Wojciech Fendler

GlyCulator: A Glycemic Variability Calculation Tool for Continuous Glucose Monitoring Data

Glycemic variability has become a major concern over the years as growing evidence is gathered on its detrimental impact on the risk of diabetes complications. Glycated hemoglobin, although ubiquitous in clinical practice, does not adequately summarize short-term glycemic variability. This gap may be addressed through the use of continuous glucose monitoring, which continuously estimates glycemia based on interstitial fluid glucose concentration. As the amount of collected data is substantial, variability of the glycemic pattern can be analyzed in context of its direction, periodicity, and amplitude. As freely available variability calculation tools are limited in number and complexity, the authors have devised a simple-to-use Web-based application, “GlyCulator,” allowing for rapid computation of glucose variability parameters from continuous glucose monitoring data.

Role of 657del5 NBN mutation and 7p12.2 (IKZF1), 9p21 (CDKN2A), 10q21.2 (ARID5B) and 14q11.2 (CEBPE) variation and risk of childhood ALL in the Polish population.

Recent studies have shown that SNPs mapping to 7p12.2 (IKZF1), 9p21 (CDKN2A), 10q21.2 (ARID5B), and 14q11.2 (CEBPE) and carrier status for recessively inherited Nijmegen Breakage syndrome (NBS) influence childhood acute lymphoblastic leukemia (ALL) risk. To examine these relationship, we analysed 398 ALL cases and 731 controls from Poland. Statistically significant association between genotype at 7p12.2 (IKZF1), 10q21.2 (ARID5B) and the NBS associated locus, 8q21.3 (NBN) and ALL risk was found; odds ratios (ORs), 1.34 (P=0.002), 1.33 (P=0.003), and 1325.21 (P=0.0028), respectively. These data provide further insights into the biological basis of ALL highlighting the existence of both common and rare disease susceptibility variants.

Clinical utility and use of DSM-IV and ICD-10 Criteria and The Memorial Delirium Assessment Scale in establishing a diagnosis of delirium after cardiac surgery.

Authors evaluated the sensitivity and specificity of DSM-IV and ICD-10 criteria and the cutoff value of the Memorial Delirium Assessment Scale (MDAS) in diagnosing postoperative delirium in 260 cardiac surgery patients. Incidence of delirium diagnosed on the basis of DSM-IV and ICD-10 criteria, and with the use of the MDAS was 11.5%, 9.2%, and 6.5%, respectively. The DSM-IV criteria for delirium were found to be more inclusive than those of ICD-10. The cutoff point of 10 of the MDAS was optimal in relation to the presence or absence of delirium after cardiac surgery.

Genetic variability and the risk of myocardial infarction in Poles under 45 years of age

Introduction Myocardial infarction is caused by the obstruction of an artery in places of atherosclerosis plaque rupture. Endothelial cells during their activation express chemoattractant and adhesion molecules whereas infiltrating inflammatory cells produce enzymes, predisposing a lesion to rupture. Material and methods We investigated the correlation between polymorphisms in the human genes E-selectin (Ser128Arg), ICAM1 (K469E), OLR1 (K167N), MMP1 (1G/2G) and MMP3 (−1612 5A/6A) and the risk of MI in young Poles under 45 years. There was no significant difference in the frequency of single nucleotide polymorphism (SNP) of the studied genes E-selectin (Ser128Arg), ICAM1 (K469E), OLR1 (K167N) and MMP3 (−1612 5A/6A) between patients with MI and controls. Results The analysis of the association of the 1G2G polymorphism with the risk of myocardial infarction indicated an odds ratio (OR) of 5.68 (95% confidence interval [95% CI] 2.60 to 12.36). Other factors associated with myocardial infarction were: smoking (OR 4.12; 95% CI 1.63–10.44), male sex (OR 16.02; 95% CI 5.90–43.46), hypercholesterolaemia (OR 2.74; 95% CI 1.29–5.83) and arterial hypertension (OR 4.56; 95% CI 1.66–14.47). Conclusions We found that only MMP1 1G/2G polymorphism is associated with myocardial infarction in the Polish population of individuals younger than 45 years. Clinical factors seemed to play a greater role in the analysed group.

Procalcitonin in the early diagnosis of nosocomial sepsis in preterm neonates

Aim:  To examine the diagnostic usefulness of procalcitonin (PCT), C‐reactive protein and immature to total neutrophil ratio (I : T) in nosocomial sepsis among neonates treated in an intensive care unit.

Coordinated increase of miRNA-155 and miRNA-196b expression correlates with the detection of the antigenomic strand of hepatitis C virus in peripheral blood mononuclear cells

A tight relationship has been revealed between cellular microRNAs (miRNAs) and the course of hepatitis C virus (HCV) replication in human hepatoma cells. Although the detection of the antigenomic HCV RNA strand in peripheral blood mononuclear cells (PBMCs) has provided evidence for viral replication in PBMCs, no reports have shown how miRNAs are affected upon HCV RNA synthesis in PBMCs. The aim of the present study was to assess if and how the expression levels of miRNA-155 and miRNA-196b in PBMCs are related to HCV replication in PBMCs of chronic hepatitis C (CHC) patients. Supporting analyses were performed to evaluate the expression of precursor pri-miR-155 (BIC) and Dicer protein. The genomic and antigenomic HCV RNA strands in PBMCs were detected by strand-specific qRT-PCR. The expression levels of miRNAs, BIC RNA and Dicer protein were assayed on PBMCs by qRT-PCR and Western blotting, respectively. miRNA-155 and miRNA-196b were detected in all studied PBMC samples, but their levels varied according to the presence of the antigenomic HCV RNA strand in PBMCs. Increased expression levels of miRNA-155 and miRNA-196b were associated with the presence of the antigenomic HCV RNA strand in PBMCs. In this group of patients higher frequency of BIC RNA and Dicer protein detection was also found. This study demonstrates that HCV RNA replication in PBMCs of CHC patients is connected with the increased and coordinated expression of miRNA-155 and miRNA-196b.

Complications of mammalian target of rapamycin inhibitor anticancer treatment among patients with tuberous sclerosis complex are common and occasionally life-threatening.

The aim of this study was to evaluate the most common adverse events (AEs) linked to everolimus therapy, a mammalian target of rapamycin (mTOR) inhibitor, in children and adolescents with tuberous sclerosis complex (TSC) hospitalized in one medical center. The study group included 18 patients with a diagnosis of subependymal giant cell astrocytoma or renal angiomyolipoma related to TSC. The median duration of therapy was 15 months. All clinical symptoms and laboratory abnormalities including complete blood count, fasting lipid profile, glucose level, and liver and kidney function tests were analyzed as potential AEs. The most common AEs of everolimus therapy were laboratory abnormalities (100% of patients) and infection complications (83 episodes in 15 patients). Infectious episodes of pharyngitis (67%), diarrhea (44%), stomatitis (39%), and bronchitis (39%) were the most common infections. They were mostly mild or moderate in severity (grade 1–2). In two cases, life-threatening conditions related to mTOR inhibitor treatment were encountered. The first was classified as grade 4 pleuropneumonia and Streptococcus pneumoniae sepsis, whereas the second was classified as death related to AE (grade 5) Escherichia coli sepsis. The most common laboratory abnormalities were hypercholesterolemia (13/18 patients – 72%) and hypertriglyceridemia (12/18 patients – 66%). Neutropenia (12/18 patents – 66%) and anemia (8/18 patients – 44%) were the most common hematologic toxicities. Everolimus treatment in TSC patients may lead to life-threatening outcomes, including sepsis and death. Long-lasting effects of everolimus treatment in the context of high incidences of different laboratory abnormalities found in TSC patients are another subject that should be researched further.

Circulating miR-29a and miR-150 correlate with delivered dose during thoracic radiation therapy for non-small cell lung cancer

BackgroundRisk of normal tissue toxicity limits the amount of thoracic radiation therapy (RT) that can be routinely prescribed to treat non-small cell lung cancer (NSCLC). An early biomarker of response to thoracic RT may provide a way to predict eventual toxicities—such as radiation pneumonitis—during treatment, thereby enabling dose adjustment before the symptomatic onset of late effects. MicroRNAs (miRNAs) were studied as potential serological biomarkers for thoracic RT. As a first step, we sought to identify miRNAs that correlate with delivered dose and standard dosimetric factors.MethodsWe performed miRNA profiling of plasma samples obtained from five patients with Stage IIIA NSCLC at five dose-points each during radical thoracic RT. Candidate miRNAs were then assessed in samples from a separate cohort of 21 NSCLC patients receiving radical thoracic RT. To identify a cellular source of circulating miRNAs, we quantified in vitro miRNA expression intracellularly and within secreted exosomes in five NSCLC and stromal cell lines.ResultsmiRNA profiling of the discovery cohort identified ten circulating miRNAs that correlated with delivered RT dose as well as other dosimetric parameters such as lung V20. In the validation cohort, miR-29a-3p and miR-150-5p were reproducibly shown to decrease with increasing radiation dose. Expression of miR-29a-3p and miR-150-5p in secreted exosomes decreased with radiation. This was concomitant with an increase in intracellular levels, suggesting that exosomal export of these miRNAs may be downregulated in both NSCLC and stromal cells in response to radiation.ConclusionsmiR-29a-3p and miR-150-5p were identified as circulating biomarkers that correlated with delivered RT dose. miR-150 has been reported to decrease in the circulation of mammals exposed to radiation while miR-29a has been associated with fibrosis in the human heart, lungs, and kidneys. One may therefore hypothesize that outlier levels of circulating miR-29a-3p and miR-150-5p may eventually help predict unexpected responses to radiation therapy, such as toxicity.

Serum microRNAs are early indicators of survival after radiation-induced hematopoietic injury.

Serum miRNAs can predict long-term radiation-induced hematopoietic injury immediately after radiation and thereby facilitate timely medical intervention and improve overall survival of exposed individuals. Spotting radiation injury with serum microRNAs Three Mile Island, Chernobyl, and Fukushima were catastrophic nuclear power plant accidents in the United States, Ukraine, and Japan, respectively. The radiation from these accidents took terrible tolls on human lives, not only at the time of the accident, but also long-term, as individuals suffer from unpredictable cancer, gut damage, and infections. Predicting such toxicity is imperfect, and current methods do not account for latent damage to organs and systems. In a crucial step toward better indicators of radiation injury, Acharya and colleagues investigated microRNA profiles and hematopoietic damage in mice exposed to various doses of total body irradiation (TBI). Mice received between 0 and 8 Gy TBI. Serum miRNA profiles distinguished animals receiving different doses of radiation, whereas bone marrow mononuclear cell counts did not. Such miRNA signatures may be useful in distinguishing humans with mild radiation-related injury from those with more severe (often nonrecoverable) bone marrow damage—even if all were exposed to sublethal doses of TBI. Importantly, animals receiving radiation mitigation in the form of amifostine, a radioprotectant, or stem cell transplant, demonstrated serum miRNA profiles that changed to match 0-Gy controls, indicating that miRNAs reflect impact of radiation (hematopoietic function) rather than dose. Similar results were obtained in “humanized” mice, suggesting the translatability of this miRNA-based approach to predicting radiation toxicity in people. Future studies with human samples will allow for validation of such indicators, as well as further investigations into novel intervention measures, to improve care of patients and enhance survival after radiation exposure. Accidental radiation exposure is a threat to human health that necessitates effective clinical planning and diagnosis. Minimally invasive biomarkers that can predict long-term radiation injury are urgently needed for optimal management after a radiation accident. We have identified serum microRNA (miRNA) signatures that indicate long-term impact of total body irradiation (TBI) in mice when measured within 24 hours of exposure. Impact of TBI on the hematopoietic system was systematically assessed to determine a correlation of residual hematopoietic stem cells (HSCs) with increasing doses of radiation. Serum miRNA signatures distinguished untreated mice from animals exposed to radiation and correlated with the impact of radiation on HSCs. Mice exposed to sublethal (6.5 Gy) and lethal (8 Gy) doses of radiation were indistinguishable for 3 to 4 weeks after exposure. A serum miRNA signature detectable 24 hours after radiation exposure consistently segregated these two cohorts. Furthermore, using either a radioprotective agent before, or radiation mitigation after, lethal radiation, we determined that the serum miRNA signature correlated with the impact of radiation on animal health rather than the radiation dose. Last, using humanized mice that had been engrafted with human CD34+ HSCs, we determined that the serum miRNA signature indicated radiation-induced injury to the human bone marrow cells. Our data suggest that serum miRNAs can serve as functional dosimeters of radiation, representing a potential breakthrough in early assessment of radiation-induced hematopoietic damage and timely use of medical countermeasures to mitigate the long-term impact of radiation.

The selected genetic polymorphisms of metalloproteinases MMP2, 7, 9 and MMP inhibitor TIMP2 in sarcoidosis

Summary Background Increased activity of metalloproteinases may play a role in the initiation and propagation of inflammation in sarcoidosis, and may also be one of the factors responsible for the development of lung fibrosis. The aim of this study was to verify whether polymorphisms of MMP2 C-735T, MMP7 A-181G, MMP9 T-1702A and tissue inhibitor of metalloproteinase (TIMP)2 G-418C predispose to sarcoidosis. Material/Methods The study included 139 patients with sarcoidosis and 100 healthy subjects. MMPs and TIMP2 mRNA were measured in peripheral blood lysate using real-time RT-PCR. DNA for genetic polymorphism was extracted from peripheral blood by GTC method. Protein concentrations in peripheral blood lysates were measured by ELISA, and MMP2 and 9 activities in BAL fluid were estimated by gel zymography. Results TT genotype in MMP9 T-1702A was more frequent in sarcoidosis (p<0.0001, OR=13.71, 95% CI 7.02–26.80) and resulted in higher expression of MMP9 mRNA (p<0.0001). No differences were found between TT and AT/AA patients in terms of radiological stage, lung function test parameters, activity markers and the presence/absence of Löfgren syndrome. There were no differences in the distribution of MMP2, MMP7 and TIMP2 polymorphisms. Messenger RNAs, as well as protein concentrations of MMP2, 7, 9, and TIMP2 were elevated in patients with sarcoidosis (p<0.0001 for each). Conclusions The TT homozygotes of MMP9 T-1702A genotype may be predisposed to sarcoidosis. Elevated MMP2, 7, 9, and TIMP2 mRNAs suggest their inducibility.