The role of combined low-dose dexamethasone suppression test and desmopressin stimulation test in the diagnosis of persistent Cushing’s disease. Case report

Choroba Cushinga wiąże się z istotnym zwiększeniem śmiertelności wskutek powikłań przewlekłej hiperkortyzolemii. Wiadomo, że 50% nieleczonych chorych umiera w ciągu 5 lat. Leczeniem z wyboru jest przezklinowa, selektywna adenomektomia. Częstość nawrotów - nawet po skutecznym leczeniu operacyjnym - jest jednak duża i wynosi od 20-25% w okresie 5-letniej obserwacji. Autorzy przedstawiają przypadek 60-letniej kobiety po 2-krotnej operacji przysadki, z postępującymi powikłaniami w zakresie układu sercowo-naczyniowego, u której stwierdzono przetrwałą chorobę Cushinga. Rozpoznanie ustalono pomimo prawidłowych wartości oznaczeń ACTH i kortyzolu w surowicy oraz 17-OHKS w moczu dobowym, wykonanych w warunkach podstawowych oraz braku ewidentnych cech gruczolaka przysadki w obrazowaniu za pomocą rezonansu magnetycznego. Chorobę Cushinga rozpoznano na podstawie łącznego testu hamowania 1 mg deksametazonu i testu stymulacyjnego z zastosowaniem desmopresyny. Opisywany przypadek wskazuje na istotną rolę testów dynamicznych - w tym testu z desmopresyną po 1 mg deksametazonu - w trudnych diagnostycznie przypadkach choroby Cushinga. (Endokrynol Pol 2010; 61 (3): 312-317)Cushing’s disease is related to a significant increase in mortality due to chronic hypercortisolaemia complications. It is known that 50% of non-treated subjects die within 5 years. Transsphenoidal selective adenomectomy is the treatment of choice. The incidence of relapses, even following a successful surgical procedure, is high and reaches 20–25% during the 5-year follow-up period. The authors discuss the case of a patient, currently aged 60, after repeat pituitary surgery, with progressive cardiovascular complications, in whom persistent Cushing’s disease was diagnosed. The diagnosis was determined despite normal plasma ACTH, serum cortisol levels, and 17-OHCS concentrations in daily urine. There was also a lack of obvious pituitary adenoma features in the magnetic resonance imaging (MRI). Persistent Cushing’s disease was diagnosed based on the combined dexamethasone desmopressin test. The presented case points to the role of provocative testing, including the desmopressin test following 1 mg of dexamethasone, for diagnostically difficult cases of Cushing’s disease. (Pol J Endocrinol 2010; 61 (3): 312-317

Wczesne, pooperacyjne stężenie kortyzolu w surowicy w ocenie skuteczności przezklinowej operacji choroby Cushinga — badanie prospektywne

Introduction: Transsphenoidal surgery (TSS) is the treatment of choice for Cushing`s disease (CD). A proper assessment of the efficacy of surgical treatment is crucial in terms of patient prognosis. The aim of this study was to evaluate the usefulness of serum cortisol measurements performed on the first post-operative day as a predictor of TSS outcome. Material and methods: This prospective study involved 36 patients with CD who were operated on using the same surgical protocol and followed up for at least 18 months (median: 30 months). We investigated the relationship between serum cortisol measurements performed on the first post-operative day and the hormonal assessment of the pituitary-adrenal axis performed after 18 months of follow-up. The adopted criteria for remission were: serum cortisol within the referral range, normal circadian rhythm, and the ability of serum cortisol to suppress to values ≤ 1.8 μg/dL after 1 mg of dexamethasone. Results: The median serum cortisol on the first post-operative day was 1.98 μg/dL. 23 patients (63.9%) were regarded as cured. In all these cured cases, the post-op cortisol was ≤ 2.5. On the other hand, in the cases of the 13 patients (36.1%) for whom the remission of CD was not confirmed, the post-op cortisol was ≥ 2.5. Conclusion: Our prospective study demonstrated that early post-operative serum cortisol measurements can serve as a simple and useful test that predicts the remission of CD. Furthermore, a post-operative cortisol ≤ 2.5 can be considered as a forecast of CD remission.Wstęp: Leczeniem z wyboru w chorobie Cushinga jest selektywna przezklinowa adenomectomia. Ocena skuteczności operacji ma kluczowe znaczenie z punktu widzenia rokowania chorych. Celem pracy była prospektywna ocena przydatności oznaczeń kortyzolu w surowicy wykonanych w 1 dobie po operacji przezklinowej gruczolaka kortykotropowego dla oceny skuteczności leczenia operacyjnego. Materiał i metody: Badanie prospektywne obejmujące 36 pacjentów z chorobą Cushinga operowanych według identycznego protokołu operacyjnego i obserwowanych przez co najmniej 18 miesięcy (mediana: 30 mies.). Oceniano związek pomiędzy stężeniem kortyzolu w surowicy o godzinie 6.00 w 1 dobie po operacji przezklinowej a oceną hormonalną osi przysadkowo-nadnerczowej wykonaną w 18 miesiącu obserwacji pooperacyjnej. Jako kryteria remisji przyjęto: normalizację stężenia kortyzolu w surowicy, prawidłowy rytm dobowy oraz obniżenie stężenia kortyzolu do wartości poniżej 1,8 μg/dl w teście z 1 mg deksametazonu. Wyniki: Mediana stężenia kortyzolu w 1 dobie po operacji przysadki wyniosła 1,98 μg/dl. 23 pacjentów (63,9%) zostało uznanych za wyleczonych z choroby Cushinga. We wszystkich tych przypadkach stężenie kortyzolu w surowicy w 1 dobie po operacji było mniejsze lub równe 2,5 μg/dl. Jednocześnie u żadnego z 13 pacjentów (36,1%) ze stężeniem kortyzolu w 1 dobie po operacji powyżej 2,5 μg/dl nie potwierdzono remisji choroby Cushinga. Wnioski: W badaniu prospektywnym wykazano, iż wczesne, pooperacyjne oznaczanie stężenia kortyzolu w surowicy jest prostym i użytecznym badaniem zapowiadającym remisję choroby Cushinga. Wykazanie stężenia kortyzolu w surowicy mniejszego lub równego 2,5 μg/dL w 1 dobie po operacji przezklinowej może być traktowane jako czynnik prognozujący remisję choroby

Insights into the substrate specificity, structure, and dynamics of plant histidinol-phosphate aminotransferase (HISN6)

Histidinol-phosphate aminotransferase is the sixth protein (hence HISN6) in the histidine biosynthetic pathway in plants. HISN6 is a pyridoxal 5′-phosphate (PLP)-dependent enzyme that catalyzes the reversible conversion of imidazole acetol phosphate into L-histidinol phosphate (HOLP). Here, we show that plant HISN6 enzymes are closely related to the orthologs from Chloroflexota. The studied example, HISN6 from Medicago truncatula (MtHISN6), exhibits a surprisingly high affinity for HOLP, which is much higher than reported for bacterial homologs. Moreover, unlike the latter, MtHISN6 does not transaminate phenylalanine. High-resolution crystal structures of MtHISN6 in the open and closed states, as well as the complex with HOLP and the apo structure without PLP, bring new insights into the enzyme dynamics, pointing at a particular role of a string-like fragment that oscillates near the active site and participates in the HOLP binding. When MtHISN6 is compared to bacterial orthologs with known structures, significant differences arise in or near the string region. The high affinity of MtHISN6 appears linked to the particularly tight active site cavity. Finally, a virtual screening against a library of over 1.3 mln compounds revealed three sites in the MtHISN6 structure with the potential to bind small molecules. Such compounds could be developed into herbicides inhibiting plant HISN6 enzymes absent in animals, which makes them a potential target for weed control agents

Phenylpiperazine 5,5-dimethylhydantoin derivatives as first synthetic inhibitors of Msr(A) efflux pump in Staphylococcus epidermidis

Herein, 15 phenylpiperazine 3-benzyl-5,5-dimethylhydantoin derivatives (1–15) were screened for modulatory activity towards Msr(A) efflux pump present in S. epidermidis bacteria. Synthesis, crystallographic analysis, biological studies in vitro and structure–activity relationship (SAR) analysis were performed. The efflux pump inhibitory (EPI) potency was determined by employing ethidium bromide accumulation assay in both Msr(A) efflux pump overexpressed (K/14/1345) and deficient (ATCC 12228) S. epidermidis strains. The series of compounds was also evaluated for the capacity to reduce the resistance of K/14/1345 strain to erythromycin, a known substrate of Msr(A). The study identified five strong modulators for Msr(A) in S. epidermidis. The 2,4-dichlorobenzyl-hydantoin derivative 9 was found as the most potent EPI, inhibiting the efflux activity in K/14/1345 at a concentration as low as 15.63 µM. Crystallography-supported SAR analysis indicated structural properties that may be responsible for the activity found. This study identified the first synthetic compounds able to inhibit Msr(A) efflux pump transporter in S. epidermidis. Thus, the hydantoin-derived molecules found can be an attractive group in search for antibiotic adjuvants acting via Msr(A) transporter

Chalcogen-Varied Imidazolone Derivatives as Antibiotic Resistance Breakers in Staphylococcus aureus Strains

In this study, a search for new therapeutic agents that may improve the antibacterial activity of conventional antibiotics and help to successfully overcome methicillin-resistant Staphylococcus aureus (MRSA) infections has been conducted. The purpose of this work was to extend the scope of our preliminary studies and to evaluate the adjuvant potency of new derivatives in a set of S. aureus clinical isolates. The study confirmed the high efficacy of piperazine derivatives of 5-arylideneimidazol-4-one (7–9) tested previously, and it enabled the authors to identify even more efficient modulators of bacterial resistance among new analogs. The greatest capacity to enhance oxacillin activity was determined for 1-benzhydrylpiperazine 5-spirofluorenehydantoin derivative (13) which, at concentrations as low as 0.0625 mM, restores the effectiveness of β-lactam antibiotics against MRSA strains. In silico studies showed that the probable mechanism of action of 13 is related to the binding of the molecule with the allosteric site of PBP2a. Interestingly, thiazole derivatives tested were shown to act as both oxacillin and erythromycin conjugators in S. aureus isolates, suggesting a complex mode of action (i.e., influence on the Msr(A) efflux pump). This high enhancer activity indicates the high potential of imidazolones to become commercially available antibiotic adjuvants

Quality of life in patients with acromegaly receiving lanreotide autogel: a real-world observational study

Introduction: Patients with acromegaly have substantially reduced quality of life (QoL). This study evaluated QoL in patients with acromegaly treated with lanreotide autogel. Material and methods: This was a prospective, non-interventional, observational, multi-centre study conducted in Poland (NCT02396966). We included patients with acromegaly, who received treatment with lanreotide autogel 120 mg for ≥ 3 months and < 3 years. Patients were assessed approximately every 4–5 months for two years (six visits). QoL was measured with the Acromegaly Quality of Life Questionnaire (AcroQoL). Results: Of 152 patients enrolled from November 2014 to May 2018 in 37 centres, 24 were excluded due to major protocol deviations. The results are reported for the study population (n = 128). At baseline, the median [95% confidence interval (CI)] time from diagnosis was 3.3 (2.8, 4.2) years, and the median time since lanreotide initiation was 13.4 (9.9, 17.3) months. Symptoms of acromegaly were present at baseline in 86% of patients (headache, 57%; sweating, 58%; joint symptoms, 64%); symptoms remained unchanged at two years in 82% of patients. At baseline, 27% of patients had hormonal control (growth hormone < 2.5 μg/L and insulin-like growth factor-1 within the normal range); hormonal control status did not change during the study period in over 81% of patients. At baseline, 88% of patients were either very satisfied or satisfied with treatment; treatment satisfaction was unchanged in 62% of patients over the study period. Mean (95% CI) AcroQoL scores at baseline were as follows: total, 50.3 (47.3, 53.3); physical dimension, 48.8 (45.2, 52.4); psychological dimension, 51.3 (48.2, 54.4); appearance subdimension, 40.7 (37.5, 43.8); and personal relations subdimension, 62.5 (58.8, 66.2). The psychological appearance subscore improved by 3.8 points (1.2, 6.5) over the two years; scores in the remaining dimensions and subdimensions did not change substantially. The total AcroQoL score remained unchanged over the two years, regardless of prior acromegaly treatment, surgery or radiotherapy, hormonal control, or lanreotide dosing interval. No new safety findings were identified. Conclusions: AcroQoL total scores and physical and psychological subscores remained stable but impaired among patients with long-lasting acromegaly treated with lanreotide autogel for two years. The psychological appearance subdimension improved numerically

Therapeutic effect of presurgical treatment with longacting octreotide (Sandostatin® LAR®) in patients with acromegaly

Introduction: The aim of this study was to assess the therapeutic effect and the safety of pre surgical treatment with long-acting octreotide in patients with acromegaly. Material and methods: This project was conducted in 25 centres across Poland as a non interventional, multicentre, observational study in patients with acromegaly, in which long-acting octreotide (Sandostatin® LAR®) was administered before surgery. They were 148 patients included into the study: 88 females and 60 males aged 18–86 years (51.3 ± 13.4). Results: Eighty patients completed the study (underwent tumour surgery). The CRF included: baseline visit, four follow-up visits every three months before surgery, and two follow-up visits every three months after surgery. Sandostatin® LAR® was administered every four weeks. The efficacy measures were as follows: change of growth hormone (GH) and insulin-like growth factor 1 (IGF-1) levels, number of patients fulfilling criteria of cure, and change of adenoma (micro- and macroadenomas) size during the treatment. Normalisation of GH and IGF-1 concentrations were obtained in 42.4 and 49.1% of patients at the end of medical therapy, respectively. Normalisation of GH and IGF-1 concentrations were obtained in 77.9 and 83.8% of patients after surgery, respectively. Reduction of microadenoma size was documented in 58.8% of patients, and in 70% of patients with macroadenomas at the end of medical therapy. In 74.0% of patients no pituitary tumour was shown on MRI after surgery. Conclusion: In conclusion, we have shown good surgical outcome in patients with acromegaly after pre-treatment with somatostatin analogue, and good tolerance and safety of the therapy, supporting the national recommendation for pre-surgical treatment with longacting somatostatin analogues in acromegaly patients

Survivin expression at the mRNA level in tumors and the protein concentration in the serum and peritoneal fluid in patients with serous ovarian tumors

Objectives: Ovarian cancer is one of the gynecological cancers that have the worst prognosis. The expression of the proteins from the IAP family (inhibitor of apoptosis protein), including survivin, is observed in many types of cancer. The aim of the study was to evaluate survivin at the mRNA level in tumors and the protein concentration in the serum and peritoneal fluid of patients with serous ovarian cancer in order to assess the relationship between the concentration of survivin and the histological subtypes of cancer. Material and methods: The study group consisted of 55 women, including patients with serous ovarian cancer (n = 30, nine low-grade serous carcinoma LGSC, 21 high-grade serous carcinoma HGSC), serous cysts (n = 10) and the control group (n = 15). The concentration of protein in the peritoneal fluid and serum was assessed using ELISA tests. The expression of survivin gene BIRC5 in the tumors was assessed using the RT-qPCR method. Results: The data that was obtained indicated that the concentration of survivin was higher in the serum of the women with serous ovarian cancer compared those that had benign tumors (p < 0.05) and the control group (p < 0.001). The survivin concentration was also higher in both the serum and peritoneal fluid in the HGSC group compared to the LGSC group (p < 0.001). The mRNA level was highest in the HGSC group, and there was a statistically significant difference compared to those in the benign tumor group and HGSC group ( p < 0.05). Conclusions: The observed changes prove that the expression level increases significantly in HGSC in both the protein and mRNA levels. Based on these findings, it can be assumed that assessing this parameter could be a useful additional indicator of the progression and differentiation of this type of cancer. However, this requires further research in a larger group of patients and possibly in other types of ovarian cancer

Molecular Insights into an Antibiotic Enhancer Action of New Morpholine-Containing 5-Arylideneimidazolones in the Fight against MDR Bacteria

In the search for an effective strategy to overcome antimicrobial resistance, a series of new morpholine-containing 5-arylideneimidazolones differing within either the amine moiety or at position five of imidazolones was explored as potential antibiotic adjuvants against Gram-positive and Gram-negative bacteria. Compounds (7–23) were tested for oxacillin adjuvant properties in the Methicillin-susceptible S. aureus (MSSA) strain ATCC 25923 and Methicillin-resistant S. aureus MRSA 19449. Compounds 14–16 were tested additionally in combination with various antibiotics. Molecular modelling was performed to assess potential mechanism of action. Microdilution and real-time efflux (RTE) assays were carried out in strains of K. aerogenes to determine the potential of compounds 7–23 to block the multidrug efflux pump AcrAB-TolC. Drug-like properties were determined experimentally. Two compounds (10, 15) containing non-condensed aromatic rings, significantly reduced oxacillin MICs in MRSA 19449, while 15 additionally enhanced the effectiveness of ampicillin. Results of molecular modelling confirmed the interaction with the allosteric site of PBP2a as a probable MDR-reversing mechanism. In RTE, the compounds inhibited AcrAB-TolC even to 90% (19). The 4-phenylbenzylidene derivative (15) demonstrated significant MDR-reversal “dual action” for β-lactam antibiotics in MRSA and inhibited AcrAB-TolC in K. aerogenes. 15 displayed also satisfied solubility and safety towards CYP3A4 in vitro