Journal of Investigative Medicine

This study aims to evaluate the potential of percutaneous patent foramen ovale (PFO) closure to improve the headache in patients with migraine and PFO, and discuss the difference between the randomized controlled trials (RCTs) and the single-center studies. Patients of migraine with a large shunt of PFO, who experienced ≥2 headache attacks per month and failed ≥2 categories of standardized medication, underwent PFO closure in First Affiliated Hospital of Xi'an Jiao Tong University. The clinical outcomes, including frequency and duration of headache attacks, Headache Impact Test (HIT-6) score, and Visual Analogue Scale (VAS) score, were evaluated at 3, 6, and 12 months of follow-up after the PFO closure. The different efficacies of the clinical outcomes between patients with and without aura as well as different grades of PFO were also evaluated, respectively. 134 patients with migraine (39 male and 95 female) with PFO were enrolled, whose average age was 39.21±11.37 years. After PFO closure, there was a significant reduction in frequency and duration of headache attacks, HIT-6 score, and VAS score at 3, 6, and 12 months’ follow-up (p<0.001). Migraine was completely relieved in 54 (40.30%) patients during 12 months’ follow-up. The frequency of migraine was reduced by >50% in 44 (32.84%) patients at 3 months’ follow-up and increased to 48 (35.82%) at 12 months’ follow-up. 31.03% patients remained residual shunt after 6 months of closure with varying improvements of headache. This study confirmed that PFO closure can effectively reduce frequency and duration of migraine and improve quality of life, but the definitive indications and long-term effect still need further research.

To investigate the predictive ability of serum matrix metalloproteinase-9 (MMP-9) in the acute phase of Kawasaki disease (KD) with coronary artery lesions (CALs). Patients with KD hospitalized in Lanzhou University Second Hospital, Northwest China, from November 2015 to January 2018 were retrospectively reviewed, and clinical trial indicators and peripheral blood specimens were collected before intravenous immunoglobulin therapy treatment. The independent risk factors were determined using multivariate regression analysis. The net reclassification improvement (NRI) and integrated discrimination improvement (IDI) were used to quantitatively evaluate the ability of MMP-9 to improve the efficiency of predicting KD with CALs. The white cell, neutrophil percentage, C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR) were higher in patients with higher MMP-9, and the monocyte percentage was higher in patients with lower MMP-9. Logistic regression analysis revealed that long-term fever; elevated CRP, ESR, platelets (PLT), and MMP-9; and low albumin (ALB) levels were independent predictors of KD with CALs. A predictive model of KD with CALs using fever duration, CRP, ESR, PLT, and ALB showed significantly improved predictive ability when MMP-9 was added to the model (the area under the curve increased by 0.02; no change in sensitivity; specificity increased from 81.48% to 87.04%; NRI value: 13.46%; IDI value: 5.00%, p<0.05). Adding MMP-9 to traditional risk factors may improve prediction of CALs, the overall predictive ability of model 2 was increased by 5%.

Galectin-3 is an inflammation biomarker associated with atrial remodeling which plays a role in the development of atrial fibrillation (AF). Atrial high-rate episode (AHRE) is related to development of clinically documented AF and stroke. The present study aimed to determine the relationship between the presence of AHRE and the coronary sinus (CS) serum sampling of galectin-3 levels in the long-term follow-up of cardiac resynchronization therapy (CRT) patients. A total of 108 consecutive CRT patients were included prospectively in the study. AHREs were defined as atrial tachyarrhythmia episodes lasting at least 6 min with atrial rate >190 beats/min detected by cardiac implantable electronic device. CS blood samples were drawn from the CS guiding catheter to perform galectin-3 measurements. Galectin-3 levels were measured via ELISA. During a mean follow-up 12.6±4.9 months, AHRE was observed in 31 (28.7%) patients and not observed in 77 (72.3%) patients. CS galectin-3 levels were significantly higher in patients with AHRE than those without AHRE (18.09±2.62 vs 13.17±3.17, respectively, p<0.001). Moreover, CS galectin-3 levels showed significant positive correlation with percent of time spent in total AHRE (r=0.436, p<0.001). Multivariate logistic regression analysis demonstrated that left atrium (LA) volume and CS galectin-3 levels were significant and independent predictors for AHRE (OR=1.127, 95% CI: 1.045 to 1.216; p=0.002, OR=1.799, 95% CI: 1.388 to 2.330; p<0.001, respectively). In this study, we determined that high CS galectin-3 levels were a predictor for the development of AHRE in CRT patients.

Genital inflammation is an established risk factor for increased HIV acquisition risk. Certain HIV-exposed seronegative populations, who are naturally resistant to HIV infection, have an immune quiescent phenotype defined by reduced immune activation and inflammatory cytokines at the genital tract. Therefore, the aim of this study was to create an immune quiescent environment using immunomodulatory drugs to mitigate HIV infection. Using an in vitro peripheral blood mononuclear cell (PBMC) model, we found that inflammation was induced using phytohemagglutinin and Toll-like receptor (TLR) agonists Pam3CSK4 (TLR1/2), lipopolysaccharide (LPS) (TLR4) and R848 (TLR7/8). After treatment with anti-inflammatory drugs, ibuprofen (IBF) and betamethasone (BMS), PBMCs were exposed to HIV NL4-3 AD8. Multiplexed ELISA was used to measure 28 cytokines to assess inflammation. Flow cytometry was used to measure immune activation (CD38, HLA-DR and CCR5) and HIV infection (p24 production) of CD4+ T cells. BMS potently suppressed inflammation (soluble cytokines, p<0.05) and immune activation (CD4+ T cells, p<0.05). BMS significantly reduced HIV infection of CD4+ T cells only in the LPS (0.98%) and unstimulated (1.7%) conditions (p<0.02). In contrast, IBF had minimal anti-inflammatory and immunosuppressive but no anti-HIV effects. BMS demonstrated potent anti-inflammatory effects, regardless of stimulation condition. Despite uniform immunosuppression, BMS differentially affected HIV infection according to the stimulation conditions, highlighting the complex nature of these interactions. Together, these data underscore the importance of interrogating inflammatory signaling pathways to identify novel drug targets to mitigate HIV infection.

Basal cell carcinoma (BCC) is the most common dermatological neoplasms in Caucasian populations. In Mexico, a prevalence of 3.9 per 1000 habitants is estimated. Recently, the macrophage migration inhibitory factor (MIF) has been related to different types of cancer. Therefore, this study aimed to investigate the genetic association of haplotypes of [-794(CATT)5-8/-173G>C]MIF gene polymorphisms and its soluble levels in BCC. A total of 360 individuals were recruited for the study, that is, 180 of the total amounts were patients with BCC histologically confirmed and the remaining 180 individuals were identified as control subjects (CS). Both polymorphisms were genotyped by PCR and PCR-RFLP (restriction fragment length polymorphism), and MIF serum levels were measured by ELISA kit. A borderline difference was found between the 55 genotype and the susceptibility to BCC (5.6% vs 1.7% in BCC and CS, respectively, OR=3.7 and p=0.04). Furthermore, the haplotype 7G showed a significant association with BCC (p=0.02, OR=1.99). Concerning MIF soluble levels, patients with BCC showed a media of 2.1 ng/mL and CS showed 4.4 ng/mL, the comparison between groups was significant (p<0.01). Our findings suggest that the 55 genotype and the haplotype 7G are associated with the susceptibility to BCC; furthermore, a significant difference was found between MIF soluble levels in both study groups.

Influenza outbreaks occur annually and account for significant morbidity and mortality. The overall burden of influenza infections, in the USA, for the 2017–2018 season, was an estimated 45 million cases, 810 000 hospitalizations and 61 000 deaths. Literature suggests that leukocyte count and differential, particularly lymphopenia and/or monocytosis, can provide diagnostic value for influenza infection. However, studies regarding these findings are limited in the adult population, particularly in the USA. The objective of this study was to determine if lymphocyte-to-monocyte ratio (L:M)<2 can be used as a screening marker for influenza infection. We performed a retrospective analysis of all patients who presented to University of Florida Health, Jacksonville, a university-affiliated tertiary care center in Jacksonville, Florida, between January 2017 and December 2018, with ‘influenza-like’ symptoms and who were subsequently admitted to the hospital. Patients were divided into two cohorts, based on whether they had laboratory-confirmed influenza versus another confirmed upper respiratory tract viral infection (influenza-like illness (ILI)). L:M was compared between the two groups and was found to be lower in the influenza group compared with the ILI group (p<0.0001). Results of this study demonstrate that a L:M<2 has significant diagnostic value in the acute phase of influenza and can be used for earlier detection and management of this disease, in order to improve clinical outcomes.

COVID-19 raised tension both within China and internationally. Here, we used mathematical modeling to predict the trend of patient diagnosis outside China in future, with the aim of easing anxiety regarding the emergent situation. According to all diagnosis number from WHO website and combining with the transmission mode of infectious diseases, the mathematical model was fitted to predict future trend of outbreak. Daily diagnosis numbers from countries outside China were downloaded from WHO situation reports. The data used for this analysis were collected from January 21, 2020 and currently end at February 28, 2020. A simple regression model was developed based on these numbers, as follows: l o g 10 ( N t + 34 ) = 0.0515 × t + 2.075 , where N t is the total diagnosed patient till the i-th day and t=1 at February 1, 2020. Based on this model, we estimate that there were approximately 34 undetected founder patients at the beginning of the spread of COVID-19 outside China. The global trend was approximately exponential, with an increase rate of 10-fold every 19 days. Through establishment of this model, we call for worldwide strong public health actions, with reference to the experiences learned from China and Singapore.

It has been suggested that immune-inflammatory processes might be involved in the etiopathogenesis of schizophrenia. Since growing evidence indicates that adipokines strongly modulate the course of immune response and inflammatory processes, it is currently suggested the contribution of those factors in the etiology of schizophrenia as well. The aim of this study was to determine the serum levels of 4 adipokines—apelin, resistin, chemerin, and omentin—in patients with schizophrenia as compared with healthy subjects. Fifty-seven adult patients with schizophrenia and 31 healthy volunteers were included in this prospective study. ELISA was used to measure the serum concentration of resistin, apelin, omentin-1, and chemerin. No difference in the mean concentration of resistin (p=0.20) and chemerin (p=0.30) between patients with schizophrenia and the healthy group was observed. Apelin concentration was significantly (p=0.004) lower in patients with schizophrenia as compared with controls. A significant difference in apelin level between men with schizophrenia and control group (p=0.04) was reported. Apelin concentration was significantly correlated with waist-to-hip ratio, whereas chemerin concentration was significantly correlated with the Positive and Negative Syndrome Scale G score. There exists evidence that apelin might be involved in the pathogenesis of schizophrenia.

MicroRNA-363-3 p (miR-363–3 p) has been reported to play a crucial role in tumor development and progression, and function as a tumor suppressor in many types of cancer. In our previous studies, we found that miRNA-363–3 p inhibited papillary thyroid carcinoma (PTC) progression by targeting PIK3CA. Meanwhile, we found that NIN1/RPN12 binding protein 1 (NOB1) was significantly upregulated in thyroid carcinoma tissue and downregulation of NOB1 expression significantly inhibited cell proliferation, migration and invasion in PTC. However, the correlation of NOB1 and miR-363–3 p has not been investigated. Here, we performed bioinformatic analysis to explore miRNA targeting NOB1. We found that NOB1 was a target of miR-363–3 p and miR-363–3 p regulated NOB1 expression at the translational and transcriptional levels by targeting its 3’ untranslated region (3′-UTR). Further, we showed that miR-363–3 p inhibited tumor progression by targeting NOB1 in vitro and in vivo. We found that overexpression miR-363–3 p or silencing NOB1 significantly increased G0/G1-phase and decreased S-phase in the human papillary thyroid cells, which led to a significant delay in cell proliferation, indicating miR-363–3 p and NOB1 are crucial for human papillary thyroid cancer tumorigenesis. Collectively, our data unveil that miR-363–3 p negatively regulates NOB1 activity by reducing its stability. This study provides a new therapeutic target for regulation of NOB1 stability to modulate human papillary thyroid cancer progression.

The study aimed to compare the clinical characteristics and outcomes of patients with different types (ordinary, severe, and critical) of COVID-19. A total of 1280 patients diagnosed with COVID-19 were retrospectively studied, including 793 ordinary patients, 363 severe patients and 124 critical patients. The impact of comorbidities on prognosis in ordinary, severe, and critical patients were compared and analyzed. The most common comorbidities were hypertension (33.0%), followed by diabetes (14.4%). The length of hospital stay and time from the onset to discharge were significantly longer in ordinary patients with comorbidities compared with those without comorbidities. Critical patients with comorbidities had significantly lower cure rate (19.3% vs 38.9%, p<0.05) and significantly higher mortality rate (53.4% vs 33.3%, p<0.05) compared with those without comorbidities. The time from onset to discharge was significantly longer in ordinary patients with hypertension compared with those without hypertension. The mortality rate of critical patients with diabetes was higher than that of patients without diabetes (71.4% vs 42.7%, p<0.05). Men had a significantly increased risk of death than women (OR=4.395, 95% CI 1.896 to 10.185, p<0.05); patients with diabetes had higher risk of death (OR=3.542, 95% CI 1.167 to 10.750, p<0.05). Comorbidities prolonged treatment time in ordinary patients, increased the mortality rate and reduced the cure rate of critical patients; hypertension and diabetes may be important factors affecting the clinical course and prognosis of ordinary and critical patients, respectively.

Remitting seronegative symmetrical synovitis with pitting edema (RS3PE) is a rare benign rheumatological condition characterized by sudden-onset symmetrical distal extremity edema. It can present as an isolated disease process or could be associated with other conditions. Rheumatoid factor and anticitrullinated protein antibodies are negative by definition. In current literature, there is paucity of data about the disease process. We performed a literature search using the PubMed database to identify 38 articles that met our inclusion and exclusion criteria. Our literature review focuses on the clinical picture and its diverse associations. Role of various acute phase reactants has also been outlined. There is a generalized consensus among clinicians on using moderate dose steroids for treatment. Other management options for refractory cases have also discussed. Value of several imaging modalities in diagnostic evaluation of this disease entity is touched on. Since RS3PE can be associated with other diseases, specifically cancer, timely diagnosis of this condition is necessary.

We investigated whether serum granzyme B (GrB) can reflect the inflammatory burden such as cross-sectional disease activity and organ-specific involvement in immunosuppressive drug-naïve patients with antineutrophil cytoplasmic antibody-associated vasculitis (AAV). Seventy-eight immunosuppressive drug-naïve patients with AAV were included in this study. At the time of the first classification, whole blood was obtained from each patient and sera was immediately isolated and stored at – 80°C. On the day of the blood sampling, we performed routine laboratory tests including antineutrophil cytoplasmic antibody tests and collected both clinical and laboratory data. AAV-specific indices included Birmingham Vasculitis Activity Score (BVAS) and Five-Factor Score (FFS). The median age of patients with AAV was 62 years and 26 patients were men. Serum GrB was not associated with the cross-sectional BVAS; however, patients with serum GrB positivity exhibited higher frequencies of otorhinolaryngological manifestation than those without (p=0.037). When serum GrB levels were compared after dividing the patients into two groups based on the presence of organ-specific involvement, patients with pulmonary involvement exhibited a significantly higher serum GrB than those without (p=0.042). On the other hand, patients with renal involvement showed a significantly lower serum GrB than those without (p=0.023). In addition, serum GrB was inversely correlated with the cross-sectional FFS (r=−0.249, p=0.028). Even though serum GrB could not reflect the inflammatory burden of AAV, serum GrB was associated with otorhinolaryngological, pulmonary, and renal involvement in immunosuppressive drug-naïve patients with AAV.

Candida auris was discovered in 2009 and has rapidly emerged as a serious public health threat with cases reported in over 20 countries worldwide. As of May 8, 2020, the Centers for Disease Control and Prevention reported a total of 1122 US cases. C. auris is often multidrug resistant, leaving few options for treatment. Sulfonamides are known to inhibit a bacterial enzyme involved in folate synthesis and may also inhibit yeast organisms by a similar mechanism. The combination of trimethoprim and sulfamethoxazole is more commonly used than either drug alone. The objective of this study was to evaluate the combination of fluconazole and trimethoprim–sulfamethoxazole against C. auris. Minimum inhibitory concentrations (MICs) of fluconazole and trimethoprim–sulfamethoxazole were determined by ETEST and broth microdilution for 11 C. auris strains. Fluconazole MICs (µg/mL) were 4–>256 by ETEST and 2–>256 by broth microdilution (73% resistant); trimethoprim–sulfamethoxazole MICs were >32 by ETEST and 32–>128 by broth microdilution (no interpretive guidelines for C. auris). Using our MIC: MIC ETEST method and a checkerboard method, we investigated the interaction of fluconazole and trimethoprim–sulfamethoxazole against all isolates. These interactions were analyzed by calculating the summation fractional inhibitory concentration with synergyof ≤0.5, additivity of >0.5–1.0, indifference of >1–4, and antagonism of >4. The combination of fluconazole and trimethoprim–sulfamethoxazole revealed synergy with three (27%) and additivity with one (9%) isolate. Indifference was found for the remaining seven (64%) isolates. With the checkerboard method, synergy was seen in 1/11 (9%) isolates with fluconazole (½ MIC) plus trimethoprim–sulfamethoxazole (1/64 MIC); additivity, in 7/11 (64%) isolates with fluconazole (1/8 MIC–1×MIC) plus trimethoprim–sulfamethoxazole (1/128 MIC–½ MIC); and indifference in 3/11 (27%) isolates. Regardless, in vitro interactions may or may not correlate with clinical outcomes. Synergy testing with additional drug combinations and isolates should be performed.