The effect of a new immunosuppressive agent, FK-506, on xenogeneic neural transplantation in rodents--comparison with cyclosporin A]

The present study was performed to compare the immunosuppressive effect of FK-506 (FK) with cyclosporin A (CyA) in xenogeneic neural transplantation in rodents. The solid grafts of embryonic ventral mesencephalic tissue from 14-day rat embryos were transplanted into the right lateral ventricle of 20 mature male mice using a stereotactic approach, and the mice were sacrificed 14 days after transplantation. The removed brains, which were sectioned coronally, were stained with antibodies against glial fibrillary acidic protein (GFAP), Lyt-2 or tyrosine hydroxylase (TH) in addition to hematoxylin-eosin and Nissl stainings. The subcutaneous (s.c.) administration of FK at a dose of 10.0 mg/kg daily for 14 days enabled the neural xenografts to survive and grow (n = 5), although all of the neural xenografts treated with CyA at a dose of 10.0 mg/kg s.c. (n = 5) or FK at a dose of 1.0 mg/kg s.c. (n = 5) daily for 14 days and ones treated without such an immunosuppressive agent (n = 5) were rejected by immunological reactions. We conclude that FK is a more powerful immunosuppressive agent than CyA in xenogeneic neural transplantation as well as in cardiac and renal allograftings.     

Nucleolar organizer region score and Ki-67 labelling index in high-grade gliomas and metastatic brain tumours

Summary Sixteen cases of malignant brain tumours comprising 6 anaplastic astrocytomas, 3 glioblastoma multiforme, 1 medulloblastoma and 6 metastatic brain tumours were investigated independently by a silver colloid method for nucleolar organizer regions (NORs) and an immunohistochemistry using a monoclonal antibody against a nuclear antigen, Ki-67, in proliferating cells. The correlation between the mean number of NORs and the percentage of Ki-67 labelled cells (Ki-67 labelling index) was examined. In addition, four normal brain tissue samples without neoplastic cells were stained for NOR.The mean number of NORs in these malignant brain tumours was significantly greater than that in normal astrocytes (p<0.001). Moreover, both the mean number of NORs and the Ki-67 labelling index in metastatic brain tumours were significantly greater than those in high-grade gliomas (p<0.001). The Ki-67 labelling index and the mean number of NORs in malignant brain tumours including metastatic brain tumours were found to be linearly related (r=0.86).These results suggest that the proliferative potential of malignant brain tumours could be evaluated by NOR score as well as Ki-67 labelling index and that such indices provide clear discrimination between high-grade gliomas and metastatic brain tumours.     

Regulatory mechanisms for the expression of a functional beta chain of interleukin 2 receptor on T4 chronic lymphocytic leukemia cells.

Monoclonal antibodies, each recognizing interleukin 2 receptor (IL-2R) alpha, or beta, were used to see the regulatory mechanisms of the expressions on leukemic cells from a patient with T4 chronic lymphocytic leukemia (T4-CLL). Cells from this patient expressed only IL-2R beta, and the expression was enhanced by medium cultivation. IL-1 enhanced the expression of not only IL-2R beta but also IL-2R alpha on the cells. Binding studies using 125I-IL-2 showed the presence of an intermediate receptor (734 sites/cell, Kd = 1.2 nM) and a few high-affinity receptor (172 sites/cell, Kd = 132 pM) on cells cultured with IL-1. IL-2 and IL-1 synergistically promoted the proliferation of the cells, suggesting that the induced IL-2R was functional. In addition, anti-IL-1 antibodies inhibited IL-2R beta expression by cultured cells, suggesting that it was dependent on IL-1 produced by the leukemic cells. These findings suggested that IL-1 might enhance the expression of IL-2R beta in a subset of human T cells, and implied a role of IL-1 in the proliferation of the leukemic T cells.     

Surgical indication to deep-seated arteriovenous malformation

The natural history of cerebral arteriovenous malformation (AVN) is still a subject of dispute. In the case of deep seated AVM ruptures, the problem is more serious because the hemorrhages often give rise to severe disability or death, depending on their location. Total extirpation of the nidus is fundamentally the best choice for treatment of AVM. It is never acceptable, however, to allow a persistent post operative deficit. Forty-seven cases of deep AVM were encountered in the Tokyo Jikei University Hospital. Total extirpation of the nidus was successful in 32 cases, while no surgery was undertaken in 15. Up to the present time we have taken three risk factors into condition in judging the indications for deep seated AVM surgery: the size of the nidus, the position of the nidus, and the pattern of demarcation around nidus, as shown on CT scan. When the nidus is bordered by a hemorrhage, cyst, or ventricular wall, dissection of the nidus is facilitated and injury to adjacent brain tissue is minimized, and this is why we included profound demarcation around the nidus as the third factor. We then determined grade of risk with respect to each factor, and counted a risk score in each case. The long-term result was judged by the response to questionnaires. Of the 15 patients who did not undergo surgery, four died on account of rebleeding. The longer the patient having deep AVM survived, the more likely the occurrence of fatal rebleeding. Of the 32 patients operated on, two died immediately after surgery, while 23 survived in an improved state or without any aggravated neurological deficit.(ABSTRACT TRUNCATED AT 250 WORDS)     

A Screening Method for Adrenoleukodystrophy Using a Dried Blood Spot on Filter Paper

The authors have devised a new, simple method for the diagnosis of adrenoleukodystrophy (ALD) using a dried blood spot sample. Fatty acid from the dried blood spot was extracted and methylated with HCl-methanol. Fatty acid methyl esters were analyzed by gas chromatography-mass spectrometry. Fatty acid composition of the blood spot from five patients with ALD and from five healthy controls was determined from the mass chromatogram of the m/z 143 ion, [(CH₂) ₆ COOCH₃]±. The ratios of tetracosanoic acid to docosanoic acid (C24:0/C22:0) and of hexacosanoic acid to docosanoic acid (C26:0/C22:0) were significantly greater in ALD patients than in controls. The C24:0/C22:0 ratios of ALD patients and of controls were 2.08 ± 0.33 and 1.47 ± 0.16 (mean ± SD), respectively. The C26:0/C22:0 ratios of ALD patients and of controls were 0.31 ± 0.024 and 0.092 ± 0.041, respectively. The fatty acid composition of the dried blood spot did not change at room temperature within a week. Since the specimens can be sent by mail, this method could be applied to the screening of other “peroxisomal” diseases, such as neonatal ALD and Zellweger syndrome, as well.     

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A feasibility study of differential delivery of levodopa ester and benserazide using site-specific intestinal loops in rats

To study the effect of varied intestinal delivery of levodopa ester, levodopa and its butyl ester were administered as bolus or continuous infusions into site-specific, in situ ligated intestinal loops of rats. Benserazide, a carboxylase inhibitor, was not administered, coadministered with ester, or infused into the duodenal loop prior to ester dosing. While the proximal colon minimally absorbed levodopa itself, it substantially absorbed the ester. Coadministration of benserazide and ester at the colon did not increase absorption; however, prior infusion of benserazide into the duodenum enhanced the colonic absorption of ester. Compared to bolus infusion, continuous delivery of the ester resulted in a more sustained levodopa concentration in plasma, and less metabolism into dopamine. The results were repeated for methyl ester, and the relative differences between the results of methyl and butyl esters versus levodopa were similar. The overall results at the duodenum, jejunum, and ileum were also comparable, likewise were those for the proximal, middle, and distal colons. The results of the study are encouraging: a combination of the continuous delivery of levodopa ester with an immediate-release of benserazide optimizes levodopa bioavailability, potentially leading to a much more effective use of levodopa in the treatment of Parkinson's patients. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:227–233, 2010     

Pulmonary embolism and cerebral venous thrombosis after thoracoscopic surgery for benign pulmonary disease

A-76-year-old woman consulted for open biopsy for a pulmonary mass. Thoracoscopic wedge resection was performed. The lesion was histologically diagnosed as nonspecific inflammation. On the first postoperative day (POD1), the patient lost consciousness transiently. Eleven hours after the first stroke, the patient experienced a second stroke together with hypoxia. Pulmonary perfusion scan on POD2 showed multiple perfusion defects, and the patient was diagnosed with pulmonary embolism (PE). Thrombolitic therapy was started. Neurological symptoms didn’t improve, and cerebral angiography on POD3 showed delayed perfusion in superficial veins. The patient was diagnosed with cerebral venous thrombosis (CVT). Thrombolytic and anticoagulant therapy had been continued, and the patient was found to have hemorrhagic cerebral infarction on POD11. After persistent therapy, the patient was discharged on POD120. Although both PE and CVT are rare complications after thoracic surgery, we must consider these complications in patients undergoing thoracic operations including thoracoscopic surgery.     

Dynamic outflow obstruction due to the transient extensive left ventricular wall motion abnormalities caused by acute myocarditis in a patient with hypertrophic cardiomyopathy: reduction in ventricular afterload by disopyramide.

A 65-year-old woman was admitted to the coronary care unit because of acute pulmonary edema. Immediate 2-dimensional and Doppler echocardiograms revealed extensive left ventricular wall motion abnormalities and left ventricular hypertrophy with extreme outflow obstruction. Although an ECG showed ST-segment elevation in the anterolateral leads, a coronary arteriogram revealed normal epicardial arteries. Heart failure was relieved after diminishing the dynamic outflow obstruction with disopyramide administration. An endomyocardial biopsy from the right ventricle on the 8th hospital day showed borderline myocarditis. Wall motion abnormalities gradually normalized within 2 weeks. It is speculated that her pulmonary edema would not have been relieved so readily without the immediate reduction in ventricular afterload by disopyramide. These clinical changes over time were observed with serial echo-Doppler examinations.