Dual effects of chlorobutanol on secretory response and intracellular Ca2+ dynamics in isolated pancreatic acini of the rat.

1. The effects of chlorobutanol, a widely used drug preservative, on exocrine response and intracellular Ca2+ dynamics were examined in isolated pancreatic acini of the rat. 2. Chlorobutanol (1 mg ml-1) markedly inhibited the secretory response to cholecystokinin octapeptide (CCK-8), carbamylcholine chloride (carbachol), or sodium fluoride, a direct G-protein activator. However, chlorobutanol itself induced a maximal release of amylase when the dose was increased to 4 mg ml-1. 3. An oscillatory fluctuation of cytoplasmic Ca2+ concentration, [Ca2+]c, induced by 5 pM CCK-8 or 0.3 microM carbachol was totally abolished in the presence of 1 mg ml-1 chlorobutanol. 4. A biphasic change in [Ca2+]c induced by 100 pM CCK-8, a rapid rise followed by a gradual decay, was transformed to an oscillatory fluctuation by the preservative. 5. Chlorobutanol inhibited 13 pM [125I]-CCK-8 or 0.5 nM [3H]-methylscopolamine chloride binding to the acinar cells in a dose-dependent manner. 6. These results indicate that chlorobutanol produces discernible pharmacological effects on the secretory response in rat pancreatic acinar cells through changes in the Ca2+ dynamics. Possible sites of action could be at a binding process of secretagogues to their receptors, at an activation process of a G-protein located in the plasma membrane, or at the processes following G-protein activation. However, the possibility that the preservative may distort the Ca(2+)-transport function of the plasma membrane or the membrane of intracellular organella, especially Ca(2+)-sequestering pools, cannot be excluded.     

Differential sensitivity of diabetic rat papillary muscles to negative inotropic effects of oxybarbiturates versus thiobarbiturates.

The negative inotropic effects of oxybarbiturates and thiobarbiturates were examined in papillary muscles isolated from streptozotocin-induced diabetic rats and in papillary muscles from age-matched control rats. The muscles from diabetic rats exhibited less negative inotropic responses to pentobarbital and secobarbital than the muscles from control rats. Conversely, the negative inotropic responses to thiopental and thiamylal were significantly enhanced in diabetic muscles. Differences in sensitivity to pentobarbital between control and diabetic muscles became less marked by treatment with ouabain or by lowering [Na+]o. Enhancement of the negative inotropic effect of thiamylal observed in diabetic muscles remained unchanged with these treatments. In both control and diabetic muscles, the negative inotropic effect of pentobarbital was completely reversed by increasing [Ca2+]o, but the effect of thiamylal was only partially reversed. These results suggest a difference in mechanism of action involved in establishment of the negative inotropic effects of oxybarbiturates vs thiobarbiturates. Oxybarbiturates appear to exclusively reduce the influx of extracellular Ca2+, whereas thiobarbiturates appear to affect Ca2+ movements at the Ca2+ storage sites in addition to the Ca2+ influx inhibition.     

Triad of thymoma,myasthenia gravis and pure red cell aplasia combined with Sjögren’s syndrome

A 36-year-old woman complained of cough and high fever. Computed tomographic scans demonstrated a mediastinal mass. A couple of months later, she developed dryness in her eyes and mouth. Biopsy of the lip confirmed the diagnosis of Sjögren’s syndrome. She underwent thymo-thymomectomy. Pathological findings of the mass revealed thymoma. At two months after surgery, she developed ptosis and dysphagia that were compatible with myasthenia gravis. The clinical symptoms were adequately controlled with prednisolone. At eleven months after surgery, she presented with severe anemia, which led to the diagnosis of pure red cell aplasia. The following treatment with cyclosporin caused hemoglobin concentration to rise. However, she continues to suffer from dryness of her eyes and mouth. The case is the first to be reported with Sjögren’s syndrome and the triad of thymoma, myasthenia gravis and pure red cell aplasia, and is compared with previously reported cases of the three conditions.     

Clinical evaluation of tumor markers in breast cancer patients

During the past 4 years, the performances of various tumor markers such as CA15-3, CEA, ferritin, beta 2-microglobulin and TPA have been evaluated in 78 cases of mammary cancer. The results were categorised according to differences in stages, difference in values from patients with recurrent tumors, the incidence of abnormal values and differences in values before and after surgery. When the incidence of values higher than the cutoff value was determined for each of stage I, II and III + IV, the rates for CEA were 14.3%, 4.9% and 27.8%, respectively, whereas those for TPA were 25.0%, 22.2% and 26.7%, respectively. In addition, for CA15-3, the incidences were 0% in stage I, 5.0% in stage II and 57.1% for combined stages III + IV. The average values for patients with recurrent tumors were 3.2 ng/ml CEA, 194.5 ng/ml ferritin, 316.2 U/l TPA and 81.3 U/ml CA15-3. The rates of abnormal values were 40.0% for CEA, 40.0% for ferritin, 85.7% for TPA and 63.6% for CA15-3. Differences in the values after surgical removal of the tumor were observed with these tumor markers: the CEA value was reduced from 1.6 +/- 1.4 to 1.1 +/- 0.5 (p less than 0.01) and the CA15-3 value from 12.2 +/- 8.4 to 9.3 +/- 4.1 (p less than 0.05), respectively, whereas that for ferritin was conversely increased from 48.9 +/- 48.0 to 74.0 +/- 70.0 (p less than 0.01). However, the values for TPA, despite showing a tendency to decrease, did not show any statistically significant alteration. The fluctuations of these marker levels in patients with recurrent tumors reflects the progress of the disease, with a sudden elevation in values indicating imminent death. The diagnostic significance of these markers is not high, but they are considered to be useful in detecting the progress or condition of a recurrent tumor.     

A case of granulocyte-colony stimulating factor producing gastric cancer]

We report a case of granulocyte-colony stimulating factor producing gastric cancer with multiple liver metastases. A 68-year-old woman who complained of epigastralgia visited our hospital. Upper gastrointestinal endoscopic examination revealed a type-2 gastric cancer. The laboratory data at admission indicated leukocytosis (35,900/microl) and a high level of serum granulocyte-colony stimulating factor (61 pg/mg). Granulocyte-colony stimulating factor producing gastric cancer was diagnosed by immunohistochemistry of biopsy specimen. Since we detected multiple liver metastases, chemotherapy was performed. Granulocyte-colony stimulating factor-producing gastric cancer is relatively rare and we summarize previous reports.     

In vivo presynaptic and postsynaptic striatal dopamine functions in idiopathic normal pressure hydrocephalus.

Differentiation of impaired gait seen in idiopathic normal pressure hydrocephalus (iNPH) from parkinsonian gait is sometimes a great challenge and important for future medication in the clinical setting. To investigate dopaminergic contribution to its pathophysiology, two aspects of the trans-synaptic dopamine functions in the striatal region in eight iNPH patients na?ve to dopaminergic drugs were examined using positron emission tomography with a presynaptic marker [11C]CFT ([11C]2-beta-carbomethoxy-3beta-(4-fluorophenyl) tropane) that binds to dopamine transporter and a postsynaptic marker [11C]raclopride that binds to D2 receptor. Quantitative values of binding potentials (BPs) for [11C]CFT and [11C]raclopride were compared between patients and eight age-matched healthy subjects. The BPs and magnetic resonance imaging-based morphometric measures in iNPH were used for correlation analyses between the magnitude of binding of these in vivo markers and clinical severity of the patients. Analysis of variance showed significant reduction in [11C]raclopride binding in the putamen and nucleus accumbens (P<0.05, corrected for multiple comparison) and unchanged striatal [11C]CFT binding in iNPH. The dorsal putamen [11C]raclopride binding correlated negatively with gait severity (r=0.720, P<0.05), and the nucleus accumbens [11C]raclopride binding correlated positively with emotional recognition score (r=0.727, P<0.05) in the disease group. No significant relationship was observed between BPs and morphometric measures. The current result of the postsynaptic D2 receptor reduction along with preserved presynaptic activity in the nigrostriatal dopaminergic system reflects a pathophysiology of iNPH. Postsynaptic D2 receptor hypoactivity in the dorsal putamen may predict the severity of gait impairment in iNPH.     

A transcrista galli, translamina terminalis approach for highly placed basilar bifurcation aneurysms

Summary Surgery for highly placed basilar bifurcation aneurysms is one of the most difficult operations in neurosurgery. Specific surgical techniques have been developed including the temporopolar, zygomatic, transzygomatic subtemporal, transclinoid trans-sellar transcavernous, and trans third ventricular approaches. The authors present some technical advances which have been developed for the transcristagalli translamina terminalis approach for the treatment of this aneurysm.     

Two cases of leiomyoma of the kidney]

Renal leiomyomas large enough to be clinically diagnosed are extremely rare. We review 30 cases of clinically diagnosed renal leiomyoma from the literature in Japan, including our 2 new cases. Case 1: In a 52-year-old man with no symptoms a renal mass was found accidentally on an ultrasonogram. CT scan showed a mass with a cystic area at the upper pole of the right kidney. Angiogram showed a hypovascular mass. Case 2: CT scan revealed a cystic mass and angiogram showed an avascular mass at the upper pole of the left kidney in a 19-year-old man having gross hematuria and left flank pain. Transperitoneal nephrectomy was done in both cases. Histologically each tumor was composed of monotonous proliferation of spindle shaped cells without atypia, which showed intense immunoreactivity for alpha-smooth muscle actin. The diagnosis of benign leiomyoma was made in each case. In a review of 30 cases, we found that renal leiomyomas occur most often in female (77%), between decades 2 and 5 of life (median: 46 years). On the angiogram it appears most often as an avascular or hypovascular mass. CT scan shows cystic or mixed solid/cystic or solid lesion, occasionally with calcification. Preoperative diagnosis is extremely difficult to be made. Histologically, fibroma, angiomyolipoma, congenital mesoblastic nephroma and leiomyosarcoma should be differentiated.     

Induction of nitric oxide synthase by cyclic AMP in rat vascular smooth muscle cells.

By measurements of NO2-/NO3- (NOx) production and Northern blot analysis, we studied the effects of a membrane-permeable cAMP derivative, 8-bromo-cAMP, on the expression of inducible nitric oxide synthase (iNOS) gene and the synthesis of NOx in cultured rat vascular smooth muscle cells (VSMCs). 8-bromo-cAMP stimulated NOx production and increased steady-state levels of iNOS mRNA in rat VSMC in a time- and dose-dependent manner. NG-monomethyl-L-arginine, a NOS inhibitor, completely blocked the 8-bromo-cAMP-induced NOx production, whose effect was partially, but significantly reversed by an excess L-arginine, but not by D-arginine. Compounds that increase intracellular cAMP levels (cholera toxin, forskolin, and 3-isobutyl-1-methylxanthine), all stimulated NOx production. Dexamethasone inhibited the stimulated NOx production, as well as the induction of iNOS mRNA by cAMP. Both actinomycin D and cycloheximide completely blocked the stimulated NOx production by cAMP. Actinomycin D abolished the cAMP-induced iNOS mRNA, whereas cycloheximide remarkably increased iNOS mRNA levels in the presence and absence of 8-bromo-cAMP (superinduction). Actinomycin D, but not dexamethasone, completely abolished the cycloheximide-induced iNOS mRNA. The half-life of cAMP-induced iNOS mRNA was approximately 2 h, whereas no decay in the cycloheximide-induced iNOS mRNA was observed during 12 h. These results demonstrate that iNOS gene is upregulated by cAMP and the superinduction of iNOS mRNA is attributable to increased mRNA stability in rat VSMC.