76 research outputs found
Long-term survival in a patient with progressive multifocal leukoencephalopathy after therapy with rituximab, fludarabine and cyclophosphamide for chronic lymphocytic leukemia
A 50-year-old male with chronic lymphocytic leukemia (CLL) was treated with fludarabine, cyclophosphamide and rituximab, which produced a complete remission. Eight months after the last dose of rituximab he had visual disturbance, diminished muscular strength in the right arm and vesicular-papular lesions in the left ophthalmic branch region of the V cranial nerve. These were initially interpreted as herpes virus encephalopathy (HVE), but brain magnetic resonance imaging (MRI) showed evidence of demyelination consistent with progressive multifocal leukoencephalopathy (PML). Cerebrospinal fluid (CSF) analysis was negative for varicella zoster virus (VZV) and John Cunningham virus (JCV) DNA. The clinical suggestion of PML prompted us to perform a brain biopsy and to start treatment with mefloquine. In the brain biopsy, histopathological features of demyelination were described and the polymerase chain reaction (PCR) identified JCV, confirming the diagnosis of PML. Treatment with mefloquine (250Â mg/week) and dexamethasone (4Â mg/day) was started and maintained for 6Â months. A year later there was an almost complete resolution of the MRI lesions and the patient achieved a stable clinical state with persisting motor impairment and severe epilepsy. The patient is alive 38Â months after diagnosis of PML, which is the longest known survival to date.Supported by grants from the Fondo de Investigaciones Sanitarias -
Ministerio de Ciencia e InnovaciĂłn (PI12/1832), Plan Nacional of I + D + I co-financed by ISCIII-SubdirecciĂłn General de EvaluaciĂłn and Fondo Europeo de Desarrollo Regional (FEDER). HG has a grant from FundaciĂłn BBVA - FundaciĂłn Carolina.S
A randomised phase 2 study comparing different dose approaches of induction treatment of regorafenib in previously treated metastatic colorectal cancer patients (REARRANGE trial)
Altres ajuts: Bayer HealthCare Pharmaceuticals Inc.Purpose: The purpose of this article is to evaluate the safety of two regorafenib dose-escalation approaches in refractory metastatic colorectal cancer (mCRC) patients. Patients and methods: Patients with mCRC and progression during or within 3 months following their last standard chemotherapy regimen were randomised to receive the approved dose of regorafenib of 160 mg QD (arm A) or 120 mg QD (arm B) administered as 3 weeks of treatment followed by 1 week off, or 160 mg QD 1 week on/1 week off (arm C). The primary end-point was the percentage of patients with G3/G4 treatment-related adverse events (AEs) in each arm. Results: There were 299 patients randomly assigned to arm A (n = 101), arm B (n = 99), or arm C (n = 99); 297 initiated treatments (arm A n = 100, arm B n = 98, arm C n = 99: population for safety analyses). G3/4 treatment-related AEs occurred in 60%, 55%, and 54% of patients in arms A, B, and C, respectively. The most common G3/4 AEs were hypertension (19, 12, and 20 patients), fatigue (20, 14, and 15 patients), hypokalemia (11, 7, and 10 patients), and hand-foot skin reaction (8, 7, and 3 patients). Median overall survival was 7.4 (IQR 4.0-13.7) months in arm A, 8.6 (IQR 3.8-13.4) in arm B, and 7.1 (IQR 4.4-12.4) in arm C. Conclusions: The alternative regorafenib dosing schedules were feasible and safe in patients with mCRC who had been previously treated with standard therapy. There was a higher numerical improvement on the most clinically relevant AEs in the intermittent dosing arm, particularly during the relevant first two cycles. Clinicaltrials.gov identifier: NCT02835924
Comparative study of the biochemical changes and volatile compound formations during the production of novel whey-based kefir beverages and traditional milk kefir
Cheese whey (CW) and deproteinised cheese whey (DCW) were investigated for their suitability as novel substrates for the production of kefir-like beverages. Lactose consumption, ethanol production, as well as organic acids and volatile compounds formation, were determined during CW and DCW fermentation by kefir grains and compared with values obtained during the production of traditional milk kefir. The results showed that kefir grains were able to utilise lactose from CW and DCW and produce similar amounts of ethanol (7.8â8.3 g/l), lactic acid (5.0 g/l) and acetic acid (0.7 g/l) to those obtained during milk fermentation. In addition, the concentration of higher alcohols (2-methyl-1-butanol, 3-methyl-1-butanol, 1-hexanol, 2-methyl-1-propanol, and 1-propanol), ester (ethyl acetate) and aldehyde (acetaldehyde) in cheese whey-based kefir and milk kefir beverages were also produced in similar amounts. Cheese whey and deproteinised cheese whey may therefore serve as substrates for the production of kefir-like beverages similar to milk kefir.The authors acknowledge the financial support from Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES), CAPES-GRICES and Lactogal for supplying cheese whey powder
Lifestyles, environmental and phenotypic factors associated with lip cancer: a caseâcontrol study in southern Spain
Paratextual subversion: Herrera and his poetry in the anotaciones
The year 1580 saw the publication of the Anotaciones a las obras de Garcilaso de la Vega by the critic and poet Fernando de Herrera (c. 1534â97). This study develops previous scholarship on the paratextual strategies employed by Herrera, especially with regard to the inclusion of his own poetry within the Anotaciones. Two Garcilasian sonnets, âDâaquella vista pura i ecelenteâ (VIII) and âSi para refrenar este desseoâ (XII), in conjunction with Herreraâs poetic responses, lie at the heart of this investigation, representing two respectively dominant cultural currents of the period: Neoplatonism and Classical mythography. It will be shown how Herrera exploits Counter-Reformation attitudes towards secularity and mythography to engage in a critique that goes deeper than the attacks previously noted by Navarreteâs 1991 study. Indeed, Herreraâs lyric occupies a central role in a complete re-evaluation of Garcilasian lyric that not only moves to subvert the supremacy of the Toledan but also the hegemonic rule of intellectuals from Castile. Herrera presents himself as a learned Andalusian model for Neoplatonic poetics and as the model for imitation for Spanish letters in the wake of the Counter-Reformation.
En 1580 el poeta y crĂtico Fernando de Herrera (c. 1534â97) publicĂł sus Anotaciones a las obras de Garcilaso de la Vega. Este artĂculo desarrolla estudios anteriores sobre esta obra en relaciĂłn con las estrategias paratextuales empleadas por Herrera, sobre todo por lo que respecta a la inclusiĂłn de su propia poesĂa en el texto de las Anotaciones. Este trabajo se centra en dos sonetos de Garcilaso, âDâaquella vista pura i ecelenteâ (VIII) y âSi para refrenar este deseoâ (XII), en conjunciĂłn con otros tantos textos poĂ©ticos de Herrera, teniendo en cuenta sus deudas con dos corrientes culturales contemporĂĄneas: el neoplatonismo y la mitologĂa clĂĄsica. Las actitudes hacia el amor neoplatĂłnico y la mitologĂa fueron explotadas por Herrera de una manera mĂĄs profunda de lo que se suele creer. En efecto, la poesĂa de Herrera ocupa un papel central en la reevaluaciĂłn completa de Garcilaso que no sĂłlo subvierte la posiciĂłn del poeta en el canon literario sino tambiĂ©n la hegemonĂa de los intelectuales de Castilla. Herrera se presenta como un andaluz sabio y defensor de la poesĂa neoplatĂłnica y como el modelo de referencia para la imitaciĂłn poĂ©tica en la nueva era que se abre con la Contrarreforma.This is the author accepted manuscript. The final version is available from Maney via http://dx.doi.org/10.1179/1468273715Z.00000000012
Micromechanical Properties of Injection-Molded StarchâWood Particle Composites
The micromechanical properties of injection molded starchâwood particle composites were investigated as a function of particle content and humidity conditions.
The composite materials were characterized by scanning electron microscopy and X-ray diffraction methods. The microhardness
of the composites was shown to increase notably with the concentration of the wood particles. In addition,creep behavior under the indenter and temperature dependence
were evaluated in terms of the independent contribution of the starch matrix and the wood microparticles to the hardness value. The influence of drying time on the density
and weight uptake of the injection-molded composites was highlighted. The results revealed the role of the mechanism of water evaporation, showing that the dependence of water uptake and temperature was greater for the starchâwood composites than for the pure starch sample. Experiments performed during the drying process at 70°C indicated that
the wood in the starch composites did not prevent water loss from the samples.Peer reviewe
New insights into the genetic etiology of Alzheimer's disease and related dementias
Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE Δ4 allele
Emergence of methicillin resistance predates the clinical use of antibiotics.
The discovery of antibiotics more than 80 years ago has led to considerable improvements in human and animal health. Although antibiotic resistance in environmental bacteria is ancient, resistance in human pathogens is thought to be a modern phenomenon that is driven by the clinical use of antibiotics1. Here we show that particular lineages of methicillin-resistant Staphylococcus aureus-a notorious human pathogen-appeared in European hedgehogs in the pre-antibiotic era. Subsequently, these lineages spread within the local hedgehog populations and between hedgehogs and secondary hosts, including livestock and humans. We also demonstrate that the hedgehog dermatophyte Trichophyton erinacei produces two ÎČ-lactam antibiotics that provide a natural selective environment in which methicillin-resistant S. aureus isolates have an advantage over susceptible isolates. Together, these results suggest that methicillin resistance emerged in the pre-antibiotic era as a co-evolutionary adaptation of S. aureus to the colonization of dermatophyte-infected hedgehogs. The evolution of clinically relevant antibiotic-resistance genes in wild animals and the connectivity of natural, agricultural and human ecosystems demonstrate that the use of a One Health approach is critical for our understanding and management of antibiotic resistance, which is one of the biggest threats to global health, food security and development
Multiancestry analysis of the HLA locus in Alzheimerâs and Parkinsonâs diseases uncovers a shared adaptive immune response mediated by HLA-DRB1*04 subtypes
Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinsonâs disease (PD) and Alzheimerâs disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1*04:07, and intermediary with HLA-DRB1*04:01 and HLA-DRB1*04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased AÎČ42. Protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1*04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues
Time to Switch to Second-line Antiretroviral Therapy in Children With Human Immunodeficiency Virus in Europe and Thailand.
Background: Data on durability of first-line antiretroviral therapy (ART) in children with human immunodeficiency virus (HIV) are limited. We assessed time to switch to second-line therapy in 16 European countries and Thailand. Methods: Children aged <18 years initiating combination ART (â„2 nucleoside reverse transcriptase inhibitors [NRTIs] plus nonnucleoside reverse transcriptase inhibitor [NNRTI] or boosted protease inhibitor [PI]) were included. Switch to second-line was defined as (i) change across drug class (PI to NNRTI or vice versa) or within PI class plus change of â„1 NRTI; (ii) change from single to dual PI; or (iii) addition of a new drug class. Cumulative incidence of switch was calculated with death and loss to follow-up as competing risks. Results: Of 3668 children included, median age at ART initiation was 6.1 (interquartile range (IQR), 1.7-10.5) years. Initial regimens were 32% PI based, 34% nevirapine (NVP) based, and 33% efavirenz based. Median duration of follow-up was 5.4 (IQR, 2.9-8.3) years. Cumulative incidence of switch at 5 years was 21% (95% confidence interval, 20%-23%), with significant regional variations. Median time to switch was 30 (IQR, 16-58) months; two-thirds of switches were related to treatment failure. In multivariable analysis, older age, severe immunosuppression and higher viral load (VL) at ART start, and NVP-based initial regimens were associated with increased risk of switch. Conclusions: One in 5 children switched to a second-line regimen by 5 years of ART, with two-thirds failure related. Advanced HIV, older age, and NVP-based regimens were associated with increased risk of switch
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