Miracle-dz/UniFAR-FTUs huggingface dataset:
Estado del primer molar permanente en niños de 6 a 11 años de edad

Introduccion: los primeros molares permanentes son considerados dientes pilares fundamentales en la cavidad bucal, su perdida precoz causa un dano irreparable, dado su papel como llave de la oclusion dentaria. Objetivo: evaluar el estado de salud del primer molar permanente. Materiales y metodos: se realizo una investigacion observacional, descriptiva y transversal en la Escuela Primaria “Raul Gomez Garcia,” perteneciente al area de salud de Milanes de la Clinica “III Congreso del PCC,” del municipio de Matanzas, en el periodo del curso academico 2013 - 2014. De un universo de 382 ninos que constituian la matricula total de la escuela, se seleccionaron mediante un muestreo aleatorio simple, una muestra de 298, de la edad de 6 a 11 anos, que tenian presente en boca los cuatro primeros molares permanentes en el momento del examen. Se estudiaron variables como: edad, sexo, superficies afectadas del primer molar permanente, estado del primer molar permanente, afectacion del paciente, e Indice epidemiologico de Clune. Los datos fueron registrados en tablas y el procedimiento estadistico dado en porcentaje. Se conto con el consentimiento de la direccion de la escuela y de los padres de los ninos. Resultados: las superficies o caras de los molares mas afectados fueron las oclusales tanto por caries (36,5 %), como obturadas (28,1 %). Del total de la muestra, 208 ninos presentaron sus cuatro primeros molares libres de caries, para un 69,8 %. Solo 1 nino fue clasificado de grave, para un 1,8 %. Conclusiones: un elevado numero de ninos presentaron sus primeros molares libres de caries dental y pocos la perdida del primer molar permanente.
The Epileptor Model: A Systematic Mathematical Analysis Linked to the Dynamics of Seizures, Refractory Status Epilepticus, and Depolarization Block

Abstract One characteristic of epilepsy is the variety of mechanisms leading to the epileptic state, which are still largely unknown. Refractory status epilepticus (RSE) and depolarization block (DB) are other pathological brain activities linked to epilepsy, whose patterns are different and whose mechanisms remain poorly understood. In epileptogenic network modeling, the Epileptor is a generic phenomenological model that has been recently developed to describe the dynamics of seizures. Here, we performed a detailed qualitative analysis of the Epileptor model based on dynamical systems theory and bifurcation analysis, and investigate the dynamic evolution of “normal” activity toward seizures and to the pathological RSE and DB states. The mechanisms of the transition between states are called bifurcations. Our detailed analysis demonstrates that the generic model undergoes different bifurcation types at seizure offset, when varying some selected parameters. We show that the pathological and normal activities can coexist within the same model under some conditions, and demonstrate that there are many pathways leading to and away from these activities. We here archive systematically all behaviors and dynamic regimes of the Epileptor model to serve as a resource in the development of patient-specific brain network models, and more generally in epilepsy research.
Comparison of efficacy from two different dosing regimens of bortezomib: an exposure–response analysis

Bortezomib is a first‐in‐class proteasome inhibitor, approved for the treatment of multiple myeloma. The originally approved dosing schedule of bortezomib results in significant toxicities that require dose interruptions and discontinuations. Consequentially, less frequent dosing has been explored to optimise bortezomib’s benefit–risk profile. Here, we performed exposure–response analysis to compare the efficacy of the original bortezomib dosing regimen with less frequent dosing of bortezomib over nine 6‐week treatment cycles using data from the VISTA clinical trial and the control arm of the ALCYONE clinical trial. The relationship between cumulative bortezomib dose and clinical response was evaluated with a univariate logit model. The median cumulative bortezomib dose was higher in ALCYONE versus VISTA (42·2 vs. 38·5 mg/m2) and ALCYONE patients stayed on treatment longer (mean: 7·2 vs. 5·8 cycles). For all endpoints and regimens, probability of clinical response correlated with cumulative bortezomib dose. Similar to results observed for VISTA, overall survival was longer in ALCYONE patients with ≥ 39·0 versus < 39·0 mg/m2 cumulative dose (hazard ratio, 0·119; P < 0·0001). Less frequent bortezomib dosing results in comparable efficacy, and a higher cumulative dose than the originally approved bortezomib dosing schedule, which may be in part be due to reduced toxicity and fewer dose reductions/interruptions.
Solid lipid nanoparticles encapsulating a fluorescent marker (coumarin 6) and antimalarials – artemether and lumefantrine: evaluation of cellular uptake and antimalarial activity

Abstract Artemisinins, the mainstay in the treatment of malaria today, are used in combination with other antimalarials to forestall resistance, as artemisinin-combination therapies. In line with the World Health Organization’s recommendation in that respect, solid lipid nanoparticles (SLN) were formulated to encapsulate two antimalarial drugs — artemether and lumefantrine. The nanoparticles were evaluated for size and solid state properties. Caco-2 cells were used to investigate the ability of the SLN to deliver its payload at the absorptive interface of the gastrointestinal tract. Mice heart endothelial cells (MHEC) were also used as marker cells to assess cellular uptake of coumarin 6 from the SLN with imaging by confocal laser scanning microscopy (CSLM). In vivo antimalarial activity was done using a standard suppressive protocol. The results of this study revealed different crystal properties for artemether and lumefantrine, which affected their solubility in the lipid matrix and thus, loading in the lipid nanoparticles. The particles of the SLN were within the range of 150 nm–500 nm with varied polydispersity indices. Wide angle X-ray diffraction analysis indicated the presence of particles of solid nature. Cellular uptake studies indicated uptake of coumarin 6 from the coumarin 6-labeled SLN. In vivo antimalarial studies indicated high clearance of parasitemia with minimal effect on hematological parameters tested.
The health-related quality-of-life of chronic obstructive pulmonary disease patients and disease-related indirect burdens

Background/Aims Many chronic obstructive pulmonary disease (COPD) patients have physical limitations. We investigated EuroQol five-dimensions five-level (EQ-5D-5L) of COPD patients to assess quality of life, and assessed indirect burden including time expenditure to visit doctor, home care rate, and caregiver related burden. Methods We recruited 355 COPD patients according to severity of airflow limitation that severity was set at 10% mild, 40% moderate, 30% severe, and 20% very severe in two primary and 11 secondary/tertiary hospitals. Eligible patients were aged ≥ 40 years, who have been diagnosed with COPD for more than 1 year. Patients were recruited between June 2015 and October 2016. Results The quality of life tended to decline with age, from mild to very severe impairment, as revealed by the EQ-5D-5L scores and the EQ visual analog scale. Family caregivers accompanied 22.6% of patients who visited outpatient clinics, and 25% of stage IV COPD patients. During emergency visits and hospitalization, this figure increased to > 60%. The home care rates were 28.5% for stage I patients, and 34.4, 31.8, and 52% for stage II to IV patients, respectively. The percentage of caregivers who stopped working was 13.6%. The EQ-5D index was strongly associated with the dyspnea scale (r = –0.64, p < 0.001). The average required time to see a doctor and visit the pharmacy was 154 minutes. Conclusions In patients with COPD, the EQ-5D index decreased and disease-related home caregiving increased with airflow limitation. We considered the caregiver- related burden when making a strategy for COPD management.
KAP1 targets actively transcribed genomic loci to exert pleomorphic effects on RNA polymerase II activity

KAP1 (KRAB-associated protein 1) is best known as a co-repressor responsible for inducing heterochromatin formation, notably at transposable elements. However, it has also been observed to bind the transcription start site of actively expressed genes. To address this paradox, we characterized the protein interactome of KAP1 in the human K562 erythro-leukaemia cell line. We found that the regulator can associate with a wide range of nucleic acid binding proteins, nucleosome remodellers, chromatin modifiers and other transcription modulators. We further determined that KAP1 is recruited at actively transcribed polymerase II promoters, where its depletion resulted in pleomorphic effects, whether expression of these genes was normally constitutive or inducible, consistent with the breadth of possible KAP1 interactors. This article is part of a discussion meeting issue ‘Crossroads between transposons and gene regulation’.
Adverse Effects of Low-Dose Methotrexate

Background Low-dose methotrexate (LD-MTX) is the most commonly used drug for systemic rheumatic diseases worldwide and is the recommended first-line agent for rheumatoid arthritis. Despite extensive clinical use for more than 30 years, few data on adverse event (AE) rates derive from randomized, placebo-controlled trials, where both causality and magnitude of risk can be inferred. Objective To investigate AE rates, risk, and risk differences comparing LD-MTX versus placebo. Design Prespecified secondary analyses of a double-blind, placebo-controlled, randomized trial. (ClinicalTrials.gov: NCT01594333). Setting North America. Participants Adults with known cardiovascular disease and diabetes or metabolic syndrome. Intervention Random allocation to LD-MTX (≤20 mg/wk) or placebo. All participants received folic acid, 1 mg/d, 6 days per week. Measurements Risks for specific AEs of interest, as well as for all AEs, were compared across treatment groups after blinded adjudication. Results After an active run-in period, 6158 patients were enrolled and 4786 randomly assigned to a group; median follow-up was 23 months and median dosage 15 mg/wk. Among the randomly assigned participants, 81.2% were male, median age was 65.7 years, and median body mass index was 31.5 kg/m2. Of 2391 participants assigned to LD-MTX, 2080 (87.0%) had an AE of interest, compared with 1951 of 2395 (81.5%) assigned to placebo (hazard ratio [HR], 1.17 [95% CI, 1.10 to 1.25]). The relative hazards of gastrointestinal (HR, 1.91 [CI, 1.75 to 2.10]), pulmonary (HR, 1.52 [CI, 1.16 to 1.98]), infectious (HR, 1.15 [CI, 1.01 to 1.30]), and hematologic (HR, 1.15 [CI, 1.07 to 1.23]) AEs were elevated for LD-MTX versus placebo. With the exception of increased risk for skin cancer (HR, 2.05 [CI, 1.28 to 3.28]), the treatment groups did not differ in risk for other cancer or mucocutaneous, neuropsychiatric, or musculoskeletal AEs. Renal AEs were reduced in the LD-MTX group (HR, 0.85 [CI, 0.78 to 0.93]). Limitation The trial was done in patients without rheumatic disease who tolerated LD-MTX during an active run-in period. Conclusion Use of LD-MTX was associated with small to moderate elevations in risks for skin cancer and gastrointestinal, infectious, pulmonary, and hematologic AEs, whereas renal AEs were decreased. Primary Funding Source National Institutes of Health.
Edwardsiella piscicida type III protein EseJ suppresses apoptosis through down regulating type 1 fimbriae, which stimulate the cleavage of caspase‐8

The type III secretion system effector EseJ plays a regulatory role inside bacteria. It suppresses the adherence of Edwardsiella piscicida (E. piscicida) to host epithelial cells by down regulating type 1 fimbriae. In this study, we observed that more macrophages infected with ΔeseJ strain of E. piscicida detached as compared with those infected with the wild‐type (WT) strain. Terminal deoxynucleotidyl transferase dUTP nick‐end labelling (TUNEL) staining and cleaved caspase‐3 examination revealed that the detachment is due to increased apoptosis, suggesting that EseJ suppresses macrophage apoptosis. However, apoptosis inhibition by EseJ is not relative to a type III secretion system (T3SS) and is not related to EseJ's translocation. Since EseJ negatively regulates type 1 fimbriae, murine J774A.1 cells were infected with ΔeseJΔfimA or ΔeseJΔfimH strains. It was demonstrated that ΔeseJ stimulates macrophage apoptosis through type 1 fimbriae. Moreover, we found that infecting J774A.1 cells with the ΔeseJ strain increased levels of cleaved caspase‐8, caspase‐9, and caspase‐3, demonstrating that EseJ inhibits apoptosis through either an extrinsic or a combination of extrinsic and intrinsic pathways. Pre‐treatment of macrophages with caspase‐8 inhibitor prior to infection with the ΔeseJ strain decreased the levels of cleaved caspase‐8, caspase‐9, and caspase‐3, indicating that the ΔeseJ strain stimulates apoptosis, mainly through an extrinsic pathway by up regulating type 1 fimbriae. Zebrafish larvae or blue gourami fish infected with the ΔeseJ strain consistently exhibited higher apoptosis than those infected with the E. piscicida WT strain or ΔeseJΔfimA strain. Taken together, we revealed that the T3SS protein EseJ of E. piscicida inhibits host apoptosis, mainly through an extrinsic pathway by down regulating type 1 fimbriae.
Structural basis of light‐harvesting in the photosystem II core complex

Photosystem II (PSII) is a membrane‐spanning, multi‐subunit pigment–protein complex responsible for the oxidation of water and the reduction of plastoquinone in oxygenic photosynthesis. In the present review, the recent explosive increase in available structural information about the PSII core complex based on X‐ray crystallography and cryo‐electron microscopy is described at a level of detail that is suitable for a future structure‐based analysis of light‐harvesting processes. This description includes a proposal for a consistent numbering scheme of protein‐bound pigment cofactors across species. The structural survey is complemented by an overview of the state of affairs in structure‐based modeling of excitation energy transfer in the PSII core complex with emphasis on electrostatic computations, optical properties of the reaction center, the assignment of long‐wavelength chlorophylls, and energy trapping mechanisms.
Promotion of cell autophagy and apoptosis in cervical cancer by inhibition of long noncoding RNA LINC00511 via transcription factor RXRA‐regulated PLD1

An increasing number of studies have explored the relationship of long noncoding RNAs (lncRNAs) with cervical cancer, yet the role of LINC00511 in cervical cancer still remains elusive. The current dissertation was intended to explore the effect of LINC00511 on cervical cancer development by regulating phospholipase D1 (PLD1) expression through transcription factor retinoic X receptor alpha (RXRA). Differentially expressed lncRNA and messenger RNA related to cervical cancer were screened by microarray‐based expression profiling. Cervical cancer and paracancerous tissues were harvested to determine the LINC00511 expression using reverse transcription‐quantitative polymerase chain reaction and western blot analysis. The relationship among LINC00511, PLD1 promoter activity, and RXRA were determined via RNA immunoprecipitation, chromatin immunoprecipitation, and dual‐luciferase reporter assays. Proliferation, autophagy, and apoptosis of cervical cancer cells were detected with a series of experiments. Tumor xenograft in nude mice was employed to determine the influence of LINC00511 and PLD1 on tumor formation and growth of cervical cancer in vivo. LINC00511 might influence the occurrence of cervical cancer by upregulating PLD1 expression via recruiting transcription factor RXRA. LINC00511 and PLD1 expressions were remarkably high in cervical cancer tissues and cells. LINC00511 combined with RXRA, and overexpression of LINC00511 in cervical cancer cells elevated PLD1 expression. Si‐LINC00511, si‐RXRA or si‐PLD1 triggered repression of proliferation and promotion of autophagy and apoptosis of cervical cancer cells. In vivo experiment, si‐LINC00511, or si‐PLD1 inhibited the tumorigenic ability of nude mice. Collectively, this study suggests that LINC00511 acts as an oncogenic lncRNA in cervical cancer via the promotion of transcription factor RXRA‐regulated PLD1.
Exploring participation after paediatric acquired brain injury

This study aimed to explore the levels of participation in a UK sample of children and young people (CYP) with an acquired brain injury (ABI) at home, school and in the community through a cross-sectional study. The Child and Family Follow-Up Survey was distributed to parents/carers of 134 CYP with ABI (CYP-ABI) who received neuro-rehabilitation from 2014 to 2016. Access and recruitment were problematic resulting in a low response rate (4%). Widespread restrictions in participation were reported by four of the five respondents with community-structured events/activities and educational activities being the most restricted. Factors impacting on participation were cognitive-based and movement skills, family stress and lack of support/encouragement in the community. Study results provide information pertaining to the feasibility of undertaking research with this population while also highlighting the restrictions to participation experienced by CYP-ABI more than two years after injury.
Decreased Circulating MANF in Women with PCOS is Elevated by Metformin Therapy and is Inversely Correlated with Insulin Resistance and Hyperandrogenism

Abstract Mesencephalic astrocyte-derived neurotrophic factor (MANF) is a novel neurotrophic factor. Although recent studies have suggested that MANF appeared to be associated with insulin resistance, the results have been inconsistent. The aim of our study was to determine the serum MANF levels in women with PCOS and controls, to investigate their relationship to insulin resistance, and to evaluate circulating MANF changes with metformin intervention in PCOS women. We conducted a series of cross-sectional and interventional studies in 90 newly diagnosed patients with PCOS and 60 age- and gender-matched controls. Oral glucose tolerance test and euglycemic-hyperinsulinemic clamps were performed to assess the glucose tolerance and insulin sensitivity. Forty-three women with PCOS were randomly assigned to six months of oral metformin therapy. Serum MANF levels were significantly lower in women with PCOS than in controls. Serum MANF levels were positively correlated with M-value and negatively correlated with body mass index (BMI), body fat percentage (FAT), homeostatic model assessment of insulin resistance (HOMA-IR), and free androgen index (FAI). Multivariate stepwise regression demonstrated that serum MANF levels were independently associated with M-value and FAI. After six months of metformin treatment, there was a significant increase in serum MANF levels in PCOS women. Serum MANF levels are decreased in women with PCOS, and are reversely related to insulin resistance and hyperandrogenism. Metformin treatment elevates serum MANF levels and alleviates insulin resistance and hyperandrogenism in PCOS women.
Survival, Neurocognitive, and Functional Outcomes After Completion of Staged Surgical Palliation in a Cohort of Patients With Hypoplastic Left Heart Syndrome

Background Management of patients with hypoplastic left heart syndrome has benefited from advancements in medical and surgical care. Outcomes have improved, although survival and long‐term functional and cognitive deficits remain a concern. Methods and Results This is a cohort study of all consecutive patients with hypoplastic left heart syndrome undergoing surgical palliation at a single center. We aimed to examine demographic and perioperative factors from each surgical stage for their association with survival and neurocognitive outcomes. A total of 117 consecutive patients from 1996 to 2010 underwent surgical palliation. Seventy patients (60%) survived to the Fontan stage and 68 patients (58%) survived to undergo neurocognitive assessment at a mean (SD) age of 56.6 months (6.4 months). Full‐scale, performance, and verbal intelligence quotient, as well as visual‐motor integration mean (SD) scores were 86.7 (16.1), 86.3 (15.8), 88.8 (17.2), and 83.2 (14.8), respectively. On multivariable analysis, older age at Fontan, sepsis peri‐Norwood, lowest arterial partial pressure of oxygen postbidirectional cavopulmonary anastomosis, and presence of neuromotor disability pre‐Fontan were strongly associated with lower scores for all intelligence quotient domains. Older age at Fontan and sepsis peri‐Norwood remained associated with lower scores for all intelligence quotient domains in a subgroup analysis excluding patients with disability pre‐Fontan or with chromosomal abnormalities. Conclusions Older age at Fontan and sepsis are among independent predictors of poor neurocognitive outcomes for patients with hypoplastic left heart syndrome. Further studies are required to identify the appropriate age range for Fontan completion, balancing a lower risk of acute and long‐term hemodynamic complications while optimizing long‐term neurocognitive outcomes.
Systematic research to overcome newly emerged multidrug‐resistant bacteria

In the 1980s, I found that the chromosomal β‐lactamase of Klebsiella pneumoniae LEN‐1 showed a very high similarity to the R‐plasmid‐mediated penicillinase TEM‐1 on the amino acid sequence level, and this strongly suggested the origination of TEM‐1 from the chromosomal penicillinases of K. pneumoniae or related bacteria. Moreover, the chromosomal K1 β‐lactamase (KOXY) of Klebsiella oxytoca was found to belong to the class A β‐lactamases that include LEN‐1 and TEM‐1, although KOXY can hydrolyze cefoperazone (CPZ) like the chromosomal AmpC‐type cephalosporinases of various Enterobacteriaceae that can hydrolyze several cephalosporins including CPZ. Furthermore, my collaborators and I found plural novel serine‐type β‐lactamases, such as MOX‐1, SHV‐24, TEM‐91, CTX‐M‐64, CMY‐9, CMY‐19, GES‐3, GES‐4, and TLA‐3, mediated by plasmids. Besides these serine‐type β‐lactamases, we also first identified exogenously acquired metallo‐β‐lactamases (MBLs), IMP‐1 and SMB‐1, in imipenem‐resistant Serratia marcescens, and the IMP‐1‐producing S. marcescens TN9106 became the index case for carbapenemase‐producing Enterobacteriaceae. I developed the sodium mercaptoacetic acid (SMA)‐disk test for the simple identification of MBL‐producing bacteria. We were also the first to identify a variety of plasmid‐mediated 16S ribosomal RNA methyltransferases, RmtA, RmtB, RmtC, and NpmA, from various Gram‐negative bacteria that showed very high levels of resistance to a wide range of aminoglycosides. Furthermore, we first found plasmid‐mediated quinolone efflux pump (QepA) and fosfomycin‐inactivating enzymes (FosA3 and FosK). We also first characterized penicillin reduced susceptible Streptococcus agalactiae, macrolide‐resistant Mycoplasma pneumoniae, as well as Campylobacter jejuni, and Helicobacter pylori, together with carbapenem‐resistant Haemophilus influenzae. We constructed a PCR‐based open reading frame typing method for rapid identification of Acinetobacter baumannii international clones.
Sub-lethal Concentrations of Phytochemicals (Carvacrol and Oregano) Select for Reduced Susceptibility Mutants of Escherichia coli O23:H52

Abstract In vitro studies aimed at studying the mechanism of action of carvacrol and oregano as natural anti-bacterial agents to control multiple antibiotic-resistant avian pathogenic Escherichia coli (APEC) strain O23:H52 isolated from chicken were performed. Derivatives with increased minimum inhibitory concentrations (MIC) to the phytochemicals were selected after growing Escherichia coli (E. coli) strain O23:H52 at sub-lethal concentrations of carvacrol and oregano for a period of 60 days. Whole-genome sequencing (WGS) of two derivatives revealed a missense mutation in cadC and marR: the genes responsible for survival mechanisms and antibiotic resistance by efflux, respectively.