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.     

Renal handling of uric acid under cyclosporin A treatment

The renal handling of uric acid during cyclosporin A (CyA) treatment was investigated by clearance studies using 24-h urine collections in 28 paediatric renal transplant recipients (CyA group), and the results were compared with those of 19 renal transplanted children treated with azathioprine and prednisolone (AZA group), 35 children with chronic renal failure (CRF) and 10 children with normal renal function (N group). Serum uric acid levels were significantly higher in the CyA group (567±156 mol/l) compared with the AZA group (378±98), the CRF group (415±119) and the N group (290±68). Mean uric acid clearances in each group measured 3.9±2.8 ml/min per 1.73 m² (CyA), 5.6±3.4 (AZA), 4.0±2.2 (CRF) and 8.4±3.7 (N). Calculation of the net tubular uric acid reabsorption per millilitre glomerular filtration rate revealed a significantly increased value of 0.53±0.15 mol/ml in the CyA group (P<0.01) compared with 0.34±0.08, 0.29±0.15 and 0.27±0.07 mol/l for the AZA, CRF and N groups respectively. We therefore conclude that CyA treatment is associated with an increased net tubular reabsorption of uric acid, which may lead to hyperuricaemia.     

Tetracycline double-labeling of iliac trabecular bone in 41 normal adults

Summary A histomorphometric evaluation of the iliac crest trabecular bone remodeling was performed after tetracycline double-labeling in 41 normal Danes (12 males and 29 females) aged 19 to 56 years. The fraction of formative (osteoid covered) and resorptive surfaces was unrelated to age but higher in males than in females (P<0.02 andP<0.05, respectively). The appositional rate (0.65±0.12 m/day) was unrelated to age and sex, whereas the fractional labeled surfaces were higher (P<0.01) in the males (0.18±0.08 m²/m²) than in the females (0.12±0.05 m²/m²), and among the females inversely related to age (R=–0.38,P<0.05). The bone formation rate at BMU level (0.50±0.20 m³/m²/day) was unrelated to sex, but among the females inversely related to age R=–0.49,P<0.01). The bone formation rate at tissue level was higher (P<0.02) in the males (0.13±0.07 m³/m²/day) than in the females (0.07±0.03 m³/m²/day) and among the females inversely correlated to age (R=–0.43,P<0.05). The age- and sex-dependent variations in the dynamic parameters underline the importance of a more elaborated normal material.     

Renal tubular dysfunction in fetal alcohol syndrome

Renal function was evaluated in six patients with fetal alcohol syndrome (FAS) and eight control subjects before and after fluid restriction and acute acid loading. Baseline serum electrolytes, creatinine clearance, fractional sodium excretion, tubular reabsorption of phosphate, urine and blood pH and osmolalities, plasma renin activity, and plasma aldosterone level were normal in all subjects, but fractional potassium excretion (FE_K) was lower in FAS patients than in control subjects (P<0.001). Despita equivalent plasma osmolalities (295±3 vs 293±2 mosmol/kg,P=0.2), the maximum urinary osmolality after 12 h of water deprivation in patients with FAS was significantly lower compared with controls (560±107 vs 965±77 mosmol/kg;P<0.001) and increased to only 578±101 mosmol/kg after vasopressin administration. After ammonium chloride loading, minimum urine pH was significantly higher in patients than in controls (5.7±0.17 vs 4.81±0.19;P<0.001). Net acid excretion and FE_K were also lower in patients than in controls (102±11 vs 139.6±11.3 Eq/min per 1.73 m² and 23.5±1.3 vs 29±1.6%, respectively;P<0.001). The data indicate a subclinical renal tubular defect in urine concentration and acidification in patients with FAS.     

Atrial natriuretic peptide and cyclic 3′5′-guanosine monophosphate as indicators of fluid volume overload in children with chronic renal failure

Plasma atrial natriuretic peptide (ANP) and cyclic 35-guanosine monophosphate (cGMP) were investigated as indicators of fluid volume overload in children and adolescents with chronic renal failure. Plasma ANP and cGMP were measured in both paediatric patients with chronic renal failure (n=17, mean serum creatinine 371±242 mol/l) and those with end-stage renal disease on haemodialysis (n=18). cGMP was higher in children with chronic renal failure than in 45 healthy controls (1.0±0.4 vs 2.1±0.8 nmol/l,P<0.01), whereas plasma ANP was similar (26.9±9.7 vs 34.0±12.3 pmol/l). Both ANP and cGMP were markedly elevated in children with end-stage renal disease before haemodialysis and fell significantly during dialysis. During dialysis body weight decreased by 1.6±0.7 kg, corresponding to 4.5±2.1% of body weight. Plasma ANP correlated positively with plasma cGMP in haemodialysed patients (r=0.43,P<0.05). Reduction in body weight and in mean arterial pressure correlated more closely with plasma ANP than with cGMP. Therefore, elevation of plasma ANP appears to indicate volume overload in children undergoing haemodialysis, but whether it can be used also in children with chronic renal failure requires further investigation     

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.     

Microcirculatory disturbances and leucocyte adherence in transplanted livers after cold storage in Euro-Collins,UW and HTK solutions

Integrity of the hepatic microcirculation and maintenance of endothelial cell viability are critical components in preventing primary non-function after liver transplantation. Therefore, hepatic microcirculation and leucocyte-endothelial interaction were studied in rat livers stored for 1 h in Euro-Collins (EC), University of Wisconsin (UW), and histidine-tryptophan-ketoglutarate (HTK) solutions and subsequently transplanted. One hour after transplantation surgery, the livers were exposed under an intravital fluorescence microscope. After injection of the leucocyte marker acridine orange (1 mol/kg), six pericentral fields were observed for 30 s and experiments were recorded continuously. The percentage of perfused sinusoids was reduced in the livers in the EC group (82.9%) in contrast to the UW (93.2%) and HTK groups (91.0%). Livers in the EC group showed a reduction in the diameters of pericentral sinusoids (7.3±0.2 m; mean±SEM) compared with the UW group (9.5±0.2 m; P<0.05) and HTK group (10.2±0.8 m; P<0.05), indicating substantial cell swelling in livers stored in EC solution. Permanent adherence of leucocytes was most frequently observed in the EC group (33.5±1%), while this phenomenon was less pronounced in the UW group (14.5+1.1%; P<0.05) and HTK group (16.3±0.7%; P<0.05). Conversely, temporary adherence of leucocytes was reduced in the EC group (19.7+1.3%) compared with the UW group (30.5+2.1%) and the HTK group (34.4+0.8%). Microcirculatory failure and cell swelling in the EC group might be due to the lack of osmotic substances or oxygen radical scavengers included in UW (allopurinol, glutathione) and HTK (mannitol) solutions. In conclusion, cold storage of livers in UW and HTK solutions results in better preservation of the microcirculation and prevention of adhesion of leucocytes after transplantation compared with the EC solution.     

Renal function in Laron syndrome patients treated by insulin-like growth factor-I

Eight children with Laron syndrome (5 males, 3 females) aged 3–14.5 years received daily subcutaneous injections of 150 g/kg recombinant insulin-like growth factor-I (IGF-I) for 5 months. The children were examined weekly for the 1st month and then once monthly. At each visit, overnight fasting blood was drawn for serum IGF-I and blood chemistry measurements and a 24-h urine collection was performed for the determination of calcium, phosphorus, creatinine and nitrogen. The main effects related to kidney function were: an initial weight gain with a mild transitory reduction in the urinary volume, an increase in serum electrolyte concentrations and a decrease in urinary electrolyte excretion. The lower than normal mean (± SEM) basal creatinine clearance (76.7±15.8 ml/min per 1.73 m²) increased towards the normal range during treatment to 124.9±13 ml/min per 1.73 m², with a mean increment of 73.4±28% (P<0.02) from basal values after 2 months of treatment, without changes in the serum creatinine. Initially an increase in blood urea nitrogen was observed together with a reduction in urinary nitrogen excretion. During the IGF-I therapy the urinary calcium excretion increased from 0.7±0.2 nmol/day to 1.5±0.3 nmol/day and the tubular reabsorption of phosphate increased from 1.24±0.06 to more than 1.38±0.04 nmol/l (P<0.002), resulting in a significant increase in serum phosphate levels from 1.51±0.06 to more than 1.63±0.04 nmol/l (P<0.005). The present study shows for the first time that long-term IGF-I deficiency in man results in a subnormal glomerular filtration rate and that chronic substitution therapy with IGF-I has marked renotropic effects identical to those ascribed to growth hormone.     

Urinary calcium and oxalate excretion in children

We have established normal values for calcium/creatinine (Ca/Cr) and oxalate/creatinine (Ox/Cr) ratios in 25 infants (aged 1–7 days) and 391 children (aged 1 month to 14.5 years) and compared these with values obtained in 137 children with post-glomerular haematuria and 27 with nephrolithiasis. Oxalate was measured by ion chromatography. Nomograms of Marshall and Robertson were used to calculate urine saturation to calcium oxalate. The Ca/Cr ratio was normally distributed whereas the Ox/Cr ratio had a log-normal distribution. The molar ratio of Ca/Cr was the lowest in the first days of life and the highest between 7 month and 1.5 years (mean±SD=0.39±0.28 mmol/mmol). Following a slight decrease it stabilised by the age of 6 years (0.34±0.19 mmol/mmol). The highest Ox/Cr values were measured during the 1st month of life [geometric mean 133 (range 61–280) mol/mmol], followed by a gradual decrease until 11 years of age [mean 24 (range 6–82) mol/mmol]. Thirty-six haematuric children had hypercalciuria (26%), 23 had absorptive hypercalciuria, 13 renal type. Children with absorptive hypercalciuria on a calcium-restricted diet had significantly higher oxalate excretion than those with renal hypercalciuria and the control group [38 (range 28–49) vs. 22 (range 16–29) and 23 (range 22–27) mol/mol respectively,P<0.01]. Calcium oxalate urine saturation of stone patients was higher than that of patients with haematuria and the normal population (1.18±0.05 vs. 1.06±0.03,P<0.03 and 0.84±0.03,P<0.001 respectively). The measurement of Ca/Cr and Ox/Cr in first-morning urine samples is suitable for screening for hypercalciuria and hyperoxaluria. Interpretation of the values requires age-specific reference values. Both calcium and oxalate determinations should be part of the evaluation of patients with haematuria, hypercalciuria or nephrolithiasis.     

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.     

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.     

Comparison of Microcomputed Tomographic and Microradiographic Measurements of Cortical Bone Porosity

Cortical bone is perforated by a network of canals that have a significant impact upon its material properties. Microcomputed tomography offers the possibility of noninvasively visualizing and quantifying cortical pores in both two and three dimensions. Establishing how two-dimensional (2D) microcomputed tomographic (CT) analysis compares with conventional methods for analyzing cortical porosity is an important prerequisite for the wider adoption of this technique and the development of three-dimensional (3D) analysis. Therefore, we compared porosity-related parameters from 2D microcomputed tomographic images with those from matching microradiographic sections. Samples from five human femora were scanned at a 10-m resolution and then sequentially sectioned and microradiographed. An average of eight image pairs were produced from each femur (total, n = 41). The repeatability and comparability of the two techniques was assessed for three parameters; cortical porosity (%), mean pore area (m²), and pore density (pores/mm²). For repeatability, no significant difference (P > 0.05) was found between the two methods for cortical porosity and mean pore area; however, pore density differed significantly (P < 0.001). For comparability, the bias (± error) between the methods was found to be 0.51% (±0.31%) for cortical porosity and –155 m² (±293 m²) for mean pore area. The bias for pore density was dependent upon measurement size with microcomputed tomographic images having 14% (±9.3%) fewer pores per millimeter squared. The qualitative and quantitative similarities between the two techniques demonstrated the utility of 2D microcomputed tomographic for cortical porosity analysis. However, the relatively poor results for pore density revealed that a higher resolution (<10 m) is needed to consistently visualize all cortical pores in human bone.     

Transplantation of kidneys donated from the USA: Long-term results and viability testing using31P-MRS

Since June 1983, 27 kidneys have been shipped to the Kidney Center at the Tokyo Women's Medical College (TWMC) from the United States. These organs were divided into two groups, based on the years of their donation; 13 kidneys were assigned to group 1 and 14 to group 2. The differences between the two groups were as follows: donor age 19.8 ± 10.0 years vs 51.9 ± 14.5 years in group 2 (P < 0.0001); total ischemic time 42 h 12 min in group 1 vs 65 h 42 min in group 2 (P = 0.0002); and Euro-Collins preservation solution in group 1 vs University of Wisconsin (UW) solution in group 2. One hundred percent of the kidneys in group 1 and 85.7 % of those in group 2 recovered their function. The lowest serum creatinine levels averaged 96 ± 38.4 mol/l and 185.8 ± 101.0 mol/l, respectively (P = 0.01). The viability of 9 out of 14 grafts in group 2 were tested using³¹P magnetic resonance spectroscopy (³¹P-MRS). The results showed that all of the grafts having a monophosphate/inorganic phosphate (MP/Pi) ratio higher than 0.3 recovered their function and those lower than 0.2 did not. The problems associated with international organ sharing are discussed, along with the difficulties encountered at TWMC.     

Specificity of urinary excretion of cross-linked N-telopeptides of type I collagen as a marker of bone turnover

Urinary excretion of cross-linked N-telopeptide of type I collagen (NTX) has been reported to be a specific indicator of bone resorption. We studied the utility of a new immunoassay for NTX as an indicator of changes in bone resorption caused by treatment with pamidronate (APD) followed by T₃. Twenty-two male subjects received either placebo (Group 1) or APD on study days 1–2 (Group 2). One week later all subjects received T₃ 100 g/day (days 8–15). Urinary NTX, pyridinoline (PYD), hydroxyproline (HYP), and creatinine (cr) were measured on 2-hour fasting urine samples at baseline (day 1), after APD/placebo (day 8), after T₃ (day 16), and at days 30 and 58. NTX/cr excretion fell 85% after treatment with APD (P<0.001 versus baseline), but not after placebo. The fall in mean urinary NTX after receiving APD was greater than the fall in PYD (25%) or HYP (31%) (P<0.001 NTX versus PYD and HYP). After treatment with APD, NTX excretion remained suppressed below baseline until day 58, whereas PYD and HYP excretion returned to baseline by study day 16. Persistence of APD's effect on bone until day 58 was suggested by the fact that serum calcium and parathyroid hormone levels had not returned to baseline by day 58. On day 16, after all subjects were treated with T₃, urinary NTX/cr rose significantly (P<0.01) in Group 1 (-bisphosphonate) but not in Group 2 (+bisphosphonate). We conclude that urinary NTX is responsive to acute thyroid hormone-induced increases and bisphosphonate-induced decreases in bone resorption, and may reflect these changes more accurately than PYD or HYP.Portions of the data presented here were presented at the Fifteenth Annual Meeting of the American Society for Bone and Mineral Research, Tampa, Florida, September 18–22, 1993.     

Serum levels of bone GLA protein (osteocalcin,BGP) and carboxyterminal propeptide of type I procollagen (PICP) in acromegly: Effects of long-term octreotide treatment

Summary We measured serum concentrations of bone Glaprotein (osteocalcin, BGP) and carboxyterminal propeptide of type I procollagen (PICP) in 14 patients with active acromegaly. Blood was collected at 0800 for measurement of bone Gla-protein (BGP), carboxyterminal propeptide of type I procollagen (PICP), and insulin-like growth factor I (IGF-I); growth hormone (GH) was then determined at 15-minute intervals for 3 hours and the integrated mean was calculated. The same protocol was repeated at regular intervals during treatment with the long-acting somatostatin analog, octreotide, 150–450 g/day for 6–33 months (median 15). In a case-control analysis, serum BGP concentrations recorded in the acromegalic patients were significantly elevated (14.2±4.2 g/liter versus 8.0±3.3 g/liter, P<0.001). Octreotide treatment induced a roughly parallel reduction in serum GH, IGF-I, and BGP. We found a significant positive correlation between BGP levels recorded before and during therapy and the logarithm of corresponding mean GH levels (r=0.67, P<0.001). Also IGF-I concentrations were positively correlated with BGP (r=0.66, P<0.001). On the other hand, PICP levels recorded in the acromegalics did not differ from control subjects (146±46 g/liter versus 127±44 g/liter, NS) and no correlation was found between either GH and PICP or IGF-I and PICP. To conclude, the present data are compatible with the view that GH and IGF-I play an important role in the control of BGP but not PICP production. It could be that BGP and PICP are submitted to different hormonal modulation.     

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.     

Increasing serum osteocalcin after glycemic control in diabetic men

The pathogenesis of diabetic osteopenia is unclear. The markers of bone metabolism may show some changes in diabetic patients. In this study, we investigated the effect of glycemic control on serum osteocalcin level and urinary hydroxyproline excretion and the relations of these markers to duration of diabetes, C-peptide status, and body mass index. Twenty-seven men with poorly controlled diabetes mellitus (DM) (HbA1>9%, fasting plasma glucose>7.8 mmol/liter) between ages 25 and 60 years (means±SD 46.6±10.4) were included in the study. Duration of diabetes was 5.8±4.7 years, body mass index (BMI) was 25.9±3.5 kg/m², and fasting C-peptide was 2.33 (1.05–3.21) g/liter. None of the patients had a disease or were treated with drugs that would interfer with calcium or phosphate metabolism and/or bone structure. They were free from chronic diabetic complications. Of these patients, 11 were lost to follow-up before metabolic control was achieved. The remaining 16 patients obtained good glycemic control (HbA1<8.3%, fasting plasma glucose <7.8 mmol/liter) and completed the study. Serum osteocalcin level and urinary hydroxyproline eceretion were determined before and after glycemic control. Urinary hydroxyproline excretion was not significantly changed by glycemic control [17.8 (7.1–23.2) versus 18.1 (10.9–28.1) mg/m² day, P>0.05]. However, serum osteocalein level was significantly elevated (5.04±1.43 versus 4.17±1.83 g/liter, P=0.04). We found no correlation among fasting plasma glucose, HbA1, and fasting serum C-peptide levels with urinary hydroxyproline excretion. There was also no correlation between serum osteocalcin and fasting plasma glucose or serum C-peptide, but HbA1 was negatively correlated with serum osteocalcin (P=0.01). No correlation was found between DM duration and BMI in the patients with serum osteocalcin level and urinary hydroxyproline excretion. To eliminate the possible effect of exogenous insulin on bone metabolism, the correlation analysis between the markers and C-peptide was further repeated in oral agents-treated patients. Serum C-peptide was not correlated to serum osteocalcin or urinary hydroxyproline in this subgroup of patients. Knowing that serum osteocalcin is a marker of bone formation, we concluded that osteoblast function may improve by glycemic control in diabetic patients; this may be due to correction of metabolic abnormalities associated with insulinopenia.     

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.     

Nocturnal rise in markers of bone resorption is not abolished by bedtime calcium or calcitonin

As assessed by urine pyridinium cross-links, bone resorption increases at night. This has been ascribed to either the nocturnal rise of serum parathyroid hormone (PTH) or immobilization. ICTP is the carboxyterminal telopeptide region of type I collagen in bone, cross-linked via pyridinium cross-links and liberated during the degradation of type I collagen. To study whether the nocturnal rise in bone resorption is seen also in serum type I collagen carboxyterminal telopeptide (ICTP) and whether this rise is abolished by bedtime calcium or calcitonin, nine healthy postmenopausal women participated in three 24 hour sessions. At 2200 hours, either 1 g of oral calcium or 200 IU of intranasal calcitonin or no treatment (control session) were given. The participants were recumbent from 2200 hours to 0600 hours. Like urinary pyridinolines, serum ICTP showed a clearcut nocturnal rise during the control session, increasing from 3.7±0.3 g/liter (mean±SE) at 2000 hours to 4.9±0.4 g/liter at 0600 hours (P<0.001). Administration of calcium did not affect either serum ICTP or urinary pyridinolines, although it decreased serum intact PTH by 18% (P<0.001) as assessed by areas under curve (AUC) after 2200 hours. Serum ICTP and urinary pyridinolines remained unchanged also after administration of calcitonin which increased the AUC for serum intact PTH by 9% (P<0.05). In conclusion, serum ICTP follows a circadian rhythm in healthy postmenopausal women. The nocturnal rise in markers of bone resorption is not due to PTH, and its dependency on the function of osteoclasts is open to question.     

Pudendal denervation affects the structure and function of the striated, urethral sphincter in female rats

Our aim was to examine the effects of denervation on urethral anatomy and urine voiding pattern. Rats usually void at one end of their cage, which gives a behavioral index of continence. The voiding preference for denervated rats was decreased to 88.8+4.7%,n=32,P<0.001, compared to improvements with time for unoperated (117±10%,n=16) or sham-operated rats (105±8%,n=5). The volume of urine or the frequency of voidings between denervated, unoperated or sham-operated rats did not differ significantly. Urethral sections were analyzed immunochemically and quantified morphometrically. Smooth muscle volume remained constant but skeletal muscle volume decreased after denervation, from 43±2% to 36±3% (P<0.05,n=5). Fiber diameter decreased from 14.3±1.4 m to 8.5±0.7 m (P<0.005). We concluded that pudendal nerve transection in female rats causes behavioral alterations in voiding and muscular atrophy of the striated sphincter.Editorial Comment: The investigation shows that peripheral pudendal transection results in a changed voiding pattern in female rats, as well as in atrophy of the striated urethral sphincter. The morphologic changes in the striated urethral sphincter are to be expected following nerve transection. Unfortunately, the investigators only compared the unoperated to the operated groups, and did not perform the comparison with the sham-operated group, which could have revealed the effect of local surgical dissection on nerve function. The change in voiding patterns following surgery, whether nerve transection was performed or not, is interesting but difficult to explain or to extrapolate to any type of urinary incontinence in humans. Unfortunately there remains no animal model for human stress incontinence. This goal remains to be realized only by further investigational efforts, as presented here.