International Union of Basic and Clinical Pharmacology. CVII. Structure and Pharmacology of the Apelin Receptor with a Recommendation that Elabela/Toddler Is a Second Endogenous Peptide Ligand.

The predicted protein encoded by the APJ gene discovered in 1993 was originally classified as a class A G protein-coupled orphan receptor but was subsequently paired with a novel peptide ligand, apelin-36 in 1998. Substantial research identified a family of shorter peptides activating the apelin receptor, including apelin-17, apelin-13, and [Pyr1]apelin-13, with the latter peptide predominating in human plasma and cardiovascular system. A range of pharmacological tools have been developed, including radiolabeled ligands, analogs with improved plasma stability, peptides, and small molecules including biased agonists and antagonists, leading to the recommendation that the APJ gene be renamed APLNR and encode the apelin receptor protein. Recently, a second endogenous ligand has been identified and called Elabela/Toddler, a 54-amino acid peptide originally identified in the genomes of fish and humans but misclassified as noncoding. This precursor is also able to be cleaved to shorter sequences (32, 21, and 11 amino acids), and all are able to activate the apelin receptor and are blocked by apelin receptor antagonists. This review summarizes the pharmacology of these ligands and the apelin receptor, highlights the emerging physiologic and pathophysiological roles in a number of diseases, and recommends that Elabela/Toddler is a second endogenous peptide ligand of the apelin receptor protein.

Thymic Neuroendocrine Neoplasms: Biological Behaviour and Therapy.

Thymic neuroendocrine neoplasms are rare tumours, but their management can often be highly problematic. While previously assumed to be essentially variants of bronchopulmonary (lung) carcinoids, they are generally more aggressive and more difficult to treat. Some 25% are associated with multiple endocrine neoplasia-1, while a higher proportion are associated with the ectopic ACTH syndrome, and occasionally both. We discuss the classification of these tumours, their biology as far as is known, and their clinical, biochemical and imaging features. We also review possible management options and suggest stratagems to optimise their treatment, which even today is far from optimal.

Endocrinological outcomes of pure endoscopic transsphenoidal surgery: a Croatian Referral Pituitary Center experience.

AIM: To analyze early remission, complications, and pituitary function recovery after pure endoscopic endonasal transsphenoidal surgery (PEETS), a novel method in pituitary adenoma treatment. METHODS: Testing of all basal hormone values and magnetic resonance imaging (MRI) were performed preoperatively and postoperatively (postoperative MRI only in nonfunctioning adenomas) in 117 consecutive patients who underwent PEETS in the period between 2007 and 2010. The series consisted of 21 somatotroph adenomas, 61 prolactinomas, and 4 corticotroph and 31 nonfunctioning adenomas. Sixty-three were macroadenomas and 54 were microadenomas. Remission was defined as hormonal excess normalization on the seventh postoperative day in functioning adenomas and as normal MRI findings approximately four months postoperatively in nonfunctioning adenomas. The presence of hypogonadism, growth hormone deficiency, and hypothyroidism was assessed on the seventh postoperative day. Hypocortisolism was assessed through necessity for replacement therapy within 18 months postoperatively. RESULTS: Remission was achieved in 84% of patients: in 100% of microadenoma and 70% of macroadenoma patients (P<0.001, odds ratio [OR], 28.16, 95% confidence interval [CI], 1.61-491.36), respectively. Endocrinological complications occurred in 17.1% of patients: in 9% of microadenoma and 24% of macroadenoma patients (P=0.049, OR, 3.06; 95% CI, 1.03-9.08). Duration of empirical hydrocortisone replacement therapy was significantly shorter in microadenoma patients (P<0.001). Thirty-five percent of preoperatively present hormonal deficiencies improved after the surgery. Between tumor types there were no significant differences in remission, complications, and normal pituitary function recovery. CONCLUSION: Patients with microadenomas had higher remission and lower complication rates following PEETS, emphasizing the necessity for early detection and treatment of pituitary adenomas. PEETS is a discussion-worthy method for microprolactinoma treatment.

Development and validation of an LC-MS/MS method for detection and quantification of in vivo derived metabolites of [Pyr1]apelin-13 in humans.

[Pyr1]apelin-13 is the predominant apelin peptide isoform in the human cardiovascular system and plasma. To date, few studies have investigated [Pyr1]apelin-13 metabolism in vivo in rats with no studies examining its stability in humans. We therefore aimed to develop an LC-MS/MS method for detection and quantification of intact [Pyr1]apelin-13 and have used this method to identify the metabolites generated in vivo in humans. [Pyr1]apelin-13 (135 nmol/min) was infused into six healthy human volunteers for 120 minutes and blood collected at time 0 and 120 minutes after infusion. Plasma was extracted in the presence of guanidine hydrochloride and analysed by LC-MS/MS. Here we report a highly sensitive, robust and reproducible method for quantification of intact [Pyr1]apelin-13 and its metabolites in human plasma. Using this method, we showed that the circulating concentration of intact peptide was 58.3 ± 10.5 ng/ml after 120 minutes infusion. We demonstrated for the first time that in humans, [Pyr1]apelin-13 was cleaved from both termini but the C-terminal was more susceptible to cleavage. Consequently, of the metabolites identified, [Pyr1]apelin-13(1-12), [Pyr1]apelin-13(1-10) and [Pyr1]apelin-13(1-6) were the most abundant. These data suggest that apelin peptides designed for use as cardiovascular therapeutics, should include modifications that minimise C-terminal cleavage.

[Relationship of regional alcohol drinking habit and cardiovascular risk factors in Croatia]. / Usporedba regionalne potrosnje alkoholnih pica i kardiovaskularnih cimbenika rizika u Hrvatskoj.

AIM: The aim was to investigate regional distribution of drinking habit and its relation to the prevalence of cardiovascular risk factors. SUBJECTS AND METHODS: Nine thousand and seventy participants older than 18 questioned during THE 2003 Croatian health Survey were analyzed and weighted data extrapolated to the adult Croatian population. Study group included subjects reporting regular intake of any type of alcohol drink (liquor, wine or beer) during the past year. Alcohol abstainers surved as a control group. RESULTS: The highest prevalence of alcohol drinking was recorded in south Croatia (32.3%, n= 215529). Alcohol drinkers were mostly men (72%). In all Croatian regions there was a rather uniform distribution of liquor drinking (6-7 glasses, 0.033 L per day). Subjects from west Croatia and the City of Zagreb mostly reported drinking wine (4-5 glasses, 0.2 L per day). A mixture of wine and water predominated in south and north Croatia (7 glasses, 0.2 L per day), whereas subjects that mainly took beer were from east and central Croatia (10 bottles, 0.33 L per day). The highest prevalence of arterial hypertension (56.6%) was found in regular alcohol drinkers from west Croatia. The highest prevalence of acute myocardial infarction (6.7-7.0%) and angina pectoris (8.2-8.6%) was observed in subjects from northn Croatia and the City of Zagreb. However, the occurrence of acute myocardial infarction was more common in regular alcohol drinkers, and of angina in abstainers. The lowest prevalence of acute myocardial infarction was recorded in regular drinkers from central Croatia (1.4%). The prevalence of stroke was generally lower in regular drinkers, with lowest prevalence in west Croatia (0.9%). CONCLUSION: Drinking habit varies among regions of the Republic of Croatia, according to the prevalence, quantity and type of alcohol beverage, and so does the distribution of cardiovascular risk factors. On comparing regional distribution of cardiovascular risk factors between regular consumers and abstainers we observed a divergent influence of alcohol consumption, especially on the occurrence of arterial hypertension and stroke.

Chronic, long-lasting, and untreated gout with concomitant dilated cardiomyopathy and exceptionally vast anasarca: case report.

Gout is the most common type of inflammatory arthritis in man caused by deposition of urate crystals into the joints as the result of elevated serum urate levels. A case of a 59-year-old patient with untreated, long-lasting gout and clinical manifestation of decompensated global dilated cardiomyopathy is presented. Examination revealed generalized pitting edema extending from both lower extremities to the sacrum, abdominal, and thoracic wall, with scrotal swelling and upper extremity involvement, an exceptionally vast generalized edema, i.e. anasarca. Proximal and distal interphalangeal joints of the hands and feet were swollen and deformed, with marked yellow tophi nodules. Laboratory studies revealed high serum uric acid concentration (546 micromol/L), decreased creatinine clearance (0.8 mL/s) and albumin concentration (27.4 g/L), as well as increased total urine protein mass (0.35 g/24 h). X-rays of the affected feet and fists showed punched-out lesions of the subchondral bone with overhanging bony margins in the first metatarsophalangeal, proximal, and distal interphalangeal joints of both hands. The extreme clinical presentation resolved upon intravenous administration of diuretics and pleurocentesis, followed by oral medications including furosemide, angiotensin-converting enzyme inhibitor, spironolactone and digoxin. Since serum urate level has been identified as an independent risk factor for the development of ischemic heart and chronic kidney disease, regulation of urate concentration is necessary, especially in patients diagnosed with gout.

Xanthogranuloma of the sellar region in a patient with sarcoidosis.

Xanthogranuloma of the sellar region is a very rare brain tumor with favorable prognosis and without reported relapses of purely xanthogranulomatous lesion after complete resection. A case is presented of a 40-year-old male diagnosed with and treated for sarcoidosis, complaining of headache, photophobia and loss of libido. Physical examination revealed generally scarce hairiness, while laboratory investigations showed panhypopituitarism. Expansive sellar and suprasellar mass compressing the floor of the third ventricle and optical chiasm was confirmed by cranial multi-slice computerized tomography (MSCT). Complete resection of the tumor mass using trans-sphenoidal approach was performed. Histopathologic analysis revealed cholesterol clefts, sparse lymphoplasmacellular infiltrates, macrophages, siderophages and foreign body giant cells around cholesterol clefts confirming the diagnosis of xanthogranuloma of the sellar region. Since preoperative diagnosis of xanthogranuloma is very difficult, therapeutic algorithm does not differ from other expansive lesions of the sellar region, but pituitary involvement should always be considered in patient with sarcoidosis since therapeutic management is non-surgical. Follow up MSCT imaging after 6 months revealed a solid, contrast-enhanced mass at the posterior base of the sella.

Hypopituitarism caused by pituitary metastasis of supraglottic laryngeal carcinoma: case report.

Intracranial metastases from laryngeal carcinoma are rarely clinically diagnosed. To our knowledge, this is the first report of hypopituitarism due to pituitary metastasis from laryngeal carcinoma. We report on a 70-year-old man who had a supraglottic squamous cell carcinoma, which was resected surgically followed by local full dose radiation therapy. Four months later, he presented with a sudden onset of diplopia, syncope, headache, general malaise and loss of appetite. Magnetic resonance imaging of the brain revealed a tumorous process of the sellar region. Endocrinological tests disclosed the presence of hypopituitarism. The tumor was subtotally resected endoscopically via endonasal transsphenoidal approach. Histopathology of tumor specimens indicated squamous cell carcinoma. Tumors of the sellar and parasellar region as in the case presented may easily be confused with pituitary adenoma. Pituitary metastases should be considered on differential diagnosis of unusual pituitary tumors, especially in patients with as well as in those without a history of malignant disease.

Pedunculated myolipoma incidentally found in hernial sac: a case report.

A case of a very rare adipocytic tumor found during corrective surgery for incisional abdominal hernia is presented. Because of uterine leiomyomas the patient underwent total abdominal hysterectomy 14 years before. During surgery of incisional hernia, a part of small intestine along with a pedunculated tumor was found in hernial sac. The tumor was attached to the medial intra-abdominal peritoneum. On examination, the tumor presented as a totally encapsulated dimorphic benign neoplasm composed of mature adipocytes and well-differentiated smooth muscle cells. Lipoblasts, floret-like giant cells, nuclear atypia, mitosis or proliferation of medium-sized arteries with thick muscular walls were not observed. Tumor cells were negative for HMB45, estrogen and progesterone. The diagnosis of myolipoma was established. This tumor commonly presents as a large quiescent mass in retroperitoneum in adult females and to our knowledge this is the first report of myolipoma in hernial sac. Characteristic findings, differential diagnosis, prognosis and the possible origin of such a neoplasm are discussed.

Mucinous cystadenoma arising in an isolated ileal duplication cyst.

INTRODUCTION: A 64-year-old woman with a 2-year history of bilateral breast carcinoma with axillary node metastasis and chemotherapy was admitted to our hospital due to tumor attached to the ileum, discovered during the routine control examination. DISCUSSION: Computerized axial tomography showed oval cystic tumor in terminal ileum that measured 7 cm in the largest diameter and shared peritoneal coat with small intestine and was filled with dense fluid. Tumor abutted intestine but did not communicate with intestinal lumen. The surgical procedure was simple because cyst was attached to the antimesenteric side of the terminal ileum and did not communicate with the adjacent intestine. Pathohistological examination showed mucinous cystadenoma with high-grade epithelial dysplasia in the isolated ileal duplication cyst. The presence of epithelial dysplasia found in duplication cyst suggested potential to undergo malignant transformation. CONCLUSION: In conclusion, we report a unique case of mucinous cystadenoma arising in isolated ileal duplication cyst. This case report expands the potential range of clinical variability of alimentary tract duplications. Surgical removal of alimentary tract duplication in patients without symptoms is also recommended because many potential complications or even malignant transformation may result from these anomalies.