Janusz Pachucki

Polymorphic mature microRNAs from passenger strand of pre-miR-146a contribute to thyroid cancer

Prior work has shown that heterozygosity G/C of single nucleotide polymorphism (SNP rs2910164) within the precursor of microRNA-146a predisposes to PTC (odds ratio = 1.62, P = 0.000007) although the mechanism was unclear. Here, we show that GC heterozygotes differ from both GG and CC homozygotes by producing 3 mature microRNAs: 1 from the leading strand (miR-146a), and 2 from the passenger strand (miR-146a*G and miR-146a*C), each with its distinct set of target genes. TaqMan analysis of paired tumor/normal samples revealed 1.5- to 2.6-fold overexpression of polymorphic miR-146a* in 7 of 8 tumors compared with the unaffected part of the same gland. The microarray data showed that widely different transcriptomes occurred in the tumors and in unaffected parts of the thyroid from GC and GG patients. The modulated genes are mainly involved in regulation of apoptosis leading to exaggerated DNA-damage response in heterozygotes potentially explaining the predisposition to cancer. We propose that contrary to previously held views transcripts from the passenger strand of miRs can profoundly affect the downstream effects. Heterozygosity for polymorphisms within the premiR sequence can cause epistasis through the production of additional mature miRs. We propose that mature miRs from the passenger strand may regulate many genetic processes.

Type 2 iodothyronine deiodinase transgene expression in the mouse heart causes cardiac-specific thyrotoxicosis

Type 2 iodothyronine deiodinase (D2) catalyzes intracellular 3, 5, 3′ triiodothyronine (T3) production from thyroxine (T4), and its messenger RNA mRNA is highly expressed in human, but not rodent, myocardium. The goal of this study was to identify the effects of D2 expression in the mouse myocardium on cardiac function and gene expression. We prepared transgenic (TG) mice in which human D2 expression was driven by the α-MHC promoter. Despite high myocardial D2 activity, myocardial T3 was, at most, minimally increased in TG myocardium. Although, plasma T3 and T4, growth rate as well as the heart weight was not affected by TG expression, there was a significant increase in heart rate of the isolated perfused hearts, from 284 ±12 to 350 ± 7 beats/min. This was accompanied by an increase in pacemaker channel (HCN2) but not α-MHC or SERCA II messenger RNA levels. Biochemical studies and 31P-NMR spectroscopy showed significantly lower levels of phosphocreatine and creatine in TG hearts. These results suggest th...

Type I 5′-iodothyronine deiodinase activity and mRNA are remarkably reduced in renal clear cell carcinoma

The purpose of this study was to compare thyroid hormone metabolism between non-cancerous tumor-surrounding human kidney tissues and renal clear cell carcinomas (RCCC). The material consisted of samples taken from 10 RCCC patients of both sexes and three grades of differentiation, G1 to G3. We showed that, similar to rat tissue, type I 5′ monodeiodinase (5′DI) expression is heterogeneous within the human kidney. We also found a poor correlation between 5′DI activity and mRNA level in noncancerous tumor-surrounding tissue suggesting significant post-transcriptional regulation of 5′DI expression by an unidentified process in the human kidney. In all RCCC tissues both 5′DI activity and mRNA levels were undetectable. This suggests either loss of human 5′DI gene expression during neoplastic transformation or the origination of RCCC from a tubular cell type that does not express 5′DI.

The effect of surgical treatment of phaeochromocytoma on concomitant arterial hypertension and diabetes mellitus in a single–centre retrospective study

Introduction Phaeochromocytoma is one of the numerous causes of secondary hypertension. Furthermore, phaeochromocytoma may first present with type 2 diabetes mellitus. The objective of our study was to evaluate the effects of adrenalectomy on patient recovery with regards to normotension and well–controlled glycaemia. Material and methods The retrospective analysis involved 67 patients with phaeochromocytoma operated between 2006 and mid-2012. The pre–operative diagnoses were made in the departments of internal medicine and endocrinology. Based on laboratory tests and diagnostic imaging, we were able to confirm the diagnosis of phaeochromocytoma in 42 (62.7%) patients. We verified the influence of adrenalectomy on the level of patient recovery, with regards to normotension and glycaemic control: arterial pressure and fasting glycaemia levels were obtained on the day of hospital discharge, at follow–up 3 months post–operatively and 1 year after surgical intervention. Results Of the 67 patients operated for phaeochromocytoma, 48 (71.6%) were treated laparoscopically, whereas 19 (28.4%) underwent open adrenalectomy. Arterial hypertension was recorded in 53 (79.1%) cases. Furthermore, among this group, diabetes mellitus coexisted in 21 (31.3%) cases. Postoperatively, 70% of cases of arterial hypertension and 90% of type 2 diabetes mellitus were cured. Additionally, a high rate of patients reported a quantitative reduced use of antihypertensive medicines. Conclusions In the majority of patients, surgical treatment of symptomatic phaeochromocytoma leads to a regression of arterial hypertension, or a reduction of the number or doses of medicines taken in ones treatment, and glucose–intolerance symptoms.

Treatment of severe life threatening hypocalcemia with recombinant human teriparatide in patients with postoperative hypoparathyroidism — a case series

INTRODUCTION Hypocalcaemia is a common postoperative complication, both after the resection of parathyroid adenoma associated with primary hyperparathyroidism and after total thyroidectomy due to thyroid cancer or nodular goitre. For a few years, in patients with postoperative hypoparathyroidism and severe hypocalcaemia, who cannot discontinue intravenous calcium preparations even with the use of high vitamin D doses, attempts have been made to add recombinant human parathormone (rhPTH) to the treatment schedule. In this work, for the first time in Poland, we demonstrate the potential use of teriparatide for the treatment of severe hypocalcaemia based on three different cases of postoperative hypoparathyroidism. MATERIAL AND METHODS Case 1. Female (52) with postoperative hypoparathyroidism, after total thyroidectomy and the removal of lower left parathyroid gland due to hyperparathyroidism, several weeks after the surgery still required intravenous calcium infusions because of tetany symptoms. Just one month of teriparatide treatment at 20 μg/0.08 mL given in daily subcutaneous injections proved sufficient to control calcium levels with oral calcium and vitamin D preparations during the next few days until total resolution of hypocalcaemia symptoms and the achievement and maintenance of laboratory normocalcaemia in the following weeks. CASE 2 Female (33) with hypoparathyroidism following total thyroidectomy in 1996 because of papillary thyroid cancer, with congenital tubulopathy associated with renal loss of calcium and magnesium, and the symptoms of tetany recurring since the day of surgery, requiring intravenous calcium administration every 2-3 days. Currently, the patient has been hospitalised because of venous port infection, the only venous access, which made intravenous therapy impossible. Because of the life-threatening condition of the patient, bridging teriparatide treatment was prepared (20 μg/0.08 mL). Complete resolution of clinical symptoms of hypocalcaemia was obtained with teriparatide doses given every 8-12 hours, which made dose reduction possible. Case 3. Female (52) after major oncological surgery because of laryngopharyngeal and cervical oesophageal cancer with the removal of parathyroid glands, fed through PEG, was admitted to hospital with the symptoms of tetany. Despite treatment intensification, the patient experienced a hypocalcaemic crisis during hospitalisation. Teriparatide treatment at 2 × 20 μg/day resulted in the resolution of tetany symptoms, with gradual normalisation of calcium-phosphate balance parameters during the following days. CONCLUSIONS Based on the analysis of these cases, the conclusion was drawn that the use of recombinant human teriparatide allows for the control of severe hypocalcaemia requiring intravenous infusions of calcium in patients with postoperative hypoparathyroidism. (Endokrynol Pol 2016; 67 (4): 403-412).

Safety and effectiveness of symptomatic hyponatremia treatment according to the European Society of Endocrinology guidelines: a retrospective study

205 mean [SD] age, 74.2 [15.9] years) diagnosed and hospitalized with hyponatremia between Septem‐ ber 2014 and October 2015 in the Department of Internal Medicine and Endocrinology at the Medical University of Warsaw (Warsaw, Poland). Based on the diagnostic protocol recommended by the guideline,10 patients with nonhypotonic hyponatremia (n = 22) and with pseudohypona‐ tremia (n = 3) were excluded from further anal‐ ysis. The remaining 181 patients with hypotonic hyponatremia were stratified in terms of sever‐ ity of symptoms into 2 subgroups: 1) the study group with severe/moderately severe symptom‐ atic hyponatremia (n = 16), who received intrave‐ nous 150 ‐ml infusions of 3% saline prior to cause‐ ‐specific treatment and were subsequently ana‐ lyzed in terms of increase of natremia, improve‐ ment of symptoms, and occurrence of adverse events/complications; and 2) the control group without severe/moderately severe symptomat‐ ic hyponatremia (n = 165) who received cause‐ ‐specific treatment without 3% saline infusions. Severe symptomatic hyponatremia was defined as “any biochemical degree of hyponatremia with presence of severe symptoms including: vomiting, cardiorespiratory distress, abnormal somnolence, seizures, and coma”, and moderately symptomat‐ ic hyponatremia was defined as “any biochemical degree of hyponatremia with presence of moder‐ ately severe symptoms including: nausea without vomiting, confusion, and headache.”10 The differences in clinical and biochemical pa‐ rameters were assessed with the Statistica soft‐ ware package v.10 (StatSoft, Tulsa, Oklahoma, United States), using the Fisher exact test, t test or Mann–Whitney test, or Kruskal–Wallis analysis of variance as appropriate. Correlations between Introduction Hyponatremia (defined as serum sodium levels below 135 mmol/l) is the most frequent dyselectrolytemia in clinical practice, which may significantly complicate treatment and increase mortality of patients.1,2 Despite its high prevalence, proper diagnosis and treatment of hyponatremia are still a challenge for many physicians.3 Until 2014, the assumed strategy of hypona‐ tremia treatment was a diagnosis‐, mechanism‐, duration ‐based approach that was difficult to ap‐ ply in everyday practice. Some of the important elements of this strategy included the assess‐ ment of patient’s blood volume and calculation of sodium and potassium deficits, while the treat‐ ment depended on whether hyponatremia was acute or chronic, which is sometimes impossible to distinguish.4-9 Moreover, the previous strate‐ gies were focused more on biochemical goals than on the patient’s clinical condition, while these parameters may not correlate with one another. In 2014, the new clinical practice guideline re‐ garding diagnostic approach and treatment of hypotonic hyponatremia in adults was devel‐ oped.10 The authors of the guideline proposed an innovative approach based on adjustment of the treatment for the clinical status of the pa‐ tient and recommended using the 3% saline in‐ fusion as the primary treatment of symptomatic patients with hypotonic hyponatremia regardless of the cause. The aim of this retrospective study was to evaluate the safety and utility of the new guideline on diagnosis and treatment of hypona‐ tremia in everyday practice.

Laparoscopic treatment of adrenal cysts — own research and literature review

MATERIAL AND METHODS Over the last 18 months we operated on six patients with large adrenal gland cysts in our centre. This consisted of 8.2% of all patients treated in said period due to adrenal gland pathologies. On ruling out malignancy or parasitic nature of the lesions, all patients were surgically treated in order to excise the cysts while leaving the gland untouched. In five patients the cysts were resected but the adrenal gland was spared. However, in one patient the adrenal gland coated the entire cystic mass, which imposed performance of adrenalectomy in addition to cystectomy. During surgeries we tried not to clip the suprarenal vein, which we managed to do in four out of six cases. RESULTS A one-year remote follow-up period revealed no cyst recurrence in ultrasound or CT, and it was possible to visualise the remaining part of the adrenal gland in all cases. CONCLUSION Thus, in our opinion resection of benign cysts is well justified and recommendable.

Thyroid Hormone Receptor β (THRB) Is a Major Target Gene for Micro-RNAs Deregulated in Papillary Thyroid Carcinoma (PTC)

This article appears in The Journal of Clinical Endocrinology & Metabolism, published December 15, 2010, 10.1210/jc.2010-1594