Case presentation of the smallest non-functional parathyroid carcinoma and review of the literature.

INTRODUCTION: Non functional parathyroid carcinoma (PC) is one of the rarest malignant neoplasms. Due to the lack of symptoms and laboratory findings, it is mostly diagnosed in late AQ2 stages, when local invasion and dissemination are already present. However, our case is an exception, because it was detected in early stage, with no local invasion present. We present a case of the smallest non-functional PC yet reported and review of the literature. CASE PRESENTATION: A 47-year-old woman was admitted to outpatient Clinic where fine-needle aspiration biopsy (FNAB) of bilateral thyroid nodules (slide 1) and central neck mass (slide 2), which was suspected to be an enlarged lymphatic nodule or parathyroid gland was performed. Results came back as Bethesda I-colloid (slide 1), and Bethesda IV (slide 2), stating that it is hard to distinguish thyroid gland oxyphil lesions from parathyroid cells. Total thyroidectomy was performed as well as excision of the left central neck mass, without any involvement of surrounding structures. Pathological examination revealed bilateral thyroid follicular nodular disease, papillary microcarcinoma, and parathyroid carcinoma with vascular and capsular invasion, measuring 10 × 8 × 7 mm. The immunohistochemical profile included positive PTH, Chromogranin A, and negative TTF1. CONCLUSION: Non-functional PC is usually diagnosed in advanced stages, already involving adjacent structures; however, this case presents a rare example. It is important not to exclude PC as a differential diagnosis in the absence of elevated Ca and PTH serum levels. Follow-up will be difficult, since there are no prognostic parameters to rely on.

Health care access of thyroid disease patients in Serbia during the COVID-19 pandemic.

PURPOSE: The aim of this study was to assess the impact of repurposing health care facilities in response to COVID-19 on the access of patients with thyroid disease to health care. METHODS: This study consisted of a web-based survey. The survey was anonymous and consisted of forty questions. RESULTS: This survey included 206 respondents. 91.3% of the respondents had health insurance through the Republic Fund of Health Insurance, 9.7% had private or both health insurances, and 3.4% did not have any health insurance. A significant proportion of respondents (60.4%) had to switch from public to private health care to reach a physician and 73.8% had to switch from public to private laboratories. For the 91.9%, this was perceived as a financial burden. Before the pandemic, 83.1% of respondents reported regular follow-up by physicians, which decreased to 44.9% during the pandemic (p < 0.01). 76.3% of the respondents regarded that their thyroid disease was managed optimally before the pandemic, while this figure declined to only 48% during the pandemic (p < 0.01). CONCLUSIONS: The COVID-19 pandemic disrupted the medical care of thyroid patients in Serbia. For the patients treated in the public health care system, access to general practice was hindered, while access to specialist care was disrupted. It led to a switch from public to private health care, which was perceived as a financial burden for almost all the respondents. However, private health care proved to be an important safety net when the public system was overwhelmed.

Serum Insulin-Like Growth Factor-1 (IGF-1) Age-Specific Reference Values for Healthy Adult Population of Serbia.

Context: Insulin-like growth factor-1 (IGF-1) is main serum surrogate marker of growth hormone (GH) secretion, used in diagnostics and treatment of GH deficiency (GHD) and acromegaly. Regional, ethnic, racial or nutritional factors obscure cross-population applicability of IGF-1 reference values. Establishment of population- and assay-specific reference values requires sizable representative cohort of healthy subjects. Subjects and Methods: In representative sample of healthy adult population of Serbia (N=1200, 21-80 years, 1:1 male:female) serum IGF-1 was analyzed by Siemens Immulite 2000 assay under uniform laboratory conditions. Upper and lower limit of reference range (5th - 95th percentile) were calculated for each of the 12 quinquennial age intervals. IGF-1 distribution was normalized and standard deviation score (SDS) calculated by Logarithmic and LMS methods. Results: IGF-1 and age correlated significantly, with most prominent decline at 21-50 years, followed by a plateau up to age of 70. Gender differences were not significant overall. Plateau in age-related IGF-1 decline was less prominent in women. Correlations of IGF-1 with body mass index (BMI) or waist to hip ratio (WHR) were insignificant. Superior IGF-1 SDS transformation was achieved with LMS method, while logarithmic method was simpler to use. Conclusions: Normative age-specific serum IGF-1 reference values were established on a representative cohort of healthy adults in Serbia. Our results support recommendations against necessity for gender-specific or BMI- and WHR-specific reference ranges. Population-based data serve to generate IGF-1 SDS, which is valuable in rational application of consensus guidelines, proper longitudinal follow-up, advancement in efficacy and safety and personalization of treatment targets.

Adiponectin resistance parameter as a marker for high normal blood pres-sure and hypertension in patients with metabolic syndrome.

INTRODUCTION: The different degrees of adiponectin/insulin sensitivity and dysfunctional adipose tissue lead to the development of hypertension (HT). This study aimed to determine adiponectin (AD) concentration in patients with metabolic syndrome (MetS) and high-normal blood pressure or hypertension and to investigate the importance of Homeostatic Model Assessment-AD (HOMA-AD) index in assessing adiponectin/insulin resistance in hypertension. METHODS: This cross-sectional study involved 150 subjects divided into two groups: with MetS (and high-normal blood pressure, n =50; and HT, n =50), and controls without MetS (n =50). In all subjects, serum adiponectin concentration was measured by enzyme-linked immunosorbent assay method. Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) and HOMA-AD index were calculated. RESULTS: The results showed that, compared to the control group, serum AD concentrations were significantly lower in patients with MetS and high-normal blood pressure (p =0.008), and the lowest in group MetS and HT (p =0.001). High AD levels and low HOMA-AD were significantly associated with decreased blood pressure values. In patients with MetS, the value of HOMA-AD≥1.13 was associated with a higher risk of developing high-normal blood pressure. Furthermore, the value of HOMA-AD≥2.63 was associated with a higher risk of developing hypertension. CONCLUSIONS: Hypoadiponectinemia is associated with hypertension, especially in the early stages of the disease. The serum AD levels and HOMA-AD index may be useful markers for identifying patients at risk for high-normal blood pressure and hypertension. HIPPOKRATIA 2020, 24(1): 3-7.

CUSHING'S SYNDROME, A RISK FACTOR FOR VENOUS THROMBOEMBOLISM IS A CANDIDATE FOR GUIDELINES.

OBJECTIVES: The present paper aims to review important contemporary information about VTE risk in endogenous and exogenous CS, as a substantial discrepancy exists between the results of a recent meta-analysis confirming the increased risk for VTE and the absence of CS in VTE guidelines. METHODS: An extensive search of relevant databases (e.g. PubMed, Google Scholar, and Scopus) was performed in order to establish the interconnectedness of the following terms: Cushing's syndrome, venous thromboembolism, deep vein thrombosis, pulmonary embolism. RESULTS: The analysis demonstrated that patients with CS have about ten times the risk for VTE, particularly during the first year following the diagnosis of CS. Oral glucocorticoid users (with iatrogenic CS) have a 3-fold increase in risk of VTE in comparison with non-users. The most recent 2019 meta-analysis encompassed 7142 patients with endogenous CS (including Cushing's disease) undergoing transsphenoidal surgery or adrenalectomy, and their risk of unprovoked VTE was almost 18 times higher in comparison with a healthy population. CONCLUSION: Over the past 50 years considerable evidence of increased VTE risk in CS has been accumulated. It pertains to both endogenous and exogenous type of CS and has been confirmed in the vast majority, if not all the available studies, including meta-analyses. Nevertheless, official CS guidelines make no mention of CS as a VTE risk factor, even though it is important that not only physicians who treat CS, but also physicians who manage patients with suspected VTE be aware of increased VTE risk.

Rare renal cell carcinoma metastasis to mandibular gingiva: A case report and literature review.

Metastatic lesions represent approximately 1% of all the intraoral lesions. They most commonly originate from lung and breast carcinomas, while the third most common source is the renal cell carcinoma. In this paper, we present the rare case of metastases of renal cell carcinoma in the mandibular gingiva of a 53-year-old male patient.

Considerations for the design and conduct of human gut microbiota intervention studies relating to foods.

With the growing appreciation for the influence of the intestinal microbiota on human health, there is increasing motivation to design and refine interventions to promote favorable shifts in the microbiota and their interactions with the host. Technological advances have improved our understanding and ability to measure this indigenous population and the impact of such interventions. However, the rapid growth and evolution of the field, as well as the diversity of methods used, parameters measured and populations studied, make it difficult to interpret the significance of the findings and translate their outcomes to the wider population. This can prevent comparisons across studies and hinder the drawing of appropriate conclusions. This review outlines considerations to facilitate the design, implementation and interpretation of human gut microbiota intervention studies relating to foods based upon our current understanding of the intestinal microbiota, its functionality and interactions with the human host. This includes parameters associated with study design, eligibility criteria, statistical considerations, characterization of products and the measurement of compliance. Methodologies and markers to assess compositional and functional changes in the microbiota, following interventions are discussed in addition to approaches to assess changes in microbiota-host interactions and host responses. Last, EU legislative aspects in relation to foods and health claims are presented. While it is appreciated that the field of gastrointestinal microbiology is rapidly evolving, such guidance will assist in the design and interpretation of human gut microbiota interventional studies relating to foods.

High likelihood for atrial fibrillation in Cushing's syndrome.

OBJECTIVE: This review analyzes the prevalence of the most important comorbidities associated with atrial fibrillation (AF) in the growing population of patients with Cushing's syndrome (CS). MATERIALS AND METHODS: The review is arranged in a way to list important risk factors for AF and the references, which suggest the significant prevalence of these particular risk factors in CS. The search is conducted on PubMed, Science Direct, Springer, Wiley, SAGE, Oxford Press, and Google Scholar. PubMed search for "Cushing's syndrome atrial fibrillation" on 8/7/2019 revealed 4 papers only. None of them either analyzed or implicated high risk for AF in CS. RESULTS: Arterial hypertension (AHT) can be found in approximately 80% of adult individuals with endogenous CS and in 20% of patients with exogenous CS. The reported prevalence of diabetes mellitus (DM) is from 13% to 47% in CS patients and the risk for de novo DM is approximately two-fold higher in individuals treated with glucocorticoids. High risk for myocardial infarction (MI) with hazard ratio (HR) 3.7 (95% confidence intervals, CI 2.4-5) in patients with endogenous CS was found. In CS patients the obesity can be detected in up to 41% and overweight in 21-48%. Left ventricular hypertrophy (LVH), pulmonary thromboembolism (PTE), infections, and hypokalemia are also more prevalent in CS as compared to healthy population. All cited comorbidities have been associated with AF. Therefore, clustering of the important factors associated with AF is confirmed repeatedly in CS. CONCLUSIONS: The prevalence of AF in CS should be studied more precisely, both in a scientific way and at the individual patient's level.

FROM DIABETES INSIPIDUS TO SELLAR XANTHOGRANULOMA - A "YELLOW BRICK ROAD" DEMANDING TEAM-WORK.

Xanthogranulomas are inflammatory lesions exceptionally rarely occurring in the sellar region. Sellar xanthogranulomas (SXG) result from secondary hemorrhage, infarction, inflammation or necrosis upon existing craniopharyngioma (CP), Rathkès cleft cyst (RCC) or pituitary adenoma (PA), or represent a stage in xanthomatous hypophysitis evolution. "Pure SXG" are independent of a preexisting lesion. A 70 year old male patient, laryngeal cancer survivor, presented with central diabetes insipidus (CDI). MRI revealed an intra-suprasellar mass of uncertain origin. Transsphenoidal surgery resulted in an efficient lesion resection with maximal pituitary sparing. Pathological report has confirmed SXG without conclusive identification of preexisting sellar lesion. Age at presentation and gender were atypical for SXG. The most frequent presenting signs of SXG were absent. Most SXG are initially misdiagnosed as CP, RCC or PA. Preoperative clinical and radiological uncertainty may impact operative planning. Differentiating from CP is crucial, due to divergent operative target goals and prognosis. Intraoperative frozen section analysis could guide surgical extensiveness. Close collaboration must include endocrinologist, neuroradiologist, neurosurgeon and pathologist. Quantity and quality of provided tissue are essential for avoiding bias in pathohistological analysis of cystic or heterogenous lesions. Awareness is needed of new pathological entities in the sellar-parasellar region. SXG should be considered in differential diagnosis of CDI-causing sellar lesions.

Functional and pharmacological analysis of agmatine administration in different cerebral ischemia animal models.

Agmatine (AgM, 100 mg/kg i.p.) effect was tested in parallel at two animal models of cerebral ischemia - rat MCAO model (60'/24 h, 60'/48 h, 90'/24 h, 90'/48 h) and gerbil global ischemia (10') model, administrated 5 min after reperfusion. Aim was to evaluate AgM effect on functional outcome 24 and 48 h after MCAO on neurological and sensor-motor function, and coordination in rats. AgM administration significantly reduced infarct volume, improved neurological score and improved post-ischemic oxidative status. Results of behavioral tests (cylinder test, beam walking test, and adhesive removal test) have shown very effective functional recovery after AgM administration. Efficiency of AgM administration in gerbils was observed in forebrain cortex, striatum, hippocampus, and cerebellum at the level of each examined oxidative stress parameter (nitric oxide level, superoxide production, superoxide dismutase activity, and index of lipid peroxidation) measured in four different time points starting at 3 h up to 48 h after reperfusion. The highest levels were obtained 6 h after the insult. The most sensitive oxidative stress parameter to AgM was nitric oxide. Additionally, we performed pharmacological analysis of AgM on rat isolated common carotid arteries. The findings imply that mixed population of potassium channels located on the smooth muscle cells was involved in common carotid artery response to AgM, with predominance of inward rectifying K+ channels. In our comparative experimental approach, judged by behavioral, biochemical, as well as pharmacological data, the AgM administration showed an effective reduction of ischemic neurological damage and oxidative stress, hence indicating a direction towards improving post-stroke recovery.

The role of oxidative stress as a risk factor for rupture of posterior inferior cerebellar artery aneurysms.

Cerebral aneurysm affects 2-5% of the population and posterior inferior cerebellar artery (PICA) aneurysms account for 1-3% of all intracranial aneurysms. Oxidative stress is known to contribute to the progression of cerebrovascular disease and it may be increased by inflammation, a key contributor to cerebral aneurysm development and rupture. The aim of this study was to examine the role of overall oxidative stress as a risk factor for rupture of PICA aneurysms. This study included 29 patients with PICA aneurysms: 18 ruptured and 11 unruptured. We determined catalase, malondialdehyde, myeloperoxidase and carbonyl groups in homogenates of excised aneurysm tissue after surgery and plasma levels of C reactive protein and fibrinogen. The patient's age and sex, size of aneurysms, multiplicity, history of previous subarachnoidal hemorrhage (SAH) and risk factors for oxidative stress such as hypertension and smoking were compared between unruptured and ruptured aneurysms. Maximal diameter and SAH history were independent predictors for aneurysm rupture. Activity of catalase was decreased while activity of myeloperoxidase, levels of malondialdehyde, carbonyl groups in aneurismal tissue and plasma levels of C reactive protein and fibrinogen were increased in patients with ruptured aneurysms. Plasma levels of C reactive protein and fibrinogen showed positive correlation with myeloperoxidase, malondialdehyde, carbonyl groups and PHASES score and negative correlation with catalase. These findings suggest that oxidative stress may contribute importantly to rupture of PICA aneurysms and plasma levels of C reactive protein and fibrinogen correlate with oxidative stress markers in tissue.

Extracranial meningiomas in the head-and-neck region: A 15 years' experience.

Meningiomas constitute a large group of tumors of the central nervous system, with the prevalence of 18%-20%. Extracranial localization of meningeomas could appear due to their extracranial origin or due to the spreading of intracranial meningeomas. In this paper, we present our 15 years' experience in the diagnosis and treatment of extra- and intracranial meningiomas invading the head-and-neck region. In the period from 2001 to 2016 at our clinic, there were five patients (three men and two women), with meningiomas of extracranial origin or meningiomas of intracranial origin, spreading into the head-and-neck region. All patients were surgically treated, with the addition of adjuvant radiation therapy in some of the cases. Postoperative and postirradiation complications were described as well.

Subchronic methionine load induces oxidative stress and provokes biochemical and histological changes in the rat liver tissue.

The aim of this study was to assess the effects of L-cysteine (Cys) (7 mg/kg) and N-acetyl-L-cysteine (NAC) (50 mg/kg) in the rat liver caused by subchronic i.p. application of methionine (Met) (0.8 mmol/kg) during 21 days. Malondialdehyde (MDA) concentration, glutathione content (GSH), catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPx), and acetylcholinesterase (AchE) activities were determined in the liver tissue and activities of liver enzymes (AST, ALT, ALP, and GGT) and concentrations of total proteins and albumin were determinated in plasma/serum. Catalase, superoxide dismutase, and acetylcholinesterase activities were increased by Cys and NAC. Met caused periportal mononuclear infiltration and rare focal necrosis of hepatocytes. In Cys- and NAC-supplemented groups, intracellular edema and microvesicular fatty changes without necrosis were noticed. We observed decrease of AST, ALT, and ALP activity in the methionine-treated group. Our results indicate that Cys and NAC application can increase activity of antioxidative enzymes and prevent intensive histological changes in liver in condition of subchronic methionine exposure.

Spectroscopic analysis of XIV century wall paintings from Patriarchate of Pec Monastery, Serbia.

The Church of the Holy Mother of God Hodegetria in Pec is decorated with wall paintings that date from the beginning of the 14th century. In terms of style they correspond to Byzantine wall paintings from the epoch of Paleologos. The painting technique and pigment pallete has been examined on micro fragments in thin cross-sections by means of optical microscopy (OM), scanning electron microscopy-energy dispersive X-ray spectroscopy (SEM-EDS) and micro- Raman spectroscopy. Use of the fresco technique and two supporting plaster layers was noted on the majority of samples, while in large blue painted areas, a combination of fresco and secco techniques was used. The SEM-EDS results showed the presence of Ca as the main component of plaster besides the traces of Si and Mg. In some samples egg white as a binder was identified. The paint film is often multilayered. Twelve pigments were identified, mainly natural earth pigments such as red ochre, yellow ochre and green earth. A mixture of pigments was used for attaining desirable optical and aesthetical impressions. As decay product only weddelite was detected in many preparatory and painted samples.

Etiology of Hypopituitarism in Adult Patients: The Experience of a Single Center Database in the Serbian Population.

There are only a few published studies related to the population-based etiology of hypopituitarism. New risks for developing hypopituitarism have been recognized in the last 10 years. Aim. To present data regarding the etiology of hypopituitarism collected in a tertiary center over the last decade. This is a cross-sectional database study. Patients and Methods. We included 512 patients (pts) with hypopituitarism, with a mean age of 45.9 ± 1.7 yrs (range: 18-82; male: 57.9%). Results. Nonfunctional pituitary adenomas were presented in 205 pts (40.5%), congenital causes in 74 pts (14.6%), while acromegaly and prolactinomas were presented in 37 (7.2%) and 36 (7.0%) patients, respectively. Craniopharyngiomas were detected in 30 pts (5.9%), and head trauma due to trauma brain injury-TBI and subarachnoid hemorrhage-SAH in 27 pts (5.4%). Survivors of hemorrhagic fever with renal syndrome (HFRS) and those with previous cranial irradiation were presented in the same frequency (18 pts, 3.5% each). Conclusion. The most common causes of hypopituitarism in our database are pituitary adenomas. Increased awareness of the other causes of pituitary dysfunction, such as congenital, head trauma, extrapituitary cranial irradiation, and infections, is the reason for a higher frequency of these etiologies of hypopituitarism in the presented database.

Ischemic preconditioning vs adenosine vs prostaglandin E1 for protection against liver ischemia/reperfusion injury.

Ischemia/reperfusion injury is still a major cause of morbidity and mortality during liver surgery and transplantation. A variety of surgical and pharmacological therapeutic strategies have been investigated to minimize the effects of ischemia/reperfusion. The aim of our study was to analyze and compare preventive influences of ischemic preconditioning, adenosine and prostaglandin E1 in the experimental model of hepatic ischemia/reperfusion injury. Adult chinchilla rabbits were divided into four groups: 10 rabbits subjected to liver ischemic preconditioning (3-min period of inflow occlusion followed by a 5-min period of reperfusion) followed by 45 min of Pringle maneuver; 10 rabbits subjected to pre-treatment with intraportal injection of adenosine followed by 45 min of Pringle maneuver; 10 rabbits subjected to pre-treatment with intraportal injection of prostaglandin E1 followed by 45 min of Pringle maneuver; and control group of 10 rabbits subjected to 45 min of inflow liver ischemia without any preconditioning. On the second postoperative day, blood samples were obtained and biochemical parameters of liver function were measured and compared. Liver tissue samples were also obtained and histopathological changes were compared. Based on biochemical and histopathological parameters, it was demonstrated that ischemic preconditioning provided the best protection against hepatic ischemia/reperfusion injury. This was probably due to a wider range of mechanisms of action of this method oriented to reduce oxidative stress and inflammation, and restore liver microcirculation and hepatocyte energy compared to the examined pharmacological strategies.

Flexible memory-alloy instrumentation for unilateral transpedicular kyphoplasty and guided cement augmentation of the thoracic spine.

The purpose of this novel study was to investigate the feasibility of unilateral transpedicular balloon kyphoplasty particularly of the upper thoracic vertebrae using an 11- gauge balloon and cement inserter, and to study the morphological parameters of the thoracic spine pedicles. We used four fresh frozen cadaveric thoracic spines with intact rib cages and skin for kyphoplasty from T1 to T12 vertebrae under C-arm fluoroscopy. The most limiting width of the pedicles 2.46+/-0.32mm was in the middle levels (T5-T8). The absolute minimum height of the pedicles was at T1 (3.80-3.87mm). All regions of the vertebral body were effectively targeted for cement augmentation. The average cement load of all the vertebral bodies was 43,22%. Using the kyphoplasty technique in combination with the pre-bent 11mm memory-alloy cement inserter allowed targeting of the desired position of the vertebral body for effective vertebral body cement augmentation.