Corticotropin-stimulated steroid profiles to predict shock development and mortality in sepsis: From the HYPRESS study.

RATIONALE: Steroid profiles in combination with a corticotropin stimulation test provide information about steroidogenesis and its functional reserves in critically ill patients. OBJECTIVES: We investigated whether steroid profiles before and after corticotropin stimulation can predict the risk of in-hospital death in sepsis. METHODS: An exploratory data analysis of a double blind, randomized trial in sepsis (HYPRESS [HYdrocortisone for PRevention of Septic Shock]) was performed. The trial included adult patients with sepsis who were not in shock and were randomly assigned to placebo or hydrocortisone treatment. Corticotropin tests were performed in patients prior to randomization and in healthy subjects. Cortisol and precursors of glucocorticoids (17-OH-progesterone, 11-desoxycortisol) and mineralocorticoids (11-desoxycorticosterone, corticosterone) were analyzed using the multi-analyte stable isotope dilution method (LC-MS/MS). Measurement results from healthy subjects were used to determine reference ranges, and those from placebo patients to predict in-hospital mortality. MEASUREMENTS AND MAIN RESULTS: Corticotropin tests from 180 patients and 20 volunteers were included. Compared to healthy subjects, patients with sepsis had elevated levels of 11-desoxycorticosterone and 11-desoxycortisol, consistent with activation of both glucocorticoid and mineralocorticoid pathways. After stimulation with corticotropin, the cortisol response was subnormal in 12% and the corticosterone response in 50% of sepsis patients. In placebo patients (n = 90), a corticotropin-stimulated cortisol-to-corticosterone ratio > 32.2 predicted in-hospital mortality (AUC 0.8 CI 0.70-0.88; sensitivity 83%; and specificity 78%). This ratio also predicted risk of shock development and 90-day mortality. CONCLUSIONS: In this exploratory analysis, we found that in sepsis mineralocorticoid steroidogenesis was more frequently impaired than glucocorticoid steroidogenesis. The corticotropin-stimulated cortisol-to-corticosterone ratio predicts the risk of in-hospital death. Trial registration Clinical trial registered with www. CLINICALTRIALS: gov Identifier: NCT00670254. Registered 1 May 2008, https://clinicaltrials.gov/ct2/show/NCT00670254 .

Investigation of THDOC effects on pathophysiological signs of Alzheimer's disease as an endogenous neurosteroid: inhibition of acetylcholinesterase and plaque deposition.

Alzheimer's disease (AD) is an advanced neurodegenerative disorder greatly accompanied by acetylcholinesterase (AChE) activation and amyloid plaque deposition. Tetrahydrodeoxycorticosterone (THDOC) is an endogenous neurosteroid that is reduced in AD patient according to previous results. It has neuroprotective effects and plays important role in neurological diseases. By considering AChE role in AD, this study investigated THDOC effects on catalytic and non-catalytic functions of the enzyme. Inhibitory effect of THDOC on hydrolytic activity of AChE was confirmed by in vitro assay (IC50 = 5.68 µM). Molecular docking analysis revealed THDOC bound tightly to the catalytic site of enzyme and inhibited substrate binding. According to in vivo experiments, neurosteroid administration causes inhibition of hyper-activated AChE in hippocampus related to rat model of AD. Staining of hippocampus tissue by plaque specific dye approved THDOC reduced plaque numbers and size in AD rats. Histological and immunoblotting experiments showed neurosteroid administration improved neurodegeneration and neuronal damages in AD rats that lead to improved spatial learning ability. Overall this study suggests, THDOC is an endogenous regulator for AChE. By considering pathophysiological and molecular similarities between AD and animal model, our results highlight THDOC as a potential therapeutic strategy in patients suffering from AD or similar cognitive disorders (Fig. 6, Ref. 28). Keywords: tetrahydrodeoxycorticosterone, acetylcholinesterase, non-catalytic function, amyloid plaque deposition, nucleus basalis of Meynert lesioned rats, neurodegeneration.

Perioperative Management and Outcome of Bilateral Adrenalectomy in 9 Dogs.

OBJECTIVE: To report perioperative care, postoperative management, and long-term outcomes in dogs undergoing bilateral adrenalectomy. STUDY DESIGN: Retrospective case series. ANIMALS: Dogs undergoing bilateral adrenalectomy from 2008 to 2013 (n=9). METHODS: Data retrieved from the record, when available, included signalment, preoperative clinical signs, laboratory data, diagnostic imaging, blood pressure measurement, preoperative treatment for adrenal gland disease, intraoperative procedures, treatments and complications, postoperative treatment and diagnostics during hospitalization, diagnostics and management following discharge, histopathologic diagnosis, and survival. RESULTS: Seven dogs underwent concurrent bilateral adrenalectomy and 2 dogs had staged adrenalectomy. Surgery was uncomplicated in most cases. All dogs received IV dexamethasone SP intraoperatively. Eight dogs received intramuscular desoxycorticosterone pivalate intraoperatively. Histopathology revealed adrenocortical adenoma (7 dogs), adrenocortical carcinoma (4), pheochromocytoma (6), and adrenocortical atrophy (1). One dog died perioperatively and the remainder died due to unrelated causes. Postoperative management of hypoadrenocorticism included oral prednisone and intramuscular desoxycorticosterone pivalate (6 dogs), oral prednisone and fludrocortisone (1), and oral fludrocortisone alone (1). The median survival time in dogs surviving to hospital discharge was 525 days (range 67-966 days). No dogs developed metastatic disease or died due to signs of hypoadrenocorticism. CONCLUSION: Based on the cases reported here, the perioperative mortality in dogs undergoing bilateral adrenalectomy may be lower than previously reported. Management of postoperative hypoadrenocorticism is both achievable and straightforward.

HYPOALDOSTERONISM IN A MATSCHIE'S TREE KANGAROO (DENDROLAGUS MATSCHIEI).

A 20-yr-old female Matschie's tree kangaroo (Dendrolagus matschiei) was diagnosed with hypoaldosteronism, a rare condition in which the body fails to produce normal amounts of the mineralocorticoid aldosterone. Aldosterone plays a key role in body salt homeostasis, increasing sodium reabsorption and promoting excretion of potassium. Hypoaldosteronism resulted in decreased appetite, lethargy, and weight loss in conjunction with hyponatremia, hyperkalemia, and hypercalcemia in this tree kangaroo. The animal was successfully managed with mineralocorticoid replacement using desoxycorticosterone pivalate. To the authors' knowledge this is the first report of hypoaldosteronism in a tree kangaroo and one of the few reports in the veterinary literature in any species.

Generalized vitiligo in a dog with primary hypoadrenocorticism.

BACKGROUND: Vitiligo is presumed to be an autoimmune disorder in the dog; primary adrenal insufficiency (Addison's disease) is associated with immune-mediated destruction of the adrenal cortex. HYPOTHESIS/OBJECTIVES: In this case report we describe a dog with primary hypoadrenocorticism that developed generalized vitiligo. CASE REPORT: A 4-year-old spayed female cross-bred dog developed signs of Addison's disease and this was confirmed by biochemical testing; the dog was treated with fludrocortisone acetate and then desoxycorticosterone pivalate. Three months after the diagnosis, the dog developed depigmentation of the whole hair coat and of several focal areas of the skin. Histopathological findings were consistent with vitiligo. CONCLUSIONS AND CLINICAL IMPORTANCE: Dogs with immune-mediated disease may develop other manifestations of immune-mediated disease, including a combination of Addison's disease and vitiligo. The cause in this case was not determined.

Successful treatment of a cat with primary hypoadrenocorticism and severe hyponatremia with desoxycorticosterone pivalate (DOCP).

A 6-year-old, castrated male Siamese cat was diagnosed with primary hypoadrenocorticism, confirmed by an adrenocorticotopic hormone (ACTH) stimulation test documenting both hypocortisolism and hypoaldosteronism. The cat was successfully treated using a combination of prednisolone and desoxycorticosterone pivalate (DOCP). This case demonstrates that DOCP can be used successfully as mineralocorticoid supplementation in cats with hypoadrenocorticism and may have a longer therapeutic duration than that in dogs.

Traitement réussi d'un chat atteint d'hypoadrénocorticisme primaire et d'hyponatrémie à l'aide de pivalate de désoxycorticostérone (DOCP). Un diagnostic d'hypoadrénocorticisme primaire a été posé pour un chat Siamois castré âgé de 6 ans et confirmé par un test de stimulation de l'hormone adrénocorticotope (ACTH) qui a documenté l'hypocortisolisme et l'hypoaldostéronisme. Le chat a été traité avec succès à l'aide d'une combinaison de prednisolone et de pivalate de désoxycorticostérone (DOCP). Ce cas démontre que le DOCP peut être utilisé avec succès en tant que supplément de minéralocorticoïdes chez les chats atteints d'hypoadrénocorticisme et peut présenter une durée thérapeutique plus longue que chez les chiens.(Traduit par Isabelle Vallières).

Hypoadrenocorticism (Addison's disease) in a Hoffmann's two-toed sloth (Choloepus hoffmanni).

A 22-yr-old, captive-born, presumed female Hoffmann's two-toed sloth (Choloepus hoffmanni) presented in respiratory distress with severe dehydration and symptoms of hypotension. During treatment, dysphagia was noted and oral examination revealed enlarged palatine tonsils and mucosal plaques. Bloodwork showed a decreased sodium:potassium ratio, a low baseline cortisol, a decreased adrenocorticotropin response test, and a blunted aldosterone stimulation test. All values were compared to a healthy male Hoffmann's two-toed sloth at the same facility. Despite aggressive medical management and treatment for hypoadrenocorticism, the sloth was found deceased. Necropsy revealed abdominal effusion, multifocal plaques throughout the upper gastrointestinal tract, and testes. Histopathology showed marked adrenal cortical atrophy and intranuclear mucosal inclusions in the gastrointestinal tract; advanced molecular techniques did not uncover any viral etiologies. This is the first reported case of hypoadrenocorticism in a sloth.

Clinical features and long-term management of cats with primary hypoadrenocorticism using desoxycorticosterone pivalate and prednisolone.

BACKGROUND: Primary hypoadrenocorticism (PH) is rare in cats and knowledge about treatment is sparse. OBJECTIVE: To describe cats with PH with a focus on long-term treatment. ANIMALS: Eleven cats with naturally occurring PH. METHODS: Descriptive case series with data on signalment, clinicopathological findings, adrenal width, and doses of desoxycorticosterone pivalate (DOCP) and prednisolone during a follow-up period of >12 months. RESULTS: Cats ranged from 2 to 10 years (median 6.5); 6 cats were British Shorthair. Most common signs were reduced general condition and lethargy, anorexia, dehydration, obstipation, weakness, weight loss, and hypothermia. Adrenal glands on ultrasonography were judged small in 6. Eight cats could be followed for 14 to 70 months (median: 28). Two were started on DOCP doses ≥2.2 mg/kg (2.2; 2.5) and 6 < 2.2 mg/kg (1.5-2.0 mg/kg, median 1.8) q28 days. Both high-dose cats and 4 low-dose cats needed a dose increase. Desoxycorticosterone pivalate and prednisolone doses at the end of the follow-up period were 1.3 to 3.0 mg/kg (median: 2.3) and 0.08 to 0.5 mg/kg/day (median: 0.3), respectively. CONCLUSIONS AND CLINICAL IMPORTANCE: Desoxycorticosterone pivalate and prednisolone requirements in cats were higher than what is currently used in dogs; thus, a DOCP starting dose of 2.2 mg/kg q28 days and a prednisolone maintenance dose of 0.3 mg/kg/day titrated to the individual need seems warranted. Small adrenal glands (width < 2.7 mm) on ultrasonography in a cat suspected of hypoadrenocorticism can be suggestive of the disease. The apparent predilection of British Shorthaired cats for PH should be further evaluated.

Efficacy of selective mineralocorticoid and glucocorticoid agonists in canine septic shock.

OBJECTIVE: Corticosteroid regimens that stimulate both mineralocorticoid and glucocorticoid pathways consistently reverse vasopressor-dependent hypotension in septic shock but have variable effects on survival. The objective of this study was to determine whether exogenous mineralocorticoid and glucocorticoid treatments have distinct effects and whether the timing of administration alters their effects in septic shock. DESIGN, SETTING, SUBJECTS, AND INTERVENTIONS: Desoxycorticosterone, a selective mineralocorticoid agonist; dexamethasone, a selective glucocorticoid agonist; and placebo were administered either several days before (prophylactic) or immediately after (therapeutic) infectious challenge and continued for 96 hrs in 74 canines with staphylococcal pneumonia. MEASUREMENTS AND MAIN RESULTS: Effects of desoxycorticosterone and dexamethasone were different and opposite depending on timing of administration for survival (p = .05); fluid requirements (p = .05); central venous pressures (p ≤ .007); indicators of hemoconcentration (i.e., sodium [p = .0004], albumin [p = .05], and platelet counts [p = .02]); interleukin-6 levels (p = .04); and cardiac dysfunction (p = .05). Prophylactic desoxycorticosterone treatment significantly improved survival, shock, and all the other outcomes stated, but therapeutic desoxycorticosterone did not. Conversely, prophylactic dexamethasone was much less effective for improving these outcomes compared with therapeutic dexamethasone with the exception of shock reversal. Prophylactic dexamethasone given before sepsis induction also significantly reduced serum aldosterone and cortisol levels and increased body temperature and lactate levels compared with therapeutic dexamethasone (p ≤ .05), consistent with adrenal suppression. CONCLUSIONS: In septic shock, mineralocorticoids are only beneficial if given prophylactically, whereas glucocorticoids are most beneficial when given close to the onset of infection. Prophylactic mineralocorticoids should be further investigated in patients at high risk to develop sepsis, whereas glucocorticoids should only be administered therapeutically to prevent adrenal suppression and worse outcomes.

[Therapy of primary hypoadrenocorticism in dogs with low dose desoxycorticosterone pivalate]. / Therapie des primären Hypoadrenokortizismus beim Hund mit niedrig dosiertem Desoxycorticosteronpivalat.

OBJECTIVE: Since 2016 the only approved drug for the treatment of primary hypoadrenocorticism (Addisons disease) in dogs in Germany is desoxycorticosterone pivalate (DOCP), namely Zycortal®. The initial dose recommended by the manufacturer is 2.2 mg/kg. Our own experience and select publications raise the suspicion that a distinctly lower initial dose would be sufficient. Mainly cost reduction motivates for dose reduction and with it comes a higher owner motivation and compliance. It was the objective of our retrospective study to show that an initial dose of 1.5 mg/kg DOCP is sufficient for controlling canine hypoadrenocorticism. MATERIAL AND METHODS: Dogs with primary hypoadrenocorticism were included if the initial starting dose was 1.5 mg/kg DOCP subcutaneously. The first, second and the last known dose of DOCP were documented. Electrolyte concentrations at the time of diagnosis as well as 10-14 days after the first injection, on the day of the second injection as well as at the last known injection were recorded. A dog was considered medically well-regulated when clinically healthy, sodium and potassium concentrations within the reference ranges, and when the responsible veterinarian did not recommended a dose alteration. RESULTS: All 13 included dogs were clinically healthy after the first or second injection. One dog received 1.6 mg/kg DOCP as last documented dose, all other dogs received ≤ 1.5 mg/kg (median: 1.3, range: 0.4-1.6) DOCP. Eleven dogs were injected once monthly, 2 dogs received injections every 60 days. The dogs were followed at least 7 months (median: 20 months, range: 7-26 months). CONCLUSION AND CLINICAL RELEVANCE: We were able to show that a starting dose of 1.5 mg/kg DOCP (Zycortal®) is sufficient for controlling primary hypoadrenocorticism in dogs. Adjustments of the dose are needed in some dogs. Regular measurement of electrolyte concentrations 10 days after treatment initiation and at the monthly DOCP injection is required for a correct disease management with DOCP.

Randomised clinical non-inferiority trial comparing two formulations of desoxycortone pivalate for the treatment of canine primary hypoadrenocorticism.

BACKGROUND: This clinical trial compared two formulations of desoxycortone pivalate (DOCP) for treating the mineralocorticoid deficit in dogs with primary hypoadrenocorticism (PH). METHODS: At veterinary clinics in the USA and France, dogs with PH (n=152) were randomised (3:1) to receive approximately monthly treatments with either the test product, Zycortal (Dechra), administered subcutaneously (n=113), or the control product, Percorten-V (Novartis Animal Health), administered intramuscularly (n=39), both at an initial dose of 2.2 mg/kg DOCP. Treatment administrators were unblinded; veterinarians assessing clinical signs were blinded; owners were blinded until at least day 90, the primary end point. Veterinarians assessed treatment outcome based on all of the following: clinical signs; sodium concentrations; potassium concentrations. Dogs received concurrent glucocorticoid therapy throughout the trial. Non-inferiority was assessed using a generalised linear mixed model to compare success rates between groups. RESULTS: Success rates at day 90 were similar between groups (per-protocol population at day 90: Zycortal 87/101, 86.2 per cent, Percorten-V 29/34, 85.1 per cent). Zycortal was non-inferior to Percorten-V as the upper limit of the 95 per cent CI for the difference between groups was 13.6 per cent. Polydipsia and polyuria were the most common clinical observations. CONCLUSION: Both products, in combination with glucocorticoid therapy, were safe and effective in treating PH.

Evaluation of a low-dose desoxycorticosterone pivalate treatment protocol for long-term management of dogs with primary hypoadrenocorticism.

BACKGROUND: Lowering the dose of desoxycorticosterone pivalate (DOCP) for the treatment of dogs with primary hypoadrenocorticism (PH) decreases costs and could lead to increased owner motivation to treat their affected dogs. OBJECTIVE: To evaluate the efficacy of a low-dose DOCP treatment protocol in dogs with PH. ANIMALS: Prospective study, 17 client-owned dogs with naturally occurring PH (12 newly diagnosed, 5 previously treated with fludrocortisone acetate [FC]). METHODS: Dogs with newly diagnosed PH were started on 1.5 mg/kg DOCP SC; dogs previously treated with FC were started on 1.0-1.8 mg/kg DOCP SC. Reevaluations took place at regular intervals for a minimum of 3 months and included clinical examination and determination of serum sodium and potassium concentrations. The DOCP dosage was adjusted to obtain an injection interval of 28-30 days and to keep serum electrolyte concentrations within the reference interval. RESULTS: Median (range) follow-up was 16.2 months (4.5-32.3 months). The starting dosage was sufficient in all but 2 dogs and had to be significantly decreased after 2-3 months to a median dosage (range) of 1.1 mg/kg (0.7-1.8). Dogs 3 years of age or younger needed significantly higher dosages compared to older dogs. None of them, however, needed the 2.2 mg/kg DOCP dosage, recommended by the manufacturer. CONCLUSIONS AND CLINICAL IMPORTANCE: A starting dosage of 1.5 mg/kg DOCP is effective in controlling clinical signs and serum electrolyte concentrations in the majority of dogs with PH. An additional dose reduction often is needed to maintain an injection interval of 28-30 days. Young and growing animals seem to need higher dosages.

Importance of sodium intake and mineralocorticoid hormone in the impaired water excretion in adrenal insufficiency.

The response of trained, conscious dogs to an acute water load was studied before adrenalectomy and under five conditions of hormonal replacement and sodium intake after adrenalectomy. Before adrenalectomy, with the dogs drinking isotonic saline, the minimal urinary osmolality (Uosm) was 47+/-7 (SEM) mOsm and free-water clearance (C(H2O)) was 8.6+/-1 ml/min. These values were not different after adrenalectomy with or without deoxycorticosterone (DOCA) if the animals continued to drink saline and receive dexamethasone. Moreover, after adrenalectomy in the presence of saline drinking both dexamethasone and DOCA could be withdrawn for up to 4 days without impairment of diluting ability (Uosm, 54+/-7 mOsm and C(H2O), 7.3+/-1 ml/min). In contrast, when the dogs drank tap water (Na intake 30 mEq/day), water loading in the absence of dexamethasone and DOCA was associated with a significantly higher Uosm (127+/-28 mOsm) and lower C(H2O) (2.7+/-0.3 ml/min). Replacing DOCA alone in the presence of this limited Na intake returned diluting ability to normal (Uosm 31+/-7 mOsm, C(H2O) 7.7+/-0.5 ml/min). Glomerular filtration rate for each animal was the same under each condition except for a significant diminution which occurred when dexamethasone and DOCA were withdrawn while the animals were on a 30 mEq sodium intake. In contrast to previous conclusions, the present results indicate that in the absence of adrenal hormones normal renal diluting ability may occur, indicating both maximal suppression of vasopressin release and maximal distal tubular impermeability to water. In the present study the diluting defect observed after adrenalectomy related to negative sodium balance and could be overcome by either replacement with DOCA or a high intake of sodium alone.

Studies on auditory thresholds in normal man and in patients with adrenal cortical insufficiency: the role of adrenal cortical steroids.

Auditory thresholds for sinusoidal tones were determined in eight patients with adrenal cortical insufficiency (four with Addison's disease and four with panhypopituitarism) and compared to those in normal volunteers. In adrenal cortical insufficiency (ACI) the auditory detection sensitivity is significantly more acute than that of normal subjects over most of the frequency range, but especially in the region of greatest hearing sensitivity of normal subjects, 1,000 to 2,000 cycles per second (cps). Treatment of the patients with deoxycorticosterone acetate decreased serum potassium concentration and produced gains in body weight but did not alter auditory detection thresholds. Treatment with prednisolone or with maintenance doses of carbohydrateactive steroids returned the auditory detection threshold to normal in every patient tested.The mechanism by which carbohydrate-active steroids affect the sensitivity of the nervous system to sound is not known. However, since the senses of taste, smell, and hearing are all affected in similar fashion by their removal and replacement, there appears to be a generalized increase in sensitivity to all sensory stimuli in patients with ACI not receiving steroids. These hormones may play a significant role in maintaining the level of responsiveness of the sensory system to incoming stimuli.

Auditory detection and perception in normal man and in patients with adrenal cortical insufficiency: effect of adrenal cortical steroids.

Auditory detection thresholds for sinusoidal tones and various tests of auditory perception were determined in 12 patients with adrenal cortical insufficiency (seven with Addison's disease and five with panhypopituitarism) and compared to those in normal volunteers. In adrenal cortical insufficiency auditory detection sensitivity was significantly more acute than normal, and judgments of loudness and of the contralateral threshold shift were made at levels more than 20 db below those of normal subjects. Thus both the lower and the upper limits of the dynamic auditory range are significantly decreased in these patients. Speech discrimination ability of the patients was significantly impaired as was their difference limens, their alternate binaural loudness balances, and their ability to localize tones in space. Treatment of the patients with deoxycorticosterone acetate decreased serum potassium concentration, raised serum sodium concentration, and produced gains in body weight but did not alter auditory detection or perception. Treatment with prednisolone or with maintenance doses of carbohydrate-active steroids returned auditory detection and perception to normal in every patient tested. The inability of the untreated patients to perform the various auditory perception tasks indicates that they have a defect in their ability to integrate incoming sensory stimuli. This defect may be related to the alteration in the timing of transmission of neural impulses along axons and across synapses which occurs in these patients when their carbohydrate-active steroid is removed. This decreased integrative capacity occurs at the same time that they are able to detect many types of sensory stimuli significantly better than normal subjects. This interrelationship between increased detection sensitivity and decreased perceptual ability is dependent upon the absence of carbohydrate-active steroids, for when these steroids are replaced both detection sensitivity and perceptual ability revert to normal.

Anticonvulsant actions of deoxycorticosterone.

PURPOSE: Adrenocorticotrophic hormone (ACTH) suppresses several types of childhood seizures, but it has many side effects. The mechanism of ACTH's anticonvulsant actions is not known. ACTH, however, releases deoxycorticosterone (DOC) - as well as cortisol - from the adrenal cortex and it has been suggested that DOC may mediate, at least in part, ACTH's anticonvulsant actions. The present study assessed DOC's anticonvulsant actions in infant rats. Age-related changes in DOC's anticonvulsant actions were also studied. METHODS: DOC's anticonvulsant actions were assessed against hippocampal-kindled, maximal pentylenetetrazol test (MMT) and maximal electroshock (MES) seizures in 15-day-old rats. Age-related changes in responsiveness to DOC were also assessed using the MMT model. RESULTS: DOC suppressed generalized convulsions in all three of the seizure models. Focal spiking in the hippocampal-kindling model, however, was not fully suppressed, even at high doses. Ataxia increased proportionally with the dose, with the time of peak seizure suppression roughly correlating with the time of peak ataxia in all models. DOC was anticonvulsant in both infant and adult rats. ED50s, however, were much higher in adults. Young rats showed ataxia at the time of testing (15 min), whereas adult rats did not, although ataxia was seen at later times. CONCLUSIONS: DOC is a potent anticonvulsant against generalized seizures, particularly in infants. It deserves a clinical test against generalized seizures in infants.

Altered Serum Thyrotropin Concentrations in Dogs with Primary Hypoadrenocorticism before and during Treatment.

BACKGROUND: Thyrotropin (TSH) can be increased in humans with primary hypoadrenocorticism (HA) before glucocorticoid treatment. Increase in TSH is a typical finding of primary hypothyroidism and both diseases can occur concurrently (Schmidt's syndrome); therefore, care must be taken in assessing thyroid function in untreated human patients with HA. OBJECTIVE: Evaluate whether alterations in cTSH can be observed in dogs with HA in absence of primary hypothyroidism. ANIMALS: Thirty dogs with newly diagnosed HA, and 30 dogs in which HA was suspected but excluded based on a normal ACTH stimulation test (controls) were prospectively enrolled. METHODS: cTSH and T4 concentrations were determined in all dogs and at selected time points during treatment (prednisolone, fludrocortisone, or DOCP) in dogs with HA. RESULTS: cTSH concentrations ranged from 0.01 to 2.6 ng/mL (median 0.29) and were increased in 11/30 dogs with HA; values in controls were all within the reference interval (range: 0.01-0.2 ng/dL; median 0.06). There was no difference in T4 between dogs with increased cTSH (T4 range 1.0-2.1; median 1.3 µg/dL) compared to those with normal cTSH (T4 range 0.5-3.4, median 1.4 µg/dL; P=0.69) and controls (T4 range 0.3-3.8, median 1.8 µg/dL; P=0.35). After starting treatment, cTSH normalized after 2-4 weeks in 9 dogs and after 3 and 4 months in 2 without thyroxine supplementation. CONCLUSIONS AND CLINICAL RELEVANCE: Evaluation of thyroid function in untreated dogs with HA can lead to misdiagnosis of hypothyroidism; treatment with glucocorticoids for up to 4 months can be necessary to normalize cTSH.

Anticonvulsant action of three neurosteroids against cortical epileptic afterdischarges in immature rats.

Neurosteroids exhibit anticonvulsant action probably by positive modulatory influence on GABA-A receptors. The action of three neurosteroids was tested against cortical epileptic afterdischarges in immature rats with implanted electrodes. Afterdischarges (ADs) were elicited by rhythmic electrical stimulation (biphasic pulses at 8 Hz frequency for 15s) of sensorimotor cortical region with a slightly suprathreshold current intensity. Drugs were administered intraperitoneally after the first afterdischarge and stimulation was repeated five more times with the same intensity. Allopregnanolone in doses of 20 and 30 mg/kg i.p. was found to be active in 12-day-old rats; there was no effect in 18-day-old rats and only a tendency in 25-day-old ones. Therefore, the effects of pregnanolone and a new derivative THDOC-conjugate (20 and 40 mg/kg) were compared with those of allopregnanolone (40 mg/kg) only in 12- and 25-day-old rats in the second part of study. All three neurosteroids blocked progressive prolongation of repeated ADs seen in control 12-day-old rats. In addition, pregnanolone was able to shorten the ADs. In contrast, duration of ADs in 25-day-old animals was significantly shorter than the duration of the first, predrug AD only after administration of the 40 mg/kg dose of pregnanolone; if corresponding ADs in the control and drug groups were compared, pregnanolone and THDOC-conjugate led to significantly shorter ADs, changes after allopregnanolone administration were statistically significant only in the fourth AD. None of the studied neurosteroids was able to suppress movements directly bound to stimulation as well as clonic seizures accompanying afterdischarges. Among the three drugs studied, pregnanolone was found to be the most potent one. As developmental changes are concerned, the youngest animals exhibited the highest sensitivity to anticonvulsant action of neurosteroids.

Coronary slow flow accompanying exertional blurred vision and effects of corticosteroids.

Background Various pathophysiological mechanisms such as microvascular and endothelial dysfunction, small vessel disease, diffuse atherosclerosis, and inflammation have been held responsible in the etiology of coronary slow flow. It is also thought to be a reflection of a systemic slow-flow phenomenon in the coronary arterial tree. Case Report A 44-year-old man presented with chest pain causing fatigue, together with blurred vision for the last 2 years, which disappeared after resting. He had used corticosteroid therapy for facial paralysis 1 month ago. Coronary slow flow was detected in all 3 major coronary arteries on coronary angiography. TIMI measurements for the left anterior descending artery, circumflex, and right coronary artery were 64, 72, and 55, respectively. In fundus fluorescein angiography, retinal vascularity was normal, the arm-to-retina circulation time was 21.8 s, and the arteriovenous transit time was 4.3 s. In the early arteriovenous phase, choroidal filling was long, with physiological patchy type. Diltiazem 90 mg/day and acetylsalicylic acid 100 mg/day were given. His chest pain and visual symptoms disappeared after medical treatment. Conclusions Physicians should be aware that glucocorticoids might cause an increase in the symptoms of coronary slow flow and some circulation problems, which might lead to systematic symptoms.

Renin-secreting tumor. Case report.

Renin-secreting tumor, though rare, should be considered in assessing severe hyperreninemic, hypertensive patients. We studied an 18-year-old girl with hypokalemic hyperreninemic hyperaldosteronism. No angiographic lesion could be detected. The plasma renin activity (PRA) of the right/left renal vein was 7.3. With a presumptive diagnosis of renin-secreting tumor (RST), the patient was operated on, and a cortical nodule was found on the right lower pole. Partial nephrectomy was followed by a rapid fall in PRA (half-life, 33-44 min) and normalization of blood pressure (BP). At 3 1/2 months postoperatively, the patient showed normotension, normokalemia, normal aldosterone, and slightly elevated PRA unresponsive to postural changes and furosemide treatment. Tumoral PRA secretion responded to postural stimulus, spironolactone use, and nitroprusside-induced hypotension. Neither the high aldosterone excretion nor hyperreninemia decreased after 3 days of DOCA; this agrees with a previously reported case suggesting the usefulness of this test in the diagnosis of RST.