Redistribution of pulmonary blood flow during hypoxic exercise.

Pulmonary blood flow (PBF) distribution was studied at rest and during exercise in rats acclimatized to chronic hypoxia (barometric pressure [PB] 370 Torr for 3 weeks, A rats) and non-acclimatized (NA) littermates. Both A and NA rats exercised in hypoxia (inspired O2 pressure [PIO2] approximately 70 Torr) or in normoxia (PlO2 approximately 145 Torr). PBF distribution was determined using fluorescent-labeled microspheres injected into the right atrium. The lungs were cut into 28 samples to determine relative scatter of specific PBF ([sample fluorescence intensity/sample dry weight)/(total lung fluorescence intensity/total lung dry weight]). Exercise produced redistribution of PBF both in NA and A rats, and this effect was larger in hypoxia than in normoxia, with minimal redistribution occurring during normoxic exercise in NA rats. The pattern of distribution varies considerably among individual animals. As a result of distribution, the previous high flow areas would be overperfused during hypoxic exercise in some rats. The results support the concept that hypoxic pulmonary vasoconstriction is not uniform and suggest that the combination of hypoxia and exercise may lead to overperfusion and capillary leak in some individuals.     

Association of human herpesvirus 6 reactivation with the flaring and severity of drug-induced hypersensitivity syndrome

BACKGROUND: Drug-induced hypersensitivity syndrome (DIHS) is an adverse reaction with clinical signs of fever, rash and internal organ involvement. In the vast majority of patients in Japan, the causative drugs for DIHS are limited to the following eight: carbamazepine, phenytoin, phenobarbital, zonisamide, mexiletine, dapsone, salazosulfapyridine and allopurinol. The association of human herpesvirus (HHV)-6 reactivation with DIHS has been reported by various groups. OBJECTIVES: To confirm the relationship between the flaring and severity of DIHS and HHV-6 reactivation. METHODS: We evaluated 100 patients with drug rash and systemic symptom(s) caused by the drugs associated with DIHS. HHV-6 reactivation was examined by serological antibody assay and quantitative real-time polymerase chain reaction assay of serial serum samples. RESULTS: Anti-HHV-6 IgG titres increased in 62 of 100 patients, 14-28 days after the onset of symptoms. These patients suffered from severe organ involvement and a prolonged course compared with 38 patients showing no reactivation of HHV-6. Significant amounts of HHV-6 DNA were detected in serum samples from 18 of the 62 patients. Flaring of symptoms such as fever and hepatitis was closely related to HHV-6 reactivation in these 18 patients. It should be emphasized that all five patients with fatal outcome and 10 patients with renal failure were in the HHV-6 reactivation group. CONCLUSIONS: A combination of immunological reaction to a drug and HHV-6 reactivation results in the severe course of DIHS. The demonstration of HHV-6 reactivation is a useful marker of diagnosis as well as prognosis in DIHS.     

Two-color lymphatic mapping using Ig-conjugated near infrared optical probes

To map the drainage patterns of the lymphatic system, multicolor optical probes must be developed, which can be interstitially administered. These agents must be of sufficient size to be retained by the lymphatic system and permit the conjugation or incorporation of fluorescent probes with varying emission wavelengths. Quantum dots fulfill these criteria, but their potential toxicity limits their application to research settings. Here, we describe the synthesis of lymphatic optical probes based on Igs conjugated with Cy5.5 and Cy7 and demonstrate in animal models that these agents can map the lymphatic drainage patterns within axillary nodes draining both the breast and upper extremity, cervical nodes draining both the ear and upper extremity, and sentinel lymph nodes draining different anatomic locations. The ability to separately and simultaneously visualize the drainage patterns from two separate lymphatic vessels may have implications for the preoperative mapping of lymph nodes before lymph node resection. The biocompatibility of fluorescently labeled Igs in comparison to other nanoparticulate fluorophores improves the chances of clinical translation. This noninvasive and biocompatible multicolor method of optical lymphangiography may elucidate the complex human lymphatic system and reduce the risk of lymphedema after surgery for melanoma and other cancers.     

Response to multiple radiation doses of fibroblasts over-expressing dominant negative Ku70

PURPOSE: To evaluate the response of cells over-expressing dominant negative (DN) Ku70 to single and multiple small radiation doses. METHODS AND MATERIALS: Clones of fibroblasts over-expressing DNKu70, DNKu70-7, DNKu70-11, and parental Rat-1 cells were irradiated under oxic or hypoxic conditions with single or multiple doses. Cells were trypsinized 0 or 6 h after irradiation to determine surviving fraction (SF). RESULTS: Oxic DNKu70-7 or -11 cells trypsinized 6 h after irradiation were 1.52 or 1.25 and 1.28 or 1.15 times more sensitive than oxic Rat-1 at SF of 0.5 and 0.1, respectively. Hypoxic DNKu70-7 or -11 cells trypsinized 6 h after irradiation were 1.44 or 1.70 and 1.33 or 1.51 times more sensitive than hypoxic Rat-1 at SF of 0.5 and 0.1, respectively. To the multiple doses, oxic and hypoxic DNKu70-7 or -11 cells were 1.35 or 1.37 and 2.23 or 4.61 times more sensitive than oxic and hypoxic Rat-1, respectively, resulting in very small oxygen enhancement ratios. Namely, enhancement caused by DNKu70 under hypoxia after multiple doses was greater than that under oxic conditions and greater than that after single dose. CONCLUSIONS: Over-expression of DNKu70 enhances cells' response to radiation given as a single dose and as multiple small doses. The enhancement after multiple doses was stronger under hypoxic than under oxic conditions. These results encourage the use of DNKu70 fragment in a gene-radiotherapy.     

Expression of nm23-Hl and nm23-H2 Proteins in Prostate Carcinoma

The nm 23 gene products/nucleoside diphosphate (NDP) kinase expression in prostate carcinomas and benign hyperplasias was evaluated immunohistochemically. Monoclonal antibodies against nm 23-H1 and nm 23-H2 proteins were prepared using the corresponding proteins fused with glutathione S-transferase as immunogens. Of the 80 cases of nonmetastatic prostate carcinoma examined, 74% (59/80) and 60% (48/80) were immunoreactive for nm 23-H1 or nm 23-H2 protein, respectively. Negative staining for nm 23-H1 occurred in 83% of metastatic lesions, while 34% were negative for nm 23-H2. All primary tumors corresponding to the metastases examined showed positive immunostaining for nm 23-H1, indicating an inverse relationship between expression of this protein and metastatic status. nm 23-H2 protein was detected in 83% of primary tumors and its expression appeared to he significantly correlated to the degree of histological differentiation. In contrast, all cases of benign prostatic hyperplasia showed elevated levels of both nm 23-H1 and nm 23-H2 expression. These data suggest that the nm 23/NDP kinase may play a role in suppressing the expression of malignant potential in prostate carcinomas.     

Changing incidence of hepatocellular carcinoma in Japan

A trend in the incidence of hepatocellular carcinoma (HCC) in Japan was studied from the data of the Osaka Cancer Registry (population, 8,512,351 in 1981) for the period of 1963-1983, the Vital Statistics of Japan, Ministry of Health and Welfare, and the Japan Autopsy Registry which contained 594,132 individually filed cases in the 26-year period from 1958 to 1983. Both cancer registry data and autopsy records showed a more than 2-fold increase in HCC incidence, particularly in the last 10 years or so, among males and a less pronounced increase in females. The same trend was borne out by the cancer registries of Nagasaki City and Miyagi Prefecture and the Vital Statistics. When studied with the autopsy data, it was found that the numbers of autopsies for cirrhosis without HCC and autopsies for HCC (with and without cirrhosis) were about the same in 1958-1961 and that currently (1980-1983) the latter is about 2 times the former. As one of the possible causes of increase in HCC incidence other than prolonged survival of patients with cirrhosis, chronic non-A, non-B hepatitis is discussed.     

THE EFFECT OF A 5HT2 RECEPTOR ANTAGONIST SARPOGRELATE (MCI-9042) TREATMENT ON PLATELET FUNCTION IN BUERGER''S DISEASE

The effect of a new, specific 5-HT₂ receptor antagonist sarpogrelate (MCI-9042) treatment on platelet function and serotonin levels in both plasma and whole blood in Buerger's disease, was assessed in a pilot study. We investigated 10 patients suffering from Buerger's disease. Sarpogrelate in a dose of 3 × 100mg a day was given p.o. for a period of 8 weeks. It was well tolerated and no major side effects were noted. It was judged to be effective in some patients as assessed by its effect on both subjective complaints and objective evaluation of ankle pressure index (API). Sarpogrelate induced a significant decrease in plasma serotonin (5-HT) concentration starting after the 4th week which lasted through to the 8th week of the study, whereas plasma tryptophan concentration increased significantly after 2 and 4 weeks. There were no changes in plasma 5-HIAA concentration. On the other hand whole blood 5-HT concentration increased significantly after 2 weeks, and there was also a tendency to increase in whole blood tryptophan concentration (p=0.052). Platelet aggregation induced by ADP and collagen did not show any statistically significant changes. Surprisingly, platelet aggregation induced by serotonin increased significantly after 2 weeks and even more so after 4 weeks of treatment, and then it returned to baseline values after 8 weeks. There was no effect on platelet count, APTT, TT and fibrinogen concentration. Copyright © 1996 Elsevier Science Ltd     

Fluctuations of euglobulin lysis time, tissue plasminogen activator, and free and total plasminogen activator inhibitor levels in plasma in daytime

Blood was taken from healthy 15 males and 10 females at 9:30 h, 10:00 h and 12:30 h. The euglobulin fraction was prepared and clotted by the addition of human thrombin. The clot lysis time shortened significantly from 9:30 h to 10:00 h (p less than 0.01) and further to 12:30 h (p less than 0.01). Plasma levels of tissue plasminogen activator (t-PA) antigens did not change from 9:30 h to 10:00 h, but slightly and significantly to 12:30 h (p less than 0.01). Plasma levels of free plasminogen activator inhibitor-1 (PAI-1) and complex of t-PA-PAI-1 decreased from 9:30 h to 10:00 h (p less than 0.02) and to 12:30 h (p less than 0.01). Plasma levels of total PAI-1 (free plus complex) decreased from 9:30 h to 10:00 h (p less than 0.01) and to 12:30 h (p less than 0.01). These results suggest that a major factor contributing to the enhanced fibrinolytic activity of the euglobulin fraction may be a level of PAI-1 (free and total).     

Spinocerebellar degeneration with prominent involvement of the motor neuron system: Autopsy report of a sporadic case

Summary A sporadic case of spinocerebellar degeneration with prominent involvement of the motor neuron system is reported. A Japanese male without contributing family history, developed cerebellar ataxia at the age of 52, followed by generalized amyotrophy and ophthalmoplegia, and died aged 58. The clinical findings were pathologically verified as degeneration of the spino-ponto-cerebellar system and the motor neuron system, the latter almost identical to those of amyotrophic lateral sclerosis. Additional subclinical changes were found in the dentate nucleus and substantia nigra. Brain-stem nuclei subserving eye movements were well preserved, suggesting a supranuclear basis for the ophthalmoplegia. This unusual combination of system degenerations has on rare occasions been reported in the heredofamilial cerebellar disorders. As a sporadic case, however, this may be the first autopsy case of spinocerebellar degeneration with severe concurrent involvement of the motor neuron system.