First, Do No Harm: The Risks Of Overtreating Children With Epilepsy

Background: Although overtreatment with antiepileptic drugs contributes to the morbidity associated with epilepsy, many children still are overtreated. Objective: To evaluate if the withdrawal of at least one antiepileptic drug (AED) in children with refractory epilepsy using polytherapy enable a better seizure control. Method: This was a prospective study. Children with refractory epilepsy using at least two AEDs were included. Once the patient, or guardian, agreed to participate in the study, one or more AED were slowly tapered off. The remaining AEDs dosages could be adjusted as needed, but a new AED could not be introduced. Results: Fifteen patients were evaluated, three girls; ages ranging from 3 to 18 (mean=8.7 years). After at least one AED withdrawal, two (13.5%) patients became seizure free, seizures improved >50% in 5 (33.5%) patients, did not change in 5 (33.5%), and seizure frequency became worse in 3 (20%). Adverse events improved in 12 patients (80%). Conclusion: The withdrawal of at least one AED is a valuable option in the treatment of selected children with refractory epilepsy.65114Camfield, C.S., Camfield, P., Gordon, K., Smith, B., Dooley, J., Outcome of childhood epilepsy: A population-based study with a simple scoring system for those treated with medication (1993) J Pediatr, 122, pp. 861-868Silva, M., MacArdle, B., MaGowan, M., Randomised comparative monotherapy trial of phenobarbitone, phenytoin, carbamazepine, or sodium valproate for newly diagnosed childhood epilepsy (1996) Lancet, 347, pp. 709-713Baulac, M., Rational conversion from antiepileptic polytherapy to monotherapy (2003) Epileptic Disord, 5, pp. 125-132Holmes, G.L., Overtreatment in children with epilepsy (2002) Epilepsy Res, 52, pp. 35-42Fischbacher, E., Effect of reduction of anticonvulsants on wellbeing (1982) Br Med J (Clin Res Ed), 285, pp. 423-424Schmidt, D., Reduction of two-drug therapy in intractable epilepsy (1983) Epilepsia, 24, pp. 368-376Alvarez, N., Discontinuance of antiepileptic medications in patients with developmental disability and diagnosis of epilepsy (1989) Am J Ment Retard, 93, pp. 593-595Guerrini, R., Belmonte, A., Genton, P., Antiepileptic drug-induced worsening of seizures in children (1998) Epilepsia, 39 (SUPPL. 3), pp. S2-S10TS, K., Holmes, G.L., EEG and clinical predictors of medically intractable childhood epilepsy (1999) Clin Neurophysiol, 110, pp. 1245-1251Huttenlocker, P.R., Hapke, R.J., A follow-up study of intractable seizures in childhood (1990) Ann Neurol, 28, pp. 699-705Ferngren, H., Akerstrom, I., Rane, A., Mono or polypharmacotherapy in institutionalized epileptic children with severe mental retardation? A team approach for optimizing antiepileptic therapy (1991) Acta Paediatr Scand, 80, pp. 458-465Dooley, J., Gordon, K., Camfield, C., Smith, E., Discontinuation of anticonvulsant therapy in children free of seizures for 1 year: A prospective study (1996) Neurology, 46, pp. 969-974Shinnar, S., Berg, A.T., Moshé, S.L., Discontinuing antiepileptic drugs in children with epilepsy:a prospective study (1994) Ann Neurol, 35, pp. 534-545Shorvon, S.D., Reynolds, E.H., Unnecessary polypharmacy for epilepsy (1977) Br Med J, 1, pp. 1635-1637Vickery, B.G., Hay, R., Engel, J., Outcome assessment for epilepsy surgery: The impact of measuring health-related quality of life (1995) Ann Neurol, 37, pp. 158-16

Monte-Carlo study of scaling exponents of rough surfaces and correlated percolation

We calculate the scaling exponents of the two-dimensional correlated percolation cluster's hull and unscreened perimeter. Correlations are introduced through an underlying correlated random potential, which is used to define the state of bonds of a two-dimensional bond percolation model. Monte-Carlo simulations are run and the values of the scaling exponents are determined as functions of the Hurst exponent H in the range -0.75 <= H <= 1. The results confirm the conjectures of earlier studies

Toward a digital analysis of environmental impacts on rodent mammary gland density during critical developmental windows

While mammographic breast density is associated with breast cancer risk in humans, there is no comparable surrogate risk measure in mouse and rat mammary glands following various environmental exposures. In the current study, mammary glands from mice and rats subjected to reproductive factors and exposures to environmental chemicals that have been shown to influence mammary gland development and/or susceptibility to mammary tumors were evaluated for histologic density by manual and automated digital methods. Digital histological density detected changes due to hormonal stimuli/reproductive factors (parity), dietary fat, and exposure to environmental chemicals, such as benzophenone-3 and a combination of perfluorooctanoic acid and zeranol. Thus, digital analysis of mammary gland density offers a high throughput method that can provide a highly reproducible means of comparing a measure of histological density across independent experiments, experimental systems, and laboratories. This methodology holds promise for the detection of environmental impacts on mammary gland structure in mice and rats that may be comparable to human breast density, thus potentially allowing comparisons between rodent models and human breast cancer studies

Associations between dietary inflammatory scores and biomarkers of inflammation in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort

Background: Since the first version of the dietary inflammatory index (DII & REG;) developed in the past decade, several other versions have been developed. However, to date no study has attempted to compare these versions with respect to their associations with biomarkers of inflammation. Objective: We aimed to investigate the relationship between four dietary inflammatory scores [DII, two energy-adjusted derivatives (E-DII and E-DIIr), and the Inflammatory Score of the Diet (ISD)], and circulating levels of several inflammatory markers and adipokines. Methods: This study included 17 637 participants from the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort with at least one marker of inflammation measured in blood. Associations between the four scores and C-reactive protein (CRP), interleukin (IL)6, IL10, IL1RA, tumor necrosis factor-a (TNFa), soluble tumor necrosis factor receptor-1 (sTNFR1), sTNFR2, leptin, soluble leptin receptor (sLeptin R), adiponectin, and High Molecular Weight (HMW) adiponectin were evaluated using multivariable linear regressions adjusted for potential confounders. Results: Positive associations were observed between the four dietary inflammatory scores and levels of CRP, IL6, sTNFR1, sTNFR2 and leptin. However, only the DII and the ISD were positively associated with IL1RA levels and only the DII and the E-DIIr were positively associated with TNFa levels. The proportion of variance of each biomarker explained by the scores was lower than 2%, which was equivalent to the Conclusions: Our results suggest that the four dietary inflammatory scores were associated with some biomarkers of inflammation and could be used to assess the inflammatory potential of diet in European adults but are not sufficient to capture the inflammatory status of an individual. These findings can help to better understand the inflammatory potential of diet, but they need to be replicated in studies with repeated dietary measurements. Crown Copyright & COPY; 2023 Published by Elsevier Ltd. This is an open access article under the CC BY-NC-N

Long-Baseline Neutrino Facility (LBNF) and Deep Underground Neutrino Experiment (DUNE) Conceptual Design Report Volume 2: The Physics Program for DUNE at LBNF

The Physics Program for the Deep Underground Neutrino Experiment (DUNE) at the Fermilab Long-Baseline Neutrino Facility (LBNF) is described

HDAC1 (histone deacetylase1) involvement in Chronic Myeloid Leukemia

The bcr-abl fusion gene originated from the balanced (9;22) translocation is the molecular hallmark and the causative event of chronic myeloid leukemia (CML). Constitutive activation and improper localization to the cytosol of p210 protein of bcr-abl induce enlargement of clonal hematopoiesis over its normal counterpart and consequently genetic instability that drives leukemic progenitor progression towards the fully transformed phenotype of blast crisis. To define a role to tyrosine kinase p210bcr-abl, we considered its impact on histone H4 acetylation status, focusing on the proceeding of enzyme HDAC1 (histone deacetylase1) during progression of the pathology. We performed molecular analysis in vitro in 32D cell clone expressing a temperature-sensitive (ts) bcr-abl mutant and in vivo in CD34+ from patients affected by CML. We observed that HDAC1 has several effects on gene expression in different phases of CML. In particular p210bcr-abl tyrosine kinase binds HDAC1, resulting in its cytoplasmic compartimentalization and consequently loss of function of HDAC1 itself: this event may be prominent in early chronic phase of the disease, when bcr-abl is the only genetic lesion and its transcription is essential for clonal hematopoiesis to proliferate and survive. It may also contribute to the disease progression by promoting clonal progenitor genomic instability driving the accumulation of additional genetic aberrations. Deregulation of transcription of genes controlling differentiation, apoptosis and growth arrest resulting from HDAC1 compartimentalization in the cytoplasm may be protagonist of more advanced stages of CML, when a fully transformed, drug-resistant phenotype emerges

Tyrosine kinase inhibotr STI571 (Imatinib) cooperates with wild type p53 on k562 cell line to enhance its pro-apoptotic effets

In order to ascertain whether p53 has a role in chronic myeloid leukemia hematopoietic progenitor response to the innovative tyrosine kinase inhibitor STI571 (Imatinib), we overexpressed a wild type (wt) p53 construct in the K562 cell line, generated from a human blast crisis and lacking endogenous p53. Wt p53 overexpression was associated with a significant reduction of bcr-abl expression levels resulting, at least in part, from post-transcriptional events affecting the stability of p210 bcr-abl fusion protein. Moreover, we demonstrated that p53 overexpression enhances the commitment to the apoptotic death fate of K562 following its in vitro exposure to 1 \ub5M STI571. Multiple mechanisms are involved in p53 impact on K562 survival: Most importantly, we found that a greater reduction of bcr-abl transcription by STI571 was associated with the overexpression of wt p53. Further studies are required to elucidate the mechanisms involved in the transcriptional repression of bcr-abl by STI571 and p53 and in their synergic effects on the clonal hematopoiesis of chronic myeloid leukemia

La tirosin-cinasi del prodotto p210 di bcr-abl sopprime l'apoptosi mitocondrio dipendente

La costitutiva attivit\ue0 tirosin-cinasica della proteina chimerica p210bcr-abl ha un ruolo centrale nella patogenesi e nella progressione della Leucemia Mieloide Cronica (LMC). Interagendo con molteplici circuiti di trasduzione del segnale mitogenico essa inibisce l'adesione delle cellule leucemiche allo stroma midollare, abroga i checkpoints del ciclo cellulare e induce resistenza all'apoptosi. Ci\uf2 che si osserva \ue8 un'abnorme espansione dell'ematopoiesi leucemica sulla controparte normale e l'instabilit\ue0 genomica che ne condiziona l'evoluzione da un fenotipo normale, caratterizzante la fase cronica, ad un fenotipo trasformato tipico della crisi blastica. I risultati dello studio qui presentato indicano che la costitutiva attivit\ue0 tirosin-cinasica di p210bcr-abl ha effetti su molteplici segnali coinvolti nella via intrinseca e nella via estrinseca della apoptosi e convergenti sulla integrit\ue0 della membrana mitocondriale. L'espressione di un costrutto sensibile in temperatura di Bcr-Abl in progenitori ematopoietici clonali (32D) e l'esposizione ad un inibitore specifico dell'attivit\ue0 tirosin-cinasica di p210bcr-abl (STI571) ci ha permesso di individuare il ruolo della proteina chimerica nella fase decisionale dell'apoptosi. P210bcr-abl causa l'overespressione dei segnali anti-apoptotici Bcl-2 e Bcl-xL, previene l'attivazione dei segnali pro-apoptotici Bid, Bad e Bax, impedendo la formazione di omodimeri ed eterodimeri tra gli stessi membri della famiglia BcI-2 a livello della membrana mitocondriale. Tale condizione blocca il rilascio di citocromo-c e di altri fattori apoptogeni dal mitocondrio. La formazione dell'apoptosoma risulta pertanto inibita, cos\uec come la cascata caspasica mitocondrio-dipendente. La definizione dei circuiti biomolecolari coinvolti nella resistenza alla morte apoptotica ha un impatto importante nel trattamento della LMC: pu\uf2 infatti aiutare ad identificare bersagli farmacologici rilevanti per la terapia della malattia in associazione all'inibizione dell'attivit\ue0 tirosin-cinasica di p210bcr-abl

NON PEPTIDIC 14-3-3 INHIBITORS AND THE USE THEREOF

The present invention refers to compounds with inhibitory activity against 14-3-3 proteins and their use in the treatment of tumor, in particular chronic myeloid leukemia. The invention also provides methods for the identification of14-3-3 protein inhibitors