Search

Purpose: Therapeutic plasma exchange (PLEX) is effective as a second-line treatment of severe relapses of multiple sclerosis (MS) that failed to respond to standard steroid therapy. Our objective was to evaluate the effectiveness of PLEX in the severe MS relapses in a cohort of patients treated at Neurology Clinic, University Clinical Centre of Serbia, Belgrade, from 2007 until 2020., Methods: This retrospective study comprised 107 MS patients with 127 severe relapses treated with PLEX. Majority of our patients suffered from relapsing remitting MS (83.2%), 12.1% had secondary progressive MS and 4.7% had primary progressive MS. Mean age was 39.2 years (range, 19-79 years), female/male ratio 2.3:1. Pulse corticosteroid treatment was used before PLEX in 99.3% of patients. Median EDSS score at nadire during relapse was 6.0 (range 2.0-10.0). After PLEX, 73.8% relapses showed a marked clinical improvement, 7.1% showed mild improvement and in 19.0% there was no improvement. Median EDSS at discharge was 4.0 (6.0 at nadir of relapse vs. 4.0 at discharge; p<0.0001) and it was sustained at the same level, 6 month after PLEX. Multivariate regression analysis showed that higher EDSS at nadir during relapse (OR=0.63, 95% CI 0.41-0.96, p=0.039) and older age (OR=1.07, 95% CI 1.02- 1.12, p=0.010) were significantly associated with poor treatment response after 6- month follow-up. Adverse events occurred in 17.3 of procedures and they were completely resolved., Conclusion: Our study in a large cohort of MS patients confirmed that PLEX is effective., (© 2024. The Author(s) under exclusive licence to Belgian Neurological Society.)

The study aimed to review the role of basal, trigger, and aspiration day progesterone levels (PLs) as predictors of in vitro fertilization (IVF) success for patients with and without endometriosis. A non-systematic review was conducted by searching papers published in English during the period of 1990-2023 in MEDLINE and PubMed, Embase, The Cochrane Library (Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, Cochrane Methodology Register), and Web of Science. The most widely used IVF predictor success was the trigger day progesterone serum level. Many studies utilize the threshold level of 1.5-2.0 ng/ml. However, the predictive power of only progesterone level failed to show high sensitivity and specificity. Contrary, progesterone level on the trigger day combined with the number of mature retrieved oocytes had the highest predictive power. High baseline progesterone level was associated with poor IVF outcomes. Research on progesterone and IVF success in patients with endometriosis is limited but indicates that endometriosis patients seem to benefit from higher progesterone concentrations (≥ 37.1 ng/ml) in IVF cycles. Currently, there is limited data for a definitive insight into the mportance of progesterone in the estimation of IVF success. Nonetheless, this summarized evidence could serve as up-to-date guidance for the role of progesterone in the prediction of IVF outcomes, both in patients with and without endometriosis., (© 2024. The Author(s), under exclusive licence to Society for Reproductive Investigation.)

Purpose: The purpose of this review is to examine the current evidence on the potential role of Mediterranean diet (MD) in the prevention and management of endocrine disorders and to highlight the importance of interdisciplinary collaboration between endocrinologists and nutritionists., Methods: A literature search was conducted using PubMed and Google Scholar databases to identify relevant studies published in English. Studies were selected based on their relevance to the role of MD in the prevention and management of endocrine disorders. The search terms included "Mediterranean diet," "endocrine disorders," "thyroid disorders," "gonadal disorders," and "neuroendocrine tumors"., Results: The studies reviewed suggest that MD may have a beneficial effect in the prevention and management of various endocrine disorders, including thyroid disorders, gonadal disorders, and neuroendocrine tumors. MD has been associated with decreased risk of nodular thyroid disease and thyroid cancer, improved male and female reproductive health, and a potential role in the management of neuroendocrine tumors. MD's anti-inflammatory and antioxidant properties, as well as its high levels of phytochemicals, may play a role in its beneficial effects., Conclusion: Interdisciplinary collaboration between endocrinologists and nutritionists is essential for the optimal management of endocrine disorders, including the potential role of MD in their prevention and management. While further research is needed, the current evidence suggests that MD may have a protective effect against endocrine disorders, and its incorporation into dietary recommendations may be beneficial., (© 2023. The Author(s).)

Purpose: Meningiomas are tumours originating from meningothelial cells, the majority belonging to grade 1 according to the World Health Organization classification of the tumours of the Central Nervous System. Factors contributing to the progression to the higher grades (grades 2 and 3) have not been elucidated yet. Senescence has been proposed as a potential mechanism constraining the malignant transformation of tumours. Senescence-associated beta-galactosidase (SA-β-GAL) and inhibitors of cyclin-dependent kinases p16 and p21 have been suggested as senescence markers., Methods: We analysed 318 meningiomas of total 343 (178 grade 1, 133 grade 2 and 7 grade 3). Tissue microarrays were constructed and stained immunohistochemically, using antibodies for SA-β-GAL, p16 and p21., Results: The positive correlation of the tumour grade with the expression of p16 (p = 0.016) and SA-β-GAL (p = 0.002) was observed. The expression of p16 and SA-β-GAL was significantly higher in meningiomas grade 2 compared to meningiomas grade 1 (p = 0.006 and p = 0.004, respectively). SA-β-GAL positivity positively correlated with p16 and p21 in the whole cohort. In grade 2 meningiomas, a positive correlation was only between SA-β-GAL and p16. Correlations of senescence markers in meningiomas grade 2 were not present., Conclusion: Our findings suggest the senescence activation in meningiomas grade 2 as a potential mechanism for the restraining of tumour growth and give hope for applying of promising senolytic therapy., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: The hypothalamic-pituitary-adrenal (HPA) axis is a neuroendocrine system involved in controlling stress responses in humans under physiological and pathological conditions; cortisol is the main hormone produced by the HPA axis. It is known that calorie restriction acts as a stressor and can lead to an increase in cortisol production. Renin-angiotensin-aldosterone system (RAAS) is a complex endocrine network regulating blood pressure and hydrosaline metabolism, whose final hormonal effector is aldosterone. RAAS activation is linked to cardiometabolic diseases, such as heart failure and obesity. Obesity has become a leading worldwide pandemic, associated with serious health outcomes. Calorie restriction represents a pivotal strategy to tackle obesity. On the other hand, it is well known that an increased activity of the HPA may favour visceral adipose tissue expansion, which may jeopardize a successful diet-induced weight loss. Very low-calorie ketogenic diet (VLCKD) is a normoprotein diet with a drastic reduction of the carbohydrate content and total calorie intake. Thanks to its sustained protein content, VLCKD is extremely effective to reduce adipose tissue while preserving lean body mass and resting metabolic rate., Purpose: The purpose of this narrative review is to gain more insights on the effects of VLCKD on the HPA axis and RAAS, in different phases of weight loss and in different clinical settings., (© 2023. The Author(s).)

Glioblastomas are aggressive and usually incurable high-grade gliomas without adequate treatment. In this study, we aimed to investigate the potential of desloratadine to induce apoptosis/autophagy as genetically regulated processes that can seal cancer cell fates. All experiments were performed on U251 human glioblastoma cell line and primary human glioblastoma cell culture. Cytotoxic effect of desloratadine was investigated using MTT and CV assays, while oxidative stress, apoptosis, and autophagy were detected by flow cytometry and immunoblot. Desloratadine treatment decreased cell viability of U251 human glioblastoma cell line and primary human glioblastoma cell culture (IC50 value 50 µM) by an increase of intracellular reactive oxygen species and caspase activity. Also, desloratadine decreased the expression of main autophagy repressor mTOR and its upstream activator Akt and increased the expression of AMPK. Desloratadine exerted dual cytotoxic effect inducing both apoptosis- and mTOR/AMPK-dependent cytotoxic autophagy in glioblastoma cells and primary glioblastoma cell culture., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: In patients with multi-vessel disease presenting with ST elevation myocardial infarction (STEMI), the efficacy and safety of ischemia-guided, vs routine non-culprit vessel angioplasty has not been adequately studied., Methods: We conducted an international, randomized, non-inferiority trial comparing ischemia-guided non-culprit vessel angioplasty to routine non-culprit vessel angioplasty, following primary PCI for STEMI. The primary outcome was the between-group difference in percent ischemic myocardium at follow-up stress MPI. All MPI images were processed and analyzed at a central core lab, blinded to treatment allocation., Results: In all, 109 patients were enrolled from nine countries. In the ischemia-guided arm, 25/48 (47%) patients underwent non-culprit vessel PCI following stress MPI. In the routine non-culprit PCI arm, 43/56 (77%) patients underwent angioplasty (86% within 6 weeks of randomization). The median percentage of ischemic myocardium on follow-up imaging (mean 16.5 months) was low, and identical (2.9%) in both arms (difference 0.13%, 95%CI - 1.3%-1.6%, P < .0001; non-inferiority margin 5%)., Conclusion: A strategy of ischemia-guided non-culprit PCI resulted in low ischemia burden, and was non-inferior to a strategy of routine non-culprit vessel PCI in reducing ischemia burden. Selective non-culprit PCI following STEMI offers the potential for cost-savings, and may be particularly relevant to low-resource settings. (CTRI/2018/08/015384)., (© 2022. The Author(s).)

Introduction: Myasthenia gravis (MG) is an autoimmune disease of the neuromuscular junction which is typically presented with muscle weakness and excessive fatigability. Majority of MG patients require long-term immune suppression. Our aim was to analyze the frequency and severity of COVID-19 infection in MG patients, as well as the frequency of vaccinated MG patients against SARS-CoV-2., Methods: We included 125 MG patients from the central Belgrade municipalities-60% females, age at MG onset 50.1 ± 19.7 years, age at testing 61.7 ± 16.8 years, anti-acetylcholine receptor (anti-AChR) positive 78% and muscle specific tyrosine kinase (MuSK) positive 8.6%., Results: One-third of our MG patients had a COVID-19 infection and they were younger compared to those without verified COVID-19. Severe COVID-19 infection was registered in 28% of MG patients, mostly in elder subjects with comorbidities such as cardiac diseases and malignancies. MG worsening was noted in 21% of patients during/after COVID-19 and 42% had COVID-19 sequelae. Majority of MG patients were vaccinated against SARS-CoV-2 (almost 70%). Vaccination was more common among MG patients with diabetes and in those with a milder form of MG. The most common types of vaccines were Sinopharm (42%) and Pfizer-BioNTech (25.6%). Adverse events were observed in 36% of vaccinated patients, with flu-like symptoms (77%) and local reactions (13%) being the most common ones. MG worsening was noticed in 5 (5.8%) patients after vaccination., Conclusion: COVID-19 has placed a significant new burden for MG patients. Elder MG patients and patients with comorbidities are in higher risk of having adverse outcome following SARS-CoV-2 infection. Percentage of vaccinated MG patients was higher than in general Serbian population., (© 2022. The Author(s) under exclusive licence to Belgian Neurological Society.)

The aim of this study was to examine the effects of hyperhomocysteinemia and aerobic physical activity on changes of cardiovascular biomarkers in sera, oxidative stress in cardiac tissue, and histomorphometric parameters of heart and aorta in rats. Experiments were conducted on male Wistar albino rats organized into four groups (n = 10, per group): C (control group): 0.9% NaCl 0.2 mL/day; H (homocysteine group): homocysteine 0.45 µmol/g b.w./day; CPA (control + physical activity group): 0.9% NaCl 0.2 mL/day and a program of physical activity on a treadmill; and HPA (homocysteine + physical activity group) homocysteine 0.45 µmol/g b.w./day and a program of physical activity on a treadmill. Substances were applied subcutaneously twice a day. Lipid peroxidation and relative activity of Mn-superoxide dismutase isoform were significantly higher in active hyperhomocysteinemic rats in comparison to sedentary animals. Atherosclerotic plaques were detected in aorta samples of active hyperhomocysteinemic rats and also, they had increased left ventricle wall and interventricular septum, and transverse diameter of cardiomyocytes compared to sedentary groups. Aerobic physical activity in the condition of hyperhomocysteinemia can lead to increased oxidative stress in cardiac tissue and changes in histomorphometric parameters of the heart and aorta, as well increased lipid parameters and cardiac damage biomarkers in sera of rats., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction and Hypothesis: Urinary incontinence (UI) and pelvic organ prolapse (POP) significantly decrease quality of life and sexual health. This study aimed to evaluate the reliability and validity of a Serbian adaptation of the short form of the Pelvic Organ Prolapse/Urinary Incontinence Sexual Function Questionnaire (PISQ-12) used in assessing sexual function in women with UI and/or POP., Methods: This study included 416 women, 310 (74.5%) with UI and/or POP and 106 (25.5%) without UI and/or POP. The adaptation of the PISQ-12 to Serbian language was performed via back-translation. The content validity of the questionnaire was conducted by experts in the field. The reliability and validity of the PISQ-12 were analyzed. Evaluation of the data was performed using Content Validity Index (CVI), Cronbach's alpha, test-retest reliability, item total correlation and confirmatory factor analysis., Results: Content validity of the Serbian PISQ-12 was 1.00 (100%). Item total correlations were between 0.459 and 0.819 (P < 0.001). The PISQ-12 had an adequate and high internal consistency (Cronbach's alpha 0.806) as well as high test-retest reliability (Pearson correlation coefficient r = 0.807; P < 0.001). Factor analysis results revealed strong construct validity. The mean scores of PISQ-12 were significantly better in the control group compared with the women with UI and/or POP. Sexual function was negatively affected by UI and/or POP as assessed with SF-36 and I-QoL questionnaires., Conclusions: This study showed that the Serbian version of the PISQ-12 is a reliable, consistent, valid and condition-specific instrument to assess sexual function in women with UI and/or POP., (© 2022. The International Urogynecological Association.)

Studies indicate that the soil, water and consequently foodstuffs in Serbia are significantly poor in zinc (Zn), and thus, it is likely that there is a Zn deficiency in the Serbian population. This study examined the Zn status in multiple clinical samples, including body fluids (serum, cerebrospinal fluid), whole blood and Zn-rich solid tissues (thyroid and brain tissue). Differences between sex and age were also considered, and comparative analysis of Zn status with other world populations was performed. Serum samples from a large number of Serbian adults approximately had twofold lower Zn amounts when compared to other populations. A similar trend was obtained for whole blood. Males had significantly higher amounts of Zn in serum, whole blood and thyroid tissue samples than females. Higher amounts of Zn were observed in the group older than 50 years. Importantly, in thyroid and brain tissues, Zn was 10- and 20-fold lower, respectively, than reported in the literature. Our results indicate that the population in Serbia could be considered Zn deficient. Therefore, adequate oral Zn supplementation and/or foodstuff fortification should be considered to prevent the deleterious effects caused by Zn deficiency., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: Hypercortisolism is associated with a high prevalence of depression and impaired health-related quality of life (QoL). According to the available literature, studies examining the depression risk in patients with adrenal incidentalomas (AI), nonfunctioning and the ones with (possible) autonomous cortisol secretion ((P)ACS) are scarce. The aim of this observational, case-control study was to screen patients with nonfunctioning adrenal incidentalomas (NAI) and the ones with (P)ACS for depression and to assess their QoL., Methods: The total studied group consisted of 92 subjects-26 with NAI, 34 with (P)ACS and 32 age-matched healthy controls (HC). To screen for depression, we used the Beck Depression Inventory-II (BDI-II) and to assess the QoL, we used the Short-Form 36 Health Survey (SF-36)., Results: Patients with (P)ACS had significantly higher BDI-II scores and substantially lower QoL than patients with NAI or HC. Midnight cortisol level was the most significant predictor of BDI-II and SF-36 score. The receiver operating characteristic curve analysis demonstrated that a midnight cortisol value of 86.95 nmol/l had a high sensitivity (82.8%) and high specificity (80%) for detection of mild depression in patients with (P)ACS., Conclusion: Screening for depression and QoL assessment should become an integral part of clinical evaluation in patients with (P)ACS., (© 2021. Italian Society of Endocrinology (SIE).)

Purpose: Whereas antithyroid drugs (ATD) are the preferred treatment modality for Graves' hyperthyroidism (GH), there is still controversy about the optimal regimen for delivering ATD. To evaluate whether 'Block and Replace' (B + R) and 'Titration' (T) regimes are equivalent in terms of frequency of euthyroidism and Graves' Orbitopathy (GO) during ATD therapy., Methods: A prospective multicentre observational cohort study of 344 patients with GH but no GO at baseline. Patients were treated with ATD for 18 months according to B + R or T regimen in line with their institution's policy., Results: Baseline characteristics were similar in both groups. In the treatment period between 6 and 18 months thyrotropin (TSH) slightly increased in both groups, but TSH was on average 0.59 mU/L (95% CI 0.27-0.85) lower in the B + R group at all time points (p = 0.026). Serum free thyroxine (FT4) remained stable during the same interval, with a tendency to higher values in the B + R group. The point-prevalence of euthyroidism (TSH and FT4 within their reference ranges) increased with longer duration of ATD in both groups; it was always higher in the T group than in the B + R group: 48 and 24%, respectively, at 6 months, 81 and 58% at 12 months, and 87 and 63% at 18 months (p < 0.002). There were no significant differences between the B + R and T regimens with respect to the fall in thyrotropin binding inhibiting immunoglobulins (TBII) or thyroid peroxidase antibodies (TPO-Ab). GO developed in 15.9% of all patients: 9.1 and 17.8% in B + R group and T group, respectively, (p = 0.096). GO was mild in 13% and moderate-to-severe in 2%., Conclusion: The prevalence of biochemical euthyroidism during treatment with antithyroid drugs is higher during T compared to B + R regimen. De novo development of GO did not differ significantly between the two regimens, although it tended to be higher in the T group. Whether one regimen is clinically more advantageous than the other remains unclear.

Purpose: Patients with Graves' orbitopathy can present with asymmetric disease. The aim of this study was to identify clinical characteristics that distinguish asymmetric from unilateral and symmetric Graves' orbitopathy., Methods: This was a multi-centre study of new referrals to 13 European Group on Graves' Orbitopathy (EUGOGO) tertiary centres. New patients presenting over a 4 month period with a diagnosis of Graves' orbitopathy were included. Patient demographics were collected and a clinical examination was performed based on a previously published protocol. Patients were categorized as having asymmetric, symmetric, and unilateral Graves' orbitopathy. The distribution of clinical characteristics among the three groups was documented., Results: The asymmetric group (n = 83), was older than the symmetric (n = 157) group [mean age 50.9 years (SD 13.9) vs 45.8 (SD 13.5), p = 0.019], had a lower female to male ratio than the symmetric and unilateral (n = 29) groups (1.6 vs 5.0 vs 8.7, p < 0.001), had more active disease than the symmetric and unilateral groups [mean linical Activity Score 3.0 (SD 1.6) vs 1.7 (SD 1.7), p < 0.001 vs 1.3 (SD 1.4), p < 0.001] and significantly more severe disease than the symmetric and unilateral groups, as measured by the Total Eye Score [mean 8.8 (SD 6.6) vs 5.3 (SD 4.4), p < 0.001, vs 2.7 (SD 2.1), p < 0.001]., Conclusion: Older age, lower female to male ratio, more severe, and more active disease cluster around asymmetric Graves' orbitopathy. Asymmetry appears to be a marker of more severe and more active disease than other presentations. This simple clinical parameter present at first presentation to tertiary centres may be valuable to clinicians who manage such patients.

It is well known the use of ketamine and etomidate in clinical practice; however, the difference in the systemic effects of these two anesthetic agents is still debatable. Thus, in the present study we aimed to compare their effects on heart, and other organs through estimation of cardiodynamics, biochemical and hematological parameters. Male Wistar rats were divided in 2 groups containing of 2 subgroups (n = 7 in each subgroup, n = 28 in total): (1) bolus injection of anesthetic ketamine (40 mg/kg b.w., i.p. n = 14); (2) bolus injection of anesthetic etomidate (20 mg/kg b.w., i.p. n = 14). The experiments were done in vitro in one subgroup of each group: cardiodynamic variables (dp/dt max , dp/dt min , heart rate), coronary flow, oxidative stress in coronary effluent and cardiac tissue homogenate, and in vivo in another subgroup: biochemical and hematological parameters, and oxidative stress in haemolysate. Significantly increased left ventricular contractility (dp/dt max ) and relaxation (dp/dt min ) were noticed in etomidate group. Creatinine (CREA), HDL cholesterol and folate were significantly higher in etomidate group, whereas amylase (AMY) and eosinophils in ketamine group. Our results suggested that ketamine has more antioxidant potential compared to etomidate, and etomidate has more favorable effects regarding cardiac performance.

Management of atrial fibrillation (AF) may be challenging in clinical practice. Given the complexity of AF patients and the continuous advances in AF clinical management, there is a need for standardized programmes aimed at collecting so-called 'real-world clinical practice data' regarding the epidemiology, diagnostic/therapeutic/management practices and assessing adherence to guidelines. Over the past 20 years, the number of registries and surveys based on real-world AF patients has been dramatically increased. In Europe, based on the Euro Heart Survey (EHS) and the EURObservational Research Programme (EORP), a large series of studies based on these prospective, observational, large-scale multicentre registries on AF have been published. This narrative review gives an overview of these two projects on AF led by the European Society of Cardiology, focusing mainly on the contribution that these studies have provided to AF management and patient outcomes. Both the EHS and the EORP registries have collected a large amount of data regarding contemporary clinical practice, and despite some limitations, mainly related to their observational nature, these registries have contributed to our knowledge and clinical management of AF patients.

Background: It is assumed that most cases of embolic stroke of undetermined source (ESUS) are of cardioembolic origin. The data about outcome after the treatment with intravenous thrombolysis (IVT) for this type of acute ischemic stroke (AIS) are limited. We aimed to compare clinical characteristics and outcomes after IVT for AIS between patients with ESUS and cardioembolic stroke (CS)., Methods: This study was a single center retrospective analysis of stroke patients treated with IVT. The Trial of ORG 10172 in Acute Stroke Treatment criteria were used to establish stroke etiology subtype at 3 months, while ESUS was considered a subset of stroke of undetermined etiology, defined according to 2014 international criteria. Functional outcome was assessed at 3 months and defined as excellent (modified Rankin scale 0-1) and favorable (modified Rankin scale 0-2)., Results: Total of 394 patients were treated with IVT; 113 had a cardioembolism, 88 had undetermined stroke subtype, of which 62 met the ESUS criteria. Patients with ESUS were on average younger (63.7 years versus 69.7 years, p = 0.001), had a lower National Institutes of Health Stroke Scale (NIHSS) score on admission (12 versus 15, p = 0.002) and lower prevalence of antiplatelets use (27.4% versus 42.5%, p = 0.04) compared with CS patients. Favorable outcome was more likely in ESUS patients, at discharge (48.4% versus 24.0%, p = 0.002) and after 3 months (71.0% versus 37.2%, p < 0.001). Hemorrhagic transformation was less frequent (17.7% versus 33.6%, p = 0.03) in ESUS patients. Independent predictors of 3‑month favorable outcome were ESUS, the absence of leukoaraiosis on computed tomography (CT) and absence of diabetes as a risk factor., Conclusion: Patients with ESUS had better outcome after IVT than patients with CS, which can be attributed to younger age and milder strokes in these patients.

Purpose: Ovarian and adrenal aging leads to a progressive decline in androgen levels and deleterious effects on the quality of life. Despite this, specific replacement is not routinely recommended in the management of women with a physiological or pathological decline in their production, mainly due to the lack of long-term follow-up safety data. The purpose of this paper was to meta-analyze and summarize the existing data about hormonal profile changes in menopausal women receiving androgen replacement treatments. Full-text articles published through May 30, 2018 were found via MEDLINE and Embase and selected according to the strict inclusion criteria., Methods: Randomized clinical trials and case-control studies were enrolled. Studies not reporting steroid serum levels or not providing a control group were excluded from the analysis. Studies enrolling women with genetic defects or severe chronic systemic diseases were excluded. 113 papers fulfilled the inclusion criteria and 56 papers were included in the analysis. Desired data were compiled and extracted by independent observers., Results: Androgen administration increases E1, E2, testosterone, DHEA and DHEAS serum levels, and reduces SHBG. However, the E1 and E2 increase is evident only when DHEA is administered., Conclusions: Whatever androgen formulation we choose in postmenopausal women, the end result is a rise in testosterone serum levels. However, DHEA regimen is also associated with an increased estrogenic availability. This might be crucial when choosing the best possible treatment for each patient individually taking into consideration if potential benefits outweigh the risks.

The purpose of this study was to describe the current practice of mentorship in clinical microbiology (CM) and infectious diseases (ID) training, to identify possible areas for improvement and to assess the factors that are associated with satisfactory mentorship. An international cross-sectional survey containing 35 questions was answered by 317 trainees or specialists who recently completed clinical training. Overall, 179/317 (56%) trainees were satisfied with their mentors, ranging from 7/9 (78%) in non-European countries, 39/53 (74%) in Northern Europe, 13/22 (59%) in Eastern Europe, 61/110 (56%) in Western Europe, 37/76 (49%) in South-Western Europe to 22/47 (47%) in South-Eastern Europe. However, only 115/317 (36%) respondents stated that they were assigned an official mentor during their training. In multivariable logistic regression analysis, the satisfaction of trainees was significantly associated with having a mentor who was a career model (OR 6.4, 95%CI 3.5-11.7), gave constructive feedback on work performance (OR 3.3, 95%CI 1.8-6.2), and knew the family structure of the mentee (OR 5.5, 95%CI 3.0-10.1). If trainees felt overburdened, 70/317 (22%) felt that they could not talk to their mentors. Moreover, 67/317 (21%) stated that they could not talk to their mentor when unfairly treated and 59/317 (19%) felt uncertain. Training boards and authorities responsible for developing and monitoring CM&ID training programmes should invest in the development of high-quality mentorship programmes for trainees in order to contribute to the careers of the next generation of professionals.

Myotonic dystrophy type 2 (DM2) is a slowly progressive, autosomal-dominant disease. This is a multisystemic disorder that affects the heart, which is one of the main causes of morbidity and mortality in DM2. The aim of the study was to define cardiac impairments in patients with DM2 and its association with sociodemographic and clinical features of patients. This retrospective study comprised 62 adult patients with DM2 hospitalized at the Neurology Clinic, Clinical Center of Serbia from 2013 until 2018, who underwent electrocardiography (ECG) and echocardiography examinations. Hypertension was observed in 42% of DM2 patients. One-fifth of DM2 patients had bradycardia, while other conduction and rhythm impairments were rare. Only one patient had a pacemaker implanted because of the first degree AV block associated with incomplete left bundle branch block. Echocardiography showed diastolic dysfunction of the left ventricle in 44% of patients, while systolic dysfunction was found in only 4%. Cardiomyopathy was observed in 18% of patients, of whom three-fourth had dilated type. Cardiac conduction and rhythm defects are relatively rare in DM2, while diastolic dysfunction is common. This suggests that regular ECG and echocardiography screening is needed in DM2. Adequate therapy should be introduced in patients with DM2 on time to reduce the frequency of heart complications and to prevent premature death.

Methionine is the precursor of homocysteine, a sulfur amino acid intermediate in the methylation and transsulfuration pathways; methionine-rich diets were used to induce hyperhomocysteinemia, and cardiovascular pathology was often observed. Other sulfur amino acids interfere with this metabolism, i.e., L-cysteine (Cys) and N-aceyl-L-cysteine (NAC), and probably also affect cardiovascular system. Their effects are controversial due to their ability to act both as anti- or pro-oxidant. Thus, this study aimed to elucidate their influence on levels of homocysteine, folate and vitamin B12, levels of different haemostatic parameters (fibrinogen, D-dimer, vWF Ag, vWF Ac) in rat serum or plasma as well as their effects on cardiac and aortic tissue histology in subchronically methionine-treated rats. Wistar albino rats were divided into 4 experimental groups: (a) control group (0.9% sodium chloride 0.1-0.2 mL/day) (n = 10) (K); (b) DL-methionine (0.8 mmol/kg/bw/day) (n = 10) (M); (c) DL-methionine (0.8 mmol/kg/bw/day) + L-cysteine (7 mg/kg/bw/day) (n = 8) (C); (d) DL-methionine (0.8 mmol/ kg/bw/day) + N-acetyl-L-cysteine (50 mg/kg/bw/day) (n = 8) (N). All substances were applied i.p., treatment duration 3 weeks. Lower levels of vitamin B12 in all the groups were found. Folate was reduced only in N group. Decreased fibrinogen was noted in C and N groups and increased D-dimer only in C. VWF activity was reduced in M and C groups. Deleterious effects in heart were observed, especially after Cys and NAC application. Aortic tissue remained unchanged. In conclusion, it could be said that sulfur amino acids have the significant impact on cardiovascular system in subchronically methionine-treated rats. This study points out the relevance of their complex interactions and deleterious effects mediated by either direct influence or procoagulant properties.

It is believed that myasthenia gravis (MG) with antibodies to muscle-specific tyrosine kinase (MuSK) is the most severe form of the disease, especially in the first years of the disease. The aim of our study was to investigate quality of life (QoL) in a population of patients with MuSK MG compared to those with MG who have antibodies to acetylcholine receptor (AChR) in their sera. The study group consisted of 35 MuSK MG patients (28 females and 7 males), while the control group included 38 AChR MG patients matched for gender, age, and duration of the disease. SF-36 questionnaire was used to evaluate the health-related QoL. Following scales were also used: Hamilton's scales for depression and anxiety, the Multidimensional Scale of Perceived Social Support, and the Acceptance of Illness Scale. Physical domain scores of QoL were similarly affected in both MuSK and AChR groups, while mental domain and total SF-36 scores were even better in MuSK MG patients. Social support was better in the MuSK group (77.3 ± 9.3 vs. 70.6 ± 14.1, p < 0.05). SF-36 total score correlated with depression (rho = 0.54, p < 0.01), anxiety (rho = 0.49, p < 0.01), and MSPSS (rho = - 0.35, p < 0.05), and depression was an independent predictor of worse QoL. Besides therapy of weakness, psychiatric treatment and different forms of psychosocial condition should be part of regular therapeutic protocols for MG. Adequate team work of health professionals and family can provide a healthy mental environment in which a MuSK MG patient would feel more comfortable in spite of the disease.

Purpose: In the early 1970s, a number of authors described the development of Balkan endemic nephropathy (BEN) in immigrants in endemic regions. The aim of this study was to examine whether immigrants in endemic regions are suffering from BEN today., Methods: The study involved 193 residents of two endemic regions divided into three groups: two groups of native residents-(1) members of BEN families, (2) members of non-BEN families, and (3) immigrants, who had moved from non-affected settlements to the endemic regions of Kolubara (38 years ago) or Semberia (20 years ago). All persons were subjected to an interview, objective examination, kidney ultrasound, and laboratory analysis to detect the presence of BEN consensus diagnostic criteria., Results: The number of immigrants with BEN biomarkers outside cutoff values was significantly lower than for BEN family members. Five BEN family members met diagnostic criteria for BEN and four for suspected BEN. Although five non-BEN family members had different combinations of BEN biomarkers, all of them had diseases other than BEN in which these biomarkers also occurred. None of the immigrants met the criteria for BEN. Nevertheless, one descendant of an immigrant, a 78-year-old male, whose mother was from a non-BEN family in the Kolubara district, exhibited all the criteria for BEN: alpha1-microglobulinuria, chronic renal failure, and anemia., Conclusion: While 30 years ago, BEN was reported equally among immigrants and natives, currently it is diagnosed in some BEN family members in the eighth decade of life, but extremely rarely in immigrants also in old age.

The aim of this study was to compare clinical cure rate, recurrence rate and time to resolution of diarrhea in patients with severe and severe-complicated Clostridium difficile infection (CDI) treated with teicoplanin or vancomycin. This two-year prospective observational study included patients with first episode or first recurrence of CDI who had severe or severe-complicated CDI and were treated with teicoplanin or vancomycin. Primary outcomes of interest were clinical cure rate at discharge and recurrence rate after eight weeks follow up, and secondary outcomes were all-cause mortality and time to resolution of diarrhea. Among 287 study patients, 107 were treated with teicoplanin and 180 with vancomycin. The mean age of patients was 73.5 ± 10.6 years. One hundred eighty six patients (64.8%) had prior CDI episode. Severe complicated disease was detected in 23/107 (21.5%) and 42/180 (23.3%) patients treated with teicoplanin and vancomycin, respectively. There was no statistically significant difference in time to resolution of diarrhea between two treatment arms (6.0 ± 3.4 vs 6.2 ± 3.1 days, p = 0.672). Treatment with teicoplanin resulted in significantly higher clinical cure rate compared to vancomycin [90.7% vs 79.4%, p = 0.013, odds ratio (OR) (95% confidence interval (CI)) 2.51 (1.19-5.28)]. Recurrence rates were significantly lower in patients treated with teicoplanin [9/97 (9.3%) vs 49/143 (34.3%), p < 0.001, OR (95%CI) 0.20 (0.09-0.42)]. There was no statistically significant difference in overall mortality rate. Teicoplanin might be a good treatment option for patients with severe CDI. Patients treated with teicoplanin experienced remarkably lower recurrence rates compared to vancomycin-treated patients.

Considering the well-known antioxidant properties of statins, it seems important to assess their impact on major markers of oxidative stress (superoxide anion radical, nitric oxide, and index of lipid peroxidation) to compare the antioxidative potentials of atorvastatin and simvastatin during the different degrees of hyperhomocysteinemia (HHcy) in rats. This study was conducted on adult male Wistar albino rats (n = 90; 4 weeks old; 100 ± 15 g body mass) in which HHcy was achieved by dietary manipulation. For 4 weeks, the animals were fed with one of the following diets: standard rodent chow, diet enriched in methionine with no deficiency in B vitamins (folic acid, B6, and B12), or diet enriched in methionine and deficient in B vitamins (folic acid, B6, and B12). At the same time, animals were treated with atorvastatin at doses of 3 mg/kg/day i.p. or simvastatin at doses of 5 mg/kg/day i.p. Levels of superoxide anion radical and TBARS were significantly decreased by administration of simvastatin in normal and high-homocysteine (Hcy) groups (p < 0.05). At 4 weeks after feeding with purified diets, the concentrations of the GSH, CAT, and SOD antioxidants were significantly affected among all groups (p < 0.05). Our results indicated that statin therapy had variable effects on the redox status in hyperhomocysteinemic rats, and simvastatin demonstrated stronger antioxidant effects than did atorvastatin.

Risk assessment of central nervous system (CNS) infection patients is of key importance in predicting likely pathogens. However, data are lacking on the epidemiology globally. We performed a multicenter study to understand the burden of community-acquired CNS (CA-CNS) infections between 2012 and 2014. A total of 2583 patients with CA-CNS infections were included from 37 referral centers in 20 countries. Of these, 477 (18.5%) patients survived with sequelae and 227 (8.8%) died, and 1879 (72.7%) patients were discharged with complete cure. The most frequent infecting pathogens in this study were Streptococcus pneumoniae (n = 206, 8%) and Mycobacterium tuberculosis (n = 152, 5.9%). Varicella zoster virus and Listeria were other common pathogens in the elderly. Although staphylococci and Listeria resulted in frequent infections in immunocompromised patients, cryptococci were leading pathogens in human immunodeficiency virus (HIV)-positive individuals. Among the patients with any proven etiology, 96 (8.9%) patients presented with clinical features of a chronic CNS disease. Neurosyphilis, neurobrucellosis, neuroborreliosis, and CNS tuberculosis had a predilection to present chronic courses. Listeria monocytogenes, Staphylococcus aureus, M. tuberculosis, and S. pneumoniae were the most fatal forms, while sequelae were significantly higher for herpes simplex virus type 1 (p < 0.05 for all). Tackling the high burden of CNS infections globally can only be achieved with effective pneumococcal immunization and strategies to eliminate tuberculosis, and more must be done to improve diagnostic capacity.

Relapse of disease is one of the most prominent characteristics of multiple sclerosis. Effectiveness of rehabilitation programmes on fatigue, self-efficacy (SE) and physical activity (PA) has not been investigated so far in context of relapse. The aim of our study was to examine if rehabilitation programme in addition to high-dose methylprednisolone (HDMP) during relapse of disease can influence fatigue, SE and PA more than corticosteroid therapy alone. Patients were randomized in control group receiving only HDMP and experimental group which was in addition included in rehabilitation programme. Outcome measures used were Fatigue Severity Scale (FSS), Multiple Sclerosis Self- Efficacy scale (MSSES), Godin Leisure-Time Exercise Questionnaire (GLTEQ), completed on baseline, 1 and 3 months later. There was no significant change in FSS in both time points, despite different trend seen between groups. The mean MSSES for function and control improved significantly in treatment group after 1 month (807.1 ± 96.8, p = 0.005; 665.3 ± 145.1, p = 0.05) and 3 months (820 ± 83.5, p = 0.004; 720.0 ± 198.2, p = 0.016.) compared to baseline values. The mean GLTEQ score was significantly higher in the treatment group compared to the control at both follow-up time points (45.7 ± 7.6, p < 0.001; 34.3 ± 22.4, p < 0.01). Rehabilitation started along with corticosteroid treatment induced significant improvement in PA compared to HDMP therapy alone. It also influenced noticeable changes in self-efficacy, but effect on fatigue was insufficient.

Objectives: This study aims to estimate the impact of disease activity, obesity, functional disability, and depression on lipid status, glycoregulation, and risk for coronary heart disease (CHD) in patients with rheumatoid arthritis (RA)., Patients and Methods: A total of 36 patients with RA (30 women and 6 men, mean age 54.9 years, mean disease duration 7.9 years) were included in this study. We estimated the impact of age, body mass index, disease activity [assessed by DAS28 index and C-reactive protein (CRP) value], functional ability (estimated using the HAQ disability index), and depression [assessed using the Beck Depression Inventory (BDI)] on glycoregulation, lipid status, and risk for CHD in our patients. Glycoregulation was assessed by measuring insulin resistance, insulin, and glucose in blood. Lipids tested in blood included total cholesterol, HDL and LDL cholesterol, and triglycerides (TG). The 10-year risk for CHD was estimated using the Framingham risk score., Results: Of 36 patients, 11 (30.6 %) fulfilled the criteria for metabolic syndrome (MS). Ten of 11 patients (90.1 %) with MS have a 10-year risk for CHD greater than 10 % compared to only 3 of 25 patients (12 %) without MS (p = 0.0001). Patients with high disease activity had lower HDL values than patients with mild or moderate disease activity (1.4 vs. 1.7 mmol/l, p = 0.04). Significant correlations were observed between CRP level and insulinemia (ρ = 0.57, p = 0.003), as well as CRP level and the HOMA index (ρ = 0.59, p = 0.002). The body mass index (BMI) correlated significantly with total cholesterol (r = 0.46, p = 0.02), LDL (ρ = 0.41, p = 0.04), and TG (ρ = 0.65, p < 0.001) in blood. The HAQ-DI did not correlate either with parameters of glycoregulation or lipid status. There was a significant positive correlation between BDI and BMI (ρ = 0.60, p < 0.001)., Conculsion: Active RA is independently associated with decreased HDL cholesterol and increased insulin resistance. Obesity was found to be an independent risk factor for increased total cholesterol, LDL cholesterol, and TG. Depressed patients with RA tend to be overweight or obese and, therefore, have an unfavorable lipid profile.

Coronary microcirculatory function after primary percutaneous coronary intervention (pPCI) in patients with acute myocardial infarction is important determinant of infarct size (IS). Our aim was to investigate the utility of coronary flow reserve (CFR) and diastolic deceleration time (DDT) of the infarct artery (IRA) assessed by transthoracic Doppler echocardiography after pPCI for final IS prediction. In 59 patients, on the 2nd day after pPCI for acute anterior myocardial infarction, transthoracic Doppler analysis of IRA blood flow was done including measurements of CFR, baseline DDT and DDT during adenosine infusion (DDT adeno). Killip class, myocardial blush grade, resolution of ST segment elevation, peak creatine kinase-myocardial band and conventional echocardiographic parameters were determined. Single-photon emission computed tomography myocardial perfusion imaging was done 6 weeks later to define final IS (percentage of myocardium with fixed perfusion abnormality). IS significantly correlated with CFR (r = -0.686, p < 0.01), DDT (r = -0.727, p < 0.01), and DDT adeno (r = -0.780, p < 0.01). CFR and DDT adeno in multivariate analysis remained independent IS predictors after adjustment for other covariates and offered incremental prognostic value in models based on conventional clinical, angiographic, electrocardiographic and enzymatic variables. In predicting large infarction (IS > 20 %), the best cut-off for CFR was <1.73 (sensitivity 65 %, specificity 96 %) and for DDT adeno ≤720 ms (sensitivity 81 %, specificity 96 %). CFR and DDT during adenosine are independent and powerful early predictors of final IS offering incremental prognostic information over conventional parameters of myocardial and microvascular damage and tissue reperfusion.

A recurrent incisional hernia resulting from the rupture of low-weight polypropylene mesh is rarely reported in the literature. Three patients with recurrent incisional hernia due to low-weight polypropylene mesh central rupture were operated 5, 7 and 13 months after initial sublay hernioplasty. The posterior myofascial layer was fully reconstructed in all patients during the hernioplasty, whereas the anterior myofascial layer was only partially reconstructed. The recurrent hernia was managed using heavy-weight polypropylene mesh; in two patients, a new sublay hernioplasty was performed and in one patient an "open preperitoneal flat mesh technique" was performed under local anaesthesia as a day case procedure. If closing of the anterior myofascial layer cannot be ensured during the incisional hernioplasty, the use of low-weight polypropylene meshes should be avoided; preference should be given to the heavy-weight polypropylene meshes.

Orbital and ocular andexal Mucosa-Associated Lymphoid Tissue Lymphoma (MALT) or ocular adnexal MALT lymphoma (OAML) is the most common of all eye non-Hodgkin lymphomas. Autoimmune inflammatory disorders and chronic infections are important etiological factors and CD5 and CD43 (sialophorin) tumor markers are significant negative prognostic factors. Disease signs and symptoms can occur a long time before diagnosis. Varieties of treatment options are available. The aim of this retrospective analysis was to compare the efficiency of different treatment options and to investigate disease outcome. Twenty OAML patients, diagnosed in the Clinic of Hematology, Clinical Centre of Serbia, between 2003 and 2013, were enrolled. In most cases, OAML developed in the eighth decade with greater incidence in the male population. Median age was 67.5 years. The median period between the appearance of local signs and symptoms and diagnosis was 7 months. The dominant sign at presentation was swelling of involved tissue (40%). The most common was orbital involvement (55%). All patients had localized disease. Observed laboratory parameters on presentation showed low disease activity. Sialophorin prognostic significance was not registered. Our patients were initially treated differently but there was no significant difference in progression-free survival (PFS) due to initial treatment option (p = 0.2957). Median PFS was 22 months (3-89), and 5-year PFS was 60%. Median overall survival (OS) was 43 months (1-105) and 5-year OS 95%. Eight patients (40%) relapsed and one patient died due to non-hematological complications. In our experience, most modern induction treatment options appear to result in the same, favorable outcome.

We assessed the relationship between the serum levels of antibodies against double-stranded DNA (dsDNA), C1q, nucleosomes, histones, C3 and C4 complement components with one another, with organ involvement and overall disease activity in patients with systemic lupus erythematosus (SLE). One hundred seventy-five sera from 99 patients with SLE, 31 sera of patients with other connective tissue diseases, and 20 sera from healthy blood donors were tested. SLE disease activity was assessed by modified SLEDAI-2K (M-SLEDAI-2K), not including complement and anti-dsDNA descriptors. Anti-dsDNA antibodies were measured by indirect immunofluorescence on Crithidia luciliae (CLIFT), standard enzyme-linked immunosorbent assay (ELISA) and ELISA for high-avidity antibodies. The most significant risk factor for renal involvement were anti-C1q antibodies (OR = 3.88, p < 0.05), high-avidity anti-dsDNA antibodies for polyserositis (OR = 7.99, p < 0.01), anti-histone antibodies for joint involvement (OR = 2.75, p < 0.05), and low C3 for cytopenia (OR = 11.96, p < 0.001) and mucocutaneous lesions (OR = 3.32, p < 0.01). Multiple linear regression analysis showed that disease activity in SLE could be predicted by the levels of antibodies against dsDNA determined by standard (p < 0.05) and high-avidity (p < 0.001) ELISA, and inversely associated with concentration of C3 (p < 0.001). Using stepwise method, high-avidity anti-dsDNA antibodies were found to be in the closest association to M-SLEDAI-2K. Moreover, positive test for high-avidity anti-dsDNA antibodies appeared as an independent risk factor for moderately to severely active disease (M-SLEDAI-2K>5) (OR = 5.5, p < 0.01). The presence of high-avidity anti-dsDNA antibodies represented a risk for renal, joint, and most importantly for serosal involvement. Our results suggest that simple and reliable ELISA for high-avidity anti-dsDNA antibodies is the test of good clinical utility for the assessment of global SLE activity.

The aim of this study was to estimate the prevalence and risk factors for the development of hallucinations in patients with Parkinson's disease (PD). This cross-sectional study included 180 consecutive, non-demented patients with PD. Out of them, 24 patients (13%) experienced some kind of hallucinations. Visual hallucinations were present in 22/24 (90%) subjects. Univariate logistic regression analysis has shown relationship between presence of hallucinations and the following variables: age of patients (p = 0.025), PD duration (p = 0.001), duration of levodopa treatment (p = 0.001), total daily dose of levodopa (p = 0.033), presence of levodopa-induced dyskinesia (p = 0.002) and their duration (p = 0.021), and experience of nightmares (p = 0.042). Hallucinations were also associated with higher scores of the UPDRS (p = 0.001), HDRS (p = 0.001) and the NPI total score (p = 0.001), and higher H-Y stages of the disease (p = 0.001). Multivariate regression analysis has demonstrated that the duration of PD (p = 0.024) as well as NPI total score (p = 0.002) was significant independent risk factors for hallucinations in PD.

The most common lacrimal sac pathology is chronic inflammation with or without occlusive fibrosis. However, a substantial number of lacrimal sac-specific pathologies were reported throughout the literature which may mimic chronic inflammation and be misdiagnosed. From a tertiary ophthalmic care centre in Serbia, in a single ophthalmic pathology laboratory, during a 7-year period (January 2004 to October 2010), a 599 consecutive lacrimal sac wall biopsy samples routinely obtained during external dacryocystorhinostomy in adult patients with clinically presumed primary acquired lacrimal drainage system obstruction were analysed. Although non-specific lacrimal sac pathology was present in the vast majority of cases (578 biopsy specimens; 96.49%), this report also reveals a relatively substantial number (21 biopsy specimens; 3.51%) of clinically non-suspected or intraoperatively unexpected primary lacrimal sac-specific pathology--among them, six lesions with malignant biological behaviour were identified: one microinvasive squamous cell carcinoma and five malignant lymhoproliferative lesions. Usefulness of routine lacrimal sac wall biopsy during surgery for primary acquired lacrimal drainage system obstruction is undoubtful and commensurate with the constant need for better understanding of the pathological processes that involve lacrimal drainage system.

Purpose: Irreversible obstruction of urine flow due to stricture of the distal ureter is one of the most frequent reasons for uroradiological intervention. Using new technologies and with appropriate stents applied at the right time, it is possible to release the stricture and avoid external drainage of urine., Materials and Methods: Our case series consists of six patients (four women, two men) initially treated by percutaneous nephrostomy due to ureteral stricture. The authors used a combined approach (both percutaneous and retrograde) because the balloon catheter could not be inserted using only one approach owing to the morphology of the stricture. The metal guidewire was inserted through a residual tract after previous nephrostomy, and the balloon catheter and a stent were introduced using a retrograde approach through the urinary bladder (four cases) or through an ileostomy positioned at the anterior abdominal wall. In five of the six cases, coated temporary ureteral stents were used., Results: In all six cases the therapeutic aim was achieved. Urine flow through the strictures was established, and the need for percutaneous nephrostomy was obviated. Neither early nor late complications (11 months after the procedure and 6 months after stent removal) associated with the procedure were recorded., Conclusion: In patients with subtotal stricture of the distal ureter, which permits passage only of a hydrophyl guidewire, a combined percutaneous retrograde approach can achieve sustainable flow of urine through the stricture using a balloon catheter and coated stents.

To report a clinical, histopathological and immunohistochemical findings in a case of primary extranodal marginal zone lymphoma of the uvea associated with massive diffuse extraocular episcleral extension and focal infiltration of the optic nerve and meninges, clinically presented as longstanding uveitis masquerade syndrome. Interventional case reports with histopathological correlation. We describe a 80-year-old male patient with a 3-year history of chronic recurrent hypertensive (pan) uveitis associated with ocular pain, unresponsive to topical and systemic anti-inflammatory, immunosuppressive, antibiotic/antiviral and antiglaucomatous therapy. Because the eye was not salvageable with conservative treatment, enucleation of blind and painful eye was performed. Findings from histopathological and immunohistochemistry examination of the enucleated eye showed an extranodal marginal zone lymphoma of the uveal tract with massive epibulbar extension and optic nerve and meningeal penetration. During almost 3 years of clinical course and 6 months after the enucleation, there were no systemic manifestations of lymphoma, and patient has not required subsequent treatment. Primary lymphoproliferative lesions of the uvea, comprising the iris, ciliary body and choroid are very rare, associated with epibulbar extension extremely and with optic nerve and menigeal penetration exceptionally. Despite its rarity, primary lymphoma of the uvea should be included in the differential diagnosis particularly in older patients with longstanding recurrent uveitis.

The aim was to assess factors that might influence health-related quality of life (HRQoL) in patients with two different neuromuscular disorders - myotonic dystrophy type 1 (DM1) and amyotrophic lateral sclerosis (ALS). A cross-sectional study was performed on 79 patients with DM1 and 74 with ALS. The HRQoL was evaluated by SF-36, Serbian version. Depressive and anxiety symptoms were assessed using the Hamilton rating scale for depression and the Hamilton rating scale for anxiety respectively. Severity of muscular involvement in DM1 was measured with MRC scale and severity of ALS with ALSFRSr score. The mean total score as well as all domain scores of SF-36 were similar in DM1 and ALS patients (p > 0.05), except that ALS patients experienced less bodily pain (p < 0.05). Depressiveness was found in 51% and marked anxiety in 38% of DM1 patients. Emotional status and severity of muscular involvement emerged as significant independent contributing factors to the total SF-36 in DMI patients (p < 0.05). Only 3% of ALS patients showed depressiveness and 4% anxiety symptoms. The factors found to contribute to HRQoL in ALS patients were severity of disease and educational level ofpatients (p < 0.05). We found significant percentage of potentially treatable emotional disturbances which together with severity of disease significantly contributed to HRQoL in DM1 patients. On the other hand, in ALS patients depressiveness and anxious symptoms were uncommon and the factors found to contribute to HRQoL were severity of disease and educational level.

The patient suffered loss of consciousness, dysarthria and right sided hemiparesis. The CT scan and MRI scans were negative. These findings are more in keeping with a diagnosis of Transient Ischemic Attack (TIA) or mild CVA. Hypoglycemia per se does not usually cause hemiparesis. The blood glucose level was low but I am not sure if one can conclude that hypoglycemia caused the above noted neurological signs and symptoms. The authors do not present any data to prove that this patient had "hypoglycemic coma".

The aim of the study was to analyse changes in histological type and age of presentation in female lung cancer patients during a period of 20 years. The obtained results are compared with those available from the literature published in various parts of the world.

It has been recognized that some patients with myelodysplastic syndromes (MDS) develop immunologic abnormalities, but little is known of its correlations to MDS-specific disease features. In a retrospective study of 284 MDS patients, we identified 32 patients (11.3%) with clinical or serologic immunological abnormalities (group A) and compared them to the remaining 252 cases (group B). Group A consisted of 20 patients with clinical signs of autoimmune disease and 12 asymptomatic patients with serologic immunological abnormalities only. Apart from significant female predominance in group A (M/F = 2.5 vs M/F = 0.7, p = 0.001), the other clinical and biological features such as median age, distribution of MDS subtypes, incidence of karyotyopic abnormalities, "abnormal" in vitro growth of GM-progenitors and survival times were similar in the two groups. Autoimmune manifestations partially responded to immunosuppressive therapy, with moderate improvement of peripheral cytopenia. In addition, CD3(+), CD4(+), CD8(+), CD19(+), and CD56(+) cells were quantified in peripheral blood of 38 patients. Matched with similarly aged healthy control group, most MDS patients showed significant lymphocytopenia, mainly due to the reduction of T-helper series (in both absolute numbers and percentage). B-cells were reduced in absolute numbers, but their percentage still overlapped with the control. No major abnormalities of natural killer cells (CD56(+)) were seen. We conclude that autoimmune diseases and asymptomatic immunologic abnormalities are common in patients with MDS, but except for female predominance, no correlation between these abnormalities and MDS-specific disease features were found.

Reports on spontaneous remissions in patients with primary myelodysplastic syndromes (MDS) occasionally appear in the literature. We report five adult patients with spontaneous remission of MDS, achieved without cytotoxic or any other treatment. These five patients represent 1.6% of 307 MDS patients, diagnosed in our Institute since 1987. According to FAB criteria, three patients had RA, and one patient had RARS and RAEB, each. All patients were women, median age of 63 yr (range 32-68 yr). Patients were without significant complaints and peripheral cytopenia was mild. Bone marrow dyshematopoiesis was also mild, mostly affecting erythroid and megakaryocytic series. At diagnosis, three patients had cytogenetic abnormalities [+8,+12; +15 and del(16)(q22)]. Median time to complete hematological and cytogenetical remission was 51 mo, while median duration of spontaneous remission was 45 mo (range 44-60 mo). As for the follow-up, none of the patients relapsed. In conclusion, although spontaneous remissions (i.e., "regression") of MDS are uncommon, better understanding of their basis may lead to crucial advances in the study of leukemogenesis.

The article is concerned with incidence, clinical features, response to therapy, and prognosis of patients with hypocellular myelodysplastic syndromes. Bone marrow (BM) cellularity <30% (or <20% in patients >70 yr) was found in 24 of 236 (10.2%) trephine biopsies. Median age was 61 yr, with significant male predominance (M/F=3.0) At diagnosis, median hemoglobin was 83 g/L, median platelet and neutrofil counts were 31x109/L and 1.2x109/L, respectively. According to FAB classification, 17 patients had RA, 6 had RAEB, and only 1 had RAEB-t. Beside marrow hypoplasia, the most prominent PH finding was megakaryocyte hypoplasia and dysplasia, found in two-thirds of cases, each. Comparison between hypocellular and normo/hypercellular MDS cases regarding clinicopathological features showed younger age, more severe cytopenia, less blood and BM blast infiltration, MK hypoproliferation, and more pronounced stromal reactions in former cases. Karyotypic abnormalities were present in 12.5% hypocellular cases, in contrast to 44.6% normo/hypercellular cases (p=0.0025). Eleven patients were treated with supportive therapy alone, six with danazol or androgens, six with immunosuppressive therapy, and one with LDARAC. However, complete or partial response was achieved in only four patients treated with danazol or androgens. None of the patients developed leukemia. Eleven patients died, so marrow insufficiency was the main cause of death. Median survival was 33 mo for hypocellular MDS, and 19 mo for normo/hypercellular MDS (p=0.09). The results confirm the existence of hypocellular variant of MDS, which seems to have better prognosis than those patients with normo/hypercellular disease.

Twenty-eight of 285 patients (9.8%) with primary myelodysplastic syndrome (MDS) survived more than 5 yr (long-term survivors). There were 21 females and 7 males, median age 60 yr (range 18-84 yr). None had circulating blasts, and 14 had refractory anemia (RA), 8 RA with ringed sideroblasts (RARS) and 6 RA with excess of blasts (RAEB). Thirty-seven percent of the 27 patients who were karyotyped had an abnormal clone, but none of them had -7/7q- or complex cytogenetic abnormalities. Only one of the 13 patients tested had abnormal (i.e., "leukemic") in vitro growth of GM progenitors. During 5 yr following the diagnosis, none of the 28 patients progressed to AML. Two patients with an initial diagnosis of RA showed progression to RAEB and CMML. After 5 yr, 23 of the 28 long-term survivors had stable disease (follow-up period ranged from 64 to 216 mo). One patient progressed to AML (113 mo after diagnosis) and another to RAEBT (80 mo after diagnosis). Eight asymptomatic patients were not treated and 12 patients received only supportive therapy. Except for 6 of 8 treated patients who responded to low-dose Ara-C, danazol, androgens, or immunosuppressive treatment, prolonged survival seemed to result mainly from the natural course of the disease. Except for Valensia score (p=0.033), other scoring systems (Bournemouth, Dusseldorf, Lille, and IPSS score) proved of relatively limited value in differentiating between intermediate (2-5 yr) and long-term survivors.

In a retrospective study of 236 patients with primary myelodysplastic syndromes (MDS), 130 cases (55.1%) revealed myelofibrosis in bone marrow biopsies. It was observed that fibrosis mostly occurs focally or patchy, and collagen deposits were found very rarely (only four patients). The histopathology of bone marrow biopsies revealed several differences between fibrotic and non-fibrotic MDS: cellularity is significantly higher, dysmegakaryopoiesis is more pronounced, plasmocytes and mast cells are more often increased, and disturbance of marrow topography (particularly of the MK- and G-line) can be found more frequently in MDS with myelofibrosis. Reticulin fibrosis occurred in all subtypes of MDS; however, there was a higher incidence in chronic myelomonocytic leukemia. The frequency of abnormal growth of GM-progenitors was significantly higher in the MDS cases with myelofibrosis, compared to the cases without fibrosis. Clinical data showed significantly higher WBC, more frequent presence of immature granulocytes, and higher percentage of myeloblasts in peripheral blood and bone marrow in MDS with myelofibrosis compared to cases without myelofibrosis. Life expectancy was reduced to 13 mo, compared with 35 mo in MDS without fibrosis (p=0.00055). Time to leukemic transformation was 32 mo in MDS with fibrosis, compared with >56 mo in MDS without fibrosis (p=0.015). Myelofibrosis therefore seems to herald a poor prognosis.

Biological and clinical significance of growth pattern of hematopoietic progenitors were investigated in 117 patients with primary myelodysplastic syndromes (MDSs) at referral. Abnormal (i.e., "leukemic" or absent) growth of GM colonies (CFU-GM) and GM clusters was found in 47% of patients with "advanced" MDS (RAEB, RAEB-t, and CMML) and in 15% of "low-risk" (RA/RARS) patients. In vitro erythropoiesis was decreased in most of the patients, with significantly lower number of BFU-E in "advanced" MDS than in RA/RARS patients. Megakaryocyte progenitors (CFU-MK) were very low or absent in almost all the patients, regardless of the FAB type. Significant correlation was demonstrated between the number of BFU-E and hemoglobin concentration and between number of CFU-MK and platelet count. Growth capacity of GM progenitors appears to be in proportion to "myeloproliferative" capacity of the malignant clone. T-cell depletion had no influence on growth capacity of hematopoietic progenitors, nor did colony growth respond in a dose-dependent manner to different concentrations of LCM. Growth capacity of MDS hematopoietic progenitors was independent of Bournemouth score, of the presence and type of cytogenetic abnormality, and of the expression of CD95 and caspase-3 antigens on bone marrow cells. However, in patients with "abnormal" growth of GM progenitors, CD34 antigen expression was significantly higher than in patients with "normal" growth. "Abnormal" GM growth was found to be independently predictive regarding the survival and the risk for AML development. In contrast, the prognostic value of erythroid and megakaryocyte cultures was found to be limited.

A case of chronic primary adrenal insufficiency without hyperpigmentation in a 64-year-old woman is reported. Due to the absence of hyperpigmentation the diagnosis was delayed and she became critically ill. During endocrine evaluation, in order to investigate the mechanism responsible for the absence of hyperpigmentation, skin biopsy was done and hormones responsible for the skin pigmentation were measured. Absence of hyperpigmentation is explained by high degree of melanosome degradation in secondary lysosomes called "compound melanosomes", which overwhelmed increased stimulation of the skin pigmentation. Melanocyte-stimulating hormones were elevated with a strikingly high beta-LPH/ACTH ratio. To our knowledge, this is the first study of pathogenic mechanisms responsible for the absence of hyperpigmentation in white Addison's disease.

A 71-year-old male patient with atypical myelodysplastic syndrome showing monosomy 7 is described. He presented with severe foot pains, trophic skin and nail changes, loss of distal pulses, all compatible with peripheral arterial occlusive disease. He had completely normal blood counts and no bleeding tendency. Prolonged bleeding time was disclosed by chance, during routine haemostatic studies. An acquired platelet dysfunction was considered, with prolonged bleeding time and large platelets that failed to aggregate in response to arachidonic acid and that had impaired response to collagen and adrenaline. The bone marrow was hypercellular, with numerous dysplastic megakaryocytes and two other slightly dysplastic myeloid lines. Cytogenetic analyses of the bone marrow cells showed a mosaic karyotype: 46,XY/45,XY,-7. On angiography, bilateral thrombosis of the iliac, superficial femoral and popliteal was disclosed. The patient was prepared with platelet transfusions. Arterial thrombectomy and amputation of the left calf were performed. Ten months later, his blood counts showed mild pancytopenia. He died at home. The authors discuss some clinical and pathogenetical aspects of such presentations of myelodysplastic syndromes.

Hypercalcaemia is a rare feature of acute lymphoblastic leukaemia (ALL) in adults, particularly of the T cell type. We report on a 24-year-old patient with T-ALL, who presented with symptoms of hypercalcaemia (vomitus, acute renal failure), bone pain, extensive osteolytic lesions and normal white cell count without circulating blasts. An increased serum tumor necrosis factor (TNF-alpha) concentration of 35 pg/ml was found; it remained elevated at 52 pg/ml four weeks later, after having achieved haematological remission. Serum concentrations of IL-1beta, IL-6 and IL-2 were within the control range. The pathophysiology of hypercalcaemia in malignancy and possible mediators of bone resorption, in particular TNF-alpha, are discussed.