Clinical Features and Outcomes of Hospitalized Adult Patients With Breakthrough COVID-19 Infections: A Propensity-Score-Matched Observational Study.

In this study, we aimed to evaluate the impact of vaccination on intensive care unit (ICU) admission and in-hospital mortality among breakthrough coronavirus disease 2019 (COVID-19) infections. A total of 3,351 adult patients hospitalized with COVID-19 in the Memorial Healthcare System (Hollywood, Florida) between June 1 and September 20, 2021, were included; 284 (8.5%) were fully vaccinated. A propensity-score-matched analysis was conducted to compare fully vaccinated patients with unvaccinated controls. Propensity scores were calculated on the basis of variables associated with vaccination status. A 1:1 matching ratio was applied using logistic regression models, ensuring balanced characteristics between the two groups. The matched samples were then subjected to multivariate analysis. Among breakthrough infections, vaccinated patients demonstrated lower incidences of ICU admission (10.3% vs. 16.4%; P = 0.042) and death (12.2% vs. 18.7%; P = 0.041) than the matched controls. Risk-adjusted multivariate analysis demonstrated a significant inverse association between vaccination and ICU admission (odds ratio = 0.52, 95% confidence interval: 0.31, 0.89; P = 0.019) as well as in-hospital mortality (odds ratio = 0.57, 95% confidence interval: 0.34, 0.94; P = 0.027). Vaccinated individuals experiencing breakthrough infections had significantly lower risks of ICU admission and in-hospital mortality. These findings highlight the benefits of COVID-19 vaccines in reducing severe outcomes among patients with breakthrough infections.

MCPIP1 restrains mucosal inflammation by orchestrating the intestinal monocyte to macrophage maturation via an ATF3-AP1S2 axis.

OBJECTIVE: Monocyte chemotactic protein-1-induced protein 1 (MCPIP1) is highly expressed in inflamed mucosa of inflammatory bowel disease (IBD) and negatively regulates immune response, while the underlying mechanisms regulating mucosal macrophage functions remain unknown. Here, we investigated the roles of MCPIP1 in modulating the differentiation and functions of intestinal macrophages in the pathogenesis of IBD. DESIGN: ScRNA-seq was used to cluster the monocyte/macrophage lineage from macrophage-specific Mcpip1-deficient (Mcpip1 ∆Mye) mice and Mcpip1 fl/fl littermates. The differentially expressed genes were confirmed by RNA-seq, luciferase assay, CUT&Tag assay and Western blotting. Effects of MCPIP1 and the activating transcription factor 3 (ATF3)-AP1S2 axis were assessed in patients with IBD. RESULTS: Mcpip1 ∆Mye mice developed more severe dextran sulfate sodium (DSS)-induced colitis characterised by an increase in macrophage migratory capacity and M1 macrophage polarisation but a decrease in the monocyte-to-macrophage maturation in gut mucosa compared with their littermates. ScRNA-seq unravelled a proinflammatory population (Ccr2+Il-1ß+Tlr2+Cx3cr1-Cd163-Mrc1-Ly6c+) of the monocyte/macrophage lineage from lamina propria CD11b+ cells and an arrest of Mcpip1 ∆Mye monocyte-to-macrophage maturation in an Atf3-Ap1s2 axis-dependent manner. Silencing of Ap1s2 or Atf3 markedly suppressed Mcpip1 ∆Mye macrophage migration, M1-like polarisation, and production of proinflammatory cytokines and chemokines. Notably, in vivo blockage of Ap1s2 ameliorated DSS-induced colitis in Mcpip1 ΔMye mice through enhancing intestinal macrophage maturation. Furthermore, MCPIP1, ATF3 and AP1S2 were highly expressed in inflamed mucosa of active patients with IBD and blockage of ATF3 or AP1S2 significantly suppressed IBD CD14+-derived M1-like macrophage polarisation and proinflammatory cytokine production. CONCLUSIONS: Macrophage-specific Mcpip1 deficiency polarises macrophages towards M1-like phenotype, arrests macrophage maturation and exacerbates intestinal inflammation in an Atf3-Ap1s2-dependent manner, thus providing novel mechanistic insight into intestinal macrophage functions during IBD.

Impact of induction therapy on cytomegalovirus infection and post-transplant outcomes in pediatric heart transplant recipients receiving routine antiviral prophylaxis.

OBJECTIVES: Induction therapy has been increasingly used in pediatric heart transplantation. This study evaluated the impact of anti-thymocyte globulin (ATG) versus basiliximab as induction therapy on post-transplant cytomegalovirus (CMV) infection, rejection at 1 year, coronary allograft vasculopathy (CAV), and mortality in pediatric heart transplant recipients receiving antiviral prophylaxis. RESULTS: Of the 96 patients (age < 18 years) analyzed, 46 (47.9%) patients received basiliximab, and 50 (52.1%) received ATG. Median follow-up was 3.0 (IQR, 1.7-4.9) years with 32.3% reporting CMV infection. The ATG group, as compared with the basiliximab group, had similar incidences of CMV infection (36% vs. 28.3%, p = .418), CMV viremia (22% vs. 19.6%, p = .769), and CMV-positive tissue biopsy (30% vs. 22%, p = .486). The ATG group had lower incidences of rejection at 1 year (16% vs. 36.9%, p = .022) and CAV (4% vs. 23.9%, p = .006) with no difference in mortality (8% vs. 15.2%, p = .343), compared with the basiliximab group. Multivariate analysis showed that induction with ATG was associated with a lower risk of rejection at 1 year (OR, .31; 95% CI, .09-.94; p = .039) with no impact on the incidences of CMV infection (HR, 2.06; 95% CI, .54-7.89; p = .292), CAV (HR, .30; 95% CI, .04-2.58; p = .275), and mortality (HR, .39; 95% CI, .09-1.82; p = .233) compared to basiliximab induction. DISCUSSION AND CONCLUSIONS: In conclusion, induction with ATG was associated with reduction in risk of rejection at 1 year with no effects on CMV infection, CAV, and mortality in pediatric heart transplant recipients with universal antiviral prophylaxis compared with basiliximab induction therapy.

Characteristics, Vaccination Status and Outcomes Among Healthy Younger Adults in a Large Public Healthcare System in the South Florida Region.

Nationally, the 18-49 years old age group are less likely to be vaccinated compared to those 50 years and older. Data describing the risk of COVID-19 severe illness that requires hospitalization among younger healthy adults is limited. In an effort to underscore the importance of vaccination and provide data that may influence COVID-19 risk perception, COVID-19 data of a sample of hospitalized non-elderly age group who clinically may not be considered as high risk for severe COVID-19 illness are presented. Specifically, this retrospective chart review (spanning the period of March 2020 to September 2021) provides a descriptive analysis examining the characteristics, vaccination status and outcomes of adults who were hospitalized at Memorial Healthcare System with laboratory-confirmed COVID-19. The study's data focuses on non-pregnant adults, aged 18-49 years old, without underlying conditions and with no reported history of smoking. As a sub-analysis, data on young and otherwise healthy pregnant females who were hospitalized with COVID-19, as well as data stratified by the pre-Delta and Delta variant dominant period are also presented. There was a total of 482 young and otherwise healthy non-pregnant adults who were hospitalized with COVID-19. Overall, more than 13% of our study population had severe COVID-19 disease. Further, a higher proportion of unvaccinated patients had severe COVID-19 compared to those who received at least one dose of the vaccine. All ventilator or ECMO placements, 30-day readmissions and deaths occurred among unvaccinated patients.

Cost-Consequence Analysis of Single-Dose Dalbavancin Versus Standard of Care for the Treatment of Acute Bacterial Skin and Skin Structure Infections in a Multisite Healthcare System.

BACKGROUND: Acute bacterial skin and skin structure infections (ABSSSIs) are common infectious diseases that cause a significant economic burden on the healthcare system. This study aimed to compare the cost-effectiveness of dalbavancin vs standard of care (SoC) in the treatment of ABSSSI in a community-based healthcare system. METHODS: This was a retrospective study of adult patients with ABSSSI treated with dalbavancin or SoC during a 27-month period. Patients were matched based on age and body mass index. The primary outcome was average net cost of care to the healthcare system per patient, calculated as the difference between reimbursement payments and the total cost to provide care to the patient. The secondary outcome was proportion of cases successfully treated, defined as no ABSSSI-related readmission within 30 days after the initiation of treatment. RESULTS: Of the 418 matched patients, 209 received SoC and 209 received dalbavancin. The average total cost of care per patient was greater with dalbavancin vs SoC ($4770 vs $2709, P < .0001). The average reimbursement per patient was $3084 with dalbavancin vs $2633 SoC (P = .527). The net cost, calculated as revenue minus total cost, was $1685 with dalbavancin vs $75 with SoC (P = .013). The overall treatment success rate was 74% with dalbavancin vs 85% with SoC (P = .004). CONCLUSIONS: Dalbavancin was more costly than SoC for the treatment of ABSSSI, with a higher 30-day readmission rate. Dalbavancin does not offer an economic or efficacy advantage.

COVID-19 infection among first responders in Broward County, Florida, March-April 2020.

BACKGROUND: First responders (FRs) may have a significant risk of coronavirus 19 (COVID-19) infection than the general population due to job-related exposures. We aimed to determine the prevalence and exposure patterns of COVID-19 among FRs. METHODS: Between March and April 2020, FRs in Broward County, Florida, were screened for COVID-19 infection by real-time reverse transcription polymerase chain reaction assay using nasopharyngeal swabs. Demographics and COVID-19 positive rate of the FRs were summarized. RESULTS: A total of 3375 FRs were screened for COVID-19 infection. The median age of FRs tested was 42 years (IQR 33-52 years), and 1464 (43.4%) were men. A total of 2902 (85.9%) were asymptomatic, and 473 (14.1%) reported symptoms associated with COVID-19. Overall, 289 (8.6%) were positive, with the highest rates among the age between 25 and 49 years. Of those testing positive, 235 (81.3%) were asymptomatic. Fourteen days after their first positive test, 81 (69.8%) of the 116 asymptomatically infected FRs were negative, and 35 (30.2%) remained positive and asymptomatic. CONCLUSIONS: The FRs in Broward County, FL, had an overall infection rate of 8.6% at the time of COVID-19 testing, and asymptomatic FRs accounted for 81.3% of infection. Active surveillance should be focused on the asymptomatic FRs with COVID-19.

The Epidemiology and Predictors of Outcomes Among Confirmed COVID-19 Cases in a Large Community Healthcare System in South Florida.

The novel coronavirus disease 2019 (COVID-19) continues to be a major public health concern. The aim of this study was to describe the presenting characteristics, epidemiology and predictors of outcomes among confirmed COVID-19 cases seen at a large community healthcare system which serves the epicenter and diverse region of Florida. We conducted a retrospective analysis of individuals with lab-confirmed SARS-CoV-2 infection who were seen, from March 2, 2020 to May 31, 2020, at Memorial Healthcare System in South Florida. Data was extracted from a COVID-19 registry of patients with lab-confirmed SARS-CoV-2 infection. Univariate and backward stepwise multivariate logistic regression models were used to determine predictors of key study outcomes. There were a total of 1692 confirmed COVID-19 patients included in this study. Increasing age was found to be a significant predictor of hospitalization, 30-day readmission and death. Having a temperature of 38 °C or more and increasing comorbidity score were also associated with an increased risk of hospitalization. Significant predictors of ICU admission included having a saturated oxygen level less than 90%, hypertension, dementia, rheumatologic disease, having a respiratory rate greater than 24 breaths per minute. Being of Hispanic ethnicity and immunosuppressant utilization greatly increased the risk of 30-day readmission. Having an oxygen saturation less than 90% and an underlying neurological disorder were associated with an increased likelihood of death. Results show that a patient's demographic, underlying condition and vitals at triage may increase or reduce their risk of hospitalization, ICU admission, 30-day readmission or death.

Maximal versus sub-maximal effort during cardiopulmonary exercise testing in adults with congenital heart disease: outcome analysis of short-term cardiac-related events.

Peak respiratory exchange ratio is an objective marker of patient effort during cardiopulmonary exercise testing. We evaluated exercise variables in 175 adult congenital heart disease patients and the impact of respiratory exchange ratio on the prognostic value of exercise variables for short-term cardiac-related events. Of 175 patients, 110 completed the exercise test with a peak respiratory exchange ratio of ≥1.10 and the remaining 65 had a peak respiratory exchange ratio of <1.10. Peak oxygen consumption, the percentage of oxygen consumption at the ventilatory threshold, peak heart rate, percentage predicted peak heart rate, double product, oxygen uptake efficiency slope, and the number of patients with exercise oscillatory ventilation were reduced significantly in patients with a respiratory exchange ratio of <1.10 compared to those with a respiratory exchange ratio of ≥1.10. After a median follow-up of 21 months, total cardiac-related events occurred in 37 (21%) patients. Multivariate Cox proportional hazard analysis showed that the percentage predicted peak oxygen consumption, and oxygen uptake efficiency slope were independent predictors of cardiac-related events only in patients with a peak respiratory exchange ratio of ≥1.10. Sub-maximal exercise performance can be preserved in adult congenital heart disease patients. The percentage predicted oxygen consumption and the oxygen uptake efficiency slope are two independent predictors for short-term cardiac-related events in adult congenital heart disease patients.

Impact of peak respiratory exchange ratio on the prognostic power of symptoms-limited exercise testing using Bruce protocol in patients with Fontan physiology.

OBJECTIVES: We evaluated the impact of peak respiratory exchange ratio on the prognostic values of cardiopulmonary exercise variables during symptoms-limited incremental exercise tests in patients with Fontan physiology. METHODS: Retrospective single-centre chart review study of Fontan patients who underwent exercise testing using the Bruce protocol between 2014 and 2018 and follow-up. RESULTS: A total of 34 patients (age > 18 years) had a Borg score of ≥7 on the Borg 10-point scale, but only 50% of patients achieved a peak respiratory exchange ratio of ≥ 1.10 (maximal test). Peak oxygen consumption, percent-predicted peak oxygen consumption, and peak oxygen consumption at the ventilatory threshold was reduced significantly in patients with a peak respiratory exchange ratio of < 1.10. Peak oxygen consumption and percent-predicted peak oxygen consumption was positively correlated with peak respiratory exchange ratio values (r = 0.356, p = 0.039). After a median follow-up of 21 months, cardiac-related events occurred in 16 (47%) patients, with no proportional differences in patients due to their respiratory exchange ratio (odds ratio, 0.62; 95% CI: 0.18-2.58; p = 0.492). Multivariate Cox proportional hazard analysis showed percent-predicted peak oxygen consumption, peak heart rate, and the oxygen uptake efficient slope were highly related to the occurrence of events in patients only with a peak respiratory exchange ratio of ≥ 1.10. CONCLUSIONS: The value of peak cardiopulmonary exercise variables is limited for the determination of prognosis and assessment of interventions in Fontan patients with sub-maximal effort. Our findings deserve further research and clinical application.

Cytomegalovirus infection and allograft rejection among pediatric heart transplant recipients in the era of valganciclovir prophylaxis.

CMV infection remains a significant cause of morbidity among pediatric HTx recipients We explored the implications of CMV infection on post-transplant outcomes among CMV risk-stratified pediatric HTx recipients receiving VGC prophylaxis. Children who underwent HTx between January 2010 and October 2016 were stratified according to CMV risk at time of transplant and evaluated for evidence of post-transplant CMV infection, rejection, CAV, and graft loss. Among 97 children, 41 (42%) were considered HR or IR risk for CMV infection and received VGC prophylaxis. CMV DNAemia was observed in 34% of children, including 71% HR, 40% IR, and 18% LR individuals. Median time to CMV DNAemia following VGC prophylaxis was 32D among HR vs 277D in IR subjects (P = .042). No difference in overall graft loss was noted among groups, but CMV HR children had decreased rejection-free survival (3.5 years) compared to IR (6 years, P = .015) and LR children (8 years, P = .0003). CMV was noted on EMB in 13% of children but was not associated with increased CAV, rejection or graft loss. High-risk CMV status was associated with decreased time to CMV infection despite VGC prophylaxis, compared to IR, and decreased rejection-free survival times compared to both IR and LR recipients. Detection of CMV on EMB was not associated with increased rejection, CAV or graft loss. Additional studies are needed to explore the impact of CMV infection on rejection-free survival in HTx recipients.

Correlation of gene expression profiling score, cardiac hemodynamics and echocardiographic parameters in asymptomatic, rejection-free pediatric heart transplant recipients.

OBJECTIVES: To correlate gene expression profiling scores obtained by AlloMap® with cardiac hemodynamics, cardiac allograft vasculopathy (CAV), and echocardiographic parameters in asymptomatic, rejection-free pediatric heart transplant (HT) recipients. METHODS: Single-institution retrospective study of 210 AlloMap scores obtained concomitantly with cardiac catheterization and echocardiogram from 55 children during follow-up after cardiac transplantation. RESULTS: The median age at HT was 5.1 years (range, 0.9-14.1), with 29 males and 26 females. AlloMap scores were high in <2 years vs ≥2 years of age at the time of HT (P = .001), and trending higher with time after HT (R2  = .04, P = .004). There was no significant difference in scores between ACR grades 0 and 1R or CAV. There was mild to modest correlation of AlloMap scores with the mean right atrial pressure (P = .002), and pulmonary capillary wedge pressure (P = .02), but no correlation was found with LV SF% (P = .3), LV EF% (P = .5), or RV FAC % (P = .8). CONCLUSIONS: Our study provides preliminary data that the AlloMap score must be studied carefully before it can be used in children, particularly in those under 2 years of age. Monitoring of serial scores for each patient could potentially reflect changes in allograft performance that may determine indications for catheterization and biopsy which needs to be validated in future studies.

Effect of mobile text messages on antiretroviral medication adherence and patient retention in early HIV care: an open-label, randomized, single center study in south Florida.

BACKGROUND: People with HIV (PHIV) with limited access to health services often experience suboptimal antiretroviral therapy (ART) adherence. We investigated whether a daily text messaging intervention improves ART adherence and retention in early HIV care in PHIV in a south Florida hospital-based clinic. METHODS: ART-naïve PHIV receiving care through the clinic's Ryan White HIV/AIDS Program were enrolled and randomly assigned to the intervention or control groups with a 1:1 ratio. The intervention group received a 1-way text message daily and the control group received standard care without receiving text message reminders for 6 months. HIV RNA and CD4 cell count were measured at baseline and post-intervention. Adherence to ART was defined as a visual analog scale of ≥ 90%. Retention in care was defined as continued engagement at study end. RESULTS: 94 ART-naïve patients were randomized and 83 (85.6%) completed the study, of which 44 were in the intervention group and 39 were in the control group. At the end of the 6-month study period, adherence to ART was 84.4% in the intervention group versus 73.5% in the control group (OR, 1.9; 95% CI 0.7-5.0; p = 0.194). Retention in care significantly improved in the intervention group compared to the control group with the odds of retention increasing by 20% (OR, 1.2; 95% CI 1.1-1.5; p = 0.006). Undetectable HIV RNA (< 50 copies/mL) was 86.7% in the intervention group versus 73.5% in the control group (OR, 2.3; 95% CI 0.8-6.9; p = 0.112). A significant increase in CD4 cell count and a decrease in HIV RNA were found at study end, with no differences between the two groups. CONCLUSIONS: In this pilot study, a one-way daily text messaging intervention did not improve ART adherence over a 6-month study period, but significantly enhanced patient retention in early HIV care. Implementation of interventions to improve adherence in this population is required.

Essential Role of Endothelial MCPIP in Vascular Integrity and Post-Ischemic Remodeling.

MCP-1-induced protein (MCPIP, also known as Zc3h12a or Regnase-1), a newly identified suppressor of cytokine signaling, is expressed in endothelial cells (ECs). To investigate the role of endothelial MCPIP in vascular homeostasis and function, we deleted the MCPIP gene specifically in ECs using the Cre-LoxP system. EC-specific MCPIP deletion resulted in systemic inflammation, increased vessel permeability, edema, thrombus formation, and premature death in mice. Serum levels of cytokines, chemokines, and biomarkers of EC dysfunction were significantly elevated in these mice. Upon lipopolysaccharide (LPS) challenge, mice with EC-specific MCPIP depletion were highly susceptible to LPS-induced death. When subjected to ischemia, these mice showed defective post-ischemic angiogenesis and impaired blood flow recovery in hind limb ischemia. In aortic ring cultures, the MCPIP-deficient ECs displayed significantly impaired vessel sprouting and tube elongation. Mechanistically, silencing of MCPIP by small interfering RNAs in cultured ECs enhanced NF-κΒ activity and dysregulated synthesis of microRNAs linked with elevated cytokines and biomarkers of EC dysfunction. Collectively, these results establish that constitutive expression of MCPIP in ECs is essential to maintaining endothelial homeostasis and function by serving as a key negative feedback regulator that keeps the inflammatory signaling suppressed.

A novel technique for simultaneous hemostasis of ipsilateral radial and ulnar artery access sites.

With the increased use of transradial artery access (TRA) for diagnostic and coronary interventional procedures, crossover to the ipsilateral ulnar artery after TRA failure is being reported more frequently. A major challenge with ipsilateral transradial and ulnar artery access is achieving efficient patent hemostasis of both the radial and ulnar arteries at the completion of the procedure. In this report, we describe two cases of failed TRA with subsequent ipsilateral ulnar artery access. A novel and practical technique of simultaneous patent hemostasis of both the ipsilateral radial and ulnar artery access sites is described, using a QuikClot® Radial® hemostasis pad and a TR Band® .

Transcription factors STAT6 and KLF4 implement macrophage polarization via the dual catalytic powers of MCPIP.

Macrophage polarization plays a critical role in tissue homeostasis, disease pathogenesis, and inflammation and its resolution. IL-4-induced macrophage polarization involves induction of STAT6 and Krüppel-like factor 4 (KLF4), which induce each other and promote M2 polarization. However, how these transcription factors implement M2 polarization is not understood. We report that in murine macrophages MCP-1-induced protein (MCPIP), induced by KLF4, inhibits M1 polarization by inhibiting NF-κB activation and implements M2 polarization using both its deubiquitinase and RNase activities that cause sequential induction of reactive oxygen species (ROS), endoplasmic reticulum (ER) stress, and autophagy required for M2 polarization. MCPIP also induces C/EBPß and PPARγ, which promote M2 polarization. Macrophages from mice with myeloid-targeted overexpression of MCPIP show elevated expression of M2 markers and reduced response to LPS, whereas macrophages from mice with myeloid-specific deletion of MCPIP manifest elevated M1 polarization with enhanced phagocytic activity. Thus, both in vivo and in vitro experiments demonstrate that the transcription factors STAT6 and KLF4 implement IL-4-induced M2 polarization via the dual catalytic activities of MCPIP.

MCP-1-induced protein attenuates post-infarct cardiac remodeling and dysfunction through mitigating NF-κB activation and suppressing inflammation-associated microRNA expression.

MCP-1-induced protein (MCPIP, also known as ZC3H12A) has recently been uncovered to act as a negative regulator of inflammation. Expression of MCPIP was elevated in the ventricular myocardium of patients with ischemic heart failure. However, the role of MCPIP in the development of post-infarct cardiac inflammation and remodeling is unknown. The objective of the present study was to investigate whether MCPIP exerts an inhibitory effect on the cardiac inflammatory response and adverse remodeling after myocardial infarction (MI). Mice with cardiomyocyte-specific expression of MCPIP and their wild-type littermates (FVB/N) were subjected to permanent ligation of left coronary artery. The levels of MCPIP were significantly increased in the ischemic myocardium and sustained for 4 weeks after MI. Acute infarct size was comparable between groups. However, constitutive overexpression of MCPIP in the murine heart resulted in improved survival rate, decreased cardiac hypertrophy, less of fibrosis and scar formation, and better cardiac performance at 28 days after MI, along with a markedly reduced monocytic cell infiltration, less cytokine expression, decreased caspase-3/7 activities and apoptotic cell death compared to the wild-type hearts. Cardiomyocyte-specific expression of MCPIP also attenuated activation of cardiac NF-κB signaling and expression of inflammation-associated microRNAs (miR-126, -146a, -155, and -199a) when compared with the post-infarct wild-type hearts. In vitro, MCPIP expression suppressed hypoxia-induced NF-κB-luciferase activity in cardiomyocytes. In conclusion, MCPIP expression in the ischemic myocardium protects against adverse cardiac remodeling and dysfunction following MI by modulation of local myocardial inflammation, possibly through mitigating NF-κB signaling and suppressing inflammation-associated microRNA expression.

Exendin-4 improves cardiac function in mice overexpressing monocyte chemoattractant protein-1 in cardiomyocytes.

The incretin hormone glucagon-like peptide-1 (Glp1) is cardioprotective in models of ischemia-reperfusion injury, myocardial infarction and gluco/lipotoxicity. Inflammation is a factor in these models, yet it is unknown whether Glp1 receptor (Glp1r) agonists are protective against cardiac inflammation. We tested the hypothesis that the Glp1r agonist Exendin-4 (Ex4) is cardioprotective in mice with cardiac-specific monocyte chemoattractant protein-1 overexpression. These MHC-MCP1 mice exhibit increased cardiac monocyte infiltration, endoplasmic reticulum (ER) stress, apoptosis, fibrosis and left ventricular dysfunction. Ex4 treatment for 8 weeks improved cardiac function and reduced monocyte infiltration, fibrosis and apoptosis in MHC-MCP1 mice. Ex4 enhanced expression of the ER chaperone glucose-regulated protein-78 (GRP78), decreased expression of the pro-apoptotic ER stress marker CCAAT/-enhancer-binding protein homologous protein (CHOP) and increased expression of the ER calcium regulator Sarco/Endoplasmic Reticulum Calcium ATPase-2a (SERCA2a). These findings suggest that the Glp1r is a viable target for treating cardiomyopathies associated with stimulation of pro-inflammatory factors.

Inflammation, endoplasmic reticulum stress, autophagy, and the monocyte chemoattractant protein-1/CCR2 pathway.

Numerous inflammatory cytokines have been implicated in the pathogenesis of cardiovascular diseases. Monocyte chemoattractant protein (MCP)-1/CCL2 is expressed by mainly inflammatory cells and stromal cells such as endothelial cells, and its expression is upregulated after proinflammatory stimuli and tissue injury. MCP-1 can function as a traditional chemotactic cytokine and also regulates gene transcription. The recently discovered novel zinc-finger protein, called MCPIP (MCP-1-induced protein), initiates a series of signaling events that causes oxidative and endoplasmic reticulum (ER) stress, leading to autophagy that can result in cell death or differentiation, depending on the cellular context. After a brief review of the basic processes involved in inflammation, ER stress, and autophagy, the recently elucidated role of MCP-1 and MCPIP in inflammatory diseases is reviewed. MCPIP was found to be able to control inflammatory response by inhibition of nuclear factor-κB activation through its deubiquitinase activity or by degradation of mRNA encoding a set of inflammatory cytokines through its RNase activity. The potential inclusion of such a novel deubiquitinase in the emerging anti-inflammatory strategies for the treatment of inflammation-related diseases such as cardiovascular diseases and type 2 diabetes is briefly discussed.

MCP-1and IL-1ß expression in the myocardia of two young patients with Type 1 diabetes mellitus and fatal diabetic ketoacidosis.

Convincing evidence exists for the early onset of diabetic cardiomyopathy and coronary artery disease (CAD) as distinct forms of cardiac disease in young patients with Type 1 diabetes mellitus (T1DM) and the pre-stages of T2DM, forms of dysregulated insulin signaling. Progression of both chronic cardiac conditions is mediated by oxidative stress and low grade inflammation. This study reports the expression of monocyte chemotactic protein-1 (MCP-1) chemokine and the interleukin (IL)-1ß inflammatory cytokine in two young patients with suboptimal metabolic control and fatal diabetic ketoacidosis (DKA), two age-matched overweight/obesity cases and two age-matched controls. In addition, markers of oxidative stress, apoptosis, collagen deposition and cardiomyocyte hypertrophy were studied. Significant expression of MCP-1 and IL-1ß was seen in the myocardia of the T1DM/DKA cases, with lesser amounts expressed in the overweight/obesity myocardia. All of the other markers except cardiomyocyte hypertrophy were expressed to a significantly greater extent in the T1DM/DKA and overweight/obesity cases in comparison to the age-matched controls. Cardiomyocyte hypertrophy was significantly greater in the overweight/obesity cases than in the T1DM/DKA or the control cases.

Elevated methemoglobin levels in patients treated with high-dose hydroxocobalamin.

OBJECTIVE: The aim of this study was to assess the impact of hydroxocobalamin (OHCbl) infusion on arterial blood gas and oximetry values in patients with vasoplegic syndrome. METHODS: Blood samples collected from 95 patients receiving OHCbl infusion were assayed using the ABL90 FLEX Plus blood gas analyzer for the concentration of methemoglobin (MetHb), total hemoglobin (tHb), carboxyhemoglobin (COHb), arterial oxygen saturation (SaO2), arterial oxygen partial pressure (PaO2), and arterial carbon dioxide partial pressure (PaCO2). Interference of OHCbl on these variables was evaluated using the measured difference between the preinfusion and postinfusion samples. RESULTS: Blood MetHb (%) measured after the infusion of OHCbl (5g) were significantly higher than the baseline levels, with a median of 4.8 (IQR, 3.0-6.5) versus 1.0 (IQR, 1.0-1.2) (P < .001). Blood COHb (%) increased from a median of 1.3 (IQR, 1.0-1.8) to 1.7 (IQR, 1.3-2.2) (P < .001) following the OHCbl infusion. No differences were seen in median levels of tHb, PaO2, PaCO2, and SaO2 between pre- and post-OHCbl treatment. CONCLUSION: The presence of OHCbl in blood clearly interfered with the oximetry measurements of the hemoglobin component fractions by falsely increasing the levels of MetHb and COHb. Blood levels of MetHb and COHb cannot be reliably determined by the co-oximetry when OHCbl is known or suspected.