Management of thyroiditis in the context of Covid-19: cause-effect and beyond.

Background: The COVID-19 pandemic hit the world in late 2019, and by 2020, everyone was affected. Severe acute respiratory syndrome coronavirus 2 (SARS CoV-2) belongs to the beta-coronavirus genre and uses the angiotensin-converting enzyme 2 (ACE2) receptor to penetrate cells. Thyroid cells are rich in such receptors. Therefore, this gland is frequently involved alongside other organs in the COVID-19 disease. Aim: To describe COVID-19 inflammation and, eventually, dysregulations of normal thyroid function in a case series of patients diagnosed in a tertiary endocrinology care centre. Patients and Methods: We described subacute thyroiditis cases related to COVID-19 infection or vaccination against SARS-CoV2 infection (clinical manifestations and evolution). We also reviewed the literature data regarding COVID-19 infection or vaccination implications in thyroid pathology. Results: The literature describes two types of thyroid involvement in SARS-CoV2 infection or vaccination: subacute thyroiditis (SAT) and non-thyroidal illness syndrome (NTIS). In our case series, 5 patients (3 males), aged 41-54 years, developed the classical clinical manifestation of SAT related to COVID-19 infection (3 patients, concomitantly to upper respiratory infection or a few weeks apart) or anti-SARS-CoV2 ARNm vaccination (1-2 weeks after the vaccine administration). Clinical, laboratory and imaging findings and the evolution (steroid anti-inflammatory treatment used in 4/5 cases) were unremarkable compared to other SAT etiologies. Conclusion: We found no differences between the "typical" viral and post-COVID-19 SAT regarding clinical presentation, severity, response to treatment, and thyroid function alteration. The only remarkable difference is the association of SAT with anti-SARS-CoV2 ARNm vaccination.

CHALLENGES OF AN OVARIAN NEUROENDOCRINE METASTASIS OF ADVANCED SMALL-CELL LUNG CARCINOMA - LITERATURE REVIEW AND CASE REPORT.

Metastatic tumors account for 5-10% of all ovarian malignancies. They are usually bilateral tumors with a multinodular surface and extensive extra ovarian spread. Lung cancer is a rare source (0.3% of metastatic ovarian tumors). Among synchronous primary cancers, ovarian cancer is most frequently associated with endometrial cancer. The differential diagnosis between a primary ovarian carcinoma, synchronous primary cancers, and metastatic ovarian carcinoma is very important, as the treatment and prognosis are markedly different. We report the case of a 25-year-old woman who had been diagnosed and treated for stage IIIB small cell lung carcinoma (SCLC). Imaging undertaken for abdominal pain revealed a unilateral 8.5 cm ovarian tumor for which adnexectomy was performed. Histology and immunohistochemistry led to the diagnosis of ovarian metastasis from SCLC, a high-grade neuroendocrine lung tumor. This patient's particular features, all infrequent in a metastatic tumor, are the lesion's unilaterality (atypical for ovarian metastases in other cancers, but often observed in SCLC), the smooth ovarian surface with intact capsule, and the absence of intra-abdominal dissemination. The patient developed liver and vertebral metastases. This report focuses on the differential diagnosis between primary and metastatic ovarian neoplasms. We performed an extensive search of the literature on SCLC and ovarian metastases. Immunohistochemistry is essential for diagnosis when imaging and the pathological evaluation of the ovarian tumor cannot make the differential diagnosis.

Iatrogenic Cushing's syndrome as a consequence of nasal use of Betamethasone spray during pregnancy.

INTRODUCTION: Glucocorticoids (GC) are largely used for their anti-inflammatory and immunosuppressive effects. Until recently "local" administration (inhalation, topical, intra-articular, ocular and nasal) was considered devoid of important systemic side effects, but there is no administration form, dosing or treatment duration for which the risk of iatrogenic Cushing's syndrome (CS) and consequent adrenal insufficiency (AI) can be excluded with certainty. PATIENTS AND METHODS: We present the case of a pregnant woman who developed overt CS with secondary AI in the second trimester of pregnancy. She had low morning plasma cortisol 6.95 nmol/L (normal non-pregnant range 166 - 507) and low ACTH level 1.54 pg/mL (normal range 7.2 - 63.3), suggestive for iatrogenic CS. A thorough anamnesis revealed chronic sinusitis long-term treated with high doses of intranasal betamethasone spray (6 - 10 applications/day, approximately 10 mg betamethasone/week, for 5 months). After decreasing the dose and switching to an alpha-1 adrenergic agonist spray, the adrenal function recovered in a few weeks without manifestations of AI. The patient underwent an uneventful delivery of a normal baby. A review of the literature showed that only a few cases with exogenous CS and consequent AI caused by intranasal GC administration were described, mostly in children, but none during pregnancy. CONCLUSION: Long-term high doses of intranasal GC may induce iatrogenic CS and should be avoided. Low levels of ACTH and cortisol should prompt a detailed anamnesis looking for various types of glucocorticoid administration.

NEONATAL SCREENING FOR CONGENITAL HYPOTHYROIDISM IN ROMANIA: DATA FROM MEDILOG MEDICAL INFORMATION REGISTRY.

OBJECTIVE: Congenital hypothyroidism (CH) is one of the common preventable causes of intellectual disability in neonates, by early detection through neonatal screening. We present the 8-year experience of the National Institute for Mother and Child Health (INSMC) in using MEDILOG national registry for the neonatal screening of CH. METHODS: Neonatal screening for CH, done by TSH measurement in dried blood spot, is organized in 5 regional centers, each with a reference laboratory. RESULTS: In 2018 80% of all the newborns, from 80% of the maternity hospitals, were registered in MEDILOG. After re-testing of TSH and T4/FT4 from venous blood in positive cases, the incidence of confirmed CH in 2018 was 1/3576 - 1/ 4746. In INSMC center (which includes 26 counties and Bucharest, out of 41 counties), in 2018 the incidence of positive CH cases at screening was 1/2094 (TSH cut-off ≥17 mIU/L) and of confirmed CH cases 1/3576 newborns. For positive screening cases, the median duration from birth to the INSMC laboratory result was 19 days: median of 9 days between screening and laboratory registration and 6 days between registration and test result. CONCLUSION: MEDILOG registry is a practical instrument for monitoring the steps of neonatal CH screening, the incidence of CH, the evolution of the diagnosed cases, for evaluation of iodine deficiency (by neonatal TSH), and also for research, with the aim of improving early disease detection and treatment.

HORMONAL THERAPY IN WOMEN OF REPRODUCTIVE AGE WITH ENDOMETRIOSIS: AN UPDATE.

Medical therapy of endometriosis is under continuous reevaluation. Hereby we updated the drugs currently available or under investigation for the hormonal treatment of endometriosis.

PHEOCHROMOCYTOMA-PARAGANGLIOMA: TRANSLATIONAL APPROACH FROM GENETICS TO CLINICAL NEUROENDOCRINOLOGY.

In the latest decade, translational medicine has played an important role. In neuroendocrine tumor field, genetic results are associated with clinical and paraclinical disease implications. This translational knowledge allows a faster action in some mutation types with aggressive outcome. In the following pages we will make a review about actualities in translational approach from genetics to clinical neuroendocrinology.

NEWS IN ACROMEGALY.

Recent updates on the epidemiology, diagnosis, complications and therapy in acromegaly have been published in the 1st 2017 issue of Pituitary journal. A review of 12 epidemiological studies published since 2004 shows that the prevalence of acromegaly ranges 2.8 - 13.7 cases per 100,000 people and the annual incidence rates range 0.2 - 1.1 cases/100,000 people. The median age at diagnosis ranges between 40.5 and 47 years. At the time of diagnosis, over 2/3 of the patients have macroadenomas. Acromegalic osteopathy is characterized by increase in bone turnover, alterations in bone microarchitecture and high risk of vertebral fractures, which occur in about 1/3 of acromegaly patients. Fractures may occur even in the presence of normal bone mineral density (BMD), in close relationship with male gender, hypogonadism, and active acromegaly. Following treatment for acromegaly in 48 patients, the mean trabecular bone score decreased by 3.0 (±7.0) %, whereas BMD at the lumbar spine increased by 3.2 (±4.9) % (both P<0.01). Alterations in trabecular bone architecture may explain the persistent fracture risk despite the increase in BMD after disease control. Stereotactic radiotherapy in acromegaly after surgery and/or during medical therapy provide tumor control in 93-100% of patients at 5-10 years and endocrinological remission in 40-60% of patients at 5 years, with a hypopituitarism rate of 10-50% at 5 years. Hypofractionated radiosurgery is an optimal option for tumors located near the optic structures, due to its lower toxicity for the optic nerves compared to single-dose radiosurgery. A dose-response model for visual pathway tolerance to SRS has been recently published.

STEREOTACTIC RADIATION THERAPY IN PITUITARY ADENOMAS, IS IT BETTER THAN CONVENTIONAL RADIATION THERAPY?

Pituitary radiotherapy (RT) has undergone important progress in the last decades due to the development of new stereotactic techniques which provide more precise tumour targeting with less overall radiation received by the adjacent brain structures. Pituitary surgery is usually first-line therapy in most patients with nonfunctioning (NFPA) and functioning adenomas (except for prolactinomas and large growth hormone (GH) secreting adenomas), while RT is used as second or third-line therapy. The benefits of RT (tumour volume control and, in functional tumours, decreased hormonal secretion) are hampered by the long latency of the effect and the potential side effects. This review presents the updates in the efficacy and safety of the new stereotactic radiation techniques in patients with NFPA, GH-, ACTH- or PRL-secreting pituitary adenomas. METHODS: A systematic review was performed using PubMed and articles/abstracts and reviews detailing RT in pituitary adenomas from 2000 to 2017 were included. RESULTS: Stereotactic radiosurgery (SRS) and fractionated stereotactic RT (FSRT) provide high rates of tumour control i.e. stable or decrease in tumour size, in all types of pituitary adenomas (median 92 - 98%) at 5 years. Endocrinological remission is however significantly lower: 44-52% in acromegaly, 54-64% in Cushing's disease and around 30% in prolactinomas at 5 years. The rate of new hypopituitarism varies from 10% to 50% at 5 years in all tumour types and as expected increases with the duration of follow-up (FU). The risk for other radiation-induced complications is usually low (0-5% for new visual deficits, cranial nerves damage or brain radionecrosis and extremely low for secondary brain tumours), however longer FU is needed to determine rates of secondary tumours. Notably, in acromegaly, there may be a higher risk for stroke with FSRT. CONCLUSION: Stereotactic radiotherapy can be an effective treatment option for patients with persistent or recurrent pituitary adenomas after unsuccessful surgery (especially if residual tumour is enlarging) and/or resistance or unavailability of medical therapy. Comparison with conventional radiation therapy (CRT) is rather difficult, due to the substantial heterogeneity of the studies. In order to evaluate the potential brain-sparing effect of the new stereotactic techniques, suggested by the current data, long-term studies evaluating secondary morbidity and mortality are needed.

Increased copeptin levels in metabolic syndrome from a Romanian population.

Rationale: Arginine vasopressin (AVP) is secreted under conditions of water deprivation. Since AVP has a low half-life in the plasma, the C-terminal fragment of AVP-precursor (copeptin) was used to estimate the AVP levels. High copeptin levels increase the risk for the development of diabetes mellitus. Aim: This study was aimed to measure copeptin levels in the metabolic syndrome (MetS) in Romanians using a competitive enzyme immunoassay. Methods and results: Patients prone to present MetS (n = 63) were compared to controls (n = 42). In the MetS group, the syndrome was confirmed in 93.6%. Affected patients displayed 85.7% obesity and insulin resistance (HOMAIR of 4.9 ± 0.4 versus 1.1 ± 0.8 in controls). Low HDL-cholesterol was less represented (47.5%). Copeptin levels were 0.6 ± 0.0 in MetS versus 0.42 ± 0.0 ng/ mL in controls (P < 0.004). Higher copeptin (0.79 to 1.83 ng/ mL) was associated with MetS, P < 0.0018, OR 20, 95%CI [3.03 - 131.7]. In ANOVA, high copeptin was equally explained by MetS or obesity (P < 0.05,α = 3.8). The best correlation was found with high triglyceride levels (P < 0.013,α = 6.3) while the correlation with HOMAIR remained not significant. Discussion: These data indicated a concordant correlation between increased copeptin and MetS or its components. In the light of epidemiological data, indicating that more than 50% of the European population has a lower daily water intake and a fraction of 25% displaying high copeptin, our data further sustained that copeptin may be a good biomarker for MetS and/ or obesity, which should be further investigated with other members of the osmoregulation pathway at both pathogenesis and genetic levels.

IODINE STATUS IN PREGNANT WOMEN AFTER A DECADE OF UNIVERSAL SALT IODIZATION IN ROMANIA.

OBJECTIVE: To assess iodine status (median urinary iodine concentration) in 118 pregnant women during the third trimester from endemic or non-endemic areas, a decade after implementation of Universal Salt Iodization in Romania. SUBJECTS AND METHODS: One hundred and eighteen pregnant women in the third trimester were included in the study group (age range: 16 - 46 years, mean age: 28.78 years). Median urinary iodine concentration (UIC) and body mass index (BMI) were evaluated. Data regarding region of provenance, smoking habits during pregnancy, education level, iodized salt intake, bread intake, iodine supplements, comorbidities (iron deficiency anemia) and birth weight were assessed. Morning urine was collected to measure median UIC. The study was approved by the Local Ethics Committee. RESULTS: Median UIC in the study group was 206 mcg/L, reflecting iodine sufficiency during pregnancy. There is a statistically significant difference between pregnant women with and without iodine supplements from rural areas (281.5 versus 196.1 mcg/L, respectively, p=0.023). In the subgroup without iodine supplementation, there was a significant difference between overweight and obese subjects vs. normal weight subjects (232.5 versus 194 mcg/L, p=0.012). Only in the subgroup with a daily intake of less than 5 slices of bread (usually containing iodized salt) we found significant differences between those with and without iodine supplements (245.2 versus 128.3 mcg/L). Iron deficiency anemia was found in 29.66% and 19.49% were current smokers during pregnancy. CONCLUSIONS: Median UIC in the study group was 206 mcg/L, reflecting iodine sufficiency during pregnancy. The difference between the subgroup with iodine supplements and the subgroup without iodine supplements was not statistically significant, probably due to the excessive consumption of bread and other bakery products which is traditional in Romania.

THYROID METASTASIS FROM CLEAR CELL CARCINOMA OF THE KIDNEY 16 YEARS AFTER NEPHRECTOMY.

The thyroid gland is one of the most vascularized organs in the body. However, metastatic disease to the thyroid gland is rare. When it does occur kidney is the most common primary tumor site, followed by melanoma, lung, breast, esophagus, uterus and colon carcinoma. We describe the case of an isolated thyroid metastasis from clear cell renal carcinoma occurring 16 years after nephrectomy. An 82 years-old woman presented for the recent growth of a right thyroid nodule, diagnosed 3 years before, when a fine needle aspiration biopsy found a benign cytology suggesting a well-differentiated follicular thyroid adenoma. Her medical history included type 2 diabetes mellitus, atrial fibrillation and a right nephrectomy for a clear cell renal carcinoma done 16 years before. The patient has lost weight but she was otherwise asymptomatic. The right lobe goiter was painless, firm, and mobile with deglutition, without signs of local compression or latero-cervical lymphadenopathy. Thyroid ultrasonography revealed an enlarged (9.9 cm) macronodular right lobe, with multiple cystic areas, with normal left lobe and a thrombus in the right internal jugular vein. Thyroid function tests were normal. The patient was suspected of thyroid carcinoma and underwent a near total thyroidectomy. Histopathological examination revealed a metastasis of clear cell renal carcinoma in the right thyroid gland lobe (8.5/5/5 cm). Further imaging showed no primary tumor or other metastases. Metastatic renal carcinoma to the thyroid should be considered in any patient presenting with a thyroid mass and a medical history of operated renal cell carcinoma, since it can occur up to 25 years after nephrectomy.

Differential impedance spectroscopy for monitoring protein immobilization and antibody-antigen reactions.

This work describes the theoretical and experimental approaches for monitoring the interfacial biomolecular reaction between immobilized antibody and the antigen binding partner using novel differential impedance spectroscopy. The prerequisite of any biosensor is the immobilization of macromolecules onto the surface of a transducer. It is clear that the function of most macromolecules changes from what is observed in solution once immobilization has occurred. In the worst case, molecules entirely lose their binding activity almost immediately after immobilization. Certain conditions (e.g., denaturation, interfacial effects based on ionic strength, surface charge, dielectric constants, etc.) at interfaces are responsible for alterations of binding activity; it is not clear whether a combination of such processes is understood. However, these processes in combination must be reliably modeled in order to predict the outcome for most macromolecules. This work presents the theoretical and practical means for elucidating the surface reactivity of biomolecular reagents using ion displacement model with antibody-antigen (Ab-Ag) reaction as the test case. The Ab-Ag reaction was directly monitored using a dual-channeled, impedance analyzer capable of 1 measurement/s using covalent immobilization chemistry and polymer-modified electrodes in the absence of a redox probe. The evidence of Ab-Ag binding was revealed through the evolution of differential admittance. The surface loading obtained using the covalent immobilization chemistry was 9.0 x 10(16)/cm2, whereas with polymer-modified electrodes, the surface loading was 9.0 x 10(15)/cm2, representing a 10 times increase in surface reactivity. The proposed approach may be applicable to monitoring other surface interfacial reactions such as DNA-DNA interactions, DNA-protein interactions, and DNA-small molecule interactions.

[Electrical changes in the middle retinal layer in diabetic retinopathy]. / Modificarile electrice în stratul retinian mediu în conditiile retinopatiei diabetice. (Studiu electroretinografic).

An electroretinographic study was undertaken on 27 diabetic patients in order to catch the electric changes arose in the mid retinal layer under ischaemic conditions. Significant diminution of the amplitude of the b wave and less significant variation of its implicit time were observed during the progression of the diabetic retinopathy. An unexplained phenomenon--the amplification of the b wave--took place in certain cases of background retinopathy and was emphasised after adaptation of retina to darkness.

[Electrical changes in the external retinal layer in the course of diabetic retinopathy (Electroretinographic study)]. / Modificarile electrice din stratul retinian extern în cursul evolutiei retinopatiei diabetice. (Studiu electroretinografic).

An electroretinographic study was undertaken on 27 diabetic subjects, in order to catch the modifications arose in the external retinal layer, that means at the photoreceptor level, in ischaemic conditions. As expected, the parameters of the a wave were significantly modified by the progression of diabetic retinopathy. Cones and rods showed a different response to ischaemia.

[Changes in the oscillatory potentials in the electroretinogram during the evolution of diabetic retinopathy]. / Modificarea potentialelor oscilatorii pe electroretinograma din cursul evolutiei retinopatiei diabetice.

Oscillatory potentials where intensely studied in diabetic patients with various degrees of retinopathy. Classical reports pointed out the early reduction of their amplitude, as well as of their latency, while a and b waves remained still normal. A prognostic value was attached to these modifications, the reduction of oscillatory potentials being correlated with a ten time higher probability of developing a high risk retinopathy. 27 diabetic patients where investigated electroretinographically by us. No significant variation of the amplitude of oscillatory potentials was observed during the progression of diabetic retinopathy.

[The effects of photocoagulation on the electrical activity of the diabetic retina]. / Consecintele fotocoagularii asupra activitatii electrice a retinei diabetice.

The aim of photocoagulation in diabetic retinopathy is to destroy ischaemic retina because this produces a vasogenic factor, responsible of neovascularization. Retinal burn reduces the number of photoreceptors and effects the transmission of nervous impulse in areas close to those coagulated. It is presumable therefore that electroretinographic parameters will be significantly modified after treatment. 23 diabetic patients where investigated, resulting 43 scotopic electroretinograms, 41 photopic electroretinograms and 46 flicker electroretinograms, each eye being considered separately. The statistic analysis showed significant alterations with laser treatment of the amplitudes of a and b waves in both scotopic and photopic conditions as well as diminished amplitude of the flicker test.

Immune responses induced by recombinant BCG strains according to level of production of a foreign antigen: malE.

A variety of viral, bacterial and parasitic antigens have been expressed in BCG and the capacity of these recombinant bacteria to induce immune responses has been well documented. However, little is known about the parameters influencing the induction of immune responses by recombinant BCG (rBCG), such as level of production and localization of the recombinant antigen. In the present study, we have constructed several rBCG strains expressing the malE gene from Escherichia coli which is either secreted or targeted to the cytoplasm or plasma membrane. Expression of malE was quantified by ELISA and localization was analyzed by flow cytometry. Even when using the same promoter, levels of cytoplasmic or membrane MalE production were far less than those from secreting strains using either mycobacterial or E. coli secretion signals. Stronger and more rapid immune responses were induced by rBCG strains with the highest levels of secreted MalE compared to cytoplasmic or membrane constructs, including both good humoral and proliferative responses in BALB/c, C57BL6 and even C3H mice, previously shown to be poor MalE responders. These results suggest that the levels of foreign antigen production play an important role in the induction of immune responses by rBCG strains.