Alpha-adrenergic receptors in platelets from patients with Raynaud's syndrome

The pathophysiologic basis for spastic Raynaud's syndrome remains undefined but may be related to altered adrenergic activity. The relationship between Raynaud's syndrome and alterations in adrenergic receptor populations was examined in the present study by evaluation of alpha 2-adrenergic receptors in platelets. Direct binding assays revealed 78 +/- 8 fm/mg protein of alpha 2-adrenergic receptors in the platelets from control subjects. Similar levels of alpha 2-adrenergic receptors were observed in patients with obstructive Raynaud's syndrome. In contrast, platelet alpha 2-adrenergic receptor levels were significantly elevated (182 +/- 15 fm/mg protein) in the platelets from patients with spastic Raynaud's syndrome. These results indicate the presence of an altered alpha 2-adrenergic receptor population in the platelets from patients with spastic Raynaud's syndrome, which may be related to the vasospasm experienced by these patients.     

Elevated serum elastase and alpha-1-antitrypsin levels in hemolytic uremic syndrome

Clinical observations and experimental studies have pointed to a role for leukocytes in the pathogenesis of the typical or epidemic form of the hemolytic uremic syndrome. As a result of these observations we measured serum elastase levels and the levels of two protease inhibitors, alpha-1-antitrypsin and alpha-2-macroglobulin in 12 patients with this syndrome. The serum elastase levels were significantly elevated in patients compared with normal individuals (421 +/- 278 vs 91 +/- 27 mg/dl, p less than 0.005) and patients with renal diseases not caused by hemolytic uremic syndrome (191 +/- 254 mg/dl, p less than 0.025). The serum alpha-1-antitrypsin levels were also significantly elevated: hemolytic uremic syndrome vs normals (774 +/- 260 vs 285 +/- 98 ng/ml, p less than 0.0001); and in hemolytic syndrome compared with patients with renal diseases not caused by hemolytic uremic syndrome (774 +/- 260 vs 335 +/- 131 ng/ml, p less than 0.0001). There were no significant differences in the alpha-2-macroglobulin levels among the three groups. There was a significant correlation between the serum elastase levels and the total white cell counts as well as between the elastase and the polymorphonuclear cell counts but not among any of these values and the serum creatinine concentrations. These results provide additional evidence favoring the possibility that leukocytes are activated in patients with hemolytic uremic syndrome.     

Effects of pravastatin on serum lipids and apolipoproteins in hyperlipidemia of the nephrotic syndrome.

The nephrotic syndrome is often accompanied by hyperlipidemia associated with an increased risk of accelerated atherosclerosis. The present study was undertaken to evaluate the effects of pravastatin, a novel competitive inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, on the serum lipids and apolipoproteins in patients with this syndrome and marked hyperlipidemia. Eleven adult patients received 10 mg of pravastatin twice daily for 4 to 8 weeks. The total serum cholesterol decreased from 426 +/- 44 to 309 +/- 18 mg/dl (-27.4%, mean +/- S.E.; p less than 0.01) following administration of pravastatin. The serum triglyceride decreased from 332 +/- 122 to 229 +/- 50 mg/dl (-30.9%), although this change was not significant. Despite the fact that the HDL cholesterol level was barely changed (51 +/- 7 to 51 +/- 6 mg/dl), the LDL cholesterol fell from 313 +/- 30 to 211 +/- 16 mg/dl (-32.5%; p less than 0.005), and the LDL to HDL cholesterol ratio fell from 7.57 +/- 1.59 to 4.94 +/- 0.88 (-34.8%; p less than 0.05). These changes caused the atherogenic index to decline from 9.6 +/- 2.4 to 6.1 +/- 1.2 (-36.5%; p less than 0.05). No significant alterations could be found among apolipoproteins A-1, A-2, B, C-2, C-3, and E. During the present study period, pravastatin was well tolerated and did not affect the serum protein, albumin, serum urea nitrogen, creatinine levels, or urine protein excretion. Also, there were no serious adverse effects. Pravastatin appears to be effective for treating patients with hyperlipidemia of the nephrotic syndrome.     

Lymphocyte release of soluble IL-2 receptors in patients with minimal change nephropathy.

Minimal change nephrotic syndrome has been reported to be a lymphocyte-mediated disorder. It has been suggested that the secretion of lymphokine(s) is involved in the pathogenesis of MCN and in determining proteinuria. The presence of a soluble form of IL-2 receptor (sIL-2R) has been previously described in the sera of patients with some autoimmune disorders. In this work, we report the detection of high sIL-2R levels, both in the plasma (mean value 844 +/- 436 U/ml versus normal value 276 +/- 86 U/ml) and urine of patients with MCN during the nephrotic phase alone. Instead, when the patients achieve stable remission, sIL-2R levels decrease to within normal values (mean value 332 +/- 272 U/ml). Furthermore, during the nephrotic syndrome we observed a significant inverse relationship between sIL-2R plasma levels and the mitogenic response to PHA (p less than 0.005). Since sIL-2R exerts a down-modulation on T-proliferative expansion, sIL-2R might represent one of the inhibitory serum factors extensively reported in the serum of patients with MCN-induced nephrotic syndrome.     

Plasma cholecystokinin response to oral fat in patients with Billroth I and Billroth II gastrectomy

The present study was undertaken to determine whether bypassing the duodenum in patients with Billroth II gastrectomy affects plasma cholecystokinin (CCK) release in response to ingestion of fat. Plasma CCK concentrations were measured by radioimmunoassay using two antibodies; antibody 1703 binds to all carboxyl-terminal CCK-peptides containing at least 14 amino acid residues, while antibody T204 is specific for the sulphated tyrosine region of CCK. There were no significant differences among fasting plasma CCK concentrations in seven patients with Billroth II gastrectomy (1.3 +/- 0.4 fmol/ml, antibody 1703; 2.6 +/- 0.4 fmol/ml, antibody T204), six patients with Billroth I gastrectomy (0.6 +/- 0.3 fmol/ml, antibody 1703; 2.9 +/- 0.5 fmol/ml, antibody T204), and nine normal subjects (0.7 +/- 0.1 fmol/ml, antibody 1703; 1.9 +/- 0.3 fmol/ml, antibody T204). Ingestion of 250 ml 20% Intralipid induced similar increases in plasma CCK in patients with Billroth II gastrectomy (11.2 +/- 2.0 fmol/ml, antibody 1703; 10.1 +/- 2.4 fmol/ml, antibody T204) as in patients with Billroth I gastrectomy (11.8 +/- 2.0 fmol/ml, antibody 1703; 8.4 +/- 1.1 fmol/ml, antibody T204). However, the increments in plasma CCK in patients with gastrectomy (11.5 +/- 1.4 fmol/ml, antibody 1703; 9.3 +/- 1.4 fmol/ml, antibody T204) were significantly (p less than 0.01) greater than those in normal subjects (4.7 +/- 0.8 fmol/ml, antibody 1703; 4.1 +/- 0.7 fmol/ml). Similarly, the integrated plasma CCK secretion in patients with Billroth II gastrectomy (510 +/- 58 fmol/ml X 120 min, antibody 1703; 458 +/- 69 fmol/ml X 120 min, antibody T204) and in patients with Billroth I gastrectomy (457 +/- 143 fmol/ml X 120 min, antibody 1703; 365 +/- 61 fmol/ml X 120 min, antibody T204) were significantly (p less than 0.05) greater than in normal subjects (230 +/- 49 fmol/ml X 120 min, antibody 1703; 162 +/- 24 fmol/ml X 120 min, antibody T204). It is concluded that the plasma CCK response to oral fat is significantly greater in patients with partial gastrectomy than in normal subjects, and that patients with Billroth I and Billroth II gastrectomy have similar increases in plasma CCK after ingestion of fat.     

Behavior of beta 2-microglobulin in patients with chronic renal failure undergoing hemodialysis, hemodiafiltration and continuous ambulatory peritoneal dialysis (CAPD)

beta 2-microglobulin (beta 2-m) is the major component of a new form of amyloid deposit found in carpal tunnel syndrome and dialysis arthropathy of long-term hemodialysis patients. In 52 patients on maintenance hemodialysis, serum beta 2-m concentration was elevated to 37.9 +/- 1.4 (normal 1.2 +/- 0.6) mg/l. It was correlated with the time on hemodialysis (r = 0.43, p less than 0.01) and was inversely correlated with residual renal function (r = 0.87, p less than 0.001). In 20 patients on CAPD, beta 2-m likewise was increased to 31.6 +/- 2.3 mg/l; daily elimination by dialysate was only 34 mg (normal 150 mg). Hemodialysis with a cuprophane membrane caused a rise in serum beta 2-m, whereas hemodiafiltration with a polysulfone membrane performed in 5 patients over 2 1/2 months was accompanied by a decrease in serum beta 2-m from 39.5 +/- 0.7 to 29.7 +/- 1.0 mg/l predialysis (19.1 +/- 1.1 postdialysis). On the other hand, beta 2-m elimination reached only approximately 100 mg per day in spite of markedly elevated serum levels. It is concluded that serum beta 2-m is massively elevated in long-term hemodialysis and CAPD patients; contrary to routine hemodialysis with cuprophane membranes, newer more permeable membranes will permit some elimination of beta 2-m. However, based on quantitative considerations it seems difficult to obtain beta 2-m concentrations in the high normal or moderately elevated range with present day techniques.     

Renal tubular reabsorption of chloride in Bartter's syndrome and other conditions with hypokalemia

Fractional distal chloride reabsorption was measured in 8 patients with Bartter's syndrome, 8 patients with comparable degrees of hypokalemia of different etiologies and 7 normal subjects during maximal diuresis induced by an intravenous infusion of 5% dextrose in water. A low fractional distal chloride reabsorption (0.55 +/- 0.01) was found only in patients with Bartter's syndrome, whose serum potassium concentrations ranged between 1.2 and 3.1 mEq/l. Non-Bartter's syndrome hypokalemic patients had serum potassium concentrations between 2.4 and 3.2 mEq/l (p NS when compared to patients with Bartter's syndrome) but their fractional distal chloride reabsorption was 0.88 +/- 0.33, significantly higher (p less than 0.001) than that of patients with Bartter's syndrome. Normokalemic control subjects had a fractional distal chloride reabsorption of 0.86 +/- 0.01, higher than patients with Bartter's syndrome (p less than 0.001) but not significantly different from patients with hypokalemia. These results suggest that there is no effect of serum potassium concentration on fractional distal reabsorption of chloride in man. Hypokalemia of a moderate to severe degree is not accompanied by obligatory renal chloride loss except in Bartter's syndrome. Chloruresis is a specific feature of Bartter's syndrome rather than an effect of hypokalemia.     

Evidence that calcium modulates circulating 25-hydroxyvitamin D in man

We previously demonstrated in normal subjects that 1,25-dihydroxyvitamin D3 (1,25(OH)2D) can prevent the increase in serum 25-hydroxyvitamin D (25-OHD) which occurs in response to vitamin D. An investigation was carried out in eight normal subjects, therefore, to determine whether increases in calcium intake would alter the response of serum 25-OHD to challenge with vitamin D. In control studies, vitamin D, 100,000 U/d for 4 d, significantly increased mean serum 25-OHD from 18 +/- 3 to 42 +/- 5 ng/ml (p less than 0.001), an increment of 24 ng/ml (133%). Mean serum calcium, ionized calcium, phosphorus, creatinine, and 1,25(OH)2D did not change. In contrast, the same dose of vitamin D and calcium, 2,000 mg/d for 4 d, administered to the same eight subjects produced an increase in mean serum 25-OHD from 19 +/- 3 to 31 +/- 4 ng/ml (p less than 0.001), an increment of only 12 ng/ml (63%) and significantly less than the control (p less than 0.02). Mean serum calcium (8.8 +/- 0.1 vs. 9.2 +/- 0.1 mg/dl, p less than 0.01) and ionized calcium (4.79 +/- 0.07 vs. 4.85 +/- 0.08 mg/dl, p less than 0.05) increased significantly in response to vitamin D and calcium, mean serum phosphorus and creatinine did not change, and mean serum 1,25(OH)2D decreased significantly (37 +/- 2 vs. 31 +/- 4 pg/ml, p less than 0.02). In a postcontrol study in six of the normal subjects, vitamin D again significantly increased mean serum 25-OHD from 17 +/- 3 to 39 +/- 9 ng/ml (p less than 0.02), an increment of 22 ng/ml (129%).(ABSTRACT TRUNCATED AT 250 WORDS)     

Hypocalcemia and nephrogenous cyclic AMP production in critically ill or injured patients.

Critically ill or injured patients often have impaired cardiovascular function. Since low ionized calcium levels can cause such changes, serum calcium and urine calcium were measured in a prospective study involving 28 criticially ill or injured patients and 16 normal controls. Serum protein levels were also measured to calculate "corrected" total calcium levels. Ionized calcium levels are difficult to measure. Since ionic hypocalcemia is thought to increase the "nephrogenous production" of cyclic AMP, cyclic AMP levels were measured in the blood and urine of these patients and the "nephrogenous" cyclic AMP calculated from the creatinine clearance. The mean total serum calcium in these patients was 7.7 +/- 0.8 mg/dl (S.D.). This was significantly lower (p less than 0.001) than our controls (9.6 +/- 0.6). When corrected for hypoproteinemia, the mean serum calcium (8.7 +/- 0.8) was still significantly lower (p less than 0.005) than control (9.4 +/- 0.5). The mean urine calcium excretion in the patients (56 +/- 66 mg/100 ml G.F.R.) was lower, but not significantly so, than in the controls (84 +/- 44 mg/100 ml G.F.R.). The "apparent nephrogenous" cyclic AMP in the study group was 2,731 +/1 1,451 pm/ml/100 ml G.F.R. The nephrogenous cyclic AMP had a negative correlation (r =-0.45) with "corrected" total calcium levels. Thus "total," "corrected" total, and "ionized" calcium levels appear to be reduced in the majority of critically ill or injured patients studied. The clinical implications of these findings and the potential value of serial cyclic AMP determinations in blood and urine will be discussed.     

Plasma eicosanoids, platelet function and cold sensitivity

As abnormal eicosanoid (prostaglandin) metabolism has been suggested as a factor in the aetiology of vasospastic diseases we have measured levels of stable eicosanoid metabolites using a radioimmunoassay in 30 normal subjects and 31 patients with Raynaud's phenomenon. There were 13 patients with primary Raynaud's, ten with Raynaud's secondary to scleroderma and eight men with vibration white finger (VWF) disease. We have also measured platelet aggregation to adenosine diphosphate (ADP), collagen and adrenaline in 19 normal subjects, 22 patients with primary Raynaud's, 12 with Raynaud's secondary to scleroderma and 14 men with VWF. When compared with our normal subjects, patients with VWF have an elevated thromboxane B2 level, with a normal 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) level. Their platelets are less sensitive to ADP and collagen. Patients with primary and secondary Raynaud's have elevated thromboxane B2 levels but this is much more marked in the secondary group. Patients with primary Raynaud's have a normal 6-keto-PGF1 alpha level but in patients with secondary Raynaud's the 6-keto-PGF1 alpha level is markedly raised. The platelets from both groups are more sensitive to ADP and collagen and this is more marked in the secondary group. Whether these phenomena are a cause or an effect of vasospasm remains unknown.     

Factors predictive of renal involvement in patients with primary Sjögren's syndrome

AIM: To identify clinical and immunological risk factors underlying the development of renal involvement in primary Sj?gren's syndrome (pSS). SUBJECTS AND METHODS: Seventy-eight patients (75 females, 3 males) with pSS were carefully interviewed and clinical and laboratory data from the time of diagnosis recorded. The baseline data on patients shown to have either latent or overt distal renal tubular acidosis (dRTA), mild proteinuria or increased urinary excretion of alpha-1 microglobulin (alpha1m) after a mean disease duration of 9 +/- 4 years, were compared to the baseline data on those who did not have these manifestations at follow-up. RESULTS: Patients with subsequent latent or overt dRTA were found to have significantly higher baseline levels of serum total gamma-globulin (24 +/- 7 vs. 19 +/- 6 g/l, p = 0.011) and serum protein (84 +/- 7 vs. 79 +/- 7 g/l, p = 0.024) compared to those with normal renal acidification capacity. The baseline levels of serum beta-2 microglobulin (beta2m) were higher in patients with an acidification defect than in those with normal acidification capacity (3.1 +/- 1.1 vs. 2.6 +/- 0.8 mg/l, p = 0.072). In those with subsequent proteinuria the levels of serum beta2m were almost significantly higher at baseline as compared to those with normal urinary protein excretion (3.1 +/- 1.4 vs. 2.5 +/- 0.8 mg/l, p = 0.052). The subgroup of pSS patients who had increased urinary alpha1m excretion as a sign of tubular proteinuria, had higher baseline levels of ESR (55 +/- 27 mm/h vs. 40 +/- 23 mm/h, p = 0.076) and significantly higher baseline levels of serum beta2m (4.6 +/- 1 .8 vs. 2.6 +/- 0.8 mg/l, p = 0.029) as compared to those with normal urinary alpha1m excretion. CONCLUSIONS: High levels of serum total gamma-globulin, serum protein and serum beta2m were the best predictors of the development of dRTA in pSS patients. High baseline levels of serum beta2m were also associated with the subsequent occurrence of mild proteinuria and increased urinary alpha1m excretion in patients with pSS.     

Parathormone, calcitonin, and vitamin D metabolites during normal fracture healing in geriatric patients

In order to study the role of calcium-regulating hormones during callus formation in elderly patients, serum levels of parathormone (PTH), calcitonin (CT), 25-hydroxyvitamin D [25-OH-D], 1,25-dihydroxyvitamin D [1,25(OH)2D], 24,25-dihydroxyvitamin D [24,25(OH)2D], and calcium (Ca) were determined in 41 patients with fractures of long bones, primarily hip fractures. The parameters were measured on admission and after eight weeks. There were almost no changes in hormone serum levels during bone repair, except for a decrease in serum levels of 1,25(OH)2D from 25.3 +/- 2.3 pg/ml on admission to 21.0 +/- 2.0 pg/ml eight weeks later (p less than .001). Patients with fractures compared to normal elderly humans have lower serum levels of PTH (0.99 +/- 0.06 ng/ml versus 1.88 +/- 0.34 ng/ml; p less than .001), 25-OH-D (10.7 +/- 1.0 ng/ml versus 17.1 +/- 1.8 ng/ml; p less than .001), and Ca (9.1 +/- 0.1 mg% versus 9.7 +/- 0.1 mg%; p less than .001) and higher serum levels of 1,25(OH)2D (25.3 +/- 2.3 pg/ml versus 17.1 +/- 2.3 pg/ml; p less than .001). Female patients have lower serum levels of 24,25(OH)2D compared to males (1.65 +/- 0.15 ng/ml versus 2.06 +/- 0.29 ng/ml; p less than .05). A similar trend was noted in serum CT levels during callus formation (0.12 +/- 0.02 ng/ml versus 0.16 +/- 0.02 ng/ml; p less than .05). Patients with subcapital fractures of the femur have significantly lower serum levels of all vitamin D metabolites on admission, compared with patients suffering from extracapsular fractures.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pathogenesis of hypoglycemia in insulinoma patients: suppression of hepatic glucose production by insulin

To determine the mechanism by which hyperinsulinemia causes hypoglycemia in insulinoma patients, rates of glucose production and utilization, and circulating levels of insulin, glucagon, alanine, lactate, and glycerol were measured in 6 insulinoma patients during development of fasting hypoglycemia and in 8 normal volunteers studied over an identical interval. Initially, insulinoma patients had a greater plasma insulin (42 +/- 9 versus 15 +/- 1 microunits/ml) and glucagon levels (214 +/- 31 versus 158 +/- 21 pg/ml) than normal subjects, P less than 0.05, but their plasma glucose levels (81 +/- 4 mg/dl) and rates of glucose production and utilization (1.71 +/- 0.08 and 1.74 +/- 0.08 mg/kg . min, respectively) were not significantly different from those of normal subjects (93 +/- 2 mg/dl, 1.93 +/- 0.11, and 1.92 +/- 0.13 mg/kg . min, respectively). During a subsequent 8-h fast, glucose production and glucose utilization decreased in both groups, but more markedly in insulinoma patients. Since glucose utilization exceeded glucose production to a greater extent in insulinoma patients than in normal subjects, plasma glucose decreased to 44 +/- 3 mg/dl in insulinoma patients, but only to 84 +/- 1 mg/dl in normal subjects (P less than 0.001). Glucose utilization in insulinoma patients never exceeded that of normal subjects. These results demonstrate that fasting hypoglycemia in the insulinoma patients is usually due to suppression of glucose production rather than to acceleration of glucose utilization, as is widely thought. A direct effect of insulin on the liver is probably responsible, since circulating levels of gluconeogenic precursors are normal and since plasma glucagon increases during development of hypoglycemia in insulinoma patients.     

Renal excretion and cyst accumulation of beta 2microglobulin in polycystic kidney disease

To determine the extent to which proximal tubule function is altered beta 2microglobulin (beta 2m), creatinine and Na were measured in serum, urine and cyst fluid of patients with autosomal dominant polycystic kidney disease and various degrees of renal insufficiency. Fractional excretion (FE beta 2m) was 0.11 +/- 0.03% in six normal subjects and 0.13 +/- 0.05% in nine patients with serum creatinine levels less than 1.6 mg/dl. In five patients with serum creatinine levels above 3.0 mg/dl, FE beta 2m was elevated (range 3.5 to 196%) and serum levels were higher than normal (30,600 +/- 6,910 micrograms/liter vs. 1,268 +/- 111). In seven patients beta 2m levels in 33 proximal cysts (cyst/serum Na greater than 0.8) equalled those in serum (cyst/serum beta 2m 0.98 +/- 0.20), whereas in 21 distal cysts (cyst/serum Na less than 0.4) beta 2m was less than in serum (cyst/serum beta 2m 0.17 +/- 0.07). Analysis of fluid in two patients with polycystic kidney nephrectomy several weeks posttransplant indicated that proximal cyst epithelium is permeable to beta 2m, but less so than to creatinine or urea. These studies show that proximal cysts cannot develop or maintain gradients for beta 2m, whereas distal cysts maintain low levels of the protein despite end-stage renal failure. The normal FE beta 2m values in nonazotemic autosomal dominant polycystic kidney disease patients and the low distal cyst levels of beta 2m in end-stage kidneys indicate that the cystic proximal nephrons do not contribute appreciably to the final urine.(ABSTRACT TRUNCATED AT 250 WORDS)     

Glucose intolerance in the carcinoid syndrome.

We assayed glucose tolerance and insulin secretion in ten patients with metastatic carcinoid tumors and the carcinoid syndrome ("active tumors") and in seven patients with metastatic carcinoid tumors without the carcinoid syndrome ("inactive tumors"). The patients with "active tumors" had elevated serum serotonin levels while the patients with "inactive tumors" had normal serum serotonin levels. Of the ten patients with "active tumors," five had diabetic and three had borderline intravenous glucose disposal rate constants (KG = 0.88 +/- 0.07, M. +/- S.E.M.). Their KG was significantly lower (p less than 0.01) than a group of age-matched normals. All of the patients with "inactive tumors" had normal KG values (KG = 1.67 +/- 0.24). Their KG did not differ from that of age-matched normal subjects. Both groups of carcinoid patients had a comparable decrease in their insulinogenic index. Two days' administration of the serotonin antagonist cyproheptadine (Cypro) to eight of the patients with "active tumors" resulted in a significant increase in the "insulinogenic index" (50%) but a nonsignificant increase in the KG (12%). Administration of p-chlorophenylalanine, a compound that blocks serotonin synthesis, resulted in an increase in both the KG (60%) and the "insulinogenic index" (55%). The insulin half-life (t1/2) of patients with "active tumors" (6.1 +/- 0.4 min.) did not differ from the t1/2 of normal subjects (6.6 +/- 0.4 min.), suggesting that the decreased plasma insulin levels following intravenous glucose were due to impaired insulin secretion rather than accelerated insulin destruction. Seven of the patients received treatment with the antitumor agent streptozotocin (Strepto). The patients received cumulative doses of from 70 to 300 mg. of Strepto per kilogram body weight with no impairment in glucose tolerance or insulin secretion. We conclude that there is high incidence of glucose intolerance (80%) and impaired insulin secretion in patients with the carcinoid syndrome and that serotonin plays a role in producing these alterations.     

Elevated plasma fibronectin levels in rats with immune and toxic glomerular diseases

We measured plasma fibronectin levels by a rocket immunoelectrophoresis in rats with chronic serum sickness induced by repeated injections of ovalbumin and in rats with epithelial nephropathy induced by a single injection of adriamycin. In the early phases of the immune model, rats presented granular deposits of IgG in the mesangial area with no or descrete proteinuria (less than 40 mg/24 h). Fibronectin levels in that group were significantly higher (450 +/- 90 micrograms/mL) than in normal rats of the same age (350 +/- 46; p less than 0.01). When animals presented IgG deposits in the capillary wall, an important nephrotic syndrome developed in most of them. Fibronectin levels then increased very significantly (863 +/- 153 micrograms/mL; p less than 0.0005). In the model of adriamycin nephropathy, fibronectin significantly increased (580 +/- 110 micrograms/mL; p less than 0.0005) from the first week, when proteinuria was in a range 40-60 mg/24 h. However, the levels were higher (860 +/- 175 micrograms/mL; p less than 0.0005) when a complete nephrotic syndrome developed. At this time, plasma fibronectin levels correlated directly in both models with the degree of proteinuria and inversely with the total serum protein concentration. Our results show that plasma fibronectin levels increased very early in animals with immune and toxic damage of the kidney. The highest elevated values found thereafter, when a full nephrotic syndrome was present, suggest an increased synthetic rate of that glycoprotein linked to that situation.     

Determinants of rhabdomyolysis in the diabetic state.

To evaluate the determinants of rhabdomyolysis in the diabetic state, we compared biochemical and clinical features of diabetic patients with (group 1, 41 patients) and without (group 2, 36 patients) rhabdomyolysis. There was no difference in values for serum potassium, bicarbonate, phosphate and calcium between the two groups. Nineteen patients in group 2 and 21 patients in group 1 were hypokalemic. The mean serum sodium level was higher (p less than 0.001) in group 1 patients (148.8 +/- 2.1 mEq/l) than in group 2 patients (135.0 +/- 1.1 mEq/l). Only 1 patient was hypernatremic in group 2, whereas 24 patients had hypernatremia in group 1. Linear regression of the creatine phosphokinase values versus serum sodium levels suggested a high correlation (p less than 0.001). The mean blood glucose level was higher (p less than 0.05) in group 1 patients (640.8 +/- 80.3 mg/dl) when compared to group 2 patients (436.0 +/- 56.7 mg/dl). There was a linear association (p less than 0.05) between the levels of blood glucose and creatine phosphokinase values in the patients with rhabdomyolysis. The mean serum osmolality was 350.3 +/- 8.2 mosm/kg in group 1 patients as compared to 304.9 +/- 3.6 mosm/kg in group 2 patients (p less than 0.001). There was also a significant correlation (p less than 0.001) between the serum osmolality levels and the serum creatine phosphokinase values in group 1 patients. We conclude that serum sodium, serum osmolality and blood glucose are major determinants for the occurrence of rhabdomyolysis in the diabetic state.     

Contrasting response to cyclosporin in refractory nephrotic syndrome

We studied the effects of cyclosporin A (CsA), given for three months, in 14 patients with nephrotic syndrome refractory to treatment with prednisone and/or other immunosuppressants. CsA was given in a starting dose of 6 mg/kg and plasma through levels (RIA) were kept between 50 and 150 ng/ml. Diagnosis included: idiopathic membranous glomerulonephritis (n = 6), focal segmental glomerulosclerosis (n = 3), minimal change disease (n = 3) and membranoproliferative glomerulonephritis (n = 2). Three patients with non-immunologically mediated nephrotic syndrome due to Alport's syndrome were studied as well. Considering all patients and diagnostic groups together, proteinuria decreased from 9.0 +/- 4.3 to 4.7 +/- 3.8 g/24 h during CsA treatment (mean +/- SD; p less than 0.01). However, serum creatinine increased from 121.8 +/- 60.5 to 150.4 +/- 64.6 mol/l (p less than 0.01) and glomerular filtration rate as estimated by 24-hour creatinine clearance fell from 85.5 +/- 33.7 to 72.1 +/- 37.2 ml/min (p less than 0.05). When compared to other diagnostic groups, fractional excretion of protein, i.e. protein excretion corrected for changes in glomerular filtration rate, fell only in IMGN (ANOVA, p less than 0.05). We conclude that CsA reduced proteinuria in patients with refractory nephrotic syndrome. In the majority of these patients this reduction could be due to a renal hemodynamic, rather than an immunomodulatory effect of the drug. Only in IMGN the latter action of the drug may be of importance.     

Vitamin D metabolism and serum binding proteins in anorexia nervosa

Serum vitamin D metabolites and other parameters of mineral metabolism were measured in 12 patients with anorexia nervosa. Serum concentrations of calcium, phosphate, albumin, alkaline phosphatase, parathyroid hormone, calcitonin, osteocalcin, and 24-hours calcium excretion were normal. Serum 25-hydroxyvitamin D (25OHD) concentration was similar in patients and normal subjects, whereas 1,25-dihydroxyvitamin D (1,25(OH)2D) levels were significantly reduced in patients (62 +/- 17 vs 82 +/- 17 pmol/l); p less than 0.05). The concentration of vitamin D-binding protein (DBP) in patients was normal, but serum binding capacity (Nmax) was diminished in anorectic patients (2.05 +/- 0.50 vs 2.53 +/- 0.51 mumol/l; p less than 0.05). The diminished serum binding capacity, in spite of normal concentrations of albumin and DBP, reflects the presence of qualitative rather than quantitative defects in serum transport proteins. Since the reduction in 1,25(OH)2D and serum binding capacity was quantitatively similar, it is likely that free 1,25(OH)2D levels would be normal.     

Low urinary calcium excretion in Bartter's syndrome

The urinary calcium excretion has been determined in 19 patients with Bartter's syndrome and found to be significantly lower than the calcium excretion in 92 healthy subjects (1.16 +/- 0.82 vs. 4.36 +/- 2.71 mmol/24 h, p less than 0.001). There were no differences in height, weight, glomerular filtration rate, urinary sodium excretion or serum calcium concentration between the patients and the control subjects to account for the disparity in calcium excretion. In the patients, the concentrations for ionized calcium, PTH, 25-OH vitamin D and 1,25-(OH)2 vitamin D were normal. A low urinary calcium excretion appears to be a characteristic feature of Bartter's syndrome. The cause remains unexplained.