Gating kinetics and ligand sensitivity modified by phosphorylation of cardiac ryanodine receptors

The effects of protein-kinase- (PKA-) dependent phosphorylation on the stationary gating kinetics of single ryanodine receptor (RyR) channels was defined. The single-channel activity from canine cardiac RyR was reconstituted into planar lipid bilayers. Exogenously applied PKA increased the single-channel open probability ( P(o)) of both native and purified cardiac RyR channels, after preincubation with ATP and Mg2+. The action of PKA on the RyR channel occurred only in the presence of ATP and adenosine 5'- O-(3-thiotriphosphate) (ATPgammaS), but not in the presence of 5'-adenylimidodiphosphate (AMP-PCP). Thus, the action of PKA requires the presence of a hydrolyzable ATP analog. PKA-induced channel activation was blocked by specific PKA inhibitors. All these results confirmed that the RyR channel can be phosphorylated by exogenous protein kinase. The gating kinetics of single RyR channels before PKA treatment were significantly altered by ATP and Mg2+ as physiological ligands. In contrast, after PKA treatment, neither ATP nor Mg2+ significantly alters the gating kinetics of these channels. PKA-dependent phosphorylation thus decreases the ATP and Mg2+ apparent sensitivity in most of the gating parameters of single RyR channels. The phosphorylated RyR channels open and close more frequently, stay open for longer, and stay closed for shorter periods. The dwell-time histograms obtained demonstrate that the phosphorylated and the dephosphorylated channels have strikingly different open and closed kinetics at physiological cytoplasmic concentrations of Mg and ATP.     

Effect of prophylactic bronchodilator treatment with intravenous colforsin daropate,a water-soluble forskolin derivative,on airway resistance after tracheal intubation

BACKGROUND: After induction of anesthesia, lung resistance increases. The authors hypothesized that prophylactic bronchodilator treatment with intravenous colforsin daropate, a water-soluble forskolin derivative, before tracheal intubation would result in decreased lung resistance and increased lung compliance after tracheal intubation when compared with placebo medication. METHODS: Forty-six adult patients were randomized to placebo or colforsin daropate treatment. Patients in the control group received normal saline; patients in the colforsin group received 0.75 microg. kg-1 x min-1 colforsin daropate intravenously until the study ended. Thirty minutes after the study began, the authors administered 5 mg/kg thiamylal and 5 microg/kg fentanyl for induction of general anesthesia and 0.3 mg/kg vecuronium for muscle relaxation. A 15-mg. kg-1. h-1 continuous infusion of thiamylal followed anesthetic induction. Four, 8, 12, and 16 min after tracheal intubation, mean airway resistance (R(awm)), expiratory airway resistance (R(awe)), and dynamic lung compliance (C(dyn)) were measured. RESULTS: Patients in the colforsin group had significantly lower R(awm) and R(awe) and higher C(dyn) after intubation than those in the control group. Differences in R(awm), R(awe), and C(dyn) between the two groups persisted through the final measurement at 16 min. At 4 min after intubation, smokers had a higher R(awm) and a lower C(dyn) than nonsmokers in the control group. After treatment by intravenous colforsin daropate, R(awm), R(awe), and C(dyn) values were similar for smokers and nonsmokers after tracheal intubation. CONCLUSIONS: Prophylactic treatment with colforsin daropate produced lower R(awm) and R(awe) and higher C(dyn) after tracheal intubation when compared with placebo medication. Pretreatment before intubation may be beneficial and advantageous for middle-aged smokers.     

Case of intracranial and spinal dissemination of primary spinal glioma

A case of glioblastoma multiforme of spinal cord followed by intracranial dissemination was reported. A 20-year-old man was admitted on Sep. 22, 1981, with motor disturbance of both legs and loss of urinary control. Neurological examination showed spastic paraplegia with bilateral Babinski signs. Abdominal and cremaster reflexes were absent. There was no abnormalities in cranial nerves and upper limbs. Cerebral CT was normal at that time. Myelography showed complete block at the level of 8th thoracic vertebra. Spinal angiography revealed abnormal vascularity at the level of Th7 fed via anterior spinal artery. Intramedullary tumor was partially removed through 5th-8th thoracic laminectomy. Total 5600 rads of irradiation was administered after the operation. The postoperative course was deteriorating. Two months after the operation paresis of both upper extremities had been developed. State of consciousness had been disturbed due to increased intracranial pressure which was subsided for a time while by ventriculoperitoneal shunt. Repeated CT showed high density spots scattered in basal cisterns spreading to all ventricular systems. He expired Feb. 21, 1982. Autopsy revealed that the whole spinal cord was covered by tumor tissue. Basal cisterns were filled with tumor tissue. The tumor was infiltrated subependymally into ventricular systems with intramedullary invasions in some places. Histological diagnosis was glioblastoma multiforme.     

A randomized clinical trial of adjuvant chemotherapy after resection in patients with stomach cancer

A study group including 55 institutions in Japan evaluated the effect of adjuvant cyclophosphamide therapy on 461 patients who had undergone curative resection for stomach cancer. Patients, who were followed up for over three years, were randomly divided into three groups: curative resection and long-term drug therapy; curative resection and short-term drug therapy; and curative resection and no drug therapy. Long-term therapy consisted of (a) twice-weekly intravenous doses of 500 mg of cyclophosphamide for four weeks and, after five weeks with no medication, (b) 100 mg/day, given orally, for 40 days and, after ten weeks with no medication, (c) 100 mg/day, given orally, for 40 days. Short-term therapy consisted of only the first course of therapy (ie, twice-weekly intravenous doses of 500 mg for four weeks). The effect of cyclophosphamide differed, depending on the patients' levels of serosal and lymph node invasion: Short-term therapy was more effective in patients with lymph node involvement, and long-term therapy was more effective in patients with serosal involvement.     

Comparison of the effects of dobutamine with dopamine and isoproterenol on inotropism and chronotropism in the mammalian heart (author's transl)

The effects of dobutamine on inotropism and chronotropism of the heart were studied in vivo and in vitro and were compared with those of dopamine and isoproterenol. These compounds increased epicardial contractile force and the heart rate of the open-chest, bilaterally vagotomized dog under pentobarbital anesthesia. The dose-ratio for the contraction was [dobutamine: dopamine: isoproterenol = 1:0.8:40] and for the heart rate, [= 1:1:300]. Both drugs augmented the twitch contraction of the isolated dog ventricular papillary muscle with the dose-ratio of [dobutamine: dopamine: isoproterenol = 1:0.7:11]. This mechanical response was associated with an elevation of the plateu voltage and an increase in repolarization of the action potential, but with no alteration of the maximum rate of rise of the action potential, the resting potential and the input membrane resistance. The discharge frequency of the rabbit S-A node pacemaker potential was accelerated chiefly due to an increase in the slope of the diastolic slow depolarization. With concentration of these catecholamines for the equivalent positive inotropic potency on the papillary muscle, this effect of isoproterenol was more potent than the effects of dobutamine and dopamine. These positive inotropic and chronotropic actions of the catecholamines were abolished by a beta-receptor antagonist. Those actions of dopamine were markedly reduced by reserpine pretreatment. In addition, dobutamine had little vascular effect. These results indicatte that dobutamine has a positive inotropic effect and a less positive chronotropic effect and that such is due to the direct action on the ventricular myocardium and the S-A node through beta 1-adrenergic receptors.     

Diagnostic value of isocount scanning in cerebrovascular diseases (author's transl)]

In the previous report the theoretical background and technical details of the isocount scanning were described. Based on clinical experiences of various brain diseases, the newly developed scanning method was confirmed to be more useful than the conventional scintiscanning. Besides the new scanning method, a new display system was also developed for the sake of more precise analysis of the isocount scanned data. This display method is called multilevel analysis or multilevel slicing of the scanned data. In the present investigation, this method was applied to thirty-two cases of cerebrovascular diseases, including seven cases of cerebral arterio-venous malformation, four cases of hypertensive intracerebral hemorrhage and twenty-one cases of cerebral infarction, positive rates being 86%, 100% and 90% respectively. In case of arterio-venous malformation, minimum size detected by the isocount method was 2 cm in diameter. To twenty one cases of the cerebral infarction, total thirty two scanning examinations were performed, including postictal follow up studies. It is often said that it is two or three weeks after the ictus when the infarcted cerebral lesion is most clearly detectable by the scintigraphic procedures, presumably due to focal neovascularizations which may occur in the lesion most prominently at this postictal stage. Contradicted to the current concept, our experiences show that abnormal dot accumulations are recognized in the scintigrams even at the earlier stage, thus among five cases of cerebral infarction scanned within a week after the ictus positive figures were obtained in four cases, two of which were examined within two days after the ictus. Focal breakdown of blood brain barrier at the acute stage is considered to be responsible for the early positivity in cerebral infarctions. In eight cases among twenty one cerebral infarctions angiographies failed to demonstrate the vessel occluded. The isocount scanning method, however, succeeded in getting positive results in seven of the eight cases. It will be emphasized that the isocount scanning is a preferable diagnostic procedure in the cerebrovascular diseases, especially when the angiography is hesitated to be performed because of the patient severely affected.     

Clinical study of bacampicillin granules in pediatrics (author's transl)]

Clinical study on bacampicillin (BAPC) granules was performed in 20 children with infectious diseases. Patients treated with BAPC granules were 10 cases of scarlet fever, 3 cases of pertussis, 3 cases of Salmonella enteritis and 4 cases of acute enteritis. Clinical results were excellent in 2, good in 9, fair in 3, poor in 4 and unknown in 2. No side effect was observed.     

Gangliogliomas in cerebral hemisphere

Gangliogliomas are rare central nervous system neoplasms. The clinical features, radiological findings and surgical results in 6 histologically proven cases of gangliogliomas in the cerebral hemisphere are reviewed. The ages varied between 8 and 58 years old at the time of diagnosis. Five patients had seizure disorders without focal neurological deficit or clinical signs of increased intracranial pressure. These 5 patients had been treated as epilepsy for 6 months to 12 years. The other one patient had right sided motor weakness and left homonymous hemianopsia without seizure disorder. Plain roentgenograms of the skull revealed abnormal calcification in 3 out of 6 patients. Angiography showed an avascular mass in all 6 patients. CT scan were examined in 5 patients. In 3 patients the tumor were isodense, 2 of which demonstrated contrast enhancement. The other 2 showed low density lesion. One showed a single large cyst and another ill-defined low density containing high density calcification. In all 5 patients mass effect was slight. Three tumors were located in the temporal lobe and another 3 in the parietal lobe. At surgery total removal was accomplished in 3 patients. One patient had subtotal removal and 3 patients partial removal. Histological study revealed figures characteristic to the ganglioglioma. The predominant glial cell was astrocytic in 4 cases and oligodendroglial component was found in the other 2 cases. All patients either completely or nearly asymptomatic at the follow up for 1 to 12 years. The clinical study in 6 cases, along with a review of the literature suggest that these epileptogenic neoplasms should be aimed at surgical removal or total extirpation if possible.