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1.
Zhongguo Zhen Jiu ; 43(12): 1384-1389, 2023 Dec 12.
Artículo en Inglés, Chino | MEDLINE | ID: mdl-38092536

RESUMEN

OBJECTIVES: To observe the clinical efficacy of moxibustion as an adjunctive treatment for rheumatoid arthritis (RA) based on conventional medication and its effects on serum sclerostin (SOST) and ß-catenin levels, exploring the potential mechanisms by which moxibustion may protect joint bones in RA patients. METHODS: Seventy-six RA patients were randomly divided into an observation group (38 cases, 3 cases dropped out) and a control group (38 cases, 4 cases were eliminated, 2 cases dropped out). The patients in the control group were treated with conventional oral medication; based on the treatment of the control group, the patients in the observation group were treated with moxibustion. The direct moxibustion was applied at Zusanli (ST 36) on both sides and ashi points around small joints, and indirect moxibustion was applied at Shenshu (BL 23) on both sides and ashi points around large joints. The treatment was given three times a week for a total of 5 weeks. The count of pain and swollen joint, morning stiffness score, disease activity score of 28 joints (DAS28), visual analogue scale (VAS) score, health assessment questionnaire (HAQ) score, and serum levels of SOST, ß-catenin, and tumor necrosis factor-α (TNF-α) were evaluated before and after treatment in the two groups. RESULTS: Compared those before treatment, after treatment, both groups showed a reduction in pain and swollen joint count (P<0.01, P<0.05), morning stiffness, DAS28, VAS, and HAQ scores (P<0.01, P<0.05), with the observation group having lower scores than the control group (P<0.01). Serum levels of SOST, ß-catenin, and TNF-α after treatment in the observation group were lower than those in both before treatment and the control group (P<0.01, P<0.05). There was a positive correlation between the difference in serum ß-catenin levels before and after treatment and the difference in serum SOST (r=0.578, P<0.001) and TNF-α (r=0.403, P<0.05) levels in the observation group. CONCLUSIONS: In addition to medication, moxibustion as an adjunctive treatment could significantly alleviate joint pain and reduce disease activity in RA patients, suggesting a potential role in joint protection. This mechanism may be related to the inhibition of the inflammatory factor TNF-α, regulation of ß-catenin levels, and reduction in the production of the endogenous negative regulator protein SOST within the Wnt/ß-catenin signaling pathway.


Asunto(s)
Artritis Reumatoide , Moxibustión , Humanos , Factor de Necrosis Tumoral alfa , beta Catenina , Puntos de Acupuntura , Artritis Reumatoide/terapia , Artralgia , Proteínas Adaptadoras Transductoras de Señales
2.
Front Pediatr ; 11: 1224113, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37492606

RESUMEN

Objective: The aim of this study was to evaluate the clinical efficacy of single-incision laparoscopy appendectomy (SILA) and traditional three-hole laparoscopy appendectomy (THLA) for the treatment of acute appendicitis in children. Methods: The clinical data of children (<14 years old) who underwent laparoscopic appendectomy at Yijishan Hospital of Wannan Medical College, Hubei Provincial Maternal Health Hospital and Qingdao Women and Children's Medical Center from January 2019 to June 2022 were retrospectively analyzed. According to the operation method, the patients were assigned to the SILA group or the THLA group. The clinical data, including the efficacy, and the surgical details, including the complications, of the two surgical methods were compared. The personal information of the children and the time of disease onset were recorded. Results: In this study, the data of 588 patients, including 385 patients in the THLA group and 203 patients in the SILA group were collected. The baseline characteristics between the two groups of patients before surgery were comparable. There was no significant difference in the average operation time between the THLA group and the SILA group (56.31 ± 1.83 min vs. 57.48 ± 1.15 min, P > 0.05). There was also no significant difference in the average length of hospital stay between the THLA group and the SILA group (6.91 ± 0.24 days vs. 7.16 ± 0.36 days, P > 0.05). However, the FLACC scores of the SILA group (3.71 ± 0.78) were significantly lower than those of the THLA group (3.99 ± 0.56) on the second postoperative day, and the difference was significant (P < 0.05). The score of the questionnaire evaluating cosmetic appearance of the postoperative abdomen was significantly higher in the SILA group (15.81 ± 0.36) than in the THLA group (13.10 ± 0.24) (P < 0.05). There was no significant difference in the incidence of postoperative complications between the two groups (P > 0.05). Conclusion: SILA is more advantageous in terms of postoperative FLACC scores and cosmetic appearance in children than THLA. There was no significant difference in the incidence of complications or other aspects between the two surgical methods.

3.
Zhen Ci Yan Jiu ; 48(5): 488-93, 2023 May 25.
Artículo en Chino | MEDLINE | ID: mdl-37247863

RESUMEN

OBJECTIVE: To observe the effects of moxibustion on the contents of leukotriene B4 (LTB4), interleukin-17 (IL-17), tumor necrosis factor-α (TNF-α) and matrix metalloproteinase -9 (MMP-9) in serum, and explore the protection mechanisms of moxibustion in the patients with rheumatoid arthritis (RA). METHODS: A total of 64 patients with RA were randomly divided into treatment group (n=31) and control group (n=33). The patients in the control group were treated with conventional medication for consecutive 5 weeks. Based on the treatment in the control group, the patients in the treatment group were treated with moxibustion at bilateral Shenshu (BL23), Zusanli (ST36) and Ashi points, 3 times a week, for consecutive 5 weeks. Separately, the visual analogue scale (VAS) score, morning stiffness score, the number of tender joints, the number of swollen joints, the score of the disease activity score of 28 joints (DAS28) were observed; the contents of rheumatoid factor (RF), erythrocyte sedimentation rate (ESR) and C-reative protein (CRP) in serum were determined by biochemical method; and the contents of LTB4, IL-17, TNF-α and MMP-9 in serum were detected by using ELISA before and after treatment in the patients of both groups. RESULTS: After treatment, VAS score, morning stiffness score, the number of tender joints, the number of swollen joints, DAS28 score, the contents of serum RF in both groups, and contents of serum CRP, ESR, LTB4, IL-17, TNF-α and MMP-9 in the treatment group were significantly reduced when compared with those before treatment (P<0.01, P<0.05). After treatment, VAS score, morning stiffness score, the number of tender joints, the number of swollen joints, DAS28 score, and the levels of LTB4, IL-17 and MMP-9 in serum were obviously lower in the treatment group when compared with the control group (P<0.01, P<0.05). In the treatment group, the changes before and after treatment in the levels of LTB4, IL-17 and TNF-α were positively correlated with that of MMP-9 (P<0.05, r>0). CONCLUSION: Moxibustion at BL23 and ST36 combined with conventional medication significantly relieves joint pain and reduce disease activity in RA patients, which may be related to the modulation of LTB4, IL-17 and MMP-9 by moxibustion.


Asunto(s)
Artritis Reumatoide , Moxibustión , Humanos , Leucotrieno B4 , Interleucina-17/genética , Factor de Necrosis Tumoral alfa/genética , Metaloproteinasa 9 de la Matriz/genética , Artritis Reumatoide/genética , Artritis Reumatoide/terapia
4.
CNS Neurosci Ther ; 29(7): 1965-1980, 2023 07.
Artículo en Inglés | MEDLINE | ID: mdl-36890655

RESUMEN

BACKGROUND: The analgesic effect of acupuncture is widely recognized, but the mechanical characteristics of acupuncture for pain relief, compared to non-steroidal anti-inflammatory (NSAIDs) and placebo medication, remain unknown. AIMS: To compare the modulation effects of acupuncture treatment with NSAIDs and placebo medication on descending pain modulation system (DPMS) in knee osteoarthritis (KOA) patients. METHODS: This study recruited 180 KOA patients with knee pain and 41 healthy controls (HCs). Individuals with KOA knee pain were divided randomly into groups of verum acupuncture (VA), sham acupuncture (SA), celecoxib (SC), placebo (PB), and waiting list (WT), with 36 patients in each group. VA and SA groups included ten sessions of puncturing acupoints or puncturing non-acupoints acupuncture treatment for two successive weeks. Celecoxib capsules were continuously given orally to patients in the SC group at a dosage of 200 mg daily for 2 weeks. In the PB group, patients received a placebo capsule once a day for 2 weeks at the same dosage as celecoxib capsules. In the WL group, patients did not receive any treatment. Patients underwent a resting-state BOLD-fMRI scan pre- and post-receiving the therapy, whereas HCs only underwent a baseline scan. Seed (ventrolateral periaqueductal gray, vlPAG, a key node in DPMS) based resting-state functional connectivity (rs-FC) was applied in the data analysis. RESULTS: All groups demonstrated improved knee pain scores relative to the initial state. There was no statistical difference between the VA and SA groups in all clinical outcomes, and vlPAG rs-FC alterations. KOA knee pain individuals reported higher vlPAG rs-FC in the bilateral thalamus than HCs. KOA knee pain patients in the acupuncture group (verum + sham, AG) exhibited increased vlPAG rs-FC with the right dorsolateral prefrontal cortex (DLPFC) and the right angular, which is associated with knee pain improvement. In contrast with the SC and PB group, the AG exhibited significantly increased vlPAG rs-FC with the right DLPFC and angular. Contrary to the WT group, the AG showed greater vlPAG rs-FC with the right DLPFC and precuneus. CONCLUSIONS: Acupuncture treatment, celecoxib, and placebo medication have different modulation effects on vlPAG DPMS in KOA knee pain patients. Acupuncture could modulate vlPAG rs-FC with brain regions associated with cognitive control, attention, and reappraisal for knee pain relief in KOA patients, compared with celecoxib and placebo medication.


Asunto(s)
Terapia por Acupuntura , Osteoartritis de la Rodilla , Humanos , Osteoartritis de la Rodilla/diagnóstico por imagen , Osteoartritis de la Rodilla/tratamiento farmacológico , Sustancia Gris Periacueductal/diagnóstico por imagen , Celecoxib/farmacología , Celecoxib/uso terapéutico , Cápsulas , Dolor/complicaciones , Antiinflamatorios no Esteroideos/farmacología , Antiinflamatorios no Esteroideos/uso terapéutico , Imagen por Resonancia Magnética
5.
Zhongguo Zhen Jiu ; 42(11): 1221-5, 2022 Nov 12.
Artículo en Chino | MEDLINE | ID: mdl-36397218

RESUMEN

OBJECTIVE: To observe the clinical efficacy of moxibustion on rheumatoid arthritis (RA) and its effect on related negative emotions, and to explore the possible mechanism. METHODS: A total of 70 patients with RA were randomized into an observation group (35 cases, 1 case dropped off) and a control group (35 cases, 2 cases dropped off). Conventional western medication therapy was adopted in the control group. On the basis of the treatment in the control group, moxibustion at Zusanli (ST 36), Shenshu (BL 23) and ashi points was adopted in the observation group, once every other day, 3 times a week, and totally 5-week treatment was required in the two groups. Before and after treatment, the scores of visual analogue scale (VAS), morning stiffness, 28-joint disease activity score (DAS28), self-rating anxiety scale (SAS) and self-rating depression scale (SDS) were observed and levels of serum 5-hydroxytryptamine (5-HT), glucocorticoid receptor (GR) and interleukin (IL)-1ß were detected by ELISA method in the two groups respectively. RESULTS: Compared before treatment, the scores of VAS and DAS28 were decreased after treatment in both groups (P<0.01, P<0.05), and the scores of morning stiffness, SAS, SDS and the serum levels of 5-HT, GR, IL-1ß were decreased after treatment in the observation group (P<0.01). After treatment, the scores of VAS, morning stiffness, DAS28, SAS, SDS and the serum levels of GR, IL-1ß in the observation group were lower than those in the control group (P<0.05, P<0.01). The clinical symptoms of RA (scores of VAS, morning stiffness and DAS28) were positively correlated with negative emotions (scores of SAS and SDS, r=0.439, P<0.01), the VAS score was positively correlated with serum levels of 5-HT (r=0.189, P<0.05) and IL-1ß (r=0.189, P<0.05). CONCLUSION: Moxibustion can improve the clinical symptoms and negative emotions in patients with RA by regulating the inflammatory reactions.


Asunto(s)
Artritis Reumatoide , Moxibustión , Humanos , Moxibustión/métodos , Serotonina , Artritis Reumatoide/terapia , Puntos de Acupuntura , Emociones
6.
Front Neurol ; 13: 953921, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-36299271

RESUMEN

Introduction: Acupuncture is an effective and safe therapy for patients with migraine without aura (MwoA), but only 41-59% of patients show improvement with this treatment. Screening positive responders to acupuncture treatment for MwoA can ensure that healthcare resources can be appropriately targeted to specific patients who would most benefit. The objective of this study is to determine whether the structure and functional activity in certain brain regions can predict analgesia response in patients with MwoA who receive acupuncture treatment. Methods and analysis: A total of 72 patients with MwoA and 72 healthy controls (HCs) will be enrolled in this study. Resting-state structural and functional magnetic resonance imaging (MRI) data will be collected from each participant at baseline. Patients with MwoA will undergo 12 sessions of acupuncture treatment for 8 weeks, twice per week in the first 4 weeks and once per week for the last 4 weeks. The follow-up will be 12 weeks. The number of days with migraine, frequency of migraine attacks, and average visual analog scale scores will be recorded in detail at weeks 0, 4, 8, 12, and 16 and at the end of follow-up (week 20). The positive response rate will be calculated as the proportion of patients with ≥50% reduction in the number of migraine days during follow-up compared with baseline. Machine learning methods will be applied to classify patients with MwoA and HCs and predict patients with response or non-response to acupuncture treatment based on multimodal MRI parameters, such as gray matter volume, regional homogeneity, amplitude of low-frequency fluctuation, fractional anisotropy, and mean diffusivity. Discussion: This study aims to establish brain structural and functional characteristics that can identify patients with MwoA who will derive analgesia benefits from acupuncture treatment. Trial registration number: http://www.chictr.org.cn/showproj.aspx?proj=65443, identifier: ChiCTR2100042915.

7.
Pain Res Manag ; 2021: 7466313, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34691317

RESUMEN

OBJECTIVE: This study aims to evaluate the efficacy of moxibustion on joint swelling and pain and the levels of C-X-C motif chemokine ligand 1 (CXCL1), ß-endorphin (ß-EP) in serum of rheumatoid arthritis (RA) patients and to investigate the anti-inflammatory and analgesic mechanism of moxibustion on improving RA. METHODS: Sixty-eight patients with RA were randomly and equally classified into the control and treatment groups. The control group was treated with routine drug therapy, while the treatment group received routine drug therapy and moxibustion. Both groups were treated for eight weeks. The symptoms and laboratory indicators of RA patients were compared in the two groups before and after intervention. RESULTS: Sixty-one patients completed the study: four patients dropped out from the treatment group and three from the control group. Trial endpoints were change (∆) in symptoms, measured by Ritchie's articular index (RAI), swollen joint count (SJC), and laboratory indicators, measured by the level of CXCL1, ß-EP, tumor necrosis factor-a (TNF-α), and interleukin-1ß (IL-1ß). ∆RAI, ∆SJC, ∆CXCL1, ∆ß-EP, ∆TNF-α, and ∆IL-1ß in the treatment group were superior to the control group (13.50 [14.50] versus 6.00 [13.00] in ∆RAI, 4.00 [3.00] versus 2.00 [4.00] in ∆SJC, 0.04 ± 0.79 ng/mL versus -0.01 ± 0.86 ng/mL in ∆CXCL1, -2.43 [5.52] pg/mg versus -0.04 [4.09] pg/mg in ∆ß-EP, 3.45 [5.90] pg/mL versus 1.55 [8.29] pg/mL in ∆TNF-α, and 6.15 ± 8.65 pg/mL versus 1.28 ± 8.51 pg/mL in ∆IL-1ß; all P < 0.05). CONCLUSION: Moxibustion can improve the joint swelling and pain symptoms in patients with RA, which may be related to the fact that moxibustion can reduce the release of inflammatory factors in patients with RA and downregulate the level of CXCL1 and increase the level of ß-EP at the same time. This trial is registered with ChiCTR-IOR-17012282.


Asunto(s)
Artritis Reumatoide , Moxibustión , Antiinflamatorios , Artritis Reumatoide/terapia , Quimiocina CXCL1 , Humanos , Factor de Necrosis Tumoral alfa , betaendorfina
8.
Front Neurol ; 12: 812504, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-35197917

RESUMEN

INTRODUCTION: Acupuncture is an efficacious and safe treatment choice for migraine prevention. Results from clinical trials have shown that non-specific effects play an important role in acupuncture's efficacy. To date, however, there is no evidence available quantitatively evaluating the effect of non-specific effects, such as patients' expectations and beliefs for acupuncturists, on acupuncture efficacy, necessitating further exploration. METHODS: A total of 156 patients with migraine without aura (MwoA) will be randomized to either junior or senior acupuncturist group, at a ratio of 1:1. The study will last 24 weeks, for each patient, comprising baseline, treatment, and follow-up phases lasting 4, 8, and 12 weeks, respectively. All patients will undergo 12 sections of acupuncture treatment delivered by either a junior or senior acupuncturist following the same acupuncture prescription and manipulation. The primary outcomes will be changes in the number of migraine days and frequency of attacks per 4 weeks cycle, relative to the baseline. Secondary outcomes will include severity of headache pain, quality of life, anxiety/depression levels, and use of non-steroidal anti-inflammatory drugs (NSAIDs) per 4 weeks cycle, compared to the baseline, as well as adverse events and rate of positive response to treatment. Prior to randomization of patients into junior or senior acupuncturist groups, the Acupuncture Expectations Evaluation Scale (AES) will be used to evaluate their expectations and belief with regards to acupuncture efficacy delivered by senior or junior acupuncturists. DISCUSSION: Results from this clinical randomized controlled trial will help to quantitatively evaluate the extent of the effect of acupuncture treatment delivered by a senior or junior acupuncturist (high relative to low expectations) in migraine patients. ETHICS AND DISSEMINATION: This trial has been approved by the Institutional Review Boards and Ethics Committees of Hospital of Chengdu University of Traditional Chinese Medicine (Approval No. 2020KL-058).

9.
Int J Mol Med ; 44(4): 1344-1356, 2019 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-31364738

RESUMEN

Rheumatoid arthritis (RA) is an autoimmune disease of unknown etiology, which occurs in ~1.0% of the general population. Increasing studies have suggested that long non­coding RNAs (lncRNAs) may serve important roles in various biological processes and may be associated with the pathogenesis of different types of disease, including RA. Astragalosides (AST) has been used as a traditional Chinese medicine for the treatment of RA. However, the mechanism underlying its therapeutic effect has remained unclear to date. Thus, there is an urgent need to elucidate the possible mechanism of AST in the treatment of RA from the perspective of lncRNAs. In the present study, the lncRNAs and mRNAs of a vehicle group, animal model group and AST treatment (control) group were determined by Arraystar Rat lncRNA/mRNA microarray. The differentially expressed genes with a fold change >1.5 and P<0.05 were selected and analyzed. Gene Ontology (GO) and pathway analysis was performed using the Database for Annotation, Visualization and Integration Discovery, and the coding­non­coding gene co­expression network was drawn based on the correlation analysis between the differentially expressed lncRNAs and mRNAs. Based on node degree and the correlation between bioinformatics analysis and RA, the critical differentially expressed lncRNAs were selected, analyzed and verified by reverse transcription­quantitative PCR (RT­qPCR) analysis. The results showed that, following AST treatment, up to 75 lncRNAs and 247 mRNAs were found to be differentially expressed among the three groups. GO and pathway analysis manifested that 135 GO terms and 17 pathways were enriched by differentially expressed genes. Four lncRNAs (MRAK012530, MRAK132628, MRAK003448 and XR_006457) were selected as the critical lncRNAs and their trend in expression showed consistency between the RT­qPCR and microarray data. In conclusion, AST had a regulatory effect on differentially expressed lncRNAs during the development of RA, and four lncRNAs could be selected as critical therapeutic targets of AST.


Asunto(s)
Artritis Experimental/genética , Medicamentos Herbarios Chinos/farmacología , Perfilación de la Expresión Génica , Regulación de la Expresión Génica/efectos de los fármacos , ARN Largo no Codificante/genética , Transcriptoma , Animales , Artritis Experimental/tratamiento farmacológico , Artritis Experimental/metabolismo , Artritis Experimental/patología , Biomarcadores , Biología Computacional/métodos , Citocinas/sangre , Citocinas/metabolismo , Modelos Animales de Enfermedad , Perfilación de la Expresión Génica/métodos , Ontología de Genes , Redes Reguladoras de Genes , Humanos , Mediadores de Inflamación/sangre , Mediadores de Inflamación/metabolismo , Masculino , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ratas
10.
Drug Des Devel Ther ; 13: 1901-1913, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31239641

RESUMEN

Objectives: To screen and study circular RNA (circRNA) expression profiles in QTXZG-mediated treatment of chronic glomerulonephritis (CGN) induced by adriamycin in rats and to research the possible roles and molecular mechanisms of QTXZG. Materials and methods: Next-generation RNA sequencing was used to identify circRNA expression profiles in CGN after QTXZG treatment compared with a CGN model group and a control group. Bioinformatics analysis was performed to predict potential target miRNAs and mRNAs. GO and pathway analyses for potential target mRNAs were used to explore the potential roles of differentially expressed (DE) circRNAs. Results: We identified 31 and 21 significantly DE circRNAs between the model group vs the control group and the model group vs the QTXZG group, respectively. Four circRNAs that resulted from the establishment of the CGN model were reversed following treatment with QTXZG. Further analysis revealed that these four circRNAs may play important roles in the development of CGN. Conclusions: This study elucidated the comprehensive expression profile of circRNAs in CGN rats after QTXZG treatment for the first time. Analysis of the circRNA-miRNA-mRNA-ceRNA network to determine potential function provided a comprehensive understanding of circRNAs that may be involved in the development of CGN. The current study indicated that therapeutic effects of QTXZG on CGN may be due to regulation of circRNA expression.


Asunto(s)
Medicamentos Herbarios Chinos/farmacología , Glomerulonefritis/tratamiento farmacológico , ARN Circular/antagonistas & inhibidores , Animales , Medicamentos Herbarios Chinos/administración & dosificación , Perfilación de la Expresión Génica , Glomerulonefritis/metabolismo , Glomerulonefritis/patología , Masculino , Medicina Tradicional China , ARN Circular/genética , ARN Circular/metabolismo , Ratas , Ratas Sprague-Dawley
11.
Allergy Asthma Immunol Res ; 8(4): 353-61, 2016 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-27126729

RESUMEN

PURPOSE: Comprehensive evaluation of anaphylaxis in China is currently lacking. In this study, we characterized the clinical profiles, anaphylactic triggers, and emergency treatment in pediatric and adult patients. METHODS: Outpatients diagnosed with "anaphylaxis" or "severe allergic reactions" in the Department of Allergy, Peking Union Medical College Hospital from January 1, 2000 to June 30, 2014 were analyzed retrospectively. RESULTS: A total of 1,952 episodes of anaphylaxis in 907 patients were analyzed (78% were adults and 22% were children). Foods are the most common cause (77%), followed by idiopathic etiologies (15%), medications (7%) and insects (0.6%). In food-induced anaphylaxis, 62% (13/21) of anaphylaxis in infants and young children (0-3 years of age) were triggered by milk, 59% (36/61) of anaphylaxis in children (4-9 years of age) were triggered by fruits/vegetables, while wheat was the cause of anaphylaxis in 20% (56/282) of teenagers (10-17 years of age) and 42% (429/1,016) in adults (18-50 years of age). Mugwort pollen sensitization was common in patients with anaphylaxis induced by spices, fruits/vegetables, legume/peanuts, and tree nuts/seeds, with the prevalence rates of 75%, 67%, 61%, and 51%, respectively. Thirty-six percent of drug-induced anaphylaxis was attributed to traditional Chinese Medicine. For patients receiving emergency care, only 25% of patients received epinephrine. CONCLUSIONS: The present study showed that anaphylaxis appeared to occur more often in adults than in infants and children, which were in contrast to those found in other countries. In particular, wheat allergens played a prominent role in triggering food-induced anaphylaxis, followed by fruits/vegetables. Traditional Chinese medicine was a cause of drug-induced anaphylaxis. Furthermore, exercise was the most common factor aggravating anaphylaxis. Education regarding the more aggressive use of epinephrine in the emergency setting is clearly needed.

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