Usefulness of dynamic digitized cerebral parenchymography for cerebral vascular disease

Aortic arch injections according to Theron's method have been performed in patients with cerebral ischemia. Digital subtraction angiograms with modified windowing (low and narrow) have been used for better visualization of cerebral parenchymal condition. This "cerebral parenchymography" allows much easier understanding of cerebral parenchymal vascularization on angiographic imaging. Although further study is necessary to estimate accurate cerebral blood flow, this technique can enable an easy and quick understanding of the overall cerebral hemodynamics.     

Pulmonary artery stenting for recurrent lung cancer after left pneumonectomy

We present a case of a patient with stenosis of the pulmonary artery which was successfully treated by implantation of a vascular endoprosthesis. A 50-year-old man underwent left pneumonectomy for lung cancer. Eleven months later, a computed tomographic scan revealed a soft tissue mass in the mediastinum and there was severe stenosis of the remaining right main pulmonary artery. A self-expandable vascular endoprosthesis was implanted in the stenotic portion. We used percutaneous cardiopulmonary support (PCPS) during the procedure. We recommend the technique of pulmonary artery stenting using PCPS as efficacious and safe.     

Turnover of synaptic membranes: age-related changes and modulation by dietary restriction

Light sensitivity and adaptation, general characteristics of rod photoreceptor cell vision, allow rods to modulate their response depending on the lighting environment to which they are exposed. In dim light, rods are maximally sensitive, whereas, in bright light, rods are essentially inactive. In the retinas of dark-adapted mice, arrestin (an inhibitory protein) is located in the rod inner segment (RIS), and transducin (an activating protein) is located in the rod outer segment (ROS). In light-adapted retinas, the proteins have reciprocal localizations. In this study, our data demonstrate that the temporal and spatial changes in the subcellular localization of arrestin and beta-transducin are correlated with the amount of light to which the animals are exposed. By using the frog Xenopus laevis and immunofluorescence confocal microscopy, our results also show that in the dark-adapted retina some arrestin remains in the ROS. The data most dramatically demonstrate that this residual arrestin is highly concentrated in the connecting cilium, the axoneme, and the microtubules associated with the disc incisures. These data suggest a structure-function relationship between the light-dependent positional status of arrestin and the elements of the rod photoreceptor cytoskeleton. The massive, rapid, light-induced reciprocal changes in the subcellular concentrations of these proteins must directly affect phototransduction and appear to be a general phenomenon by which photoreceptor cells rapidly and transiently regulate the trafficking and subcellular concentration of a variety of signal transduction proteins within the RIS and ROS. Hereditary mutations in the components of the movement mechanism should lead to defects in vision and possibly blindness.     

De novo formation and rupture of an aneurysm. Case report

The authors describe a case of de novo formation and rupture of an aneurysm located at the junction of the left internal carotid artery and the superior hypophyseal artery in a middle-aged woman 2 months after another aneurysm, located on the anterior communicating artery, had been clipped. This case is rare because of the short interval between the last angiographic study performed at the first operation and the diagnosis of the de novo aneurysm; in this case the interval was only 47 days, compared with other cases in the literature in which the intervals were 3 to 34 years. Aneurysms can enlarge considerably in 2 to 4 weeks and can rupture at or soon after their formation. This case provides insight into aneurysm formation and rupture.     

Prognostic Value of Loss of Heterozygosity around three Candidate Tumor Suppressor Genes on Chromosome 10q in Astrocytomas

We thoroughly examined loss of heterozygosity (LOH) around three candidate tumor suppressor genes on chromosome 10q to determine whether LOH of each tumor suppressor gene is associated with the previously defined clinical prognostic indices. We also examined whether LOH can help predict prognostic variables in astrocytomas.We selected samples from 40 astrocytomas (grades 2–4), performed Ki-67 immunostaining, and counted positive cells. Using DNA from aliquots of tumor blocks and leukocytes, we investigated LOH around the PTEN, NEURL, and DMBT1 genes (10q23.3–26.1) with the silver staining procedure. We then statistically evaluated the relationship among histological features, regional LOH on chromosome 10q, and survival. The mean survival period for patients with LOH around PTEN was 7.2 months after surgery, while that for patients without LOH around PTEN was 21.4 months. Thus, LOH around PTEN was closely associated with a reduced overall survival (p = 0.0020) but LOH at NEURL or DMBT1 was not (p > 0.05).The combined features of an increase in histological grading and Ki-67-positive cells and the presence of LOH around PTEN significantly correlated with poor prognosis. These factors may be useful predictors of survival, and LOH analysis of tumor suppressor genes on chromosome 10q can contribute greatly to the treatment of patients with astrocytoma.     

Inhibition of nucleotide excision repair by fludarabine in normal lymphocytes in vitro, measured by the alkaline single cell gel electrophoresis (Comet) assay.

Alkylating agents or platinum analogues initiate several excision repair mechanisms, which involve incision of the DNA strand, excision of the damaged nucleotide, gap filling by DNA resynthesis, and rejoining by ligation. The previous study described that nucleotide excision repair permitted incorporation of fludarabine nucleoside (F-ara-A) into the repair patch, thereby inhibiting the DNA resynthesis. In the present study, to clarify the repair kinetics in view of the inhibition by F-ara-A, normal lymphocytes were stimulated to undergo nucleotide excision repair by ultraviolet C (UV) irradiation in the presence or absence of F-ara-A. The repair kinetics were determined as DNA single strand breaks resulting from the incision and the rejoining using the alkaline single cell gel electrophoresis (comet) assay. DNA resynthesis was evaluated in terms of the uptake of tritiated thymidine into DNA. The lymphocytes initiated the incision step maximally at 1 h, and completed the rejoining process within 4 h after UV exposure. UV also initiated thymidine uptake, which increased time-dependently and reached a plateau at 4 h. A 2-h pre-incubation with F-ara-A inhibited the repair in a concentration-dependent manner, with the maximal inhibition by 5 mM. This inhibitory effect was demonstrated by the reduction of the thymidine uptake and by the inhibition of the rejoining. A DNA polymerase inhibitor, aphidicolin, and a ribonucleotide reductase inhibitor, hydroxyurea, were not so inhibitory to the repair process as F-ara-A at equimolar concentrations. The present findings suggest that inhibition of nucleotide excision repair may represent a novel therapeutic strategy against cancer, especially in the context of resistant cells with an increased repair capacity.     

Bone Marrow Transplantation for Hematologicai Diseases in Hokkaido--June 1985 to December 1991

Bone marrow transplantation (BMT) was started in Hokkaido in1985. In the present report we have reviewed the clinical outcomeof patients treated with BMT for hematologicai diseases in Hokkaido.Fifty-eight allogeneic and 19 autologous transplants were registeredby December 1991. The underlying diseases consisted of 47 leukemias,14 lymphomas, 10 aplastic anemias and six myelodysplastic syndromes.Among the allogeneic BMT cases, 55 were human leuhocyte antigen(HLA) identical and three were mismatched. Among the autologousBMT patiets, two recieved their marrow purged with 4-hydroperoxycyclophosphamideand five, with monoclonal antibodies and complements. The conditioningregimens used for malignancies were chiefly cyclophosphamide(CY) plus total body irradiation, or busulfan plus CY. In manycases, cytokines were used for rapid recovery of decreased leukocytes.Engraftment was observed in 50 out of 52 evaluated allogeneicand 18 out of 19 autologous transplants. Ten allogeneic patientssuffered from severe acute graft-versus-host diseases (GVHD),and extensive chronic GVHD appeared in 16 patients. Relapseswere observed in four cases of allogeneic BMT and six of autologous.BMT. The major complications were interstitial pneumonitis (IP)and severe infections. Long-term, survival rates were almost60% in both allogeneic and autologous transplants. Mild acuteGVHD and limited chronic GVHD increased the survival rates.The results indicated that substantial problems such as GVHD,IP and relapses must be controlled in the near future for animproved outcome to be made possible.     

Macrophage infiltration correlates with tumor stage and angiogenesis in human malignant melanoma: possible involvement of TNFalpha and IL-1alpha

We examined whether macrophage infiltration is associated with angiogenesis in cutaneous melanoma. The numbers of macrophages and microvessels increased significantly with increasing depth of tumor and with tumor angiogenesis. Macrophage infiltration thus appeared to provide a useful diagnostic marker for the progression of cutaneous melanoma. We further examined whether human melanoma cells produce angiogenic factors in response to macrophage-derived cytokines, tumor necrosis factor alpha (TNFalpha) and interleukin-1 alpha (IL-1alpha). Treatment of melanoma cells with TNFalpha and IL-1alpha in vitro enhanced the production of interleukin-8 (IL-8) and vascular endothelial growth factor (VEGF), and of basic fibroblast growth factor (bFGF) to a lesser degree, in human melanoma cells. Lipopolysaccharide (LPS)-activated human monocytes enhanced production of IL-8, VEGF, TNF alpha, as well as IL-1alpha, but not bFGF. Co-culture of human monocytes and human melanoma cells was also found to significantly enhance production of IL-8 and VEGF in the absence and presence of LPS, compared with either monocytes or melanoma cells alone. The production of IL-8 and VEGF from co-cultured melanoma cells and LPS-activated monocytes was blocked when anti-TNF-alpha antibody or anti-IL-1alpha antibody was co-administrated. This is direct evidence that production of the potent angiogenic factors IL-8 and VEGF from melanoma cells is up-regulated through TNFalpha and/or IL-1alpha secreted by activated monocytes/macrophages, influencing both tumor growth and angiogenesis in melanomas.     

In vivo efficacy and toxicity of 5-fluorocytosine/cytosine deaminase gene therapy for malignant gliomas mediated by adenovirus

We evaluated the therapeutic efficacy and neurotoxicity of adenovirus-mediated transduction of the cytosine deaminase (CD) gene and 5-fluorocytosine (5-FC) for experimental malignant brain tumors. The 5-FC sensitivity in 9 L cells infected by an adenovirus vector expressing CD (AdexCACD) was increased 1700-fold compared with control cells. Rats bearing 9 L brain tumors were treated with an intratumoral injection of AdexCACD followed by intraperitoneal administration of 5-FC. The rats demonstrated remarkable inhibition of tumor growth by magnetic resonance imaging, and 7 of 10 rats survived for >90 days. To evaluate the potential side-effects of the 5-FC/CD gene therapy, rats were treated with an intracerebral injection of AdexCACD into the right basal ganglia and with 5-FC. The magnetic resonance imaging showed a highly enhanced area on the gadollinium-enhanced T1-weighted image at 18 days postinjection. Pathologically, this corresponded to an area of necrosis with surrounding apoptotic cells. In addition, there was demyelination and gliosis with enlargement of the lateral ventricles. These results suggest that the 5-FC/CD gene therapy may provide an anticancer effect for malignant brain tumors in humans, but also show that there are neurotoxic effects on normal brain tissue.