To cite this article: Isidoro‐García M, Sanz C, García‐Solaesa V, Pascual M, Pescador DB, Lorente F, Dávila I. PTGDR gene in asthma: a functional, genetic, and epigenetic study. Allergy 2011; 66: ...1553–1562.
Background: Asthma affects more than 300 million individuals in the world. Several studies have demonstrated the importance of the genetic component. The aim of this study is to develop a holistic approach, including genetic, epigenetic, and expression analysis to study the Prostaglandin D2 receptor gene (PTGDR) in asthmatic patients.
Methods: In this study, 637 Caucasian individuals were included. Genetic variants were characterized by sequencing, and haplotype and diplotype combinations were established. Electrophoretic mobility shift assays (EMSAs) were performed with different promoter variants. An epigenetic analysis of PTGDR was for the first time developed by MassArray assays, and gene expression was determined by real‐time polymerase chain reaction.
Results: The −197T>C (Fisher’s P = 0.028) and −613C>T (Fisher’s P < 0.001) polymorphisms were found to be significantly associated with allergic asthma and allergy to pollen and mites, respectively. In addition, several haplotype and diplotype combinations were associated with different allergy and asthma phenotypes. The presence of the −613C>T SNP determined variations in the EMSAs. Moreover, consistent differences in the methylation and expression patterns were observed between asthmatic patients and controls determining a 2.34‐fold increase of PTGDR gene expression in asthmatic patients.
Conclusions: Genetic combinations described have functional implications in the PTGDR promoter activity by changing the transcription factors affinity that will help characterize different risk groups. The differences observed in the transcription factors affinity and in the methylation pattern bring insight into different transcription regulation in these patients. To the best of our knowledge, this is the first work in which the implication of genetic and epigenetic factors of PTGDR has been characterized pointing to putative therapeutic targets.
Background
Secondary hyperparathyroidism (SHPT) is a matter of concern after biliopancreatic diversion (BPD). The aim of this study was to investigate the relationship between SHPT, 25(OH)D, and ...calcium after BPD.
Design
A retrospective analysis in obese patients after BPD performed between 1998 and 2016.
Methods
Patients with at least 1 year of follow-up were included. SHPT was considered when PTH > 65 pg/mL in the absence of an elevated corrected calcium. 25(OH)D (ng/mL) status was defined as: deficiency < 20, insufficiency 20–29.9, and sufficiency ≥ 30.
Results
In total, 321 patients were included (76.6% women), with mean age 43.0 (10.5) years. Median follow-up was 6.0 (IQR 3.0–9.0) years. Mean body mass index was 49.8 (7.0) kg/m
2
. SHPT increased to a maximum of 81.9% in the ninth year of follow-up (95% CI: 1.5–9.1). Two years after surgery, 33.9% of patients with 25(OH)D sufficiency had SHPT (
p
= 0.001). Corrected calcium levels were lower in patients with PTH > 65 pg/mL when compared with PTH < 65 pg/mL; 1 year: 8.96 vs 9.1 mg/dL and 5 years: 8.75 vs 9.12 mg/dL (
p
< 0.01). After surgery, patients with PTH > 65 pg/mL and 25(OH)D sufficiency had lower corrected calcium levels when compared with subjects with PTH and 25(OH)D in normal range. Two years: 9.0 vs 9.2 mg/dL (
p
< 0.05) and 4 years: 8.9 vs 9.2 mg/dL (
p
< 0.01).
Conclusions
Once 25(OH)D is sufficient, the increase in PTH persists associated with a decrease in serum corrected calcium. It is important to ensure a sufficient calcium intake in these patients in order to avoid SHPT and osteomalacia in the future.
Bariatric surgery (BS) is an effective treatment. However, there have been concerns regarding the negative effect on the bone. The aim of this study was to assess changes in bone metabolism and the ...risk of fracture after biliopancreatic diversion (BPD).
A retrospective analysis of obese patients undergoing BPD between 1998 and 2017 was conducted, and patients with at least 1 year of follow-up were included. The incidence of fracture and of changes in bone metabolism was studied.
In total, 216 patients were included (78.2% female), with a mean age of 42.5(10.6) years. The median follow-up was 6.8(IQR 10.2-3.2) years. The mean body mass index (BMI) was 49.7(6.3) kg/m
. 13.2% (n=29) suffered a bone fracture after surgery; the time until the first fracture was 7.9(3.8) years (55.2% secondary to a casual fall). The rate of fracture incidence was 19.6 per 1000 person-years (95%CI: 1.3-2.7), prevalence was 13.4% (95%CI: 8.9-18.0). The risk of bone fractures seems to increase with longer postoperative evolution time. PTH (pg/ml) levels were significantly higher in patients with fractures (1 year, 98.1 vs. 77.8; 5 years, 162.5 vs. 110.3 p<0.05, adjusted HR 1.10; 95%CI 1.01-1.11). Subjects with a higher %EWL had less risk of fractures after surgery (adjusted HR 0.97; 95%CI 0.94-0.99). Moreover, 25(OH)D levels were lower, and osteocalcin and β-Crosslaps levels were slightly higher (not significant) in patients with fractures.
BPD is related to important changes in bone metabolism, which can lead to an increased risk of bone fractures. Assessing the risk of fractures should be part of BS patient care.
Genetic association study in nasal polyposis Benito Pescador, D; Isidoro-García, M; García-Solaesa, V ...
Journal of investigational allergology & clinical immunology,
2012, Letnik:
22, Številka:
5
Journal Article
Recenzirano
Nasal polyposis (NP) is a chronic inflammatory disease of the upper airways with a variable clinical course and unknown pathogenesis that often coexists with other conditions. Considering the ...possibility of genetic predisposition, we decided to analyze whether polymorphisms in LTC4S, CYSLTR1, PTGDR, and NOS2A were associated with NP.
The study population comprised 486 Caucasian individuals. Polyposis and aspirin intolerance were diagnosed following the recommendations of the European Position Paper on Rhinosinusitis and Nasal Polyps. Genotypes were determined using polymerase chain reaction amplification and direct sequencing.
The -444A > C LTC4S polymorphism was significantly associated with NP and atopy (P = .033) and with NP and atopic asthma, (P =.012). In addition, a significant association was found when the (CCTTT) repetition of the NOS2A gene was present more than 14 times in patients with NP and asthma (P = .034), in patients with polyposis and intolerance to nonsteroidal anti-inflammatory drugs (P = .009), and in patients with the aspirin triad (P = .005). The PTGDR diplotype CCCT/CCCC (-613CC, -549CC, -441CC and -197TC) was more frequent in patients with NP (P = .043), NP with asthma (P = .013), and the aspirin triad (P = .041).
NP was associated with specific polymorphisms only when it occurred with related phenotypes. Our results suggest that this genetic background plays a more relevant role in the development of the associated clinical features of nasal polyposis than in simple polyposis.
Palliative Sedation at Home: A Scoping Review Garcia, Ana Cláudia M.; Isidoro, Geovanna M.; Paiva, Eliza Mara D. C. ...
American journal of hospice & palliative medicine,
02/2023, Letnik:
40, Številka:
2
Journal Article
Recenzirano
Palliative Sedation (PS) is an effective measure for the relief of refractory symptoms in end-of-life patients. This intervention can be performed at home, respecting the patients' and their ...families' decisions. A scoping review was performed to map the available evidence in the literature on the performance of PS at home. This review included 23 studies. Most were conducted in European countries with adult cancer patients. Patients, family members and healthcare providers participated in the decision making regarding the use of PS at home. PS was used primarily to manage refractory symptoms (pain, delirium, dyspnea, and others), and in 1 of the studies PS was mentioned as a possible intervention for shortening life. The most commonly used medication was midazolam and the average duration ranged from 4 h to 7 days. There are few reports on adverse events related to PS. This intervention seems to be a feasible possibility for the management of refractory symptoms in patients at the end of life, despite the fact that it can represent specific challenges for healthcare providers, patients and families. However, the literature is limited regarding PS in children and in people with diseases other than cancer, as well as on the evaluation of possible adverse effects related to this intervention. Furthermore, it is essential to have a broad ethical, clinical and legal debate on whether to consider the use of PS for the purpose of shortening life in specific cases.
Exposure of fertilized eggs of the sea urchin Paracentrotus lividus to an electromagnetic field of 75-Hz frequency and low amplitudes (from 0.75 to 2.20 mT of magnetic component) leads to a dramatic ...loss of synchronization of the first cell cycle, with formation of anomalous embryos linked to irregular separation of chromatids during the mitotic events. Because acetylcholinesterase (ACHE) is thought to regulate the embryonic first developmental events of the sea urchin, its enzymatic activity was assayed in embryo homogenates and decreased by 48% when the homogenates were exposed to the same pulsed field. This enzymatic inactivation had a threshold of about 0.75 ± 0.01 mT. The same field threshold was found for the effect on the formation of anomalous embryos of P. lividus. Moreover, ACHE inhibitors seem to induce the same teratological effects as those caused by the field, while blockers of acetylcholine (ACh) receptors are able to antagonize those effects. We conclude that one of the main causes of these dramatic effects on the early development of the sea urchin by field exposure could be the accumulation of ACh due to ACHE inactivation. The crucial role of the membrane in determining the conditions for enzyme inactivation is discussed.
The presence of complex karotypes with frequent numerical and structural abnormalities has been reported in 20 to 50% of multiple myeloma (MM) patients. This variability is mainly due to the ...difficulty of conventional cytogenetics to obtain tumor metaphases representative of all possible neoplastic clones in MM. To gain insight into the real incidence of numerical chromosome changes in MM we have studied by fluorescence in situ hybridization technique 15 different human chromosomes, 1, 3, 6, 7, 8, 9, 10, 11, 12, 13, 15, 17, 18, X, and Y, in a series of 52 MM patients. In all cases, the DNA index assessed by a propidium iodide/CD38 double-staining technique with flow cytometry was simultaneously investigated for correlation, with fluorescence in situ hybridization results. Additional aims of this study were 1) to analyze whether the abnormalities detected were common to all plasma cells or were present in only a subpopulation of tumor cells, 2) to explore changes caused by disease progression, and 3) to establish possible associations among the altered chromosomes. Although the overall incidence of numerical abnormalities was 67%, this frequency increased to 80% in the 41 cases in which 7 or more chromosomes were analyzed. Trisomies were significantly more common than monosomies (84% versus 16%). Chromosomes 9 and 15 were the most frequently altered (52% and 48% of cases, respectively), with all of their abnormalities corresponding to trisomies. The most frequent losses involved chromosomes 13 (26%) and X in females (32%). Other common numerical changes corresponded to chromosomes 1 (39%), 11 (37%), 6 (32%), 3 (31%), 18 (29%), 7 (28%), and 17 (22%). By contrast, chromosomes 8(13%), 10(8%), and 12(3%) were rarely altered. DNA aneuploidy by flow cytometry was detected in 67% of patients, and a high degree of correlation was observed between the DNA index obtained by flow cytometry and the chromosome index derived from fluorescence in situ hybridization studies, calculated according to two mathematical formulas (coefficient of correlation of 0.82 and 0.91 when at least 7 or 12 chromosomes were considered, respectively). The frequency of numeric chromosome aberrations was higher in those patients with progressive disease and, interestingly, trisomy of chromosome 8 was exclusively detected in this latter group of patients. Our study shows that, with the exception of chromosome 8, a possible marker of clonal evolution, the numeric chromosome changes are present in nearly all malignant plasma cells (r > 0.84). Finally, frequent associations between chromosomal aberrations were observed (ie, chromosomes 6, 7, 9, and 17; 7 and 15; and 11 and 17). By excluding them, it was found that two triple combinations of chromosome-specific probes, chromosomes 1 and 9 together with either chromosome 13 or 15, could be a useful marker for detection of residual disease, as it permits the identification of most MM patients displaying numerical changes.
Abstract Background Allergy and autoimmunity are important immunological entities underlying chronic diseases in children. In some cases both entities develop simultaneously in the same patient. ...FOXP3 gene codes for a transcription factor involved in regulation of the immune system. Considering that regulatory T cells are involved in controlling immunological disease development, and the relevant role of FOXP3 in this kind of T cells, the objective of this study was to analyse the FOXP3 gene in the most prevalent autoimmune diseases and/or allergies in childhood in a European population. Methods A total of 255 Caucasian individuals, 95 controls and 160 patients diagnosed with allergic, autoimmune or both diseases were included in this study. The molecular analysis of FOXP3 was performed by DNA sequencing following the recommendations for quality of the European Molecular Genetics Quality Network. Genomic DNA was extracted from peripheral blood of all participants and was amplified using the polymerase chain reaction. After the visualisation of the amplified fragments by agarose gel-electrophoresis, they were sequenced. Results Thirteen different polymorphisms in FOXP3 gene were found, seven of which had not been previously described. The mutated allele of SNP 7340C>T was observed more frequently in the group of male children suffering from both allergic and autoimmune diseases simultaneously ( p = 0.004, OR = 16.2 1.34–195.15). Conclusions In this study we identified for first time genetic variants of FOXP3 that are significantly more frequent in children who share allergic and autoimmune diseases. These variants mainly affect regulatory sequences that could alter the expression levels of FOXP3 modifying its function including its role in Treg cells.
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