Publications by authors named "Rafael Pérez"

55 Publications

Opportunities of super high-density olive orchard to improve soil quality: Management guidelines for application of pruning residues.

J Environ Manage 2021 Jun 5;293:112785. Epub 2021 Jun 5.

ETSIAM, University of Cordoba, Spain. Electronic address:

Applying pruning residues in the lanes of olive groves has become a popular practice because it is economical and accrues benefits for soil and water management. This study presents an analysis of the impact of different rates of pruning residue on soil properties, in particular related with soil quality. Over 4 annual campaigns, chopped pruning residues used as a mulch were analyzed in terms of composition, coverage and moisture content to evaluate their effects on the amount of soil organic carbon (-10 cm and -20 cm) and CO emissions, temperature and moisture. The experiment was carried out in a super-intensive olive orchard in Cordoba (SE, Spain) and used four amounts of fresh pruning residue: 7.5 t ha(T1), 15.0 t ha (T2) and 30.0 t ha (T3), with a control T0 = 0.0 t ha. Mulch mean leaf fraction was 46.0 ± 17.5% (±SD) and initial water content, 24.8 ± 8.6%. The mulching benefits for soil moisture were observed in amounts of pruning residue >7.5 t ha, which are only produced in super-intensive olive groves or in orchards with high tree densities. The low impact of the treatments on soil moisture was explained by the dramatic annual variations in residue moisture contents, caused by the regimes of high temperatures and rainfall-evapotranspiration deficits inherent to the Mediterranean Basin climate. Thus, the mulching capacity only resulted efficient when the residues were still humid in spring. In addition, 15.0 t ha of pruning residues was the threshold to provide significant increases in soil organic carbon at depths of 0-20 cm. Thus, accumulating pruning residue in lanes at rates of over 15 t ha (T2 and T3) is more convenient than a uniform distribution with lower amounts, due to the low mineralization rates occurring during warm seasons and the larger inputs of OM increasing the annual balance of SOC.
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http://dx.doi.org/10.1016/j.jenvman.2021.112785DOI Listing
June 2021

A high magnesium concentration in citrate dialysate prevents oxidative stress and damage in human monocytes .

Clin Kidney J 2021 May 30;14(5):1403-1411. Epub 2020 Aug 30.

Dpto de Biología de Sistemas, Universidad de Alcalá, Alcalá de Henares, Madrid, Spain.

Background: The use of dialysis fluids (DFs) during haemodialysis has been associated with increased oxidative stress and reduced serum magnesium (Mg) levels, contributing to chronic inflammation. Since the role of Mg in modulating immune function and reducing oxidative stress has been demonstrated, the aim of this study was to characterize whether increasing the Mg concentration in DFs could protect immune cells from oxidative stress and damage.

Methods: The effect of citrate [citrate dialysis fluid (CDF), 1 mM] or acetate [acetate dialysis fluid (ADF), 3 mM] dialysates with low (0.5 mM; routinely used) or high (1 mM, 1.25 mM and 2 mM) Mg concentrations was assessed in THP-1 human monocytes. The levels of reactive oxygen species (ROS), malondialdehyde (MDA) and oxidized/reduced (GSSG/GSH) glutathione were quantified under basal and inflammatory conditions (stimulation with lipopolysaccharide, LPS).

Results: The increase of Mg in CDF resulted in a significant reduction of ROS production under basal and inflammatory conditions (extremely marked in 2 mM Mg; P 0.001). These effects were not observed in ADF. Interestingly, in a dose-dependent manner, high Mg doses in CDF reduced oxidative stress in monocytes under both basal and inflammatory conditions. In fact, 2 mM Mg significantly decreased the levels of GSH, GSSG and MDA and the GSSG/GSH ratio in relation to 0.5 mM Mg.

Conclusions: CDF produces lower oxidative stress than ADF. The increase of Mg content in DFs, especially in CDF, could have a positive and protective effect in reducing oxidative stress and damage in immune cells, especially under inflammatory conditions.
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http://dx.doi.org/10.1093/ckj/sfaa131DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8087128PMC
May 2021

On Race and the Environment in the COVID-19 Pandemic.

Am J Med Sci 2020 10 13;360(4):327-328. Epub 2020 Jul 13.

Jane & Leonard Korman Respiratory Institute, Thomas Jefferson University, Philadelphia, PA, United States.

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http://dx.doi.org/10.1016/j.amjms.2020.07.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7357512PMC
October 2020

The Coronavirus Pandemic - At the Beginning of the Learning Curve.

Am J Med Sci 2020 08 3;360(2):105-106. Epub 2020 Jun 3.

Jane & Leonard Korman Respiratory Institute, Thomas Jefferson University, Philadelphia, Pennsylvania. Electronic address:

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http://dx.doi.org/10.1016/j.amjms.2020.06.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7832918PMC
August 2020

Conducting Clinical Research in the Era of Covid-19.

Am J Med Sci 2020 09 10;360(3):213-215. Epub 2020 Jun 10.

Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, Philadelphia, Pennsylvania; Jane & Leonard Korman Respiratory Institute, Thomas Jefferson University, Philadelphia, Pennsylvania. Electronic address:

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http://dx.doi.org/10.1016/j.amjms.2020.06.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7283065PMC
September 2020

Sex-Based Differences in Interstitial Lung Disease.

Am J Med Sci 2020 11 25;360(5):467-473. Epub 2020 Apr 25.

Department of Medicine, Division of Pulmonary, Allergy and Critical Care, Sidney Kimmel College of Medicine; Jane & Leonard Korman Respiratory Institute, Jefferson Health, Thomas Jefferson University, 834 Walnut St, Philadelphia, PA 19107 USA. Electronic address:

Interstitial lung diseases comprise a family of progressive pulmonary disorders that are often idiopathic or associated with various systemic diseases and that is characterized by bilateral lung involvement with inflammation and tissue remodeling or fibrosis. The impact of sex, including the anatomic and physiologic traits that one is born with, on the development and progression of interstitial lung diseases is not entirely clear. Variances between men and women are driven by differences in male and female biology and sex hormones, among other differences, but their role remains uncertain. In this review, we summarize sex-related differences in the epidemiology and progression of certain interstitial lung diseases with a focus on the connective tissue related interstitial lung diseases, idiopathic pulmonary fibrosis, and sarcoidosis. We also discuss cellular and pre-clinical studies that might shed light on the potential mechanisms responsible for these differences in the hope of unveiling potential targets for intervention and stimulating research in this needed field of investigation.
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http://dx.doi.org/10.1016/j.amjms.2020.04.023DOI Listing
November 2020

Increasing the Magnesium Concentration in Various Dialysate Solutions Differentially Modulates Oxidative Stress in a Human Monocyte Cell Line.

Antioxidants (Basel) 2020 Apr 15;9(4). Epub 2020 Apr 15.

Departamento de Biología de Sistemas, Universidad de Alcalá, 28871 Alcalá de Henares, Madrid, Spain.

Oxidative stress is exacerbated in hemodialysis patients by several factors, including the uremic environment and the use of dialysis fluids (DFs) Since magnesium (Mg) plays a key role in modulating immune function and in reducing oxidative stress, we aimed to evaluate whether increasing the Mg concentration in different DFs could protect against oxidative stress in immunocompetent cells in vitro. Effect of ADF (acetate 3 mM), CDF (citrate 1 mM), and ACDF (citrate 0.8 mM + acetate 0.3 mM) dialysates with Mg at standard (0.5 mM) or higher (1, 1.25, and 2 mM) concentrations were assessed in THP-1 monocyte cultures. Reactive oxygen species (ROS) and malondialdehyde (MDA) levels were quantified under basal and uremic conditions (indoxyl sulfate (IS) treatment). Under uremic conditions, the three DFs with 0.5 mM Mg promoted higher ROS production and lipid damage than the control solution. However, CDF and ACDF induced lower levels of ROS and MDA, compared to that induced by ADF. High Mg concentration (1.25 and/or 2 mM) in CDF and ACDF protected against oxidative stress, indicated by reduced ROS and MDA levels compared to respective DFs with standard concentration of Mg. Increasing Mg concentrations in ADF promoted high ROS production and MDA content. Thus, an increase in Mg content in DFs has differential effects on the oxidative stress in IS-treated THP-1 cells depending on the dialysate used.
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http://dx.doi.org/10.3390/antiox9040319DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7222382PMC
April 2020

α-adrenergic heteroreceptors are required for stress-induced reinstatement of cocaine conditioned place preference.

Neuropsychopharmacology 2020 08 19;45(9):1473-1481. Epub 2020 Feb 19.

Vanderbilt Center for Addiction Research, Vanderbilt University School of Medicine, Basic Sciences, Nashville, TN, United States.

The α-adrenergic receptor (α-AR) agonist guanfacine has been investigated as a potential treatment for substance use disorders. While decreasing stress-induced reinstatement of cocaine seeking in animal models and stress-induced craving in human studies, guanfacine has not been reported to decrease relapse rates. Although guanfacine engages α-AR autoreceptors, it also activates excitatory G-coupled heteroreceptors in the bed nucleus of the stria terminalis (BNST), a key brain region in driving stress-induced relapse. Thus, BNST α-AR heteroreceptor signaling might decrease the beneficial efficacy of guanfacine. We aimed to determine the role of α-AR heteroreceptors and BNST G-GPCR signaling in stress-induced reinstatement of cocaine conditioned place preference (CPP) and the effects of low dose guanfacine on BNST activity and stress-induced reinstatement. We used a genetic deletion strategy and the cocaine CPP procedure to first define the contributions of α-AR heteroreceptors to stress-induced reinstatement. Next, we mimicked BNST G-coupled α-AR heteroreceptor signaling using a G-coupled designer receptor exclusively activated by designer drug (G-DREADD) approach. Finally, we evaluated the effects of low-dose guanfacine on BNST cFOS immunoreactivity and stress-induced reinstatement. We show that α-AR heteroreceptor deletion disrupts stress-induced reinstatement and that BNST G-DREADD activation is sufficient to induce reinstatement. Importantly, we found that low-dose guanfacine does not increase BNST activity, but prevents stress-induced reinstatement. Our findings demonstrate a role for α-AR heteroreceptors and BNST G-GPCR signaling in stress-induced reinstatement of cocaine CPP and provide insight into the impact of dose on the efficacy of guanfacine as a treatment for stress-induced relapse of cocaine use.
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http://dx.doi.org/10.1038/s41386-020-0641-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7360592PMC
August 2020

Pamrevlumab, an anti-connective tissue growth factor therapy, for idiopathic pulmonary fibrosis (PRAISE): a phase 2, randomised, double-blind, placebo-controlled trial.

Lancet Respir Med 2020 01 28;8(1):25-33. Epub 2019 Sep 28.

University of Washington Medical Center, Seattle, WA, USA.

Background: Connective tissue growth factor (CTGF) is a secreted glycoprotein that has a central role in the process of fibrosis. This study was designed to assess the safety, tolerability, and efficacy of pamrevlumab (FG-3019), a fully recombinant human monoclonal antibody against CTGF, in idiopathic pulmonary fibrosis. The aim was to establish whether pamrevlumab could slow, stop, or reverse progression of idiopathic pulmonary fibrosis.

Methods: The phase 2, randomised, double-blind, placebo-controlled PRAISE trial was done at 39 medical centres in seven countries (Australia, Bulgaria, Canada, India, New Zealand, South Africa, and the USA). Patients with idiopathic pulmonary fibrosis and percentage of predicted forced vital capacity (FVC) of 55% or greater were enrolled and randomly assigned (1:1) by use of interactive responsive technology to intravenous infusion of pamrevlumab 30 mg/kg or placebo every 3 weeks over 48 weeks (16 infusions). The primary efficacy outcome was change from baseline in percentage of predicted FVC at week 48. Disease progression (defined as a decline from baseline in percentage of predicted FVC of ≥10%, or death) at week 48 was a key secondary efficacy outcome. All patients in the pamrevlumab group received at least one dose of the study drug and were analysed for safety. Two patients in the placebo group were excluded from the intention-to-treat population for the efficacy analyses because of enrolment error. This trial is registered with ClinicalTrials.gov, NCT01890265.

Findings: Between Aug 17, 2013, and July 21, 2017, 103 patients were randomly assigned (50 to pamrevlumab and 53 to placebo). Pamrevlumab reduced the decline in percentage of predicted FVC by 60·3% at week 48 (mean change from baseline -2·9% with pamrevlumab vs -7·2% with placebo; between-group difference 4·3% [95% CI 0·4-8·3]; p=0·033). The proportion of patients with disease progression was lower in the pamrevlumab group than in the placebo group at week 48 (10·0% vs 31·4%; p=0·013). Pamrevlumab was well tolerated, with a safety profile similar to that of placebo. Treatment-emergent serious adverse events were observed in 12 (24%) patients in the pamrevlumab group and eight (15%) in the placebo group, with three patients on pamrevlumab and seven on placebo discontinuing treatment. Of the three (6%) deaths in the pamrevlumab group and six (11%) in the placebo group, none was considered treatment related.

Interpretation: Pamrevlumab attenuated progression of idiopathic pulmonary fibrosis and was well tolerated. Now in phase 3 development, pamrevlumab shows promise as a novel, safe, and effective treatment for idiopathic pulmonary fibrosis.

Funding: FibroGen.
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http://dx.doi.org/10.1016/S2213-2600(19)30262-0DOI Listing
January 2020

Granulomatous Inflammation and the Lymphatic System-Perhaps a New Target for Intervention in Tuberculosis and Sarcoidosis.

Bioessays 2019 11 23;41(11):e1900167. Epub 2019 Sep 23.

Department of Medicine, Division of Pulmonary, Allergy & Critical Care Medicine, and Jane and Leonard Korman Respiratory Institute, Thomas Jefferson University, Philadelphia, PA, 19107, USA.

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http://dx.doi.org/10.1002/bies.201900167DOI Listing
November 2019

Diagnostic Accuracy of CYFRA21-1 in the Differential Diagnosis of Pleural Effusions.

Anticancer Res 2019 Sep;39(9):5071-5076

Department Internal Medicine, Althaia Xarxa Assistencial Universitària de Manresa, Manresa, Spain.

Background/aim: Approximately 20% of pleural effusions are associated with cancer; about 50% require invasive procedures to perform diagnosis. Determination of the concentration of soluble cytokeratin 19-fragments (CYFRA21-1) may help identify patients with malignant effusions. However, pathologies other than cancer can increase its concentration. The identification of these possible false positives with routine tests CRP, ADA, % polymorphonuclear cells (PN) may improve diagnostic accuracy. This study aimed to determine the diagnostic accuracy of CYFRA21-1 in the detection of malignant pleural effusions and the possible false positives.

Materials And Methods: Analysis of CYFRA21-1, adenosine deaminase (ADA), C-reactive protein (CRP), and the percentage of polymorphonuclear leukocytes (PN%) in the fluid from 643 consecutive undiagnosed pleural effusions was performed.

Results: CYFRA21-1 showed 38.7% sensitivity and 97.3% specificity at 175 ng/ml cut-off. Effusions not suspicious of a false-positive showed 39.0% sensitivity and 98.2% specificity, while effusions suspicious of false positive showed lower sensitivity (36.4%) and specificity (95.0%).

Conclusion: The diagnostic accuracy of CYFRA21-1 in pleural effusions can be improved by classification according to the possibility of false positives.
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http://dx.doi.org/10.21873/anticanres.13700DOI Listing
September 2019

Immunogenicity and Safety of the Adjuvanted Recombinant Zoster Vaccine in Chronically Immunosuppressed Adults Following Renal Transplant: A Phase 3, Randomized Clinical Trial.

Clin Infect Dis 2020 01;70(2):181-190

GSK, Wavre, Belgium.

Background: The incidence of herpes zoster is up to 9 times higher in immunosuppressed solid organ transplant recipients than in the general population. We investigated the immunogenicity and safety of an adjuvanted recombinant zoster vaccine (RZV) in renal transplant (RT) recipients ≥18 years of age receiving daily immunosuppressive therapy.

Methods: In this phase 3, randomized (1:1), observer-blind, multicenter trial, RT recipients were enrolled and received 2 doses of RZV or placebo 1-2 months (M) apart 4-18M posttransplant. Anti-glycoprotein E (gE) antibody concentrations, gE-specific CD4 T-cell frequencies, and vaccine response rates were assessed at 1M post-dose 1, and 1M and 12M post-dose 2. Solicited and unsolicited adverse events (AEs) were recorded for 7 and 30 days after each dose, respectively. Solicited general symptoms and unsolicited AEs were also collected 7 days before first vaccination. Serious AEs (including biopsy-proven allograft rejections) and potential immune-mediated diseases (pIMDs) were recorded up to 12M post-dose 2.

Results: Two hundred sixty-four participants (RZV: 132; placebo: 132) were enrolled between March 2014 and April 2017. gE-specific humoral and cell-mediated immune responses were higher in RZV than placebo recipients across postvaccination time points and persisted above prevaccination baseline 12M post-dose 2. Local AEs were reported more frequently by RZV than placebo recipients. Overall occurrences of renal function changes, rejections, unsolicited AEs, serious AEs, and pIMDs were similar between groups.

Conclusions: RZV was immunogenic in chronically immunosuppressed RT recipients. Immunogenicity persisted through 12M postvaccination. No safety concerns arose.

Clinical Trials Registration: NCT02058589.
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http://dx.doi.org/10.1093/cid/ciz177DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6938982PMC
January 2020

Dorsal BNST α-Adrenergic Receptors Produce HCN-Dependent Excitatory Actions That Initiate Anxiogenic Behaviors.

J Neurosci 2018 10 27;38(42):8922-8942. Epub 2018 Aug 27.

Vanderbilt Center for Addiction Research,

Stress is a precipitating agent in neuropsychiatric disease and initiates relapse to drug-seeking behavior in addicted patients. Targeting the stress system in protracted abstinence from drugs of abuse with anxiolytics may be an effective treatment modality for substance use disorders. α-adrenergic receptors (α-ARs) in extended amygdala structures play key roles in dampening stress responses. Contrary to early thinking, α-ARs are expressed at non-noradrenergic sites in the brain. These non-noradrenergic α-ARs play important roles in stress responses, but their cellular mechanisms of action are unclear. In humans, the α-AR agonist guanfacine reduces overall craving and uncouples craving from stress, yet minimally affects relapse, potentially due to competing actions in the brain. Here, we show that heteroceptor α-ARs postsynaptically enhance dorsal bed nucleus of the stria terminalis (dBNST) neuronal activity in mice of both sexes. This effect is mediated by hyperpolarization-activated cyclic nucleotide-gated cation channels because inhibition of these channels is necessary and sufficient for excitatory actions. Finally, this excitatory action is mimicked by clozapine--oxide activation of the G-coupled DREADD hM4Di in dBNST neurons and its activation elicits anxiety-like behavior in the elevated plus maze. Together, these data provide a framework for elucidating cell-specific actions of GPCR signaling and provide a potential mechanism whereby competing anxiogenic and anxiolytic actions of guanfacine may affect its clinical utility in the treatment of addiction. Stress affects the development of neuropsychiatric disorders including anxiety and addiction. Guanfacine is an α2A-adrenergic receptor (α2A-AR) agonist with actions in the bed nucleus of the stria terminalis (BNST) that produces antidepressant actions and uncouples stress from reward-related behaviors. Here, we show that guanfacine increases dorsal BNST neuronal activity through actions at postsynaptic α2A-ARs via a mechanism that involves hyperpolarization-activated cyclic nucleotide gated cation channels. This action is mimicked by activation of the designer receptor hM4Di expressed in the BNST, which also induces anxiety-like behaviors. Together, these data suggest that postsynaptic α2A-ARs in BNST have excitatory actions on BNST neurons and that these actions can be phenocopied by the so-called "inhibitory" DREADDs, suggesting that care must be taken regarding interpretation of data obtained with these tools.
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http://dx.doi.org/10.1523/JNEUROSCI.0963-18.2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6191524PMC
October 2018

Oxygen-dependent laser inactivation of murine norovirus using visible light lasers.

Virol J 2018 07 31;15(1):117. Epub 2018 Jul 31.

Center for Advanced Studies in Photonics Research, University of Maryland Baltimore County, Baltimore, USA.

Background: Previous work indicated that an ultrashort pulse (USP) 425 nm laser is capable of inactivating murine norovirus (MNV: Virol. J. 11:20), perhaps via an impulsive stimulated Raman scattering (ISRS) mechanism, and does not substantially damage human plasma proteins (PLOS One 9:11). Here, further investigation of virus inactivation by laser light is performed.

Methods: In this study, we evaluate whether inactivation of MNV is specific to the USP wavelength of 425 nm, or if it occurs at other visible wavelengths, using a tunable mode-locked Ti-Sapphire laser that has been frequency doubled to generate femtosecond pulses at wavelengths of 400, 408, 425, 450, 465, and 510 nm. Continuous Wave (CW) lasers are also applied. Singlet oxygen enhancers are used to evaluate the sensitivity of MNV to singlet oxygen and oxygen quenchers are used to evaluate effects on virus inactivation as compared to untreated controls.

Results: > 3 log inactivation of MNV pfu occurs after irradiation with an average power of 150 mW at wavelengths of 408, 425 or 450 nm femtosecond-pulsed light for 3 h. Thus results suggest that the mechanism by which a laser inactivates the virus is not wavelength-specific. Furthermore, we also show that irradiation using a continuous wave (CW) laser of similar power at 408 nm also yields substantial MNV inactivation indicating that inactivation does not require a USP. Use of photosensitizers, riboflavin, rose bengal and methylene blue that generate singlet oxygen substantially improves the efficiency of the inactivation. The results indicate a photochemical mechanism of the laser-induced inactivation where the action of relatively low power blue laser light generates singlet oxygen.

Conclusion: Results suggest formation of short-lived reactive oxygen species such as singlet oxygen by visible laser light as the cause of virus inactivation rather than via an ISRS mechanism which induces resonant vibrations.
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http://dx.doi.org/10.1186/s12985-018-1019-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6069788PMC
July 2018

A 54-Year-Old Man With Anasarca, Dyspnea, and Recurrent Bilateral Pleural Effusions.

Chest 2017 08;152(2):e39-e44

Norton Thoracic Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ. Electronic address:

Case Presentation: A 54-year-old African-American man presented with 2 years of progressively worsening dyspnea and anasarca. Over the past 6 months he gained 30 lbs with worsening lower extremity, abdominal wall, and scrotal edema. A recent workup for cardiac, renal, and liver disease, including two-dimensional echocardiogram, liver and renal function tests, and abdominal ultrasound, was unremarkable. He reported a 15-pack year history of smoking and quit 3 years ago. Chest radiograph at that time revealed bilateral pleural effusions that were both reportedly milky in appearance when drained by thoracenteses.
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http://dx.doi.org/10.1016/j.chest.2017.03.018DOI Listing
August 2017

Scleroderma-related interstitial lung disease.

Respir Med Case Rep 2017 15;22:109-112. Epub 2017 Jul 15.

Department of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, University of Louisville Health Sciences Center, Louisville, KY, USA.

Scleroderma-related interstitial lung disease (SSc-ILD) is a pulmonary fibrosing disorder characterized by systemic inflammation and progressive scarring of the lungs that leads to respiratory failure. Although certain immunosuppressive therapies may slow disease progression, current treatment strategies are not curative; consequently, SSc-ILD continues to be a major cause of morbidity and mortality. We present four cases of SSc-ILD that emphasize the importance of early screening and detection, close follow-up, and aggressive management. We also highlight the need for well-conducted clinical trials designed to identify new and effective treatments.
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http://dx.doi.org/10.1016/j.rmcr.2017.07.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5524221PMC
July 2017

Evaluation of two strategies for the interpretation of tumour markers in pleural effusions.

Respir Res 2017 05 25;18(1):103. Epub 2017 May 25.

Department Internal Medicine, Althaia Xarxa Assistencial Universitària de Manresa, Manresa, Catalonia, Spain.

Background: Pleural effusions present a diagnostic challenge. Approximately 20% are associated with cancer and some 50% require invasive procedures to perform diagnosis. Determination of tumour markers may help to identify patients with malignant effusions. Two strategies are used to obtain high specificity in the differential diagnosis of malignant pleural effusions: a) high cut-off, and b) fluid/serum (F/S) ratio and low cut-off. The aim of this study is to compare these two strategies and to establish whether the identification of possible false positives using benign biomarkers - ADA, CRP and % of polymorphonuclear cells - improves diagnostic accuracy.

Methods: We studied 402 pleural effusions, 122 of them malignant. Benign biomarkers were determined in pleural fluid, and CEA, CA72-4, CA19-9 and CA15-3 in pleural fluid and serum.

Results: Establishing a cut-off value for each TM for a specificity of 100%, a joint sensitivity of 66.5% was obtained. With the F/S strategy and low cut-off points, sensitivity was 77% and specificity 98.2%, Subclassifying cases with negative benign biomarkers, both strategies achieved a specificity of 100%; sensitivity was 69.9% for single determination and 80.6% for F/S ratio.

Conclusions: The best interpretation of TM in the differential diagnosis of malignant pleural effusions is obtained using the F/S ratio in the group with negative benign biomarkers.
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http://dx.doi.org/10.1186/s12931-017-0582-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5445332PMC
May 2017

Magnitude of Treatment Abandonment in Childhood Cancer.

PLoS One 2015 30;10(9):e0135230. Epub 2015 Sep 30.

Department of Medical Oncology, Max Healthcare, New Delhi, India.

Background: Treatment abandonment (TxA) is recognized as a leading cause of treatment failure for children with cancer in low-and-middle-income countries (LMC). However, its global frequency and burden have remained elusive due to lack of global data. This study aimed to obtain an estimate using survey and population data.

Methods: Childhood cancer clinicians (medical oncologists, surgeons, and radiation therapists), nurses, social workers, and psychologists involved in care of children with cancer were approached through an online survey February-May 2012. Incidence and population data were obtained from public sources. Descriptive, univariable, and multivariable analyses were conducted.

Results: 602 responses from 101 countries were obtained from physicians (84%), practicing pediatric hematology/oncology (83%) in general or children's hospitals (79%). Results suggested, 23,854 (15%) of 155,088 children <15 years old newly diagnosed with cancer annually in the countries analyzed, abandon therapy. Importantly, 83% of new childhood cancer cases and 99% of TxA were attributable to LMC. The annual number of cases of TxA expected in LMC worldwide (26,166) was nearly equivalent to the annual number of cancer cases in children <15 years expected in HIC (26,368). Approximately two thirds of LMC had median TxA ≥ 6%, but TxA ≥ 6% was reported in high- (9%), upper-middle- (41%), lower-middle- (80%), and low-income countries (90%, p<0.001). Most LMC centers reporting TxA > 6% were outside the capital. Lower national income category, higher reliance on out-of-pocket payments, and high prevalence of economic hardship at the center were independent contextual predictors for TxA ≥ 6% (p<0.001). Global survival data available for more developed and less developed regions suggests TxA may account for at least a third of the survival gap between HIC and LMC.

Conclusion: Results show TxA is prevalent (compromising cancer survival for 1 in 7 children globally), confirm the suspected high burden of TxA in LMC, and illustrate the negative impact of poverty on its occurrence. The present estimates may appear small compared to the global burden of child death from malnutrition and infection (measured in millions). However, absolute numbers suggest the burden of TxA in LMC is nearly equivalent to annually losing all kids diagnosed with cancer in HIC just to TxA, without even considering deaths from disease progression, relapse or toxicity-the main causes of childhood cancer mortality in HIC. Results document the importance of monitoring and addressing TxA as part of childhood cancer outcomes in at-risk settings.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0135230PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4589240PMC
June 2016

Clinical utility of determining tumor markers in patients with signs and symptoms of cancer.

Clin Chem Lab Med 2015 Feb;53(3):485-91

Background: Diagnosing patients with signs or symptoms suggestive of cancer is difficult. Serum tumor markers (TM) may be useful, but it is known that a range of pathologies other than cancer can increase their concentrations and so TM data must be interpreted with caution. The aim of this study is to determine the diagnostic accuracy of TMs in patients with signs or symptoms of cancer.

Methods: We prospectively studied 234 patients seen at rapid diagnostic units who presented signs or symptoms suggestive of cancer. Ninety patients had wasting syndrome, 74 had pulmonary symptoms and 70 other presentations. CYFRA21-1, CEA, CA19-9, total bilirubin and creatinine were determined. The final diagnosis was obtained after 6 months' follow-up. Patients were classified according to the absence (group A) or presence (group B) of abnormal bilirubin or creatinine.

Results: Of the 234 patients studied, 103 (44.0%) had tumors diagnosed. Cut-off points for each TM were calculated for a specificity of 100%. For the total group, the values were CYFRA21-1, 15 μg/L, CEA, 43.8 μg/L and CA19-9, 7428 KU/L, with an overall sensitivity of 46.6%. For group A (n=142), the following cut-off points were established: CYFRA21-1, 7.8 μg/L, CEA, 13.8 μg/L and CA19-9, 101 KU/L, obtaining a sensitivity of 68.6%. For group B (n=92), the values were the same as for the whole group, and a sensitivity of 42.4% was achieved.

Conclusions: We conclude that TMs can aid diagnosis in these patients with signs or symptoms suggestive of cancer. Their sensitivity can be improved by using different cut-off points in the presence and absence of renal and hepatic dysfunction.
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http://dx.doi.org/10.1515/cclm-2014-0410DOI Listing
February 2015

Pulmonary necrobiotic nodules in Crohn's disease: a rare extra-intestinal manifestation.

Respir Care 2014 Dec 15;59(12):e190-2. Epub 2014 Jul 15.

Department of Pulmonary, Critical Care, and Sleep Disorders Medicine.

Pulmonary necrobiotic nodules represent a rare extra-intestinal manifestation of Crohn's disease. Histologically, they are composed of sterile aggregates of inflammatory cells with necrosis. The differential diagnosis is broad, and exclusion of infectious etiologies is mandatory before starting immunosuppressive therapy. Here, we present the fifth reported case of pulmonary necrobiotic nodules in Crohn's disease. Our patient had new-onset Crohn's disease associated with both cavitating and non-cavitating lung nodules that were confirmed to be necrobiotic nodules by biopsy. The patient was started on mesalamine and prednisone, with subsequent improvement of his gastrointestinal symptoms and regression of the necrobiotic nodules.
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http://dx.doi.org/10.4187/respcare.03176DOI Listing
December 2014

Neurological picture. Acute appearance of a carotid pseudoaneurysm during coughing.

J Neurol Neurosurg Psychiatry 2015 Jan 15;86(1):120. Epub 2014 Jul 15.

Virgen del Rocío University Hospital, Seville, Andalusia, Spain.

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http://dx.doi.org/10.1136/jnnp-2014-308412DOI Listing
January 2015

Mounier-Kuhn syndrome. Imaging and bronchoscopic findings.

Am J Respir Crit Care Med 2014 Jul;190(1):e2-3

Department of Pulmonary, Critical Care and Sleep Disorders Medicine, University of Louisville, Louisville, Kentucky.

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http://dx.doi.org/10.1164/rccm.201307-1306IMDOI Listing
July 2014

A 63-year-old man with a chronic cough and an endobronchial lesion. Diagnosis: Endobronchial hamartoma.

Chest 2014 Apr;145(4):919-922

Department of Pulmonary, Critical Care, and Sleep Disorders Medicine, University of Louisville, Louisville, KY.

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http://dx.doi.org/10.1378/chest.13-1965DOI Listing
April 2014

Castleman's disease and primary effusion lymphoma in a HIV-positive patient.

Int J STD AIDS 2014 May 28;25(6):455-7. Epub 2013 Nov 28.

Department of Medicine, Division of General Internal Medicine, Palliative Medicine, and Medical Education, University of Louisville, Louisville, KY, USA.

We present a case of primary effusion lymphoma (PEL) occurring simultaneously with Castleman's disease in the same patient. Castleman's disease is distinct from PEL, although both are associated with HHV-8. Other cases have debated whether the coexistence of PEL and Castleman's disease is a recurrence of an original PEL tumour in an extracavitary site, or a secondary HHV-8-associated lymphoma distinct from primary PEL. Our case, along with those described previously, show that co-occurrence of PEL and Castleman's disease is possible and plausible. PEL needs to be included in the differential diagnosis in any HIV-positive patient who presents with a pleural effusion, and diagnosis requires only a simple thoracentesis and appropriate immunohistochemistry.
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http://dx.doi.org/10.1177/0956462413512805DOI Listing
May 2014

Left bundle branch block in atrial fibrillation patients without heart failure.

Int J Cardiol 2013 Oct 3;168(6):5460-2. Epub 2013 Aug 3.

Servizo de Cardioloxía, Complexo Hospitalario Universitario de Santiago de Compostela (CHUS), SERGAS, Santiago de Compostela, Spain. Electronic address:

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http://dx.doi.org/10.1016/j.ijcard.2013.07.250DOI Listing
October 2013

Rheological blood behavior is not only influenced by cardiovascular risk factors but also by aging itself. Research into 927 healthy Spanish Mediterranean subjects.

Clin Hemorheol Microcirc 2013 Jan;54(3):287-96

Hemorheology and Haemostasis Unit, Service of Clinical Pathology, La Fe University Hospital, Valencia, Spain.

It is not well-established whether the alterations that the hemorheological profile undergoes with aging are an effect of concomitant cardiovascular risk factors or are due to age itself. To clarify this issue, we investigated the effect of age on blood rheology in a population of 927 healthy subjects from eastern Spain aged between 16-85 years, divided into four age groups (<30, 30-44, 45-50, ≥60 years) with and without cardiovascular risk factors. We determined blood viscosity, corrected blood viscosity (BVc), plasma viscosity (PV), erythrocyte aggregation (EA), erythrocyte deformability (EEI60) and fibrinogen, along with glucose and plasma lipids. We found that corrected blood viscosity (p = 0.007), plasma viscosity, erythrocyte aggregation, fibrinogen, glucose, and plasma lipids increased with age (p < 0.001). When subjects with cardiovascular risk factors were excluded, the effect of age on blood rheology persisted for all the cited parameters (p < 0.028). EEI60 increased with age (p = 0.033), and it was attributable to a concomitant increase in mean corpuscular volume (p < 0.001). In the Pearson's correlations, age was related to all the parameters analyzed (P < 0.019). The logistic regression analysis revealed that PV ≥1.30 mPa·s, BVc ≥4.90 mPa·s and EA1 ≥8.3 were associated with age ≥60 years (*p = 0.049, *p = 0.013, *p = 0.045, respectively). These results indicate that, although the presence of cardiovascular risk factors influences rheological properties, aging itself is associated with deterioration of rheological blood behavior, mostly related to inflammatory and lipidic changes.
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http://dx.doi.org/10.3233/CH-131734DOI Listing
January 2013

Pulmonary IgG4+ Rosai-Dorfman disease.

BMJ Case Rep 2013 Apr 10;2013. Epub 2013 Apr 10.

Department of Pulmonary, Critical Care & Sleep Medicine, University of Louisville, Pulmonary, Louisville, Kentucky, USA.

Rosai-Dorfman disease (RDD) is a rare non-malignant proliferation of histiocytes of unknown aetiology that mainly affects lymph nodes. Here we report a case of RDD that presented a diagnostic dilemma due to its atypical presentation and the overlap with IgG4 disease. Our case presented with interstitial lung involvement without lymphadenopathy. Open lung biopsy suggested the diagnosis of RDD. However, the predominant IgG4 positive plasma cells together with the absence of lymphadenopathy were not typical of RDD. Within 1 year, the patient developed diffuse lymphadenopathy and immunohistochemical staining of lymph node aspirates confirmed the diagnosis. Despite trials of corticosteroid therapy, the disease progressed.
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http://dx.doi.org/10.1136/bcr-2012-008324DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3644931PMC
April 2013

Comparison of immune peripheral blood cells in tuberculin reactor cattle that are seropositive or seronegative for Mycobacterium bovis antigens.

Vet Immunol Immunopathol 2013 Jun 15;153(3-4):194-201. Epub 2013 Mar 15.

Facultad de Medicina Veterinaria y Zootecnia, Universidad Nacional Autónoma de México, Circuito exterior, Ciudad Universitaria, C.P. 04510, D.F., Mexico.

Bovine tuberculosis (bTB) is a major economic problem in animal husbandry and is a public health risk in nonindustrialized countries. It is generally accepted that protection against TB is generated through cell-mediated immunity. Previous investigations have shown that WC1(+) γδ, CD4(+) and CD8(+) T-cell subpopulations are important in the immune response to bTB. It is known that changes in the immune balance from a dominant T helper 1 (Th1)-type response toward a more prominent Th2 response may be observed during disease progression. In this study, we aimed to investigate immune peripheral blood cells in tuberculin reactor cattle that are seropositive or seronegative for Mycobacterium bovis antigens, using flow cytometry and hematological analysis. The evaluation of the T cell subpopulations revealed a decrease in CD8(+) T cells of the seropositive and seronegative animals compared with the control animals (p=0.0001). Moreover, the seropositive group exhibited a lower percentage of CD8(+) T cells than the seronegative group. The percentage of B cells was significantly increased in the seropositive group compared with the seronegative group and the control group (p=0.0009). No difference was observed in the percentage of WC1(+) γδ and CD4(+) T cells among the groups. Furthermore, following 24h of peripheral blood culture with bovine purified protein derivative (PPD), both apparently infected groups showed an increase in the levels of cellular activation compared with the control group (p<0.0001). The seropositive group displayed a higher level of cellular activation than the seronegative group. In both apparently infected groups, the hematological analysis showed an increase in total leukocyte (p=0.0012), lymphocyte (p=0.0057), monocyte (p=0.0010) and neutrophil (p=0.0320) counts in comparison with the healthy animals. Our results demonstrated differences in immune peripheral blood cells of tuberculin reactor cattle that are seropositive or seronegative for M. bovis antigens, probably due to different stages of bTB among the groups. The percentages of CD8(+) T cells, B cells and the T cell activation levels may represent biomarkers for the progression of the disease. However, general characteristics shared by both apparently infected groups as lymphocytosis and monocytosis may also be indicative of the disease. Further experiments are required to understand the variations between cellular and humoral immunities throughout the course of bTB infection. A detailed knowledge of the peripheral blood cells involved in all stages of the bTB immune response of naturally infected cattle is essential for the optimal exploitation of diagnosis and vaccination models.
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http://dx.doi.org/10.1016/j.vetimm.2013.02.016DOI Listing
June 2013

Smoking-related interstitial fibrosis (SRIF) and pulmonary hypertension.

BMJ Case Rep 2013 Mar 11;2013. Epub 2013 Mar 11.

Department of Pulmonary, Critical Care & Sleep Medicine, University of Louisville, Louisville, Kentucky, USA.

Smoking-related interstitial fibrosis (SRIF) is a relatively new term used to describe chronic interstitial fibrosis that can develop in smokers. The association of SRIF with pulmonary hypertension has not been described. We present a 55-year-old man with an extensive smoking history who presented for evaluation of insidious onset of dyspnoea on exertion and hypoxaemic respiratory failure. Physical examination was unremarkable. Pulmonary function testing demonstrated a marked reduction of the diffusion capacity with no obstruction or restriction. Ventilation perfusion scan showed no evidence of thromboembolic disease. High-resolution chest CT revealed minimal biapical pleural parenchymal scarring and subtle dependent atelectasis. Serological markers for connective tissue diseases were negative. Open lung biopsy was consistent with SRIF. Vascular intimal proliferation consistent with pulmonary hypertension was also noted. Right heart catheterisation yielded mild pulmonary hypertension and treatment was initiated with tadalafil and bosentan.
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http://dx.doi.org/10.1136/bcr-2013-008970DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3618800PMC
March 2013