Impaired adrenal cortex reserve in patients with rheumatic and musculoskeletal diseases who relapse upon tapering of low glucocorticoid dose.

OBJECTIVES: To examine adrenal cortex reserve in patients with rheumatic and musculoskeletal diseases (RMD) who relapse upon tapering of low glucocorticoid dose, despite concomitant treatment with disease-modifying anti-rheumatic drugs (DMARDs). METHODS: A morning standard dose of 250 mcg tetracosactide (Synacthen test) was given in 25 consecutive patients (13 rheumatoid arthritis, 2 psoriatic arthritis, 5 systemic lupus erythematosus, 2 dermatomyositis, 1 systemic sclerosis, 2 temporal arteritis) at the time of relapse upon small reductions (1-2 mg daily) of low prednisolone dose (<7.5 mg daily), while being on stable concomitant treatment with methotrexate, leflunomide, hydroxychloroquine, azathioprine, mycophenolate, tofacitinib, belimumab, anti-TNF, anti-IL-6 or anti-IL-1 regimens (n=14; 3; 9; 1; 2; 1; 1; 5; 2; 1, respectively). Sex-matched apparently healthy individuals (n=45) served as controls. RESULTS: Baseline cortisol levels and time-integrated cortisol response to tetracosactide were lower in patients than controls (12.01±4.47 vs. 15.63±4.16 mcg/dl, p=0.001, and 1050±286 vs. 1284±182, p<0.001, respectively). No significant associations were observed between the cortisol response to tetracosactide and age, duration of disease or glucocorticoid treatment. An abnormal Synacthen test, indicative of adrenal insufficiency, presumably secondary to chronic glucocorticoid administration, was noted in 5/25 patients. The remaining 20 patients (80%) had normal Synacthen test demonstrating, however, lower cortisol response than controls, independently of age (ß-coefficient=-0.373, p=0.033). CONCLUSIONS: Patients with RMD in remission under DMARDs who relapse upon concomitant low glucocorticoid dose tapering should be tested for iatrogenic adrenal insufficiency. Whether a marginally normal Synacthen test should discourage further attempts to withdraw glucocorticoid treatment in these patients warrants further investigation.

A computational drug repositioning method applied to rare diseases: Adrenocortical carcinoma.

Rare or orphan diseases affect only small populations, thereby limiting the economic incentive for the drug development process, often resulting in a lack of progress towards treatment. Drug repositioning is a promising approach in these cases, due to its low cost. In this approach, one attempts to identify new purposes for existing drugs that have already been developed and approved for use. By applying the process of drug repositioning to identify novel treatments for rare diseases, we can overcome the lack of economic incentives and make concrete progress towards new therapies. Adrenocortical Carcinoma (ACC) is a rare disease with no practical and definitive therapeutic approach. We apply Heter-LP, a new method of drug repositioning, to suggest novel therapeutic avenues for ACC. Our analysis identifies innovative putative drug-disease, drug-target, and disease-target relationships for ACC, which include Cosyntropin (drug) and DHCR7, IGF1R, MC1R, MAP3K3, TOP2A (protein targets). When results are analyzed using all available information, a number of novel predicted associations related to ACC appear to be valid according to current knowledge. We expect the predicted relations will be useful for drug repositioning in ACC since the resulting ranked lists of drugs and protein targets can be used to expedite the necessary clinical processes.

Rituximab, IVIg, and Tetracosactide (ACTH1-24) Combination Immunotherapy ("RITE-CI") for Pediatric Opsoclonus-Myoclonus Syndrome: Immunomarkers and Clinical Observations.

Opsoclonus-myoclonus syndrome (OMS) is a neuroinflammatory disorder with pervasive morbidity that warrants better treatments. Twelve children with moderate/severe OMS (total score 23 ± 6) who did not remit to multiple immunotherapies were evaluated for neuroinflammation in a case-control study using cerebrospinal fluid (CSF) lymphocyte subset analysis by flow cytometry, chemokine/cytokine analysis by enzyme-linked immunoadsorption assay (ELISA), and oligoclonal bands by immunofixation with isoelectric focusing. Observations made on empirical treatment with rituximab, IVIg, and tetracosactide combination immunotherapy (coined "RITE-CI") were analyzed. All of the patients tested for multiple inflammatory markers were positive; 75% had ≥3 CSF markers. Fifty percent had CSF oligoclonal bands; 58%, B cell expansion; and 50 to 100%, elevated concentrations of multiple chemokines and neuronal/axonal marker neurofilament light chain. After RITE-CI, total score dropped significantly in the group (-85%, p < 0.0001) from moderate to trace, and by 2 to 4 severity categories in each patient. The 24-week schedule was well tolerated and clinically effective for moderate or severe OMS, as were other schedules. RITE-CI is feasible and effective as rescue therapy and presents an initial option for children with moderate/severe OMS. Though preliminary, the schedule can be adjusted to patient severity, propensity for relapse, and other factors.

Adrenal insufficiency in neonates after cardiac surgery with cardiopulmonary bypass.

BACKGROUND: Cardiopulmonary bypass (CPB) may lead to adrenal insufficiency (AI). Emerging evidence supports association of AI with morbidity after cardiac surgery. AIMS: The aim of this study was to define AI incidence in neonates undergoing complex cardiac surgery with CPB and its association with intraoperative post-CPB outcomes. METHODS: Forty subjects enrolled in a prior randomized control trial who received preoperative methylprednisolone as part of our institutional neonatal bypass protocol were included. No intraoperative steroids were given. ACTH stimulation tests were performed: preoperatively and 1 h after separation from CPB. AI was defined as <9 µg·ml-1 increase in cortisol at 30 min post cosyntropin 1 mcg. Clinical outcomes were collected up to 90 min after CPB. RESULTS: 2/40 (5%) subjects had preoperative AI vs 13/40 (32.5%) post-CPB AI, P ≤ 0.001. No significant difference was observed in age, gestational age, weight, CPB time, circulatory arrest, or STAT category between subjects with or without post-CPB AI. ACTH decreased from preoperative values 127.3 vs 35 pcg·ml-1 [median difference = 81.8, 95% CI = 22.7-127.3], while cortisol increased from 18.9 vs 75 µg·dl-1 [median difference = 52.2, 95% CI = 36.3-70.9]. Post-CPB AI was associated with increased median colloid resuscitation, 275 vs 119 ml·kg-1 [median difference = 97.8, 95% CI = 7.1-202.2]; higher median peak lactate, 9.4 vs 6.9 mg·dl-1 [median difference = 3.2, 95% CI = 0.04-6.7]; median post-CPB lactate, 7.9 vs 4.3 mg·dl-1 , [median difference 3.6, 95% CI = 2.1-4.7], and median lactate on admission to CICU, 9.4 vs 6.0 mg·dl-1 [median difference = 3, 95% CI = 1.1-4.9]. No difference was observed in blood pressure or vasoactive inotrope score at any time point measured in operating room (OR). Higher initial post-CPB cortisol correlated with decreased cosyntropin response. CONCLUSIONS: Neonatal cardiac surgery with CPB and preoperative methylprednisolone leads to AI as determined by low-dose ACTH stimulation test in one-third of patients. AI is associated with increased serum lactate and colloid resuscitation in OR. Impact of preoperative methylprednisolone on results is not defined. Benefit of postoperative steroid administration in neonates with post-CPB AI warrants further investigation.

Adrenal insufficiency in patients with stable non-cystic fibrosis bronchiectasis.

BACKGROUND & OBJECTIVES: Suppressed adrenal responses associated with inhaled steroid use have been reported in patients with bronchiectasis and have been shown to be associated with poor quality of life. This study was undertaken to examine the prevalence of suppressed cortisol responses in stable bronchiectasis and determine their correlation with the use of inhaled corticosteroids, radiologic severity of bronchiectasis and quality of life (QOL) scores. METHODS: In this case-control study, cases were patients with bronchiectasis and suppressed cortisol responses and controls were healthy volunteers, and patients with bronchiectasis without suppressed cortisol responses. Symptoms, lung function test values, exercise capacity, HRCT severity scores for bronchiectasis, exacerbations, inhaled corticosteroid use and quality of life scores were compared between patients with and without suppressed cortisol values. RESULTS: Forty consecutive patients with bronchiectasis and 40 matched controls underwent 1-µg cosyntropin testing. Baseline cortisol (mean difference -2.0 µg/dl, P=0.04) and 30-minute stimulated cortisol (mean difference -3.73 µg/dl, P=0.001) were significantly lower in patients with bronchiectasis. One patient had absolute adrenal insufficiency and 39.5 per cent (15/38) patients with bronchiectasis had impaired stimulated responses. Baseline and stimulated cortisol responses were unaffected by inhaled steroids (O.R 1.03, P=0.96). SGRQ scores were negatively correlated with body mass (r= -0.51, P=0.001) and bronchiectasis severity (r=0.37, P=0.019), but not related to baseline or stimulated cortisol responses. INTERPRETATION & CONCLUSIONS: Our results showed that the impaired adrenal responses to 1-µg cosyntropin were common in patients with bronchiectasis. This was not associated with the use of inhaled steroids or severity of bronchiectasis. Poor health status was associated with advanced disease and not with cortisol responses to the 1-µg cosyntropin test.

Assessing adrenal status in patients before and immediately after coronary artery bypass graft surgery.

OBJECTIVE: Patients with cortisol deficiency poorly tolerate any systemic inflammatory response syndrome (SIRS), and may die if not treated with sufficient exogenous glucocorticoids. Controversy surrounds what constitutes a 'normal' adrenal response in critical illness. This study uses conventional tests for adrenal insufficiency to investigate cortisol status in patients undergoing elective coronary artery bypass surgery, a condition frequently associated with SIRS. DESIGN: A prospective, observational study. METHODS: Thirty patients with impaired left ventricular function (ejection fraction >23% <50%) underwent basal ACTH measurement, and a short cosyntropin test (250 µg, i.v.) 1 week preoperatively, and at +4 h following induction of general anaesthesia. Preoperatively, a 30 min cortisol level post cosyntropin >550 nmol/l was taken as a normal response. RESULTS: Prior to surgery, all patients had a normal response to cosyntropin. Postoperatively, eight patients (26.7%) did not achieve stimulated cortisol levels >550 nmol/l and the mean peak cortisol postoperatively was lower (1048 vs 730 nmol/l; P<0.001). There was a significant rise in ACTH after surgery (21 vs 184 ng/l; P=0.007) and reduction in Δ-cortisol post cosyntropin (579 vs 229 nmol/l; P<0.001). There was no change in basal cortisol pre- and post-operatively (447 vs 501; P=0.4). All patients underwent routine, uneventful postoperative recovery. CONCLUSION: Up to one quarter of patients with a normal cortisol status preoperatively demonstrated a raised ACTH and deficient cortisol response postoperatively. Despite these responses, all patients had uneventful outcomes. These data reinforce the need for caution when interpreting results of endocrine testing following major surgery or in the intensive care environment, and that prognostic value of these results may be of limited use.

Case detection, diagnosis, and treatment of patients with primary aldosteronism: an endocrine society clinical practice guideline.

OBJECTIVE: Our objective was to develop clinical practice guidelines for the diagnosis and treatment of patients with primary aldosteronism. PARTICIPANTS: The Task Force comprised a chair, selected by the Clinical Guidelines Subcommittee (CGS) of The Endocrine Society, six additional experts, one methodologist, and a medical writer. The Task Force received no corporate funding or remuneration. EVIDENCE: Systematic reviews of available evidence were used to formulate the key treatment and prevention recommendations. We used the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) group criteria to describe both the quality of evidence and the strength of recommendations. We used "recommend" for strong recommendations and "suggest" for weak recommendations. CONSENSUS PROCESS: Consensus was guided by systematic reviews of evidence and discussions during one group meeting, several conference calls, and multiple e-mail communications. The drafts prepared by the task force with the help of a medical writer were reviewed successively by The Endocrine Society's CGS, Clinical Affairs Core Committee (CACC), and Council. The version approved by the CGS and CACC was placed on The Endocrine Society's Web site for comments by members. At each stage of review, the Task Force received written comments and incorporated needed changes. CONCLUSIONS: We recommend case detection of primary aldosteronism be sought in higher risk groups of hypertensive patients and those with hypokalemia by determining the aldosterone-renin ratio under standard conditions and that the condition be confirmed/excluded by one of four commonly used confirmatory tests. We recommend that all patients with primary aldosteronism undergo adrenal computed tomography as the initial study in subtype testing and to exclude adrenocortical carcinoma. We recommend the presence of a unilateral form of primary aldosteronism should be established/excluded by bilateral adrenal venous sampling by an experienced radiologist and, where present, optimally treated by laparoscopic adrenalectomy. We recommend that patients with bilateral adrenal hyperplasia, or those unsuitable for surgery, optimally be treated medically by mineralocorticoid receptor antagonists.

[Prenatal ACTH-depot therapy]. / Prenatalna terapia ACTH-depot.

ACTH-depot therapy is one of the therapeutic methods in threatening abortion or premature labor, introduced by Prof. R. Klimek in the 60-ies of the last century. Administration of syntetic ACTH is the method of first choice in treatment of neuroendocrinologically complicated pregnancy, safe for mother as for infant. The first trials of application of this method disclosed good results determined by very high birth rate of at term pregnancies (96%) and delivery of live infants, in comparison to 18.5% or 37% supported pregnancies treated conservatively, in the same group of women previously. Because hypothalamic hormones induce synthesis of enzyme-oxytocinase, it becomes possible to observe the development of pregnancy in women treated with ACTH-depot by CAP-level determination. In women with hypothalamic hypofunction, level of oxytocinase is low, increasing slowly, sometimes even its decrease is observed. Current multiple ACTH-depot doses: 0.5 mg i.m. are routinely used, instead of hitherto applied series of 3 injections in the second and third trimester. Number of doses depend on: levels of oxyto-cinase, rate of its increase, reactivity of patient and progression of pregnancy. Administration of ACTH-depot seems to be more beneficial than aministration of corticoids, because this hormone does not cross the placenta, but increases the production of endogenic hormones. Unwelcome symptoms of ACTH-depot treatment are similar to those observed in course of the corticold therapy, but they are less expressed. Development of features connected with hypercatabolism of proteins like: muscular atrophy, striae and osteoporotic changes, are not observed. Only single therapy with ACTH-depot causes regression of clinical symptoms of threatening premature labor, without necessity of tocolitic treatment. Thanks to steroidogenesis, normalisation of the number of preterm labors and respiratory disorders decreases.

Effect of dose on response to adrenocorticotropin in extremely low birth weight infants.

CONTEXT: Various cosyntropin doses are used to test adrenal function in premature infants, without consensus on appropriate dose or adequate response. OBJECTIVE: The objective of this study was to test the cortisol response of extremely low birth weight infants to different cosyntropin doses and evaluate whether these doses differentiate between groups of infants with clinical conditions previously associated with differential response to cosyntropin. DESIGN: The design was a prospective, nested study conducted within a randomized clinical trial of low-dose hydrocortisone from November 1, 2001, to April 30, 2003. SETTING: The setting was nine newborn intensive care units. PATIENTS: The patients included infants with 500-999 g birth weight. INTERVENTION: The drug used was cosyntropin, at 1.0 or 0.1 microg/kg, given between 18 and 28 d of birth. MAIN OUTCOME MEASURE: We measured the cortisol response to cosyntropin. RESULTS: Two hundred seventy-six infants were tested. Previous hydrocortisone treatment did not suppress basal or stimulated cortisol values. Cosyntropin, at 1.0 vs. 0.1 microg/kg, yielded higher cortisol values (P < 0.001) and fewer negative responses (2 vs. 21%). The higher dose, but not the lower dose, showed different responses for girls vs. boys (P = 0.02), infants receiving enteral nutrition vs. not (P < 0.001), infants exposed to chorioamnionitis vs. not (P = 0.04), and those receiving mechanical ventilation vs. not (P = 0.02), as well as a positive correlation with fetal growth (P = 0.03). A response curve for the 1.0-microg/kg dose for infants receiving enteral nutrition (proxy for clinically well infants) showed a 10th percentile of 16.96 microg/dl. Infants with responses less than the 10th percentile had more bronchopulmonary dysplasia and longer length of stay. CONCLUSIONS: A cosyntropin dose of 0.1 microg/kg did not differentiate between groups of infants with clinical conditions that affect response. We recommend 1.0 microg/kg cosyntropin to test adrenal function in these infants.

[Treatment of West syndrome]. / Lijecenje Westovog sindroma.

PURPOSE: West syndrome (WS) is one of the catastrophic epileptic syndromes in infancy characterized by a triad of infantile spasms, psychomotor deterioration and hypsarrhythmic EEG pattern. WS is commonly associated with poor long-term outcome, especially in symptomatic cases, with development of other seizure types, impaired cognitive and psychosocial functioning. The aim of our study was to evaluate the efficacy of the control of infantile spasms using synthetic ACTH or vigabatrin in newly diagnosed cases and to correlate it with the underlyning causes, outcome and adverse effects. PATIENTS AND METHODS: The database of children with WS seen at the Neuropediatric Unit and followed at outpatient clinics from January 1, 1994 until December 31, 2003 were reviewed. The diagnosis of WS following the criteria of ILAE was made in 32 patients. RESULTS: Data were collected for 32 children (9 girls and 23 boys). According to the etiology, 5 (15.6%) were cryptogenic, and 1 (3.1%) was idiopathic. In 26 (81.2%) symptomatic cases, hypoxic-ischemic encephalopathy (69.2%) was the most common etiologic factor, followed by central nervous system anomaly including malformation of cortical development (11.5%), and Sturge Weber syndrome (3.8%), and chromosomal translocation with Down syndrome (11.5%). In 65.1% of symptomatic cases birth occurred prematurely. The mean age at spasm onset was 5.8 months, and mean age at diagnosis and treatment 7.2 months. Between 1994 and 1996 synthetic ACTH was used for treatment of WS in 7 patients (1 cryptogenic and 6 symptomatic), spasm control was achieved in 6, hypsarrhythmia disappeared in 5, and vigabatrin was added after synthetic ACTH in 3 patients. In one child synthetic ACTH was stopped because of arterial hypertension. All children had Cushing syndrome. After 1996, vigabatrin was administrated to 5 children with cryptogenic and 20 children with symptomatic WS. In 22/32 spasm control was achieved within 15 days. Synthetic ACTH was added in 3 children with spasms and hypsarrhythmia disappeared in 1 child. There was no recurrence of WS. The mean follow-up in 27 children was 4.6 (0.5 to 9.9 years) whereas 5 were lost from follow-up. Of 6/27 children with cryptogenic WS, 1 had idiopathic WS, 3 had normal psychomotor development and 2 had psychomotor retardation, without epileptic fits and still receiving AED. Of 21/27 children with symptomatic WS 76.2% had severe psychomotor retardation, 42.8% had epilepsy, 23.8% had intractable epileptic fits, and 2 children with Down syndrome were without epilepsy and without AED. Lennox-Gastaut syndrome developed in 14.2% (3/21 children); 1 of them died at the age of 3.5 years from acute gastric bleeding during the administration of synthetic ACTH, and an other child died at the age of 5.5 years from infection and respiratory insufficiency. The mortality rate was 7.4% (2/27 children). DISCUSSION AND CONCLUSION: The cryptogenic etiology is associated with a very low risk of poor outcome in WS. In children with normal development and regular school performance an idiopathic etiology can be presumed. The children with Down syndrome had a relatively benign outcome with regard to seizure control compared with symptomatic infantile spasms in the general population. In symptomatic WS caused by hypoxic-ischemic encephalopathy the outcome was linked with coexistence of other forms of epilepsy and neurologic deficit. The poor prognosis concerning intractable nature of the seizures and serious neurologic deficit is recorded in children with malformation of cortical development and Sturge Weber syndrome. The outcome of these children is determined by the brain damage other than by epilepsy itself. Regarding the treatment with synthetic ACTH or vigabatrin, the control of WS was the same for cryptogenic and symptomatic forms, one drug may be effective if the other drug fails. Synthetic ACTH can have many side effects, even death. The visual field defect is associated with vigabatrin, but can be avoided with careful funduscopic follow-up. Vigabatrin can be suggested as the first drug for WS; if spasms persist after 15 days with a dose of 150 mg/kg, synthetic ACTH should be considered.

Adrenocorticotropin reverses hemorrhagic shock in anesthetized rats through the rapid activation of a vagal anti-inflammatory pathway.

OBJECTIVE: Several melanocortin peptides have a prompt and sustained resuscitating effect in conditions of hemorrhagic shock. The transcription nuclear factor kappaB (NF-kappaB) triggers a potentially lethal systemic inflammatory response, with marked production of tumor necrosis factor-alpha (TNF-alpha), in hemorrhagic shock. Here we investigated whether the hemorrhagic shock reversal produced by the melanocortin ACTH-(1-24) (adrenocorticotropin) depends on the activation of the recently recognized, vagus nerve-mediated, brain "cholinergic anti-inflammatory pathway". METHODS AND RESULTS: Anesthetized rats were stepwise bled until mean arterial pressure (MAP) stabilized at 20-25 mm Hg. The severe hypovolemia was incompatible with survival, and all saline-treated animals died within 30 min. In rats intravenously (i.v.) treated with ACTH-(1-24), neural efferent activity along vagus nerve (monitored by means of a standard system for extracellular recordings) was markedly increased, and the restoration of cardiovascular and respiratory functions was associated with blunted NF-kappaB activity and with decreased TNF-alpha mRNA liver content and TNF-alpha plasma levels. Bilateral cervical vagotomy, pretreatment with the melanocortin MC(4) receptor antagonist HS014, atropine sulfate or chlorisondamine, but not with atropine methylbromide, prevented the life-saving effect of ACTH-(1-24) and the associated effects on NF-kappaB activity and TNF-alpha levels. HS014 and atropine sulfate prevented, too, the ACTH-(1-24)-induced increase in neural efferent vagal activity, and accelerated the evolution of shock in saline-treated rats. CONCLUSIONS: The present data show, for the first time, that the melanocortin ACTH-(1-24) suppresses the NF-kappaB-dependent systemic inflammatory response triggered by hemorrhage, and reverses shock condition, by brain activation (in real-time) of the "cholinergic anti-inflammatory pathway", this pathway seeming to be melanocortin-dependent.

Plasma cortisol response to 1-24 adrenocorticotropin in patients with treated/untreated sellar & suprasellar mass lesions.

BACKGROUND & OBJECTIVES: One microgram short synacthene test is widely recommended as a screening test for evaluation of hypothalamo-pituitary-adrenocortical axis in patients with secondary adrenal insufficiency. Information on adequacy of cortisol response to this dose at different periods of the day in patients with hypothalamic-pituitary disorders is not available. Hence, this study was designed to assess the adequacy of cortisol response to 1 microg 1-24 adrenocorticotropin (ACTH) at 0800 h and 1600 h in patients with sellar and suprasellar mass lesions. METHODS: Thirty five consecutive patients with sellar and suprasellar mass lesions with mean age of 43.0+/-14.4 yr and 36 healthy controls with mean age of 32.3+/-9.0 yr were studied after obtaining informed consent. Maintenance doses of glucocorticoids in these patients were discontinued appropriately. On day 1, prestimulated and stimulated plasma cortisol samples at 0800 h and at 30 and 60 min following i.v. bolus of 1 microg 1-24 ACTH were collected. While on day 3, plasma cortisol samples were similarly collected at 1600 h. Cortisol estimation was done by a sensitive and specific radioimmunoassay. Stimulated plasma cortisol of 500 nmol/l or higher was defined as a normal response. RESULTS: In healthy controls, the prestimulated and peak cortisol levels at 0800 h (377.5+/-93.3 and 729.1+/-183.2 nmol/l) were higher (P<0.001 and P<0.01) than those at 1600 h (230.1+/-75.7 and 665.8+/-138.6 nmol/l). All subjects had a cortisol response of 500 nmol/l or higher in response to 1 microg 1-24 ACTH both at 0800 and 1600 h. In the patients' group, the prestimulated plasma cortisol at 0800 h (250.3+/-169.7 nmol/l) was higher (P<0.001) than that at 1600 h (166.3+/-128.9 nmol/l), while the peak cortisol response was comparable (P>0.05) in the morning as well as in the evening (490.9+/-309.4 vs 464.8+/-318.4). In 27 patients (77%) the morning and evening stimulated cortisol response to 1 microg 1-24 ACTH was consistent (normal in 13 and subnormal in 14) but was discrepant in the remaining 8 (23%). In 7 of these 8 patients, cortisol response was normal at 0800 h but not at 1600 h, while in only one, normal response was seen at 1600 h but not at 0800 h. INTERPRETATION & CONCLUSION: The demonstration of normal peak cortisol response to 1 microg 1-24 ACTH at 0800 h but not at 1600 h in substantial number of patients with sellar and suprasellar mass lesions suggests preference to morning for performing this test.

[Inaugural unilateral adrenal hematoma of an antiphospholipid syndrome]. / Hématome surrénalien unilatéral inaugural d'un syndrome des antiphospholipides.

INTRODUCTION: A primary antiphospholipid syndrome is a very rare cause of adrenal haemorrhage. OBSERVATION: A 51 year-old man presented with a unilateral adrenal haemorrhage, enhanced by the prescription of Synacthène during the 4 days that preceded. There was no adrenal deficiency but the immunological control revealed the presence of anti-phospholipid antibodies. After 2 years of follow-up, adrenal controls have not shown any underlying tumour or endocrine insufficiency. COMMENTS: Adrenal involvement is described in the anti-phospholipid syndrome and may present in the form of adrenal deficiency in the case of occasionally only microscopic bilateral haemorrhages. Furthermore, Synacthène is known to induce adrenal haemorrhages although this complication remains rare. Moreover, any unilateral adrenal haemorrhage requires subsequent follow-up for several months or even years in order to eliminate any underlying tumour and to control the absence of any adrenal deficiency if the involvement is bilateral.

Action of metyrapone and tetracosactrin to modify cisplatin-induced acute and delayed emesis in the ferret.

Cisplatin 5 mg/kg, i.p., induced an acute (day 1) and delayed (days 2 and 3) emetic response in the ferret that was used to investigate the potential anti-emetic activity of metyrapone and tetracosactrin and their potential interaction. The 11beta-hydroxylase enzymes inhibitor metyrapone 10-30 mg/kg, i.p., dose dependently potentiated the acute cisplatin-induce retching+vomiting response by up to 219% at the highest dose (P<0.001) but failed to affect significantly delayed emesis (P>0.05). The adrenocorticotropic hormone (ACTH) mimetic tetracosactrin 0.1 mg/kg, i.m., antagonised significantly the acute and delayed emetic response by 98% (P<0.01) and 75% (P<0.001), respectively. The anti-emetic action of tetracosactrin on acute but not delayed emesis was prevented by combination with metyrapone 10 mg/kg, i.p. Tetracosactrin 0.1 mg/kg, i.m., failed to modify apomorphine (0.25 mg/kg, s.c.)-induced emesis. The potential anti-emetic mechanism of action of metyrapone and tetracosactrin to modulate emesis is discussed.

[Tuberculosis spondylodiscitis in a neurological service in Nouakchott]. / Spondylodiscites tuberculeuses dans le service de Neurologie à Nouakchott.

It is about a retrospective study dealing with the place of tuberculous spondylitis with discitis among medullary wounds hospitalized in our service from January 1995 to June 1998 and their medical care. Twenty reports have been done making: 30.30% of our medullary wounds. We have noted a male prevalence and precocity. The flaccido-spastic paraplegia with sensitive level prevails the clinical chart (45%) this in correlation with thoracic and lumbar localization predominance (75%) at the radiography. All patients have had for their benefit an anti-tuberculous treatment and eleven among them had also tetracosactide (synactène retard). This has allowed us to observe a quick recovery of the motor deficit for nine patients: 81.8% of the patients who have had the therapeutic association; 45% of the whole. No patient had an operation.

[The comparison of the effectiveness of treatment of multiple sclerosis relapse with high doses of methylprednisolone, alpha-24 corticotropin and cyclophosphamide]. / Porównanie skutecznosci leczenia rzutu stwardnienia rozsianego duzymi dawkami metyloprednizolonu, alpha-24 kortykotropina i cyklofosfamidem.

The effectiveness of treatment was compared in groups of patients with definite multiple sclerosis (MS) given respectively: methylprednisolone, alpha-24 corticotropine and cyclophosphamide combined with corticotropine. Clinical improvement was assessed by means of the expanded disability status scale (EDSS). The significant results were noted in patients treated with methylprednisolon and corticotropine combined with cyclophosphamide (1.5 in EDSS) for the first time, when compared to subsequent treatment. Within the patients in a more advanced stage of the disease, undergoing subsequent treatment, those given corticotropine displayed the best improvement (1.5 in EDSS), but without statistical significance. The authors suggest methylprednisolone or corticotropine combined with cyclophosphamide are the most effective immunosuppressive treatment in the initial phase of MS.

Adrenal dynamic responses to physiologic and pharmacologic adrenocorticotropic hormone stimulation before and after ovarian steroid modulation in women with polycystic ovary syndrome.

OBJECTIVE: To test the hypothesis that in women with polycystic ovary syndrome (PCOS), adrenal cytochrome P450c 17alpha activity is different after physiologic vs. pharmacologic ACTH stimulation and that ovarian activity promotes adrenal hyperactivity that is different after physiologic vs. pharmacologic ACTH stimulation. DESIGN: Prospective controlled pilot study. SETTING: Reproductive endocrinology unit of an academic medical center. PATIENT(S): Six women with PCOS who had adrenal hyperandrogenism were compared with four women with normal ovulation. INTERVENTION(S): Adrenal dynamic blood sampling was performed before and after 6 months of GnRH agonist administration. MAIN OUTCOME MEASURE(S): Comparison of physiologic and pharmacologic ACTH-stimulated levels of progesterone, 17-hydroxyprogesterone, and androgens before and after ovarian steroid modulation. RESULT(S): In women with PCOS, exaggerated responses of androstenedione and 11beta-hydroxyandrostenedione as well as elevated ratios of 17-hydroxyprogesterone to progesterone and of androstenedione to 17-hydroxyprogesterone after physiologic ACTH stimulation did not persist after GnRH-agonist administration. Three of the six women with PCOS had an increased response of androstenedione and a ratio of androstenedione to 17-hydroxyprogesterone that were >2 SD above the mean of those in the women with normal ovulation after pharmacologic ACTH stimulation; this finding persisted after GnRH-agonist administration. CONCLUSION(S): In women with PCOS, increases in adrenal androgen sensitivity after physiologic ACTH stimulation reflected in both arms of cytochrome P450c 17alpha activity may be influenced by ovarian activity. However, 17,20-lyase hyperactivity in a subset after pharmacologic ACTH stimulation may be an intrinsic adrenal disorder.

[Cranial pachymeningitis or unknown origin]. / Pachyméningite crânienne de cause indéterminée.

Pachymeningitis of unknown origin is uncommon and is usually associated with headaches, cranial nerve lesions and cerebellar ataxia. Magnetic resonance imaging is particularly contributive to diagnosis. The default diagnosis must however be confirmed by brain biopsy. Treatment is not well defined. Basically, corticosteroid therapy, or immunosuppressive therapy in case of failure, is known to have little effect on the brain lesion. We report here a case characterized by headache associated with partial regression of the radiographic lesions.