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Milicevic N.M.,Institute of Histology and Embryology | Trbojevic-Stankovic J.B.,Clinical Center Dr Dragisa Misovic | Drachenberg C.B.,University of Maryland Baltimore County | Milicevic Z.,Institute of Histology and Embryology
Pathology and Oncology Research | Year: 2010

The spleen is composed of several tissue compartments and the respective histoquantitative data are essential for complete understanding of immune or pathological processes in this organ. The aim of our study was to determine and compare the stereologic parameters of all tissue compartments of the gunshot-injured and blunt-injured human spleen. The model-based stereology with point-counting method was utilized to study the volume densities of red pulp, perifollicular zone, marginal zone, white pulp (follicles and periarteriolar lymphoid sheath), and connective tissue. The areal numerical density (the number of follicles per mm2 of tissue section), the numerical density (the number of follicles per mm3 of tissue) of lymphoid follicles and the mean follicle diameter were also determined. Our study provides stereological parameters for all tissue compartments of the human spleen. No morphometric differences were registered between tissue compartments of the blunt-injured and gunshot-injured spleen. As the gunshot-injured spleen was taken as presumably unstimulated in immunological regard, our results suggest that both gunshot-injured and blunt-injured organs may be used as models of the normal human spleen. © 2009 Arányi Lajos Foundation.


Marzese D.M.,John Wayne Cancer Institute | Scolyer R.A.,Royal Prince Alfred Hospital | Scolyer R.A.,University of Sydney | Scolyer R.A.,Melanoma Institute Australia | And 14 more authors.
Neuro-Oncology | Year: 2014

Background: The brain is a common target of metastases for melanoma patients. Little is known about the genetic and epigenetic alterations in melanoma brain metastases (MBMs). Unraveling these molecular alterations is a key step in understanding their aggressive nature and identifying novel therapeutic targets. Methods: Genome-wide DNA methylation analyses of MBMs (n = 15) and normal brain tissues (n = 91) and simultaneous multigene DNA methylation and gene deletion analyses of metastatic melanoma tissues (99 MBMs and 43 extracranial metastases) were performed. BRAF and NRAS mutations were evaluated in MBMs by targeted sequencing. Results: MBMs showed significant epigenetic heterogeneity. RARB, RASSF1, ESR1, APC, PTEN, and CDH13 genes were frequently hypermethylated. Deletions were frequently detected in the CDKN2A/B locus. Of MBMs, 46.1% and 28.8% had BRAF and NRAS missense mutations, respectively. Compared with lung and liver metastases, MBMs exhibited higher frequency of CDH13 hypermethylation and CDKN2A/B locus deletion. Mutual exclusivity between hypermethylated genes and CDKN2A/B locus deletion identified 2 clinically relevant molecular subtypes of MBMs. CDKN2A/B deletions were associated with multiple MBMs and frequently hypermethylated genes with shorter time to brain metastasis. Conclusions: Melanoma cells that colonize the brain harbor numerous genetically and epigenetically altered genes. This study presents an integrated genomic and epigenomic analysis that reveals MBM-specific molecular alterations and mutually exclusive molecular subtypes. © The Author(s) 2014.


Vukojevic K.,University of Split | Vukojevic K.,University of Mostar | Petrovic D.,Institute of Histology and Embryology | Saraga-Babic M.,University of Split
Gene Expression Patterns | Year: 2010

Expression of the neural crest marker nestin was studied in glial and neuronal progenitors of developing human spinal ganglia using immunohistochemistry in 10 conceptuses, 5-10 weeks old. Quantification was performed by counting the ratio of positive cells in the total cell number, expressed as mean ± SD and by the Mann-Whitney test. Strong expression of nestin in the 5th-6th developmental week (56%) decreased to 49% in the foetal period. During the same period, number of PGP9.5-positive cells increased from 38% to 42%. At earliest stages, the number of cells expressing GFAP was two folds higher (21%) than S100 (11%). During further development, their number nearly levelled (23% and 28%, respectively), and finally reached level of 25% for GFAP and 40% for S100. While expression of nestin was constantly higher in the dorsal parts of spinal ganglia, number of PGP9.5-, GFAP- and S100-positive cells was higher in their ventral parts, thus indicating ventral to dorsal direction of spinal ganglia differentiation. Co-localization of nestin and GFAP or nestin and S100 was observed during the whole investigate period, while PGP9.5 did not co-localize with nestin. Some ganglion cells simultaneously co-expressing GFAP and S100 might be satellite cells and immature Schwann cells. We suggest that some nestin-positive cells might be capable to differentiate into neurons during the earliest stages of development. Gangliogenesis seems to be important process during the whole ganglion development. Continuous presence of neural crest cells during development might be important in regenerative processes following damage of the spinal ganglia. © 2009 Elsevier B.V. All rights reserved.


Charrua A.,Institute of Histology and Embryology | Charrua A.,University of Porto | Avelino A.,Institute of Histology and Embryology | Avelino A.,University of Porto | And 2 more authors.
Handbook of Experimental Pharmacology | Year: 2011

The persisting interest around neurotoxins such as vanilloids and botulinum toxin (BoNT) derives from their marked effect on detrusor overactivity refractory to conventional antimuscarinic treatments. In addition, both are administered by intravesical route. This offers three potential advantages. First, intravesical therapy is an easy way to provide high concentrations of pharmacological agents in the bladder tissue without causing unsuitable levels in other organs. Second, drugs effective on the bladder, but inappropriate for systemic administration, can be safely used as it is the case of vanilloids and BoNT. Third, the effects of one single treatment might be extremely longlasting, contributing to render these therapies highly attractive to patients despite the fact that the reasons to the prolonged effect are still incompletely understood. Attractive as it may be, intravesical pharmacological therapy should still be considered as a second-line treatment in patients refractory to conventional oral antimuscarinic therapy or who do not tolerate its systemic side effects. However, the increasing off-label use of these neurotoxins justifies a reappraisal of their pharmacological properties. © 2011 Springer-Verlag Berlin Heidelberg.


Maric G.,University of Belgrade | Gazibara T.,University of Belgrade | Zaletel I.,University of Belgrade | Labudovic Borovic M.,University of Belgrade | And 4 more authors.
Acta Physiologica Hungarica | Year: 2014

Eating process is an aggregate of complex and different forms of behavior. Its regulation is based on energy homeostasis and appetite control which includes two components: the homeostatic and the hedonistic control. Important signals in appetite regulation are gut-derived hormones. They are produced by enteroendocrine cells in response to nutrient and energy intake, and achieve their effects by influencing brain structures involved in food intake regulation. The key brain structure involved in this process is the hypothalamus. Gut hormones reach the hypothalamus from the circulation or by the vagal nerve via the nucleus of the solitary tract. Among gut peptides, ghrelin is the only orexigenic hormone, leading to an increase in food intake and body weight. All others, such as cholecystokinin, glucagon like peptide-1, oxyntomodulin, peptide tyrosine tyrosine or pancreatic polypeptide, are anorexigenic, leading to decrease in food intake. Also, gut-derived endocannabinoids exert orexigenic effect on appetite. Keeping in mind the growing problem of obesity, the crucial issue when considering gut derived peptides is to understand their mechanisms of acting because of potential role in clinical therapy, and discovering long-lasting gut peptides or their analogues, with no or minimal side effects. © 2014 Akadémiai Kiadó, Budapest.


Santos-Silva A.,Hospital Of Sao Joao | Charrua A.,Institute of Histology and Embryology | Charrua A.,University of Porto | Cruz C.D.,Institute of Histology and Embryology | And 7 more authors.
Autonomic Neuroscience: Basic and Clinical | Year: 2012

Purpose: To evaluate the effect of a transient receptor potential vanilloid 1 (TRPV1) antagonist GRC 6211 on neurogenic detrusor overactivity (NDO) of spinal origin. Materials and methods: Cystometries under urethane anaesthesia were obtained in 14 chronic spinalized rats to confirm NDO. Two groups were created. In the first one (n= 10), GRC 6211 (0.01, 0.1 and 1. mg/kg weight) was administered via the duodenum in cumulative doses and cystometries performed 150. min after the administration of each dose of the drug. In the second group (n= 4), used as control, the animals were submitted to cystometries during 12. hours, without administration of GRC 6211. Frequency and amplitude of bladder contractions were recorded in both groups. Results: The mean (±SDev) bladder detrusor muscle contraction frequency of spinalized rats was 0.7±0.27 contractions/min. GRC 6211 produced a significant dose-dependent effect, with the frequency diminished to 0.53±0.23, 0.40±0.20 and 0.20±0.13 contractions/min, respectively. The mean (± SDev) amplitude of bladder contractions was 48.4±4.4 cmH 2O. After administration of 0.01mg/kg, 0.1mg/kg and 1mg/kg of GRC 6211, the amplitude decreased to 47.1±4.3, 45.6±5.6 and 40.2±4.1 cmH 2O respectively. The effect was significant at 0.1 and 1mg/kg doses. Cystometries performed in the control group of spinalized rats showed no evidence of detrusor fatigue caused by the urethane anaesthesia and long duration of the experiment. Conclusion: TRPV1 antagonists may be very effective in reducing NDO of spinal origin. This finding may have profound implications for the pathogenesis and future treatment options of patients with spinal NDO. © 2011 Elsevier B.V.


Hasanbegovic L.,Biochemical Immunological Haematological Medical Laboratory Ilidza | Alicelebic S.,Institute of Histology and Embryology | Sljivo N.,Institute of Histology and Embryology
Acta Informatica Medica | Year: 2015

Background: the most widely used tumor marker in ovarian cancer, often considered the 'gold standard' is CA125 but reliable clinical evidence demonstrates that human epididymis protein (HE4), used alone or in combination with CA125, substantially improves the accuracy of screening and/or disease monitoring. Aim: to evaluate the reliability of the determination a tumor marker HE4 in comparison with CA125 on the Elecsys analyzer 2010 in epithelial ovarian cancer, benign ovarian cyst and healthy controls. Methods: we prospectively determined CA125 and HE4 serum levels in the Biochemical-Immunological-Haematological "Medical Laboratory" Ilidza, Sarajevo, B&H between June 1st and December 31st 2011. Electro-chemiluminescence immunoassay (ECLIA) methods for quantitative determination in vitro were performed on the Roche/Hitachi Elecsys 2010 Immunoassay Analyzer. Standard methods of descriptive statistics were performed for the data analysis. Results: univariate statistical analyze of tumor marker control serum revealed a high reliability for both CA125 and HE4 determination (p>0.05). Levey-Jennings charts of quality control data show that the target and the obtained values of both markers control sera do not differ significantly in relation to the ideal value. In a total number of 60 patients compared values of tumor markers show a high correlation (r=0.85). This study confirmed higher sensitivity and specificity of HE4 tumor marker compared with CA125. ROC-AUC values show that the diagnostic performance of HE4 was significantly higher compared with CA125. Conclusion: We concluded that HE4 was better than CA125 as a single tumor marker. © 2015 Lejla Hasanbegovic, Selma Alicelebic, Nedeljka Sljivo.


PubMed | Biochemical Immunological Haematological Medical Laboratory Ilidza and Institute of Histology and Embryology
Type: Journal Article | Journal: Acta informatica medica : AIM : journal of the Society for Medical Informatics of Bosnia & Herzegovina : casopis Drustva za medicinsku informatiku BiH | Year: 2015

the most widely used tumor marker in ovarian cancer, often considered the gold standard is CA125 but reliable clinical evidence demonstrates that human epididymis protein (HE4), used alone or in combination with CA125, substantially improves the accuracy of screening and/or disease monitoring.to evaluate the reliability of the determination a tumor marker HE4 in comparison with CA125 on the Elecsys analyzer 2010 in epithelial ovarian cancer, benign ovarian cyst and healthy controls.we prospectively determined CA125 and HE4 serum levels in the Biochemical-Immunological-Haematological Medical Laboratory Ilidza, Sarajevo, B&H between June 1(st) and December 31(st) 2011. Electro-chemiluminescence immunoassay (ECLIA) methods for quantitative determination in vitro were performed on the Roche/Hitachi Elecsys 2010 Immunoassay Analyzer. Standard methods of descriptive statistics were performed for the data analysis.univariate statistical analyze of tumor marker control serum revealed a high reliability for both CA125 and HE4 determination (p>0.05). Levey-Jennings charts of quality control data show that the target and the obtained values of both markers control sera do not differ significantly in relation to the ideal value. In a total number of 60 patients compared values of tumor markers show a high correlation (r=0.85). This study confirmed higher sensitivity and specificity of HE4 tumor marker compared with CA125. ROC-AUC values show that the diagnostic performance of HE4 was significantly higher compared with CA125.We concluded that HE4 was better than CA125 as a single tumor marker.


PubMed | Institute of Histology and Embryology, Comenius University, Cytopathos Ltd and Slovak University of Technology in Bratislava
Type: Journal Article | Journal: Biological trace element research | Year: 2016

Foreign substances get into the internal environment of living bodies and accumulate in various organs. Cristobalite and hematite particles in the glial cells of pons cerebri of human brain with diagnosis of Behhet disease with scanning electron microscopy (SEM), energy-dispersive microanalysis (EDX), and transmission electron microscopy (TEM) with diffraction were identified. SEM with EDX revealed the matter of irregular micrometer-sized particles sometimes forming polyhedrons with fibrilar or stratified structure. It was found in some particles Ti, Fe, and Zn. Some particles contained Cu. TEM and electron diffraction showed particles of cristobalite and hematite. The presence of the particles can be a result of environmental effect, disruption of normal metabolism, and transformation of physiologically iron-ferrihydrite into more stable form-hematite. From the size of particles can be drawn the long-term accumulation of elements in glial cells.


Objective: Vascular endothelial growth factor A (VEGF) and its receptor KDR play central roles in angiogenesis and vascular repair, which occur in diabetic vascular complications, such as MI. The aim of our study was to investigate if polymorphisms rs2071559 and rs2305948 in the kinase insert domain-containing receptor (KDR) gene are associated with myocardial infarction (MI) in Caucasians with type 2 diabetes (T2DM). Design and methods: The association of KDR - 604T>C (rs2071559) and 1192G>A (rs2305948) polymorphisms was tested in a case-control cross-sectional study including 171 subjects with T2DM and MI compared to 855 subjects with T2DM without coronary artery disease (CAD). In addition, VEGF serum levels were analyzed in 98 subjects with type 2 diabetes without CAD. Results: A significantly higher frequency of the CC genotype of the KDR - 604T>C (rs2071559) polymorphism was found in diabetic patients with MI compared to diabetic patients without CAD (27.5% vs. 21.1%, p = 0.04). On the other hand, the 1192G>A (rs2305948) polymorphism was not associated with MI in subjects with type 2 diabetes. Significantly higher VEGF serum levels were found in subjects with the - 604CC genotype compared to those with other (CT + TT) genotypes (73.8 ± 22.1 ng/l vs. 58.1 ± 18.5 ng/l; p < 0.01). Multiple logistic regression analysis adjusted for age, arterial hypertension, LDL cholesterol, HDL cholesterol and hsCRP revealed that carriers of the - 604CC genotype (rs2071559) had a 1.6-fold higher risk for MI (OR = 1.6; 95% CI = 1.1-2.1; p = 0.022). Conclusion: The present study demonstrates that the CC genotype of the KDR - 604T>C polymorphism (rs2071559) is a possible risk factor for MI in Caucasians with T2DM. © 2014 The Canadian Society of Clinical Chemists.

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