Little evidence for cell fusion between recipient and donor-derived cells

Despite recent advances in immunosuppressive therapy, accelerated coronary atherosclerosis remains a major problem in the long-term survival of cardiac transplant recipients. However, the pathogenesis of the transplant-associated atherosclerosis remains largely unknown. Here, we investigated the origin of the vascular cells that contribute to graft vasculopathy. We performed heterotopic heart transplantation using genetically modified mice that express LacZ or green fluorescent protein (GFP) ubiquitously and constitutively. At 4 weeks after transplantation, the graft coronary arteries developed neointimal hyperplasia, expressing several smooth muscle cell markers. Most of the neointimal cells were composed of recipient cells but not graft medial smooth muscle cells. We seldom detected neointimal cells that were positive for both LacZ and GFP. When we transplanted wild-type cardiac allografts into the chimeric mice whose bone marrow cells had been replaced with those of LacZ-mice or GFP-mice, we observed that most of the neointimal cells were derived from the bone marrow. These findings suggest that recipient bone marrow-derived cells contribute to the pathogenesis of graft arteriosclerosis. Spontaneous cell fusion between recipient and donor-derived cells seems to be a rare event, if it occurs at all.     

The mechanisms of immune-to-brain communication in inflammation as a drug target

There is considerable evidence that the peripheral immune system can signal the brain to elicit a sickness response during infection and inflammation. The induction of the sickness response involves the expression of proinflammatory cytokines such as interleukin (IL)-1beta, tumor necrosis factor-alpha (TNF-alpha), and IL-6, both in the periphery and in the brain. The mechanisms by which peripheral cytokines can affect brain function have been the subject of much debate. The precise mechanisms by which cytokines signal the central nervous system (CNS) are unknown, but possibilities include: 1) the direct entry of cytokine into the brain across the blood-brain barrier by a saturable transport mechanism: 2) the interaction of cytokine with circumventricular organs such as the orgnum vasculosum of the lamina terminalis [OVLT] and area postrema, which lack the blood-brain barrier; and 3) activation of afferent neurons of the vagus nerve. Increasing evidence has suggested that the afferent vagus nerve is an important pathway for immune-to-brain communication. However, there are inconsistent findings for the involvement of the afferent vagus nerve in the mediation of transmitting inflammatory signals to the brain. Thus, we describe here the functional relevance of the vagal afferent nerve in mediating these effects. An understanding of the mechanisms involved in immune-to-brain communication should permit us to create new drugs as therapeutic targets to decrease sickness or promote recovery. This review focuses on recent discoveries of the multipathway mechanisms for the induction of sickness behavior mediated through neuroimmune interactions in the CNS.     

Phase I clinical and pharmacokinetic study of orally administeredN 4-palmitoyl-1-β-d-arabinofuranosylcytosine

A phase I study ofN ⁴-palmitoyl-1-β-d-arabinofuranosylcytosine (PLAC) was conducted in 88 patients; 36 with solid tumors and 52 with hematological malignancies, using 2 different schedules. Schedule 1 employed a single oral administration and Schedule 2, 5-day consecutive daily oral administration. In Schedule 1, the daily dose was initiated with 1 mg kg^?1 which was escalated up to 24 mg kg^?1 according to the modified Fibonacci’s method. Side effects included nausea, vomiting and skin rashes, but myelosuppression was not seen within this dose range. In Schedule 2, the daily dose was started with 1 mg kg^?1 which was escalated up to 24 mg kg^?1. Major side effects were nausea, vomiting and amorexia, and mild myelosuppression was noted at 12 mg kg^?1 or more. The dose-limiting toxicity was gastrointestinal toxicity, which appeared at 3.3 mg kg^?1 or more and became frequent at 7 mg kg^?1 or more. Pharmacokinetic study revealed that the plasma concentrations of PLAC and ara-C, obtained by the oral intake of 3.3 mg kg^?1 or more of PLAC, were sufficient for these compounds to exert cytotoxic effects on various human leukemia cellsin vitro. Based on these observations and plausible mechanism of action of PLAC, further clinical study should be carried out in a treatment schedule of considerably prolonged administration period with 3.3–6 mg kg^?1 day^?1 of PLAC.     

A comparison of mass screening for breast cancer using mammography and physical examination alone in Japan

To compare the sensivity of breast cancer screening methods by conventional physical examination and film mammography, a trial of mass screening for breast cancer using mammography was principlly carried out in asymptomatic women over 50 years of age in Tokushima Prefecture. In this trial craniocaudal and mediolateral oblique imagings of the breast using two-view film mammography and physical examination, using inspection and palpation of the breasts were performed independently. Breast cancer was detected in 8 of a total of 950 examinees by mammography alone, and no cases of breast cancer were detected by physical examination. The detection rate of breast cancer was 0.84%, that is 7 times higher than that (0.12%) obtained by conventional mass screening using physical examination alone. The detection rate increased especially in the sixth and seventh decades of life. The stage of the detected breast cancer was stage 0 (Tis) in 5 cases and stage I, with a tumor size of 1.0 cm or less, in 3 cases. All 8 cases were in the early stage, and they underwent breast conservation therapy. Based on these results, it is recommended to employ mammography in breast cancer screening for asymptomatic women aged over 50 years. We consider mammography alone may be sufficient for mass screening for breast cancer in these subjects. The present study was supported in part by a Grant-in-Aid for Cancer Research (No.5-43, Chief Reaseacher; C. Kido) from the Ministry of Health and welfare of Japan.     

Nationwide randomized comparative study of daunorubicin and aclarubicin in combination with behenoyl cytosine arabinoside, 6-mercaptopurine,and prednisolone for previously untreated acute myeloid leukemia

Aclarubicin was evaluated in combination chemotherapy for adult acute myeloid leukemia in a randomized trial involving 58 institutions throughout Japan. Behenoyl cytosine arabinoside (BH-AC)daunorubicin, 6-mercaptopurine, and prednisolone (DMP) was compared with BH-ACaclarubicin, 6-mercaptopurine, and prednisolone (AMP). In the 360 evaluable cases among the 433 cases enrolled, complete remission (CR) rates were 63.7% (116/182) for BH-ACDMP and 53.9% (96/178) for BH-ACAMP (P=0.0587). Median survival periods and 7-year survival rates were 15.8 months and 19.3% for BH-ACDMP and 9.5 months and 20.2% for BH-ACAMP (P=0.0091 according to the generalized Wilcoxon test [GW],P=0.196 according the log-rank test [LR]). Median disease-free survival periods were 15.4 months for BH-ACDMP and 14.1 months for BH-ACAMP (P=0.851 by GW,P=0.439 by LR). Among the 346 cases of extramurally confirmed FAB subtypes, CR rates were 67.9% (19/28) with BH-ACDMP and 31.8% (7/22) with BH-ACAMP for subtype M3 (P=0.011) and 63.3% (93/147) with BH-ACDMP and 56.8% (84/148) with BH-ACAMP (P=0.254) for subtypes M1, M2, M4, and M5. Diarrhea, ileus, pneumonia, and renal failure were more frequent with BH-ACAMP than with BH-ACDMP. The results indicate, at least on the basis of the long-term outcome, that BH-ACAMP has antileukemic effects on subtypes M1, M2, M4, and M5 that are comparable with those of BH-ACDMP.This work was supported by a grant-in-aid from the Japanese Foundation for Multidisciplinary Treatment of Cancer (Cooperative Project 2)     

Radical polymerization of vinyl monomers by captodative substituted dimers

Polymerization of vinyl monomers such as styrene, methyl methacrylate, and vinyl acetate was carried out in the presence of the captodative substituted dimers 1 – 6 at 50 to 110°C. It was found that the dimer initiates the radical polymerization of these monomers, even of vinyl acetate. The initiation ability of the dimers depends on the nature of both captive and dative groups as well as the substituent at a remote position. The kinetic study suggests that in the polymerization initiated by the dimers primary-radical termination and chain transfer play a minor role.     

Massive ovarian edema associated with polycystic ovary

A 14-year-old girl with massive ovarian edema (MOE) of the right ovary and a polycystic ovary is presented. The right ovary was moderately enlarged and incompletely twisted. Histologically, it showed diffuse interstitial edema and multiple cysts, frequently surrounded by a line of luteinized cells. Such cysts are suspected to consist of highly degenerative ovarian follicles, in addition to an edematous corpus albicans and cystic change in the edematous stroma. Focal edematous change and occasional indefinite cystic structures, as seen in the left polycystic ovary of our patient, indicate an early stage of MOE. The pathogenesis of MOE in the present case was therefore suspected to be based on the underlying state of bilateral polycystic ovary. The luteinized cells would have been derived from granulosa cells and from the internal theca cells of the follicles in addition to stromal cells.     

Associated change of transthoracic electrical impedance with regional ventilation of the lung

Based on previous results which suggested that transthoracic electrical-impedance variations correspond to ventilatory air-volume changes within the lung, the capability of the impedance method to detect regional ventilatory changes was tested. Three groups of tetrapolar electrodes were attached to the right-middle and bilateral-diaphragmatic lobe areas on the thoraxes of dogs. Injecting either a single current of 50 kHz or two currents of 50 and 55 kHz simultaneously through these electrodes, impedance changes were measured simultaneously during ventilatory manipulations in either the right-diaphragmatic and mediastinal lobes or the mediastinal lobe. Individual placements of the electrodes detected an independent impedance variation, which corresponded reasonably with the air-volume fluctuation within the right-middle and bilateral-diaphragmatic lobes. No response was observed from the bilateral-diaphragmatic lobe areas on selective manipulation in the mediastinal lobe. From these results, it is clear that the method can detect regional ventilatory variations which occur within the lobe in the immediate vicinity of the electrode.