scholarly journals Impact of genetic and non-genetic factors on hepatic CYP2C9 expression and activity in Hungarian subjects

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Ferenc Fekete ◽  
Katalin Mangó ◽  
Máté Déri ◽  
Evelyn Incze ◽  
Annamária Minus ◽  
...  
Keyword(s):  
Genetic Factors ◽  
Accurate Estimation ◽  
Mrna Levels ◽  
Cytochrome P450 Enzymes ◽  
Acid Therapy ◽  
Cyp2c9 Genotype ◽  
Amoxicillin Clavulanic Acid ◽  
Inflammatory Drugs ◽  
The Impact ◽  
Cyp2c9 Activity

AbstractCYP2C9, one of the most abundant hepatic cytochrome P450 enzymes, is involved in metabolism of 15–20% of clinically important drugs (warfarin, sulfonylureas, phenytoin, non-steroid anti-inflammatory drugs). To avoid adverse events and/or impaired drug-response, CYP2C9 pharmacogenetic testing is recommended. The impact of CYP2C9 polymorphic alleles (CYP2C9*2, CYP2C9*3) and phenoconverting non-genetic factors on CYP2C9 function and expression was investigated in liver tissues from Caucasian subjects (N = 164). The presence of CYP2C9*3 allele was associated with CYP2C9 functional impairment, and CYP2C9*2 influenced tolbutamide 4′-hydroxylase activity only in subjects with two polymorphic alleles, whereas the contribution of CYP2C8*3 was not confirmed. In addition to CYP2C9 genetic polymorphisms, non-genetic factors (co-medication with CYP2C9-specific inhibitors/inducers and non-specific factors including amoxicillin + clavulanic acid therapy or chronic alcohol consumption) contributed to the prediction of hepatic CYP2C9 activity; however, a CYP2C9 genotype–phenotype mismatch still existed in 32.6% of the subjects. Substantial variability in CYP2C9 mRNA levels, irrespective of CYP2C9 genotype, was demonstrated; however, CYP2C9 induction and non-specific non-genetic factors potentially resulting in liver injury appeared to modify CYP2C9 expression. In conclusion, complex implementation of CYP2C9 genotype and non-genetic factors for the most accurate estimation of hepatic CYP2C9 activity may improve efficiency and safety of medication with CYP2C9 substrate drugs in clinical practice.

scholarly journals Acute Pancreatitis as a Complication of Antiepileptic Treatment: Case Series and Review of the Literature

2021 ◽  
Vol 13 (1) ◽  
pp. 98-103
Author(s):  
Agnieszka Pawłowska-Kamieniak ◽  
Paulina Krawiec ◽  
Elżbieta Pac-Kożuchowska
Keyword(s):  
Valproic Acid ◽  
Acute Pancreatitis ◽  
Metabolic Disorders ◽  
Genetic Factors ◽  
Clinical Symptoms ◽  
Gallstone Disease ◽  
Young Patients ◽  
Case Series ◽  
Review Of The Literature ◽  
Acid Therapy

Acute pancreatitis (AP) appears to be rare disease in childhood. In children, it has a different aetiology and course, and requires different management than in adult patients. The diagnosis of AP is based on at least two of the three criteria, which include typical clinical symptoms, abnormalities in laboratory tests and/or imaging studies of the pancreas. There are many known causes leading to AP in children including infections, blunt abdominal trauma, genetic factors, gallstone disease, metabolic disorders, anatomical defects of the pancreas, systemic diseases, as well as drugs, including antiepileptic drugs, and especially preparations of valproic acid. In our study, we present four cases of young patients diagnosed with acute pancreatitis as a complication of valproic acid therapy and we present a review of the literature. We believe that the activity of pancreatic enzymes should be monitored in children treated with valproate preparations in the case of clinical symptoms suggesting AP.

scholarly journals Driver Liability Assessment in Vehicle Collisions in Spain

2021 ◽  
Vol 18 (4) ◽  
pp. 1475
Author(s):  
Almudena Sanjurjo-de-No ◽  
Blanca Arenas-Ramírez ◽  
José Mira ◽  
Francisco Aparicio-Izquierdo
Keyword(s):  
Road Safety ◽  
Accurate Estimation ◽  
Main Hypothesis ◽  
Self Organizing Maps ◽  
Safety Measures ◽  
Vehicle Collisions ◽  
Promising Tool ◽  
Visual Clustering ◽  
Open Question ◽  
The Impact

An accurate estimation of exposure is essential for road collision rate estimation, which is key when evaluating the impact of road safety measures. The quasi-induced exposure method was developed to estimate relative exposure for different driver groups based on its main hypothesis: the not-at-fault drivers involved in two-vehicle collisions are taken as a random sample of driver populations. Liability assignment is thus crucial in this method to identify not-at-fault drivers, but often no liability labels are given in collision records, so unsupervised analysis tools are required. To date, most researchers consider only driver and speed offences in liability assignment, but an open question is if more information could be added. To this end, in this paper, the visual clustering technique of self-organizing maps (SOM) has been applied to better understand the multivariate structure in the data, to find out the most important variables for driver liability, analyzing their influence, and to identify relevant liability patterns. The results show that alcohol/drug use could be influential on liability and further analysis is required for disability and sudden illness. More information has been used, given that a larger proportion of the data was considered. SOM thus appears as a promising tool for liability assessment.

scholarly journals Pro-Inflammatory Microenvironment Modulates the Transfer of Mutated TP53 Mediated by Tumor Exosomes

2021 ◽  
Vol 22 (12) ◽  
pp. 6258
Author(s):  
Rossana Domenis ◽  
Adriana Cifù ◽  
Catia Mio ◽  
Martina Fabris ◽  
Francesco Curcio
Keyword(s):  
Cancer Progression ◽  
Rare Event ◽  
Tp53 Gene ◽  
Mrna Levels ◽  
Inflammatory Microenvironment ◽  
Hepatic Cells ◽  
Mutational Status ◽  
Sw480 Cells ◽  
Tumor Exosomes ◽  
The Impact

Exosomes released from tumor cells are instrumental in shaping the local tumor microenvironment to allow cancer progression. Recently, it has been shown that tumor exosomes carry large fragments of dsDNA, which may reflect the mutational status of parental cells. Although it has been described that a stressful microenvironment can influence exosomal cargo, the effects on DNA packing and its transfer into recipient cells have yet to be investigated. Here, we report that exosomes derived from SW480 (human colorectal adenocarcinoma cell line) cells can carry dsDNA fragments containing the entire coding sequence of both TP53 and KRAS genes, harboring the SW480-related TP53 c.818G > A and KRAS c.35G > T typical mutations. We also report the following: that cell stimulation with lipopolysaccharides (LPS) promotes the selective packaging of the TP53 gene, but not the KRAS gene; that exosomes secreted by SW480 cells efficiently transfer the mutated sequences into normal CCD841-CoN colon epithelial and THLE-2 hepatic cells; that this mechanism is more efficient when the cells had been previously incubated with pro-inflammatory cytokines; that the TP53 gene appears actively transcribed in both recipient cells; and that mutated mRNA levels are not influenced by cytokine treatment. Our data strongly suggest that pro-inflammatory stimulation promotes the horizontal transfer of an oncogene by exosomes, although this remains a rare event. Further studies are needed to assess the impact of the oncogenic transfer by exosomes in malignant transformation and its role in tumor progression.

scholarly journals Spinal Cord Injury Increases Pro-inflammatory Cytokine Expression in Kidney at Acute and Sub-chronic Stages

Inflammation ◽  
2021 ◽  
Author(s):  
Shangrila Parvin ◽  
Clintoria R. Williams ◽  
Simone A. Jarrett ◽  
Sandra M. Garraway
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Inflammatory Response ◽  
Inflammatory Cytokine ◽  
Cardiovascular Health ◽  
Mrna Levels ◽  
Post Injury ◽  
Cord Injury ◽  
And Function ◽  
The Impact

Abstract— Accumulating evidence supports that spinal cord injury (SCI) produces robust inflammatory plasticity. We previously showed that the pro-inflammatory cytokine tumor necrosis factor (TNF)α is increased in the spinal cord after SCI. SCI also induces a systemic inflammatory response that can impact peripheral organ functions. The kidney plays an important role in maintaining cardiovascular health. However, SCI-induced inflammatory response in the kidney and the subsequent effect on renal function have not been well characterized. This study investigated the impact of high and low thoracic (T) SCI on C-fos, TNFα, interleukin (IL)-1β, and IL-6 expression in the kidney at acute and sub-chronic timepoints. Adult C57BL/6 mice received a moderate contusion SCI or sham procedures at T4 or T10. Uninjured mice served as naïve controls. mRNA levels of the proinflammatory cytokines IL-1β, IL-6, TNFα, and C-fos, and TNFα and C-fos protein expression were assessed in the kidney and spinal cord 1 day and 14 days post-injury. The mRNA levels of all targets were robustly increased in the kidney and spinal cord, 1 day after both injuries. Whereas IL-6 and TNFα remained elevated in the spinal cord at 14 days after SCI, C-fos, IL-6, and TNFα levels were sustained in the kidney only after T10 SCI. TNFα protein was significantly upregulated in the kidney 1 day after both T4 and T10 SCI. Overall, these results clearly demonstrate that SCI induces robust systemic inflammation that extends to the kidney. Hence, the presence of renal inflammation can substantially impact renal pathophysiology and function after SCI.

Abstract P315: Vascular AT1 Angiotensin Receptors Do Not Contribute to Albuminuria or Hyperfiltration in Diabetes

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Matthew A Sparks ◽  
Stacy Johnson ◽  
Rishav Adhikari ◽  
Edward Diaz ◽  
Aaron Kupin ◽  
...  
Keyword(s):  
Kidney Injury ◽  
Renin Angiotensin System ◽  
Diabetic Control ◽  
Angiotensin Receptors ◽  
Mrna Levels ◽  
Glucose Levels ◽  
Blood Glucose Levels ◽  
Significant Difference ◽  
Akita Mice ◽  
The Impact

Blockade of the renin angiotensin system (RAS) reduces albuminuria, attenuates hyperfiltration, and slows the progression of diabetic nephropathy (DN) by preventing vasoconstriction and subsequent increases in glomerular hydrostatic pressure. Since RAS blockade disrupts Ang II signaling in all tissues, the specific contribution of vascular actions of AT1 receptors in DN has been difficult to delineate. Therefore, we generated 129 SvEv mice with cell-specific loss of AT1A from VSMCs (SMKOs) using Cre-loxp . To eliminate AT1R from VSMCs, we crossed the SMKO mice with AT1BR -/- mice, lacking the minor AT1B isoform. To study the impact of vascular AT1R in DN, we crossed the AT1B- null SMKOs with mice having the Ins2 C96Y AKITA mutation, which develop DM1 early. To enhance kidney injury, mice underwent uninephrectomy (UNX) at 11wks. Blood glucose levels were elevated (~500mg/dL) and similar at 10, 16 and 24wks between the two groups. Prior to UNX, albuminuria was similar between Control AKITA and AT1B- null SMKO AKITA (62±10 Control AKITA versus 107±27 μg/24hrs SMKO AKITA, P=NS). Albuminuria increased with age in both Control Akita and AT1B- null SMKO AKITA but without significant differences between the groups at 16wks (307±106 vs 313±117 μg/24hrs; P=NS) or 24wks (494±236 versus 730±217 μg/24hrs; P=NS), despite a trend toward higher albuminuria in AT1B- null SMKO AKITAs. There was no significant difference in GFR (using FITC-inulin) between non-diabetic Control and AT1B- null SMKO (15.6±1.2 vs 14.8±0.8 μl/min/g BW), and hyperfiltration was observed in both Control AKITA (23.7±2.4 μl/min/g BW; P=0.003) and AT1B- null SMKO AKITA mice (20.7±1.7 μl/min/g BW; P=0.01) relative to their non-diabetic comparators. However, there was no significant difference in GFR between ControlAKITA and AT1B- null SMKO AKITA (P=NS). Finally we measured mRNA levels of putative kidney injury markers by RTqPCR and found no differences in levels of Col1A1 , NGAL , or TGFB1 mRNA between Control AKITA and AT1B null SMKO AKITA. Our studies indicate that the absence of vascular AT1R responses is not sufficient to reduce albuminuria and prevent hyperfiltration in a mouse model of DN. This suggests that blockade of AT1R in other cell lineages may contribute to beneficial actions of ARBs in DN.

Exploring the use of gpr and satellite-based snow data for snowmelt runoff predictions

2021 ◽  
Author(s):  
Ilaria Clemenzi ◽  
David Gustafsson ◽  
Jie Zhang ◽  
Björn Norell ◽  
Wolf Marchand ◽  
...  
Keyword(s):  
Remote Sensing ◽  
Spatial Distribution ◽  
Data Assimilation ◽  
Snow Water Equivalent ◽  
Distribution Model ◽  
Accurate Estimation ◽  
Snowmelt Runoff ◽  
Snow Water ◽  
Snow Distribution ◽  
The Impact

<p>Snow in the mountains is the result of the interplay between meteorological conditions, e.g., precipitation, wind and solar radiation, and landscape features, e.g., vegetation and topography. For this reason, it is highly variable in time and space. It represents an important water storage for several sectors of the society including tourism, ecology and hydropower. The estimation of the amount of snow stored in winter and available in the form of snowmelt runoff can be strategic for their sustainability. In the hydropower sector, for example, the occurrence of higher snow and snowmelt runoff volumes at the end of the spring and in the early summer compared to the estimated one can substantially impact reservoir regulation with energy and economical losses. An accurate estimation of the snow volumes and their spatial and temporal distribution is thus essential for spring flood runoff prediction. Despite the increasing effort in the development of new acquisition techniques, the availability of extensive and representative snow and density measurements for snow water equivalent estimations is still limited. Hydrological models in combination with data assimilation of ground or remote sensing observations is a way to overcome these limitations. However, the impact of using different types of snow observations on snowmelt runoff predictions is, little understood. In this study we investigated the potential of assimilating in situ and remote sensing snow observations to improve snow water equivalent estimates and snowmelt runoff predictions. We modelled the seasonal snow water equivalent distribution in the Lake Överuman catchment, Northern Sweden, which is used for hydropower production. Simulations were performed using the semi-distributed hydrological model HYPE for the snow seasons 2017-2020. For this purpose, a snowfall distribution model based on wind-shelter factors was included to represent snow spatial distribution within model units. The units consist of 2.5x2.5 km<sup>2</sup> grid cells, which were further divided into hydrological response units based on elevation, vegetation and aspect. The impact on the estimation of the total catchment mean snow water equivalent and snowmelt runoff volume were evaluated using for data assimilation, gpr-based snow water equivalent data acquired along survey lines in the catchment in the early spring of the four years, snow water equivalent data obtained by a machine learning algorithm and satellite-based fractional snow cover data. Results show that the wind-shelter based snow distribution model was able to represent a similar spatial distribution as the gpr survey lines, when assessed on the catchment level. Deviations in the model performance within and between specific gpr survey lines indicate issues with the spatial distribution of input precipitation, and/or need to include explicit representation of snow drift between model units. The explicit snow distribution model also improved runoff simulations, and the ability of the model to improve forecast through data assimilation.</p>

scholarly journals TWIST1 and TWIST2 regulate glycogen storage and inflammatory genes in skeletal muscle

2015 ◽  
Vol 224 (3) ◽  
pp. 303-313 ◽  
Author(s):  
Jonathan M Mudry ◽  
Julie Massart ◽  
Ferenc L M Szekeres ◽  
Anna Krook
Keyword(s):  
Skeletal Muscle ◽  
Metabolic Diseases ◽  
Glycogen Synthesis ◽  
C2c12 Cells ◽  
Acid Oxidation ◽  
Diabetic Patients ◽  
Mrna Levels ◽  
Intact Mouse ◽  
Mouse Muscle ◽  
The Impact

TWIST proteins are important for development of embryonic skeletal muscle and play a role in the metabolism of tumor and white adipose tissue. The impact of TWIST on metabolism in skeletal muscle is incompletely studied. Our aim was to assess the impact of TWIST1 and TWIST2 overexpression on glucose and lipid metabolism. In intact mouse muscle, overexpression of Twist reduced total glycogen content without altering glucose uptake. Expression of TWIST1 or TWIST2 reducedPdk4mRNA, while increasing mRNA levels ofIl6,Tnfα, andIl1β. Phosphorylation of AKT was increased and protein abundance of acetyl CoA carboxylase (ACC) was decreased in skeletal muscle overexpressing TWIST1 or TWIST2. Glycogen synthesis and fatty acid oxidation remained stable in C2C12 cells overexpressing TWIST1 or TWIST2. Finally, skeletal muscle mRNA levels remain unaltered inob/obmice, type 2 diabetic patients, or in healthy subjects before and after 3 months of exercise training. Collectively, our results indicate that TWIST1 and TWIST2 are expressed in skeletal muscle. Overexpression of these proteins impacts proteins in metabolic pathways and mRNA level of cytokines. However, skeletal muscle levels of TWIST transcripts are unaltered in metabolic diseases.

scholarly journals Prevalence of Nonopioid and Opioid Prescriptions Among Commercially Insured Patients with Chronic Pain

Pain Medicine ◽  
2018 ◽  
Vol 20 (10) ◽  
pp. 1948-1954 ◽  
Author(s):  
Gabrielle F Miller ◽  
Gery P Guy ◽  
Kun Zhang ◽  
Christina A Mikosz ◽  
Likang Xu
Keyword(s):  
Chronic Pain ◽  
International Classification Of Diseases ◽  
The United States ◽  
Design Data ◽  
Classification Of Diseases ◽  
Drastic Increase ◽  
Inflammatory Drugs ◽  
Insured Patients ◽  
Evidence Based Guidelines ◽  
The Impact

Abstract Objective The increased use of opioids to treat chronic pain in the past 20 years has led to a drastic increase in opioid prescribing in the United States. The Centers for Disease Control and Prevention’s (CDC’s) Guideline for Prescribing Opioids for Chronic Pain recommends the use of nonopioid therapy as the preferred treatment for chronic pain. This study analyzes the prevalence of nonopioid prescribing among commercially insured patients with chronic pain. Design Data from the 2014 IBM® MarketScan® databases representing claims for commercially insured patients were used. International Classification of Diseases, Ninth Revision, codes were used to identify patients with chronic pain. Nonopioid prescriptions included nonsteroidal anti-inflammatory drugs (NSAIDs), analgesics/antipyretics (e.g., acetaminophen), anticonvulsants, and antidepressant medications. The prevalence of nonopioid and opioid prescriptions was calculated by age, sex, insurance plan type, presence of a depressive or seizure disorder, and region. Results In 2014, among patients with chronic pain, 16% filled only an opioid, 17% filled only a nonopioid prescription, and 28% filled both a nonopioid and an opioid. NSAIDs and antidepressants were the most commonly prescribed nonopioids among patients with chronic pain. Having prescriptions for only nonopioids was more common among patients aged 50–64 years and among female patients. Conclusions This study provides a baseline snapshot of nonopioid prescriptions before the release of the CDC Guideline and can be used to examine the impact of the CDC Guideline and other evidence-based guidelines on nonopioid use among commercially insured patients with chronic pain.

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