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.

Intranasal calcitonin suppresses increased bone resorption during short-term immobilization: a double-blind study of the effects of intranasal calcitonin on biochemical parameters of bone turnover.

Immobilization is associated with increased bone resorption and decreased bone formation. We evaluated in a double-blind trial the effect of intranasal administration of salmon calcitonin on biochemical parameters of bone turnover in 32 patients immobilized for a prolapsed intervertebral disk. Calcitonin in a dose of two times 200 IU/day partially inhibited the increase in the fasting 2 h urinary hydroxyproline/creatinine ratio (OHPr/Cr) and calcium/creatinine ratio (Ca/Cr). The increase in OHPr/Cr was 40% less in the calcitonin group compared to the placebo group (P = 0.01), and the increase in Ca/Cr was 80% less in the calcitonin group (P = 0.04). Calcitonin also partially inhibited the increase in serum cross-linked carboxyl-terminal telopeptide of collagen type I (P < 0.05). The decrease in serum 1,25-dihydroxyvitamin D after 10 days of immobilization was significantly less in the calcitonin-treated group than in the placebo group (14 versus 29%, respectively; P < 0.05). Intranasal calcitonin did not influence the pain scores as measured with a visual analog scale (VAS). The tolerability of the nasal calcitonin preparation was excellent. We conclude that nasal salmon calcitonin counteracts the early increase in bone resorption induced by immobilization.

Effect of a single infusion of aminohydroxypropylidene on calcium and bone metabolism in healthy volunteers monitored during 2 months.

Recently, bisphosphonates have been used to prevent postmenopausal bone loss. As the effects of bisphosphonates on normal bone metabolism are unknown, 3-amino-1-hydroxypropylidene-1,1-diphosphonate (APD) was studied in healthy subjects. The effects of a single 20-mg APD infusion on biochemical parameters of calcium and bone metabolism were investigated during 2 months in 10 healthy male volunteers. This single moderate dose of APD reduced biochemical parameters of bone resorption during the time of follow-up. After 2 months, urinary hydroxyproline excretion was still below the basal level. The decreased serum calcium levels did not return to basal values. Biochemical parameters of bone formation, serum alkaline phosphatase and osteocalcin, showed a slight increase during the first month after stimulation of the parathyroids and a corresponding increase in serum 1,25-dihydroxyvitamin D. These formation parameters decreased thereafter, probably representing coupling between bone resorption and bone formation.

Long-term consequences of fracture of the lower leg: cross-sectional study and long-term longitudinal follow-up of bone mineral density in the hip after fracture of lower leg.

The purpose of this study was to investigate whether bone loss in the hip, occurring after a fracture of the lower leg, persists many years after the fracture. In a long-term follow-up we measured bone mineral density (BMD) by dual-energy X-ray absorptiometry (DXA) of both hips and the lumbar spine in a group of 11 patients, 5 years after a fracture of the lower leg. These patients were part of an earlier study, evaluating bone loss in the hip, up to 1 year after fracture of the lower leg. In this follow-up study, 5 years after fracture, loss from baseline BMD in the trochanteric region of the ipsilateral hip was 4.7% (p=0.04), whereas after a year in this group there was a decrease of 12.5% from baseline. On the contralateral side, hardly any change occurred. In the ipsilateral femoral neck, 5 years after fracture, BMD decreased by 2.9% (p=0.10), after 1 year loss from baseline was 5.1%. In a cross-sectional study we examined the differences in BMD of both hips, measured by DXA, in a group of 19 elderly patients reporting a fracture of the lower leg, with a mean time of 9.3 years after fracture. In this study, we found a 4.7% lower BMD in the trochanteric region of the hip on the fractured side compared with the nonfractured side (p=0.006), and a 2.9% lower BMD in the femoral neck (p=0.25). We conclude that, after fracture of the lower leg, BMD in the ipsilateral hip decreases significantly, with maximal bone loss after 1 year. After 5 years recovery has occurred, but not to baseline. Thereafter, significant excess bone loss is still observed in the trochanteric region. This persisting lower BMD may lead to an increased risk of another fracture in later years.

Additional weight-bearing during exercise is more important than duration of exercise for anabolic stimulus of bone: a study of running exercise in female rats.

Mechanical loading is necessary for maintenance of skeletal integrity, but the most effective type, intensity, and duration of exercise are not known. In vivo experiments have indicated that the strain generated by the stimulus is more important than the duration of the stimulus. To elucidate this question, we studied 5-month-old female Wistar rats exercised on a motor-driven exercise belt for 17 weeks, 5 days per week (average velocity 20 m/min). Group 1 served as controls, group 2 was trained for 30 min, group 3 was trained for 30 min with a 50-g backpack, and group 4 was trained for 15 min with a 50-g backpack. Total body bone mineral content (BMC), bone mass of the lower extremities (LEBMC), total body lean soft-tissue mass (LSTM), and total body fat-tissue mass (FTM) were measured by dual-energy absorptiometry (DXA) at 0, 6, and 17 weeks. The BMC increased more in group 4 than in controls (15% vs. 8%, p < 0.03). In the other two intervention groups, no significant increases of total body BMC occurred compared with controls, although a trend was observed (12%). The LEBMC increased significantly in all exercising groups after 17 weeks, being 16% in group 2, 15% in group 3, and 20% in group 4, compared with 6% in controls (p < 0.05). The increase in LSTM after 6 weeks was most pronounced in group 3, at 20%, compared with 10% in the control group (p < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Therapy of organophosphate poisoning: the marmoset as a model for man.

1 The ability of various bis-pyridinium oximes to restore organophosphate-inhibited neuromuscular transmission in vitro was compared in human intercostal and marmoset diaphragm muscles. 2 HI-6 (2-hydroxyiminomethyl-pyridinium-1-methyl-4'-carbamoyl-pyridinium-1'-methyl ether dichloride monohydrate) appeared very effective against VX (O-ethyl S-2-diisopropylaminoethyl methylphosphonothioate) and sarin in both muscles, whereas obidoxim was quite effective against tabun. 3 Against soman, HI-6, HS-6 (2-hydroxyiminomethyl-pyridinium-1-methyl-3'-carbamoyl-pyridinium-1'-methyl ether dichloride dihydrate) and obidoxim had little effect in the human muscle and only slight activity in the marmoset muscle; HGG-12 (2-hydroxyiminomethyl-pyridinium-1-methyl-3'-phenylcarbonyl-pyridinium-1'-methy l ether dichloride) and benzyl-P2A (1-benzyl-2-hydroxyiminomethyl-pyridinium methanesulphonate) were ineffective. 4 Anaesthetized, atropinized marmosets were poisoned with soman (4 X LD50, i.v.) and subsequently treated with HI-6, HS-6 or HGG-12. Only HI-6 and HS-6 were marginally effective in restoring respiration and neuromuscular transmission. 5 Marmoset muscle is a reasonable model for human muscle for the study of organophosphate poisoning and therapy.

Poland anomaly in mother and daughter.

We report on Poland anomaly in a mother and her daughter. Further family history was negative for abnormalities of the hands or the pectoralis major muscle. A review of published cases of familial Poland anomaly is presented. Implications concerning the possible etiology of familial cases of Poland anomaly are given.

Progressive hypercalcemia during continuous arterio-venous ultrafiltration (SCUF).

A case report is described of a patient who developed severe hypercalcemia during slow continuous arterio-venous ultrafiltration (SCUF). Which was instituted because of refractory congestive heart failure with pulmonary edema. The hypercalcemia was due to a preexisting mild hyperparathyroidism and aggressive fluid removal by SCUF. The differential diagnosis of hypercalcemia in the intensive care ward is discussed.

The dependence of the blood level of the oxime HS-6 on the severity of organophosphate poisoning.

Atropinised anaesthetised rats were injected i.v. with 4, 6 or 8 X LD50 of the organophosphorous anticholinesterase soman. Subsequent treatment with one dose of HS-6 (100 mg/kg, i.v.) delayed respiratory failure by 1 h or more; a further postponement was obtained when an additional HS-6 infusion was given. At the same infusion rate, HS-6 blood levels after 4 X LD50 soman remained stationary, but rose after the higher soman doses. The rise was greater the higher the soman dose had been. This rapid rise in oxime blood levels after high doses of organophosphate may seriously complicate therapy.

The efficacy of some bis-pyridinium oximes as antidotes to soman in isolated muscles of several species including man.

Previous results had shown that bis-pyridinium oximes, particularly HI-6 are quite effective therapeutically in soman-poisoned rats and mice in vivo and in the rat diaphragm preparation in vitro. The aim of the present study was to investigate the efficacy of bis-pyridinium oximes on soman-inhibited neuromuscular transmission in muscle preparations from several species including man. The muscles tested were preparations of rat diaphragm and intercostal muscle, guinea-pig diaphragm, dog external intercostal muscle and human external interscotal muscle. These muscles were stimulated indirectly with field stimulation. With a few exceptions the preparations were exposed to soman for 2.5 or 15 min. In some cases different exposure times were employed or the organophosphate sarin was administered instead of its analogue soman. After the degree of inhibition of neuromuscular transmission had been established, oximes were added to the bath fluid. After washout 15 min later, recovery of neuromuscular transmission was tested. Subsequently, a second dose of soman was administered to investigate whether the recovery observed had been caused by cholinesterase reactivation. The results of these experiments indicate that the oximes tested, mostly HI-6, were quite effective as soman antidotes in muscle preparations of rats, guinea-pigs and dogs. In the human preparation while these oximes were quite effective after sarin intoxication they were essentially without effect against soman.

Analysis of oxime-induced neuromuscular recovery in guinea pig, rat and man following soman poisoning in vitro.

The bispyridinium oximes HS6 and HI6 were tested in vitro for their ability to restore neuromuscular function in soman-poisoned tissue, using diaphragm and intercostal muscle of the rat and guinea pig and intercostal muscle of man. It was found that the oxime-mediated recovery of function in both tissues of the rat and guinea pig was composed of direct oxime actions, AChE reactivation and adaptation. In the human intercostal muscle, however, only adaptation was observed. These findings might suggest that HS6 and HI6 may have only limited value in the treatment of soman poisoning in man. However, recovery of function in rodent tissues was consistently greater in the diaphragm than in the intercostal muscle and, since human diaphragm tissue was not included in this study the therapeutic efficacy of these oximes in this tissue remains unknown.

Further studies on the therapy of organophosphorous anti-cholinesterase intoxication with veratrinic compounds; the role of calcium.

Experiments were carried out to investigate the role of calcium in the therapy of soman intoxication with 9-anthroic acid (ANCA), a compound with veratrine-like pharmacological properties. The effects of ANCA on the respiratory paralysis and on the calcium content of the blood and that of the hindleg muscles were determined in anaesthetized, atropinized rats injected with 4 times LD50 soman. The respiratory paralysis which in control animals occurs within a few min after the injection of soman can be delayed about 2.5 hr by treatment with ANCA. It was found that ANCA causes a small decrease of the blood calcium content, an effect which is potentiated by soman. A comparison was made between the calcium accumulation in the indirectly stimulated gastrocnemius-soleus muscles in these animals with that in the non-stimulated muscles on the other side. Whereas the injection of soman or ANCA alone caused no change, the combination of the two drugs induced a two-fold increase in the accumulation of calcium in the stimulated muscles. The non-stimulated muscles remained unaffected. The accumulation of calcium in the stimulated muscles induced by soman and ANCA could be partly antagonized by lowering the free calcium concentration of the blood by EDTA. Moreover, treatment with EDTA improved the therapeutic effects of ANCA. It is concluded that the therapy of soman poisoning with ANCA falls short in completely preventing respiratory failure since ANCA causes an accumulation of calcium in the stimulated muscles of soman-poisoned animals.

The diagnosis of Horner's syndrome. Use and limitations of the cocaine test.

We prospectively studied the value of the cocaine test in the diagnosis of Horner's syndrome, by performing the test in 20 control subjects and in 20 patients with a provisional diagnosis of Horner's syndrome. Photographic testing of the darkness reflex of the pupil was used as an independent criterion of oculosympathetic dysfunction, and confirmed the diagnosis in 12 of the 20 patients. A mydriatic response to cocaine that was at least 1.0 mm less than in the unaffected eye occurred only with Horner's syndrome (7 patients). On the other hand, if the difference is smaller than 1.0 mm the chance that the patient does not have Horner's syndrome is only around 60%. There was no relationship between the magnitude of the response to cocaine and the site of the lesion in the sympathetic system.

Localization of Horner's syndrome. Use and limitations of the hydroxyamphetamine test.

The pupillary response to hydroxyamphetamine eye-drops has been advocated as a test for sub-dividing patients with Horner's syndrome into those with lesions of the 1st or 2nd sympathetic neurone (normal dilatation) and those with lesions of the 3rd neurone (no or minimal dilatation). We compared the response of the right and the left eye in 40 control subjects and also in 25 consecutive patients with Horner's syndrome from a known lesion. In the controls, 1 eye might dilate up to 1.0 mm less than the other. In the patients, abnormally weak dilatation (difference with the other eye more than 1.0 mm) occurred only with lesions of the 3rd neurone, but in only 4 of 10 such cases. Of the other 6 patients with a lesion of the 3rd neurone, 2 had a minimal response of the normal eye, and 4 showed subsequent recovery of oculosympathetic function (which suggests that denervation had not occurred). In conclusion, an abnormal hydroxyamphetamine test reliably indicates a lesion of the 3rd neurone, but a normal test provides little diagnostic aid.

Horner's syndrome. Criteria for oculosympathetic denervation.

The darkness reflex of the pupil was examined by taking photographs under standard bright lighting conditions, and after 5 and 10 s of uninterrupted darkness. The study involved 40 control subjects and 12 patients with a presumed Horner's syndrome. No control subject showed a dilatation lag (compared with the other eye) of 0.5 mm or more in the first 5 s of darkness. This criterion allows exclusion of a fortuitous combination of "physiological anisocoria" and "physiological ptosis".

Organophosphate poisoning: a method to test therapeutic effects of oximes other than acetylcholinesterase reactivation in the rat.

A method was developed to study exclusively those therapeutic effects of oximes that are not related to reactivation of organophosphate-inhibited acetylcholinesterase (AChE). The model uses the organophosphorus compound crotylsarin (CRS), which proved to be a potent, irreversible, peripherally and centrally active AChE inhibitor with a very short biological half-life. CRS-inhibited AChE appeared to age very rapidly, because in vitro addition of oximes immediately following inhibition, did not result in any AChE reactivation. Anaesthetized, atropinized and artificially ventilated rats were intoxicated with 3 x LD50 CRS and treated 5 min later with the bispyridinium oxime HI-6. Fifty percent of these animals survived more than 24 h following termination of artificial ventilation at 10 min after oxime treatment. The mean survival time of the remaining animals was 66 min, whereas all untreated animals died within 4 min. HI-6, when added in vitro to isolated intact hemidiaphragms, or to diaphragm or brain homogenates from rats which had been killed 1 min following 3 x LD50 CRS, failed to reactivate the inhibited AChE. If blood was sampled (before and) after HI-6 administration to CRS-intoxicated rats, no HI-6-induced AChE reactivation was observed. Yet, a clear improvement of the neuromuscular transmission in the hindleg muscles of these animals was found following HI-6 injection. With this model, decisive evidence is obtained that non-reactivating effects of HI-6 by themselves are therapeutically relevant.

Soman levels in kidney and urine following administration to rat, guinea pig, and marmoset.

Concentrations of C(+/-)P(+/-)-soman (1,2,2-trimethylpropyl methylphosphonofluoridate) in urine of anaesthetized, atropinized and artificially ventilated rats, guinea pigs and marmosets were determined 1-4 h after iv administration of 1-6 LD50 of the agent and in the kidneys 1 h after iv administration of 2-6 LD50 14C-C(+/-)P(+/-)-soman. The concentrations of the toxic C(+/-)P(-)-isomers in both urine and kidneys of the rat were at least two orders of magnitude higher than the corresponding levels in the two other species. Relatively high urine concentrations were also found for C(+/-)P(+/-)-soman-intoxicated (6 LD50) rats pretreated with the nontoxic soman analogue PDP (1,2,2-trimethyl dimethylphosphinate), which considerably decreases the persistence of C(+/-)P(-)-soman in rats, or the carboxylesterase inhibitor CBDP [2-(o-cresyl)-4H-1:3:2-benzodioxaphosphorin-2-oxide]. The lethal effect brought about by intravesical administration of C(+/-)P(+/-)-soman in rats showed that the agent can easily be reabsorbed from the bladder. It is concluded, that this reabsorption does probably not explain the previously observed persistence and "late toxicity" of C(+/-)P(+/-)-soman in rats, although the amount of renally excreted C(+/-)P(-)-soman (ca. 1% of the administered dose) should be sufficient for a toxicologically significant effect.

Loss of bone in the proximal part of the femur following unstable fractures of the leg.

We evaluated the subsequent loss of bone from the proximal part of the ipsilateral and contralateral femora and from the lumbar spine of seven men and nine women who had a fracture of the tibia. The average age was sixty years. All of the fractures were unstable, and the involved leg bore no weight for an average of eight weeks. The bone mineral density was measured with dual-energy x-ray absorptiometry of the lumbar spine and of the femoral neck and the trochanteric region of both hips immediately after the fracture, after the period of immobilization, and at approximately three, six, and twelve months after the fracture. During the period of immobilization, the bone mineral density of the trochanteric region decreased an average of 9 +/- 7 per cent on the side of the fracture, compared with the value immediately after the fracture, but there was no change on the contralateral side (p < 0.01). At twelve months, the average decrease in the trochanteric area was 15 +/- 10 per cent on the side of the fracture, compared with the value immediately after the fracture, but again there had been no change on the uninjured side (p < 0.01). The bone mineral density of the femoral neck on the side of the fracture had decreased 6 +/- 6 per cent at twelve months, compared with a decrease of 2 +/- 4 per cent on the uninjured side (p < 0.05). The bone mineral density of the lumbar spine decreased only during the period of unloading of the fractured leg (1 +/- 2 per cent, p = 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

The diagnosis of Horner's syndrome.

We studied the accuracy of the clinical diagnosis of Horner's syndrome in 62 patients. The final criterion was serial photography of the darkness reflex of the pupil. This technique confirmed oculosympathetic dysfunction in only 50%. The positive predictive value of the clinical diagnosis could be increased to more than 80% by measuring the degree of miosis and ptosis on single photographs, or by assuming independent confirmation of the clinical diagnosis by a second observer. However, the chance that a patient who is judged normal in this way does still have oculosympathetic dysfunction remains 25% (photographs) to 40% (second observer). Testing with cocaine is more specific and slightly more sensitive than estimating or measuring the degree of miosis and ptosis.

External ophthalmoplegia, juvenile parkinsonism and axonal polyneuropathy in two siblings.

In one of two siblings a clinical disorder was described, consisting of a slowly progressive juvenile parkinsonism with extensor plantar responses, external ophthalmoplegia with severe ptosis and a motor and sensory polyneuropathy. The younger sibling had only juvenile parkinsonism, Unilateral ptosis and a motor and sensory polyneuropathy. Their father was neurologically normal except for a unilateral ptosis. There did not seem to be consanguinity in this family.