Hormonal control of postnatal development of renal tubular transport of weak organic acids

We have postulated that the maturation of the renal transport mechanism for weak organic acids is controlled by thyroid and adrenal hormones. Administration of T₃ and T₄ (20 g/100 g body wt. for 3 days) to immature rats enhanced by 50% the accumulation of p-aminohippurate (PAH) in renal cortical slices of 5- to 30-day-old rats. The effect of T₃ was lower, while T₄ had no effect, in 50- and 105-day-old animals. Enhancement of PAH transport became apparent 24 h and disappeared by 9 days after the end of hormone treatment. Administration of a booster dose of T₃ (1 g/100 g body wt.) on day 9 brought the level of PAH accumulation to values similar to those observed 24 h after the end of the initial 3 days of T₃ administration. Dexamethasone administration (80 mg/100 g body wt. for 3 days) affected PAH uptake only in cortical slices obtained from 5-day-old rats. Changes in PAH accumulation did not correlate with changes in kidney weight or protein synthesis, indicating that they were mediated by the hormones rather than being consquent to growth.     

Developmental changes in the renal capacity for sulfate reabsorption in the guinea pig

During growth, immature guinea pigs maintain a positive inorganic sulfate balance. In the present study, renal clearance techniques were used to determine the maximum renal capacity for sulfate reabsorption [T_mR_si/glomerular filtration rate (GFR)] in three groups of guinea pigs at different stages of development (10–34 days, 35–80 days and >120 days of age). These ages are comparable to infant, adolescent, and adult guinea pigs. The guinea pigs were weaned at 10 days and then maintained on normal guinea pig chow (0.13% sulfate). The T_mR_si/GFR was determined by infusions of increasing concentrations of sulfate (0–16.8 mol/min). T_mR_si/GFR was significantly greater in young (infant and adolescent) than in older (adult) guinea pigs (2.20±0.26mol/ml and 1.80±0.27 mol/ml vs 0.942±0.08 mol/ml,P<0.05). These results demonstrate that the tubular capacity for inorganic sulfate reabsorption per milliliter of glomerular filtrate is enhanced in immature guinea pigs and decreases with age.     

Pharmacokinetics of ganciclovir in pediatric renal transplant recipients

Ganciclovir (GCV) is effective in preventing and treating cytomegalovirus (CMV) infection in solid organ transplant recipients. The aims of the present study were to determine the pharmacokinetics of GCV administered intravenously (IV) and orally (p.o.) as pre-emptive anti-CMV therapy in pediatric renal transplant recipients and to monitor trough levels and side-effects during pre-emptive therapy. Eleven pediatric renal transplant recipients (aged 11.0±3.9 years) were included. The diagnosis of CMV infection, based on two positive pp-65 CMV blood antigen tests at 1 week apart, was made at 39±12 days post renal transplantation. They received IV GCV at a dose of 5.0±0.3 mg/kg per 12 h for 15 days, followed by GCV p.o. at a dose of 46.7±8.2 mg/kg per 12 h for 3 months. Pharmacokinetics (PK) were studied at steady state and GCV plasma concentrations were measured by high-performance liquid chromatography. After IV GCV administration, PK parameters were: C₀=0.84±0.66 g/ml; C_max=11.77±2.82 g/ml; AUC_{0–12 h}=42.29±17.57 g/ml per hour; Cl=0.13±0.05 l/h per kg. After p.o. GCV administration, PK parameters were: C₀=1.08±0.68 g/ml; C_max=2.70±1.07 g/ml; AUC_{0–12 h}=18.97±9.36 g/ml per hour; Cl/F=2.97±1.42 l/h per kg. Bioavailability (F) was 4.9±1.2%. Pre-dose concentrations (C₀) measured under p.o. GCV (n=51) were 1.29±0.80 g/ml (8 C₀ values were below 0.5 µg/ml). Pp-65 CMV blood antigen tests became negative after 16±11 days of treatment. GCV was well tolerated. Because of the limited bioavailability, the recommended high doses of p.o. GCV (50 mg/kg per 12 h) were administered and were associated with trough levels over 0.5 µg/ml. In 1 patient who received an erroneously low dosage p.o., CMV resistance to GCV appeared, requiring foscarnet.     

Extracorporeal cisplatin removal using direct hemoperfusion under hepatic venous isolation for hepatic arterial chemotherapy: An experimental study on pharmacokinetics

This study was undertaken to pharmacokinetically evaluate the efficacy of direct hemoperfusion under hepatic venous isolation (HVI-DHP) to cisplatin (CDDP) removal during hepatic arterial infusion. CDDP (2–4 mg/kg) was administered continuously to mongrel dogs through the hepatic artery for 10 min. Plasma levels and tissue concentrations were then compared between animals receiving CDDP alone (group 1, n=4) and those treated with additional HVI-DHP for 20 min (group 2, n=6). The peak CDDP levels in the right external jugular vein (systemic level) were 6.10±1.31 (mean±SD) and 1.41±0.12 g/ml in groups 1 and 2 at a dosage of 2 mg/kg, respectively (P<0.01). The estimated drug removal rates in group 2 animals at dosages of 2 and 4 mg/kg were 45.7 (mean, n=5) and 46.9% (n=1), respectively. The tissue concentrations of CDDP of the liver 30 min after the initiation of infusions were similar in both groups. The values of the liver, the heart, and the kidney were 1.90±0.55, 0.50±0.16, and 3.90±2.50 g/g of wet tissue weight, respectively, in group 1. In contrast, tissue levels of the heart and the kidney in group 2 animals were significantly reduced, with the values at a dosage of 2 mg/kg being 0.21±0.03 g/g (P<0.01) and 0.86±0.53 g/g (P<0.05), respectively. This study demonstrated that the extrahepatic distribution of CDDP during hepatic arterial infusion can be reduced significantly by the concomitant use of HVI-DHP.     

Serum immunosuppresive acidic protein in renal cell carcinoma

Summary Serum immunosuppresive acidic protein (IAP) was determined in 45 patients with renal cell carcinoma (20 preoperative and 25 postoperative) and 12 healthy adults. The mean values of serum IAP in patients with renal cell carcinoma of low stage (566.3±197.7 g/ml) and high stage (936.9±208.8 g/ml) were statistically higher than those of controls (368.8±84.5 g/ml). Positive rate of IAP levels was found in 58.3% and 100% of patients with low stage and high stage, respectively. The mean value of serum IAP was 756.4±361.0 g/ml in patients with metastases, while patients without metastases had a value of 434.7±170.9 g/ml. There was a statistically significant difference between the two populations. These results suggest that IAP levels appear to provide a useful diagnostic and followup marker in renal cell carcinoma patients.     

Pharmacokinetic profile of a new fluoride preparation: Sustained-release monofluorophosphate

The pharmacokinetic profiles of a sustained-release monofluorophosphate (MFP-SR) preparation (76 mg) and of plain MFP (76 mg) were compared in six osteoporotic females. These studies were performed in a randomized, crossover, double-blind design to select a preparation that would result in therapeutic serum levels while avoiding high serum peak values. Following a single dose of 76 mg MFP-SR, the serum fluoride levels remained within the accepted therapeutic range (5–10 M/liter) for 24 hours. In contrast, following a single dose of 76 mg plain MFP, serum fluoride levels exhibited a wide circadian fluctuation and serum levels approximately threefold higher than those of the MFP-SR preparation (9.5±1.6 vs 3.5±0.8 M/liter, P<0.005). Compared with plain MFP, the sustained-release MFP had a significantly lower peak concentration (C_max MFP-SR: 10.6 ±3 vs C_maxMFP: 18.9±5 M/liter, P<0.005) and a significantly longer absorption lag time (T_maxMFP-SR 7.3±1.6 vs T_maxMFP: 3.0±0.6 h, P<0.05). Twenty-four-hour urinary fluoride excretion after ingestion of plain or SR fluoride was significantly increased from pretreatment values documenting absorption with either MFP formulation. Our results show that the use of sustained-release MFP preparation that we tested prevents the development of high peak levels associated with the use of plain MFP preparations. Furthermore, a single dose of MFP-SR resulted in serum fluoride levels within the accepted range of 5–10 M/liter for 24 hours.     

Natural killer activity and serum immunosuppressive acidic protein levels in esophageal and gastric cancers

The natural killer (NK) activity of peripheral blood mononuclear cells and serum immunosuppressive acidic protein (IAP) levels were examined in patients with esophageal or gastric cancer, before and after surgery. Patients with stage IV esophageal or stage IV gastric cancer had significantly lower NK activity (39.5±14.8% and 37±11.6%, respectively), and also higher serum IAP levels (778±264 g/mL and 633±156 g/mL, respectively), than the corresponding control values (50±5.6% and 375±26 g/mL, respectively). Patients with esophageal or gastric cancer who underwent curative resection had high NK activity (54.8±11.6% and 54.8±8.0%, respectively), and low IAP levels (471±116 g/mL and 490±42 g/mL, respectively), compared with those who underwent non-curative resection. Patients who underwent non-curative resection had lower NK activity and higher serum IAP levels than those who underwent curative resection, even 1 month after surgery. Mononuclear cells in the regional lymph nodes and tumor specimens showed significantly lower NK activity than those in the peripheral blood and spleen. Thus, NK activity and the IAP level reflected the immunocompetence, clinical course, and surgical curability of those patients. NK cells appeared not to have any significant antitumor activity in the regional lymph nodes or in the tumor itself, although they were still active in the peripheral blood.     

Scanning electron microscopy-electron probe microanalysis study of the interface between apatite and wollastonite-containing glass-ceramic and rabbit tibia under load-bearing conditions after long-term implantation

Glass-ceramic implants containing oxy- and fluoroapatite [Ca₁₀(PO₄)₆(O, F₂)] and -wollastonite (CaSiO₃) were studied under load-bearing conditions in a segmental replacement model in the tibia of the rabbit. A 16-mm segment of the middle of the tibial shaft was resected at a point distal to the junction of the tibia and the fibula. The defect was replaced by a 15 mm-long hollow, cylindrical implant that was fixed by intramedullary nailing using Kirschner wire. The implants were 9 mm in diameter and 15 mm long bearing a central hole 3.05 mm in diameter. The rabbits used were killed 6 months, 1 year, 18 months, and 2 years after implantation. The interface between the bone and the glass-ceramic was investigated by scanning electron microscopy-electron-probe microanalysis (SEM-EPMA).None of the glass-ceramic implants broke, and the glass-ceramic had bonded directly to the bone tissue without any intervening soft tissue. A calcium-phosphorus layer (Ca-P layer) was observed at the glass-ceramic/bone interface. This layer was 30–100 m thick at 6 months after implantation, 60–110 m thick at 1 year after implantation, 80–200 m thick at 18 months, and 120–350 m thick at 2 years. At the lateral surface of the glass-ceramic uncovered by the bone, the calcium-phosphorus layer was 50–80 m thick at 6 months after implantation, 250–450 m thick at 1 year, 300 400 m thick at 18 months, and 300 m thick at 2 years. The thickness of the calcium-phosphorus layer increased moderately after long-term implantation. However, it was difficult to estimate the rate of increase in the thickness of calciumphosphorus layer.     

Renal tubular differentiation in mouse and mouse metanephric culture

Sodium-potassium adenosine triphosphatase (Na-K-ATPase) activity was measured by microassay, and the surface density of basolateral membranes was measured morphometrically in postglomerular segments of single tubules isolated from normally developing, intact mouse kidneys and from transfilter metanephric cultures. Proximal tubule Na-K-ATPase activity was 1092±480 pmol/mm per hour in newborn mice, increasing to 2462±258 in 1-week-old and 3470–578 pmol/mm per hour in adult mice. The Na-K-ATPase activity in newborn mice was approximately one-third of the activity in adult mice. Tubular Na-K-ATPase in transfilter metanephric culture was 972±536 pmol/mm per hour, a mean value almost identical to that in newborn mice. The surface density of basolateral cell membranes was 1.36±0.60 m²/m³ in newborn mice and 1.34±0.45 m²/m³ in 1-week-old mice, increasing to 2.70±0.98 m²/m³ in 4-week-old mice and 2.89±0.51 m²/m³ in adult mice. The surface density of tubular basolateral cell membranes in transfilter metanephric culture was 1.13±0.51 m²/m³, not significantly different from the surface density in newborn mice. The calculated mean surface area of basolateral membranes per unit tubular length was greater in cultures than in newborns, however, because total epithelial volume per unit length was significantly larger in the cultured tubules. Membrane surface area in intact mice increased with age, the surface area per unit length of tubule in adults being 4.6 times the area in newborn animals. The ratio of enzyme activity to membrane surface area more than doubled in the 1st week of life without any increase in the density or surface area of basolateral membranes. The ratio fell thereafter, as membrane area increased with maturation, to a value in the adult animal three-fourths of that in the newborn. The early postnatal increase in enzyme activity, beginning almost immediately after birth, possibly relates to an increased density of enzyme sites on the membrane. The postnatal spurt in enzyme activity, without a corresponding increase in membrane area, suggests that tubules have considerable functional reserve in generating a complement of sodium pumps. The studies of proximal tubules grown in metanephric culture show that the basolateral membranes and the sodium pump are initiated independently of renal blood flow and tubular fluid flow, presumably as inherent characteristics. The functional data confirm the similarity, already shown by morphometric studies, between natural tubules and those grown in culture.     

Isoamylase levels in bone marrow transplant patients are affected by total body irradiation and not by graft-versus-host disease

The mean total serum amylase levels in patients was 3.2±0.5 kat/l (±SE) before total body irradiation (TBI) prior to bone marrow transplantation of which 50% was due to pancreatic isoamylase and 50% salivary isoamylase. Total serum amylase increased to a maximum of 100.3±12.3 kat/l on the first day after TBI and most of this increase was due to an increase in salivary isoamylase (90.0±12.1 kat/l). In association with this, all patients had clinical symptoms of parotitis. An increase in pancreatic isoamylase was found in 27% of the patients; however; none of them had clinical symptoms of pancreatitis. Serum amylase levels returned to normal within 5 days after TBI but then decreased to subnormal values, remaining below the normal range for 3 weeks. Pancreatic isoamylase returned to pre-irradiation levels 1.5 months after TBI, while salivary isoamylase remained low for the rest of the observation time. TBI of 7.5 Gy at 26 cGy/min gave significantly lower salivary amylase at 2 days after TBI compared with 10 Gy at 4 cGy/min: 32±4 versus 76±13 kat/l (P<0.05). At 2.5 and 6 months after TBI significantly higher total amylase levels were recorded for patients treated with 7.5 Gy of TBI compared with 10 Gy: 2.5±0.4 and 2.7±0.3 versus 2.0±0.5 and 0.8±0.3 kat/l, respectively (P<0.01, P<0.05, respectively). Acute or chronic GVHD did not affect acinar cells in this investigation.     

Effects of intravenous nitroglycerin combined with dopamine on intracranial pressure and cerebral arteriovenous oxygen difference in patients with acute subarachnoid haemorrhage

Summary The effects of intravenous nitroglycerin (NTG) combined with dopamine on intracranial pressure (ICP) and cerebral arteriovenous oxygen difference (AVDO₂) were studied in 11 patients with acute subarachnoid haemorrhage (SAH). The study was performed on Days 1 to 3 of SAH after aneurysmal clipping. Treatment consisted of an intravenous drip infusion of NTG in increasing incremental doses of 0.5, 1.0, 1.5, 2.0, and 2.5 g/kg/min at one-hour intervals. Dopamine (5 to 10 g/kg/min) was also given concurrently to maintain systemic blood pressure. ICP values before NTG administration ranged from 7 to 24 mmHg (mean, 11.91±5.30 mmHg). ICP began to increase immediately after the adminisration of NTG 0.5 g/kg/min and peaked at 14.64±5.93 mmHg 10 minutes after onset of infusion. Thereafter, ICP gradually returned to pretreatment levels. Increasing the dose of NTG failed to induce further significant rises in ICP. Mean AVDO₂ before NTG administration was 4.69±0.62 ml/dl. This parameter showed no significant change during NTG infusion, although cerebral perfusion pressure decreased to between 75% to 94% of the control value after NTG administration. These results indicate that continuous NTG infusion combined with dopamine does not have adverse effects on ICP (the ICP increase is minimal and transient) and may even have beneficial effects on CBF in patients with acute SAH.     

Urinary protein excretion and renal function in children with IgA nephropathy

Renal haemodynamics and the pattern of urinary protein excretion were studied in 38 children (21 boys, 17 girls) with biopsy-proven IgA nephropathy (IgAN), 0.4–16.8 (median 5.3) years after onset of the disease. Glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) were evaluated by clearances of inulin and para-aminohippuric acid. Serum and urinary albumin, IgG and beta₂-microglobulin (2) were determined and the excretion rates, clearances, and fractional clearances were calculated. The patients were grouped according to the type and the amount of proteinuria. Mean GFR and ERPF were significantly decreased (107±3 and 580±17 ml/min per 1.73 m², respectively) versus controls (119±2 and 627±14 ml/min per 1.73 m², respectively). Grouped according to albumin excretion rates, non-albuminuric patients had normal GFR, while mean GFR was reduced in patients with micro-albuminuria (106±3 ml/min per 1.73 m²) and albuminuric patients (92±7 ml/min per 1.73 m²). IgG excretion increased with increasing albuminuria, but the selectivity index was lower in albuminuric patients than in patients with micro-albuminuria. Albuminuric patients had also higher blood pressure than those with micro-albuminuria. 2 excretion did not discriminate between patients with impaired renal function. The results suggest that childhood IgAN is not a benign kidney disease. After a median duration of 5 years of the disease a number of children had impaired renal function. Mean GFR was reduced most in the albuminuric patients but was also decreased in micro-albuminuric patients, indicating that micro-albuminuria may be a predictor of more severe disease.     

Demonstration of calmodulin-sensitive calcium translocation by isolated osteoclast plasma membrane vesicles

Summary Plasma membrane vesicles were prepared from chicken osteoclasts, and active calcium transport was demonstrated in a spectrofluorimetric assay using the fluorescent calcium concentration indicator, fura-2. Transport activity was inhibited by quercetin (10 M), sodium vanadate (10 M), and the anticalmodulin agents, compound 48/80 (20 and 200 g/ml) and calmidazolium (10 and 20 M). The transport rate (V_max, 1.3 nmol/mg protein/min) was not altered in the presence of the protonophore, nigericin (1 M), indicating that proton transport was not driving calcium transport. Release of accumulated calcium in the vesicles occurred with the addition of bromo-A23187 (5 M) or ionomycin (5 M). Increasing calcium transport occurred with increasing calcium concentration. Finally, the calmodulin content of the vesicles was demonstrated to be 54–134 U/mg protein. These results demonstrate that a calmodulin-sensitive, ATP-dependent calcium transporter is present in the osteoclast plasma membrane.     

Hyaluronic acid uptake in the assessment of sinusoidal endothelial cell damage after cold storage and normothermic reperfusion of rat livers

The uptake of hyaluronic acid (HA) was used to assess preservation damage to sinusoidal endothelial cells (SEC) during cold storage and subsequent normothermic reperfusion of rat livers. After 8, 16, 24, and 48 h storage in University of Wisconsin (UW) solution, livers were gravity-flushed via the portal vein with a standard volume of cold UW solution containing 50 g/l HA. The effluent was collected for analysis of HA, aspartate aminotransferase (AST), and lactate dehydrogenase (LDH). The mean uptake of HA at 0 h was 59.1%±4.6% (mean±SEM). After 8 h of storage, HA uptake was similar (55.5%±7.3%), whereas after 16 h of storage it was reduced to 34.7%±5.8%. At 24 and 48 h of storage, no uptake of HA was found. In a second series of experiments, livers were stored in UW solution and subsequently reperfused for 90 min with a Krebs-Henseleit solution (37°C) in a recirculating system containing 150 g/l HA. Following 8 h of storage, 34.6%±8.0% of the initial HA concentration was taken up from the perfusate. After 16 and 24 h of storage, no uptake of HA was found. The results of this study indicate that damage to SEC occurs progressively during storage, leading to zero uptake of HA by the rat livers at 24 h of cold ischemia time. Additional reperfusion injury to the SEC was demonstrated by the reduced ability of the SEC to take up HA following normothermic reperfusion. The uptake of exogenous HA in preserved livers, used as a tool to assess SEC injury, enables the detection of early preservation damage.     

Deferoxamine and aluminum clearance in pediatric hemodialysis patients

Mobilization of aluminum by deferoxamine and the subsequent clearance from plasma by hemodialysis with or without charcoal hemofiltration was studied in four pediatric patients. Deferoxamine, 10–20 mg/kg, followed by dialysis with a Travenol CA50 dialyzer produced reductions in mean plasma aluminum levels from 2433±729 nmol/l (65.5±19.6 g/l) to 1727±554 nmol/l (46.5±14.9 g/l) during dialysis. The use of a charcoal cartridge in the circuit resulted in a reduction in mean plasma aluminum levels 2459±591 nmol/l (66.2±15.9 g/ml) to 1380±106 nmol/l (35.8±2.9 g/l). In one patient, high-flux dialysis produced a reduction from 2140 nmol/l (55.6 g/l) to 1134 nmol/l (29.4 g/l). No patients suffered direct adverse reactions to low-dose deferoxamine, although two patients had previously exhibited potential aluminum neurotoxicity after rapid increases in plasma aluminum levels with deferoxamine in higher doses. Aluminum levels must be monitored closely during deferoxamine therapy in uremic children to minimize the risk of exacerbating aluminum neurotoxicity.     

Connective tissue metabolism in children with chronic renal failure

To assess the characteristics of connective tissue metabolism in chronic renal failure (CRF), urinary excretion of glycosaminoglycan (GAG) fractions and hydroxyproline (HYP) was determined in ten patients with CRF and in ten age-matched healthy children. CRF was found to be associated with elevated free HYP (19.9±6.1 vs 9.8±3.6 mol/day,P<0.05) and depressed peptide HYP excretion (33.1±13.5 vs 225.2±17.7 mol/day,P<0.01), a low rate of total GAG excretion (7.0±2.4 vs 16.1±1.9 mol uronic acid/day,P<0.05) with low chondroitin 4 — sulphate + chondroitin 6 — sulphate (Ch-Ss) (14.0±9.9 vs 65.0±22.1%) and a high proportion of non-sulphated or under-sulphated fractions, i.e. hyaluronic acid + chondroitin + heparan sulphate (HA+Ch+HS) (75.3±11.4 vs 31.5±5.7%). Urinary 3-methyl-histidine (3-met-HIS) excretion and plasma essential free amino acids did not differ in the two groups. In response to haemodialysis no consistent change occurred in urinary excretion of 3-met-HIS, peptide-bound HYP, total GAG or percentage distribution of individual GAG fractions. After haemodialysis all plasma amino acids decreased significantly, and there was a significant increase in urinary excretion of free HYP (P<0.05). We conclude that the alterations in urinary excretion of total and individual GAGs observed in CRF may reflect disturbed connective tissue metabolism which does not appear to be accounted for by protein malnutrition or enhanced protein breakdown and remains uninfluenced by haemodialysis therapy.     

NMR studies of phosphate metabolism in the isolated perfused kidney of developing rats

During growth, the capacity for renal phosphate (Pi) reabsorption varies as a function of Pi demand. These changes occur in the absence of changes in extracellular concentration of Pi and are also observed in renal cells cultured in defined media. These findings suggest a direct regulatory effect of intracellular Pi on its transport systems. We postulate that a low intracellular Pi concentration ([Pi]_i) occurs in the developing kidney as a consequence of differences in Pi metabolism between growing and mature cells and that a low [Pi]_i, in turn, leads to adaptive changes in renal Pi transport. In order to assess this hypothesis, we used³¹P-nuclear magnetic resonance (NMR) to measure the intracellular concentrations of NMR-visible Pi and phospho-metabolites and the rates of Pi turnover due to adenosine triphosphate (ATP) synthesis, in isolated perfused kidneys of 3- to 4-week-old and 12- to 13-week-old rats. The [Pi]_i was lower (1.7±0.1 vs 2.7±0.1 mM,P<0.05) in kidneys of growing than of adult rats, while the ATP (2.9±0.3 vs 2.8±0.5 mM) and adenosine diphosphate (ADP)(–0.2 mM) concentrations were similar at the two ages, consistent with a high phosphorylation potential in the kidneys of the younger animals. Radiofrequency irradiation of the -P of ATP resulted in reduction in the intensity of the Pi resonance of 62±5% in the newborn and 38±3% in the adult (P<0.05). The corresponding 1.6-fold higher fractional turnover rate of the Pi pool in the younger than in the older rats accounts for the similar rates of ATP synthesis at the two ages (30±7 vs 35±4 mol/min per g,P>0.3), despite the smaller intracellular Pi pool present in the younger than in the older animals. The low [Pi]_i may stimulate the synthesis of 1,25 hydroxivitamin D₃ and the expression of Pi transport related proteins. The high phosphorilation potential drives the ATP flux necessary for growth related transport and biosynthetic processes.     

Piboserod (SB 207266), a selective 5-HT4 receptor antagonist, reduces serotonin potentiation of neurally-mediated contractile responses of human detrusor muscle

The aim of this study is to evaluate the potency of piboserod (SB 207266), a selective 5-HT₄ receptor antagonist, at inhibiting the 5-HT₄-mediated potentiating effect of serotonin (5-HT) on the neurally-mediated contractile responses of human detrusor strips to electrical field stimulations (EFS). Strips of human detrusor muscle were mounted in Krebs-HEPES buffer under a resting tension of 500 mg and EFS (20 Hz, 1 ms duration at 300 mA for 5 s) was applied continuously at 1 min intervals. After stabilization of the EFS-induced contractions, concentration-response curves to 5-HT (0.1 nM–100 M) were constructed in the absence or presence of 1 or 100 nM of piboserod. The experiments were performed in the presence of methysergide (1 M) and ondansetron (3 M) to block 5HT₁/5HT₂ and 5-HT₃ receptors, respectively. 5-HT potentiated the contractile responses to EFS of human bladder strips in a concentration-dependent manner, with a maximum mean of 60.0±19.9% of the basal EFS-evoked contractions. Piboserod did not modify the basal contractions but concentration-dependently antagonized the ability of 5-HT to enhance bladder strip contractions to EFS. In presence of 1 and 100 nM of piboserod, the maximal 5-HT-induced potentiations were reduced to 45.0±7.9 and 38.7±8.7%, respectively. A mean apparent antagonist dissociation constant value (K_B) of 0.56±0.09 nM was determined. These data show the ability of piboserod to antagonize with high potency the enhancing properties of 5-HT on neurally-mediated contractions of isolated human bladder strips. Therefore, the 5-HT₄ receptor might represent an attractive pharmacological target for the treatment of overactive bladder.     

Microscopic analysis of autograft bone applied at the interface of porous-coated devices in human cancellous bone

Summary This study describes the response of human cancellous bone when autologous bone chips are added at operation to the interface between host bone and porous-coated implants. During the first operation of a staged bilateral total knee arthroplasty, seven patients consented to have paired porous-coated devices implanted into their opposite medial femoral condyle. One device of each pair had autologous bone chips applied to the porous-coating, and the other was not grafted and was a control. The devices were removed en bloc at the second total knee arthroplasty 6 to 49 weeks later. Backscattered electron imaging showed significantly more bone (p0.05) in the porous-coating of the implant treated with autologous bone chips which significantly increased (p0.05) the amount of bone available at the interface. The grafted devices had a mineral apposition rate of 1.04±0.20 m/day for the interface and 0.81±0.09 m/day for the peripheral bone. This compared with corresponding figures of 1.03±0.38 m/day and 0.79±0.19 m/day at the ungrafted devices. The mineral apposition rate at the interface of the porous-coated implants was significantly increased (p0.05) relative to the host bone in the periphery. Our results support the view that autologous bone chips are effective in attaching cementless porous-coated total knee replacements to the human skeleton by bone ingrowth.

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Résumé Nous avons étudié la réponse de l'os spongieux humain et le taux de remodelage osseux aprés insertion chirurgicale de copeaux d'os autologue (COA) à l'interface entre os et implants poreux. Au cours du premier temps d'une arthroplastie totale bilatérale du genous, nous avons implanté, chez 7 malades consentants, deux dispositifs à revêtement poreux dans le condyle interne du fémur opposé. L'un a été recouvert de COA avant d'être mis en place, l'autre a été placé tel quel pour servir de contrôle. Ces dispositifs ont été explantés en bloc avec l'os avoisinant lors de la deuxième arthroplastie, 6 à 49 semaines après leur insertion. Les études en microscopie électronique ont montré une augmentation significative (p0.05) de la quantité d'os sur la surface poreuse recouverte de COA. Le taux d'apposition minérale (TAM) moyen était de 1,04±0,20 m/jour à l'interface et de 0,81±0,09 m/jour au niveau de l'os spongieux adjacent. Pour les implants non greffés le TAM était de 1,03±0,38 m/jour à l'interface et de 0,79±0,19 m/jour au niveau du spongieux périphèrique. Le TAM à l'interface des implants à revêtement poreux est significativement augmenté (p±0.05) par rapport à l'os receveur avoisinant.

     

Glomerular adaptation in uninephrectomized young rats

To study the glomerular adaptation during compensatory renal growth starting in infancy, we assessed afferent effective ultrafiltration pressure (P_UF), glomerular filtration area and hydraulic conductivity in rats uninephrectomized (Nx) or sham-operated (S) at 5 days of age. Rats were fed a normal protein diet and studied at 20 and 60 days of age. Single nephron glomerular filtration rate was significantly higher in Nx than in S rats both at 20 days of age (mean ± SEM: 15.0±1.5 vs 7.4±0.7 nl/min) and 60 days of age (80.7±4.6 vs 43.5±3.2 nl/min). Afferent effective P_UF, estimated by the stop-flow method, was significantly higher in Nx than in S rats both at 20 days (22.5±0.8 vs 18.3±0.4 mmHg) and 60 days (28.3±1.0 vs 23.2±1.1 mmHg). The filtering area per glomerulus, calculated as the area of the glomerular basement membrane facing both the endothelial and the epithelial cells, but not the mesangial cells, was not different in Nx and in S rats at 20 days (3.0±0.3 vs 2.8±0.1 10⁴ m²), but it was significantly greater in Nx than in S rats at 60 days (23.3±3.7 vs 9.9±0.9 10⁴ m²). The hydraulic conductivity determined in isolated glomeruli was similar in Nx and in S rats at 20 days of age (1.40±0.11 vs 1.69±0.23 l/min·mmHg· cm²) but was significantly decreased in 60-day-old Nx rats, compared with S rats of the same age (1.52±0.11 vs 2.35±0.17 l/min·mmHg·cm²). In summary, this study showed that the glomerular response to the ablation of renal tissue in infancy is characterized by an immediate increase in P_UF, a slow increase in filtration area and a lower hydraulic conductivity.