The modulatory effect of endogenous parathyroid hormone on the action of hydrochlorothiazide in pseudohypoparathyroidism type I

We compared the effect of orally administered 100 mg of hydrochlorothiazide (HCTZ) among eight patients with pseudohypoparathyroidism (PHP) type I, 11 patients with idiopathic hypoparathyroidism (IHP), and 12 patients with primary hyperparathyroidism (1^oHPT). Patients with PHP type I or with IHP were studied during the treatment with 1-hydroxylated metabolites of vitamin D₃. HCTZ raised serum levels of calcium (Ca) in 1^oHPT (P<0.001) and PHP type I (P<0.01) but did not increase urinary excretion of Ca. Serum parathyroid hormone (PTH) in PHP type I decreased (P<0.02) after HCTZ administration in response to the increase in serum Ca. HCTZ did not raise serum levels of Ca in IHP but increased urinary excretion of Ca in this group (P<0.01). HCTZ suppressed tubular reabsorption of phosphate (P) in IHP (P<0.01) and 1^oHPT (P<0.05) but not in PHP type I. Urinary excretion of cAMP did not change after HCTZ administration in PHP type I, IHP, or 1^oHPT. Endogenous PTH modulated the effects of HCTZ on Ca mobilization from bone and renal reabsorption of Ca in PHP type I with normal or high serum levels of PTH and in 1^oHPT with high serum levels of PTH. The inhibitory effect of HCTZ on renal tubular reabsorption of P (probably from proximal tubules) was independent of PTH. The resistance to this inhibitory effect of HCTZ on P reabsorption in PHP type I suggested a proximal tubular dysfunction in this disorder.     

Pentoxifylline and intravenous gamma globulin combination therapy for acute Kawasaki disease

We compared the efficacy of oral administration of pentoxifylline (PTX) and intravenous infusions of gamma globulin (IVGG) combination therapy with that of IVGG in reducing the frequency of coronary-artery lesions (CAL) in children with Kawasaki disease (KD), in a randomized trial. All patients with KD received acetylsalicylic acid (30 mg/kg per day), until the 30th day, after the onset of fever, followed by daily acetylsalicylic acid at a dose of 3-5 mg/kg per day there-after, and intravenous IVGG, 200 mg/kg per day, for 5 consecutive days. In addition, patients randomly assigned to PTX and IVGG combination therapy groups received oral PTX at a dosage of 10 mg/kg per day (low-dose) or 20 mg/kg per day (high-dose), in three divided doses until the 30th day. Patients with KD were all free from CAL prior to treatment. We assessed the presence of CAL by two-dimensional echocardiography which was also done prior to treatment and then twice a week after hospital admission. We detected CAL in 3 of 18 patients (16.7%) in the IVGG therapy group, as compared with 2 of 18 patients (11.1%) in the low-dose PTX and IVGG combination therapy group. There were no significant differences between the two groups. In the next study, we detected CAL in 3 of 21 patients (14.3%) in the IVGG therapy group, as compared with none of 22 patients (0%) in the high-dose PTX and IVGG combination therapy group (² = 6.4, P < 0.02). No adverse side-effects were observed in 79 patients with KD.     

Changes in immune function following surgery for esophageal carcinoma.

Changes in immune function due to surgical injury have been well-documented. Immunosuppression is one of the causes of infectious complications leading to organ dysfunction in critical illness. It is not known what kind of surgery in the daily clinical practice causes immunosuppression. Stress response and immune function following surgery for esophageal carcinoma, assuming a highly-stressed operation, were studied and then compared with the stress response and immune function following gastric surgery, a moderately-stressed procedure. Forty patients who underwent esophagectomy and 39 patients receiving gastric operation were studied. The concentrations of serum interleukin-6 (IL-6) were measured preoperatively, at 1, 2, and 6 h, and at 1, 3, and 10 d after operation. Total protein, serum albumin, rapid turnover protein, serum CRP, and cortisol were measured before operation and at 1, 3, 7, and 21 d after operation. ConA- and PHA-stimulated lymphocyte proliferation, IgA, IgG, and IgM were also measured preoperatively, and on 7 and 21 d following surgery. The patients were fed exclusively by total parenteral nutrition (TPN). A striking rise of IL-6 was observed, with a peak in both groups at 1 to 6 h following operation. The peak values were 419+/-30 pg/mL, which was approximately twice as high in the esophagectomy patients as in the gastrectomy patients (195+/-40 pg/mL). CRP and cortisol also increased after operation, and these increases were also significantly greater in the esophagectomy patients. ConA- and PHA-stimulated lymphocyte proliferation decreased significantly 7 d after esophagectomy (P<0.05), but was unchanged in the patients receiving gastrectomy. Suppression of cellular immunity correlated significantly with serum cortisol, and was preceded by a rise in serum IL-6. The IgA, IgG, and IgM levels, however, remained unchanged from their preoperative values throughout the study in both groups. Nutritional status in terms of serum protein, albumin, and rapid turnover protein, decreased postoperatively, but there was no difference between the two groups. It is, therefore, concluded that cell-mediated immunosuppression, preceded by a hyperinflammatory response, is an observable reaction in patients following esophageal surgery, but not in patients undergoing gastric surgery.     

Investigation of the atrial pacemaker site and rate of the dog heart by the multi-electrodes mapping system

The site of impulse origin in the right atrium is generally considered to be a single static locus within the sinoatrial (SA) node. However, it has been recognized that the pacemaker site may shift as a consequence of changes in physiological and pathological conditions. To determine the role of the atrial pacemaker complex including the superior pacemaker site, SA node and inferior pacemaker site quantitatively, we investigated atrial rate and the earliest activation region (EAR) from the isochronal activation sequence map by 48 unipolar electrodes and the mapping system. The epicardial activation sequence of the right atrium including the SA node region was obtained from the 48 electrodes, which were fixed to two flexible templates made of soft plastic plates. Using the mapping system, we found that (1) the EAR was shifted by the sympathetic or parasympathetic neural activity, (2) parasympathetic activity predominates over the sympathetic activity not only on heart rate, but also on the location of the EAR, and (3) the role of the inward Ca2+ current, hyperpolarization inward current and delayed rectifier K+ current, of the pacemaker cells distributed in the atrial pacemaker complex is different in the dog heart in situ.     

ATP-Dependent efflux of CPT-11 and SN-38 by the multidrug resistance protein (MRP) and its inhibition by PAK-104P

Non-P-glycoprotein-mediated multidrug-resistant C-A120 cells that overexpressed multidrug resistance protein (MRP) were 10.8- and 29. 6-fold more resistant to 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin (CPT-11) and SN-38, respectively, than parental KB-3-1 cells. To see whether MRP is involved in CPT-11 and SN-38 resistance, MRP cDNA was transfected into KB-3-1 cells. The transfectant, KB/MRP, which overexpressed MRP, was resistant to both CPT-11 and SN-38. 2-[4-Diphenylmethyl)-1-piperazinyl]ethyl-5-(trans-4,6-dimethyl-1,3 , 2-dioxaphosphorinan-2-yl)-2, 6-dimethyl-4-(3-nitrophenyl)-3-pyridinecarboxylate P-oxide (PAK-104P) and MK571, which reversed drug resistance in MRP overexpressing multidrug-resistant cells, significantly increased the sensitivity of C-A120 and KB/MRP cells, but not of KB-3-1 cells, to CPT-11 and SN-38. The accumulation of both CPT-11 and SN-38 in C-A120 and KB/MRP cells was lower than that in KB-3-1 cells. The treatment with 10 microM PAK-104P increased the accumulation of CPT-11 and SN-38 in C-A120 and KB/MRP cells to a level similar to that found in KB-3-1 cells. The ATP-dependent efflux of CPT-11 and SN-38 from C-A120 and KB/MRP cells was inhibited by PAK-104P. DNA topoisomerase I expression, activity, and sensitivity to SN-38 were similar in the three cell lines. Furthermore, the conversion of CPT-11 to SN-38 in KB-3-1 and C-A120 cell lines was similar. These findings suggest that MRP transports CPT-11 and SN-38 and is involved in resistance to CPT-11 and SN-38 and that PAK-104P reverses the resistance to CPT-11 and SN-38 in tumors that overexpress MRP.