Publications by authors named "Cristina Muñoz"

24 Publications

  • Page 1 of 1

Post-transplant cyclophosphamide for GVHD prophylaxis compared to ATG-based prophylaxis in unrelated donor transplantation.

Ann Hematol 2021 Feb 2;100(2):541-553. Epub 2020 Nov 2.

Department of Hematology and Hemotherapy, Hospital General Universitario Gregorio Marañón, Madrid, Spain.

Post-transplant cyclophosphamide (PTCY) effectively prevents graft-versus-host disease after unmanipulated HLA-haploidentical HSCT. The use of PTCY in the unrelated donor HSCT setting is less explored. We conducted a retrospective study of 132 consecutive patients undergoing a matched or 9/10 mismatched unrelated donor HSCT in 4 centers in Spain, 60 with anti-thymocyte globulin (ATG)-based prophylaxis combined with MTX-CsA, and 72 using a PTCY-based regimen. Peripheral blood stem cells were used as graft in most patients (111 patients, 84%); mMUD donors were balanced between groups. Cumulative incidences of grades II-IV and III-IV acute GVHD at 100 days were lower in the PTCy group (46% vs. 67%, p = 0.008; 3% vs. 34%, p = 0.003), without statistically significant differences in the 2-year cumulative incidence of chronic moderate-severe GVHD. At 2 years, no significant differences were observed in overall survival, event-free survival, cumulative incidence of relapse, and non-relapse mortality. GVHD was the most frequent cause of NRM in the ATG group. No differences were observed between groups in the composite endpoint of GVHD-free and relapse-free survival. In this study, PTCy combined with additional immunosuppression after MUD/mMUD HSCT showed a reduction of aGVHD rate with safety results comparable to those obtained with the ATG-based prophylaxis.
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http://dx.doi.org/10.1007/s00277-020-04317-7DOI Listing
February 2021

Novel academic center model for Spanish-speaking patients in the southeastern United States.

Prev Med Community Health 2020 Jul 28;3(1). Epub 2020 Jul 28.

School of Medicine, University of North Carolina, Chapel Hill, North Carolina, USA.

Latinos form the largest U.S. minority and will account for one quarter of the population by 2050. Immigration trends from 1995-2010 challenged health systems in "new destination" regions such as the southeastern U.S., with Latino population increases of 200-400%, and a minimal bilingual health workforce. Academic medical centers and safety net hospitals are challenged to respond beyond the interpreter paradigm of care delivery to provide efficient, cost-effective and compassionate care that complies with the U.S. Title VI mandates. We describe the design and successful implementation of an academic model in the care of Spanish-speaking patients in the pediatric and adult primary care and subspecialty settings in the University of North Carolina Health Care System. This model leverages a limited bilingual workforce to maximize the extent and quality of language-concordant care for this population The innovative features of the UNC Center for Latino Health (CELAH) is based upon five principles: patient navigation, a medical home, a block-scheduling system, a "virtual clinic" model using existing space, and leveraged cost-neutral resources. Patients are scheduled to specific half-day sessions in specialty clinics and matched with bilingual faculty and staff. This facilitates door-to-door care in Spanish for patients, the majority of whom are immigrants from rural Mexico and Central America with limited English and health literacy. CELAH is considered an academic transition model in anticipation of an adequate bilingual health workforce in 1-2 decades. As a hub, this clinical platform supports unique programs in medical education, translational and health equity research, community outreach, and faculty engagement.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7461717PMC
July 2020

Transjugular Intrahepatic Portosystemic Shunt for Very Severe Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome (VOD/SOS) after Unmanipulated Haploidentical Hematopoietic Stem Cell Transplantation with Post-transplantation Cyclophosphamide.

Biol Blood Marrow Transplant 2020 11 11;26(11):2089-2097. Epub 2020 Aug 11.

Department of Hematology, Hospital General Universitario Gregorio Marañón, Madrid, Spain; Gregorio Marañón Health Research Institute, Madrid, Spain.

Hepatic veno-occlusive disease or sinusoidal obstruction syndrome (VOD/SOS) is a threatening complication after both autologous and allogeneic hematopoietic stem cell transplantation (HSCT), with high mortality rates despite early medical treatment, including the use of defibrotide (DF). We retrospectively analyzed 185 unmanipulated haploidentical (haplo-) HSCT with post-transplantation cyclophosphamide as graft-versus-host disease prophylaxis performed consecutively between 2011 and June 2019 in a single center. Seventeen patients (9.2%) were diagnosed with VOD/SOS. Based on revised European Society for Blood and Marrow Transplantation severity criteria, the VOD/SOS cases were classified as mild in 2 patients (11.7%), moderate in 2 (11.7%), severe in 2 (11.7%), and very severe in 11 (64.9%). Thirteen patients (76%) were treated with DF, including all patients with severe or very severe VOD/SOS, except 1 patient with CNS hemorrhage. Sixteen patients (94%) were alive at day +100 after HSCT. Seven patients (41%) with very severe VOD/SOS were treated with transjugular intrahepatic portosystemic shunt (TIPS) owing to rapid clinical or analytical deterioration or refractory hepatorenal syndrome despite medical treatment, including DF. TIPS insertion was performed at a median time since VOD/SOS diagnosis of 4 days (range, 1 to 28 days) without technical complications in any case. The median hepatic venous pressure gradient before and after TIPS treatment was 24 mmHg (range, 14 to 29 mmHg) and 7 mmHg (range, 2 to 11 mmHg), respectively, with a median drop of 16 mmHg (range, 9 to 19 mmHg). Following TIPS insertion, all patients showed clinical improvement with hepatomegaly, ascites, and renal failure resolution, and all showed analytical improvement with reduced alanine aminotransferase (ALT), creatinine, and international normalized ratio values, except for patient 2, whose indication for TIPS was refractory hepatorenal syndrome with a normal ALT level. The 6 patients who had initiated DF before TIPS insertion completed 21 days of treatment. All patients met the criteria for complete remission (CR) at a median of 8 days after TIPS insertion (range, 2 to 82 days). The 100-day overall survival was 100%. For patients with rapid progressive VOD/SOS, early TIPS insertion allowed completion of DF therapy. The use of TIPS together with DF resulted in CR and no associated complications with no VOD/SOS-associated mortality despite high severity. In our experience, timely and individualized use of TIPS significantly improves outcomes of very severe VOD/SOS after haplo-HSCT. Therefore, TIPS should be promptly considered in rapidly progressive cases.
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http://dx.doi.org/10.1016/j.bbmt.2020.08.006DOI Listing
November 2020

Posttransplant cyclophosphamide vs cyclosporin A and methotrexate as GVHD prophylaxis in matched sibling transplantation.

Blood Adv 2019 11;3(21):3351-3359

Servicio de Hematología, Hospital General Universitario Gregorio Marañon, Madrid, Spain.

Posttransplant cyclophosphamide (PTCy) effectively prevents graft-versus-host disease (GVHD) after HLA-haploidentical hematopoietic stem cell transplantation (HSCT). The use of PTCy in HLA-identical HSCT is less explored. We conducted a retrospective study of 107 consecutive patients undergoing an HLA-identical sibling (10/10) HSCT in 2 centers in Spain, 50 with GVHD prophylaxis with methotrexate-cyclosporin A (MTX-CsA) and 57 using a PTCy-based regimen with additional immunosuppression. Graft source was unmanipulated mobilized peripheral blood stem cells (PBSC) in most patients (97 patients, 91%). Cumulative incidences of grade II to IV and III to IV acute GVHD at 100 days were lower in the PTCy group (22.6% vs 52.2%, P = .0015; 8.8% vs 24.4%, P = .016), without statistically significant differences in the 2-year cumulative incidence of chronic moderate to severe GVHD (16.7% vs 26%, P = .306). At 2 years, no statistically significant differences were observed in OS (78% vs 56%, P = .088), EFS (62.5% vs 48%, P = .054), relapse (28% vs 27%, P = .47), and NRM (8.8% vs 24%, P = .054). The composite endpoint of GVHD and relapse-free survival (GRFS) was favorable for the PTCy group (24% vs 48%, P = .011), PTCy being the sole independent factor identified in the multivariate analysis for this endpoint. In this study, PTCy combination with additional immunosuppression using mostly PBSCs grafts showed a reduction of acute GVHD rate and an impact on GRFS, with safety results comparable with those obtained with MTX-CsA. Further prospective studies are needed to confirm these observations..
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http://dx.doi.org/10.1182/bloodadvances.2019000236DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6855126PMC
November 2019

Specific Inhibition of the Classical Complement Pathway Prevents C3 Deposition along the Dermal-Epidermal Junction in Bullous Pemphigoid.

J Invest Dermatol 2019 12 20;139(12):2417-2424.e2. Epub 2019 Jun 20.

Department of Dermatology, Medical University of Vienna, Vienna, Austria.

Deposition of autoantibodies (α-BP180 and BP230) and complement along the dermal-epidermal-junction is a hallmark of bullous pemphigoid and was shown to be important for pathogenesis. Given the adverse effects of standard treatment (glucocorticoids, immunosuppressants), there is an unmet need for safe and effective therapies. In this phase 1 trial, we evaluated the safety and activity of BIVV009 (sutimlimab, previously TNT009), a targeted C1s inhibitor, in 10 subjects with active or past bullous pemphigoid (NCT02502903). Four weekly 60 mg/kg infusions of BIVV009 proved sufficient for inhibition of the classical complement pathway in all patients, as measured by CH50. C3c deposition along the dermal-epidermal junction was partially or completely abrogated in 4 of 5 patients, where it was present at baseline. BIVV009 was found to be safe and tolerable in this elderly population, with only mild to moderate adverse events reported (e.g., headache, fatigue). One serious adverse event (i.e., fatal cardiac decompensation) occurred at the end of the post-treatment observation period in an 84-year-old patient with a history of diabetes and heart failure, but was deemed unlikely to be related to the study drug. This trial provides the first results with a complement-targeting therapy in bullous pemphigoid, to our knowledge, and supports further studies on BIVV009's efficacy and safety in this population.
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http://dx.doi.org/10.1016/j.jid.2019.04.025DOI Listing
December 2019

Frequency, characteristics, and outcome of PTLD after allo-SCT: A multicenter study from the Spanish group of blood and marrow transplantation (GETH).

Eur J Haematol 2019 Jun 10;102(6):465-471. Epub 2019 Apr 10.

Hospital Clínico de Valencia, Valencia, Spain.

Post-transplant lymphoproliferative disorder (PTLD) is an infrequent complication of allogeneic stem cell transplant (allo-SCT).

Aims: To estimate the frequency and management of PTLD in Spain and to identify prognostic factors influencing outcomes.

Methods: Multicenter, retrospective analysis of allo-SCT performed in 14 transplant units over a 15-year period.

Results: 102 PTLD were diagnosed among 12 641 allo-SCT, leading to an estimated frequency of 0.8%. PTLD was diagnosed at a median of 106 days after SCT. Eighty-seven cases (85%) were diagnosed between 2007 and 2013. At diagnosis, 22% and 17% of the patients had gastrointestinal tract and CNS involvement. Eighty-seven (85%) received rituximab treatment, alone or in combination with immunosuppression reduction, with an ORR of 50.6%. With a median follow-up for survivors of 58 months, the 2-year overall survival (OS) was 33% and the PTLD-related mortality 45%. Age ≥ 40 years, malignant underlying disease, non-response to rituximab, and severe thrombocytopenia or lymphocytopenia at PTLD diagnosis were associated with worse overall survival.

Conclusions: Only a small proportion of allografted patients were diagnosed a PTLD. Its clinical course was highly aggressive, and prognosis poor, especially in those failing rituximab. The prognostic impact found of the platelet, and lymphocyte count at diagnosis requires further confirmation.
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http://dx.doi.org/10.1111/ejh.13226DOI Listing
June 2019

Factors predicting peripheral blood progenitor cell mobilization in healthy donors in the era of related alternative donors: Experience from a single center.

J Clin Apher 2019 Aug 29;34(4):373-380. Epub 2019 Jan 29.

Hematology and Hemotherapy Department, Hospital General Universitario Gregorio Marañón, Madrid, Spain.

Background: Poor mobilization results are unexpected after G-CSF-induced peripheral blood stem cell collection in healthy donors. However, 2%-5% of the donors are poor mobilizers. Factors predicting CD34+-cell yield after mobilization in related alternative donors are still poorly known.

Patients And Methods: Baseline characteristics and efficacy results of G-CSF induced mobilization of 159 adult healthy donors in our institution from 2008 to 2016 were retrospectively analyzed. All donors received 10 μg/kg of G-CSF once a day subcutaneously for 4 days. Leukapheresis started on the 5th day of G-CSF treatment. Donors were classified as poor mobilizers if they had less than 20 000 CD34 + cell/mL peripheral blood count in the 5th day of G-CSF treatment or if they needed three or more leukapheresis for graft collection.

Results: Age, weight, and platelet count before and after mobilization were significantly different between poor and good mobilizers. Poor mobilizers (n = 16) were older (50.6 vs 41.7 years, P = 0.002), weight lower (64 vs 75 kg, P = 0.00) and showed a lower platelet count before (199.5 vs 219.0 × 10 /L, P = 0.03) and after (192.5 vs 206 × 10 /L, P = 0.019) mobilization. In the multivariate analysis only the 30% of the variability of mobilization was explained by the model (sensitivity 80%, specificity 70%).

Conclusion: In this cohort of healthy donors in a single institution, older age, less weight, and lower platelet count was associated with poorer mobilization. With clinical and analytic factors it is not possible to predict more than 30% of the variability. Further studies are needed to investigate new variables.
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http://dx.doi.org/10.1002/jca.21685DOI Listing
August 2019

Human Papillomavirus Correlates With Histologic Anal High-Grade Squamous Intraepithelial Lesions in Hispanics With HIV.

J Low Genit Tract Dis 2018 Oct;22(4):320-325

Department of Biostatistics and Epidemiology, Graduate School of Public Health, University of Puerto Rico, Medical Sciences Campus, San Juan, Puerto Rico.

Objective: To estimate the magnitude of association between anal infection with high-risk human papilloma virus (HR-HPV) types and severity of biopsy-confirmed histopathological anal squamous intraepithelial lesions (SILs) among a clinic-based sample of HIV-infected adults in Puerto Rico.

Methods: This cross-sectional study analyzed data from medical records of adult patients who visited a specialized anal neoplasia clinic from June 2015 to December 2017 (n = 239); sociodemographics, behavioral risk factors, medical history, clinical data, and pathology reports were collected. The magnitude of association between anal HR-HPV and severity of anal SIL, adjusted for potential confounders, was assessed using a multinomial logistic model.

Results: A 78.7% of patients had anal HR-HPV infection, 43.9% had histopathological low-grade SIL (LSIL), and 37.7% had histopathological high-grade SIL (HSIL). The prevalence of anal HR-HPV infection was 63.6% among patients with no anal SIL, 70.5% for those with LSIL and 95.6% for those with HSIL. After adjusting for different predictors, patients with anal HR-HPV infection were more likely to have HSIL (odds ratio, 11.0; 95% confidence interval, 3.2-37.2) than those without anal HR-HPV infection, whereas no significant excess was observed for LSIL (odds ratio, 1.4; 95% confidence interval, 0.6-3.1).

Conclusions: This study showed a strong association between anal HR-HPV infection and HSIL. Likewise, a high prevalence of anal HR-HPV infection and presence of anal SIL was observed among HIV-infected individuals. Our result highlights the importance of screening for anal HR-HPV infection and anal SIL and optimizing strategies for HPV vaccination in HIV-infected individuals.
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http://dx.doi.org/10.1097/LGT.0000000000000416DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7375752PMC
October 2018

Periodontitis and oral human papillomavirus infection among Hispanic adults.

Papillomavirus Res 2018 06 16;5:128-133. Epub 2018 Mar 16.

Cancer Control and Population Sciences Program, Puerto Rico Comprehensive Cancer Center, University of Puerto Rico, San Juan, Puerto Rico.

Introduction: Research on the association between periodontitis and oral human papilloma virus (HPV) infection is inconsistent. The cross-sectional association of severe periodontitis with oral HPV infection was investigated in a sample of Hispanic adults.

Methods: Data from the 2014-2016 San Juan Overweight Adults Longitudinal Study (n = 740) was analyzed. Periodontitis assessment and self-collection of oral HPV samples followed the National Health and Nutrition Examination Survey methodology. Periodontitis was defined using the Centers of Disease Control and Prevention/American Academy of Periodontology definition. HPV typing was performed using polymerase chain reaction. Multivariate logistic regression models were used to calculate odds ratios (ORs) and 95% confidence intervals (CIs).

Results: 5.7% of participants had oral HPV infection and 20.3% had severe periodontitis. Adults with severe periodontitis had higher odds of oral HPV infection than those with none/mild disease (OR=2.9, 95% CI: 1.0-8.4, p < 0.05) in multivariable analysis. Adults with clinical attachment loss≥ 7 mm and pocket depth PD≥ 6 mm had 2- to 3-fold higher odds of HPV infection.

Conclusions: Severe periodontitis was positively associated to oral HPV infection. Longitudinal evaluation of periodontal inflammation's role in acquisition and persistence of oral HPV infection is needed, as periodontitis screening could identify individuals at increased risk of HPV-related oral malignancies.
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http://dx.doi.org/10.1016/j.pvr.2018.03.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5886954PMC
June 2018

Association of marijuana use with oral HPV infection and periodontitis among Hispanic adults: Implications for oral cancer prevention.

J Periodontol 2018 05;89(5):540-548

Department of Biostatistics and Epidemiology, Graduate School of Public Health, University of Puerto Rico Medical Sciences Campus, San Juan, Puerto Rico.

Background: Despite limited data, research suggests that marijuana use is associated with oral HPV infection and periodontitis, two potential oropharyngeal cancer risk factors. We assessed these associations in a Hispanic adult population in Puerto Rico.

Methods: A cross-sectional study of 735 adults assessed marijuana use, determined through an audio computer-assisted self-interview, and periodontitis and self-collection of oral HPV samples following the National Health and Nutrition Examination Survey methodology. The Centers of Disease Control and Prevention/American Academy of Periodontology definition was used for periodontitis. HPV typing was performed using polymerase chain reaction with modified L1 consensus primers (MY09/MY11).

Results: 26.5% of adults reported lifetime use of marijuana, 2.7% were frequent users (lifetime use ≥ 26 times, past year use ≥ 6 times, and past 30-day use ≥2 times), 5.7% had oral HPV infection, and 20.1% had severe periodontitis. The multivariate logistic regression analysis showed that frequent marijuana users were more likely to have severe periodontitis (OR = (2.93, 95%: 1.08-7.96)) than never/once lifetime users after adjusting for age, sex, healthcare coverage, smoking, binge drinking, number of oral sex partners, and oral HPV infection. However, frequent marijuana use was not associated with oral HPV infection.

Conclusion: Marijuana use was associated with periodontitis, but not with oral HPV infection. Further evaluation of the role of marijuana use in oral HPV infection and periodontitis may inform novel preventive public health strategies, as marijuana users could be at increased risk of oral cancer.
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http://dx.doi.org/10.1002/JPER.17-0372DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6647026PMC
May 2018

Unequal Recovery? Federal Resource Distribution after a Midwest Flood Disaster.

Int J Environ Res Public Health 2016 05 17;13(5). Epub 2016 May 17.

Department of Geographical & Sustainability Sciences, University of Iowa, Iowa City, IA 52242, USA.

Following severe flooding in 2008, three Iowa communities acquired over 1000 damaged properties to support disaster recovery and mitigation. This research applies a distributive justice framework to analyze the distribution of disaster recovery funds for property acquisition. Two research questions drive the analysis: (1) how does recovery vary by acquisition funding source; and (2) what is the relationship between recovery and vulnerable populations? Through spatial econometric modeling, relative recovery is compared between two federal programs that funded the acquisitions, and across socially vulnerable populations. The results indicate both distributive and temporal inequalities in the allocation of federal recovery funds. In particular, Latino and elderly populations were associated with lower recovery rates. Recommendations for future research in flood recovery and acquisitions are provided.
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http://dx.doi.org/10.3390/ijerph13050507DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4881132PMC
May 2016

Methods in HPV Surveillance: Experiences from a Population-Based Study of HPV Infection among Women in the San Juan Metropolitan Area of Puerto Rico.

P R Health Sci J 2015 Sep;34(3):117-27

Department of Biostatistics and Epidemiology, Graduate School of Public Health, University of Puerto Rico Medical Sciences Campus, San Juan, PR.

This article describes the methodology of the first population-based study of human papillomavirus (HPV) infection among women aged 16-64 years residing in the San Juan Metropolitan Area of Puerto Rico (PR). The sample was identified through a complex sampling design of households. The sampling frame was selected in four stages, using census tracts maps from the Census Bureau. Women completed a face-to-face interview and a computer-assisted self-interview using the Audio CASI system, for the collection of demographic, clinical, and lifestyle variables, and sampling acceptability. Anal, cervical, and oral specimens were collected through self-collection methods for HPV DNA testing using a modified pool of MY09/MY11 consensus HPV L1 and human ß-globin amplification primers. Anthropometric measurements were taken using the Third National Health and Nutrition Examination Survey methodology. Blood samples were collected to create a bio-repository for future HPV-related studies. Fifty census tract blocks were randomly selected. We recruited 566 women, with a response rate of 83.4%. Response rates did not vary by age-group (p>0.05); although they varied by socioeconomic (SES) census block stratums (p<0.05), response rates were good (>75%) in all SES strata. All participants agreed to respond to the surveys and provide the requested anogenital and oral samples. Overall, more than 98% understood and more than 50% felt comfortable with the cervical, anal, and oral self-collection methods used. This article documents the feasibility of performing population-based studies for HPV surveillance in women in PR.
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September 2015

Inhibitory killer cell immunoglobulin-like receptor (iKIR) mismatches improve survival after T-cell-repleted haploidentical transplantation.

Eur J Haematol 2016 May 23;96(5):483-91. Epub 2015 Jul 23.

Servicio de Hematología y Hemoterapia, Hospital General Universitario Gregorio Marañón, Madrid, Spain.

Alloreactivity triggered by interaction between killer cell immunoglobulin-like receptors (KIRs) and natural killer (NK) cells plays a role in the graft-versus-tumor effect after hematopoietic stem cell transplantation (SCT). Our aim in this study was to evaluate this role in the setting of T-cell-repleted haploidentical SCT with postinfusion high-dose cyclophosphamide (PT-Cy). We included 33 patients. Among patient-donor pairs with at least 1 inhibitory KIR (iKIR) gene mismatch, event-free survival (EFS) and cumulative incidence of relapse 1 year after transplant were significantly better (85% vs. 37% [P = 0.008] and 18% vs. 46% [P = 0.041], respectively). A subanalysis in 12 patients with Hodgkin's lymphoma (HL) showed an improvement in EFS 1 year after transplant in those patients with KIR ligand mismatch (100% vs. 25%, P = 0.012), although overall survival (OS) was not affected (85% vs. 80%, P = 0.2). Eight of 12 patient-donors pairs presented iKIR mismatches. Of note, this outcome was better in the small subgroup, both for EFS (100% vs. 25%, P = 0.012) and for OS (100% vs. 37%, P = 0.004). Our data suggest that in the setting of T-cell-repleted haploidentical SCT with PT-Cy, iKIR mismatch is associated with improved survival, with particularly good results for both iKIR and KIR ligand mismatches in patients with HL.
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http://dx.doi.org/10.1111/ejh.12616DOI Listing
May 2016

Clinical and Virological Characteristics of Early and Moderate Preterm Infants Readmitted With Viral Respiratory Infections.

Pediatr Infect Dis J 2015 Jul;34(7):693-9

From the *Pediatrics Department, Severo Ochoa Hospital, Leganes; and †Respiratory Viruses and Influenza Laboratory, Centro Nacional de Microbiología, ISCIII, Madrid, Spain.

Background: Rehospitalization of children born prematurely (referred to as preterm children) caused by severe respiratory infections is common. Most studies have focused on respiratory syncytial virus infection. We designed a study to determine the virological and clinical characteristics of severe respiratory infections of children born early (<32 weeks) and moderate preterm (32 to 36 weeks), and compared them with full term (FT; ≥37 weeks) children who were subsequently admitted with respiratory illness.

Methods: A 7-year observational prospective study was conducted on preterm and FT children, less than 14 years old hospitalized with respiratory infection. The presence of 16 respiratory viruses in nasopharyngeal aspirates was sought. Clinical and virological characteristics of subjects were compared among term and preterm children.

Results: We studied 411 respiratory hospital admissions of 262 preterm children who were compared with 2057 respiratory hospital admissions of term children. In 78.6% of preterm episodes, at least 1 respiratory virus was identified. The most frequent viruses were respiratory syncytial virus (29%), rhinovirus (25%) and human bocavirus (13%). Human metapneumovirus and parainfluenza virus were significantly more frequent in preterm than in term children (P < 0.001 and P = 0.017, respectively). Early preterm (EPT) infants admitted with bronchiolitis presented more hypoxia (P = 0.08), longer hospital stay (P = 0.05), more infiltrate on chest radiograph (P = 0.02) and more antibiotic treatment (P = 0.02) than moderate preterm (MPT) infants. Moreover, MPT needed more intensive care unit admission than FT infants (P < 0.001). Regarding wheezing episodes, EPT patients showed significantly more infiltrate/atelectasis (P < 0.001), longer oxygen therapy (P = 0.039) and longer hospital stay (P = 0.07) than MPT children, although similar percentage of intensive care unit admission was seen in both groups. MPT-wheezy children needed longer hospital stay than FT (P = 0.05). Previous bronchiolitis and EPT were independent factors associated with multiple wheezing admissions.

Conclusion: Our results demonstrate that besides respiratory syncytial virus, other viruses mainly rhinovirus and human bocavirus are important pathogens in severe respiratory infections in preterm children. Human metapneumovirus and parainfluenza virus seem also to play a significant role in this group of children. There is increased medical resource utilization, not only among EPT but also in MPT hospitalized children with respiratory infections as many of them require more medical support than FT children.
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http://dx.doi.org/10.1097/INF.0000000000000718DOI Listing
July 2015

Magneto-plasmonic nanoparticles as theranostic platforms for magnetic resonance imaging, drug delivery and NIR hyperthermia applications.

Nanoscale 2014 Aug;6(15):9230-40

Department of Chemical Engineering, Aragon Institute of Nanoscience (INA), University of Zaragoza, Campus Río Ebro-Edificio I+D, C/Poeta Mariano Esquillor S/N, 50018-Zaragoza, Spain.

PEGylated magneto-plasmonic nanoparticles with a hollow or semi-hollow interior have been successfully synthesized and their physico-chemical characteristics have been investigated. The hollow interior space can be used to store drugs or other molecules of interest whereas magnetic characterization shows their potential as contrast agents in magnetic resonance imaging (MRI) applications. In addition, their plasmonic characteristics in the near infrared (NIR) region make them efficient in photothermal applications producing high temperature gradients after short irradiation times. We show that by controlling the etching conditions the inner silica shell can be selectively dissolved to achieve a hollow or semi-hollow interior without compromising the magnetic or plasmonic characteristics of the resulting nanoparticles. Magnetic measurements and transmission electron microscopy observations have been used to demonstrate the precise control during the etching process and to select an optimal concentration of the etching reagent and contact time to preserve the inner superparamagnetic iron oxide-based nanoparticles and the plasmonic properties of the constructs. Drug loading capabilities were also evaluated for both semi-hollow and as-synthesized nanoparticles using Rhodamine B isothiocyanate as a model compound. The nanoparticles produced could be potentially used as "theranostic" nanoparticles with both imaging capabilities and a dual therapeutic function (drug delivery and hyperthermia).
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http://dx.doi.org/10.1039/c4nr01588fDOI Listing
August 2014

Prognostic impact of minimal residual disease analysis by flow cytometry in patients with acute myeloid leukemia before and after allogeneic hemopoietic stem cell transplantation.

Eur J Haematol 2014 Sep 29;93(3):239-46. Epub 2014 Apr 29.

Servicio de Hematología y Hemoterapia, Hospital General Universitario Gregorio Marañón, Madrid, Spain; Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain.

Allogeneic stem cell transplantation (allo-SCT) has become the treatment of choice in patients with intermediate-risk and high-risk acute myeloid leukemia (AML). The quality of response to treatment, assessed in terms of detection of minimal residual disease (MRD), has been consistently associated with prognosis and clinical outcome in patients with AML. The aim of the present study was to evaluate the prognostic impact of analyzing MRD in bone marrow using 4-color multiparametric flow cytometry (MFC) in 29 patients with AML before and after allo-SCT. Eighteen patients who were shown to be MRD-negative [≤0.1% leukemia-associated immunophenotypes (LAIPs)] by MFC at transplantation and underwent allo-SCT had lower rates of relapse (15% vs. 66%, P = 0.045), better overall 1-yr survival (83% vs. 52%, P = 0.021) and a lower cumulative incidence of relapse (P = 0.032) than patients who were MRD-positive (>0.1%). All post-transplant MRD-positive patients underwent a therapeutic intervention after transplant (tapering of immunosuppression, donor lymphocyte infusion, or re-transplant) with the intention of preventing relapse. Disease was controlled and MRD disappeared in five of these patients. Disease recurred in the other seven patients. We can conclude that follow-up with MFC for the detection of MRD in AML before and after SCT is useful for predicting relapse. In the post-transplant setting, monitoring of MRD by MFC could be a key preemptive intervention.
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http://dx.doi.org/10.1111/ejh.12336DOI Listing
September 2014

The strawberry pathogenesis-related 10 (PR-10) Fra a proteins control flavonoid biosynthesis by binding to metabolic intermediates.

J Biol Chem 2013 Dec 16;288(49):35322-32. Epub 2013 Oct 16.

From the Instituto de Hortofruticultura Subtropical y Mediterránea (IHSM-UMA-Consejo Superior de Investigaciones Científicas), Departamento de Biología Molecular y Bioquímica, Universidad de Málaga, 29071 Málaga, Spain.

Pathogenesis-related 10 (PR-10) proteins are involved in many aspects of plant biology but their molecular function is still unclear. They are related by sequence and structural homology to mammalian lipid transport and plant abscisic acid receptor proteins and are predicted to have cavities for ligand binding. Recently, three new members of the PR-10 family, the Fra a proteins, have been identified in strawberry, where they are required for the activity of the flavonoid biosynthesis pathway, which is essential for the development of color and flavor in fruits. Here, we show that Fra a proteins bind natural flavonoids with different selectivity and affinities in the low μm range. The structural analysis of Fra a 1 E and a Fra a 3-catechin complex indicates that loops L3, L5, and L7 surrounding the ligand-binding cavity show significant flexibility in the apo forms but close over the ligand in the Fra a 3-catechin complex. Our findings provide mechanistic insight on the function of Fra a proteins and suggest that PR-10 proteins, which are widespread in plants, may play a role in the control of secondary metabolic pathways by binding to metabolic intermediates.
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http://dx.doi.org/10.1074/jbc.M113.501528DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3853281PMC
December 2013

Polyphenol composition in the ripe fruits of Fragaria species and transcriptional analyses of key genes in the pathway.

J Agric Food Chem 2011 Dec 4;59(23):12598-604. Epub 2011 Nov 4.

Instituto de Hortofruticultura Subtropical y Mediterránea, Universidad de Málaga-Consejo Superior de Investigaciones Científicas, Departamento de Biología Molecular y Bioquímica, Facultad de Ciencias, Universidad de Málaga, Campus de Teatinos s/n, E-29071 Málaga, Spain.

Polyphenolics are important secondary metabolites in strawberry as they fulfill a wide variety of physiological functions and are beneficial to human health. Seventeen structurally well-defined phenolic compounds including phenylpropanoids, flavonols, flavan-3-ols, and anthocyanins were individually analyzed by LC-MS in the ripe fruits of two cultivars of the commercial strawberry (Fragaria × ananassa Duch., Rosaceae) as well as in accessions of F. vesca, F. moschata, and F. chiloensis. Metabolic analysis revealed that the majority of the compounds analyzed accumulated in a genotype-dependent manner. Transcriptional studies of genes encoding for enzymes of the biosynthetic pathway such as phenylalanine ammonia-lyase, cinnamic acid 4-hydroxylase, chalcone synthase, and flavonoid 3'-hydroxylase could partially explain the different levels of polyphenolics observed in the Fragaria species. The results can provide a sound basis for selecting markers for the development of cultivars with high phenolic content, which can be of value for the food industry.
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http://dx.doi.org/10.1021/jf203965jDOI Listing
December 2011

Pandemic H1N1 influenza-associated hospitalizations in children in Madrid, Spain.

Influenza Other Respir Viruses 2011 Nov 22;5(6):e544-51. Epub 2011 Jul 22.

Pediatrics Department, Hospital Infanta Elena, Valdemoro, Madrid, Spain.

Objective: To describe the epidemiological and clinical characteristics of children hospitalized with 2009 pandemic influenza (pH1N1) in Madrid, Spain.

Patients/methods: We included patients less than 14 years of age admitted to one of 18 hospitals in Madrid, Spain, between May 1 and November 30, 2009 and diagnosed with pH1N1 by polymerase chain reaction. A retrospective chart review was conducted and data were compared by age, presence of high-risk medical conditions, and pediatric intensive care unit (PICU) admission.

Results: A total of 517 pH1N1 cases were included for final analysis. One hundred and forty-two patients (27·5%) had predisposing underlying illnesses, with immunosuppression (36 children, 7%) and moderate persistent asthma (34, 6·6%) being the most common ones. Patients with underlying medical conditions had longer hospital stays [median 5, interquartile range (IQR) 3-8 days, versus median 4, IQR 3-6, P < 0·001] and required intensive care (20·4% versus 5·9%, P < 0·001) and mechanical ventilation more frequently than previously healthy children. Globally, intensive care was required for 51 patients (10%) and invasive mechanical ventilation for 12 (2%). Pediatric intensive care unit admission was significantly associated with abnormal initial chest X-ray [Odds Ratio (OR) 3·5, 95% confidence interval (CI) 1·5-8·5], underlying neurological condition (OR 3·1, CI 1·2-7·5) and immunosuppression (OR 2·9, 1·2-6·8). Five patients (0·9%) died; two with severe neurological disease, two with leukemia, and one with a malignant solid tumor.

Conclusions: Children with underlying medical conditions experienced more severe pH1N1 disease. Risk factors for admission to the PICU included underlying neurological conditions, immunosuppression and abnormal initial chest X-ray.
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http://dx.doi.org/10.1111/j.1750-2659.2011.00272.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5780672PMC
November 2011

The strawberry fruit Fra a allergen functions in flavonoid biosynthesis.

Mol Plant 2010 Jan 29;3(1):113-24. Epub 2009 Oct 29.

Departamento de Biología Molecular y Bioquímica, Universidad de Málaga, Málaga, Spain.

The strawberry Fra a 1 allergen is a homolog of the major birch pollen allergen Bet v 1. It is synthesized by red ripe fruits of Fragaria x ananassa while white fruits of a mutant genotype, which is known to be tolerated by individuals affected by allergy, are devoid of it. Proteomic analyses have shown that Fra a 1 is down-regulated in the tolerated white-fruited genotype along with enzymes of the anthocyanin pigment pathway. In this study, we report the spatial and temporal expression of three Fra a genes that encode different isoforms, and the transient RNAi-mediated silencing of the Fra a genes in strawberry fruits of the red-fruited cultivar Elsanta with an ihpRNA construct. As a consequence of reduced levels of Fra a mRNAs, fruits were obtained that produced significantly decreased levels of anthocyanins and upstream metabolites. This effect is consistent with the parallel down-regulation of the phenylalanine ammonia lyase (FaPAL) and to a lesser extent of the chalcone synthase (FaCHS) transcript levels also found in these fruits. In naturally occurring white-fruited genotypes of F. chiloensis and F. vesca, Fra a transcript levels are higher than those of the red-fruited varieties, likely to compensate for the low expression levels of FaPAL and FaCHS in these mutant genotypes. The results demonstrate that Fra a expression is directly linked to flavonoid biosynthesis and show that the Fra a allergen has an essential biological function in pigment formation in strawberry fruit.
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http://dx.doi.org/10.1093/mp/ssp087DOI Listing
January 2010

Discovery of biomarkers that reflect the intake of sodium selenate by nutritional proteomics.

J Chromatogr Sci 2009 Oct;47(9):840-3

Department of Chemical Engineering, University of Santiago of Chile, Santiago, Chile.

Selenium offers important health benefits, including the prevention of some types of cancer. The traditional selenium indexes, such as selenium concentration, do not account for the metabolic status of this element regarding its chemoprotective effect. Then, the knowledge of a group of proteins that respond to selenium supplementation could be useful in the assessment of the metabolic status of selenium. The effect of dietary supplementation of rats with sodium-selenate on the blood plasma proteome is investigated. A group composed of six rats is fed a basic diet supplemented with sodium-selenate at 1.9 microg of Selenium per g of food, and a control group is fed a diet that covers the minimum selenium requirements, each for ten weeks. A proteomic approach is used to both quantify the changes in the abundance of some plasmatic proteins and to identify them. Fibrinogen, apolipoproteins, haptoglobin, and transthyretin changed significantly their abundance due to selenium administration. Those proteins are indirectly related to selenium metabolism. Then, the change in the proteomic profile due to selenium supplementation could probably be considered as a new index to assess the metabolic status of selenium. This index might help in the prevention of some diseases by nutritional diagnosis and, consequently, the adequate dietary recommendation.
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http://dx.doi.org/10.1093/chromsci/47.9.840DOI Listing
October 2009

Overexpression of wild-type creatine transporter (SLC6A8) restores creatine uptake in primary SLC6A8-deficient fibroblasts.

J Inherit Metab Dis 2006 Apr-Jun;29(2-3):345-6

Department of Clinical Chemistry, Metabolic Unit, VU University Medical Center, De Boelelaan 1118, 1081 HV, Amsterdam, The Netherlands.

In the study reported, we prove that mutations in the SLC6A8 gene are responsible for SLC6A8 deficiency, a cerebral creatine deficiency syndrome (CCDS), since overexpression of the wild-type SLC6A8 open reading frame (ORF) restores the creatine uptake profile in SLC6A8-deficient fibroblasts.
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http://dx.doi.org/10.1007/s10545-006-0271-6DOI Listing
January 2007

Facial translocation approach in the management of central skull base and infratemporal tumors.

Laryngoscope 2004 Jun;114(6):1047-51

Department of Otolaryngology, Hospital Universitario Central de Asturias, and the Instituto Universitario de Oncología del Principado de Asturias, Universidad de Oviedo, Oviedo, Spain.

Objectives/hypothesis: The objectives were to systematize the indications of various types of facial translocation and to present a technical modification to avoid some sequelae of this approach.

Study Design: Retrospective analysis was made of patients treated with different types of facial translocation approach to resect nasopharyngeal, infratemporal, and sinonasal tumors.

Methods: Thirty-nine patients underwent facial translocation approaches for neoplasms originally involving the nasopharynx (27) infratemporal fossa (7), and nasal cavity (5). Of the 21 malignant tumors, 2 were stage T2, 5 were stage T3, and 14 were stage T4. From the entire series of patients, 10 received a unilateral medial translocation, 3 a bilateral medial translocation, 25 a standard facial translocation, and 1 an extended medial facial translocation.

Results: Fifteen patients (38%) developed some kind of complication, such as wound infection (nine cases) and osteomyelitis and cerebrospinal fluid leak (five cases each). Two patients died as a result of postoperative complications (5.2%). Overall 5-year survival for malignant tumors was 43%. Neither the histological appearance of the tumor nor the T stage influenced the survival of patients. Survival of patients with intracranial involvement was significantly decreased compared with patients with involvement of other areas (P =.0003).

Conclusion: The facial translocation approach offers an excellent exposure in tumors with large degree of involvement of the nasopharynx, infratemporal fossa, nasal cavity, and maxillary sinus. More limited osteotomies are indicated in smaller tumors. The use of midfacial degloving minimizes the number of sequelae of these approaches.
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http://dx.doi.org/10.1097/00005537-200406000-00017DOI Listing
June 2004