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Distribution of rotavirus genotypes in three Croatian regions among children ≤5 years of age (2012–2014)
Get PDFObjectives: Rotavirus is the major cause of severe diarrhea in young children worldwide. In countries like Croatia, where rotavirus vaccine has not been introduced in the national immunization program, prospective surveillance is necessary to establish the diversity of rotavirus strains. The aim of this study was to describe the prevalence and geographical distribution of rotavirus strains in Croatia and to detect the possible emergence of novel strains. -----
Methods: The study was conducted among children ≤5 years of age with acute gastroenteritis at three hospitals located in different geographical regions of Croatia, during the years 2012 to 2014. Rotavirus was detected in stools using an immunochromatographic assay and then sent for further molecular analysis. -----
Results: Genotyping of 822 rotaviruses showed that the predominant circulating strain was G1P[8] (61.9%), followed by G2P[4] (19.5%), G1P[4] (3.9%), and G3P[8] (2.9%). A high prevalence of reassortants among common human rotavirus genotypes was detected (7.7%). Possible zoonotic reassortants were found, including G8 and G6 strains. The latter is described for the first time in Croatia. -----
Conclusions: This study represents pre-vaccination data that are important for decisions regarding immunization strategies in Croatia. The high prevalence of 'common' rotavirus strains circulating in Croatia may advocate for rotavirus vaccine introduction, but further surveillance is necessary to monitor the possible emergence of novel genotypes
Utjecaj farmakogenetičkih varijacija CYP2D6 i ABCB1 na liječenje pripravkom risperidona s produljenim oslobađanjem [Impact of pharmacogenetic variations of CYP2D6 and ABCB1 on the long-acting risperidone treatment]
Get PDFThe practical relevance of polymorphisms of multidrug resistance protein (ABCB1) and breast cancer resistance protein (ABCG2) for treatment with long-acting intramuscular (LAI) risperidone is largely unknown. We explored the relationship between these polymorphisms and cytochrome P450 (CYP) 2D6 phenotype in their effects on drug disposition and clinical outcomes in adults with schizophrenia. In a 24-week observational study, patients initiated on LAI-risperidone (n=101) were genotyped enzymes (CYP2D6*3,*4,*5,*6,*41,dupl; CYP3A4*22,CYP3A5*3), transporters (ABCG2 421C>A; ABCB1 1236C>T, 2677G>T/A, 3435C>T) and evaluated for steady-state (weeks 6-8) plasma levels of dose-corrected risperidone, 9-OH-risperidone, risperidone+9-OH-risperidone (active moiety) and for symptom severity (Positive and Negative Syndrome Scale, PANSS, baseline, weeks 12 and 24).
CYP2D6 normal/ultrarapid metabolizer (NM/UM) phenotype (vs. all others) was associated with 17-23% lower exposure in ABCG2 wild-type homozygotes, and with 43-55% lower exposure in ABCG2 variant allele carriers (reduced transporter function). ABCB1 polymorphisms had no effect. NM/UM phenotype tended to less PANSS reduction. ABCG2 variant allele was associated with 4-5-times higher odds of a relevant PANSS reduction, while ABCB1 predominantly wild-type genotype (normal transporter function) (vs. all others) was associated with 60-65% lower odds (effects unconditional on CYP2D6 phenotype). With ABCB1 predominantly wild-type genotype, active moiety level had no effect on clinical response; otherwise, the lower level was associated with a greater symptoms reduction.
CYP2D6 phenotype effect on exposure to LAI-risperidone is relevantly conditional on ABCG2 421C>A polymorphism. ABCG2 and ABCB1 (1236C>T, 2677G>T/A, 3435C>T) polymorphisms effects on risperidone efficacy are clinically relevant and not related to systemic disposition
Tumor tissue hnRNP M and HSP 90α as potential predictors of disease-specific mortality in patients with early-stage cutaneous head and neck melanoma: a proteomics-based study
Get PDFBackground: Breslow tumor thickness and mitotic rate are standardly used for risk stratification of patients with malignant melanoma. However, their prognostic value is relatively limited and a need for improved prognostication has been advocated. We aimed to screen the tumor tissue proteome in a search for potentially useful prognostic factors in early-stage cutaneous head and neck melanoma. -----
Methodology and findings: Proteomic profiles of archival formalin-fixed tissue samples of 31 patients (age 23-90 years) with early-stage head and neck cutaneous malignant melanoma (American Joint Committee on Cancer, AJCC, stage I/II) were determined and expression intensities were compared to those of melanocytic nevi, yielding ratios used in data analysis. Medical charts were retrospectively reviewed to determine time elapsed since diagnosis to disease-specific death or censoring. In a multivariate recursive partitioning analysis (as per AJCC guidelines), higher expression levels of heterogeneous nuclear ribonucleoprotein M (hnRNP M) [n = 18, HR = 1.94 vs. the entire cohort; HR = 5.95 (95%CI 2.43-14.5) for "high" vs. "low" (n = 13)] and of heat shock protein 90 alpha (HSP 90α) [n = 17, HR = 2.09 vs. the entire cohort; HR = 4.59 (95%CI 1.87-11.2) for "high" vs. "low" (n = 14)] were each independently strongly associated with higher mortality (accounting for clinical and standard pathohistological features). Higher Breslow thickness and mitotic rate were associated with higher mortality only when proteomic data were disregarded. -----
Conclusions and significance: Data suggest that tumor tissue expression of hnRNP M and/or of HSP 90α deserve further investigation and clinical validation as potential novel risk stratification aids in patients with stage I-II cutaneous head and neck malignant melanoma
Vrijednost testova agregacije trombocita u procjeni paravalvularne regurgitacije nakon transkateterske ugradnje aortnog zaliska [Validity of platelet aggregation tests in the assessment of paravalvular regurgitation after transcatheter aortic valve implantation]
Get PDFTranscatheter aortic valve implantation (TAVI) is a globally approved treatment method for patients with severe aortic stenosis (AS). Due to increased shear stress, these patients have disturbed platelet reactivity (PR). The aim of the research is to investigate whether successful TAVI corrects PR. The hypothesis is that there will be no change in PR in case of significant paravalvular regurgitation (PVR), due to persistent shear stress. The study included 40 patients with severe AS who underwent successful TAVI. PR was measured at 5 time points (2 before and 3 after the implantation) using Multiplate® analyser in response to three platelet aggregation agonists. The degree of PVR was determined using transesophageal echocardiography. Significant PVR was observed in 25% of the cases after initial implantation, and in 5% at the end of the procedure. Consecutive measurements of PR, revealed a significant reduction in PR in all three tests, 10 minutes after initial implantation, with continuous reduction in subsequent measurements. The lowest PR values were reached on the 3rd day after TAVI. The results indicate that a successful TAVI induces a decrease in PR, regardless of the platelet activation pathway. However, no association between PVR and PR has been observed, which is why PR cannot be used to asses PVR. These findings add new insights and new knowledge to understanding complex relations in intravascular milieu, following TAVI
Tlr2 deficiency is associated with enhanced elements of neuronal repair and caspase 3 activation following brain ischemia
Get PDFThe aim of this study was to apply multimodal in vivo imaging to assess the influence of altered
innate immunity on brain repair after ischemic lesion. Tlr2-deficient mice were compared to wild type
controls, as they lack Tlr2-mediated pro-inflammatory signaling triggered by postischemic necrosis.
The ischemic lesion was induced by transient middle cerebral artery occlusion for 60 min, followed by
brain imaging and analysis at four time points until 28 days after ischemia. Multimodal in vivo imaging
involved a combination of 3 modalities: (1) magnetic resonance imaging by T2-weighted scans to
assess brain lesion size, (2) bioluminescence imaging of Gap43-luc/gfp transgenic mice to visualize
the axonal remodeling, and (3) caged-luciferin bioluminescence imaging of DEVD-luciferin allowing
for visualization of caspase 3 and 7 activity in Gap43-luc/gfp mice. This enabled innovative correlation
of the MRI-determined lesion size to photon fluxes obtained by bioluminescence imaging. Our data
revealed that following ischemia, Tlr2-deficient mice had higher Gap43 expression and higher levels
of caspases 3 and 7 activity, which was accompanied by enhanced levels of synaptic plasticity markers
DLG4 and synaptophysin when compared to wild type controls. Altered inflammation in Tlr2-deficient
mice was accompanied by enhanced elements of post-stroke repair, in particular during the chronic
phase of recovery, but also with delayed final consolidation of the brain lesion
Genome-wide miRNA profiling reinforces the importance of miR-9 in human papillomavirus associated oral and oropharyngeal head and neck cancer
Get PDFHead and neck cancer is the sixth most common malignancy worldwide, predominantly developing
from squamous cell epithelia (HNSCC). The main HNSCC risk factors are tobacco, excessive alcohol use,
and the presence of human papillomavirus (HPV). HPV positive (+) cancers are etiologically different
from other HNSCC and often show better prognosis. The current knowledge regarding HNSCC miRNA
profiles is still incomplete especially in the context of HPV+ cancer. Thus, we analyzed 61 freshly
collected primary oral (OSCC) and oropharyngeal (OPSCC) SCC samples. HPV DNA and RNA was
found in 21% cases. The Illumina whole-genome small-RNA profiling by next-generation sequencing
was done on 22 samples and revealed 7 specific miRNAs to HPV+ OSCC, 77 to HPV+ OPSCC, and
additional 3 shared with both; 51 miRNAs were specific to HPV− OPSCC, 62 to HPV− OSCC, and 31
shared with both. The results for 9 miRNAs (miR-9, -21, -29a, -100, -106b, -143 and -145) were assessed
by reverse transcription-quantitative polymerase chain reaction on the whole study population. The
data was additionally confirmed by reanalyzing publicly available miRNA sequencing Cancer Genome
Atlas consortium (TCGA) HNSCC data. Cell signaling pathway analysis revealed differences between
HPV+ and HPV− HNSCC. Our findings compared with literature data revealed extensive heterogeneity
of miRNA deregulation with only several miRNAs consistently affected, and miR-9 being the most likely
HPV related miRNA
Microncronucleus index in epithelial exfoliated cells of urothelium and buccal mucosa, and peripheral blood lymphocytes of patients with papillary urothelial carcinoma
Get PDFIntroduction: Bladder urothelial cell carcinoma (UCC) is an increasingly prevalent cancer worldwide, and thus, gaining a better understanding of its identifiable risk factors is a global priority. -----
Aim: This study addressed this public health need with the understanding that cancer-initiating events, such as chromosome breakage, loss and rearrangement, can be reasonably used as biomarkers to evaluate an individual’s cancer risk. -----
Methods: Overall, forty bladder cancer patients and twenty controls were evaluated for genomic instability. To the best of the investigators’ knowledge, this is the first study to perform micronucleus (MN) assays simultaneously in urothelial exfoliated cells (UEC), buccal exfoliated cells (BEC), and peripheral blood lymphocytes (PBL) in first-diagnosed, non-smoker bladder UCC patients. Additionally, the frequency of nucleoplasmic bridges (NPBs) and nuclear buds (NBUDs) in PBL was evaluated. -----
Results: The MN indices in UEC, BEC, and PBL, as well as the indices of NPBs and NBUDs, were significantly higher in patients than in controls. Different levels of genomic instability were found also in relation to tumour grade and tumour muscle invasion. -----
Conclusions: MN assays, particularly in UEC, may be used to identify individuals who are at high risk of developing UCC, as single or as additional triage test to UroVysion FISH test. Our results further validate the efficacy of such biomarkers as predictors of genomic instability
Serum concentrations of free fatty acids are associated with 3-month mortality in acute heart failure patients
Get PDFBackground: Plasma free fatty acids (FFA) are higher in heart failure (HF) patients compared to healthy controls. Considering that the extent of FFA elevation in HF might mirror the severity of HF, we hypothesized that the serum levels of FFA may be a useful prognostic indicator for 3-month mortality in acute heart failure (AHF). ----- Methods: We analyzed the serum samples of AHF patients obtained at admission to the emergency department. Serum levels of FFA were analyzed using an enzymatic reagent on an automatic analyzer. ----- Results: Out of 152 included AHF patients that were originally included, serum samples of 132 patients were available for the quantification of FFA. Of these, 35 (26.5%) died within 3 months of onset of AHF. These patients had significantly higher serum levels of FFA compared to AHF patients who were alive 3 months after onset of AHF. Univariable logistic regression analyses showed a significant positive association of FFA levels with 3-month mortality (odds ratio [OR] 2.76 [95% confidence interval 1.32-6.27], p = 0.010). Importantly, this association remained significant after adjusting for age and sex, as well as for further clinical and laboratory parameters that showed a significant association with 3-month mortality in the univariate analyses. ----- Conclusions: We conclude that the admission serum levels of FFA are associated with 3-month mortality in AHF patients. Therefore, measurements of circulating FFA levels may help identifying high-risk AHF patients
The selective peroxisome proliferator-activated receptor alpha modulator (SPPARMα) paradigm: conceptual framework and therapeutic potential
Get PDFIn the era of precision medicine, treatments that target specific modifiable characteristics of high-risk patients have the
potential to lower further the residual risk of atherosclerotic cardiovascular events. Correction of atherogenic dyslipidemia,
however, remains a major unmet clinical need. Elevated plasma triglycerides, with or without low levels of high-density
lipoprotein cholesterol (HDL-C), offer a key modifiable component of this common dyslipidemia, especially in insulin resistant
conditions such as type 2 diabetes mellitus. The development of selective peroxisome proliferator-activated receptor
alpha modulators (SPPARMα) offers an approach to address this treatment gap. This Joint Consensus Panel appraised
evidence for the first SPPARMα agonist and concluded that this agent represents a novel therapeutic class, distinct from
fibrates, based on pharmacological activity, and, importantly, a safe hepatic and renal profile. The ongoing PROMINENT
cardiovascular outcomes trial is testing in 10,000 patients with type 2 diabetes mellitus, elevated triglycerides, and low
levels of HDL-C whether treatment with this SPPARMα agonist safely reduces residual cardiovascular risk
Targeting tumor markers with antisense peptides: an example of human prostate specific antigen
Get PDFThe purpose of this paper was to outline the development of short peptide targeting of the human prostate specific antigen (hPSA), and to evaluate its effectiveness in staining PSA in human prostate cancer tissue. The targeting of the hPSA antigen by means of antisense peptide AVRDKVG was designed according to a three-step method involving: 1. The selection of the molecular target (hPSA epitope), 2. the modeling of an antisense peptide (paratope) based on the epitope sequence, and 3. the spectroscopic evaluation of sense-antisense peptide binding. We then modified standard hPSA immunohistochemical staining practice by using a biotinylated antisense peptide instead of the standard monoclonal antibody and compared the results of both procedures. Immunochemical testing on human tissue showed the applicability of the antisense peptide technology to human molecular targets. This methodology represents a new approach to deriving peptide ligands and potential lead compounds for the development of novel diagnostic substances, biopharmaceuticals and vaccines