The effect of nitric oxide on retinal blood flow during hypoxia in cats

PURPOSE: To investigate how nitric oxide (NO) contributes to the regulation of retinal circulation during rest and hypoxia in cats. METHODS: N(G)-nitro-L-arginine-methyl ester (L-NAME; n = 7), an NO synthase inhibitor; N(G)-nitro-D-arginine methyl ester (D-NAME; n = 6), the inactive isomer; or phosphate-buffered saline (PBS; n = 7) was injected intravitreously. Hypoxia was induced in the cats by the administration of 10% oxygen. Vessel diameter and blood velocity were measured simultaneously in the anesthetized cats with a laser Doppler velocimetry system, and the retinal blood flow (RBF) and wall shear rate (WSR) were calculated as an index of shear stress on the retinal vessel wall. RESULTS: After intravitreous injection of L-NAME, the vessel diameter (-8.1% +/- 2.0%, P < 0.01), velocity (-17.0% +/- 3.7%, P < 0.01), and RBF (-29.4% +/- 4.6%, P < 0.01) significantly decreased compared with the preinjection level. In the PBS group, maximum increases above the prehypoxia diameter (13.7% +/- 3.5%, P < 0.01), velocity (39.5% +/- 8.6%, P < 0.01), RBF (73.9% +/- 10.6%, P < 0.01), and WSR (28.3% +/- 7.1%, P < 0.01) were observed during hypoxia. In the L-NAME group, those changes substantially decreased in response to hypoxia. D-NAME was inactive with regard to RBF during rest and hypoxia. CONCLUSIONS: These results suggest that NO may be continuously produced in the retina during rest and contributes to increased RBF during hypoxia. In addition, the increased WSR during hypoxia indicates that NO plays an important role in retinal hypoxic hyperemia through a flow-induced mechanism.     

Nobiletin as a tyrosinase inhibitor from the peel of Citrus fruit

A tyrosinase inhibitor was isolated from the peel of Citrus fruit by activity-guided fractionation, and identified as 3',4',5,6,7,8-hexamethoxyflavone (nobiletin) by comparison with reported spectral data. Nobiletin (IC50 of; 46.2 microM) exhibited more potency than Kojic acid (IC50; 77.4 microM) used as a positive control, and it was found to be potentially an effective inhibitor of the production of melanin.     

Successful treatment of multicentric reticulohistiocytosis with alendronate: evidence for a direct effect of bisphosphonate on histiocytes

We describe the case of a 44-year-old Japanese woman with severe nodular erythematous skin lesions and arthritis mutilans who was admitted for further treatment of multicentric reticulohistiocytosis. Skin and synovial biopsies showed heavy infiltration with tartrate-resistant acid phosphatase-positive histiocytes and multinucleated giant cells. Immunohistochemical analysis showed that some of the mononuclear cells in the skin were positive for RANKL. After 1 month of Alendronate, an aminobisphosphonate, given at a dosage of 10 mg once a week intravenously for the first 6 weeks and then once a month thereafter, the arthritis and skin nodules improved, and the remission has continued for more than 2 years. The findings in this patient suggest that osteoclast-like multinucleated giant cells differentiate locally in the skin from infiltrating histiocytes with the help of RANKL-positive stromal cells and that alendronate acts directly on cells of monocyte/macrophage lineage in humans. Thus, alendronate should be added to the list of drugs for the treatment of multicentric reticulohistiocytosis.     

High levels of serotonin transporter occupancy with low-dose clomipramine in comparative occupancy study with fluvoxamine using positron emission tomography

CONTEXT: Serotonin transporters (5-HTT) are regarded as one of the major therapeutic targets of antidepressants. However, there have only been a few studies about 5-HTT occupancy, and in particular, data concerning classical antidepressants are still limited. OBJECTIVE: To investigate the relationship between 5-HTT occupancy and a wide range of antidepressant dosing protocols.Design, Setting, and PARTICIPANTS: Antidepressant occupancies of 5-HTT were measured using positron emission tomography (PET) with [11C](+)McN5652. Twenty-seven healthy volunteers were measured with and without pretreatment with single low doses of antidepressants, and long-term doses were evaluated in 10 patients. Scan data were collected between December 12, 1995, and August 7, 2002, and data were analyzed during the 2001-2002 period at the National Institute of Radiological Sciences (Chiba, Japan).Intervention Four different doses of clomipramine hydrochloride (5-50 mg) and 3 different doses of fluvoxamine maleate (12.5-50 mg) were used for single administration. Long-term doses were 20 to 250 mg per day for clomipramine hydrochloride, and 25 to 200 mg per day for fluvoxamine maleate.Main Outcome Measure Occupancies in the thalamus were calculated using the individual baseline of [11C](+)McN5652 for single-dose studies and 2 long-term-dose studies, and the mean value of healthy volunteers as the baseline for 8 long-term-dose studies. The average data from inactive enantiomers [11C](-)McN5652 were used for the estimation of nonspecific binding. RESULTS: Occupancy of 5-HTT increased in a curvilinear manner. Even 10 mg of clomipramine hydrochloride showed approximately 80% occupancy, which was comparable with that of 50 mg of fluvoxamine maleate. Estimated median effective dose (ED50) of clomipramine hydrochloride was 2.67 mg for oral dose and 1.42 ng/mL for plasma concentration; those of fluvoxamine maleate were 18.6 mg and 4.19 ng/mL, respectively. CONCLUSIONS: Clinical doses of clomipramine and fluvoxamine occupied approximately 80% of 5-HTT, and dose escalation would have minimal effect on 5-HTT blockade. Ten milligrams of clomipramine hydrochloride was enough to occupy 80% of 5-HTT in vivo.     

An improved,simple screening method for detection of glucose-6-phosphate dehydrogenase deficiency

We established a new, simple and rapid screening method for detection of glucose-6-phosphate dehydrogenase (G6PD)-deficiency by using a new formazan substrate, 2-(2-methoxy-4-nitrophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfophenyl)-2H tetrazolium monosodium salt (WST-8) with a hydrogen carrier of 1-methoxyphenazine methosulfate (1-methoxy PMS), instead of a combination of 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H tetrazolium bromide (MTT) and phenazine methosulfate (PMS), as used in many previous formazan methods. WST-8 does not react with haemoglobin, and the formed formazan is highly water-soluble, differing from MTT. Thus, the whole procedure can be performed in aqueous solution in a tube or well without any special equipment other than micropipettes. Within 1 h at room temperature, the strong orange colour of the WST-8 formazan formed in normal blood samples could be distinguished, by naked eye, from G6PD-deficient blood samples with less than 50% residual activity. We also found that reagents in the WST-8/1-methoxy PMS method were more resistant against exposure to sunlight than those in an MTT/PMS method. As the new method is both qualitative and quantitative, it is possible to express G6PD activity as increase of NADPH concentration by reading absorbance at 460 nm after incubation for 30 or 60 min.     

Efficacy of active core rewarming using fluid heating system HOTLINE before and during the operation in a patient with for panperitonitis in state of shock and hypothermia

A 62-year-old man was transported to the emergency room. He was in the state of shock and hypothermia of 34.2 degrees C. Fluid therapy was started using a HOTLINE to raise the body temperature, with vasopressors, vitamin B1 and sodium bicarbonate after checking arterial blood gas. Diagnosis of panperitonitis was made and operation was started immediately. We used HOTLINE before and during the operation. Body temperature returned to normal ranges, and hemodynamic state was stabilized at the end of the operation. After the operation, he received controlled artificial ventilation and nutrition support with intravenous hyperalimentation. Though he was complicated with disseminated intravascular coagulation, he went to general ward 17 days, and was discharged at 47 days after the operation. Sepsis accompanied with hypothermia leads to poor prognosis. We used fluid therapy with rapid-heating, and obtained good outcome. HOTLINE is effective for hypothermia in an emergency patient, because its effect is sure and does not obstruct the examination and management.     

Tandem high-dose chemotherapy supported by autologous peripheral blood stem cell transplantation for recurrent soft tissue sarcoma

BACKGROUND: Patients with recurrent soft tissue sarcoma (STS) are seldom curable, with 5-year survival rates of less than 10% in all large series. The role of high-dose chemotherapy (HDC) with hematopoietic stem cell support in this disease has not been established. CASE REPORT: We report on two patients with recurrent STS who were treated with tandem HDC supported by autologous peripheral blood stem cell transplantation (PBSCT). One patient with malignant fibrous histiocytoma recurred with multiple lung metastases. This patient achieved a partial response after two cycles of induction chemotherapy consisting of ifosfamide and epirubicin. During four cycles of induction chemotherapy, peripheral blood stem cells (PBSCs) were harvested. Tandem high-dose ICE regimen (ifosfamide 3 g/m2 on days-7 to -3, carboplatin 400 mg/m2 on days-7, -5 and 3, etoposide 500 mg/m2 on days-7, -5 and 3) supported by autologous PBSCT gave rise to further regression of the tumors. Another patient with malignant hemangiopericytoma was treated by tandem high-dose ICE regimen supported by autologous PBSCT after the 3rd removal of abdominal tumors. Relapse-free intervals until the 1st, 2nd and 3rd relapses were 40, 19 and 22 months, respectively. Tandem high-dose ICE regimen might delay the relapse. CONCLUSION: These observations suggest that a tandem high-dose ICE regimen with autologous PBSCT is feasible with some clinical efficacy in the control of refractory STS.