Single-dose new insulin glargine 300 U/ml provides prolonged, stable glycaemic control in Japanese and European people with type 1 diabetes.

AIMS: Two single-dose studies were conducted in Japan and Europe to compare the pharmacokinetic (PK) and pharmacodynamic (PD) profiles of new insulin glargine 300 U/ml (Gla-300) and insulin glargine 100 U/ml (Gla-100) in people with type 1 diabetes mellitus. METHODS: In two double-blind, randomized, crossover studies, 18 Japanese participants (aged 20-65 years) and 24 European participants (aged 18-65 years) with glycated haemoglobin levels ≤9.0% (≤75 mmol/mol) received single subcutaneous doses of Gla-300, 0.4, 0.6 and 0.9 U/kg (0.9 U/kg in the European study only), and Gla-100, 0.4 U/kg. A 36-h euglycaemic clamp procedure was performed after each dosing. RESULTS: The serum insulin glargine concentration (INS) and glucose infusion rate (GIR) developed more gradually into more constant and prolonged profiles with Gla-300 than with Gla-100. In support of this, the times to 50% of glargine exposure and insulin activity were longer for all Gla-300 doses than for Gla-100 during the 36-h clamp period, indicating a more evenly distributed exposure and metabolic effect beyond 24 h. Exposure to insulin glargine and glucose utilization were lower with the 0.4 and 0.6 U/ml Gla-300 doses in both studies compared with the 0.4 U/ml Gla-100 dose. Glucose-lowering activity was detected for up to 36 h with all doses of Gla-300. CONCLUSIONS: Single-dose injections of Gla-300 present more constant and prolonged PK and PD profiles compared with Gla-100, maintaining blood glucose control for up to 36 h in euglycaemic clamp settings in Japanese and European participants with type 1 diabetes.

The PEBP2beta/CBF beta-SMMHC chimeric protein is localized both in the cell membrane and nuclear subfractions of leukemic cells carrying chromosomal inversion 16.

The chromosomal inversion (16)(p13q22), which is associated with the M4-eosinophilia subtype of human acute myeloid leukemia, causes the fusion of two distinct genes. The polypeptide encoded by the chimeric gene, PEBP2p/CBFp-SMMHC, retains the ability to interact with, and dominantly interfere with the function of proteins possessing the Runt homology domain. The Runt protein homologs constitute the DNA binding subunit of the PEBP2/CBF transcription factor. We examined the subcellular localization of PEBP2beta/CBFbeta-SMMHC, as well as that of Runt protein homologs in leukemic cells carrying inversion 16 by immunoblot analysis. A significant amount of the PEBPbeta/CBFbeta-SMMHC protein was recovered from the nuclear fraction along with the Runt protein homologs. Furthermore, some of both polypeptides was retained in the DNA pellet that represents the material remaining after extraction of nuclear fraction with high salt. These observations suggest that the so-called dominant interfering effect of PEBPbeta/CBFbeta-SMMHC on PEBP2/CBF occurs inside the nucleus. In addition, we could detect PEBP2beta/CBFbeta-SMMHC in the cytoplasmic membrane fraction as well. The function of this membrane-located PEBP2beta/CBFbeta-SMMHC, if any, appears to be unrelated to that of Runt protein homologs.

Ca(2+)-independent contraction of uterine smooth muscle induced by vanadate and its inhibition by Ca2+.

Vanadate, 30 microM, contracts uterine smooth muscle of estrogen-dominated non-pregnant rats in Ca(2+)-free medium after preincubation with 3 mM EGTA. In spite of the phosphorylation of the myosin light chain during this contraction, studies with fura-2 suggested that this contraction was not accompanied by an increase in the cytosolic Ca2+ level. Inhibitors of the myosin light chain kinase and protein kinase C partly inhibited this contraction. Vanadate seems to enter the cell through anion channels to inhibit phosphatases, resulting in phosphorylation via basal activities of the myosin light chain kinase and protein kinase C. An increase in the cytosolic free Ca2+ level resulted in relaxation of the contracting muscle in the same manner as in the oxytocin-induced Ca(2+)-free contraction.

Role of glomerular eicosanoid production in the obstructed kidney.

The regional production of prostaglandin E2 and thromboxane B2 was investigated in the kidney with unilateral or bilateral ureteral obstruction for 24 hours in rats. The production of these eicosanoids was highest in the inner medulla both with or without ureteral obstruction, although the production rate by the tubules was relatively low in the obstructed kidney compared to the sham-operated control. A greater production of these vasoactive compounds was noted by glomeruli from the kidneys with unilateral or bilateral obstruction and the contralateral kidney with unilateral obstruction. Glomeruli obtained from the kidney with unilateral obstruction produced more thromboxane B2 than the kidney with bilateral obstruction, and the resultant TxB2/PGE2 ratio was higher in the unilaterally obstructed kidney. This difference in the glomerular thromboxane B2 production may be responsible for the haemodynamic changes between unilateral and bilateral ureteral obstructions. An increased prostaglandin E2 production by glomeruli from the contralateral kidney with unilateral obstruction may contribute to a compensatory response.

Enhanced glomerular phospholipase activity in the obstructed kidney.

Previous study demonstrated that an increment of glomerular eicosanoid production may contribute to the haemodynamic changes in the obstructed kidney. To elucidate the mechanisms responsible for enhanced glomerular eicosanoid production, the present study was designed to investigate activities of related enzymes by isolated glomeruli from rat kidney with unilateral ureteral obstruction (UUO) or bilateral ureteral obstruction (BUO) for 24 hours. The activity of phospholipase A2 (PLA2) was determined by monitoring 14C] arachidonate release using 14C] phosphatidylcholine (PC) or 14C] phosphatidylethanolamine (PE) as a substrate. Phospholipase C (PLC) activity was assayed by measuring the release of [3H] inositol triphosphate [3H] IP3 from [3H] phosphatidylinositol 4,5 biphosphate ([3H] IP2). The activity of PE-specific PLA2 was increased in glomeruli from the kidney with BUO and the contralateral kidney of unilateral ureteral obstruction (CLK). PLC activity was significantly greater in the cytosolic fraction of glomeruli from kidneys with UUO, BUO and CLK compared to sham-operated control. The activity of PC-specific PLA2 was not significantly increased in any group. These results indicate that the increased synthesis of eicosanoids by glomeruli from obstructed kidney may be mediated by enhanced activities of PE-specific PLA2 and PLC. The increased activities of these phospholipases by glomeruli from CLK may contribute to a compensatory response.

[Absorption of the urinary constituents from canine ileum].

To clarify the mechanism of metabolic changes after using intestinal segments as a urinary tract, absorption of urinary constituents from the ileum was studied in dogs. An isolated distal ileum (30 cm in length) was anastomosed to the urinary bladder in each dog. Although these animals maintained the normal renal function throughout the experimental period, mild acidosis was noticed one month after anastomosis and it became severe after six months. Stagnation of a urine-like solution (artificial urine: AU) in the isolated ileum resulted in an absorption of 66% of the instilled solvent on average during 60 minutes. The average absorption rates of each AU constituent were as follows: sodium 63%, potassium 80%, chloride 83%, phosphorus 68%, magnesium 34%, urea nitrogen 93% creatinine 56%, and ammonia 97%. On the contrary, calcium increased in the stagnated fluid by 21%. In spite of the severe histologic changes in the villi of the ileal mucosa, which became atrophic and flat, no deterioration in the absorptive capacity of the AU constituents was noticed during the six month experimental period. Furosemide administration suppressed the absorption of urinary constituents, especially water and sodium. On the other hand, the absorption of urea nitrogen and ammonia was scarcely affected. Perfusion of the isolated ileum with AU (0.5 ml/min) for 60 minutes resulted in an absorption of 59% of the solvent and 50 to 86% of each constituent. The rate of absorption was reduced after increment of the perfusion rate. In conclusion, the absorption of urinary constituents occurs rapidly and significantly. The absorptive capacity remains longer regardless the severity of histological changes of the ileal mucosa.(ABSTRACT TRUNCATED AT 250 WORDS)

[Investigation of factors affecting the progression of polycystic kidney disease and effects of percutaneous reduction of cystic size].

Factors affecting the progression of autosomal dominant adult type polycystic kidney disease were analysed in 27 cases. The patients ages ranged from 10 to 74 (mean 44) years old and the serum creatinine values were within the normal limits except two cases, in which the values were 2.4 mg/dl and 2.1. They were followed for from 2 years to 12 years (mean 5.6 years). During the followup period, 6 cases showed elevation of the serum creatinine values and hemodialysis was necessary in 4 cases. There was a tendency of higher morbidity rate of hypertension, proteinuria, hematuria and pyuria in the cases with decreased renal function. These factors may have participated in the progression of polycystic kidney disease. Cystic fluid analysis was performed by percutaneous puncture of more than hundred cysts in 27 cases. The results showed that the cystic fluid components of most cysts of the well functioning kidneys were similar to those of serum values: so-called proximal cysts. On the other hand, in the cases with decreased renal function, there were many cysts with lower sodium concentration and higher creatinine values: so-called distal cysts. The results suggest that the existence of so-called distal cysts may indicate poorer prognosis. DMSA renoscintigraphy was useful for followup polycystic kidney patients because of the uptake of the radionuclide was decreased before rising the serum creatinine value. In 6 cases, the cysts were instilled with 95% ethanol. Followup ultrasonography and DMSA renoscintigraphy revealed a marked reduction of the cystic size and an improvement of DMSA uptake.(ABSTRACT TRUNCATED AT 250 WORDS)

[Effect of furosemide on the obstructed kidney].

The effect of furosemide on the obstructed kidney was studied in dogs. In control kidneys (n = 4) the renal blood flow (RBF) was increased transiently after intravenous infusion of 20 mg of furosemide; from 12.9 +/- 1.2 to 14.8 +/- 1.4 ml/min/kg.B.W. No change in the renal pelvic pressure was observed. Urine flow increased from 0.47 +/- 0.12 to 4.98 +/- 1.15 ml/min at 20 minutes after furosemide administration. Increases in the fractional fluid excretion rate (V/GFR), the fractional sodium excretion rate (FENa) and the fractional potassium excretion rate (FEK) were observed and the maximum values were obtained at 20 minutes after furosemide administration. In two-week unilateral incompletely obstructed kidneys (incomplete UUO; n = 5), RBF was lower than that of the control kidney, whereas a tendency of transient increase was also noticed after furosemide administration; from 8.4 +/- 1.9 to 10.5 +/- 2.3 ml/min/kg.B.W. The renal pelvic pressure increased immediately and transiently after furosemide infusion. Increase in the urine flow was significant, but the value was lower than that of control, and the maximum value was marked at 20 minutes after furosemide administration. V/GFR, FENa and FEK were also increased in incomplete UUO, but the peak values were lower than those of control. In two-week unilateral completely obstructed kidneys (complete UUO; n = 5), RBF was markedly decreased (3.14 +/- 0.38 ml/min/kg.B.W.), and no significant increase was noticed after furosemide administration. The renal pelvic pressure was gradually and continuously increased after furosemide infusion. The fractional excretion rate of pelvic urine components was variable. In particular, V/GFR was significantly increased 60 minutes after furosemide administration.(ABSTRACT TRUNCATED AT 250 WORDS)

[mRNA expression of chemokines in rat kidneys with ureteral obstruction].

BACKGROUND: It has been demonstrated that leukocyte infiltration, mainly of macrophages and lymphocytes, into obstructed kidneys (OBK) of rats during unilateral ureteral obstruction (UUO). Chemokines (C-C subfamily) may be involved in this mechanisms. Thus, we accessed the gene expression of chemokines in renal cortex of rats with UUO. MATERIALS AND METHODS: Female SD rats were sacrificed at various time points after UUO. mRNA expression of MCP-1, RANTES and MIP-1 alpha was determined by semi-quantitative RT-PCR. RESULTS: Control kidneys (CNK) showed a weak mRNA expression of MCP-1, RANTES and MIP-1 alpha. OBKs showed an increase in MCP-1 at 2 hours of UUO and a significant increase at 4 hours of UUO as compared with CNKs or contralateral unobstructed kidneys (CLK). The mRNA levels of RANTES and MIP-1 alpha were not increased until 72 hours of UUO in CLKs or OBKs. There were slight, but significant, differences of RANTES and MIP-1 alpha expression between OBKs and CNKs at 120 hours of UUO. CONCLUSIONS: We suggest that the early increase in MCP-1 contributes to the leukocyte infiltration and that RANTES and MIP-1 alpha plays a partial role in a late increases.

[Laparoscopic investigation of 74 cases of nonpalpable testis].

BACKGROUND: The objective of this study is to evaluate the results and advantages of laparoscopic investigation of nonpalpable testis. METHOD: Since March 1986 to May 1996, we performed laparoscopy to investigate 88 nonpalpable testes of 74 cases under general anesthesia. On condition that testis was found intraabdominally, orchiectomy or orchiopexy was performed subsequently. With a finding of vas deferens and/or spermatic vessels entering into internal ring, inguinal canal was explored surgically. If both vas deferens and spermatic vessels were absent or blind-ending intraabdominally, no further examination was performed with a diagnosis of vanishing testis. RESULTS: Location of testes found in this study were as follows. Twenty three (26.1%) testes were found intraabdominally, 36 (40.9%) were intracanalicularly, 13 (14.8%) were distal to external inguinal ring, and 16 (18.2%) were vanishing testes. To those 39 (44.3%) intraabdominal and vanishing cases did not need inguinal exploration. CONCLUSION: In conclusion, a laparoscopic examination for nonpalpable testis is the most effective and less invasive procedure to make sure or preclude the location of the gonad. And in 18% of those who were enrolled in this study, no further surgical interventions were needed. An accurate locating of nonpalpable testis permits site-specific planning of surgical management.

[Urethral indwelling catheter, intermittent self-catheterization and urinary infection].

Once a catheter has been passed into the bladder without contamination, there are several possible routes of subsequent infection during drainage period, such as: 1. Entry of bacteria alongside the catheter in the urethra. 2. Introduced bacteria adhered easily to the indwelling catheter and drainage system and colonized. 3. The catheter tip is covered rapidly by various nutrient materials which becomes a good culture medium of stuck bacteria, which is a supply source of bacteria into the bladder urine. 4. Although the motile bacilli ascend very slowly through the stagnant tube and no bacteria ascend against a slowly moving column, rapid transport of organisms occurs in the swirling fluid caused by the passage of rising air bubbles. 5. Continuous urethral catheter drainage permits an average residual urine volume of 7.3 ml. 6. The catheter destroys the antibacterial defense mechanisms of the urinary bladder. The reasons why in many cases of intermittent self-catheterization (CID) urine becomes sterile despite non-sterile procedure, are as follows. In addition to that CIC has none of the disadvantages of the indwelling catheter, it improves the vesical defense mechanisms deteriorated by high pressure voiding. The number of bacteria reintroduced during catheterization is relatively small and they can be eradicated by usual scheduled catheterization within 4-5 hours without residual urine. CIC must be started before trabeculation or diverticuli are formed, in which bacteria remain. Actual determination of residual urine volume after catheterization will help to prescribe a rational program of CIC.

[Estimation of glomerular filtration rate from the urinary excreted contrast medium concentration].

In the animal experiments, glomerular filtration rate (GFR) values were estimated from the urinary response to the intravenously administrated iopamidol. By introducing some reasonable assumptions, mass balance equations about the contrast medium were transformed and GFR was defined as the ratio of logarithm of urinary concentration by time. Urinary concentrations were determined by measuring the photodensity on the X-ray film of urine specimens. Obtained values of GFR were well fitted to those obtained by the analysis of the plasma disappearance curve. The advantage of this method is that measurement of urinary volume is not necessary.

[Obstructive and reflux nephropathy].

Urinary tract obstruction and vesicoureteral reflux have marked effects on renal function. Renal interstitial fibrosis and glomerular hypertrophy with subsequent focal segmental glomerulosclerosis like changes are a common consequence of chronic obstruction and vesicoureteral reflux. Evidence suggests that vasoactive compounds and cytokines such as angiotensin II, nitric oxide, eicosanoids, TNF, TGF, EGF, PDGF, bFGF have a role in the hemodynamic and structural abnormalities that occur following obstruction of the urinary tract or vesicoureteral reflux. Use of modulators for these compounds appears to be beneficial for treatment of obstructive or reflux nephropathy in near future.