OBJECTIVE: It is known that long-term stress leads to trauma and very often to depression. Usually, the diagnosis of depression is dealt with by psychiatrists who, based on conversations and questions, diagnose the patient\'s illness and condition. Unfortunately, this diagnosis is not always reliable. To prevent the development of disease, it is necessary to detect illness in a timely manner. One of the indications of the possibility of the onset of disease is a disturbance in the level of hormones in the body, especially cortisol. The purpose of this study was to develop a mathematical model for cortisol variation resulting from stress which would be useful in making conclusions about depressive states.
METHODS: Rapid changes in cortisol concentration, according to ultradian rhythms, which are much faster than the daily circadian rhythm, is modelled as a truly nonlinear oscillator. The mathematical model contains two coupled first order differential equations. The stress is modeled as a pulsating action, described with a periodic trigonometric function, and cortisol production as a cubic nonlinear one. Three models for cortisol variation are considered: 1) the pure nonlinear model, 2) the periodically excited system, 3) and the chaotic system. The results from the study are supported with experimental measurements.
RESULTS: Without stress, cortisol variation is of an oscillatory type with a constant steady-state amplitude. Intensive stress causes a resonant phenomenon in cortisol oscillatory variation. The occasion is short and is usually without consequences. For long stress periods deterministic chaos occurs which permanently changes the levels of cortisol. This phenomenon is an indicator of depression. Results from the suggested models are compared with experimentally obtained ones and good quantitative agreement is obtained.
CONCLUSIONS: The nonlinear oscillator is a good model for indication of depression. The model provides not only general conclusions, but also individual ones, if personal characteristics are taken into consideration. Response of the model depends not only on the input data related to stress, but also on the system parameters that specify each individual. Findings obtained from this study have implications for the medical diagnosis and treatment of depression.

Familial Glucocorticoid Deficiency encompasses a broad spectrum of monogenic recessive disorders that theoretically solely abrogate cortisol biosynthesis. In reality, delineating clear genotype-phenotype correlations in this disorder is made complicated by marked phenotypic heterogeneity even within kindreds harbouring identical variants. Phenotypes range from isolated glucocorticoid insufficiency to cortisol deficiency plus a variety of superimposed features including salt-wasting and hypoaldosteronism, primary hypothyroidism, hypogonadism and growth defects. Furthermore, mutation type, domain topology and perceived enzyme activity do not always predict disease severity. Given the high burden of disease and implications of a positive diagnosis, genetic testing is crucial in the management of patients warranting detailed delineation of genomic variants including viable functional studies.

BACKGROUND: Pathological fractures have been reported in equids with pituitary pars intermedia dysfunction (PPID) but their prevalence and pathogenesis is unknown.
OBJECTIVE: To compare: (1) bone mineral density (BMD) in weight bearing and nonweight bearing bones in PPID+ equids and aged and young PPID- controls; and (2) biomechanical properties of the fourth lumbar vertebral body in PPID+ equids and aged PPID- equids.
METHODS: Case-control study: five PPID+ equids and six aged and four young PPID- control horses.
METHODS: PPID status was based on clinical signs and necropsy examination of the pituitary gland (PG). The lumbar vertebral column, right front third metacarpus (MC3), left hind third metatarsus (MT3), and PG were removed after euthanasia. BMD was determined by quantitative computed tomography of regions of interest (ROI) in each bone and biomechanical testing was performed on the fourth lumbar vertebral body. Serum concentrations of parathormone (PTH), ionised Ca++ , 25-hydroxyvitamin D, and osteocalcin (OC) were also measured. Data were analysed using one-way ANOVA and correlation analyses.
RESULTS: BMD of trabecular and cortical regions of interest (ROI) of the third, fourth (L4), and fifth lumbar vertebrae were significantly lower in PPID+ equids as compared with aged (p < 0. 001) and young (p < 0.01) PPID- controls. In contrast, no differences were found in BMD of trabecular or cortical ROIs of MC3 and MT3 between groups. No differences were detected in force at fracture, displacement at fracture, Young\'s modulus or strain of L4 between PPID+ and aged PPID- horses. No differences were found in serum PTH, ionised Ca++ , 25-hydroxyvitamin D, or OC concentrations between groups.
CONCLUSIONS: Limited number of equids studied and variation in test results.
CONCLUSIONS: BMD of nonweight bearing bones can be decreased with PPID and could increase risk of developing pathological fractures.

BACKGROUND: The basal (bACTH) and post-thyrotropin-releasing hormone stimulation concentration of adrenocorticotropin (pACTH) are recommended for diagnosis of pituitary pars intermedia dysfunction (PPID). Many factors influence bACTH (e.g., disease, age, month) and some affect the results only in autumn (e.g., breed, colour, sex). There are discrepancies about the impact of feeding on b/pACTH.
OBJECTIVE: To determine whether feeding, month, age, breed, colour, sex and body condition score affect b/pACTH.
METHODS: Prospective crossover.
METHODS: Sixty-one animals were divided into groups: healthy, PPID, treated-PPID. The b/pACTH was measured three times (1 mg protirelin; blood collection after 10 min; mid-November to mid-July) after different feedings: fasting, hay, hay + grain. Friedman\'s test was applied to evaluate the influence of feeding on b/pACTH and linear mixed model to evaluate impact of further factors.
RESULTS: The b/pACTH was not significantly affected by feeding (p = 0.7/0.5). The bACTH was lowest in healthy (29.3 pg/mL, CI 9-49.5 pg/mL) and highest in PPID-group (58.9 pg/mL, CI 39.7-78.1 pg/mL). The pACTH was significantly lower in healthy (396.7 pg/mL, CI 283.2-510.1 pg/mL) compared to PPID (588.4 pg/mL, CI 480.7-696.2 pg/mL) and treated-PPID group (683.1 pg/mL, CI 585.9-780.4 pg/mL), highest in July (881.2 pg/mL, CI 626.3-1136.3 pg/mL) and higher in grey (723.5 pg/mL, CI 577.5-869.4 pg/mL) than other colours (338.7 pg/mL, CI 324.8-452.5 pg/mL). The size of effect for those variables was >0.5.
CONCLUSIONS: Small number of animals, subsequent bACTH measurements were significantly lower in each horse.
CONCLUSIONS: There was no evidence that feeding influences the b/pACTH. There was evidence that pergolide affects the bACTH but it had little effect on pACTH. Further investigation of the impact of month and coat colour on b/pACTH is warranted to better interpret the results.

Epileptic spasms during infancy represent a devastating and refractory epilepsy syndrome. To advance studies on mechanisms and treatment using available mouse mutant models, we transferred our validated rat model of epileptic spasms to mice. Initially, we determined sensitivity of C57BL/6J mice to various doses (12-20 mg/kg) of NMDA on postnatal day 11 (P11) and P15. We primed mice with different doses of betamethasone (0.4-2.0 mg/kg) prenatally on gestational day (G)14 or G12 and tested spasms on P11. We also tested 2 different ACTH treatment paradigms (0.3 or 1.0 mg/kg) in prenatally primed as well as naïve mice. Data show that spasms in P11 mice, can be induced with the highest yield after 12 mg/kg dose of NMDA. Prenatal priming on G14 did not modify response to NMDA or sensitize spasms to ACTH. The betamethasone priming on G12 resulted in an increase in the number of NMDA-triggered spasms. Data indicate that the model transfer from rats to mice is non-linear and differences in prenatal brain development, metabolic rates, as well as sensitivity to convulsant drugs have to be considered.

Patients with secondary adrenal insufficiency can present with impaired free water excretion and hyponatremia, which is due to the enhanced secretion of vasopressin (AVP) despite increased total body water. AVP is produced in magnocellular neurons in the paraventricular nucleus of the hypothalamus (PVH) and supraoptic nucleus and in parvocellular corticotropin-releasing factor (CRF) neurons in the PVH. This study aimed to elucidate whether magnocellular AVP neurons or parvocellular CRF neurons coexpressing AVP are responsible for the pathogenesis of hyponatremia in secondary adrenal insufficiency. The number of CRF neurons expressing copeptin, an AVP gene product, was significantly higher in adrenalectomized AVP-floxed mice (AVPfl/fl) than in sham-operated controls. Adrenalectomized AVPfl/fl mice supplemented with aldosterone showed impaired water diuresis under ad libitum access to water or after acute water loading. They became hyponatremic after acute water loading, and it was revealed under such conditions that aquaporin-2 (AQP2) protein levels were increased in the kidney. Furthermore, translocation of AQP2 to the apical membrane was markedly enhanced in renal collecting duct epithelial cells. Remarkably, all these abnormalities observed in the mouse model for secondary adrenal insufficiency were ameliorated in CRF-AVP-/- mice that lacked AVP in CRF neurons. Our study demonstrates that CRF neurons in the PVH are responsible for the pathogenesis of impaired water excretion in secondary adrenal insufficiency.

UNASSIGNED: Skin pigmentation after adrenalectomy occurs due to an increase in adrenocorticotropic hormone (ACTH) following adrenal insufficiency. ACTH-induced pigmentation usually appears as generalized hyperpigmentation and is known to appear after bilateral adrenalectomy. We report a case of unusual transient hyperpigmentation that developed immediately after unilateral adrenalectomy for pheochromocytoma and spontaneously resolved without corticosteroid supplementation.
UNASSIGNED: A 29-year-old woman was admitted to the hospital due to sudden-onset chest pain and headache. A 2.8-cm left adrenal mass with heterogeneous enhancement was incidentally found in chest computed tomography during the evaluation. Multiple old infarctions were observed in brain magnetic resonance imaging (MRI), and left ventricular thrombi were found by echocardiography. Biochemical evidence confirmed the diagnosis of pheochromocytoma, while serum ACTH and cortisol levels were within normal ranges. The patient underwent laparoscopic left adrenalectomy via a posterior retroperitoneal approach and recovered without immediate postoperative complications. On day 3 after surgery, a crescent-shaped café-au-lait skin pigmentation occurred on both the subcostal and the lumbar areas of the abdomen. Serial serum cortisol slightly decreased during the immediate postoperative period and recovered on day 3. Serum ACTH was elevated. Under close observation without corticosteroid supplementation, the pigmentation faded on day 8 after surgery. On day 15, the pigmentation clearly disappeared and serum ACTH decreased to within the normal range. A month later, ACTH and all adrenal hormones were within normal range.
UNASSIGNED: We hypothesized that skin pigmentation appeared due to an imbalance of the hypothalamic-pituitary-adrenal (HPA) axis after resection of one adrenal gland. Skin pigmentation may be the first and early manifestation of adrenal insufficiency in patients who undergo unilateral adrenalectomy due to a non-Cushing\'s tumor. Therefore, a careful physical examination may allow early detection of adrenal insufficiency and optimal treatment planning.

Radiotherapy is a useful adjuvant treatment for patients with Cushing\'s disease that is not cured by surgery. In particular, Gamma Knife radiosurgery (GKRS) has been increasingly used worldwide as the preferred radiation technique in patients with persistent or recurrent Cushing\'s disease. The most widely accepted criterion for hormonal remission after GKRS is normalization of urinary free cortisol (UFC) levels. When a clear biological target is not identified, irradiation of the whole pituitary gland can be considered. The 5-year probability of remission is 65%-75%. Normalization of hypercortisolism usually occurs within 3 years from GKRS treatment and control of tumor growth is optimal, approaching more than 90%. No clear predictor of a favorable outcome has emerged up to now, except for the experience of the treating team. In the largest series, development of partial or complete hypopituitarism occurred between 15% and 36%. Severe side effects of GKRS, such as optic neuropathy and oculomotor palsy, are uncommon but have been documented in patients previously exposed to radiation. Recurrence of disease has been reported in as high as 16%-18% of the patients who achieved normalization of UFC levels in the two largest series, whereas smaller series did not describe late failure of GKRS. The reason for this discrepancy is unclear, as is the relationship between hormonal and tumoral recurrence. Another unresolved issue is whether treatment with adrenal blocking drugs can jeopardize the results of GKRS. GKRS is an effective second-line treatment in patients with Cushing\'s disease not cured by surgery. Hypopituitarism is the most frequent side effect of GKRS, whereas severe neurologic complications are uncommon in radiation-naïve patients.

Cushing\'s syndrome (CS) shows diverse signs such as centripetal obesity, moon face, and buffalo hump, which can complicate the diagnosis. Facial features including eyelid edema, as an underrecognized sign, can be diagnostic clues for an excess of corticoids in a CS patient.

The relevance of vasopressin (AVP) of magnocellular origin to the regulation of the endocrine stress axis and related behaviour is still under discussion. We aimed to obtain deeper insight into this process. To rescue magnocellular AVP synthesis, a vasopressin-containing adeno-associated virus vector (AVP-AAV) was injected into the supraoptic nucleus (SON) of AVP-deficient Brattleboro rats (di/di). We compared +/+, di/di, and AVP-AAV treated di/di male rats. The AVP-AAV treatment rescued the AVP synthesis in the SON both morphologically and functionally. It also rescued the peak of adrenocorticotropin release triggered by immune and metabolic challenges without affecting corticosterone levels. The elevated corticotropin-releasing hormone receptor 1 mRNA levels in the anterior pituitary of di/di-rats were diminished by the AVP-AAV-treatment. The altered c-Fos synthesis in di/di-rats in response to a metabolic stressor was normalised by AVP-AAV in both the SON and medial amygdala (MeA), but not in the central and basolateral amygdala or lateral hypothalamus. In vitro electrophysiological recordings showed an AVP-induced inhibition of MeA neurons that was prevented by picrotoxin administration, supporting the possible regulatory role of AVP originating in the SON. A memory deficit in the novel object recognition test seen in di/di animals remained unaffected by AVP-AAV treatment. Interestingly, although di/di rats show intact social investigation and aggression, the SON AVP-AAV treatment resulted in an alteration of these social behaviours. AVP released from the magnocellular SON neurons may stimulate adrenocorticotropin secretion in response to defined stressors and might participate in the fine-tuning of social behaviour with a possible contribution from the MeA.