Treatment of severe psychosis due to ectopic Cushing's syndrome.

Severe psychosis in patients with Cushing's syndrome is rare and generally difficult to treat. We report a 46-yr-old woman suffering from Cushing's syndrome caused by an inoperable ACTH-producing lung carcinoma. She was initially treated with chemotherapy and radiotherapy. Six months later she presented with severe psychosis. Laboratory findings revealed a severe hypokalemia and metabolic alkalosis, which was caused by extremely high serum ACTH (788 ng/l) and cortisol (4.2 micromol/l). She was unresponsive to treatment with conventional antipsychotic drugs; she was therefore sedated and intubated. Treatment was started i.v. with etomidate, which blocks the cortisol synthesis, and orally by nasogastric tube with mifepristone, which competes with cortisol for binding to their receptors. To counteract adrenal insufficiency, she received corticosteroids. After 5 days there was a normalization of the ACTH, cortisol levels, and the metabolic disorders. After discontinuing etomidate she was extubated; there were no signs of psychosis observed. Computed tomography (CT) scan of the brain showed no metastasis, however CT scan of the abdomen showed liver metastasis and bilateral adrenal enlargement. Unfortunately, the clinical situation worsened and the patient died due to progression of the metastasis. This case report demonstrates the efficacy of a treatment of mifepristone with etomidate in a patient with an ectopic ACTH-producing Cushing's syndrome.

[Timing of administration of sulfonyl urea derivatives]. / Het juiste innametijdstip van sulfonylureumderivaten.

In daily practice the optimal time of administration of sulphonylurea derivatives is not always clear. Administration 30 minutes prior to meals allegedly offers the advantage that an active plasma level has been reached when food enters the gastrointestinal tract. Alleged disadvantages are higher risk of hypoglycaemia and poor compliance. In publications from Medline 1966-1999 the 24-hour availability of sulphonylurea derivates was the same after administration at different times. The absorption rate of glibenclamide and tolbutamide was not affected by food. Study results concerning gliclazide were contradictory. The absorption rate of glipizide was reduced after ingestion during breakfast. In several, partly the same, small studies the findings concerning the variation of the glucose level in time in patients with type 2 diabetes mellitus were equivocal. The pharmacokinetic and pharmacodynamic evidence that sulphonylurea derivatives should be taken 30 minutes before meals appears to be so limited that in our opinion it is out-weighed by the potential risk that this advice may compromise the drug compliance of users.

Ambulatory blood pressures and autonomic nervous function in normoalbuminuric type I diabetic patients.

BACKGROUND: In insulin-dependent diabetes mellitus (IDDM) patients with normal urinary albumin excretion (UAE) controversy exists about the presence of blood pressure (BP) elevation and an attenuation of BP decline during sleep. SUBJECTS AND METHODS: These issues were studied in 60 IDDM patients and 55 healthy control subjects with 24 h ambulatory blood pressure monitoring. In addition, in the IDDM patients two cardiovascular reflex tests were performed to study autonomic nervous function. RESULTS: 55 IDDM patients had 4.4/3.1 mm Hg higher 24 h systolic/diastolic pressures when compared with 55 healthy matched controls (P = 0.005/0.009). The diastolic BP decline during sleep was significantly attenuated in IDDM patients compared to healthy volunteers (18.9 vs 22.2%, P = 0.01). The maximum/minimum (max/min) ratio of the RR' interval of the lying to standing test (lower values indicating (incipient) parasympathetic dysfunction) was positively related to the decline of the diastolic BP during sleep in the diabetic patients. This relationship did not persist after adjusting for decline of heart rate during sleep. CONCLUSIONS: IDDM patients with normal UAE, compared with healthy control subjects, have higher BPs during both the waking and sleeping periods and a decreased diastolic BP decline during sleep. In these patients both the diastolic BP decline and the heart rate decline during sleep were related to the max/min ratio. These findings are consistent with the hypothesis that attenuation of diastolic BP decline during sleep is at least partly due to (incipient) damage to the parasympathetic nervous system, which, through a blunted heart rate decline, leads to a decreased decline of cardiac output during sleep.

Endothelial dysfunction precedes development of microalbuminuria in IDDM.

In patients with insulin-dependent diabetes mellitus (IDDM), microalbuminuria is a predictor of widespread severe microangiopathy and macroangiopathy. Patients with microalbuminuria show generalized dysfunction of the vascular endothelium, but it is unknown whether endothelial dysfunction precedes the development of microalbuminuria. We examined a cohort of 17 IDDM patients at baseline and on three occasions during a follow-up of (median) 64 months (range 51-89). All had normal (< 15 micrograms/min) urinary albumin excretion (UAE) at the first three examinations. At the fourth examination, 11 patients had normal UAE and 6 had microalbuminuria (median 25.7 micrograms/min [range 15.3-42.8]). Compared with patients with normal UAE, microalbuminuric patients had significantly higher plasma levels of von Willebrand factor (vWF), a marker of endothelial dysfunction, at the second (200% [168-274] vs. 131% [69-186]), third (208% [188-270] vs. 125% [82-190]), and fourth examinations (231% [202-269] vs. 132% [88-208], P < 0.0001), but not at baseline (128% [98-161] vs. 122% [87-210]). An increase in vWF preceded the occurrence of microalbuminuria by approximately 3 years. The groups did not differ with regard to age, diabetes duration, blood pressure, mean glycated hemoglobin and cholesterol, smoking habits, or extent of retinopathy. Endothelial dysfunction, as estimated by plasma vWF concentration, precedes and may predict the development of microalbuminuria in IDDM.

Telepathology: frozen section diagnosis at a distance.

Telepathology may be used to provide a frozen section service to hospitals without a department or institute of pathology. We have developed a telepathology system using the commercially available Integrated Services Digital Network (ISDN). The main software and hardware elements of our system are: Apple Macintosh workstations, a program for simultaneous transfer of image, voice and data, and a data bank for storage of patients' data and microscopic images. A picture instrument manager (PIM) makes remote control of microscopes or other instruments possible. The system connects the Department of Pathology of the University of Basel with the Regional Hospital of Samedan, 250 km away, and the Regional Hospital of Burgdorf, 100 km away. During a period of 20 months, frozen sections with the hospitals in Samedan and Burgdorf were performed in 53 patients. Between 54 and 58 s were required for the transfer of a diagnostic 8-bit grey level image containing 341 +/- 26.1 (standard error) kbytes (n = 13) or a diagnostic 24-bit colour image containing 165 +/- 16.9 kbytes (n = 40). Frozen section diagnosis was completed in 20-40 min. True-positive diagnoses of malignant tumours were achieved in 85.7% of cases (sensitivity = 0.857). No false-positive diagnosis was made. In 3 of the 53 cases telepathological diagnosis was not possible for technical reasons.

Telepathology with an integrated services digital network--a new tool for image transfer in surgical pathology: a preliminary report.

We describe a low-cost telepathology system working via a commercial integrated services digital network (ISDN) and consisting of modular software and hardware elements. The main elements are Apple Macintosh workstations; a software program for the simultaneous transfer of pictures, voice, and data; and procedures for image processing and general administration of all the information generated. Additionally, the system allows remote control of any peripheral instruments by a "picture-instrument manager." The transfer rate is currently 64 kbit/s; it will be extended to 128 kbit/s (ISDN basic rate) in the near future and to 2 Mbit/s (ISDN primary rate) in the next 2 years. The system was tested by the regional hospital in Samedan, Switzerland, and the Department of Pathology, University of Basel, Basel, Switzerland, a distance of 250 km, by offering a remote frozen section service to the regional hospital in 16 cases. Fifty-four to 58 seconds were needed for the transfer of a diagnostic 8-bit grey-level image containing 341 (median value) +/- 26.1 (standard error) kbytes (n = 13) or a diagnostic 24-bit color image containing 165 (median value) +/- 16.9 (standard error) kbytes (n = 3). The time required for a diagnostic session was between 25 and 35 minutes.

Diurnal variation in urinary protein excretion in diabetic nephropathy.

We examined the diurnal variation in urinary excretion rate of albumin, IgG and beta 2-Microglobulin (beta 2-M) in healthy volunteers (n = 24), and in patients with type I diabetes mellitus having normal albumin excretion rate (less than 20 micrograms/min; n = 16), incipient diabetic nephropathy (albumin excretion rate 20-200 micrograms/min; n = 12) and clinical diabetic nephropathy (albumin excretion rate greater than 200 micrograms/min; n = 12). Diurnal variation was defined as [(overnight minus daytime): daytime excretion rate] times 100%. Median diurnal variation in albumin excretion rate in the various groups varied from -32 to -57%, and in IgG excretion rate from -42 to -65%, being not significantly different between the proteins or between the groups. Diurnal variation in beta 2-M excretion rate was similar in healthy volunteers and in patients with normal albumin excretion rate or incipient diabetic nephropathy (median -36 to -43%), but significantly reduced in patients with clinical diabetic nephropathy (median 0%; P less than 0.005), nine of whom had elevated beta 2-M excretion rates, suggesting tubular dysfunction. Except for beta 2-M excretion rate in patients with clinical diabetic nephropathy, the diurnal variations in albumin excretion rate, IgG excretion rate and beta 2-M excretion rate were larger than the diurnal variation in creatinine excretion rate (median -7 to -11%, P less than 0.005). Diurnal variations in albumin excretion rate and IgG excretion rate were highly correlated (r = 0.89, P less than 0.00001). These data suggest that similar mechanisms may account for diurnal variations in albumin excretion rate and IgG excretion rate.(ABSTRACT TRUNCATED AT 250 WORDS)

[A patient with hypersensitive carotid sinus syndrome]. / Een patiënt met het hypersensitieve-sinus caroticus-syndroom.

We describe a patient with carotid sinus hypersensitivity that is cardiodepressive as well as vasodepressive. He was treated with AV-sequential pacing after which his complaints were reduced considerably. The various forms of carotid sinus hypersensitivity and their therapeutic consequences are discussed.

The usefulness of an oral calcium tolerance test in the choice of management of patients with idiopathic hypercalciuria.

We studied 40 patients with calcium urolithiasis and idiopathic hypercalciuria in an attempt to identify patients with an absorptive or renal type of hypercalciuria. An oral calcium tolerance test was performed in all patients, resulting in a rise in serum calcium in all cases (2.35 +/- 0.09 mmol/l vs 2.49 +/- 0.09 mmol/l; P less than 0.001). This was also true for serum phosphate (0.96 +/- 0.17 mmol/l vs 1.09 +/- 0.18 mmol/l; P less than 0.001), TmPO4/GFR (0.95 +/- 0.19 mmol/l vs 1.20 +/- 0.25 mmol/l; P less than 0.001) and fasting calcium excretion (3.14 +/- 1.16 mmol/100 l GF vs 6.17 +/- 2.02 mmol/100 l GF; P less than 0.001). All patients showed a drop in nephrogenous cAMP excretion (1.33 +/- 0.95 nmol/dl GF vs 0.74 +/- 0.72 nmol/dl GF; P less than 0.001). iPTH levels declined significantly (2.70 +/- 1.50 pmol/l vs 2.11 +/- 1.19 pmol/l; P less than 0.001). However, discordant individual changes in suppression of nephrogenous cAMP excretion, and rises in fasting calcium excretion prohibited a distinction between the absorptive or renal type of hypercalciuria. It is concluded that an oral calcium tolerance test is not helpful in the choice of management of patients with idiopathic hypercalciuria.

Identifying patients with incipient diabetic nephropathy. Should 24-hour urine collections be used?

It is not clear whether 24-hour or overnight urine collections should be used to identify patients with incipient diabetic nephropathy (defined as persistent urinary albumin excretion rate [AER] of 20 to 200 micrograms/min). We therefore studied diurnal variations in AER in type I diabetics with normal AER (n = 16) and incipient (n = 12) and clinical (defined as persistent AER greater than 200 micrograms/min) nephropathy (n = 12), and in healthy controls (n = 24). In all groups AER was lowest at night. In some patients of all groups, marked diurnal variations were observed. Twenty-four-hour urine collections classified all patients correctly. Overnight urine collections, however, misclassified patients with incipient nephropathy as having normal AER in 4 of 12, 7 of 12, or 3 of 7 cases, depending on which cutoff level was used. We conclude that 24-hour urine collections are more sensitive than overnight samples in identifying patients with incipient diabetic nephropathy.

Malignant insulinoma: is combined treatment with verapamil and the long-acting somatostatin analogue octreotide (SMS 201-995) more effective than single therapy with either drug?

The efficacy of treatment with either verapamil (V), the long-acting somatostatin analogue octreotide (OCT) alone, and the combined treatment (V + OCT) were studied in a patient with a symptomatic metastasized malignant insulinoma. Treatment with V alone resulted in a slight increase in blood glucose levels. Treatment with OCT alone resulted in a clear increase in blood glucose levels. Treatment with V + OCT was slightly more effective than single therapy with either drug but could not prevent hypoglycaemic episodes completely. It is also shown that the effect of treatment with V and OCT alone on glucoregulatory hormones is completely different. While treatment with V did not inhibit insulin secretion, treatment with OCT clearly did. Treatment with OCT might also modify counterregulatory hormone secretion during hypoglycaemia.

Aggravation of hypoglycemia in insulinoma patients by the long-acting somatostatin analogue octreotide (Sandostatin).

Recently somatostatin analogues were successfully used to control insulin-induced hypoglycemia in patients with insulinoma. We observed a transient decrease in glucose levels and symptomatic hypoglycemia after administration of the long-acting somatostatin-analogue octreotide (Sandostatin) in two insulinoma patients. We studied the acute effects of octreotide (administered before breakfast) on blood glucose and gluco-regulatory hormones in these patients. In one patient, we studied the effects of glucagon replacement and changing the time of breakfast (relative to octreotide administration) on octreotide-associated changes in blood glucose and glucoregulatory hormones. Compared with control levels, octreotide therapy reduced insulin levels. During hypoglycemia glucagon and growth hormone levels were suppressed, but cortisol levels appropriately increased. The increase in catecholamine levels was normal in one patient, but markedly attenuated in the other. A transient decrease in serum glucose after octreotide was absent after glucagon replacement, but present when breakfast was taken before administration of octreotide. We conclude that in patients with insulinoma, octreotide therapy may be associated with clinically important hypoglycemia, during which counterregulatory hormone secretion may be attenuated.

Does thyroid function influence serum beta 2-microglobulin?

In 24 patients with hyperthyroidism (15 with Graves' disease and 9 with toxic nodular goitre), serum beta 2-microglobulin (beta 2-m) levels were measured prior to and during 6 wk of treatment with carbimazole. The same schedule was followed in 7 patients with hypothyroidism, but their treatment consisted of levothyroxin in increasing doses. In 16 of the patients with hyperthyroidism, beta 2-m was initially found to be increased. In all these patients an increased beta 2-m declined to normal or near-normal levels. The patients with hypothyroidism had a normal medium serum beta 2-m. During substitution there was a tendency for the serum beta 2-m to decline. Indirect arguments are stated for the hypothesis that both in Graves' disease and in toxic nodular goitre activated T-lymphocytes are modulated in their function by carbimazole acting as an immunosuppressing agent. Moreover, we conclude that thyroid hormone levels are not directly responsible for the increased serum beta 2-m concentrations in hyperthyroidism.

The effect of age on the renal response to PTH infusion.

The renal responses to PTH infusion were compared in two age groups of healthy subjects. Basal nephrogenous cyclic AMP (NcAMP) was higher (1.68 +/- 0.74 vs. 0.97 +/- 0.50 nmol/dl GF; P less than 0.05) and TmPO4/GFR was lower (0.93 +/- 0.21 vs. 1.16 +/- 0.14 mmol/liter; P less than 0.025) in 10 elderly subjects compared with 12 young adults. Creatinine clearance was decreased in the elderly (84.8 +/- 25.7 vs. 144.7 +/- 43.2 ml/min; P less than 0.005) and serum iPTH tended to be increased (0.15 +/- 0.11 vs. 0.11 +/- 0.03 pmol/liter). Following the infusion of 3 IU bPTH/kg bodyweight, no significant differences in delta NcAMP and delta TmPO4/GFR were seen between the groups. When responses were expressed as percentual change of basal level, elderly subjects showed a % NcAMP of 1831 +/- 1200 which was comparable with 2038 +/- 1503% in young adults. However, the percentual change in TmPO4/GFR was significantly higher in elderly persons (24.2 +/- 11.9 vs. 11.9 +/- 8.0%; P less than 0.01). In young subjects, virtually absent TmPO4/GFR responses were found in 3 cases with a relatively low basal TmPO4/GFR (between 0.92 and 0.98 mmol/liter), but these cases showed normal increases in NcAMP. Elderly subjects retained a considerable delta TmPO4/GFR notwithstanding a basal TmPO4/GFR below 0.92 in seven out of 10 cases. These results confirm the existence of a slight increase in parathyroid activity in the elderly. In addition, they suggest an augmented sensitivity of the renal tubule concerning PO4 reabsorption in elderly subjects. It is speculated that this phenomenon is related to the fall in bone mineral retention in senescence and might reflect a defense mechanism against phosphate overload.

Metabolism of phosphate and sulfate groups modifying the P0 protein of peripheral nervous system myelin.

We have examined the metabolism of phosphate and sulfate groups modifying the P0 protein, the major protein of peripheral nervous system myelin, using an in vitro incubation system. Incorporation of [3H]leucine into the P0 peptide backbone decreased approximately 25-fold between 10 and 90 days of age, a finding reflecting a decreased rate of myelin synthesis in the older animals. In contrast, incorporation of [32P]phosphate into P0 decreased only four- to fivefold, a result indicating that phosphate groups are metabolized independently of the peptide backbone. Developmental decreases in the incorporation of sulfate groups into P0 were similar to those seen for leucine, an observation suggesting that this modifying group is metabolized together with the peptide backbone as a single metabolic entity. The time course of labeling of P0 isolated from the starting homogenate and from myelin was also compared. Results are consistent with sulfation of P0 protein taking place before insertion of newly synthesized P0 into myelin. In contrast, incorporation of phosphate into P0 appears to involve both the newly synthesized pool and the preexisting pool of P0 in myelin. Presumably, entry of phosphate into P0 in myelin involves turnover of preexisting phosphate groups and rephosphorylation by myelin protein kinases. Developmental decreases in the specific activity of P0 phosphate groups in myelin are consistent with the presence of a small, rapidly turning-over pool of phosphorylated P0 (perhaps associated with the axon-myelin interface), which does not increase to the same extent as the marked increase in bulk myelin that occurs during development.

End-organ resistance to PTH infusion in hypercalcaemic and normocalcaemic patients with solid tumours.

Ten hypercalcaemic patients with solid tumours were studied to evaluate the renal response on PTH infusion as assessed by nephrogenous cAMP excretion and maximum tubular re-absorption of phosphate. In addition, 20 normocalcaemic patients, 11 with an adenocarcinoma and 9 with a squamous cell carcinoma, were studied. All cancer patients had moderately extensive disease. Results were compared with those of 9 patients with primary hyperparathyroidism and with 10 elderly controls. All groups studied had comparable renal function, magnesium and 25-hydroxy-vitamin D levels. Comparable results were obtained in patients with an adenocarcinoma and in controls. cAMP response (delta nephrogenous cAMP) was significantly lower in the hypercalcaemic patients with a solid tumour compared with the controls (8.13 +/- 4.68 nmol/100 ml glomerular filtrate vs 29.52 +/- 25.62 nmol/100 ml glomerular filtrate; P less than 0.005). In the group of patients with primary hyperparathyroidism delta nephrogenous cAMP was 13.41 +/- 7.54 nmol/100 ml glomerular filtrate (P less than 0.06 vs controls). The group of patients with a squamous cell cancer showed an intermediate value of 14.83 +/- 10.74 nmol/100 ml glomerular filtrate (P less than 0.025 vs the normocalcaemic adenocarcinoma patients, but NS vs controls). In two hypercalcaemic patients with a solid tumour in whom PTH infusion was repeated after normalization of serum calcium no influence on renal responsiveness was observed. Responses of maximum tubular re-absorption of phosphate were lowest in the group of hypercalcaemic patients with a solid tumour and in the patients with primary hyperparathyroidism compared with controls (0.11 +/- 0.10 vs 0.22 +/- 0.09 mmol/l and 0.09 +/- vs 0.22 +/- 0.09 mmol/l; P less than 0.025 and P less than 0.005, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

The renal sensitivity for endogenous parathormone in patients with primary hyperparathyroidism, vitamin D deficiency and renal stones.

Baseline levels and increases in urinary cyclic AMP excretion (UcAMP) and immunoreactive parathormone (iPTH) were studied before and during infusion of EDTA in euparathyroid patients with renal stones (n=11), patients with primary hyperparathyroidism (PHP; n=14) and patients with vitamin D deficiency (n = 12). In all three groups, EDTA evoked a significant rise in iPTH and UcAMP. In patients with PHP and in those with vitamin D deficiency, there was a sufficiently close relationship between increments in iPTH (delta iPTH) and in UcAMP (delta UcAMP) (r = 0.90, P less than 0.001 and r = 0.67, P less than 0.02, respectively) to use this model to assess renal sensitivity for changes to endogenous PTH levels. We quantified sensitivity of the kidney for PTH, by calculating the ratio delta UcAMP/delta TPTH for the three studied groups. The ratio was comparable in patients with renal stones (16.7 +/- 10.3) and PHP (13.8 +/- 4.9, P greater than 0.10), but was significantly increased in patients with vitamin D deficiency (33.2 +/- 17.9; P less than 0.01 versus patients with renal stones and P less than 0.01 versus patients with PHP). Within the group of patients with PHP there was no correlation between baseline serum calcium concentrations and the ratio delta UcAMP/delta TPTH. It is concluded that in patients with vitamin D deficiency, renal sensitivity to PTH is increased compared with patients with PHP and euparathyroid patients with renal stones, perhaps an expression of a teleological useful adaptation of end organ sensitivity.