[Details and indications of pallidotomy and thalamotomy for Parkinson's disease].

Pallidotomy has recently regained acceptance as an effective treatment for Parkinson's disease. From our 50 cases of unilateral pallidotomy and 10 cases of staged bilateral pallidotomy, details and indications of the procedure is described. The unilateral pallidotomy is quite effective for L-dopa induced dyskinesia, which usually completely disappears soon after the operation. The effect is long-lasting. When on-off phenomenon exists, unilateral pallidotomy improves off-stage rigidity or akinesia. Symptoms during on-stage are not changed. Indications of pallidotomy is that(1) L-dopa induced dyskinesia, and(2) on-off phenomenon. Bilateral pallidotomy, even by staged one, causes severe drooling, or speech disturbance(the volume of the voice decreases and the articulation worsens), and is not recommended. Vim thalamotomy is, on the other hand, the established treatment for tremor of Parkinson's disease or of essential tremor. The effect is long-lasting. Rigidity or akinesia is not expected to be improved so much.

The role of Alx-4 in the establishment of anteroposterior polarity during vertebrate limb development.

We have determined that Strong's Luxoid (lstJ) [corrected] mice have a 16 bp deletion in the homeobox region of the Alx-4 gene. This deletion, which leads to a frame shift and a truncation of the Alx-4 protein, could cause the polydactyly phenotype observed in lstJ [corrected] mice. We have cloned the chick homologue of Alx-4 and investigated its expression during limb outgrowth. Chick Alx-4 displays an expression pattern complementary to that of shh, a mediator of polarizing activity in the limb bud. Local application of Sonic hedgehog (Shh) and Fibroblast Growth Factor (FGF), in addition to ectodermal apical ridge removal experiments suggest the existence of a negative feedback loop between Alx-4 and Shh during limb outgrowth. Analysis of polydactylous mutants indicate that the interaction between Alx-4 and Shh is independent of Gli3, a negative regulator of Shh in the limb. Our data suggest the existence of a negative feedback loop between Alx-4 and Shh during vertebrate limb outgrowth.

cDNA cloning and functional analysis of p28 (Nas6p) and p40.5 (Nas7p), two novel regulatory subunits of the 26S proteasome.

We employed cDNA cloning to deduce the complete primary structures of p28 and p40.5, two novel subunits of PA700 (also called 19S complex), a 700 kDa multisubunit regulatory complex of the human 26S proteasome. These polypeptides consisted of 226 and 376 amino acids with calculated molecular masses of 24428 Da and 42945 Da, and isoelectric points of 5. 68 and 5.46, respectively. Intriguingly, p28 contained five conserved motifs known as 'ankyrin repeats', implying that this subunit may contribute to interaction of the 26S proteasome with other protein(s). Computer-assisted homology analysis revealed high sequence similarities of p28 and p40.5 with yeast proteins, termed Nas6p and Nas7p (non-ATPase subunits 6 and 7), respectively, whose functions are as yet unknown. Disruption of these yeast genes, NAS6 and NAS7, had no effect on cell viability, indicating that neither of the two subunits is essential for proliferation of yeast cells. However, the NAS7, but not NAS6, disruptant cells caused high sensitivity to heat stress, being unable to proliferate at 37 degreesC.

2B1 antigen characteristically expressed on extracellular matrices of human malignant tumors is a large chondroitin sulfate proteoglycan, PG-M/versican.

2B1 is a monoclonal antibody against a large proteoglycan isolated from human yolk sac tumor (M. Sobue et al., Histochem. J., 21: 455-460, 1989). The antigen is expressed in a variety of embryonal tissues as well as most if not all malignant tumor tissues. However, the expression in normal adult tissues is limited to some tissues, such as the smooth muscle layers of the aorta. We characterized the 2B1 antigen isolated from the conditioned medium of human malignant fibrous histiocytoma and found that immunological and biochemical properties are identical to those of a large chondroitin sulfate proteoglycan, PG-M/versican. Partial amino acid sequences of peptides obtained from the core protein by V8 protease digestion and subsequent SDS-PAGE were detected in the reported amino acid sequence of human PG-M/versican with a complete identity. Furthermore, 2B1 was distinctly reactive to the expressed protein by transfection of the cDNA for the shortest form into mouse cells. The results indicate that the antigen is the PG-M core protein, and the epitope may be in one of the globular domains. It is thus likely that PG-M/versican is one of the extracellular matrix components characteristic of human malignant tumors.

Combination therapy with cisplatin and nifedipine inducing apoptosis in multidrug-resistant human glioblastoma cells.

The authors found that multidrug-resistant human glioblastoma GB-1 cells demonstrated significantly more resistance to cisplatin than did nondrug-resistant human glioblastoma U87-MG cells (p < 0.1). They therefore attempted to determine whether calcium channel blockers enhance the antitumor activity of cisplatin against GB-1 cells. Nifedipine, a dihydropyridine calcium channel blocker, significantly enhanced the antitumor effect of cisplatin on GB-1 cells (p < 0.05). In the absence of normal extracellular Ca++, nifedipine enhanced the cytotoxicity of cisplatin. In addition, the antitumor activity of combined cisplatin and nifedipine was inhibited both by actinomycin D and cycloheximide, suggesting that such activity is dependent upon new RNA and protein synthesis. Surprisingly, DNA fragmentation assay demonstrated that synergism between cisplatin and nifedipine resulted in apoptosis (programmed cell death) at a relatively low concentration of cisplatin, which when tested alone did not induce apoptosis. In addition, it was demonstrated that nuclei from GB-1 cells lacked a Ca(++)-dependent endonuclease that degrades chromatin into nucleosomes and that calcium ionophore A 23187 did not decrease the viability of GB-1 cells. The above findings suggest the hypothesis that the noncytotoxic agent nifedipine synergistically enhances the antitumor effect of cisplatin on multidrug-resistant GB-1 cells lacking Ca(++)-dependent endonuclease, and subsequently induces apoptosis via its interaction with an as yet uncharacterized functional site other than the calcium channel on GB-1 cells.

Combination therapy with cisplatin and nifedipine induces apoptosis in cisplatin-sensitive and cisplatin-resistant human glioblastoma cells.

We attempted to determine whether calcium channel blockers (CCBs) enhance the anti-tumour activity of cis-diamminedichloroplatinum (cisplatin) against both cisplatin-sensitive human glioblastoma U87 MG cells and cisplatin-resistant U87-MG-CR cells, the latter of which we developed for resistance to cisplatin. Nifedipine, a dihydropyridine class CCB, significantly enhanced the anti-tumour effect of cisplatin on these two cell types in vitro and in vivo. Our findings also indicated that, in the absence of normal extracellular Ca2+ nifedipine was capable of enhancing the cytotoxicity of cisplatin. In addition, this anti-tumour activity was partially inhibited by actinomycin D and cycloheximide, suggesting that it is possibly dependent upon new RNA and protein synthesis. Interestingly, ultrastructural analysis, DNA fragmentation assay and cell cycle analysis demonstrated that synergism between cisplatin and nifedipine results in apoptosis (programmed cell death) at a relatively low concentration of cisplatin, which when tested alone did not induce apoptosis. Furthermore, we demonstrated that nuclei from these cells lack a Ca(2+)-dependent endonuclease that degrade chromatin in the linker region between nucleosomes. In conclusion, our studies suggest that the non-cytotoxic agent nifedipine is able to synergistically enhance the anti-tumour effects of cisplatin on U87-MG and U87-MG-CR cells lacking a Ca(2+)-dependent endonuclease and subsequently to induce apoptosis via interaction of nifedipine with an as yet uncharacterised functional site other than a calcium channel on target cells.

Hemodynamic mechanisms of antianginal action of calcium channel blocker nisoldipine in dynamic exercise-induced angina.

To investigate the mechanism of antianginal action of the calcium channel blocker nisoldipine and to determine the reproducibility of the clinical and hemodynamic events induced by supine leg exercise, 30 patients with stable effort angina pectoris were studied. They were divided into two groups; one group of 19 patients received a single 10-mg dose of nisoldipine orally, and the other group of 11 patients received a single dose of placebo orally. Chest pain was induced in all of 30 patients during the control exercise test. After nisoldipine administration, chest pain was not induced in 13 of 19 patients and was of lessened severity in five patients with the same work load as those performing control exercise. ST segment at peak exercise showed less severe depression after nisoldipine. Systemic vascular resistance was reduced by 38% (p less than 0.001) at rest and 22% (p less than 0.001) at peak exercise, and coronary vascular resistance was reduced by 31% (p less than 0.01) at rest and 18% (p less than 0.01) at peak exercise. Pulmonary artery wedge pressure fell from 6 +/- 1 to 3 +/- 1 mm Hg (p less than 0.001) at rest and from 28 +/- 3 to 11 +/- 2 mm Hg (p less than 0.001) at peak exercise. Coronary sinus flow at rest and myocardial oxygen uptake both at rest and during exercise was not modified by nisoldipine. However, coronary sinus flow at peak exercise increased significantly from 219 +/- 24 to 249 +/- 31 ml/min (p less than 0.01) after nisoldipine, and myocardial oxygen uptake was not significantly changed despite decreased coronary vascular resistance. The clinical and hemodynamic events induced by the exercise during invasive studies (except pulmonary artery wedge pressure at rest) were reproducible after placebo administration. Our data demonstrate that increased coronary blood flow could be the major mechanism of the antianginal action of nisoldipine in supine leg exercise-induced angina.

The effects of antianginal drugs on left ventricular function in patients with effort angina pectoris. Comparison among isosorbide dinitrate, nifedipine and propranolol by PANOVA.

To study the acute effects of ISDN, nifedipine, propranolol and placebo on cardiac function in patients with myocardial ischemia and to characterize their hemodynamic effects by PANOVA, we repetitively performed exercise radionuclide angiography (RNA) following random assignment of each drug in 20 patients with effort angina pectoris. We obtained exercise response curves of hemodynamic parameters determined by RNA. ANOVA was performed to analyze the sizes (average height) of those response curves, and PANOVA (principal component analysis, PCA, combined with ANOVA) to analyze differences in the profiles (patterns) of the curves. By conventional analysis of variance followed by a Scheffé type multiple comparison, end-diastolic volume after ISDN, which was significantly smaller than those after the other drugs at rest (p less than 0.01), was similar to those after nifedipine and propranolol during exercise (96.4 +/- 4.6 ml/m2 vs. 94.8 +/- 5.1 ml/m2 and 97.1 +/- 4.9 ml/m2, respectively). Systemic vascular resistance after nifedipine, which was also significantly lower than those after the other drugs at rest (p less than 0.05), was not different from that after placebo during exercise (16.9 +/- 1.1 units vs. 18.7 +/- 1.3 units). Thus, this analysis was considered insufficient to fully differentiate the characteristics of each drug. By PANOVA, the profiles of LVEF with these three antianginal drugs were similar, and significantly differentiated from that of placebo (p less than 0.05). This indicated that the antianginal effect could be represented by the profiles of the response curves of LVEF, using PANOVA. Evaluating the underlying hemodynamic mechanisms of these drugs by PANOVA, ISDN was significantly differentiated from nifedipine and propranolol by the profile of end-diastolic volume (p less than 0.05). The characteristics of nifedipine were clearly demonstrated by the size and profile of systemic vascular resistance, and those of propranolol were also differentiated by the size and profile of the double product and P-V index. Hence, it is concluded that with the aid of PANOVA, the changes in hemodynamic parameters during ischemia can be evaluated in a manner that is highly effective in differentiating the characteristics of the effects of antianginal drugs in patients with angina pectoris.

Factors that affect oxygen affinity of hemoglobin in chronic hemodialysis patients.

To investigate various factors that possibly affect oxygen affinity of hemoglobin (Hb-O2 affinity) in chronic hemodialysis (HD) patients, we determined P50 at standard condition (P50std), 2,3-diphosphoglycerate (2,3-DPG) content in red blood cells, serum inorganic phosphorus (S-Pi), Hb, and arterial blood gas analysis in 55 HD patients. P50std in HD patients was higher than that in normal controls (26.6 +/- 1.6 vs. 25.4 +/- 1.4 mm Hg; p less than 0.001). We could find neither an effect of alkalizating agents for HD (acetate vs. bicarbonate) nor an effect of the underlying disease (diabetics vs. nondiabetics) on Hb-O2 affinity. There were significant positive correlations between P50std and the duration of HD therapy (r = 0.598; p less than 0.001) and between P50std and SPi (r = 0.476; p less than 0.001), contrasting with the absence of correlation between P50std and Hb. Forward stepwise multiple-regression analysis demonstrated that the duration of HD therapy played the most important roles in determining P50std, followed by SPi and PO2. These data suggest that the major factor influencing Hb-Os affinity in chronic HD therapy is the duration of the therapy and that the minor factors are SPi and PO2.

Pubertas praecox and hypothalamic hamartoma.

Precocious puberty of cerebral origin is classified into pseudoprecocious puberty and true precocious puberty. Pseudoprecocious puberty is caused by HCG secreting tumours. True precocious puberty is caused by various hypothalamic diseases. Among them, hypothalamic hamartoma is the most common cause. Precocious puberty is caused by elevated blood pituitary gonadotropin concentration, secondary to the elevated hypothalamic LHRH secretion. The hypothalamic hamartoma is not infrequently associated with laughing (gelastic) seizures as well as convulsions. Diagnosis of a hypothalamic hamartoma is easily made by CT. Although the hypothalamic hamartoma is difficult to operate on, the value of surgery is stressed for treatment of precocious puberty. This is also confirmed by recent reports.

The influence of low frequency acupuncture on a demand pacemaker.

Various complications with demand pacemakers have been known to originate from their own sensing mechanisms. In these complications, electromagnetic interference is one of the well known causes of oversensing with demand pacemakers. The influence of low frequency acupuncture as a specific type of electromagnetic interference on a demand pacemaker was examined during a cervical operation. It was found that low frequency acupuncture is a cause of electromagnetic interference with demand pacemakers. Therefore, caution should be exercised when using the low frequency acupuncture on a pacemaker patient.

Amenorrhea-galactorrhea syndrome with craniopharyngioma.

Two cases of craniopharyngioma presenting with amenorrhea-galactorrhea syndrome due to hyperprolactinemia are reported. After operation and irradiation, the tumor reduced markedly in size. Coincidental decrease in plasma prolactin level and restoration of menstruation seem to support the view that the hypothalamic prolactin inhibiting factor (PIF) had played an important role in hyperprolactinemia in these two patients.

Precocious puberty due to a hypothalamic hamartoma.

A case of precocious puberty due to a hypothalamic hamartoma is presented. Concentrations of plasma LH and FSH, testosterone and its derivatives were found to be elevated. Circadian rhythms of LH were also observed. After removal of the mass, plasma LH and FHS concentrations declined to nearly half the preoperative levels.

Subdural effusion and brain tumor: case report and survey of the literature.

Optic glioma associated with bilateral subdural effusion in a four-month-old male infant is reported. Review of the cases with subdural effusion or hematoma and brain tumor in the world literature was made. When subdural effusion is found in a newborn or an older infant, the possibility of an associated brain tumor must be considered. Care also should be taken to search for an underlying brain tumor and to exclude dural metastasis when we deal with chronic subdural hematoma in an adult.