Cushing's syndrome due to ectopic ACTH production by (neuroendocrine) prostate carcinoma.

Ectopic adrenocorticotropin (ACTH) secretion accounts for less than 10% of all causes of endogenous Cushing's syndrome (CS) and is usually associated with neuroendocrine tumors and small cell carcinoma of the lung. We report the case of a 62-year-old man with CS due to ectopic ACTH production by small cell carcinoma of the prostate. He presented with severe hypercortisolism and associated symptoms. Plasma neuron specific enolase (NSE) was grossly elevated. Despite performing a laparoscopic bilateral adrenalectomy, the patient died as a result of sepsis with multi-organ failure. Post-mortem immunohistochemical staining of prostate tumor tissue showed ACTH expression. ACTH staining was also performed in four additional patients with small cell carcinoma of the urinary tract without CS. None of these additional cases showed a positive staining for ACTH. Although a rare cause of ectopic ACTH production, neuroendocrine prostate carcinoma should be considered in male patients with Cushing's syndrome, in particular in those with an occult source of ACTH overproduction.

Paraganglioma of the urinary bladder.

Since paragangliomas of the urinary bladder are rare and not easily recognised, histological examination is often the only leading key to diagnosis. We report on a patient with a paraganglioma of the urinary bladder. Although the patient presented with classical signs and symptoms, these were only appreciated after histological examination of a transurethral resection specimen had elucidated the correct diagnosis.

The effect of corticotrophin on liver-type lipase activity in adrenals, liver and high-density lipoprotein subfractions in the rat.

Hypercortisolism was induced in rats by the administration of a corticotrophin analogue (Synacthen depot). The effect of this treatment during different periods was studied in normally fed and overnight-fasted rats. The activity of liver-type lipases, i.e., of lipases similar to the heparin-releasable lipase of rat liver (liver lipase), was determined in the adrenal gland and in the liver. Short-term (16 h) treatment had no effect on the lipase activity in the adrenal gland. During prolonged treatment, however, the lipase activity rose to 600-700% of control values in 10 days and from then on remained constant. The effect was similar in fed and overnight-fasted rats. The lipase activity in the liver decreased upon Synacthen administration. In the fed rats a decrease of 25% of the initial value was found after 16 h, 40% after 3 days and 50% after 20 days of treatment. In overnight-fasted rats the lowering of the lipase activity was less marked than in fasted controls. Serum lipid levels and high-density lipoprotein (HDL) subclass concentrations were also measured. The cholesterol concentration in the lipoproteins with a density greater than 1.050 g/ml (HDL) was elevated in rats treated for 3-20 days. If the rats were treated for longer than 10 days, overnight fasting led to a normalization of the HDL-cholesterol levels. After separation of the HDL into two subfractions, a relatively 'light' apolipoprotein E-rich fraction and a more 'heavy' apolipoprotein A-I-rich fraction, in fed and fasted animals treated with Synacthen for 3 days both HDL subfractions were elevated. After 10 days treatment only the apolipoprotein A-I-rich HDL fraction was still enhanced in both fed and fasted rats.

Circulating and liver-bound salt-resistant hepatic lipases in the golden hamster.

The serum of male golden hamsters was found to contain a circulating triacylglycerol hydrolase activity (serum lipase). In vitro, the enzyme activity was slightly activated by 1 M NaCl (+20%) and inhibited by rat serum (-29%). The hamster liver contained an enzyme with similar characteristics (liver lipase). This enzyme was released into the circulation after intravenous administration of heparin. Both lipase activities were further characterized and compared. The serum lipase had a pH optimum of 9, which was higher than that of the liver enzyme (pH 8.0). The serum enzyme did not bind to Sepharose-heparin columns in contrast to the liver lipase, which could be eluted from the column with 0.75 M NaCl. A polyclonal antibody preparation raised against the heparin-releasable salt-resistant lipase from rat liver inhibited both the hamster serum enzyme and the liver enzyme completely. The affinity of the antibodies towards the hamster enzymes was lower than the affinity towards the rat liver enzyme, but similar with that towards the hamster enzymes in the serum and the liver. A panel of five monoclonal antibodies raised against the rat enzyme did not bind either of the hamster enzymes. If the hamsters were fed a normal lab chow, the lipase activity in the serum amounted up to 110 +/- 20 mU (mean +/- S.D., n = 16) per ml serum (about 600 mU per animal), the liver contained 200 +/- 41 mU per g tissue (total about 800 mU per animal). In animals fed a cholesterol-enriched diet, the serum activity increased by 82% and the liver activity by 27%.

Value of estrogenic recruitment before chemotherapy: first randomized trial in primary breast cancer.

PURPOSE: Several preclinical studies showed that short-term pretreatment of breast cancer cells with estrogens can increase the antitumor efficacy of different cytotoxic drugs. Some early clinical studies in patients with advanced breast cancer did seem to support these findings. Therefore, the efficacy of estrogenic recruitment followed by chemotherapy was compared with that of chemotherapy alone in a randomized phase III study in women with lymph node-positive primary breast cancer. PATIENTS AND METHODS: Three hundred twenty-eight patients with stage II/IIIA breast cancer who were younger than 66 years of age were randomly allocated to chemotherapy with fluorouracil, doxorubicin, and cyclophosphamide (FAC) or FAC plus pretreatment with ethinyl estradiol (EE(2)). FAC (500, 50, and 500 mg/m(2), respectively) was administered intravenously once every 4 weeks for four cycles. EE(2) (0.5 mg) was administered orally, both 24 hours and immediately preceding FAC chemotherapy. RESULTS: Patient and tumor characteristics and chemotherapy dosages were comparable in both treatment groups. Of 318 assessable patients, with a median follow-up of 6.8 years, 177 patients had a relapse and 127 died. No significant differences were observed between the two treatment groups with respect to relapse-free, local recurrence-free, and overall survival according to univariate and multivariate analyses adjusted for age, menopausal status, tumor size, grade, number of positive nodes, and steroid-receptor status. The power for the detection of an increase of 50% in the median relapse-free survival was 80%. CONCLUSION: Estrogenic recruitment of breast cancer cells before FAC chemotherapy did not influence the efficacy of adjuvant chemotherapy in stage II/IIIA breast cancer patients after a follow-up of 6.8 years.

Disparate effects of ACTH (1-24) and corticosterone on lipoprotein lipase in rat adipose tissue.

The effects of corticosterone and ACTH(1-24) on lipoprotein lipase (LPL) activity of rat epididymal fat tissue were studied. Hypercorticism induced by s.c. administration of 10 mg corticosterone acetate for 3 days led to a decrease in LPL activity. This decrease could be prevented by treatment of the rats simultaneously with synthetic ACTH(1-24). Adrenalectomy also reduced LPL activity. Corticosterone and ACTH(1-24) treatment had a similar effect on LPL activity in adrenalectomized and intact rats. These results indicate that ACTH(1-24) may affect adipose tissue LPL in the rat by a mechanism in which corticosterone is not involved.

Clinical experience with simvastatin compared with cholestyramine.

Simvastatin (MK733), derived from lovastatin by substituting CH3 for H at the 2' position, is a potent hydroxymethylglutaryl coenzyme A (HMG CoA) reductase inhibitor. Its cholesterol-lowering effect in 40 patients with heterozygous familial hypercholesterolaemia was more pronounced (an LDL-cholesterol reduction of 43%) than that of cholestyramine monotherapy in a matched group of 20 patients (30% reduction). The combination of the 2 drugs for 50 patients who tolerated cholestyramine was even more effective (a 54% reduction of LDL-cholesterol). The other changes were as follows: total cholesterol (simvastatin [S] -36%, cholestyramine [C] -23%, both drugs in combination [S + C] -45%); HDL-cholesterol (S +16%, C +9%, S + C +20%); triglyceride (S -21%, C +11%, S + C -17%); and the apolipoprotein B/apolipoprotein A ratio (S -51%, C -39%, S + C -67%). Cholestyramine caused more gastrointestinal adverse effects (12 of 20 patients), whereas a transaminase increase was seen both with cholestyramine (2 of 20 patients) and simvastatin (3 of 40 patients) and with the combination (6 of 50 patients). Treatment with simvastatin decreases the atherogenic potential of plasma more than cholestyramine monotherapy and causes fewer adverse effects. For those patients who tolerate cholestyramine, the combination of the drugs is even more potent.

The effect of Synacthen administration on lipoprotein lipase activity in the epididymal fat pad of the rat.

Conflicting data have been reported on the influence of (excess) glucocorticoids on lipoprotein lipase (LPL) activity in adipose tissue. To solve this problem hypercorticism was induced in rats by treatment for varying periods with Synacthen, a synthetic corticotrophin-1-24 preparation, and LPL was measured in the epididymal fat pads using different methods. In extracts of defatted tissue preparations from overnight fasted rats treated for 3 days with Synacthen we observed an increase in LPL activity (acetone-ether powder LPL) to values similar to those found in normally fed controls. In contrast, the heparin-elutable part of LPL activity in the tissue was not influenced by the Synacthen treatment. This activity remained significantly lower in overnight fasted animals, Synacthen treated or not, than in normally fed rats. Adrenalectomy lowered the acetone-ether powder LPL activity of the epididymal adipose tissue in fasted as well as in fed rats. In fasted rats it prevented the stimulation of the LPL activity by Synacthen.

Effects of synacthen on lipid metabolism in the perfused epididymal fat pad of the rat.

Rats were treated with Synacthen, a synthetic corticotrophin analogue, to induce hypercorticism. The epididymal fat pad was selectively cannulated and perfused. In fasted rats acetone ether powder lipoprotein lipase (LPL) activity rose during treatment to levels found in fed controls. In fed animals no further rise in LPL activity was observed during Synacthen treatment. However, the heparin-elutable LPL activity did not change during this treatment in fasted nor fed animals. Pharmacologic levels of insulin in the perfusion medium caused an increase in heparin-releasable LPL activity as a percentage of total fat pad LPL activity (15% v 48%). Hydrolysis of chylomicrons was higher in fasted three days treated animals then in controls (10 +/- 4% v 2 +/- 2%). In this group a higher uptake of liberated free fatty acids was found (2.6 +/- 1.5% v 1.0 +/- 0.5% in controls). The increase in hydrolysis rate and uptake of fatty acids in the treated fasted animals could not be explained by an increase in releasable LPL activity. Fatty acid release from the fat pad was lower in treated animals than in controls (fasted and fed), basally as well as after adrenalin stimulation. The observation that the epididymal fat pad retains its weight during hypercorticism may therefore be ascribed to an increased influx of fatty acids from increased hydrolysis of TG-rich particles and to an inhibited efflux of fatty acids from the adipocyte. The discrepancy between the LPL activity extractable from an acetone ether powder and the heparin releasable LPL activity suggests impairment of the transport of LPL from the adipocyte to the heparin releasable pool at the endothelium.

Inhibition of hepatic cholesterol synthesis by the alpha 1-adrenoceptor blocker doxazosin in the hypercholesterolemic golden hamster.

The effect of treatment with the alpha 1-specific adrenoceptor blocker, Doxazosin, on lipid parameters was studied in male Golden hamsters fed a cholesterol-enriched diet. Within 1 week the Doxazosin-treated animals had a lower plasma (-12%) and hepatic (-30%) cholesterol content than the cholesterol-fed controls. De novo cholesterol synthesis in the liver was lowered by 39% in the Doxazosin-treated animals. These data indicate that the reported beneficial effect of alpha 1-blockade on plasma cholesterol levels may be due to lowering of the hepatic cholesterol synthesis.

Unexplained recurrent pneumonia: a post-childhood case of chronic granulomatous disease.

A 31-year-old patient was recurrently admitted because of pneumonia. Specialised leukocyte function tests revealed the diagnosis of an X-linked type of chronic granulomatous disease. Treatment with interferon-gamma successfully prevented new infections.

A rare cause of haemolytic anaemia: paroxysmal nocturnal haemoglobinuria in an elderly patient.

Paroxysmal nocturnal haemoglobinuria (PNH) is an acquired haemopoietic stem cell disorder characterised clinically by chronic haemolytic anaemia with acute episodes, thrombosis and bone marrow failure. It is a rare condition, which usually occurs in younger people. Immunophenotyping and flow cytometry play a key role in diagnosing PNH. Treatment is mainly supportive. Because it is so rare, delay in diagnosis is not uncommon in patients with PNH, which has a considerable impact on patient management and prognosis. We present this case to draw attention to this rare cause of haemolytic anaemia, which should be considered in any patient, of any age, who has signs of chronic haemolysis.

Bilateral adrenal enlargement as a first sign of systemic vasculitis.

In this case-report we describe the fatal outcome of systemic vasculitis. A 51-year-old man was hospitalised with constant abdominal pain, chest pain, anorexia, fatigue, weight loss, dyspeptic complaints, and a period of high fever at home. Bilateral adrenal enlargement was found without a plausible cause. Endoscopy revealed a reflux oesophagitis grade I, which was treated with famotidine. His complaints disappeared without further treatment. Five days after release from hospital the patient was re-admitted with subfebrile temperature followed by an Addison's crisis due to primary adrenal failure. Laboratory tests for systemic illness were all negative. He was treated with high-dose corticosteroids. Right adrenal biopsy revealed haemorrhage, possibly of older age. After 10 days he returned with severe kidney and heart failure. He was transported to another hospital for haemodialysis. Unfortunately the patient passed away because of cardiac arrhythmias. Postmortem investigation revealed inflammation of middle-sized and small arteries in the adrenal glands, heart, lung and thyroid. In the kidneys, mesangio-proliferative glomerulonephritis was found. A definite classification of the vasculitis could not be made because of the high-dose corticosteroids therapy. Possibly, the haemorrhage of both adrenal glands was caused by venous thrombosis due to the hypercoagulable state, which is often observed in vasculitis.

Rhabdomyolysis associated with influenza A virus infection.

Rhabdomyolysis is characterized by local or generalized skeletal muscle necrosis. It is caused by many clinical conditions and drug or alcohol abuse. Clinical symptoms are muscle pain and muscle weakness. Laboratory investigations show a rise in serum creatine phosphokinase and electrolyte disturbances. The most serious complication is acute renal failure. We present a patient with rhabdomyolysis and renal failure associated with a recent Influenza A virus infection.

Insulin autoimmune syndrome: the second Dutch case.

The insulin autoimmune syndrome (IAS) is the third leading cause of spontaneous hypoglycaemia in Japan. Here, we describe the second Dutch case. An 81-year-old man was analysed for collapse and attacks of disorientation, and was found to be hypoglycaemic during such an episode. The performed fasting test appeared to be positive. High levels of insulin and C-peptide postprandially and insulin antibodies were found. IAS was diagnosed.

High renin and prorenin in plasma and pleural exudate of a patient with the ovarian hyperstimulation syndrome.

We present the case of a 35-year-old woman with a severe ovarian hyperstimulation syndrome (OHSS) as a complication of ovulation induction for primary infertility. The clinical picture showed massively enlarged ovaries, pleural effusion and haemoconcentration. She needed a thoracentesis for evacuation of the large pleural effusion. High levels of renin and prorenin were observed in plasma and pleural exudate.

[Spur-cell anemia in alcoholic liver cirrhosis]. / 'Spur-cell'-anemie bij alcoholische levercirrose.

Spur-cell anaemia is a severe haemolytic disorder which may occur in patients with alcoholic liver cirrhosis. Characteristics are the bizarre shape of erythrocytes and the elevated cholesterol content in the membrane of the erythrocyte. The pathophysiology and possibilities for treatment are discussed with reference to a personal case. The patient described was treated with a cholesterol synthesis inhibitor, but no effect on the transfusion demand was noted. Splenectomy appears to be the best treatment. If splenectomy is not an option, frequent transfusions are the only therapy.

[Acute pancreatitis caused by chylomicronemia syndrome]. / Acute pancreatitis door het chylomicronemie-syndroom.

Pancreatitis caused by chylomicronaemia was diagnosed in three patients, two men of 36 and 51 years and a woman of 33 years. All three patients had a combined hyperlipidaemia, with severely elevated levels of triglycerides and cholesterol. Secondary causes of hypertriglyceridaemia such as uncontrolled diabetes mellitus, alcohol abuse, and non-compliance with diet and lipid lowering drug therapy caused aggravation of the lipid disorder. It is important to consider chylomicronaemia as a possible cause of pancreatitis, as treatment of the lipid disorder with diet and, if necessary, drugs can prevent recurrence of pancreatitis.

[Hypercalcemia in sarcoidosis]. / Hypercalciëmie bij sarcoïdose.

In a 56-year-old man hypercalcaemia and kidney function impairment were the presenting symptoms of sarcoidosis. The diagnosis was supported by the finding of elevated 1,25-dihydroxyvitamin D levels and of a cluster of epithelioid macrophages in aspirated bone marrow. By exclusion of other granulomatous diseases and a favourable reaction of the hypercalcaemia and renal function to treatment with prednisone the diagnosis was confirmed. The relationship between the autonomous extrarenal production of 1,25-dihydroxyvitamin D and the hypercalcaemia is discussed.

Hypocalcaemic laryngospasm in the emergency department.

A 51-year-old African male presented to the emergency department with a sore throat, a productive cough and a striking pinched voice. Investigation revealed severe hypocalcaemia (0.97 mmol/l) with a prolonged QT interval on ECG. The authors administered intravenous calcium in the emergency department, which instantly improved the quality of the patient's voice. He was eventually diagnosed with primary hypoparathyroidism and an upper airway infection. Severe hypocalcaemia is a life-threatening condition. Identifying laryngospasm as an atypical presentation in the presence of a concomitant airway infection and prompt treatment in the emergency department are critical.