“Despite recent advances in antibiotic therapy and intensi


“Despite recent advances in antibiotic therapy and intensive care, sepsis is still considered to be the most common cause of death in intensive care units. Excessive production of reactive oxygen species plays an important role in the pathogenesis

of sepsis. Recently, it has been suggested that molecular hydrogen (H(2)) exerts a therapeutic antioxidant activity by selectively reducing hydroxyl radicals (center dot OH, the most cytotoxic reactive oxygen species) and effectively protects against organ damage induced by I/R. Therefore, we hypothesized that H(2) treatment had a beneficial effect on sepsis. In the present study, we found that H(2) inhalation www.selleckchem.com/products/bindarit.html starting at 1 and 6 h after cecal ligation and puncture (CLP) or sham operation significantly improved the survival rate of septic mice with moderate or severe CLP in a concentration-and time-dependent manner. Furthermore, moderate or severe CLP mice showed significant multiple organ damage characterized by the increases of lung myeloperoxidase activity, wet-to-dry 432 weight ratio, protein concentration in bronchoalveolar lavage, serum biochemical parameters, and organ histopathologic scores at 24 h after CLP operation, which was significantly attenuated by 2% H(2) treatment. In addition, we found that the beneficial effects of H(2) treatment on sepsis and sepsis-associated

organ damage were associated with the decreased levels of oxidative product, increased activities of antioxidant enzymes, and reduced levels of high-mobility group box 1 in serum and AZD6094 solubility dmso tissue. Thus, H(2) GS-7977 cost inhalation may be an effective therapeutic strategy

for patients with sepsis.”
“Background: The IALT, JBR. 10, ANITA and Cancer and Leukemia Group B 9633 trials compared adjuvant chemotherapy with observation for patients with resected non-small-cell lung cancer (R-NSCLC). Data from the metastatic setting suggest high tumor class III beta-tubulin (TUBB3) expression is a determinant of insensitivity to tubulin-targeting agents (e.g. vinorelbine, paclitaxel). In 265 patients from JBR.10 (vinorelbine-cisplatin versus observation), high TUBB3 was an adverse prognostic factor and was associated (nonsignificantly) with ‘greater’ survival benefit from chemotherapy. We explored this further in additional patients from JBR.10 and the other three trials.\n\nPatients and methods: TUBB3 immunohistochemical staining was scored for 1149 patients on the four trials. The original JBR.10 cut-off scores were used to classify tumors as TUBB3 high or low. The prognostic and predictive value of TUBB3 on disease-free survival (DFS) and overall survival (OS) was assessed by Cox models stratified by trial and adjusted for clinical factors.\n\nResults: High TUBB3 expression was prognostic for OS [hazard ratio (HR) = 1.27 (1.07-1.51), P = 0.008) and DFS [HR = 1.30 (1.11-1.53), P = 0.001).

(C) 2009 International Federation of 3

(C) 2009 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd All rights reserved.”
“Today, professional nurses around the world are stepping up to meet the needs of individuals with Crohn disease, using their specialized knowledge and skills that demonstrate areas of expertise

that have not always existed. The gastrointestinal-specific knowledge being used by these 21st-century nurses exists today because progressive efforts of nurses in previous decades moved the profession www.selleckchem.com/products/jnk-in-8.html of nursing forward. The purpose of this article was to describe and analyze the development of the role of nurses in responding to new challenges patients with Crohn disease face since the emergence of the disease in the early 20th century. The authors used traditional historic research methods to conduct the study. Primary sources include nursing journals and textbooks published in the 20th and 21st centuries and documents archived at The Mount Sinai Hospital in New York City, where Burrill B. Crohn conducted his seminal work. The significance of the findings is that the changing role of nurses in

caring for patients with Crohn disease mirrors the professionalization of nursing this website during the 20th and early 21st centuries.”
“Specific targeting of tumors by combined delivery of drugs and of imaging agents represents an attractive strategy for treatment of cancer. The aim of the present study was to investigate whether neural cell adhesion molecule (NCAM)-targeted check details liposomes may enhance drug delivery and allow magnetic resonance imaging (MRI) in a severe combined immunodeficient mouse model of NCAM-positive Kaposi’s sarcoma. NCAM-binding peptide-coated liposomes loaded with both doxorubicin and a lipophilic gadolinium (Gd) derivative were generated. NCAM-targeted liposomes induced an 123 enhanced in vitro doxorubicin internalization within Kaposi’s cells as detected by MRI

with respect to untargeted polyethylene glycol liposomes. Internalization resulted in enhanced apoptosis. In vivo weekly administration of NCAM-targeted liposomes containing 5 mg/kg doxorubicin for 4 consecutive weeks induced a significant reduction of tumor mass and vascularization and enhanced cell necrosis and apoptosis with respect to untargeted liposomes. These effects were associated with an enhanced concentration of doxorubicin within the tumor and a reduced systemic toxicity of doxorubicin. By electron microscopy, NCAM-targeted liposomes were detected mainly within tumor cells whereas the untargeted liposomes were mainly accumulated in the extracellular space. Gd-labeled liposomes allowed the MRI visualization of drug delivery in the tumor region. The intensity of MRI signal was partially hampered by the “quenching” of the attainable relaxation enhancement on endosomal entrapment of the Gd-labeled liposomes. In conclusion, targeting NCAM may be a suitable strategy for specific drug delivery and imaging by liposomes in NCAM-expressing tumors.

Purpose The purpose of this in vitro study was to

evalua

Purpose. The purpose of this in vitro study was to

evaluate the influence of digitizing techniques on the fit of implant-retained crowns with 2 antirotational features. Material and Methods. An experimental working cast housing a tissue-level dental implant was created. Resin-retained abutments with different antirotational features were connected to the implant. Optical impressions of 2 abutment types were obtained separately with 1 chairside and 2 laboratory approaches. Alumina silicate restorations were milled from chairside optical impressions, and ceramic oxide cores were milled from laboratory optical impressions. Restoration fit was evaluated from axial sections of restorations with silicone materials representing the check details 432 marginal and axial gaps. SN-38 Axial and marginal fits were measured on digital photographs of the sectioned specimens with a computer program. Two-way ANOVA was used to compare differences between abutments with 2 different antirotational features and digitizing techniques separately for the marginal and axial fits of single implant-retained crowns. A post hoc least significant difference test was used to compare digitizing techniques

(alpha=.05). Results. Significant differences in the marginal fit of single-implant-retained crowns were found among digitizing techniques (P=.011) and between antirotational features (P smaller than .001). No significant difference in the axial fit of single-implant-retained crowns was found among digitizing techniques (P=.905) or between antirotational features (P=.075). Conclusions. Within the limitations of this in vitro study,

the marginal fit of single-implant-retained crowns was affected by antirotational abutment features. Furthermore, digitizing techniques were found to play an important role in the marginal fit of single-implant-retained restorations.”
“Recently, nanomaterials have been utilized in various fields. In particular, amorphous nanosilica particles are increasingly being used in a range of applications, including cosmetics, Alvespimycin Cytoskeletal Signaling inhibitor food technology, and medical diagnostics. However, there is concern that the unique characteristics of nanomaterials might induce undesirable effects. The roles played by the physical characteristics of nanomaterials in cellular responses have not yet been elucidated precisely. Here, by using nanosilica particles (nSPs) with a diameter of 70 nm whose surface was either unmodified (nSP70) or modified with amine (nSP70-N) or carboxyl groups (nSP70-C), we examined the relationship between the surface properties of nSPs and cellular responses such as cytotoxicity, reactive oxygen species (ROS) generation, and DNA damage. To compare the cytotoxicity of nSP70, nSP70-N, or nSP70-N, we examined in vitro cell viability after nSP treatment.

The mRNA findings were confirmed at the enzyme activity level by

The mRNA findings were confirmed at the enzyme activity level by measuring the glucuronidation of 1-naphthol, a

very good substrate for UGT1A6, as well as estradiol that is not glucuronidated by this enzyme. The results revealed that 1-naphthol glucuronidation activity was high in both the differentiated and undifferentiated cells, whereas estradiol glucuronidation was only detected in the differentiated cells. Thus, Caco-2 cell differentiation plays a major role in UGT expression and ensuing metabolic reactions.”
“Osteoarticular complications are common in human brucellosis, but the pathogenic mechanisms involved are largely unknown. In this manuscript, we described an immune mechanism for inflammatory bone loss in response to infection by Brucella abortus. We established a requirement for MyD88 and TLR2 in TNF-alpha-elicited osteoclastogenesis in response to B. abortus infection. CS from macrophages infected selleck screening library with B. abortus induced BMM to AZD8055 molecular weight undergo osteoclastogenesis. Although B. abortus-infected macrophages actively secreted IL-1 beta, IL-6, and TNF-alpha, osteoclastogenesis depended on TNF-alpha, as CS from B. abortus-infected macrophages failed to induce osteoclastogenesis in BMM from TNFRp55(-/-) mice. CS from B. abortus-stimulated

MyD88(-/-) and TLR2(-/-) macrophages failed to express TNF-alpha, and these CS induced no osteoclast formation compared with that of the WT or TLR4(-/-) macrophages. Omp19, a B. abortus lipoprotein model, recapitulated the cytokine production and subsequent osteoclastogenesis induced by the whole bacterium. All phenomena were corroborated using Stattic purchase human monocytes, indicating that this mechanism could play a role in human osteoarticular brucellosis. Our results indicate that B. abortus, through its lipoproteins, may be involved

in bone resorption through the pathological induction of osteoclastogenesis. J. Leukoc. Biol. 91: 285-298; 2012.”
“The late-phase of long-term potentiation (L-LTP), the cellular correlate of long-term memory, induced at some synapses facilitates L-LTP expression at other synapses receiving stimulation too weak to induce L-LTP by itself. Using glutamate uncaging and two-photon imaging, we demonstrate that the efficacy of this facilitation decreases with increasing time between stimulations, increasing distance between stimulated spines and with the spines being on different 432 dendritic branches. Paradoxically, stimulated spines compete for L-LTP expression if stimulated too closely together in time. Furthermore, the facilitation is temporally bidirectional but asymmetric. Additionally, L-LTP formation is itself biased toward occurring on spines within a branch. These data support the Clustered Plasticity Hypothesis, which states that such spatial and temporal limits lead to stable engram formation, preferentially at synapses clustered within dendritic branches rather than dispersed throughout the dendritic arbor.

It is our hope that this study will raise awareness among obesity

It is our hope that this study will raise awareness among obesity researchers on the essential need for reference gene validation in gene expression studies.”
“Background and Purpose-Infarct size and location are thought to correlate with different mechanisms of lacunar infarcts. We examined the relationship between the size and shape of lacunar infarcts and vascular risk factors and outcomes. Methods-We studied 1679 participants in the Secondary Prevention JNK activity inhibition of Small Subcortical Stroke trial with a lacunar infarct visualized on diffusion-weighted imaging. Infarct volume was measured planimetrically, and shape was classified based on visual analysis after 3-dimensional

reconstruction of axial MRI slices. Results-Infarct shape was ovoid/spheroid in 63%, slab in 12%, stick in 7%, and multicomponent in 17%. Median infarct volume was smallest in ovoid/spheroid

relative to other shapes: 0.46, 0.65, 0.54, and 0.90 mL, respectively VE-821 mouse (P smaller than 0.001). Distributions of vascular risk factors were similar across the 4 groups except that patients in the ovoid/spheroid and stick groups were more often diabetic and those with multicomponent had significantly higher blood pressure at study entry. Intracranial stenosis did not differ among groups (P=0.2). Infarct volume was not associated with vascular risk factors. Increased volume was associated with worse functional status at baseline and 3 months. Overall, 162 recurrent strokes occurred during an average of 3.4 years of follow-up with no difference in recurrent ischemic stroke rate by shape or volume. Conclusions-In patients with recent lacunar stroke, vascular Selleckchem NSC 23766 risk factor profile was similar among the different infarct shapes and sizes. Infarct size correlated with worse short-term functional outcome. Neither shape nor volume was predictive of stroke recurrence.”
“To determine genetic characteristics of the maternal lineage of the Kiso horse based on polymorphisms of the mitochondrial DNA

D-loop region, we collected blood samples from 136 Kiso horses, 91% of the entire population, and sequenced 411 bp from 15,437 to 15,847 in the region. First of all, we estimated the demographic history; by searching homology between the obtained and known sequences using Basic Local Alignment Search Tool, by mismatch analysis to evaluate the mutation processes using Arlequin, and by building a phylogenetic tree showing the relationship of the mtDNA haplotypes for 24 horse breeds around the world using Molecular Evolutionary Genetics Analysis softwear. The results suggested that various horses that came to Japan stayed at Kiso region and became ancestors of Kiso horse and also genetically supported the theory that the Kiso horse was historically improved by other Japanese native horse breeds.

NOD1 is thought to be involved in the immune homeostasis mediated

NOD1 is thought to be involved in the immune homeostasis mediated by intestinal microbiota as well as the host

defense against infection. In this study, we identified 12 synonymous and nine nonsynonymous single nucleotide polymorphisms (SNPs) in the coding sequence of porcine NOD1 within major commercial breeds in the swine industry. Among the nonsynonymous SNPs, two amino-acid alterations located in the leucine-rich repeats region, glycine to glutamic acid at position BI 6727 641 (G641E) and aspartic acid to asparagine at position 918 (D918N), impaired iE-DAP-induced activation of nuclear factor-kappa B. These alleles showed the recessive mode of inheritance and therefore are likely to be maintained in pig populations at high frequencies. These results suggest the possibility high throughput screening assay for improvement in disease resistance by eliminating the G641E and D918N alleles of NOD1 from commercial pig populations. (C) 2014 Elsevier Ltd. All rights reserved.”
“The adherence of monocytes

to vascular endothelial cells is an important early event in atherogenesis. Monocyte adherence to endothelial cells is induced by oxidized low-density lipoprotein (LDL) and mediated by multiple cell-adhesion molecules, including vascular cell-adhesion molecule I and intercellular cell-adhesion AC220 cell line molecule 1. Enhanced endothelial expression of these molecules by oxidized LDL has been shown to be a critical step in foam cell formation and the development of atherosclerosis. Recent Studies have demonstrated that tea catechin, especially (-)-epigallocatechin-3-gallate, inhibits the expression of these molecules by endothelial cells in response to stimulation with oxidized

LDL or inflammatory cytokines and the expression of CD11b by monocytic leukocytes. An in vivo study using apolipoprotein E-deficient mice has demonstrated that tea catechin extracts prevent the development of atherosclerosis and that (-)epigallocatechin-3-gallate effectively reduces the progression of accelerated atherosclerotic plaque formation induced by cuff injury. These data suggest that tea catechin may provide a unique approach to reduce atherosclerosis, although further studies will be necessary to clarify the precise mechanism of these effects, especially the role of metabolites of catechin and the target sites of these compounds.”
“Insulin resistance, of which the incidence is dramatically increasing in Western societies, is usually regarded as a pathological condition. However, arguments can be provided that insulin resistance may be a normal physiological mechanism to let cells and organs deal with the competition for various sources of energy, especially under circumstances of energy stress.

Moreover prostate tissues from carcinoma and benign hypertrophy c

Moreover prostate tissues from carcinoma and benign hypertrophy cases were analyzed for individuating clinical-pathological implications of MCT1 and MCT4 expression. Results: Transformed prostate epithelial (TPE) and prostate cancer (PCa) cells express both MCT1 and MCT4 and demonstrated variable dependence on

aerobic glycolysis for maintaining their proliferative rate. In glucose-restriction the presence of L-lactate determined, after 24 h of treatment, in PCa cells the up-regulation of MCT1 and of cytochrome c oxidase subunit I (COX1), and reduced the activation of AMP-activated protein kinase respect to untreated cells. The blockade of MCT1 function, performed by si RNA silencing, determined an appreciable antiproliferative effect when L-lactate was utilized as energetic fuel. Accordingly L-lactate released by high glycolytic human diploid fibroblasts WI-38 sustained survival and growth of TPE and PCa cells in ARO 002 low glucose culture medium. In parallel, the treatment with conditioned medium from PCa cells was sufficient to induce glycolytic metabolism in WI-38 cells, with upregulation of HIF-1a and MCT4. Co-injection of PCa cells with high glycolytic WI-38 fibroblasts determined an impressive increase in tumor growth rate in a xenograft model that was abrogated by MCT1 silencing in PCa cells. The possible interplay based

on L-lactate check details shuttle between tumor and stroma was confirmed also in human PCa tissue where we observed a positive correlation between stromal MCT4 and tumor MCT1 expression. Conclusions: Our data demonstrated that PCa progression may benefit of MCT1 expression in tumor cells and of MCT4 in tumor-associated stromal cells. Therefore, MCTs may result promising therapeutic targets in DZNeP different phases of neoplastic transformation according to a strategy aimed to contrast the energy metabolic adaptation of PCa cells to

stressful environments.”
“Objectives To report the outcome of patients diagnosed with cervical intraepithelial neoplasia 2, 3 (CIN 2, 3) during pregnancy, who were treated by large loop excision of the transformation zone (LLETZ) in the first trimester or were followed up conservatively and treated after delivery. Methods Patients diagnosed with CIN 2, 3 during pregnancy who were treated with LLETZ or were conservatively followed up were included. Complications of the LLETZ, pathologic results, and pregnancy outcome of both groups were examined after delivery. Results Thirty-one patients were included in the study. Eighteen were conservatively followed up and 13 underwent LLETZ during the first 14 weeks of pregnancy. Four patients (12.9%) in the study group were diagnosed with invasive cervical cancer. From women who underwent LLETZ, 9 patients continued their pregnancy, 7 of which had term normal deliveries and 2 had late preterm deliveries.

Results: We found 1359 incident AF events in 100 074 person-y

\n\nResults: We found 1359 incident AF events in 100 074 person-years selleck screening library of follow-up. Unadjusted 5-year event rates differed by cohort (AGES, 12.8 cases/1000 person-years; CHS whites, 22.7 cases/1000 person-years; and FHS, 4.5 cases/1000 person-years) and by race (CHS African Americans, 18.4 cases/1000 person-years). The strongest risk factors in all samples were age and heart failure. The relative risks for incident AF associated with risk factors were comparable across cohorts and race groups. After recalibration for baseline incidence and risk factor distribution, the Framingham algorithm, reported in C statistic, performed reasonably well in all samples:

AGES, 0.67 (95% confidence interval [CI], 0.64-0.71); CHS whites, 0.68 (95% CI, 0.66-0.70); and CHS African Americans, 0.66 (95% CI, 0.61-0.71). Risk factors combined in

the algorithm explained between 47.0% (AGES) and 63.6% (FHS) of the population-attributable risk.\n\nConclusions: Risk of incident AF in community-dwelling whites and African Americans can be assessed reliably by routinely available and potentially modifiable clinical variables. Seven risk factors accounted for up to 64% of risk.”
“By means of a multicentre retrospective study based on the failure of 418 aseptic PND-1186 nmr unicondylar knee arthroplasties (UKA) our aims were to present the different types of revision procedure used in failed UKAs, to establish a clear operative strategy for each type of revision and to better define the indications for each type of revision.\n\nAseptic loosening was the principal cause of failure

(n = 184, 44 %) of which 99 cases were isolated tibial loosening (23.5 % of the whole series and 54 % of all loosening), 25 were isolated femoral loosening (six and 13.6 %) and 60 were both femoral and tibial loosening (14.3 and 32.6 %). The next most common causes of failure were progression of arthritis (n = 56, 13.4 %), polyethylene wear (n = 53, 12.7 %), implant positioning errors (n = 26), technical difficulties (n = six) and implant failure (n = 16, 3.8 % of cases). Data collection was performed online using OrthoWave see more (TM) software (Aria, Bruay Labuissiere, France), which allows collection of all details of the primary and revision surgery to be recorded.\n\nA total of 426 revisions were performed; 371 patients underwent revision to a total knee arthroplasty (TKA) (87 %), 33 patients (7.7 %) were revised to an ipsilateral UKA, 11 (2.6 %) patients underwent contralateral UKA (ten) or patellofemoral arthroplasty (one) and 11 patients (2.6 %) underwent revision without any change in implants.\n\nBefore considering a revision procedure it is important to establish a definite cause of failure in order to select the most appropriate revision strategy.

We emphasize the role of circadian rhythmic orchestration in cell

We emphasize the role of circadian rhythmic orchestration in cellular metabolism with a potential in cancer development. (C) 2013 Elsevier Inc.

All rights Rabusertib mouse reserved.”
“PURPOSE. To explore the crucial role of the human corneal epithelium-derived proallergic cytokine thymic stromal lymphopoietin (TSLP) in initiation and regulation of immune responses.\n\nMETHODS. Primary corneal epithelial cells, established from donor limbal explants, were treated with 11 microbial ligands and proinflammatory and Th2 cytokines, alone or in combination. TSLP mRNA and protein were determined by real-time PCR and ELISA, respectively. NF-kappa B activation was detected by immunostaining and Western blot.\n\nRESULTS. TSLP was found to be expressed by human corneal epithelium and its cultures. TSLP in corneal epithelial cells were largely induced in a concentration-dependent fashion by polyI:C, flagellin, and FSL-1, the ligands for toll-like receptor (TLR)-3, -5, and -6, respectively. Compared with the control, TSLP mRNA was increased by

60-, 12- and 8-fold and TSLP protein increased selleck chemicals llc by 67-, 19- and 7-fold by these three ligands, respectively. The proinflammatory (TNF-alpha and IL-1 beta) and Th2 (IL-4 and IL-13) cytokines moderately induced TSLP expression and production. IL-4 and -13 strongly synergized with PolyI:C, flagellin, and TNF-alpha to promote TSLP production in ex vivo tissues and in vitro cultures of corneal epithelium. PolyI: C, flagellin, click here or TNF-alpha also induced NF-kappa B p65 protein nuclear translocation. The NF-kappa B inhibitor quinazoline blocked p65 nuclear translocation and further suppressed TSLP expression and production induced by these stimuli.\n\nCONCLUSIONS. These findings provide the first evidence of TSLP induction in the human eye and suggest the novel phenomenon that human corneal epithelium-derived TSLP may serve as a link between the innate and adaptive immune responses. TSLP may become a novel therapeutic target for allergic and inflammatory ocular surface diseases. (Invest Ophthalmol Vis Sci. 2009; 50: 2702-2709) DOI:10.1167/iovs.08-3074″
“Background: The dysfunction of hypothalamic-pituitary-adrenal

(HPA) axis in major depression includes hyperactivity and reduced feedback inhibition. Atrial natriuretic peptide (ANP) is able to reduce the HPA-axis response to stress and has an anxiolytic effect in rodents and humans. We hypothesized that patients with depression would have an attenuated N-terminal proANP (NT-proANP) response to acute exercise compared to healthy controls. Secondly, we aimed to assess the effect of antidepressants on NT-proANP response to acute exercise.\n\nMethods: We examined 132 outpatients with mild to moderate depression (ICD-10) and 44 healthy controls, group matched for age, sex, and BMI. We used an incremental bicycle ergometer test as a physical stressor. Blood samples were drawn at rest, at exhaustion, and 15, 30, and 60 min post-exercise.


“Given the well-documented adverse side effects of sorafen


“Given the well-documented adverse side effects of sorafenib, many sorafenib-treated patients may need the reduced initial dose of the compound, and an alternative sorafenib-based therapy, which exerts similar clinical benefit, is anticipated. An angiostatic therapy with sorafenib is considered one of the promising approaches for

chemoprevention of hepatocellular carcinoma. The aim of the current study was to elucidate the combination effect of low dose of sorafenib and angiotensin-II receptor blocker (ARB) on hepatocarcinogenesis, especially in conjunction with angiogenesis. BIIB057 manufacturer The chemopreventive effect on the development of liver preneoplastic lesions, angiogenesis, and several indices was elucidated in rats. We also performed several sets of in vitro https://www.selleckchem.com/products/cftrinh-172.html experiments to examine the mechanisms involved. Using a non-diabetic rat model of steatohepatitis with choline deficient l-amino acid-defined diet, sorafenib demonstrated marked inhibition of preneoplastic lesions in a dose dependent manner. Combined treatment with ARB (losartan) at a clinically comparable dose and half dose of sorafenib resulted in the inhibitory effect equivalent to that of common dose of sorafenib along with suppression of hepatic neovascularization and potent angiogenic factor, vascular

endothelial growth factor. Furthermore, similar combined inhibitory outcomes were observed in several sets of in vitro studies. Since the combinatorial treatment using low doses of sorafenib and ARB could sufficiently induce inhibitory effect on the development of preneoplastic lesions at the magnitude similar to the conventional dose of sorafenib, this regimen may provide new strategy for patients intolerant of the usual dose of sorafenib in the future.”
“BackgroundZonisamide is a new generation antiepileptic drug (AED) widely used in children with refractory epilepsy, although until recently, it was used

to a large extent as off-label ERK inhibitor datasheet or unlicensed medication due to the lack of evidence-based studies. Children have a different pharmacokinetic profile than adults and an adult dose regimen cannot be directly translated into pediatric use. Patients and MethodsIn this retrospective noninterventional study of the medical records of 75 children with pharmacoresistant epilepsy, the pharmacokinetics, efficacy and safety of zonisamide were examined. The dose-to-concentration ratio, the daily weight-normalized dose of zonisamide divided by its plasma concentration, was used as a measure of clearance. In addition, data on the efficacy of zonisamide to reduce seizures and reported adverse events were extracted from the medical records and analyzed.