Publications

Summary OBJECTIVE Sleeping sickness (African trypanosomiasis) is an anthropozoonosis transmitted by the tsetse fly. The treatments of choice are the antiparasitic agents suramin and/or melarsoprol. Experimental infection of animals with Trypanosoma brucei results in inflammatory lesions in the pituitary and/or the thyroid gland. In biochemical terms, these animals have hypothyroidism. We evaluated the functional integrity of the hypothalamic‐pituitary‐thyroid axis in patients with African trypanosomiasis before, during and after specific therapy. DESIGN Prospective, controlled, cross‐sectional study. PATIENTS AND MEASUREMENTS Sixty‐five patients with sleeping sickness (31 female, 34 male; aged 18–66; 32 with haemolymphatic sleeping sickness receiving suramin i.v., 33 with cerebral sleeping sickness receiving melarsoprol) and 13 control subjects (6 female, 7 male; aged 21–60) were enrolled in a cross‐sectional study after giving informed consent. Fourteen patients were studied shortly after admission for sleeping sickness, 19 in the middle of the course of treatment, 18 at the end of the 5‐week treatment period, and 14 patients after cure. All subjects underwent a TRH stimulation test at 1200 with bolus injection of 400 μ g TRH i.v. Blood was drawn for determination of fT3, fT4, TSH, rT3, TNF‐ α , IL‐1 and IL‐6 at 0 minutes and TSH at 60 minutes. All hormones and cytokines were determined by RIA or ELISA. RESULTS Baseline TSH concentrations (mean ± SEM) were elevated in unmedicated patients with sleeping sickness compared to normal subjects (2.6 ± 0.4 vs 1.4 ± 0.2 mU7l; P = 0.01), whereas f T3 (2.7± 0.5 vs 5.8 ± 0.3 pmol/l; P = 0.0002) and fT4 concentrations (10.3 ± 1.2 vs 15.4 ± 0.8 pmol/l; P = 0.007) were low. Stimulated TSH concentrations did not significantly differ from normal controls. Reverse T3 concentration in patients with sleeping sickness were normal (2.2 ± 0.3 vs 2.4 ± 0.2 nmol/l; P = NS). During the course of treatment, baseline TSH, f T3 and fT4 concentrations slowly returned to normal and were indistinguishable from controls after cure. Plasma concentrations of TNF‐α (16.0 ± 4.1 vs 2.9 ± 1.4 ng/l in controls; P=0.003) and interleukin‐6 (19.2 ± 7.3 vs 1.3 ± 0.2 ng/l; P = 0.0001), but not interleukin‐1 β (2.0 ± 0.2 vs 0.9 ± 0.2, ng/l P = NS), were elevated, when thyroid function impairment and disease activity were at their maximum, but gradually decreased into the normal range with therapy. We found a negative correlation between baseline cytokine concentrations and fT3 concentrations (TNF‐α: r = 0.34, P = 0.003; IL‐6: r =–0.43, P = 0.0001). CONCLUSIONS We conclude that unmedicated sleeping sickness is associated with significant impairment of thyroid function, which is reversed with specific therapy. Elevated TSH concentrations and low f T3 and f T4 concentrations suggest primary hypothyroidism in patients with sleeping sickness. However, an additional pituitary and/or hypothalamic component cannot be excluded. This impairment may be due to the elevated plasma cytokine concentrations found in these patients or may be the result of parasitic thyroiditis.

Leptin is secreted by the white adipose tissue and modulates energy homeostasis. Nutritional, neural, neuroendocrine, paracrine, and autocrine factors, including the sympathetic nervous system and the adrenal medulla, have been implicated in the regulation of leptin secretion. Classic congenital adrenal hyperplasia (CAH) is characterized by a defect in cortisol and aldosterone secretion, impaired development and function of the adrenal medulla, and adrenal hyperandrogenism. To examine leptin secretion in patients with classic CAH in relation to their adrenomedullary function and insulin and androgen secretion, we studied 18 children with classic CAH (12 boys and 6 girls; age range 2-12 yr) and 28 normal children (16 boys and 12 girls; age range 5-12 yr) matched for body mass index (BMI). Serum leptin concentrations were significantly higher in patients with CAH than in control subjects (8.1 +/- 2.0 vs. 2.5 +/- 0.6 ng/ml, P = 0.01), and this difference persisted when leptin values were corrected for BMI. When compared with their normal counterparts, children with CAH had significantly lower plasma epinephrine (7.1 +/- 1.3 vs. 50.0 +/- 4.2, P < 0.001) and free metanephrine concentrations (18.4 +/- 2.4 vs. 46.5 +/- 4.0, P < 0.001) and higher fasting serum insulin (10.6 +/- 1.4 vs. 3.2 +/- 0.2 microU/ml, P < 0.001) and testosterone (23.7 +/- 5.3 vs. 4.6 +/- 0.5 ng/dl, P = 0.003) concentrations. Insulin resistance determined by the homeostasis model assessment method was significantly greater in children with classic CAH than in normal children (2.2 +/- 0.3 vs. 0.7 +/- 0.04, P < 0.001). Leptin concentrations were significantly and negatively correlated with epinephrine (r = -0.50, P = 0.001) and free metanephrine (r = -0.48, P = 0.002) concentrations. Stepwise multiple linear regression analysis indicated that serum leptin concentrations were best predicted by BMI in both patients and controls. Gender predicted serum leptin concentrations in controls but not in patients with classic CAH. No association was found between the dose of hydrocortisone and serum leptin (r = -0.17, P = 0.5) or insulin (r = 0.24, P = 0.3) concentrations in children with CAH. Our findings indicate that children with classic CAH have elevated fasting serum leptin and insulin concentrations, and insulin resistance. These most likely reflect differences in long-term adrenomedullary hypofunction and glucocorticoid therapy. Elevated leptin and insulin concentrations in patients with CAH may further enhance adrenal and ovarian androgen production, decrease the therapeutic efficacy of glucocorticoids, and contribute to later development of polycystic ovary syndrome and/or the metabolic syndrome and their complications.

Abstract: Cushing disease (CD) is a common cause of endogenous hypercortisolism in childhood. Its skin manifestations include striae, facial acne, hirsutism, acanthosis nigricans, fungal infections, hyperpig‐mentation and easy bruisability. We followed 36 children and adolescents with CD (14 boys and 22 girls), to define the natural history of skin disease in endogenous hypercortisolism. Physical examination and 24 hour urinary free Cortisol (UFC) and 17‐hydroxycorticosteroid (17‐OHS) excretion values were obtained preoperatively and quarterly for 18 months. Preoperatively our patients exhibited purple subcutaneous striae (77.7%), steroid‐induced acne (58.3%), hirsutism (63.7% of the 22 girls), acanthosis nigricans (27.7%), ecchymoses (27.7%), hyperpigmentation (16.6%), and fungal infections (11.1%). The levels of UFC and 17‐OHS preoperatively were 351.84 ± 243.85 μg/m 2 /day (mean ± SD) and 17.92 ± 7.86 mg/g creatinine/day, respectively. No correlation was found between these levels and the severity of the lesions. All patients were cured. Symptoms decreased dramatically within the 3 postoperative months and progressively disappeared within the first year of the follow‐up period with the exception of light‐colored striae; they were present in 5.6% of the patients at 18 months postoperatively. No acanthosis nigricans or hyperpigmentation were observed at 3 months postoperatively. Hirsutism was not present at 9 months postoperatively. We conclude that in children with CD the skin is affected at multiple sites; however, the severity of the manifestations does not correlate with the biochemical indices of the disease. With the exception of striae, cutaneous effects of endogenous hypercortisolism completely heal within the first year after surgical cure of the disease.

It has been demonstrated that Brain-Derived Neurotrophic Factor (BDNF) is a mediator of neuroprotective and neuroplastic processes, and that serum BDNF is representative of central concentrations as well. Interestingly, there is evidence that BDNF levels are elevated in response to exercise. PURPOSE: This study aimed at investigating the acute and chronic effects of a full season swimming training on serum BDNF, both at rest and after a maximal exercise bout in young athletes. METHODS: Twelve well-trained male swimmers (14.08±1.0 yrs) participated in the study. Measurements were carried out at the beginning of the training season (T1) as well as pre- and post- taper of each of the two competitive periods (i.e., T2, T3 for the first macrocycle, and T4, T5 for the second macrocycle, respectively). At each of the above time points, blood samples were collected pre- and 1 hour post a maximal, 400m swimming testing. Serum BDNF levels were measured by ELISA. Adjustment for exercise-induced plasma volume changes was performed before data analysis. Two-way ANOVA with repeated measures was used for statistics. RESULTS: A significant pre-post testing difference was observed at T2 (p=0.048). In addition, a main effect of time was found among the 5 time points (T1-T5; p=0.000). Moreover, both pre- and post- testing responses had a similar profile exhibiting a decline from T1 to T3 (pre: 23,412±2,504 pg/ml vs 3,433±669 pg/ml, post: 23,004±3,410 pg/ml vs 2,743±550 pg/ml) and from T4 to T5 (pre: 19,428±1,097 pg/ml vs 11,993±969 pg/ml, post: 22,111±1,455 pg/ml vs 12,838±1,763 pg/ml), and an increase from T3 to T4 (pre: 3,433±669 pg/ml vs 19,428±1,097 pg/ml, post: 2,743±550 pg/ml vs 22,111±1,455 pg/ml). CONCLUSIONS: To the authors’ best knowledge this is the first study examining the acute and chronic BDNF responses during one season training in young athletes. These findings indicate that long-term swimming training can affect the resting and acute (pre-post testing) circulating BDNF in young swimmers.

There have been few reports of factitious Cushing syndrome. To characterize the clinical and laboratory features leading to this unusual diagnosis, we describe 6 patients (5 women, 1 man), ages 31-44, identified retrospectively among 860 patients evaluated for hypercortisolism at the National Institutes of Health Clinical Center. All six patients had multiple surgeries unrelated to Cushing syndrome and a history of depression or anxiety. Four patients had close contact with the medical profession, three a history of drug abuse, and three had undergone previous treatment for Cushing syndrome. The physical features of Cushing syndrome were variable and not helpful in the differential diagnosis with endogenous Cushing syndrome. Four patients had striking variability in urine-free cortisol (UFC) and 17-hydroxysteroid (17-OHCS) values from low to high. Adrenal computed tomography, performed in two patients, showed small adrenal glands (n = 1) or a left-sided mass (n = 1), and adrenal magnetic resonance imaging, performed in one patient, showed atrophic glands. Pituitary magnetic resonance imaging, carried out in four patients, was either normal (n = 1) or exhibited questionable signs of microadenoma (n = 3). Determination of synthetic glucocorticoids by high pressure liquid chromatography (HPLC) was positive in the four patients in whom it was performed. Factitious Cushing syndrome is a difficult diagnosis. To conserve time and resources, high pressure liquid chromatography analysis of urine steroids, the most definitive test for the factitious disorder, should be performed whenever there is clinical suspicion of glucocorticoid abuse.

Greek adolescent students experience high levels of educational stress during the school period. In this cross-sectional study, we examined various factors associated with educational stress in Greece. The study was conducted using a self-report questionnaire survey in Athens, Greece, between November 2021 and April 2022. We studied a sample of 399 students (61.9% females; 38.1% males, with a mean age of 16.3 years). We found that several factors, such as age, sex, study hours, and health status of the adolescents, were associated with the subscales of the Educational Stress Scale for Adolescents (ESSA), Adolescent Stress Questionnaire (ASQ), Rosenberg Self-Esteem Scale (RSES), and State-Trait Anxiety Inventory (STAI). Older age, female sex, family status, parental profession, and the number of study hours were positively associated with the amount of stress, anxiety and dysphoria-related symptoms reported by the students, including pressure from studying, worry about grades, and despondency. Future research studies are needed to aid specialized interventions for adolescent students to effectively deal with their academic challenges.