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A functional variant in the serotonin receptor 7 gene (HTR7), rs7905446, is associated with good response to SSRIs in bipolar and unipolar depression
Get PDFPredicting antidepressant response has been a clinical challenge for mood disorder. Although several genome-wide association studies have suggested a number of genetic variants to be associated with antidepressant response, the sample sizes are small and results are difficult to replicate. Previous animal studies have shown that knockout of the serotonin receptor 7 gene (HTR7) resulted in an antidepressant-like phenotype, suggesting it was important to antidepressant action. In this report, in the first stage, we used a cost-effective pooled-sequencing strategy to sequence the entire HTR7 gene and its regulatory regions to investigate the association of common variants in HTR7 and clinical response to four selective serotonin reuptake inhibitors (SSRIs: citalopram, paroxetine, fluoxetine and sertraline) in a retrospective cohort mainly consisting of subjects with bipolar disorder (n=359). We found 80 single nucleotide polymorphisms (SNPs) with false discovery rate < 0.05 associated with response to paroxetine. Among the significant SNPs, rs7905446 (T/G), which is located at the promoter region, also showed nominal significance (P < 0.05) in fluoxetine group. GG/TG genotypes for rs7905446 and female gender were associated with better response to two SSRIs (paroxetine and fluoxetine). In the second stage, we replicated this association in two independent prospective samples of SSRI treated patients with major depressive disorder: the MARS (n=253, P=0.0169) and GENDEP studies (n=432, P=0.008). The GG/TG genotypes were consistently associated with response in all three samples. Functional study of rs7905446 showed greater activity of the G allele in regulating expression of HTR7. The G allele displayed higher luciferase activity in two neuronal related cell lines, and estrogen treatment decreased the activity of only the G allele. Electrophoretic mobility shift assay suggested that the G allele interacted with CCAAT/enhancer-binding protein beta transcription factor (TF), while the T allele did not show any interaction with any TF. Our results provided novel pharmacogenomic evidence to support the role of HTR7 in association with antidepressant response
Adiponektin i omentin u masnom tkivu vrata i serumu bolesnika s metaboličkim rizikom [Adiponectin and omentin in the adipose tissue of the neck and in blood serum of patients with metabolic risk]
Get PDFAim. In assuming that a portion of the adipose tissue within the neck region acts as an ectopic compartment, we intend to determine the expression of adiponectin and omentin-1 within the subcutaneous and paracarotid adipose tissue of the neck, analyze the relationship of serum adipocytokine levels and evaluate the metabolic risk factors in our examinees. -----
Materials and methods. 60 patients who underwent neck surgery were included in the study. Routine laboratory tests, anthropometric measurements and measurements of the carotid intima-media thickness were performed. Serum concentrations of total adiponectin and omentin-1 were determined. Expression of the adiponectin and omentin-1 genes in subcutaneous and paracarotid neck adipose tissue was analyzed. -----
Results. We found a statistically significant difference between the expression of adiponectin in subcutaneous and in paracarotid adipose tissue. Circulating levels of adiponectin were higher in subjects without metabolic syndrome and positively correlated with the level of HDL-cholesterol and negatively correlated with the neck and waist circumferences, glucose and insulin levels and the HOMA index. We did not find a statistically significant difference in the expression of omentin-1 between the subcutaneous and the paracarotid compartments nor did we did find a correlation between the omentin-1 expression in the tissues using our analyzed variables. The serum level of omentin-1 has a statistically significant negative correlation with body weight, BMI and triglyceride levels. We found a statistically significant positive correlation of neck circumference with body mass, waist circumference, BMI, insulin level and HOMA index. -----
Conclusion. These results support the fact that, although relatively small, the adipose tissue of the neck is positioned as a significant and specific depot with a possible parachrine and systemic influence and as a depot that is an independent predictor of metabolic risk beyond the existing standards of measurement
Vrednovanje klasifikacijskih kriterija za sistemski eritemski lupus [Validation of classification criteria for systemic lupus erythematosus]
Get PDFSystemic lupus erythematosus (SLE) is a chronic autoimmune disease with heterogenuous clinical presentations. Most widely used ACR classification from 1997 (ACR-97) shows high specificity and acceptable sensitivity in classifiying patients with established SLE, but its value declines in early stages and in milder cases. SLICC group has published new, revised (SLICC-12) criteria which have shown higher sensitivity, but lower specificity than the ACR-97 criteria.
The objective of this study was to validate SLICC-12 and ACR-97 classifications on a patient cohort from UHC Zagreb. It comprised 308 patients with SLE (n=146) and SLE-allied conditions (n=162). Sensitivity and specificity, as well as sensitivity and specificity according to disease duration were compared between two classifications. Merit of every criterium to diagnosing SLE was calculated using logistic regression analysis.
A clear distinction between SLICC-12 and ACR-97 criteria is observed. Sensitivity of SLICC-12 criteria is significantly higher with a tendency to rise with disase duration. ACR-97 criteria have shown higher specificity. Specificity of SLICC-12 criteria is low and declines with disease duration. Comparing the overall value of the new SLICC-12 classification to ACR-97 criteria, the new criteria show superiority in our patients.
Although SLICC-12 criteria show superiority to ACR-97, and are more successful in diagnosing early SLE, specificity in our population is too low. Our results contribute to the current initiative for developing new criteria for SLE
Significance of traditional masculinity for the prediction of injuries and accidents in male adolescents [Značenje tradicionalne maskulinosti u predviđanju ozljeda i nesreća adolescenata muškog spola]
Get PDFYoung men's health-related behaviors are part of a network of gendered relations and
structures in the society. These behaviors increase the risk from injuries. Harmful notions of
masculinity may increase the (needless) vulnerability of young men and increase their
morbidity and mortality.
The association between expressed attitudes toward traditional masculinity norms and
personal and environmental factors, health-risk behaviors, and injuries among high school
students was analyzed in this cross-sectional study with a sample of over 2000 students from
diverse schools in Zagreb. The Croatian version of the Male Role Norm Inventory-
Adolescent-revised (MRNI-A-r) was used to analyze traditional masculinity norms and beliefs
about appropriate behavior for adolescent boys.
The greater endorsement of traditional masculinity norms was associated with behaviors that
may lead to injuries and deaths: alcohol and drug use, fighting and weapon carrying and lack
of traffic protection. This research failed to demonstrate that greater scores on the MRNI-A-r
scale were associated with the most prevalent injury events.
The endorsement of traditional masculinity norms may help identify young men more likely
to be involved in behaviors that have the potential to cause injuries and death. Changing how
male adolescents endorse traditional masculinity may have the potential of reducing health
risk behaviors of youth in Croatia
Povezanost polimorfizma gena za kemokine CXCL9 i CXCL10 s pojavom akutnog odbacivanja jetrenoga presatka [Association between CXCL9 and CXCL10 chemokine gene polymorphisms and acute graft rejection after liver transplantation]
Get PDFAcute cellular rejection (ACR) is a clinically important event that negatively affects the survival of the graft and the recipient. As potent T cell- chemoattractants, CXCL9 and CXCL10, have been demonstrated to play a central role in the immune response against transplant tissue, leading to ACR. While increased serum concentrations of CXCL9/10 are associated with ACR occurrence, the association between CXCL9/10 single nucleotide polymorphisms (SNPs) and ACR after liver transplantation (LT) remains unknown. SNPs of CXCL9 (rs10336) and CXCL10 (rs3921) were determined by polymerase chain reaction in 215 recipients transplanted due to alcoholic cirrhosis with or without hepatocellular carcinoma. 27.4% recipients were diagnosed with ACR that was defined as biopsy-proven within 6 months after LT. Recipients that developed ACR had significantly higher MELD scores pre-LT and received significantly younger liver grafts. There was no association between CXCL9/10 genotypes and overall incidence of ACR, the severity of ACR and the number of rejection episodes. However, patients with CXCL9 genotype AA developed ACR earlier, suggesting the involvement of CXCL9-mediated processes in ACR development
Otkrivanje prognostičkih čimbenika u bolesnika s karcinomom prostate pomoću proteomske analize tumorskoga tkiva [Discovering prognostic factors in prostate cancer patients using tumor tissue proteomic analysis]
Get PDFThe biggest obstacle in improving prostatic carcinoma patients' survival rates today is the difficulty of differentiating between indolent and aggressive tumors, caused by the complex and extremely heterogeneous nature of the disease.
The objective of this research project was to discover a group of proteins with significantly differing expressions between healthy and tumor tissue, using proteomic analysis, and two-dimensional gel electroforesis (2-DE), together with mass spectrometry. Twelve patients with even samples of healthy and tumor tissue (the Gleason sum: 6(3+3), or 7 (3+4 ili 4+3)) took part. Eighteen differentially exappropriated proteins were singled out as their specific functions made them classifiable either as potential tumor biomarkers, or healthy tissue biomarkers.
Proteoms were correlated with relapse frequency and applied oncological treatment. In the participants who were observed to have more aggresive disease, the protein expression was visibly stronger for proteins that were part of the malignant transformation. Additionally, we explored and visually showed the connection between differently produced proteins within each patient's sample pair, using STRING software. Individual carcinoma proteom analysis uncovers a molecular protein-level interaction network. Combined with classic clinical-pathohistological indicators, this offers new insight into every participant's tumor fenotype and stage of advancement
Cefpodoxime proxetil as a therapeutic option in switching therapy for infective endocarditis in children: case reports and literature review
Get PDFInfective endocarditis (IE) is uncommon in children, affecting predominantly subjects with congenital heart disease (CHD) and patients with indwelling central lines. The principles of antibiotic treatment in paediatric population are similar to those in adults. Prolonged intravenous administration of bactericidal rather than bacteriostatic agents is preferred. Outpatient intravenous therapy after initial treatment in the hospital may be considered only in selected patients. Partial oral treatment has been described in cases of left-sided, uncomplicated IE caused by common pathogens in adult patients. There are no guidelines or trials in paediatric population regarding switching therapy from intravenous to oral route. We present two cases of IE in children caused by uncommon pathogenic bacteria (Abiotrophia defectiva and Haemophilus parainfluenzae) successfully treated with oral third-generation cephalosporin - cefpodoxime proxetil after initial intravenous therapy. This paper provides observations on different therapeutic approach for IE in children as well as another potential use of cefpodoxime proxetil
Progressive multifocal leukoencephalopathy developing after obinutuzumab treatment for chronic lymphocytic leukemia
Get PDFIdentifying characteristics of thalamo-cortical changes and their relationship with symptoms in schizophrenia [Utvrđivanje obilježja talamo-kortikalnih promjena i njihovog odnosa sa simptomima u shizofreniji]
Get PDFHypothesis of the doctoral thesis was that, using resting-state functional magnetic resonance imaging (fMRI), patients diagnosed with schizophrenia would exhibit stable and specific patterns of thalamic connectivity changes that will show different relationship with specific symptoms of psychotic disorders.
The aims of the study were to characterize in a more detailed way changes in thalamo-cortical connectivity (over- and under-connectivity) in a clinical sample compared to healthy controls, by using state-of-the-art resting-state functional resonance and Human Connectome Project protocols, as well as to more specifically determine within-thalamus differences and their relative contribution to described connectivity changes. Finally, the aim was to determine relationship between identified connectivity changes and specific symptoms of the disorder.
Subjects for the study were pooled from multiple centers, as part of an existing initiative, Bipolar-Schizophrenia Network on Intermediate Phenotypes (B-SNIP) consortium, created with a goal of investigating intermediate phenotypes across psychotic disorders. Study procedures and data analyses were done under the approved Yale University project Characterizing Clinical and Pharmacological Neuroimaging Biomarkers. Following identification of subjects that passed stringent quality controls for fMRI data, and matching with the clinical and healthy control populations, study included 436 psychosis probands (167 schizophrenia patients, 119 schizoaffective disorder patients, and 150 patients diagnosed with bipolar disorder with history of psychosis) and 219 matched healthy controls. Whole-thalamus seed-based analyses were used to determine thalamic connectivity changes, followed by parcellation of thalamus using a priori defined functional subnuclei, and data-driven clustering, to define details of the thalamo-cortical dysconnectivity in schizophrenia and psychotic disorders.
Both in schizophrenia, and in the wider psychosis spectrum, there was a robust pattern of thalamic over-connectivity with sensory and motor regions, as well as with associative areas tasked with integration of lower-level inputs, and under-connectivity with cerebellar regions. Interestingly, previously reported under-connectivity with prefrontal regions was evident only in dorsal attention functional thalamic subnucleus connectivity map. Nine functional thalamic subnuclei showed relatively different thalamic connectivity changes, ranging from altogether missing effects to wide-spread over- /under-connectivity, but overall followed same general dysconnectivity pattern described for the whole thalamus. Clustering analyses revealed that the data-driven clustering, released from constraints of a priori defined thalamic subnuclei, resulted in solutions that significantly differed from existing functional subnuclei or anatomical divisions, with areas centered on mediodorsal nucleus and ventral lateral areas driving the dysconnectivity effect. In schizophrenia, thalamo-cortical connectivity changes showed relationship with negative symptoms, as well as with excitation and disorganization subscale scores, suggesting that a more pronounced over- or under-connectivity effect predicted more pronounced specific symptoms. Under-connectivity effect of the dorsal attention functional subnucleus (including reduced connectivity with prefrontal cortical regions) also correlated with disorientation.
In conclusion, thalamo-cortical dysconnectivity patterns of seemingly correlated over- and under-connectivity effects seems to be robustly present in schizophrenia, but also across the psychosis spectrum. Although the same general pattern exists across different thalamic regions, its extent differs among different thalamic functional subnuclei suggesting that the effect is driven by specific associative functional subnuclei. Finally, although thalamo-cortical connectivity changes might be linked to a more non-specific disease severity or trait indicators, negative symptoms, disorganization, and excitation seem to be connected more directly to those changes than positive symptoms or emotional dysregulation