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.

Clinical Next Generation Sequencing Reveals an H3F3A Gene as a New Potential Gene Candidate for Microcephaly Associated with Severe Developmental Delay, Intellectual Disability and Growth Retardation.

Microcephaly is characterized by significant clinical and genetic heterogeneity, therefore reaching the genetic diagnosis remains challenging in this group of disorders. We describe a case of a girl with secondary microcephaly, associated with severe developmental delay, intellectual disability, growth retardation and dysmorphic features. For purposes of clinical genetic diagnostic testing, we performed trio whole exome sequencing in the proband and unaffected parents. We found a heterozygous de novo missense variant in the H3F3A gene in the proband (NM_ 002107.4: c.185T>G), which is absent from the gnomAD and from the Slovenian Genome databases. The identified variant affects a highly conserved leucine residue at position 62 of the histone H3 protein (H3.3) and is predicted to affect the physicochemical properties of the affected protein. Mouse models, which demonstrated involvement of H3.3 protein in the control of neuronal- and glial-specific gene expression patterns that control synaptic connectivity and behavioral plasticity. Additionally, we also identified similar cases reported in the ClinVar database. These arguments support the possible pathogenic role of the reported genetic variant and thus suggest a novel molecular mechanism for this syndromic form of microcephaly.

Sustainability of Endovenous Iron Deficiency Anaemia Treatment: Hospital-Based Health Technology Assessment in IBD Patients.

Iron deficiency anaemia (IDA) is the main extraintestinal manifestation affecting patients with inflammatory bowel disease (IBD). The Health Technology Assessment approach was applied to evaluate the sustainability of intravenous (IV) iron formulations in the Italian hospital setting, with particular focus on ferric carboxymaltose. Data on the epidemiology of IBD and associated IDA, in addition to the efficacy and safety of IV iron formulations currently used in Italy, were retrieved from scientific literature. A hospital-based cost-analysis of the outpatient delivery of IV iron treatments was performed. Organizational and ethical implications were discussed. IDA prevalence in IBD patients varies markedly from 9 to 73%. IV iron preparations were proven to have good efficacy and safety profiles, and ferric carboxymaltose provided a fast correction of haemoglobin and serum ferritin levels in iron-deficient patients. Despite a higher price, ferric carboxymaltose would confer a beneficial effect to the hospital, in terms of reduced cost related to individual patient management and additionally to the patient by reducing the number of infusions and admissions to healthcare facilities. Ethically, the evaluation is appropriate due to its efficacy and compliance. This assessment supports the introduction of ferric carboxymaltose in the Italian outpatient setting.

The sustainability of influenza vaccination programs: considerations and perspectives from Italy.

Influenza constitutes an annually recurring threat to society, from both the clinical and economic points of view. The impact of influenza is often underestimated, especially among frail elderly people, who are at increased risk of serious complications, including hospitalization and death. In Italy, around 10 million individuals aged 65 years and older are at risk of contracting influenza, and it can be estimated that the lack of a vaccination strategy would lead to more than 2 million cases and about 30,000 deaths. However, adherence to routinely recommended adult immunizations remains suboptimal despite the availability of safe and effective vaccines. Indeed, a monitoring program from the National Institute of Health in Italy has shown that influenza vaccination coverage in the elderly dropped to 49% in the 2014-2015 season, which is far below the maximum values (68%) recorded in the 2005-2006 season. The current situation in Italy imposes a need for greater sustainability in order to face the challenges related to the changing epidemiological situation, demographic transition and social transformations. Our review sums up the key elements of influenza vaccine sustainability and makes suggestions for improving the organizational structure of the present initiatives.

Efficacy and Mechanisms of Action of Fecal Microbiota Transplantation in Ulcerative Colitis: Pitfalls and Promises From a First Meta-Analysis.

BACKGROUND: Inflammatory bowel disease (IBD) is the results of a chronic inflammatory process deriving from disequilibrium between self-microbiota composition and immune response. METHODS: New evidence, coming from Clostridium difficile infection, clearly showed that active and powerful modulation of microbiota composition by fecal microbiota composition (FMT) is safe, easy to perform, and efficacious, opening new frontiers in gastrointestinal and extra-intestinal diseases. FMT has been proposed also for IBD as well as other non-gastrointestinal conditions related to intestinal microbiota dysfunctions, with good preliminary data. RESULTS: In this setting, ulcerative colitis (UC) represents one of the most robust potential indications for FMT after C difficile colitis. CONCLUSIONS: In the present review, we focus on FMT and its application on ulcerative colitis, clarifying mechanisms of actions and efficacy data, trough completion of a meta-analysis on available randomized, controlled trial data in UC. Because microbiota is so crucially involved in this topic, a short review of microbial alterations in UC will also be performed.

Free light chains ratio as a marker to estimate prognosis and survival in patients with multiple myeloma and primary amyloidosis.

PURPOSE: The aim of this study was to evaluate the significance of free light chains ratio (FLC ratio) as a prognostic factor for remission, progression and survival in patients with multiple myeloma (MM) and primary amyloidosis. METHODS: The concentrations of immunoglobulins and FLC ratio were measured using immunonephelometry. A total of 101 patients from 3 different disease groups were investigated during a 7-year period: 1) MM (n=95); 2) nonsecretory multiple myeloma (NSMM) (n=3); and 3) primary amyloidosis (n=3). Reference range for FLC ratio was 0.26-1.65. RESULTS: According to the International Staging System (ISS) for MM, abnormal serum FLC ratio was < 0.03 or > 32. Patients with MM and highly or intermediately abnormal FLC ratio and a combination of adverse risk factors (56.9%) had median survival of 26 months (range 16-38), as opposed to patients with normal or slightly changed values of FLC ratio without adverse risk factors (43.1%) with median survival of 45 months (range 27-69). Also, all of the patients with NSMM had slightly changed values of FLC ratio corresponding to low risk of disease progression. In patients with primary amyloidosis, 33.3% had slightly changed values of FLC ratio corresponding to low risk of disease progression, as opposed to 66.7% with abnormal FLC ratio, corresponding to high risk. CONCLUSION: Abnormal FLC ratio in the examined groups could be an independent risk factor of disease progression and worse prognosis.

Obesity and metabolic syndrome during the menopause transition in Serbian women.

BACKGROUND: Abdominal obesity and metabolic syndrome are known to increase in prevalence from premenopause to postmenopause. Both are well recognized predictors of cardiovascular disease and diabetes in women. Aims The primary objective of this study was to assess the presence of obesity and metabolic syndrome during the menopause transition in Serbian women who attended health-care centers. The secondary objective was to evaluate the prevalence of ischemic heart disease, stroke and diabetes in this group. METHODS: Our results present a part of the national epidemiological cross-sectional study assessing prevalence of metabolic syndrome and obesity in Serbia. In all, 1076 women attending 20 health-care centers were assessed. Women were divided into five groups: premenopausal, perimenopausal, early and late postmenopausal and geripausal. Medical history, waist circumference, blood glucose, lipids, and blood pressure were recorded. RESULTS: The mean body mass index of all women was 28.5 ± 4.9 kg/m(2). The mean waist circumference of all women was 92 ± 12.5 cm. Both were significantly lower in premenopausal women than in other women. Metabolic syndrome was present in 72% of women, with a significant difference in prevalence between premenopausal women and other groups. High triglyceride levels and hypertension were the most commonly present components of metabolic syndrome. Ischemic heart disease, stroke and diabetes occurred significantly more often in postmenopausal and geripausal women. CONCLUSION: The majority of Serbian women attending health-care centers have abdominal obesity and metabolic syndrome which significantly increase in prevalence in the perimenopausal years. This indicates that preventive measures should be focused on diabetes and cardiovascular disease in the perimenopause.

Biogerontology in Serbia.

UNLABELLED: Aging is caused by gradual accumulation of cell and tissue damage. Accumulation of damage begins early and continues progressively throughout life, resulting after several decades in the overt frailty, disability and diseases associated with aging. In Serbia during the last few years, several different institutions participated in the investigation in the aging process: (1) Changes in hormone signaling with aging-the age-related increase in insulinemia and glucose metabolism deregulation was found to be attributed to changes in insulin signaling as demonstrated on murine models. (2) Changes in immunological response in aging-along with involution of thymic lymphoepithelial tissue, it has been demonstrated on a murine model that early thymocyte differentiational steps within the CD4-8-double negative developmental stage are age-sensitive. (3) Changes in cholesterol metabolism and oxidative processes in aging-the beneficial effect of long-term dietary restriction on ageing, was explained as effect on cholesterol metabolism. (4) Alzheimer's disease-the connection between neurodegenerative processes associated to the Alzheimer's disease and the function of the Na-K-ATPase which is known to be altered by ageing has been experimentally shown. CONCLUSION: The recent work of Serbian investigators suggest some new evidence that aging process influences the hormone signaling, immunological response, cholesterol metabolism and oxidative processes.

Demographic characteristics of patients with laryngeal cancer and their socioeconomic status.

PURPOSE: To define demographic characteristics of patients with laryngeal cancer in central Serbia, and to investigate possible relationships between their socioeconomical status and the appearance of laryngeal cancer. METHODS: 100 patients (cases) with histologically verified laryngeal cancer were investigated. The control group consisted of 100 patients (controls) having no cancer. A questionnaire was filled in by both cases and controls and comparison between the groups was carried out by individual matching of demographic characteristics and socioeconomical status. RESULTS: 91% of the cases and controls were male (mean age 60 years). Most of the cases had lower educational level and poorer socioeconomical status compared to controls, whilst no difference was found between the 2 groups concerning their living in urban or rural environment. CONCLUSION: It was not possible to correlate urban environment (air pollution) as risk factor. People of lower educational level and poor socioeconomical status had increased risk of getting laryngeal cancer.

[Orbital complications of rhinosinusitis].

INTRODUCTION: Orbital complications were observed in 53 patients (1.35%, n=53/3912 of all treated patients; 11.04%, n= 53/480 of hospitalized patients). Complications in the orbit can occur in 3-5% of adults with the inflammatory condition of sinuses, while the percentage in children ranges from 0.5-8%. OBJECTIVE: The objective of our work was to determine the frequency of the occurence of orbital complications of the rhinosinal inflammatory origin in a group of adults and children. METHOD: The retrospective analysis of patients treated of rhinosinusitis in the period 1992 to 2007, in the Clinical Center in Kragujevac. RESULTS: In the period of 15 years, a total number of 3912 patients were treated for inflamatory conditions of paranasal cavities. Orbital complications were found in 53 patients (1.35%, n=53/3912 of all treated patients). The number of children showing orbital complications caused by rhinosinusitis was 0.79%, while the number of adults was 1,88%. Acute rhinosinusitis in children was manifested as orbital complication in 14 patients (n=14/15, 93.33%), while 33 adults (n=33/38, 86.84%) had the exarcerbation of the chronic rhinosinusitis at the time of diagnosis of orbital complication. 80% of examined children had the maxillary and ethmoid sinus infected (n=12/15), while the adults most often had polysinusitis (n=22/38, 57.89%). In the juvenile age the most frequent complication was the cellulitis of the orbite (n=7/15, 46.66%), while in the adults it was the subperiostal absces (n=14/38, 36.84%). The adults were mostly treated surgically (n=31/38, 81.58%), while the children were treated by using conservative treatment (n=13/15, 86.67%). There were no cases of mortality. CONCLUSION: The prevention of complications is based on the adequate and timely treatment of acute sinusitis in children, as well as the curative treatment of chronical processes in adults.

[A-mode ultrasonography and roentgenography in diagnosing chronic nonpolypoid maxillary rhinosinusitis].

OBJECTIVES: The aim is to demonstrate diagnostic alternatives for A-mode ultrasonography in examining chronic nonpolypoid rhinosinusitis, its implementation, as well as its advantages and disadvantages in regards to roentgenography. METHOD: The prospective research conducted included patients with chronic nonpolypoid rhinosinusitis, at 79 maxillary sinuses. Chronic diseases are classified into two separate categories depending on the clinical entity. Comparative analysis of the ultrasound and roentgenography findings was conducted for both, while the status of the maxillary sinuses obtained by sunusoscopy provided the gold standard. RESULTS: Generally speaking, the reliability of the A-mode ultrasonography in diagnosing chronic nonpolypoid diseases in maxillary sinuses was of a somewhat greater degree in comparison to roentgenography, amounting to 72.15% in relation to 60.76%. There is no statistically significant divergence in relation to the foregoing methods. A-mode ultrasonography is more helpful in the process of identifying liquid contents, and can be less utilized in identifying hypertrophic mucous membrane. CONCLUSION: Ultrasonography is efficient, economical and quite simple for the implementation. Its chief advantage is to be perceived in the fact that both the patient and the examiner avoid being exposed to ionized radiation. Ultrasonography and roentgenography suggest lesser degree of utility and represent a triage method in detecting chronic nonpolypoid pathological conditions.

Antimicrobial effect of water-soluble muscadine seed extracts on Escherichia coli O157:H7.

Water-soluble extracts were prepared from purple (cultivar Ison) and bronze (cultivar Carlos) muscadine seeds with or without heating. The Ison extracts had strong antimicrobial activity against a cocktail of three strains of Escherichia coli O157: H7. This extract had higher acidity (pH 3.39 to 3.43), total phenolics (2.21 to 3.49 mg/ml), tartaric acid (5.6 to 10.7 mg/ml), tannic acid (5.7 to 8.1 mg/ml), and gallic acid (0.33 to 0.59 mg/ml) than did the Carlos extracts. Heat treatment on both extracts increased antimicrobial activity, possibly because of increased acidity, tartaric acid, total phenolics, and individual phenolics. Heating of Ison extracts increased ellagic acid up to 83%. Up to 10.7 mg/ml tartaric acid alone was not as effective against E. coli O157:H7 as were water-soluble seed extracts. This finding suggests the involvement of other factors, such as tannic and gallic acids, in inactivation of this pathogen. Water-soluble muscadine seed extracts may be useful for incorporation into juice and other beverage products as natural preservatives.

Distribution of high-risk HPV types in Yugoslav women with cervical neoplasia.

PURPOSE: The purpose of this study was to determine the frequency of high-risk types of human papillomavirus (HPV) infection, namely type 16, 18, 31 and 33, among Yugoslav women diagnosed with different grades of squamous intraepithelial lesion (SIL), as well as to investigate the relationship between HPV infection and age, parity, age at first intercourse, number of sexual partners and residence of the patients, all of which are considered risk-factors. PATIENTS AND METHODS: DNA was isolated from cervical swabs of 72 women using phenol/chloroform/isoamylalcohol extraction. Detection of HPV DNA in patients' genomic DNA was performed using the polymerase chain reaction (PCR) method with type-specific primer pairs, and amplification products were analyzed using 2% agarose and 10% polyacrylamide gel electrophoresis. RESULTS: Thirty out of 72 (41.7%) patients with cervical intraepithelial neoplasia (CIN) were HPV-positive and 8 of them were double positives. HPV31 was the most frequent high-risk HPV type in this group of patients (13.9%). Eighty percent of the high-grade SIL (HSIL) patients were HPV-positive and 38.8% of the low-grade SIL (LSIL) patients were HPV-positive. Compared to HPV-negative women, the HPV-positive ones were younger, had started sexual activity earlier, and overall had more sexual partners. CONCLUSION: Our study showed that oncogenic HPV types are responsible for the transition of LSIL to HSIL, and for its further progression to an invasive carcinoma of the cervix. Thus, HPV typing should become a widely used method for identifying women with increased risk for developing HSIL and invasive cervical cancer. We also concluded that sexual behavior is connected with the frequency of HPV infection. Henceforth, introduction of prophylactic measures could reduce the incidence of HPV infected women in our country.

[Embolization therapy of a femoral hemangiolipoma with intra-osseous invasion]. / Embolisationstherapie eines Oberschenkelhämangiolipoms mit intraossaler Ausdehnung.

The paper presents the case of a gigantic inoperable hemangiolipoma of the right upper leg with infiltration into femur. Performed embolization therapy resulted in satisfactory subjective and objective improvement.

Therapeutic embolization of aneurysmal bone cyst.

Results of therapeutic embolization of aneurysmal bone cysts in five patients are described. Transcatheter arterial embolization was performed with Ivalon and Gelfoam particles and Gianturco coils. The postembolization period was characterized by complete relief of pain and decrease in size of the aneurysmal bone cyst in all patients. In patients whose follow-up was longer than 12 months, sclerosis and recalcification of bone were present. There were no complications.

[Computer tomography and spinal angiography in the diagnosis of spinal angioma]. / Ein Beitrag der Computertomographie und der spinalen Angiographie zur Diagnostik eines Wirbelangioms.

The computer tomographic and angiographic features of spinal angiomas are described. The authors observed 21 cases and, on the basis of this material, they deal with the clinical features, radiological appearances, disease patterns, forms of treatment, and prognosis. CT and angiography produce a fairly uniform and typical appearance, permitting diagnosis before therapy. Problems in differential diagnosis and errors in interpretation are enumerated.