, fatty acids, and ceramides, including acylceramides) is reduced or unchanged at 24 and 48 h, it increases significantly 72 h after exposure to UVB. Therefore, the delayed disruption of the permeability barrier following acute UVB exposure results from the arrival of a band of lamellar body-incompetent (i.e., damaged) cells at the SG/SC interface. The subsequent, rapid recovery of the barrier, in turn, results from compensatory hyperplasia of subjacent, undamaged SS/SG cells, generating increased numbers and contents of LB. These results underscore the critical role of the stratum compactum in mediating barrier function, and suggest that beneficial therapeutic effects of UV exposure may be due to enhanced lipid production and barrier regeneration.

Magnetic resonance galactography for a patient with nipple discharge.

A new method of galactography using magnetic resonance imaging for a patient with nipple discharge is developed. The method is as follows; coronal T1-weight images are obtained after an injection of contrast medium of 1 mmol/L Gd-DTPA directly into the discharge duct, before and after rapid intravenous infusion of Gd-DTPA. A case of a 29-year-old woman with ductal carcinoma in situ with minimal invasion is reported, in which all portions of the entire discharge duct system is clearly shown as viewed from the surface and the surrounding area is enhanced with Gd-DTPA. The enhanced area is coincidental with the extent of the disease. This magnetic resonance galactography for patients with nipple discharge may be used to supplement conventional mammography and/or galactography especially for the evaluation of the extent of disease, although it is somewhat inferior to mammographic galactography in terms of differential diagnosis of ductal disease.

Local delivery of antithrombotic drug prevents restenosis after balloon angioplasty in atherosclerotic rabbit artery.

We investigated the ability of various antithrombotic drugs, delivered locally, to prevent restenosis after angioplasty in hypercholesterolemic rabbits. After dilating atherosclerotic iliac stenoses by balloon angioplasty, a low dose of heparin or a new antithrombotic drug, such as low molecular weight heparin (fragmin), argatroban, or batroxobin, was delivered locally using the balloon double-occlusion technique. In 1 group, high-dose heparin was administered intravenously. Animals that received no drugs served as a control group. After angioplasty, the stenotic segment was dilated and the mean percentage luminal stenosis fell from 89% to 9% in the group that received locally delivered heparin, from 88% to 7% in the group that received locally delivered argatroban, from 87% to 11% in the group that received locally delivered fragmin, from 88% to 15% in the group that received locally delivered batroxobin, from 82% to 18% in the group that received i.v. heparin (p < 0.0001 compared with before angioplasty in each case), and from 84% to 17% in the control group (p < 0.005 compared with before angioplasty). Twenty-eight days after angioplasty, the percentage luminal stenosis remained at 14% in the group that received locally delivered argatroban, 15% in the group that received locally delivered fragmin, and 28% in the group that received locally delivered batroxobin, whereas it increased to 45% in the group that received i.v. heparin, 30% in the group that received locally delivered heparin and 72% in the control group (p < 0.05 compared with after angioplasty in each case). Thus, local delivery low doses of new antithrombotic drugs prevents restenosis after angioplasty without affecting systemic coagulability; heparin, whether administered locally or intravenously, was less effective than the new drugs in preventing restenosis.

Involvement of the endogenous opioid system in the drinking behavior of schizophrenic patients displaying self-induced water intoxication: a double-blind controlled study with naloxone.

Previously we found significant suppression of polydipsia in a schizophrenic patient with PIP syndrome (psychosis, intermittent hyponatremia, and polydipsia). Suppression was obtained with a small dose of naloxone injected once every 2 weeks in long-term repeated studies. We attempted to confirm the effect of naloxone on PIP syndrome by using a double-blind controlled study. The body weights of eight schizophrenic inpatients with PIP syndrome were checked five times daily, and the maximum weight gain during 1 day was chosen as an index of their polydipsia. Naloxone (0.6 mg in three divided doses) or placebo (saline) injection was given once every 2 weeks three times. Assignment to either the naloxone or placebo series was done randomly in a double-blind, crossover design. Naloxone decreased the maximum weight gain per day significantly in five cases. However, naloxone also increased weight gain significantly in three cases. There was no correlation of the weight-increasing effect of naloxone with the duration and intensity of excessive drinking. Our findings showed that the endogenous opioid system might be related to compulsive drinking behavior in the PIP syndrome and that opioid antagonists such as naloxone or naltrexone could be useful in the therapy of PIP syndrome.

Induction of thrombolysis and prevention of thrombus formation by local drug delivery with a double-occlusion balloon catheter.

The efficacy of the local delivery of an antithrombotic drug in preventing thrombosis and enabling thrombolysis was investigated in 29 dogs. An antithrombotic drug (heparin, 25 U/kg), or an antithrombin (argatroban, 0.05 mg/kg) was infused into injured canine iliac arteries, using a double-occlusion balloon catheter, and the preventive effect of the drug was evaluated. Local delivery of low-dose tissue-type plasminogen activator (t-PA; Tisokinase, 50,000 U; Kowa, Nagoya and Asahi Chemical Industries, Fuji, Japan) into thrombosed canine iliac arteries, using the same catheter, or intravenous infusion of low-dose or high-dose t-PA (30,000 U/kg) was also performed. Angiographically, stenotic thrombosis was 2% by local delivery of argatroban and 7% by local delivery of heparin (P < 0.01 vs each control; 47% and 51% respectively). Thrombotic stenosis, as observed by angiography, decreased from 91% to 9% after local delivery of t-PA, and from 94% to 52% in controls. Local delivery of t-PA effectively reduced the thrombus size (P < 0.01 vs control). After systemic intravenous delivery of low-dose t-PA, no reduction of residual thrombotic stenosis, was observed. Reduction of residual thrombotic stenosis after intravenous delivery of high-dose t-PA, was similar to that achieved by local delivery of the drug. Angioscopy demonstrated a similar trend. High-dose drug delivery reduced systemic coagulability. Local delivery of an antithrombotic drug, using a double-occlusion balloon catheter, effectively prevented thrombus formation, and local delivery of t-PA induced thrombolysis without exerting a significant influence on coagulability.

Local treatment with an antithrombotic drug reduces thrombus size in coronary and peripheral thrombosed arteries.

Since the treatment of thrombotic disease by antithrombotic drugs may be associated with bleeding complications, a local delivery technique for administration of the drug may be useful. The efficacy of low-dose local delivery of an antithrombotic drug on thrombosis was investigated in 73 dogs. The antithrombotic drug (heparin, 25 U/kg, antithrombin: argatroban, 0.05 mg/kg, or defibrinogenating agent: batroxobin, 0.05 U/kg) was infused locally to a 1-h-old thrombus, and no drug was given in controls. The effect of the local delivery on the thrombus was evaluated. Low- and high-dose systemic drug delivery was also evaluated. The mean reduction in thrombotic coronary stenosis observed by angiography was 30.3% with argatroban, 22% with heparin, and 20.8% with batroxobin (P < 0.005 vs controls). Systemic delivery of low-dose heparin or argatroban did not induce any change in thrombus size. With high-dose systemic drug delivery (heparin 250 U/kg, argatroban 0.5 mg/kg), the mean reduction of thrombotic stenosis was 15.2% with heparin and 32.8% with argatroban (P < 0.005 vs controls). In the iliac arterial thrombosis, after local delivery of the drugs, the mean reduction of thrombotic stenosis observed by angiography was 24.4% in the argatroban group, and 19.2% in the heparin group (P < 0.05 vs controls, respectively). With high-dose systemic heparin delivery, the mean reduction of the thrombotic stenosis was 13.2% (P < 0.01 vs control). Angioscopy also demonstrated a similar trend. The high-dose drug delivery reduced systemic coagulability. Thus, local delivery of an antithrombotic agent can reduce the thrombus size in the coronary and iliac arteries without having any significant influence on coagulability.

Naloxone attenuates drinking behavior in psychiatric patients displaying self-induced water intoxication.

1. The present study was performed to examine the effect of naloxone on drinking behavior in three schizophrenic inpatients with psychosis, intermittent hyponatremia, and polydipsia. 2. Their body weight were checked five times daily and the maximum weight gain during a day was chosen as an index of their polydipsia. 3. After control recording for six weeks, a daily naloxone (0.6 mg) injection series was performed once every two weeks for three series (six weeks). Withdrawal of this drug for six weeks resulted in weight gain recovering to control level. 4. The present study showed that naloxone seems to be a potential treatment for psychiatric patients displaying self-induced water intoxication and that endogenous opioid systems are involved in the compulsive drinking behavior of this syndrome.

Loss of vasoreactivity by laser thermal energy or argon laser irradiation.

Vasoreactivity of laser-treated vessels was investigated in two different experimental conditions. The canine left circumflex coronary artery (LCx) was lased under perfusion with Krebs-bicarbonate buffer by means of a thermal laser (hot-tip probe, HT) at 7 W for 6 seconds and an argon laser beam through a 300 microns optical fiber at 3 W (tip power) for 1 second at 12 spots. A nontreated segment of the LCx served as a control. Two 3-mm long segments were obtained from the treated segment: one to measure the results of potassium (K) induced contraction, and another 3, 4 diaminopyridine (DAP; K channel inhibitor) induced contraction. In 11 instances, coronary angiography of the perfused artery showed less than 50% stenosis after laser treatment. The segments were then mounted isometrically with 1 g tension in Krebs-bicarbonate buffer. Contraction was induced either with 30 mM KCI or 10(-2) M DAP and expressed as developed tension (gram; g). KCI induced vasocontraction of 4.15 +/- 0.93 g in the control, 0.33 +/- 0.71 g in laser irradiated segments (P < 0.0001 vs control), and 0.02 +/- 0.06 g in thermally-treated segments (P < 0.0001 vs control). DAP induced vasocontraction of 5.21 +/- 1.32 g in the control, 0.39 +/- 0.83 g in laser irradiated segments (P < 0.0001 vs control), and 0.07 +/- 0.13 g in thermally treated segments (P < 0.001 vs control). In 4 instances, more than 50% stenosis remained and additional balloon dilatation reduced the stenosis to less than 50%. The lesions also showed reduced vasoreactivity. In vivo thermal angioplasty resulted in reduced vasoreactivity compared to control in 4 anesthetized dogs. Thus, laser and thermal angioplasty reduced vasoreactivity induced by either KCI or 3, 4 DAP. Neither acetylcholine at 10(-6) M nor papaverine at 10(-4) M was able to induce relaxation of treated segments. In conclusion, 1) the lased coronary artery loses its vasoreactivity to either a constrictive or relaxing agent, 2) although stenosis may be produced by laser energy, additional balloon dilatation can reduce residual stenosis, and 3) laser thermal or argon laser angioplasty may prevent severe coronary spasm.

[A case of frontal lobe syndrome followed by serial 123I-IMP SPECT].

Single photon emission computed tomography (SPECT) studies with N-isopropyl-p-[123I]iodoamphetamine (IMP) were performed in a 58-year-old man with frontal lobe syndrome. He had abulia and personality changes suggesting frontal lobe impairment. Six follow-up SPECT studies were conducted during 18 months from the onset. On the first scan, no abnormal pattern of regional cerebral blood flow (rCBF) was found. On the second scan, a mild reduction of rCBF was observed in bilateral frontal lobes. Through the third to sixth scans, a progressed reduction of rCBF in bilateral frontal lobes was confirmed by a semi-quantitative regions-of-interest analysis. Contrarily, abulia was improved, and personality change was not progressed during that period. Magnetic resonance imaging on admission revealed only a small subdural hematoma and high intensity areas in the right frontal lobe, which were resolved at the time of the sixth SPECT scan. It is suggested that rCBF studies by SPECT is not necessary concordant with psychiatric symptoms, and has possible limitations in pathophysiological evaluation for psychiatric disorders.

Naloxone attenuates drinking behavior in a schizophrenic patient displaying self-induced water intoxication.

This study was performed to examine the effect of naloxone on drinking behavior in a schizophrenic inpatient with psychosis, intermittent hyponatremia, and polydipsia (PIP syndrome). His body weight was checked five times daily, and the maximum and minimum weight gains during a day were chosen as an index of polydipsia. Both daily (0.6 mg) and repeated (0.6 mg for 6 days) injections of naloxone suppressed his weight gain significantly for 2 weeks. Withdrawal of the drug for 4 weeks resulted in weight gain recovering to control level. Thereafter, a second trial was performed to examine the long-term effect of this treatment. A daily naloxone (0.6 mg) injection series was performed once every 2 weeks for six series (12 weeks). This drug regimen also suppressed his weight gain in a continuous fashion. The study showed that naloxone seems to be a potential treatment for PIP syndrome and that endogenous opioid systems play a part in the compulsive drinking behavior of the PIP syndrome.

Benzene exposure in a Japanese petroleum refinery.

Time-weighted average (TWA) intensity of exposure of workers to benzene vapor during a shift was monitored by diffusive sampling technique in a Japanese petroleum refinery. The subjects monitored (83 in total) included refinery operators, laboratory personnel and tanker-loading workers. The results showed that the time-weighted average exposures are well below 1 ppm in most cases. The highest exposure was recorded in 1 case involved in bulk loading of tanker ships, in which exposure of over 1 ppm might take place depending on operational conditions. The observation was generally in agreement with levels previously reported.