Comparison of the fine-scale genetic structure of three dipterocarp species.

We investigated the fine-scale genetic structure of three tropical-rainforest trees, Hopea dryobalanoides, Shorea parvifolia and S. acuminata (Dipterocarpaceae), in Peninsular Malaysia, all of which cooccurred within a 6-ha plot in Pasoh Forest Reserve. A significant genetic structure was found in H. dryobalanoides, weaker (but still significant) genetic structure in S. parvifolia and nonsignificant structure in S. acuminata. Seeds of all three species are wind dispersed, and their flowers are thought to be insect pollinated. The most obvious difference among these species is their height: S. parvifolia and S. acuminata are canopy species, whereas H. dryobalanoides is a subcanopy species. Clear differences were also found among these species in their range of seed dispersal, which depends on the height of the release point; so taller trees disperse their seed more extensively. The estimates of seed dispersal area were consistent with the degree of genetic structure found in the three species. Therefore, tree height probably had a strong influence on the fine-scale genetic structure of the three species.

Marked reduction of mortality in salt-loaded Dahl salt-sensitive rats by the new, selective endothelin ETA receptor antagonist, J-105859.

OBJECTIVE: To examine the chronic effects of a newly synthesized, potent and selective endothelin (ET) ETA receptor antagonist, J-1 05859, on mortality in salt-loaded Dahl salt-sensitive (DS) rats and to confirm the potential of this compound as an ETA antagonist METHODS: Vehicle and J-105859 were administered to salt-loaded DS rats for 12 weeks. Throughout the experimental period, blood pressure was measured continuously using a telemetry system and the survival rate was determined. The surviving animals were subsequently sacrificed and autopsy was performed. Binding and functional assays were also carried out to characterize J-1 05859. RESULTS: The Ki values of J-1 05859 for cloned human ETA and ETB were 0.025 and 48 nmol/l, respectively. J-105859 inhibited ET-1-induced contractions in rabbit iliac artery (pA2 = 10.08) and BQ-3020 (ETB agonist)-induced contractions in pulmonary artery (pA2 = 7.63). The pressor response to intravenous (i.v.) ET-1 (0.5 nmol/kg) was significantly inhibited by J-1 05859 at a dose of 0.03 mg/kg i.v. Chronic treatment with J-1 05859 [0.1 and 1 mg/kg per day orally (p.o.)] from the prehypertensive stage decreased the mortality of salt-loaded DS rats and markedly inhibited the development of brain lesions. The survival rates in the control and J-1 05859 (0.1 and 1 mg/kg per day) groups were 34, 80 and 100%, respectively. Development of hypertension was markedly inhibited at a dose of 1 mg/kg per day. CONCLUSION: J-105859 is a selective, potent, orally active ETA-selective antagonist ETA antagonists may reduce morbidity as well as mortality in salt-sensitive hypertension.

[A case of neurofibromatosis type 1 associated with arteriovenous fistula caused by re-bleeding of a vertebral dissecting aneurysm].

We described a dissecting aneurysm of the vertebral artery (VA), which was associated with neurofibromatosis type 1 (NF1). A 41-year-old man was referred to our hospital because of abrupt, severe headache. A CT scan revealed diffuse subarachnoid hemorrhage (SAH) predominantly in the prepontine cistern. The angiograms showed a string sign in the left VA, just distal to the posterior inferior cerebellar artery (PICA). The vertebral dissection was considered responsible for SAH, and endovascular occlusion of the left VA was attempted. During the intervention, the patient complained of severe neck pain at the time of selective vertebral angiography, which revealed an arteriovenous fistula. The VA was occluded proximal to the PICA with GDC, which covered the fistula. Open surgery confirmed the two unruptured aneurysms. Intracranial dissection is rarely reported in association with NF1. However, ateriovenous fistula is not an uncommon combination with dissecting aneurysm and the extracranial segment of the VA is a characteristic target. Anatomical feasibility is conceivably the pathogenesis.

[A case of peduncular hallucination after aneurysmal subarachnoid hemorrhage].

We reported a case of peduncular hallucination after aneurysmal subarachnoid hemorrhage (SAH). The patient underwent endovascular embolization of an intracranial aneurysm using the Guglielmi detachable coils (GDCs) 9 days after SAH. On the 11th day, she reported visual hallucination: a maggot was on the ceiling, or a soldier who wore green clothes was standing by a locker. The hallucination was vivid, well-formed and associated with insomnia, suggesting peduncular hallucination. A computed tomographic (CT) scan revealed small infarctions of right frontal lobe, which were not responsible for the visual hallucination. Hyperdynamic therapy relieved the visual hallucination 23 days after SAH. It was conceivable that vasospasm was the cause of the infarction and visual hallucination. Only 4 cases with peduncular hallucination after SAH were reported in conjunction with vasospasm. The symptom may be concealed by disturbance of consciousness. Visual hallucination should be considered as a sign of cerebral vasospasm, and an appropriate treatment should be done at right time.

Significance of rises in urinary bicarbonate contents and pH related with increased atmospheric carbon dioxide in Tokyo.

Atmospheric carbon dioxide concentration was measured at several locations in Tokyo, for two weeks, in December, 1995 and 1996, and was found to be increased up to 550 ppm, while it was shown by us to be 450 ppm in December, 1994. These results demonstrate that atmospheric carbon dioxide is steadily increasing at faster rates in Tokyo than we expect, though it has been considered that the atmospheric carbon dioxide is still as much as 350 ppm. Bicarbonate concentration and pH of urine of 13 medical students in Tokyo were also measured for the same period in December of 1995 and 1996, and were found to be significantly increased compared with the values that were reported in the past. Furthermore, urinary bicarbonate and pH were extensively increased, when 4 and 5 students made 3-hour car trip in two different cars with all windows closed, where carbon dioxide was increased up to about 5000 ppm within 1 hour. These results support our previous hypothesis that the increase of atmospheric carbon dioxide may be reflected by the increase of urinary bicarbonate and pH. Our results also suggest that the environmental situation is being seriously aggravated in Tokyo, year by year, in terms of atmospheric carbon dioxide.

Synthesis and structure-activity relationships of 2-substituted D-tryptophan-containing peptidic endothelin receptor antagonists: importance of the C-2 substituent of the D-tryptophan residue for endothelin A and B receptor subtype selectivity.

Continuing studies on modifications of potent cyclic pentapeptide endothelin (ET) receptor antagonists, represented by BQ-123, and potent linear tripeptide derivative ET receptor antagonists, represented by BQ-788, are described herein. The introduction of D-tryptophan analogues with C-2 substituents in these peptidic ET antagonists resulted in potent ET receptor antagonists with various ETA/ETB subtype selectivity. Combined ETA/ETB receptor antagonists were found in both cyclic pentapeptide and linear tripeptide series with 2-halo- and 2-methyl-D-tryptophans. In contrast, compounds with 2-cyano-D-tryptophan were ETB receptor-selective antagonists. The C-2 substituent of the D-tryptophanyl residue appeared to be very important for the discrimination of ETA/ETB subtype selectivity of the antagonists. The potent ET receptor antagonists with various ETA/ETB subtype selectivity synthesized in this study may be useful tools for elucidating the physiological and pathophysiological roles of ET and ET receptors.

Cyclic pentapeptide endothelin A receptor antagonists with attenuated in vivo clearance.

A series of analogues of BQ-123 (1), a potent cyclic pentapeptide endothelin A receptor antagonist, with amino acids linked to the side-chain of the Pro residue via an ester linkage was synthesized. All analogues synthesized exhibited potent endothelin A receptor binding affinity similar to that of 1. Of the synthesized analogues, the Lys, Arg and N alpha,N epsilon-dimethyllysine analogues, 9d-f, exhibited about a three-fold attenuation of in vivo clearance compared with 1. In rats, these analogues exhibited a 3-fold-higher plasma concentration and a longer retention time in plasma as compared with those of 1. The attenuated in vivo clearance was thought to be a consequence of decreased extraction of the compounds from the blood via the hepatic anion transport system, which efficiently extracts 1 from the blood.

Structure-activity relationships of cyclic pentapeptide endothelin A receptor antagonists.

Analogues of the natural product endothelin A (ETA) receptor antagonists cyclo(-D-Trp1-D-Glu2-Ala3-D-Val4-Leu5-) (1) and cyclo(-D-Trp1-D-Glu2-Ala3-D-alloIle4-Leu5-) (2) were prepared and tested for inhibitory activity against [125I]endothelin (ET-1) binding to protein ETA receptors. The DDLDL chirality sequence of the natural products appeared to be critical for inhibitory activity because conversion of either D-Trp or D-Glu (or both) in 1 to the corresponding L-isomer(s) abolished this property. Systematic modifications at each position of the natural products clarified the structure-activity relationships and led to highly potent and selective ETA receptor antagonists. Most replacements of D-Trp1 and Leu5 with other amino acids caused a significant loss of inhibitory activity. In contrast, replacement of D-Glu2 with D-Asp2 enhanced the activity. With regard to the Ala3 position, all analogues with imino acids, independent of being cyclic or acyclic, showed higher affinities than did the amino acid analogues. In addition, most replacements with amino acids, which had various functional groups in their side chains, did not significantly modify ETA binding affinity. The D-Val4/D-alloIle4 position was very important for inhibitory activity, and a beta-position branched D-amino acid or a D-heteroarylglycine was preferable at this position. Among synthesized cyclic pentapeptides, compound 36 (BQ-518) was the most potent ETA receptor antagonist, with a pA2 of 8.1 against ET-1-induced vasoconstriction in isolated porcine coronary arteries. This compound also showed the greatest selectivity between ETA and ETB receptors (IC50 for human ETA = 1.2 nM, IC50 for human ETB = 55 microM). In contrast, compound 8 (BQ-123) is a highly soluble, potent, and selective ETA receptor antagonist (pA2 = 7.4, IC50 for human ETA = 8.3 nM, IC50 for human ETB = 61 microM). The sodium salt of 8 is practically freely soluble in saline. These compounds are useful tools for not only in vitro but also in vivo pharmacological studies.

Retinotopic and nonretinotopic field potentials in cat visual cortex.

Two types of field potentials were identified in cat visual cortex using contrast reversal of oriented bar gratings: a short-latency fast-local component with a retinotopic organization similar to that seen with single-unit discharges at the same cortical site, and a slow, nonretinotopic component with a longer peak latency. The slow-distributed component had an extensive receptive field mapped by measuring the amplitude of binary kernels and showed strong inhibitory interactions within the receptive field. The peak latency of the slow-local component increased with distance from the retinotopic center, suggesting a possible conduction delay. Both components showed some orientation bias depending on the laminar location, but the bias could be independent of the orientation preferred by single units in the immediate vicinity. The present findings indicate that locally generated field potentials reflect cortical mechanisms for nonlinear integration over wide areas of the visual field.

[Long survival after removal of a huge brain tumor which had metastasized from a lung cancer: case report].

Patients with large metastatic brain tumors are considered to have poor prognosis. We report a case of a patient with more than 33 months survival after complete resection of a huge temporal tumor which had metastasized from a lung cancer. A 57-year-old woman presented left hemiparesis and disturbance of consciousness. Magnetic resonance images revealed a huge cystic mass lesion in the right temporal lobe. After a macroscopically complete excision of the tumor, she received radiation therapy (whole brain 50 Gray). She had received lung surgery for the primary lung cancer, 2 years prior to brain metastasis. Histological examination showed papillary tubular adenocarcinoma which was similar to the previously resected lung cancer. Thirty three months after the resection of the intracranial tumor, she has no neurological deficits and no signs of recurrence of either brain tumor or lung tumor. We discuss the size of metastatic brain tumor and the postoperative prognosis of patients with metastatic brain tumor.

Regeneration of norepinephrine-containing fibers in occipital cortex of adult cats.

Regeneration of norepinephrine (NE)-containing nerve fibers in occipital cortex of adult cats was studied using morphological and biochemical methods. Initially, degeneration of cortical NE fibers was induced by direct infusion of 6-hydroxydopamine (6-OHDA) for a week. Cortical reinnervation by NE fibers continuously proceeded throughout 52 weeks, the longest survival period studied, after stopping 6-OHDA infusion. The rate of the reinnervation was slower in mature cortex than that obtained earlier in immature cortex. The present results indicate that the regenerative ability of the central NE neurons is universal, not limited to the immature brain. It is implied that the central NE neurons are equipped with a transmitter-specific repair mechanism throughout life.

Treatment of severe localized cerebral vasospasm following recurrent hemorrhage from middle cerebral artery aneurysm--case report.

A 52-year-old female presented with localized but severe cerebral vasospasm induced by recurrent aneurysmal subarachnoid hemorrhage. The middle cerebral artery (MCA) aneurysm was clipped and the subarachnoid hematoma evacuated 1 day after recurrent hemorrhage. The cerebral vasospasm, localized in a region near the MCA aneurysm, was reduced by papaverine and nicardipine vasodilating agents delivered via an Ommaya cerebrospinal fluid reservoir placed at craniotomy.

Experimental study on the indications for barbiturate therapy. Change in haemodynamics and the influence of dopamine.

The effect of barbiturates on the cerebral haemodynamics and the influence of dopamine on barbiturates were investigated using 20 cats, and clinical indication of barbiturate therapy is discussed. Cerebral blood flow, oxygen extraction fraction, and cerebro-vascular resistance as well as physiological variables were evaluated at various concentrations of barbiturates in the blood. Thiamylal caused simultaneous reduction of mean arterial blood pressure and cerebral blood flow. As the disruption of autoregulation proceeded, cerebro-vascular resistance and oxygen extraction fraction increased till the barbiturate-induced coma stage. Furthermore, cerebro-vascular resistance increased much more markedly by the combined use of dopamine. Clinically, our results indicate barbiturates would increase cerebral circulatory disturbances caused by vasospasm following subarachnoid haemorrhage because barbiturates further increase cerebro-vascular resistance. Then again, the combined use of dopamine is not preferable because of deterioration in vasospasm.

Endothelin-binding inhibitors, BE-18257A and BE-18257B II. Structure determination.

The structures of novel endothelin-binding inhibitors, BE-18257A and BE-18257B, were elucidated by spectral analyses and chemical studies. Both inhibitors were found to have a cyclic pentapeptide structure containing three D-form amino acid residues, namely, the structures of BE-18257A and BE-18257B were elucidated to be cyclo(-D-Glu-L-Ala-D-Val-L-Leu-D-Trp-) and cyclo(-D-Glu-L-Ala-allo-D-Ile-L-Leu-D-Trp-), respectively.

[Treatment of malignant gliomas by selective intraarterial infusion chemotherapy with high-dose ACNU and autologous bone marrow transplantation--preliminary report].

Six patients with malignant gliomas were treated by selective intracarotid infusion of ACNU at 15 mg/kg (about 600 mg per m2) or 10 mg/kg with or without radiotherapy and rescue of autologous bone marrow transplantation after surgery. These high doses of ACNU were well tolerated if bone marrow rescue was performed and granulocyte colony stimulating factor was used. With the development of microcatheters for use in selective intraarterial infusion, it has become possible to cannulate the major artery and infuse drugs at high dose into the artery feeding the tumor. The complication of ocular toxicity can be avoided by using the Tracker-18 or Balt (Magic) angiographic catheter. On the other hand, drug dosage and infusion rate must be chosen carefully, because of the increased likelihood of local arteritis and local necrosis caused by high dosage of ACNU. In the present study, local arteritis or cerebral infarction in the area of the middle cerebral artery was considered to have been prevented by extending the infusion time to 80 minutes. When combined with radiotherapy, 10 mg/kg of ACNU and 80 min. of infusion time were found to be optimal in relation to brain tolerance.

Influence of dopamine on cerebral blood flow, and metabolism for oxygen and glucose under barbiturate administration in cats.

The effect of dopamine during barbiturate therapy was investigated in 29 cats including 5 sham-operated cats. According to Kiersey's classification of electro-encephalographic patterns, physiological variables, cerebral metabolic rates for oxygen and glucose, cerebral blood flow (CBF), and intracranial pressure (ICP), etc. were evaluated in each electro-encephalographic pattern. Oxygen-glucose index was calculated and used as an indicator for aerobic or anaerobic metabolism of glucose. Group 1 (12 cats), to which only thiamylal was administered, maintained aerobic glycolysis due to a parallel reduction of cerebral metabolic rates for oxygen and glucose (about half of the initial value at Kiersey's fifth pattern) in spite of reduction of CBF and mean arterial blood pressure (MABP). Group 2 (12 cats), to which dopamine was administered in addition to thiamylal due to a reduction of MABP, showed anaerobic glycolysis though MABP and CBF were maintained. These findings are ascribed to an increase of cerebral metabolic rate for glucose up to 130% of the initial value though cerebral metabolic rate for oxygen decreased down to half of the initial value: The beneficial effect of barbiturate on cerebral metabolism was reduced by use of dopamine. ICP was reduced in both groups. Our result indicates that administration of extracellular fluid may be preferable for treatment of hypotension during barbiturate therapy than dopamine medication.

Papillary meningioma arising from the confluens sinuum with multidirectional extension through venous sinuses.

Successful removal of a meningioma arising from the confluens sinuum is described. This tumor extended multidirectionally through the venous sinuses (superior sagittal sinus, bilateral transverse sinuses, straight sinus, and occipital sinus) and protruded like a club in nodular pattern from the left inner surface of the confluens sinuum into the left occipital lobe. The tumor was completely removed via a bilateral large parieto-occipito-suboccipital craniotomy. Angiographically, unusual venous drainage from the vein of Galen into the superior sagittal sinus was demonstrated. Histologically, this tumor was a papillary meningioma characterized by two types of papillary structure in many areas.

Long-term survival after removal of primary intracranial malignant melanoma. Case report.

A 57-year-old male with primary intracranial malignant melanoma who survived 9 years and 6 months is reported. He underwent surgical removal of the tumour three times during the decade 1978 to 1988, and received chemo-immuno-radiotherapy during that time. Acute tumour growth, suggesting tumour dissemination, was seen in the CT scans after the third removal of recurrent tumour, but then it disappeared after combined chemoradiotherapy with DTIC. He gradually became inactive, probably because of brain atrophy caused by high-dose radiotherapy and chemotherapy, and died of renal failure without any sign of recurrence on CT scans.

[Treatment of malignant gliomas with high-dose ACNU and autologous bone marrow transplantation].

Two patients with malignant gliomas located in the frontal lobe were treated by supraophthalmic intracarotid infusion of high-dose ACNU 15 mg/kg (ca. 600 mg/m2) combined with a total 60 Gy of irradiation after surgery. Irradiation therapy was started 13 days (case 1) and 10 days (case 2) after surgery, and single chemotherapy with ACNU 1,020 mg (case 1) and 1,100 mg (case 2) was performed when 36 Gy of whole brain irradiation was done. Chemotherapy was followed by autologous bone marrow transplantation containing 6.8 X 10(9) and 8.9 X 10(8) nucleated cells, respectively. Nadirs of white cell counts on 9 days in case 1 and 14 days in case 2 after chemotherapy were 280 cells and 240 cells/mm3, respectively, and the white cell counts less than 1,000/mm3 continued for 7 and 12 days, respectively. Local irradiation was started again when the number of white cells became more than 1,000/mm3 and 24 Gy was completed in each case. CT scanning carried out on discharge demonstrated no apparent abnormal high density area by contrast medium in both cases. These two patients did not show severe side effects at 10 months in case 1 and at 3 months in case 2 after high dose ACNU therapy, and remained progression-free at that time. Dose 15 mg/kg of ACNU may be the maximum tolerable dose patients can recover from severe myelosuppression, caused by high dose ACNU therapy combined with irradiation therapy, by marrow rescue.