Publications by authors named "Francisco Arnalich"

55 Publications

Frequency, risk factors, and outcomes of hospital readmissions of COVID-19 patients.

Sci Rep 2021 07 2;11(1):13733. Epub 2021 Jul 2.

Internal Medicine Department, 12 de Octubre University Hospital, Av. de Córdoba, s/n, 28041, Madrid, Spain.

To determine the proportion of patients with COVID-19 who were readmitted to the hospital and the most common causes and the factors associated with readmission. Multicenter nationwide cohort study in Spain. Patients included in the study were admitted to 147 hospitals from March 1 to April 30, 2020. Readmission was defined as a new hospital admission during the 30 days after discharge. Emergency department visits after discharge were not considered readmission. During the study period 8392 patients were admitted to hospitals participating in the SEMI-COVID-19 network. 298 patients (4.2%) out of 7137 patients were readmitted after being discharged. 1541 (17.7%) died during the index admission and 35 died during hospital readmission (11.7%, p = 0.007). The median time from discharge to readmission was 7 days (IQR 3-15 days). The most frequent causes of hospital readmission were worsening of previous pneumonia (54%), bacterial infection (13%), venous thromboembolism (5%), and heart failure (5%). Age [odds ratio (OR): 1.02; 95% confident interval (95% CI): 1.01-1.03], age-adjusted Charlson comorbidity index score (OR: 1.13; 95% CI: 1.06-1.21), chronic obstructive pulmonary disease (OR: 1.84; 95% CI: 1.26-2.69), asthma (OR: 1.52; 95% CI: 1.04-2.22), hemoglobin level at admission (OR: 0.92; 95% CI: 0.86-0.99), ground-glass opacification at admission (OR: 0.86; 95% CI:0.76-0.98) and glucocorticoid treatment (OR: 1.29; 95% CI: 1.00-1.66) were independently associated with hospital readmission. The rate of readmission after hospital discharge for COVID-19 was low. Advanced age and comorbidity were associated with increased risk of readmission.
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http://dx.doi.org/10.1038/s41598-021-93076-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8253752PMC
July 2021

Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor Blockers Withdrawal Is Associated with Higher Mortality in Hospitalized Patients with COVID-19.

J Clin Med 2021 Jun 15;10(12). Epub 2021 Jun 15.

Internal Medicine Department, Gregorio Marañón University Hospital, 28007 Madrid, Spain.

Our main aim was to describe the effect on the severity of ACEI (angiotensin-converting enzyme inhibitor) and ARB (angiotensin II receptor blocker) during COVID-19 hospitalization. A retrospective, observational, multicenter study evaluating hospitalized patients with COVID-19 treated with ACEI/ARB. The primary endpoint was the incidence of the composite outcome of prognosis (IMV (invasive mechanical ventilation), NIMV (non-invasive mechanical ventilation), ICU admission (intensive care unit), and/or all-cause mortality). We evaluated both outcomes in patients whose treatment with ACEI/ARB was continued or withdrawn. Between February and June 2020, 11,205 patients were included, mean age 67 years (SD = 16.3) and 43.1% female; 2162 patients received ACEI/ARB treatment. ACEI/ARB treatment showed lower all-cause mortality ( < 0.0001). Hypertensive patients in the ACEI/ARB group had better results in IMV, ICU admission, and the composite outcome of prognosis ( < 0.0001 for all). No differences were found in the incidence of major adverse cardiovascular events. Patients previously treated with ACEI/ARB continuing treatment during hospitalization had a lower incidence of the composite outcome of prognosis than those whose treatment was withdrawn (RR 0.67, 95%CI 0.63-0.76). ARB was associated with better survival than ACEI (HR 0.77, 95%CI 0.62-0.96). ACEI/ARB treatment during COVID-19 hospitalization was associated with protection on mortality. The benefits were greater in hypertensive, those who continued treatment, and those taking ARB.
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http://dx.doi.org/10.3390/jcm10122642DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8232748PMC
June 2021

The human-specific duplicated α7 gene inhibits the ancestral α7, negatively regulating nicotinic acetylcholine receptor-mediated transmitter release.

J Biol Chem 2021 Jan-Jun;296:100341. Epub 2021 Jan 28.

Department of Pharmacology and Therapeutics, Medical School, Universidad Autónoma de Madrid, Madrid, Spain. Electronic address:

Gene duplication generates new functions and traits, enabling evolution. Human-specific duplicated genes in particular are primary sources of innovation during our evolution although they have very few known functions. Here we examine the brain function of one of these genes (CHRFAM7A) and its product (dupα7 subunit). This gene results from a partial duplication of the ancestral CHRNA7 gene encoding the α7 subunit that forms the homopentameric α7 nicotinic acetylcholine receptor (α7-nAChR). The functions of α7-nAChR in the brain are well defined, including the modulation of synaptic transmission and plasticity underlying normal attention, cognition, learning, and memory processes. However, the role of the dupα7 subunit remains unexplored at the neuronal level. Here, we characterize that role by combining immunoblotting, quantitative RT-PCR and FRET techniques with functional assays of α7-nAChR activity using human neuroblastoma SH-SY5Y cell variants with different dupα7 expression levels. Our findings reveal a physical interaction between dupα7 and α7 subunits in fluorescent protein-tagged dupα7/α7 transfected cells that negatively affects normal α7-nAChR activity. Specifically, in both single cells and cell populations, the [Ca] signal and the exocytotic response induced by selective stimulation of α7-nAChR were either significantly inhibited by stable dupα7 overexpression or augmented after silencing dupα7 gene expression with specific siRNAs. These findings identify a new role for the dupα7 subunit as a negative regulator of α7-nAChR-mediated control of exocytotic neurotransmitter release. If this effect is excessive, it would result in an impaired synaptic transmission that could underlie the neurocognitive and neuropsychiatric disorders associated with α7-nAChR dysfunction.
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http://dx.doi.org/10.1016/j.jbc.2021.100341DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7949125PMC
August 2021

Vitamin C and vitamin C plus E improve the immune function in the elderly.

Exp Gerontol 2020 12 19;142:111118. Epub 2020 Oct 19.

Biochemistry Department, Hospital La Paz, Madrid, Spain.

With aging the immune response is impaired. This immunosenescence, in which an alteration of the redox state of the immune cells appears, is involved in the rate of aging. Since leukocyte function is a good marker of health and predictor of longevity, the effects of daily oral administration of the antioxidant vitamin C (500 mg), or both vitamin C (500 mg) and vitamin E (200 mg) on several blood neutrophil (adherence, chemotaxis, phagocytosis, and superoxide anion levels) and lymphocyte (adherence, chemotaxis, proliferation, interleukin-2 secretion and natural killer activity) functions were studied in healthy elderly men and women. These parameters were analysed before supplementation, after 3 months of supplementation, and 6 months after the end of supplementation. The results showed that vitamin C, in elderly participants, improved the immune functions studied which achieved values close to those of young adults. These effects were maintained in several functions after 6 months without supplementation. Similar effects were found in the elderly supplemented with both vitamin C and E. Thus, a short period of vitamin C or vitamin C and E ingestion, with the doses used, improves the immune function in elderly men and women and could contribute to a healthy longevity.
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http://dx.doi.org/10.1016/j.exger.2020.111118DOI Listing
December 2020

A Cohort of Patients with COVID-19 in a Major Teaching Hospital in Europe.

J Clin Med 2020 Jun 4;9(6). Epub 2020 Jun 4.

Internal Medicine Department, La Paz University Hospital-IdiPAZ, Universidad Autónoma de Madrid, 28046 Madrid, Spain.

Background: Since the confirmation of the first patient infected with SARS-CoV-2 in Spain in January 2020, the epidemic has grown rapidly, with the greatest impact on the region of Madrid. This article describes the first 2226 adult patients with COVID-19, consecutively admitted to La Paz University Hospital in Madrid.

Methods: Our cohort included all patients consecutively hospitalized who had a final outcome (death or discharge) in a 1286-bed hospital of Madrid (Spain) from 25 February (first case admitted) to 19 April 2020. The data were manually entered into an electronic case report form, which was monitored prior to the analysis.

Results: We consecutively included 2226 adult patients admitted to the hospital who either died (460) or were discharged (1766). The patients' median age was 61 years, and 51.8% were women. The most common comorbidity was arterial hypertension (41.3%), and the most common symptom on admission was fever (71.2%). The median time from disease onset to hospital admission was 6 days. The overall mortality was 20.7% and was higher in men (26.6% vs. 15.1%). Seventy-five patients with a final outcome were transferred to the intensive care unit (ICU) (3.4%). Most patients admitted to the ICU were men, and the median age was 64 years. Baseline laboratory values on admission were consistent with an impaired immune-inflammatory profile.

Conclusions: We provide a description of the first large cohort of hospitalized patients with COVID-19 in Europe. Advanced age, male sex, the presence of comorbidities and abnormal laboratory values were more common among the patients with fatal outcomes.
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http://dx.doi.org/10.3390/jcm9061733DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7356883PMC
June 2020

Proof-of-concept trial of the combination of lactitol with and for the eradication of intestinal OXA-48-producing .

Gut Pathog 2020 7;12:15. Epub 2020 Apr 7.

5Servicio de Medicina Interna, Hospital Universitario La Paz, Paseo de La Castellana 261, 28046 Madrid, Spain.

Background: The major reservoir of carbapenemase-producing (CPE) is the gastrointestinal tract of colonized patients. Colonization is silent and may last for months, but the risk of infection by CPE in colonized patients is significant.

Methods: Eight long-term intestinal carriers of OXA-48-producing (OXA-PE) were treated during 3 weeks with daily oral lactitol (Emportal), and (Infloran). Weekly stool samples were collected during the treatment period and 6 weeks later. The presence of OXA-PE was investigated by microbiological cultures and qPCR.

Results: At the end of treatment (EoT, secondary endpoint 1), four of the subjects had negative OXA-PE cultures. Three weeks later (secondary endpoint 2), six subjects were negative. Six weeks after the EoT (primary endpoint), three subjects had negative OXA-PE cultures. The relative intestinal load of OXA-PE decreased in all the patients during treatment.

Conclusions: The combination of prebiotics and probiotics was well tolerated. A rapid reduction on the OXA-PE intestinal loads was observed. At the EoT, decolonization was achieved in three patients. NCT02307383. EudraCT Number: 2014-000449-65.
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http://dx.doi.org/10.1186/s13099-020-00354-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7137496PMC
April 2020

Re: Microbial keratitis following intracorneal ring implantation.

Clin Exp Optom 2019 09 11;102(5):535. Epub 2019 May 11.

Department of Ophthalmology, Medical University of Innsbruck, Innsbruck, Austria.

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http://dx.doi.org/10.1111/cxo.12905DOI Listing
September 2019

Anti-tumoral activity of the human-specific duplicated form of α7-nicotinic receptor subunit in tobacco-induced lung cancer progression.

Lung Cancer 2019 02 28;128:134-144. Epub 2018 Dec 28.

Department of Pharmacology and Therapeutics, School of Medicine, Universidad Autónoma de Madrid-IdiPAZ, Madrid, Spain. Electronic address:

Objectives: Tobacco smoking is strongly correlated with the onset and progression of non-small cell lung cancer (NSCLC). By activating α7 nicotinic acetylcholine receptors (α7-nAChRs) in these tumors nicotine and its tobacco-derived nitrosamine, NNK, contribute to these oncogenic processes. Here, we investigated whether the human-specific duplicated form of the α7-nAChR subunit (dupα7) behaves as an endogenous negative regulator of α7-nAChR-mediated tumorigenic activity induced by tobacco in NSCLC cells, similarly to its influence on other α7-nAChR-controlled functions in non-tumor cells.

Methods: Two human NSCLC cell lines, lung adenocarcinoma (A549) and squamous cell carcinoma of the lung (SK-MES-1), both wild-type or with stable overexpression of dupα7 (A549 or SK-MES-1), were used to investigate in vitro anti-tumor activity of dupα7 on nicotine- or NNK-induced tumor progression. For this purpose, migration, proliferation or epithelial-mesenchymal transition (EMT) were examined. The anti-tumor effect of dupα7 on nicotine-promoted tumor growth, proliferation or angiogenesis was also assessed in vivo in an athymic mouse model implanted with A549 or A549 xenografts.

Results: Overexpression of dupα7 in both cell lines almost completely suppresses the in vitro tumor-promoting effects induced by nicotine (1 μM) or NNK (100 nM) in wild-type cells. Furthermore, in mice receiving nicotine, A549 xenografts show: (i) a significant reduction of tumor growth, and (ii) decreased expression of cell markers for proliferation (Ki67) or angiogenesis (VEGF) compared to A549 xenografts.

Conclusion: Our study demonstrates, for the first time, the in vitro and in vivo anti-tumor capacity of dupα7 to block the α7-nAChR-mediated tumorigenic effects of tobacco in NSCLC, suggesting that up-regulation of dupα7 expression in these tumors could offer a potential new therapeutic target in smoking-related cancers.
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http://dx.doi.org/10.1016/j.lungcan.2018.12.029DOI Listing
February 2019

Interaction of the α7-nicotinic subunit with its human-specific duplicated dupα7 isoform in mammalian cells: Relevance in human inflammatory responses.

J Biol Chem 2018 09 13;293(36):13874-13888. Epub 2018 Jul 13.

From the Departamento de Farmacología y Terapéutica, Facultad de Medicina and

The α7 nicotinic receptor subunit and its partially duplicated human-specific dupα7 isoform are coexpressed in neuronal and non-neuronal cells. In these cells, α7 subunits form homopentameric α7 nicotinic acetylcholine receptors (α7-nAChRs) implicated in numerous pathologies. In immune cells, α7-nAChRs are essential for vagal control of inflammatory response in sepsis. Recent studies show that the dupα7 subunit is a dominant-negative regulator of α7-nAChR activity in oocytes. However, its biological significance in mammalian cells, particularly immune cells, remains unexplored, as the duplicated form is indistinguishable from the original subunit in standard tests. Here, using immunocytochemistry, confocal microscopy, coimmunoprecipitation, FRET, flow cytometry, and ELISA, we addressed this challenge in GH4C1 rat pituitary cells and RAW264.7 murine macrophages transfected with epitope- and fluorescent protein-tagged α7 or dupα7. We used quantitative RT-PCR of α gene expression levels in peripheral blood mononuclear cells (PBMCs) from patients with sepsis to analyze its relationship with PBMC α7 mRNA levels and with serum concentrations of inflammatory markers. We found that a physical interaction between dupα7 and α7 subunits in both cell lines generates heteromeric nAChRs that remain mainly trapped in the endoplasmic reticulum. The dupα7 sequestration of α7 subunits reduced membrane expression of functional α7-nAChRs, attenuating their anti-inflammatory capacity in lipopolysaccharide-stimulated macrophages. Moreover, the PBMC's dupα7 levels correlated inversely with their α7 levels and directly with the magnitude of the patients' inflammatory state. These results indicate that dupα7 probably reduces human vagal anti-inflammatory responses and suggest its involvement in other α7-nAChR-mediated pathophysiological processes.
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http://dx.doi.org/10.1074/jbc.RA118.003443DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6130954PMC
September 2018

Impact of Nucleos(t)ide Reverse Transcriptase Inhibitors on Blood Telomere Length Changes in a Prospective Cohort of Aviremic HIV-Infected Adults.

J Infect Dis 2018 10;218(10):1531-1540

Hospital Universitario La Paz-IdiPAZ, Madrid, Spain.

Background: Tenofovir is a potent inhibitor of human telomerase. The clinical relevance of this inhibition is unknown.

Methods: A prospective cohort of human immunodeficiency virus (HIV)-infected participants with suppressed virological replication was recruited to compare whole-blood telomere length (measured by quantitative multiplex polymerase chain reaction analysis) in participants with current exposure to tenofovir disoproxil fumarate (TDF) to that in participants never exposed to TDF.

Results: A total of 172 participants were included: 67 were in the TDF group, and 105 were in the non-TDF group (75 were receiving 2 nucleosides [of whom 69 were receiving abacavir], 25 were receiving a nucleos[t]ide reverse transcriptase inhibitor [N{t}RTI]-sparing regimen, and 5 were receiving lamivudine as the only nucleoside). After 2 years, the mean blood telomere length increased significantly in the whole cohort. The TDF group had significantly smaller gains in telomere length than the non-TDF group. In the analysis restricted to participants receiving N(t)RTIs, TDF exposure was not associated with an independent negative effect. In the non-TDF group, participants treated with 2 nucleosides also had significantly smaller gains in telomere length than those receiving N(t)RTI-sparing regimens or lamivudine as the only nucleoside.

Discussion: In HIV-infected adults with prolonged virological suppression, treatment with TDF or abacavir was associated with smaller gains in blood telomere length after 2 years of follow-up.
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http://dx.doi.org/10.1093/infdis/jiy364DOI Listing
October 2018

Francisella philomiragia: Think of Chronic Granulomatous Disease.

J Clin Immunol 2018 04 16;38(3):257-259. Epub 2018 Apr 16.

Internal Medicine Department, La Paz Universitary Hospital, Madrid, Spain.

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http://dx.doi.org/10.1007/s10875-018-0498-7DOI Listing
April 2018

Expression patterns for nicotinic acetylcholine receptor subunit genes in smoking-related lung cancers.

Oncotarget 2017 Sep 4;8(40):67878-67890. Epub 2017 Jul 4.

Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid, Spain.

Cigarette smoking is associated with increased risk for all histologic types of lung cancer, but why the strength of this association is stronger for squamous cell carcinoma than adenocarcinoma of the lung (SQC-L, ADC-L) is not fully understood. Because nicotine and tobacco-specific nitrosamines contribute to carcinogenesis by activating nicotinic acetylcholine receptors (nAChRs) on lung tumors and epithelial cells, we investigated whether differential expression of nAChR subtypes in these tumors could explain their different association with smoking. Expression of nAChR subunit genes in paired tumor and non-tumor lung specimens from 40 SQC-L and 38 ADC-L patients was analyzed by quantitative PCR. Compared to normal lung, both tumors share: i) transcriptional dysregulation of (α3, α5, β4 subunits) at the chromosomal locus that predisposes to lung cancer; and ii) decreased expression of (dupα7 subunit); this last subunit negatively modulates α7-nAChR activity in oocytes. In contrast, (α7 subunit) expression was increased in SQC-L, particularly in smokers and non-survivors, while (α4 subunit) expression was decreased in ADC-L. Thus, over-representation of cancer-stimulating α7-nAChR in SQC-L, also potentiated by smoking, and under-representation of cancer-inhibiting α4β2-nAChR in ADC-L could explain the different tobacco influences on the tumorigenic process in each cancer type.
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http://dx.doi.org/10.18632/oncotarget.18948DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5620221PMC
September 2017

A System Dynamics Model to Predict the Human Monocyte Response to Endotoxins.

Front Immunol 2017 3;8:915. Epub 2017 Aug 3.

Innate Immunity Group, IdiPAZ, La Paz University Hospital, Madrid, Spain.

System dynamics is a powerful tool that allows modeling of complex and highly networked systems such as those found in the human immune system. We have developed a model that reproduces how the exposure of human monocytes to lipopolysaccharides (LPSs) induces an inflammatory state characterized by high production of tumor necrosis factor alpha (TNFα), which is rapidly modulated to enter into a tolerant state, known as endotoxin tolerance (ET). The model contains two subsystems with a total of six states, seven flows, two auxiliary variables, and 14 parameters that interact through six differential and nine algebraic equations. The parameters were estimated and optimized to obtain a model that fits the experimental data obtained from human monocytes treated with various LPS doses. In contrast to publications on other animal models, stimulation of human monocytes with super-low-dose LPSs did not alter the response to a second LPSs challenge, neither inducing ET, nor enhancing the inflammatory response. Moreover, the model confirms the low production of TNFα and increased levels of C-C motif ligand 2 when monocytes exhibit a tolerant state similar to that of patients with sepsis. At present, the model can help us better understand the ET response and might offer new insights on sepsis diagnostics and prognosis by examining the monocyte response to endotoxins in patients with sepsis.
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http://dx.doi.org/10.3389/fimmu.2017.00915DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5540970PMC
August 2017

Impact of Antiretroviral Treatment Containing Tenofovir Difumarate on the Telomere Length of Aviremic HIV-Infected Patients.

J Acquir Immune Defic Syndr 2017 09;76(1):102-109

*HIV Unit, Internal Medicine Service, Hospital Universitario La Paz-IdiPAZ, Madrid, Spain; †Microbiology Service, Hospital Universitario La Paz-IdiPAZ, Madrid, Spain; ‡Universidad de Alcalá de Henares, Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública (CIBERESP), Madrid, Spain; and §Instituto de Investigaciones Biomédicas CSIC/UAM, IdiPAZ, Biomarkers and New Therapies and CIBER de enfermedades raras (CIBERER), Madrid, Spain.

Objective: To evaluate the in vivo relevance of the inhibitory effect of tenofovir on telomerase activity observed in vitro.

Design: Cross-sectional study of HIV-infected patients with suppressed virological replication (HIV RNA <50 copies/mL for more than 1 year).

Methods: Telomere length in whole blood was measured by quantitative real-time polymerase chain reaction. We performed a multivariate analysis to elucidate variables associated with telomere length and also evaluated the association between telomere length and use of tenofovir difumarate (TDF) adjusted by significant confounders.

Results: 200 patients included, 72% men, median age 49 (IQR 45-54.5), 103 with exposure to a TDF containing antiretroviral treatment (ART) regimen (69.9% for more than 5 years) and 97 never exposed to a TDF containing ART regimen. In the multivariate analysis, significant predictors of shorter telomere length were older age (P = 0.008), parental age at birth (P = 0.038), white race (P = 0.048), and longer time of known HIV infection (10-20 and ≥20 years compared with <10 years, P = 0.003 and P = 0.056, respectively). There was no association between TDF exposure and telomere length after adjusting for possible confounding factors (age, parental age at birth, race, and time of HIV infection). Total time receiving ART and duration of treatment with nucleoside reverse transcriptase inhibitors were associated with shorter telomere length, but these associations were explained by time of known HIV infection.

Conclusions: Our data do not suggest that telomerase activity inhibition caused by TDF in vitro leads to telomere shortening in peripheral blood of HIV-infected patients.
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http://dx.doi.org/10.1097/QAI.0000000000001391DOI Listing
September 2017

Solid Platelet Rich Plasma in Corneal Surgery.

Ophthalmol Ther 2016 Jun 14;5(1):31-45. Epub 2016 May 14.

Department of Cornea and Refractive Surgery, VISSUM, Alicante, Spain.

Unlabelled: Solid eye platelet-rich plasma (E-PRP) concentrates platelets in a small volume of plasma which contains a high concentration of important growth factors and cell adhesion molecules. These cell adhesion molecules and growth factors occupy a major role in wound healing and enhance the physiological procedure at the site of the injury or the surgery. There are different materials used to tectonically maintain the solid clot attached at the site where treatment is necessary. Although AM may be used for this purpose, other biomaterials such a bovine pericardium or autologous fibrin membrane are at least as effective with less interdonor variations, no biological hazards, providing a better surgical alternative than the biologically so variable amniotic membrane patch. Solid platelet-rich plasma in the form obtained in ophthalmology, E-PRP, is a reliable and effective surgical coadjuvant to promote corneal wound healing in severe corneal ulcers and corneal perforations, and may be associated with other ocular surface reconstruction procedures.

Funding: Supported in part by a grant from the Spanish Ministry of Science and Innovation, Centro para el Desarrollo Tecnológico Industrial (CDTI), CENIT: "Customized Eye Care", CeyeC (CEN-20091021).
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http://dx.doi.org/10.1007/s40123-016-0051-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4909678PMC
June 2016

Acute respiratory distress syndrome after convalescent plasma use: treatment of a patient with Ebola virus disease contracted in Madrid, Spain.

Lancet Respir Med 2015 Jul 31;3(7):554-62. Epub 2015 May 31.

Department of Internal Medicine, La Paz-Carlos III University Hospital, IdiPAZ, Madrid, Spain. Electronic address:

Background: In the current epidemic of Ebola virus disease, health-care workers have been transferred to Europe and the USA for optimised supportive care and experimental treatments. We describe the clinical course of the first case of Ebola virus disease contracted outside of Africa, in Madrid, Spain.

Methods: Herein we report clinical, laboratory, and virological findings of the treatment of a female nurse assistant aged 44 years who was infected with Ebola virus around Sept 25-26, 2014, while caring for a Spanish missionary with confirmed Ebola virus disease who had been medically evacuated from Sierra Leone to La Paz-Carlos III University Hospital, Madrid. We also describe the use of experimental treatments for Ebola virus disease in this patient.

Findings: The patient was symptomatic for 1 week before first hospital admission on Oct 6, 2014. We used supportive treatment with intravenous fluids, broad-spectrum antibiotics, and experimental treatments with convalescent plasma from two survivors of Ebola virus disease and high-dose favipiravir. On day 10 of illness, she had acute respiratory distress syndrome, possibly caused by transfusion-related acute lung injury, which was managed without mechanical ventilation. Discharge was delayed because of the detection of viral RNA in several bodily fluids despite clearance of viraemia. The patient was discharged on day 34 of illness. At the time of discharge, the patient had possible subacute post-viral thyroiditis. None of the people who had contact with the patient before and after admission became infected with Ebola virus.

Interpretation: This report emphasises the uncertainties about the efficacy of experimental treatments for Ebola virus disease. Clinicians should be aware of the possibility of transfusion-related acute lung injury when using convalescent plasma for the treatment of Ebola virus disease.

Funding: La Paz-Carlos III University Hospital.
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http://dx.doi.org/10.1016/S2213-2600(15)00180-0DOI Listing
July 2015

Human monocytes undergo functional re-programming during sepsis mediated by hypoxia-inducible factor-1α.

Immunity 2015 Mar 3;42(3):484-98. Epub 2015 Mar 3.

Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A(∗)STAR), Biopolis, #04-06 Immunos building, 8A Biomedical Grove, Singapore 138648, Singapore. Electronic address:

Sepsis is characterized by a dysregulated inflammatory response to infection. Despite studies in mice, the cellular and molecular basis of human sepsis remains unclear and effective therapies are lacking. Blood monocytes serve as the first line of host defense and are equipped to recognize and respond to infection by triggering an immune-inflammatory response. However, the response of these cells in human sepsis and their contribution to sepsis pathogenesis is poorly understood. To investigate this, we performed a transcriptomic, functional, and mechanistic analysis of blood monocytes from patients during sepsis and after recovery. Our results revealed the functional plasticity of monocytes during human sepsis, wherein they transited from a pro-inflammatory to an immunosuppressive phenotype, while enhancing protective functions like phagocytosis, anti-microbial activity, and tissue remodeling. Mechanistically, hypoxia inducible factor-1α (HIF1α) mediated this functional re-programming of monocytes, revealing a potential mechanism for their therapeutic targeting to regulate human sepsis.
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http://dx.doi.org/10.1016/j.immuni.2015.02.001DOI Listing
March 2015

Cerebral volumes, neuronal integrity and brain inflammation measured by MRI in patients receiving PI monotherapy or triple therapy.

J Int AIDS Soc 2014 2;17(4 Suppl 3):19578. Epub 2014 Nov 2.

Internal Medicine, H.U. La Paz, Madrid, Spain.

Introduction: Penetration of protease inhibitors (PI) in the central nervous system (CNS) is limited. Therefore, there are concerns about the capacity of PI monotherapy (MT) to control HIV in CNS and preserve brain integrity.

Methods: Exploratory case-control study designed to compare neuronal integrity and brain inflammation in HIV-suppressed patients (>2 years) with and without neurocognitive impairment (NI), treated with MT or triple therapy (TT), 3-Tesla cerebral magnetic resonance image (MRI) and spectroscopy (MRS) were used to evaluate neuronal integrity (volume of cerebral structures and MRS levels of N-acetyl-aspartate (NAA)) and brain inflammation (MRS levels of myo-inositol (MI) and choline (CHO)). MRS biomarkers were measured in 4 voxels located in basal ganglia, frontal (2) and parietal lobes. A comprehensive battery of tests (14 tests - 7 domains) was used to diagnose neurocognitive impairment (1).

Results: We included 18 neurocognitively impaired patients (MT: 10, TT: 8) and 21 without NI (MT: 9; TT: 12, Table 1). Subset of patients with NI: cerebral volumes and MRS biomarkers were mostly similar between MT and TT with exception of the right cingulate nucleolus volume (MT: 8854±1851 vs TT: 10482±1107 mm(3); p<0.04), CHO levels in basal ganglia (MT: 0.44±0.05 vs TT: 0.37±0.03 MMOL/L; p<0.01) and the NAA levels in parietal lobe (MT: 1.49±0.12 vs 1.70±0.13 MMOL/L; p<0.01). Subset of patients without NI: cerebral volumes and MRS biomarkers were mostly similar between MT and TT with exception of MI levels in frontal lobe (MT: 1.20±0.36 vs 0.81±0.25 MMOL/L; p=0.01).

Conclusions: We did not find significant differences in cerebral volumes or MRS biomarkers in most areas of the brain. However, we found higher levels of inflammation and neuronal damage in some brain areas of patients who received MT. This observation has to be taken into caution while we could not adjust our results by potential confounders. Further investigation is needed to confirm these preliminary results.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4224931PMC
http://dx.doi.org/10.7448/IAS.17.4.19578DOI Listing
January 2016

A new IRAK-M-mediated mechanism implicated in the anti-inflammatory effect of nicotine via α7 nicotinic receptors in human macrophages.

PLoS One 2014 26;9(9):e108397. Epub 2014 Sep 26.

Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid, IdiPAZ, Madrid, Spain.

Nicotine stimulation of α7 nicotinic acetylcholine receptor (α7 nAChR) powerfully inhibits pro-inflammatory cytokine production in lipopolysaccharide (LPS)-stimulated macrophages and in experimental models of endotoxemia. A signaling pathway downstream from the α7 nAChRs, which involves the collaboration of JAK2/STAT3 and NF-κB to interfere with signaling by Toll-like receptors (TLRs), has been implicated in this anti-inflammatory effect of nicotine. Here, we identifiy an alternative mechanism involving interleukin-1 receptor-associated kinase M (IRAK-M), a negative regulator of innate TLR-mediated immune responses. Our data show that nicotine up-regulates IRAK-M expression at the mRNA and protein level in human macrophages, and that this effect is secondary to α7 nAChR activation. By using selective inhibitors of different signaling molecules downstream from the receptor, we provide evidence that activation of STAT3, via either JAK2 and/or PI3K, through a single (JAK2/PI3K/STAT3) or two convergent cascades (JAK2/STAT3 and PI3K/STAT3), is necessary for nicotine-induced IRAK-M expression. Moreover, down-regulation of this expression by small interfering RNAs specific to the IRAK-M gene significantly reverses the anti-inflammatory effect of nicotine on LPS-induced TNF-α production. Interestingly, macrophages pre-exposed to nicotine exhibit higher IRAK-M levels and reduced TNF-α response to an additional LPS challenge, a behavior reminiscent of the 'endotoxin tolerant' phenotype identified in monocytes either pre-exposed to LPS or from immunocompromised septic patients. Since nicotine is a major component of tobacco smoke and increased IRAK-M expression has been considered one of the molecular determinants for the induction of the tolerant phenotype, our findings showing IRAK-M overexpression could partially explain the known influence of smoking on the onset and progression of inflammatory and infectious diseases.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0108397PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4178160PMC
December 2015

NFκB2/p100 is a key factor for endotoxin tolerance in human monocytes: a demonstration using primary human monocytes from patients with sepsis.

J Immunol 2014 Oct 15;193(8):4195-202. Epub 2014 Sep 15.

Tumor Immunology Laboratory, IdiPAZ, La Paz Hospital, 28046 Madrid, Spain; Innate Immunity Group, IdiPAZ, La Paz Hospital, 28046 Madrid, Spain;

Endotoxin tolerance (ET) is a state of reduced responsiveness to endotoxin stimulation after a primary bacterial insult. This phenomenon has been described in several pathologies, including sepsis, in which an endotoxin challenge results in reduced cytokine production. In this study, we show that the NFκ L chain enhancer of activated B cells 2 (NFκB2)/p100 was overexpressed and accumulated in a well-established in vitro human monocyte model of ET. The p100 accumulation in these cells inversely correlated with the inflammatory response after LPS stimulation. Knocking down NFκB2/p100 using small interfering RNA in human monocytes further indicated that p100 expression is a crucial factor in the progression of ET. The monocytes derived from patients with sepsis had high levels of p100, and a downregulation of NFκB2/p100 in these septic monocytes reversed their ET status.
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http://dx.doi.org/10.4049/jimmunol.1400721DOI Listing
October 2014

A comparative study of neurocognitively impaired patients receiving protease inhibitor monotherapy or triple-drug antiretroviral therapy.

J Acquir Immune Defic Syndr 2014 Dec;67(4):419-23

*HIV Unit, Internal Medicine Service, Hospital Universitario La Paz, IdiPAZ, Madrid, Spain; †Microbiology Service, Hospital Universitario La Paz, IdiPAZ, Madrid, Spain; ‡Psychiatry Service, Hospital Universitario La Paz, IdiPAZ, Madrid, Spain; and §Clinical Pharmacology Service, Hospital Universitario La Paz, IdiPAZ, Madrid, Spain (Dr Lakatos is now with Department of Infectious Diseases, Saint Laszlo Teaching Hospital of Semmelweis University, Budapest, Hungary).

In a cross-sectional study of aviremic neurocognitively impaired patients receiving protease inhibitors as triple-drug therapy (n = 30) or as monotherapy (n = 22), we found no statistically significant differences in the types of cognitive domains involved or severity of cognitive deficit. Cerebrospinal fluid concentrations of total proteins, total tau, myelin basic protein, neuron-specific enolase, β2 microglobulin, S100B protein, or prevalence of cerebrospinal fluid HIV-RNA detection by standard (6.3% vs 7.1% P = 1) or ultrasensitive assays (50% vs 71.4%, P = 0.28) were similar in both groups. These results do not suggest important differences in the pattern of neurocognitive impairment between groups receiving very different antiretroviral strategies.
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http://dx.doi.org/10.1097/QAI.0000000000000337DOI Listing
December 2014

A prospective cohort study of neurocognitive function in aviremic HIV-infected patients treated with 1 or 3 antiretrovirals.

Clin Infect Dis 2014 Dec 11;59(11):1627-34. Epub 2014 Aug 11.

HIV Unit-Internal Medicine Service.

Background: The evolution of neurocognitive performance in aviremic human immunodeficiency virus (HIV)-positive patients treated with <3 antiretrovirals is unknown.

Methods: We prospectively included aviremic (≥1 year) HIV-positive patients, without concomitant major neurocognitive confounders, currently receiving boosted lopinavir or darunavir as monotherapy (n = 67) or triple antiretroviral therapy (ART) (n = 67) for ≥1 year. We evaluated neurocognitive function (7 domains) at baseline and after 1 year. We performed analysis of covariance to evaluate if 1 additional year of exposure to monotherapy compared with triple ART had an effect on Global Deficit Score (GDS) changes after adjustment for potential confounders. We also compared the evolution of neurocognitive performance and impairment rates.

Results: Intention-to-treat analysis showed that monotherapy did not influence 1-year GDS change after adjustment for significant confounders (age, ethnicity, duration of therapy, hepatitis C virus status, and HOMA-IR index); the adjusted effect was -0.04 (95% confidence interval, -.14 to .05; P = .38). Neurocognitive stability was observed with monotherapy and triple therapy (GDS crude mean change, -0.09 [95% confidence interval, -.16 to -.01] vs -0.08 [-.14 to -.02]), after 1 year of follow-up, similar proportions of patients changed neurocognitive status from impaired to unimpaired (monotherapy, 4 of 18 [22.2%]; triple therapy, 4 of 19 [21.1%]; P = .91) and vice versa (monotherapy, 5 of 44 [10.2%] and triple therapy, 3 of 45 [6.3%]; P = .48). Similar results were observed in an on-treatment analysis and with use of clinical ratings instead of GDS changes.

Conclusions: The number of antiretrovirals included in the ART regimen does not seem to influence the evolution of neurocognitive function in HIV-infected patients with suppressed plasma viremia.
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http://dx.doi.org/10.1093/cid/ciu640DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4650773PMC
December 2014

Usefulness of α7 nicotinic receptor messenger RNA levels in peripheral blood mononuclear cells as a marker for cholinergic antiinflammatory pathway activity in septic patients: results of a pilot study.

J Infect Dis 2015 Jan 4;211(1):146-55. Epub 2014 Aug 4.

Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma.

Background: Stimulation of the vagus nerve in the so-called cholinergic antiinflammatory pathway (CAP) attenuates systemic inflammation, improving survival in animal sepsis models via α7 nicotinic acetylcholine receptors on immunocompetent cells. Because the relevance of this regulatory pathway is unknown in human sepsis, this pilot study assessed whether the α7 gene expression level in septic patients' peripheral blood mononuclear cells (PBMC) might be used to assess CAP activity and clinical outcome.

Methods: The PBMCs α7 messenger RNA levels were determined by real-time quantitative reverse-transcription polymerase chain reaction in 33 controls and 33 patients at enrollment and after their hospital discharge. Data were analyzed to find significant associations between α7 level, vagally mediated heart rate variability as an indirect reflection of CAP activity, serum concentrations of different inflammation markers, and clinical course.

Results: Septic patients' α7 levels were significantly increased and returned to control values after recovery. These α7 levels correlated directly with the vagal heart input and inversely with the magnitude of the patient's inflammatory state, disease severity, and clinical outcome.

Conclusions: This study reveals that the PBMC α7 gene expression level is a clinically relevant marker for CAP activity in sepsis: the higher the α7 expression, the better the inflammation control and the prognosis.
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http://dx.doi.org/10.1093/infdis/jiu425DOI Listing
January 2015

Mitochondrial DAMPs induce endotoxin tolerance in human monocytes: an observation in patients with myocardial infarction.

PLoS One 2014 5;9(5):e95073. Epub 2014 May 5.

Tumor Immunology Lab, IdiPAZ, Hospital La Paz, Madrid, Spain; Innate Immunity Group, IdiPAZ, La Paz Hospital, Madrid, Spain.

Monocyte exposure to mitochondrial Danger Associated Molecular Patterns (DAMPs), including mitochondrial DNA (mtDNA), induces a transient state in which these cells are refractory to further endotoxin stimulation. In this context, IRAK-M up-regulation and impaired p65 activity were observed. This phenomenon, termed endotoxin tolerance (ET), is characterized by decreased production of cytokines in response to the pro-inflammatory stimulus. We also show that monocytes isolated from patients with myocardial infarction (MI) exhibited high levels of circulating mtDNA, which correlated with ET status. Moreover, a significant incidence of infection was observed in those patients with a strong tolerant phenotype. The present data extend our current understanding of the implications of endotoxin tolerance. Furthermore, our data suggest that the levels of mitochondrial antigens in plasma, such as plasma mtDNA, should be useful as a marker of increased risk of susceptibility to nosocomial infections in MI and in other pathologies involving tissue damage.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0095073PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4010397PMC
June 2015

Pattern of neurocognitive function in patients receiving boosted protease inhibitor monotherapy: a detailed neuropsychological study.

J Neurovirol 2014 Aug 24;20(4):362-70. Epub 2014 Apr 24.

HIV Unit, Internal Medicine Service, Hospital Universitario La Paz, IdiPAZ, Paseo de la Castellana 261, 28046, Madrid, Spain,

It is unknown if, compared to a triple drug antiretroviral therapy, boosted protease inhibitor monotherapy leads to worse results in specific neuropsychological processes. In our study, we included patients virologically suppressed (≥1 year), on antiretroviral therapy, without concomitant major neurocognitive confounders, receiving boosted lopinavir or darunavir as monotherapy (n = 96) or as triple therapy with two nucleoside reverse transcriptase inhibitors (n = 95). All patients underwent a comprehensive neuropsychological test battery (14 neuropsychological measures, covering seven domains). Both groups were compared in average score distributions and rates of neuropsychological deficits. Similar comparisons were conducted only for patients with neurocognitive impairment. In the adjusted analysis, we found only small differences between groups in the entire sample: better verbal learning (p = 0.02; d = 0.28) and verbal recall scores (p < 0.01; d = 0.25) in patients on boosted protease inhibitor monotherapy and slightly better motor skills with dominant hand (p = 0.02; d = 0.23) scores in patients on triple therapy. No greater proportion of deficits in the protease inhibitor monotherapy group was found in any neuropsychological measure. In neurocognitively impaired patients, we found similar outcomes in verbal learning, verbal recall, and motor skills with dominant hand but with larger effect sizes. Close similarities in the neurocognitive pattern between groups question the clinical relevance of the number of neuroactive drugs included in the regimen. These results also suggest that peripheral viral load control may be a good indicator of brain protection.
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http://dx.doi.org/10.1007/s13365-014-0251-9DOI Listing
August 2014

Biofilm vs. planktonic bacterial mode of growth: which do human macrophages prefer?

Biochem Biophys Res Commun 2013 Nov 14;441(4):947-52. Epub 2013 Nov 14.

Tumor Immunology Laboratory, IdiPAZ, La Paz Hospital, Spain.

Although the natural mode of bacterial growth in nature is as biofilm, almost all antimicrobial and immunological tests are routinely developed using planktonic inoculums. Bacterial biofilms protect the microbial community from external damage and promote the persistence of chronic infections. In this study, interactions between human macrophages and bacterial inoculums of planktonic and biofilm modes of growth have been explored using Escherichia coli (E. coli) K12. Human macrophages phagocytize planktonic E. coli more efficiently than bacteria grown in a biofilm. Moreover, they prefer to phagocytize planktonic bacteria. In this context, CD64 expression is involved. Our data indicate that bacteria with "a biofilm background" avoid phagocytosis by naïve macrophages, which could create a favorable environment for chronic infection. Our findings were corroborated in a clinical O25b-ST131 ESBL-producer E. coli isolate, which caused urinary tract infections.
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http://dx.doi.org/10.1016/j.bbrc.2013.11.012DOI Listing
November 2013

Neurocognitive impairment in patients treated with protease inhibitor monotherapy or triple drug antiretroviral therapy.

PLoS One 2013 25;8(7):e69493. Epub 2013 Jul 25.

HIV Unit-Internal Medicine Service, Hospital Universitario La Paz-IdiPAZ, Madrid, Madrid, Spain.

Background: In patients who remain virologically suppressed in plasma with triple-drug ART a switch to protease inhibitor monotherapy maintains high rates of suppression; however it is unknown if protease inhibitor monotherapy is associated to a higher rate of neurocognitive impairment.

Methods: In this observational, cross-sectional study we included patients with plasma virological suppression (≥ 1 year) without concomitant major neurocognitive confounders, currently receiving for ≥ 1 year boosted lopinavir or darunavir as monotherapy or as triple ART. Neurocognitive impairment was defined as per the 2007 consensus of the American Association of Neurology. The association between neurocognitive impairment and protease inhibitor monotherapy, adjusted by significant confounders, was analysed.

Results: Of the 191 included patients--triple therapy: 96, 1-2 years of monotherapy: 40 and >2 years of monotherapy: 55--proportions (95% CI) with neurocognitive impairment were: overall, 27.2% (20.9-33.6); triple therapy, 31.6% (22.1-41.0); short-term monotherapy, 25.0% (11.3-38.7); long-term monotherapy: 21.4% (10.5-32.3); p = 0.38. In all groups, neurocognitive impairment was mildly symptomatic or asymptomatic by self-report. There were not significant differences in Global Deficit Score by group. In the regression model confounding variables for neurocognitive impairment were years on ART, ethnicity, years of education, transmission category and the HOMA index. Adjusted by these variables the Odds Ratio (95% CI) for neurocognitive impairment of patients receiving short-term monotherapy was 0.85 (0.29-2.50) and for long-term monotherapy 0.40 (0.14-1.15).

Conclusions: Compared to triple drug antiretroviral therapy, monotherapy with lopinavir/ritonavir or darunavir/ritonavir in patients with adequate plasma suppression was not associated with a higher rate of asymptomatic neurocognitive impairment than triple drug ART.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0069493PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3723908PMC
March 2014

Plasma levels of mitochondrial and nuclear DNA in patients with massive pulmonary embolism in the emergency department: a prospective cohort study.

Crit Care 2013 May 24;17(3):R90. Epub 2013 May 24.

Introduction: Cell-free plasma mitochondrial DNA (mt-DNA) and nuclear DNA (n-DNA) are biomarkers with prognostic utility in conditions associated with a high rate of cell death. This exploratory study aimed to determine the plasma levels of both nucleic acids in patients with massive and submassive pulmonary embolism (PE) and to compare them with other biomarkers, such as heart-type fatty acid-binding protein (H-FABP) and troponin I (Tn-I) METHODS: This was a prospective observational study of 37 consecutive patients with massive PE, 37 patients with submassive PE, and 37 healthy subjects. Quantifications of plasma mt-DNA and n-DNA with real-time quantitative polymerase chain reaction (PCR), and plasma H-FABP and Tn-I by commercial assays, were done on blood samples drawn within 4 hours after presentation at the emergency department.

Results: Plasma mt-DNA and n-DNA concentrations were much higher in patients with massive PE (median, 2,970 GE/ml; interquartile range (IQR), 1,050 to 5,485; and 3,325 GE/ml, IQR: 1,080 to 5,790, respectively) than in patients with submassive PE (870 GE/ml and 1,245 GE/ml, respectively; P < 0.01) or controls (185 GE/ml and 520 GE/ml, respectively). Eighteen patients with massive PE died of a PE-related cause by day 15 of observation. Plasma mt-DNA and n-DNA values were 2.3-fold and 1.9-fold higher in the subgroup of nonsurviving patients than in survivors. H-FABP and Tn-I values were also higher in patients with massive PE who died (7.3 ng/ml and 0.023 ng/ml, respectively) than in those who survived (6.4 ng/ml, and 0.016 ng/ml, respectively). By receiver operating curve (ROC) analysis, the best cutoff values for predicting 15-day mortality were 3,380 GE/ml for mt-DNA, 6.8 ng/ml for H-FABP, 3,625 GE/ml for n-DNA, and 0.020 ng/ml for Tn-I, based on the calculated areas under the curve (AUCs) of 0.89 (95% confidence interval (CI), 0.78 to 0.99), 0.76 (95% CI, 0.69 to 093), 0.73 (95% CI, 0.58 to 0.91), and 0.59 (95% CI, 0.41 to 0.79), respectively. By stepwise logistic regression, a plasma mt-DNA concentration greater than 3,380 GE/ml (adjusted odds ratio (OR), 8.22; 95% CI, 1.72 to 39.18; P < 0.001) and a plasma value of H-FBAP >6.8 ng/ml (OR, 5.36; 95% CI, 1.06 to 27.08; P < 0.01) were the only independent predictors of mortality.

Conclusions: mt-DNA and H-FBAP might be promising markers for predicting 15-day mortality in massive PE, with mt-DNA having better prognostic accuracy.
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http://dx.doi.org/10.1186/cc12735DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3707013PMC
May 2013

Mixed Acanthamoeba and multidrug-resistant Achromobacter xyloxidans in late-onset keratitis after laser in situ keratomileusis.

J Cataract Refract Surg 2012 Oct;38(10):1853-6

Cornea Unit, Ophthalmology Department, Ramón y Cajal University Hospital, Madrid, Spain.

A 31-year-old woman developed a spontaneous flap interface keratitis in the left eye 6 years after a laser in situ keratomileusis (LASIK) enhancement. Cultures and polymerase chain reaction (PCR) were positive for Achromobacter xyloxidans resistant to first- and second-generation cephalosporin, aminoglycosides, and quinolones and also positive for Acanthamoeba T4. Treatment with topical fortified ceftazidime, topical chlorhexidine, and voriconazole and oral voriconazole did not stop the progression of the disease. Flap amputation revealed persistence of Acanthamoeba but not Achromobacter. Six weeks after flap amputation, the infiltrate had resolved, PCR was negative for Acanthamoeba, and the cornea had fully epithelialized. To our knowledge, this is the first report of post-LASIK infectious keratitis caused by mixed infection of Achromobacter xyloxidans and Acanthamoeba occurring years after the procedure without apparent ocular trauma. It is also the first report of the use of combined systemic and topical voriconazole as a therapy for Acanthamoeba keratitis after LASIK.
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http://dx.doi.org/10.1016/j.jcrs.2012.08.022DOI Listing
October 2012
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