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Blood pressure, diet and the progression of nephropathy in patients with type 1 diabetes and hypertension.

To examine the relationships between the normal dietary intakes of protein and phosphate, blood pressure, and the progression of diabetic nephropathy, we prospectively studied 20 Type 1 diabetic subjects of mean age 43 +/- 10 years (SD) with early nephropathy (mean serum creatinine 115 +/- 43 mumol l-1) over 1 year. Three-monthly measurements of blood pressure, glycaemic control, and normal dietary intake (3-day weighed food records) and 6-monthly measurements of glomerular filtration rate (using a single injection of chromium 51-EDTA) were made. GFR changed at a median rate of -0.89 ml min-1 1.73 m-2 month-1 (range +0.85 to -2.55 ml min-1 1.73 m-2 month-1). Mean dietary protein intake (1.22 g kg-1; range 0.78 to 1.55 g kg-1) and phosphate intake (21.5 mg kg-1; range 14.1 to 30.4 mg kg-1) were not significantly related to the rate of change in GFR. Only mean systolic blood pressure was significantly related to change in GFR, and accounted for 45% of the variability in GFR decline in the 18 subjects who completed the study (r = 0.67; R2 = 0.449; F1,16 = 13.2; p < 0.005; 95% confidence interval for r: 0.336-0.867). A mean systolic blood pressure of 140 mmHg or below was associated with no significant decline in GFR over a median period of 13 months.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

Periparturient rise in fecal egg counts associated with prolactin concentration increase in French Alpine dairy goats.

Previous data on periparturient relaxation of immunity during gastrointestinal nematode infection in goats are scarce and conflicting; one study carried out in fiber (Angora) goats showed a positive association of fecal egg counts with prolactin concentrations around parturition, whereas the two other available studies dealing with dairy goats, gave divergent results. The objectives of the study were thus to assess the occurrence of a periparturient rise in fecal egg counts in dairy goats and to examine a possible relationship between the level of milk production and the intensity of the periparturient rise. A total of 28 French Alpine grazing dairy goats naturally infected with Teladorsagia, Trichostrongylus, and Oesophagostomum were allocated into two groups according to their reproductive status; group 1 (n = 7) consisted of nonpregnant lactating animals in the 3rd month of lactation, whereas group 2 (n = 21) was composed of dry goats at 6 weeks before term. Fecal egg counts, pepsinogen and phosphate blood concentrations, blood eosinophil counts, and prolactin concentrations were individually monitored at weekly intervals for 12 weeks (from midwinter to early spring). The mean fecal egg counts were significantly higher in pregnant goats during the 2 weeks before (668 versus 242 eggs per gram of feces (epg), P < 0.05) and the 2 weeks after (962 versus 279 epg, P < 0.01) parturition as compared with nonpregnant lactating animals. No significant difference was seen in the composition of larval cultures between the two groups of animals, with Oesophagostomum infective larvae being found predominantly, particularly at the time of parturition. Pepsinogen and phosphate concentrations as well as blood eosinophil counts were similar between the two groups throughout the survey and indicated a moderate larval challenge. The mean prolactin concentration measured in pregnant goats was significantly higher (P < 0.01) at the time of parturition (298 versus 130 ng ml(-1)) and at 4 weeks after parturition (387 versus 193 ng ml(-1)) than that determined in nonpregnant animals. Furthermore, a significant correlation (rs = 0.30, df = 79; P < 0.01) between fecal egg counts and prolactin concentrations was recorded for the pregnant goats during the 4-weeks period around parturition.

Animals↗

Multiple mechanisms linked to platelet activation result in lysophosphatidic acid and sphingosine 1-phosphate generation in blood.

Lysophosphatidic acid (LPA) and sphingosine 1-phosphate (Sph1P) production was examined in vitro under conditions that simulated blood clotting. Several approaches were utilized to elucidate the metabolic pathways. 1) Platelet phospholipids were labeled using [32P]orthophosphate, and the production of [32P]Sph1P and LPA was examined. Thrombin stimulation of platelets resulted in rapid secretion of Sph1P stored within the platelet. In contrast, LPA was neither stored within nor secreted from platelets. Nonetheless, extracellular levels of LPA gradually increased following stimulation. 2) Stable-isotope dilution mass spectrometry was used to quantify the molecular species of LPA generated from platelets in vitro. Only 10% of the LPA generated following thrombin stimulation was associated with platelets, the remaining 90% was contained within the extracellular medium. The acyl composition of LPA produced by platelets differed depending on the presence or absence of plasma in the incubation. 3) The fate of exogenously added fluorescent phospholipid analogs was determined. Incubation of [(7-nitro-2-1,3-benzoxadiazol-4-yl)amino]dodecanoyl-(NBD)-labeled phosphatidylcholine, phosphatidylethanolamine, and phosphatidylserine with the supernatant fractions from thrombin-stimulated platelets yielded no LPA production. However, these lipids were converted to the corresponding lysolipids by released PLA1 and PLA2 activities. When incubated with plasma or serum the NBD-labeled lysophospholipids were readily converted to LPA. Inhibitors of lysophospholipase D and the biological activity of LPA were detected in plasma. These results suggest that the bulk of LPA produced through platelet activation results from the sequential cleavage of phospholipids to lysophospholipids by released phospholipases A1 and A2 and then to LPA by plasma lysophospholipase D.

Animals↗

Controlled delivery of 1,3-bis(2-chloroethyl)-1-nitrosourea from ethylene-vinyl acetate copolymer.

1,3-Bis(2-chloroethyl)-1-nitrosourea (BCNU) has been found to be an effective chemotherapeutic agent against brain tumors. However, because it has a very short half-life in plasma, the exposure of neoplastic cells to BCNU is very brief. The delivery of BCNU may be enhanced by using controlled release polymers. We measured the release of BCNU from ethylene-vinyl acetate copolymer (EVAc) into blood, phosphate buffer, and brain tissue. BCNU-EVAc cylinders that weighed 60 mg were implanted in the peritoneum of rats, and BCNU was detected in blood for 6 days. Studies carried out in vitro showed that BCNU was released from EVAc at a decreasing rate for 195 h. BCNU-EVAc cylinders that weighed 15 mg were implanted either intracranially (i.c.) or i.p. in Fischer 344 rats. Controlled release of BCNU from the i.c. BCNU-EVAc implants was observed over 9 days, with peak drug levels of 49.6 micrograms/g of brain tissue in the implanted hemisphere. The BCNU levels in the contralateral hemisphere and the peripheral circulation were much lower and were detectable for only 1 day. By contrast, peak BCNU levels in the brain from the i.p. BCNU-EVAc implants were 2.7-3.0 micrograms/g for only 12 h, accompanied by peak BCNU levels in blood of 1.0 micrograms/ml tapering over 1 day. These results demonstrate the controlled release of intact BCNU from EVAc in vitro and in vivo. Furthermore, the i.c. implants resulted in localized, prolonged, high levels of the drug in the implanted hemisphere. Hence, the i.c. controlled delivery of BCNU may be more efficacious for the treatment of localized brain tumors.

Animals↗

Studies on citrate-phosphate-dextrose (CPD) blood supplemented with adenine.

The effect of varying adenine concentrations in citrate-phosphate-dextrose (CPD) blood was studied in an attempt to optimize the storage conditions for human erythrocytes with regard to posttransfusion viability and oxygen release function. The maintenance of diphosphoglycerate (DPG) was impaired by adenine supplementation; this effect was closely related to the adenine concentration. A 0.25 mM adenine concentration in CPD blood improved the adenosine triphosphate (ATP) levels and the posttransfusion viability markedly, without appreciably impairing the DPG maintenance. The results suggest that CPD solution supplemented with adenine to give a 0.25 mM concentration in the blood is a better preservative for human erythrocytes than the commonly used acid-citrate-dextrose (ACD), CPD, and ACD-adenine solutions with regard to posttransfusion viability and oxygen release function. Adenine addition to this low concentration is not expected to cause renal damage even after massive transfusion.

Adenine↗

Enhanced vesiculation exacerbates complement-dependent hemolysis in glucose-6-phosphate dehydrogenase deficient red blood cells.

Glucose-6-phosphate dehydrogenase (G6PD) deficient red blood cells (RBCs) are known to be more susceptible to oxidant-induced hemolysis. Erythrocytes from G6PD-deficient individuals are significantly more susceptible to Ca(2+)-induced vesiculation than normal control cells. The enhanced susceptibility of G6PD-deficient RBCs to Ca(2+)-induced vesiculation is not due to ATP depletion. The remnant G6PD-deficient RBCs following vesiculation are more sensitive to complement-mediated hemolysis than control normal RBCs. A strong positive correlation exists between the level of Ca(2+)-induced vesiculation and the extent of complement mediated hemolysis.

Calcium↗

Unveiling extracellular inorganic phosphate signals from blood in human cardiac 31P NMR spectra.

31P NMR spectra of the human heart are usually contaminated by signals that originate from blood. The main blood signals are 2,3-diphosphoglycerate (2,3-DPG), which overlap and sometimes obscure the signal of myocardial inorganic phosphate used to calculate intracellular pH and to monitor metabolic changes in the heart. In this work we demonstrate, first, that even without proton decoupling the resolution of such spectra can be high enough to evaluate intracellular inorganic phosphate of myocardium in about 70% of the spectra and, second, that extracellular inorganic phosphate from blood contributes a signal in the chemical shift region of the 2-phosphate signal of 2,3-DPG.

2,3-Diphosphoglycerate↗

Repeatabilities of serum constituents in Holstein-Friesians affected by feeding, age, lactation, and pregnancy.

Effects of feeding regimen (pasture and drylot), physiological stage (lactating pregnant, lactating nonpregnant, and dry), and age on metabolites in blood serum were measured in 100 Holstein Friesian cows over 18 mo. Calcium, cholesterol, uric acid, total protein, albumin, and alkaline phosphatase were affected by physiological stage, whereas feeding regimen affected creatinine. Inorganic phosphate, blood urea nitrogen, glucose, lactic dehydrogenase, and glutamic oxaloacetic transaminase were affected by the interaction of stage and regimen. Age of animal affected cholesterol, glucose, and lactic dehydrogenase. Variances among and within cows were not consistent across physiological stages providing different repeatabilities for each stage. For example, total protein was highly repeatable in the two lactating stages but only moderately repeatable in dry animals (.61, .73, .26). Alkaline phosphatase and creatinine had consistently high repeatabilities.

Aging↗

Intraperitoneal phosphate administration in hungry bone syndrome.

Hypophosphatemia complicating parathyroidectomy for secondary hyperparathyroidism in renal failure is usually corrected by the oral or intravenous routes. We present a case in which those methods of treatment were not possible, and the phosphate was administered intraperitoneally. Phosphate was added as one molar sodium diphosphate solution to the dialysis fluid. In our case the procedure was well tolerated, phosphate blood levels were rapidly corrected, no alterations in calcium, magnesium or other parameters were detected and the patient was discharged in good condition. In selected cases of hungry bone syndrome after parathyroidectomy, intraperitoneal phosphate can be used safely.

Adult↗

Skeletal manifestations of moderate phosphate diabetes.

Six patients, with vertebral osteoporosis and reflex sympathetic algodystrophy syndrome of the lower limbs, due to moderate diabetes, are presented. Osteoporosis was documented by low CT scan bone density and moderate decrease of bone trabecular volume. Histomorphometric studies found a mild increase of resorption areas. All patients had unremarkable serum phosphorus level (mean: 0.91 +/- 0.13) but increase of urinary phosphorus excretion was documented by phosphate clearance higher than 20ml/mm, phosphate tubular reabsorption lower than 80% and TmPo4/GFR lower than 0.8mmol/l. Phosphate clearance and phosphate tubular reabsorption are studied in two control groups. Mild phosphate diabetes, of unknown incidence and prevalence (need for prospective studies) may be the vector of osteoporosis, vertebral and peripheral. The diagnosis of PD requires determination of phosphate clearance, phosphate tubular reabsorption, TmPo4/GFR and these tests may be useful in the diagnostic work up of bone demineralization disorders. We thought that osteoporosis could be the result of progressive dissolution of bone apatite crystals necessary to maintain normal or sub-normal blood phosphate level in spite of the phosphate diabetes.

Adult↗

Pseudohypoparathyroidism presenting with bony deformities resembling rickets.

Pseudohypoparathyroidism (PHP), characterized by hypocalcemia, hyperphosphatemia and elevated parathormone level, may rarely be associated with bony deformities resembling rickets. The authors report two siblings with clinical and radiological features suggestive of rickets unresponsive to treatment with vitamin D. Low serum calcium, elevated serum phosphate, normal renal functions, raised tubular maximum of phosphate and high serum parathormone were suggestive of PHP. Treatment with 1-hydroxyvitamin D and calcium carbonate led to decrease in bone pain, increase in height and weight and resolution of radiological features. PHP should be suspected in patients with bony deformities, hypocalcemia, elevated blood phosphate levels and normal renal functions.

Bone Diseases↗

Muscle glycogen storage following prolonged exercise: effect of timing of ingestion of high glycemic index food.

This study examined the effect of delaying the ingestion of carbohydrate on muscle glycogen storage following prolonged exhaustive exercise. Six endurance trained men cycled on two separate occasions at a workload corresponding to 70% VO2max for 2 h followed by four "all-out" 30-s sprints. Following exercise, subjects were fed five high glycemic index (HGI) meals over a 24-h period, with the first three being fed either at 0-4 h (IT) or 2-6 h (DT) at 2-h intervals. Muscle biopsies were taken immediately after exercise and at 8 and 24 h post-exercise and analyzed for glycogen and glucose-6-phosphate. Blood samples were obtained prior to and at 30, 60, and 90 min after each meal and analyzed for glucose and insulin. No differences were observed in the incremental glucose and insulin areas after each meal when IT and DT were compared. In addition, no differences were observed in muscle glycogen or glucose-6-phosphate any time in the two trials. These data indicate that delayed feeding of a HGI meal by 2 h has no effect on the rate of muscle glycogen resynthesis at 8 and 24 h post-exercise, providing that sufficient carbohydrate is ingested during the recovery period.

Adult↗

Acute clinical tolerance of creatinol O-phosphate.

Acute clinical tolerance to N-methyl-N-(beta-hydroxyethyl) guanidine O-phosphate (creatinol O-phosphate, COP) was investigated in volunteer human subjects without heart or renal disease and without other serious illness. COP was administered i.v. at three different dosages, 1020 mg (group A), 2040 mg (group B) and 3060 mg (group C), in comparison with a placebo (group D). Arterial pressure, heart rate, ECG pattern and a complete blood analysis showed no change at any COP dosage, with the exception of blood phosphate, which increased in groups B and C. Cumulative urinary excretion of phosphate and creatinine and diuresis increased, whereas other urine parameters did not change. The phosphate and creatinine increases derived from the COP molecule and the increase in diuresis from a simple osmotic process required to dilute the phosphate in the tubular fluid. All these alterations were statistically significant and dose-related with COP and had been expected. COP proved to be a very well tolerated drug without any evident side effect.

Adolescent↗

Long-term effects of intravenous 1 alpha (OH)D3 combined with CaCO3 and low-calcium dialysis on secondary hyperparathyroidism and biochemical bone markers in patients on chronic hemodialysis.

The effects of intravenous administration of 1 alpha-hydroxycholecalciferol [1 alpha (OH)D3] in combination with CaCO3 and 'low-calcium dialysis' (1.25 mmol/l) on plasma (p) parathyroid hormone (PTH) and biochemical bone markers (osteocalcin, alkaline phosphatase, procollagen type 1 c-terminal extension peptide) were examined in 54 patients on chronic hemodialysis with either normal or elevated PTH. Increasing doses of 1 alpha (OH)D3 were administered intravenously under careful control of p-Ca2+ and inorganic phosphate. Blood samples were obtained 1 week before the start of treatment and then every 2nd week. 20 patients with initially normal PTH levels (23.5 +/- 4.17 pg/ml) and 34 patients with initially elevated PTH levels (301 +/- 45 pg/ml) were followed for up to 88 weeks. The present investigation: demonstrated: (1) 'Low-calcium hemodialysis' (1.25 mmol/l) made it possible to use larger doses of CaCO3 and to reduce the doses of an aluminium-containing oral phosphate binder. A decrease in p-Ca2+ during dialysis was induced, and special care had to focus on the compliance to CaCO3, in order not to aggravate the secondary hyperparathyroidism. (2) The combination of 'low-calcium hemodialysis', CaCO3, and pulse intravenous 1 alpha (OH)D3 prevented the development of secondary hyperparathyroidism in patients with normal PTH levels and induced a long-term suppression of p-PTH (106 +/- 25 pg/ml, 88 weeks) in the patients with secondary hyperparathyroidism. By careful monitoring, severe hypercalcemia and hyperphosphatemia were avoided. There were no indications, clinically or biochemically, of development of adynamic bone disease. (3) Bone lesions were healed and a decrease of the bone mineral content in lumbar spine and femoral neck of patients with both normal and elevated PTH levels prevented. (4) The present results may suggest that PTH might be of influence on that regulation of procollagen type 1 c-terminal extension peptide.

Adult↗