Tc-99m tetrofosmin myocardial perfusion SPECT after dipyridamole combined with low-level exercise in the diagnosis of coronary artery disease

Tc-99m tetrofosmin is a lipophilic, cationic perfusion imaging agent that changes to Tl-201 in detecting coronary artery disease during exercise testing. The purpose of this study is to evaluate the usefulness of Tc-99m tetrofosmin dipyridamole stress imaging combined with low level exercise for the detection of coronary artery disease. We examined 42 patients and 10 normal volunteers who also underwent coronary angiography. A one-day protocol was used: in the stress study, 296 MBq of tetrofosmin was injected and in the rest study 888 MBq was injected. After intravenous administration of dipyridamole (0.142 mg/kg/min for 4 minutes), the patient was exercised on a bicycle ergometer for 3 min (25 Watts). Tetrofosmin was injected 2 minutes after dipyridamole infusion during the exercise. Single photon emission computed tomographic images were obtained 30 minutes after the tracer injection. Images were interpreted as abnormal in 36 of 42 patients with coronary artery disease, and normal in all of 10 normal volunteers. The overall sensitivity of detection of coronary artery disease was 83.3% and the normalcy rate was 100%. The diagnostic values for the detection of significant stenosis in the three major arteries were: LAD sensitivity 83%, specificity 92%; LCX sensitivity 47%, specificity 91%; RCA sensitivity 75%, specificity 83%. Of the 66 arteries with more than 50% stenosis, 48 arteries were correctly identified. Of the 36 with more than 70% stenosis, 31 were identified. Scintigraphic evidence of multivessel disease was found in only 9 patients (50%). A protocol of Tc-99m tetrofosmin SPECT combined with low level exercise after dipyridamole is therefore useful for the detection of the coronary artery disease.     

VALUE OF COMPUTED TOMOGRAPHY FOR EVALUATING THE INJECTION SITE IN ENDOSONOGRAPHY‐GUIDED CELIAC PLEXUS NEUROLYSIS

Endosonography‐guided celiac plexus neurolysis (EUS‐CPN) safely and effectively relieves pain associated with intra‐abdominal malignancies when the neurolytic is accurately injected. We applied contrast medium to evaluate the ethanol injection sites in patients who received EUS‐CPN due to abdominal pain caused by malignancies. We injected, under the guidance of endoscopic ultrasonography (EUS), ethanol containing 10% contrast medium into the celiac plexus of patients with intra‐abdominal pain due to malignancies. Immediately after the endoscopic therapy, patients underwent computed tomography (CT) to confirm the injection site. Images of distribution of injected solutions were classified into three groups. Injected solution dispersed in unilateral and bilateral anterocrural space was defined as ‘unilateral injection’ or ‘bilateral injection’, respectively. Injected solution located out of the anterocrural space was defined as ‘inappropriate injection’. Pre‐ and postprocedure pain was assessed using a standard analog scale. Before and 2, 4, 8, 12, and 16 weeks after the procedure, pain scores were evaluated. From April 2003 to May 2005, 13 patients were enrolled in this study. Improvement of pain score in the ‘bilateral injection’ and ‘unilateral injection’ groups was significantly superior to the change in the ‘inappropriate injection’ group. Although EUS‐CPN was effective in eight of 13 patients (61.5%), additional EUS‐CPN to the ‘inappropriate injection group’ increased the response rate to 84.6%. Injection of ethanol to the anterocrural space by EUS‐CPN produced adequate pain relief. Immediate examination by CT for confirmation of injection sites after EUS‐CPN would increase the likelihood of induction of pain relief.     

Angiotensin I-converting enzyme inhibitor improves reactive hyperemia in elderly hypertensives with arteriosclerosis obliterans.

Endothelial function in elderly hypertensive patients with arteriosclerosis obliterans has not been evaluated. We examined whether antihypertensive drugs improve vasodilatory response to reactive hyperemia of the limbs in elderly hypertensive patients (83 +/- 8 [SD] years) without (n=46, 0.9 < or = ankle-brachial pressure index < or = 1.4) and with (n=24) arteriosclerosis obliterans (ankle-brachial pressure index < 0.2). Patients were randomized for treatment with monotherapy of either temocapril (14 with and 26 without arteriosclerosis obliterans) or amlodipine (10 with and 20 without arteriosclerosis obliterans) for 6 months. Blood flows of the forearms and legs were measured by strain-gauge plethysmography. The vasodilatory response to the release of compression of the forearms and thighs at 200 mmHg or 20 mmHg more than systolic blood pressure for 5 min and to sublingual administration of nitroglycerin (0.3 mg) was assessed. The maximum reactive hyperemic flow in 35 legs with arteriosclerosis obliterans was significantly (p < 0.001) decreased compared to the value in legs in the control hypertensive subjects. Moreover, maximum reactive hyperemic flow in the forearms of patients with arteriosclerosis obliterans was significantly (p = 0.002) decreased compared to that in the control subjects. Blood pressure was similarly decreased by treatment with temocapril or amlodipine. Response to nitroglycerin (0.3 mg) was not changed by either drug. Treatment with temocapril significantly improved maximum reactive hyperemic flow of not only the legs and forearms in control hypertensives but also the legs and forearms in patients with arteriosclerosis obliterans, and attenuated the worsening of activity of daily living in these patients, although treatment with amlodipine did not. These results suggest that the angiotensin-converting enzyme inhibitor temocapril has a beneficial effect on endothelial function in elderly patients with arteriosclerosis obliterans.     

Treatment with hypotensive agents affects the impaired relaxation of the penile corpus cavernosum in hypertensive rats.

Treatment of erectile dysfunction (ED) in hypertensive subjects remains to be formally established. There is currently no standardized treatment for ED in hypertensive subjects. In this study, we tested our hypothesis that hypotensive drugs would improve impaired relaxation in the corpus cavernosum of spontaneously hypertensive rats (SHR). Ten-week-old SHR was treated with amlodipine, imidapril or hydralazine for 4 weeks. Although all three drugs achieved an equivalent decrease in systolic blood pressure (SBP), only amlodipine and imidapril induced an increase in relaxation in response to electrical field stimulation (EFS) of the corpus cavernosum. In the case of amlodipine, this effect was dose- and SBP-dependent. Nitric oxide (NO)-dependent relaxation was increased by amlodipine over a wide range of EFS frequencies, was increased by imidapril at low EFS frequencies, and was decreased by hydralazine. Carbon monoxide (CO)-dependent relaxation was only increased by hydralazine, and this increase occurred over a wide range of frequencies. The NOx and cGMP levels in the EFS-stimulated corpus cavernosum were increased by amlodipine. Amlodipine did not affect the thiobarbituric acid-reacting substance levels in the serum and the corpus cavernosum, but did decrease superoxide dismutase activity in the tissue. Imidapril and hydralazine inhibited the acetylcholine-induced relaxation in the corpus cavernosum. Sodium nitroprusside-induced relaxation in the tissue was increased by amlodipine. All three agents similarly inhibited the phenylephrine-induced contraction. These results suggest that impaired neurogenic relaxation in the corpus cavernosum of SHR is improved by amlodipine and imidapril through an increase in the synthesis and/or release of neuronal NO, but not CO, and presumably the inhibited detumescence of erection, which is induced by norepinephrine being released from sympathetic neuron. These findings indicate that amlodipine and imidapril may ameliorate the decreased relaxation of cavernous smooth muscle in the setting of hypertension.     

Synergistic effect of recombinant interleukin-2 on the inhibition of growth of adenocarcinoma 755 by mitomycin

The increase in life-span (ILS) of tumor-bearing mice caused by recombinant interleukin-2 (RIL-2) was studied in the solid tumor adenocarcinoma 755 system. With long-term treatment (Days 5-12), RIL-2 (10(5) U/mouse) showed a weak effect (24% ILS), but short-term RIL-2 treatment (Days 5-8 or 9-12) had hardly any effect. Mitomycin, at 2 mg/kg (maximum nontoxic dose), caused 35% ILS with Days 5-8 treatment and only 12% ILS with Days 9-12 treatment. Sequential treatment with mitomycin (Days 5-8) and RIL-2 (Days 9-12) markedly enhanced antitumor activity (88% ILS). This value is significantly greater than that of mitomycin alone or RIL-2 alone (P less than 0.01). Furthermore, mitomycin followed by RIL-2 markedly augmented killing activity of spleen cells that are cytotoxic in vitro. These results indicate that RIL-2 markedly affects the inhibition of growth of a tumor treated with an antitumor agent.     

Dispersion of Pressure to the Head in Brain/NeuroSurgery

Skin and soft tissue defects are sometimes problematic especially when the defects large, contaminated, irradiated, or poor blood supplied. The human mesenchymal stem cells (hMSCs) are proliferated upon basic fibroblast growth factor (bFGF) stimuli in vitro and in vivo. In this experiment, the skin and soft tissue defects are investigated if the wounds are able to be reepithelialized or accelerated by hMSCs, bFGF and porcine‐derived bilayered skin template.
1.5 × 1.5 cm² nude rat skin and soft tissue defects including panniculus carnosus are excised and 1 × 10⁶ hMSCs and various doses of bFGF (1–100 μg) applied. Before and after normal reepithelialization, the tissues are tested for protein expressions by immunohistochemistry and Western blotting.
The wound sizes are significantly decreased at day 7 with hMSCs with 1, 10, or 100 μg bFGF compared to hMSCs‐alone or medium‐only. All the wounds healed by day 42. 42 Kda and 38 Kda human‐derived pancytokeratin expressions, which do not cross‐react with murine antigens, by Western blotting significantly augmented by 10 μg bFGF compared to hMSCs‐alone. The epidermal immunolocalizations such as integrin α3 and SKALP (Skin‐derived Anti Leukoproteinase) are greatly elevated in time and dose‐dependent manner. Human pan‐cytokeratin expressions are immunoreactive even at day 42.
These data suggest the skin and soft tissue wound healing is accelerated by hMSCs together with bFGF, partly by means of differentiation of hMSCs toward epidermal components.     

Pathological effects on mice by gambierol, possibly one of the ciguatera toxins

Gambierol was isolated from Gambierdiscus toxicus, which causes ciguatera fish poisoning. The acute toxicological effects induced in mice by synthesized gambierol were studied. The lethal doses were about 80 μg/kg by i.p. and i.v., and 150 μg/kg by p.o. The main injury by this toxin was observed in the lung, and secondary in the heart, resulting in systemic congestion. Another toxic effect was seen in the stomach, inducing hypersecretion and ulceration. With survival from the severe stage during the initial 3 h, recovery was favorable, especially after 4 days. Additional effects were not evident during 1-week post-administration observation.     

Pharmacokinetic Study of Mitomycin C with Emphasis on the Influence of Aging

Mitomycin C (MMC) at a dose of 8 mg/m² was administered by short intravenous infusion to 14 cancer patients. All patients had normal renal, hepatic, cardiac and bone marrow functions. The plasma level of MMC, which was determined by high-performance liquid chromatography over a 24–h period after the infusion, fitted the 2-compartment model curve except for one patient. There was a significant correlation between the area under the time versus concentration curve (AUC) of MMC and the age of patients ( r = 0.558, P < 0.05). Pharmacokinetic parameters in one of the older (a 69-year-old male) patients were extremely different from those of the other 13 patients. This patient experienced severe myelosuppression, probably due to the markedly increased AUC of MMC. Our results suggest that a patient's age has a significant influence on the pharmacokinetics of MMC in patients with normal major organ functions and that in some patients, MMC pharmacokinetics may be altered, possibly due to interpatient variation in the activation or metabolic pathway of MMC.     

Impaired cardiovascular autonomic function in Parkinson's disease with visual hallucinations.

We assessed the relations of visual hallucinations (VH) to cardiovascular autonomic dysfunction in patients with Parkinson's disease (PD). The subjects were 37 patients without VH (VH(-)) and 31 with VH (VH(+)). Autonomic function was evaluated on the basis of cardiac 123-radioiodinated metaiodobenzylguanidine (123I-MIBG) uptake and hemodynamic testing with Valsalva maneuver. Systolic blood pressure (SBP) and plasma norepinephrine concentrations (NE) were measured by tilt-table testing. 123I-MIBG uptake was lower in VH(+) than VH(-). Hemodynamic studies showed that VH(-) had only cardiac sympathetic and parasympathetic dysfunction, while VH(+) additionally had reduced vasomotor sympathetic functions. The fall in SBP during tilt-table testing was greater in VH(+) than VH(-). NE and its difference in the supine and upright positions were decreased in VH(+). We conclude that cardiac and vasomotor sympathetic dysfunction is more severe in VH(+) than in VH(-). Severe dysfunction in PD with VH is probably attributed to Lewy-body lesions or neuronal loss in sympathetic ganglia, the central autonomic system, or both.     

Antiproliferative effects of NKH477, a forskolin derivative, on cytokine profile in rat lung allografts.

OBJECTIVE: NKH477 was recently identified as a water-soluble forskolin derivative and was reported to prolong survival of murine cardiac allografts. However, the mechanism of the efficacy is not clear in vivo. The aim of this study was to investigate the immunosuppressive effects of NKH477 on acute lung allograft rejection in the rat model and its mechanism of action in vivo. METHODS: Left lungs were transplanted orthotopically from Brown-Norway donors to Lewis recipients. Recipient rats were untreated or treated daily with different doses of NKH477. Grafts were excised on Day 3 or Day 5 to determine histopathological rejection and expressions of interleukin (IL)-2, IL-4, IL-10, and interferon (IFN)-gamma by enzyme-linked immunosorbent assay. The cytokine expression at Day 3 or Day 5 was also evaluated in recipient spleens by immunohistochemistry. Furthermore, mesenteric lymph node cells from recipients at Day 5 were cultured alone or stimulated with donor antigens for 72 hours to determine cell proliferation by means of thymidine incorporation. RESULTS: NKH477 significantly extended allograft survival time in a dose-dependent manner and reduced histopathological rejection. Treatment with NKH477 inhibited IFN-gamma and IL-10 expression, whereas expression of these cytokines were markedly upregulated in the untreated allografts. Expression of IL-2 and IL-10 also increased in the spleen of untreated allorecipients. NKH477 suppressed expression of both cytokines in the spleen. In addition, lymphocyte proliferation was inhibited in NKH477-treated recipients as compared with untreated recipients. CONCLUSION: These results suggest that NKH477 exerts an antiproliferative effect on lymphocytes in vivo with an altered cytokine profile in rat recipients of lung allografts.