Total times to treatment completion and clinical outcomes in odontogenic sinusitis.

BACKGROUND: Multidisciplinary collaboration is essential for effective odontogenic sinusitis (ODS) management. One point of debate has been the optimal timing of primary dental treatment and endoscopic sinus surgery (ESS), but differences in time to completion of these treatment pathways have not been studied. METHODS: A retrospective cohort study was conducted on ODS patients from 2015 to 2022. Demographic and clinical variables were recorded, and various durations of time were analyzed from rhinologic consultation through treatment completion. Resolution of sinusitis symptoms and purulence on endoscopy was also recorded. RESULTS: Eighty-nine ODS patients were analyzed (47.2 % male, median 59 years-old). Of the 89 ODS patients, 56 had treatable dental pathology, and 33 had no treatable dental pathology. Median time to treatment completion for all patients was 103 days. Of 56 ODS patients with treatable dental pathology, 33 had primary dental treatment, and 27 (81 %) required secondary ESS. In patients who underwent primary dental treatment followed by ESS, median time from initial evaluation to treatment completion was 236.0 days. If ESS was pursued primarily followed by dental treatment, median time from initial evaluation to treatment completion was 112.0 days, which was significantly shorter than if dental treatment was pursued primarily (p = 0.002). Overall symptomatic and endoscopic resolution was 97.8 %. CONCLUSIONS: After dental and sinus surgical treatment, ODS patients experienced 97.8 % resolution of symptoms and purulence on endoscopy. In patients with ODS due to treatable dental pathology, primary ESS followed by dental treatment resulted in a shorter overall treatment duration than primary dental treatment followed by ESS.

Effectiveness of beta blockers in patients with and without a history of myocardial infarction.

PURPOSE: Studies demonstrating mortality benefit of beta blockers (BB) after myocardial infarction (MI) were conducted before the era of percutaneous intervention and widespread use of statins. Recent retrospective studies show inconsistent results regarding which subgroups of coronary artery disease (CAD) patients' benefit. Most studies did not account for medication changes over time. We evaluated the association of time-varying BB exposure with death in CAD patients with or without a history of MI. METHODS: This retrospective cohort study included all patients with MI and those with coronary disease but no MI at a single health care system who also had health insurance from January 1, 1997, to June 30, 2011. Pharmacy claims data were used to estimate BB exposure over 6-month rolling windows. The primary endpoint was all-cause death. The effect of BB exposure was tested using time-updated Cox proportional hazards models. RESULTS: We identified 6220 patients with MI and 21,285 patients with CAD but no MI. Among patients who suffered MI, BB exposure was associated with a 31% relative risk reduction in all-cause death (hazard ratio [HR] 0.69, P = 0.001). Among subjects who survived 3 years after MI, BB retained a protective association (HR 0.71, P = 0.001). Among CAD-only patients, BB exposure was also associated with risk reduction (HR 0.85, P = 0.001). CONCLUSION: Among patients with CAD, BB exposure is associated with reduced risk of death. The association is strongest among those who have suffered MI. This favorable association appears durable beyond 3 years.

Impact of a specialty trained billing team on an academic otolaryngology practice.

PURPOSE: To determine how the incorporation of specialty specific training for coders within a focused billing team affected revenue, efficiency, time to reimbursement, and physician satisfaction in an academic otolaryngology practice. MATERIALS AND METHODS: Our academic otolaryngology department recently implemented a new billing system, which incorporated additional training in otolaryngology surgical procedures for medical coders. A mixed model analysis of variance was used to compare billing outcomes for the 6 months before and 6 months after this new approach was initiated. The following metrics were analyzed: Current Procedural Terminology codes, total charges, time between services rendered and billing submission, and time to reimbursement. A survey of department physicians assessing satisfaction with the system was reviewed. RESULTS: There were 4087 Current Procedural Terminology codes included in the analysis. In comparing the periods before and after implementation of the new system, statistically significant decreases were found in the mean number of days to coding completion (19.3 to 12.0, respectively, p < 0.001), days to posting of charges (27.0 to 15.2, p < 0.001), days to final reimbursement (54.5 to 27.2, p < 0.001), and days to closure of form (179.2 to 76.6, p < 0.001). Physician satisfaction with communication and coder feedback increased from 36% to 64% after initiation of the new program. CONCLUSIONS: The implementation of additional specialty training for medical coders in the otolaryngology department of a large medical system was associated with improved revenue cycle efficiency. Additionally, this model appears to improve physician satisfaction and confidence with the coding system.

Postoperative pain with or without nasal splints after septoplasty and inferior turbinate reduction.

PURPOSE: To determine the effect of intranasal Doyle splints on postoperative pain following septoplasty and inferior turbinate reduction (ITR). Changes in Nasal Obstruction Symptom Evaluation (NOSE) scores were also evaluated. MATERIALS AND METHODS: A prospective cohort study conducted from January 2017 to January 2019. Patients were recruited if they experienced nasal obstruction due to septal deviation and inferior turbinate hypertrophy, and failed a one-month trial of intranasal corticosteroids. All patients underwent septoplasty with ITR, and either had Doyle splints or no splints placed. Patients were prescribed hydrocodone-acetaminophen 5-325 mg and asked to keep a daily log of pain medication use and visual analog scale (VAS) scores. Pain logs and NOSE scores were compared between patients who had splints versus patients who had no splints placed after septoplasty and ITR over the first postoperative week. NOSE scores were also collected at every postoperative visit (1 week, 1 month, and 6 months). RESULTS: Fifty-seven patients were enrolled (37 splints, 20 no-splints). The median postoperative pain VAS score was 3.0 (interquartile range [IQR] 2.0-5.0) for the splint group and 4.0 (IQR 2.0-5.0) for the no-splint group (P = 0.906). The median postoperative pain medication requirement in morphine equivalents at the first postoperative visit was 5.4 mg/day (IQR 2.0-13.3) for the splint group and 8.4 mg/day (IQR 1.8-15.3) for the no-splint group (P = 0.833). CONCLUSIONS: There were no statistically significant differences in postoperative pain VAS scores or pain medication use between the two groups. All patients experienced significant reductions in NOSE scores postoperatively.

Renal release of N-acetyl-seryl-aspartyl-lysyl-proline is part of an antifibrotic peptidergic system in the kidney.

The antifibrotic peptide N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) is released from thymosin-ß4 (Tß4) by the meprin-α and prolyl oligopeptidase (POP) enzymes and is hydrolyzed by angiotensin-converting enzyme (ACE). Ac-SDKP is present in urine; however, it is not clear whether de novo tubular release occurs or if glomerular filtration is the main source. We hypothesized that Ac-SDKP is released into the lumen of the nephrons and that it exerts an antifibrotic effect. We determined the presence of Tß4, meprin-α, and POP in the kidneys of Sprague-Dawley rats. The stop-flow technique was used to evaluate Ac-SDKP formation in different nephron segments. Finally, we decreased Ac-SDKP formation by inhibiting the POP enzyme and evaluated the long-term effect in renal fibrosis. The Tß4 precursor and the releasing enzymes meprin-α and POP were expressed in the kidneys. POP enzyme activity was almost double that in the renal medulla compared with the renal cortex. With the use of the stop-flow technique, we detected the highest Ac-SDKP concentrations in the distal nephron. The infusion of a POP inhibitor into the kidney decreased the amount of Ac-SDKP in distal nephron segments and in the proximal nephron to a minor extent. An ACE inhibitor increased the Ac-SDKP content in all nephron segments, but the increase was highest in the distal portion. The chronic infusion of a POP inhibitor increased kidney medullary fibrosis, which was prevented by Ac-SDKP. We conclude that Ac-SDKP is released by the nephron and is part of an important antifibrotic system in the kidney.

Variation in patterns of health care before suicide: A population case-control study.

BACKGROUND: The United States has experienced a significant rise in suicide. As decision makers identify how to address this national concern, healthcare systems have been identified as an optimal location for prevention. OBJECTIVE: To compare variation in patterns of healthcare use, by health setting, between individuals who died by suicide and the general population. DESIGN: Case-Control Study. SETTING: Eight healthcare systems across the United States. PARTICIPANTS: 2674 individuals who died by suicide between 2000 and 2013 along with 267,400 individuals matched on time-period of health plan membership and health system affiliation. MEASUREMENTS: Healthcare use in the emergency room, inpatient hospital, primary care, and outpatient specialty setting measured using electronic health record data during the 7-, 30-, 60-, 90-, 180-, and 365-day time periods before suicide and matched index date for controls. RESULTS: Healthcare use was more common across all healthcare settings for individuals who died by suicide. Nearly 30% of individuals had a healthcare visit in the 7-days before suicide (6.5% emergency, 16.3% outpatient specialty, and 9.5% primary care), over half within 30 days, and >90% within 365 days. Those who died by suicide averaged 16.7 healthcare visits during the year. The relative risk of suicide was greatest for individuals who received care in the inpatient setting (aOR = 6.23). There was both a large relative risk (aOR = 3.08) and absolute utilization rate (43.8%) in the emergency room before suicide. LIMITATIONS: Participant race/ethnicity was not available. The sample did not include uninsured individuals. CONCLUSIONS: This study provides important data about how care utilization differs for those who die by suicide compared to the general population and can inform decision makers on targeting of suicide prevention activities within health systems.

Association of Regulatory Genetic Variants for Protein Kinase Cα with Mortality and Drug Efficacy in Patients with Heart Failure.

PURPOSE: Protein kinase C alpha (gene: PRKCA) is a key regulator of cardiac contractility. Two genetic variants have recently been discovered to regulate PRKCA expression in failing human heart tissue (rs9909004 [T → C] and rs9303504 [C → G]). The association of those variants with clinical outcomes in patients with heart failure (HF), and their interaction with HF drug efficacy, is unknown. METHODS: Patients with HF in a prospective registry starting in 2007 were genotyped by whole genome array (n = 951). The primary outcome was all-cause mortality. Cox proportional hazards models adjusted for established clinical risk factors and genomic ancestry tested the independent association of rs9909004 or rs9303504 and the variant interactions with cornerstone HF pharmacotherapies (beta-blockers or angiotensin-converting enzyme inhibitors/angiotensin receptor blockers) in additive genetic models. RESULTS: The minor allele of rs9909004, but not of rs9303504, was independently associated with a decreased risk for all-cause mortality: adjusted HR = 0.81 (95% CI = 0.67-0.98), p = 0.032. The variants did not significantly interact with mortality benefit associated with cornerstone HF pharmacotherapies (p > 0.1 for all). CONCLUSIONS: A recently discovered cardiac-specific regulatory variant for PRKCA (rs9909004) was independently associated with a decreased risk for all-cause mortality in patients with HF. The variant did not interact with mortality benefit associated with cornerstone HF pharmacotherapies.

Role of connecting tubule glomerular feedback in obesity related renal damage.

Zucker obese rats (ZOR) have higher glomerular capillary pressure (PGC) that can cause renal damage. PGC is controlled by afferent (Af-Art) and efferent arteriole (Ef-Art) resistance. Af-Art resistance is regulated by factors that regulate other arterioles, such as myogenic response. In addition, it is also regulated by 2 intrinsic feedback mechanisms: 1) tubuloglomerular feedback (TGF) that causes Af-Art constriction in response to increased NaCl in the macula densa and 2) connecting tubule glomerular feedback (CTGF) that causes Af-Art dilatation in response to an increase in NaCl transport in the connecting tubule via the epithelial sodium channel. Since CTGF is an Af-Art dilatory mechanism, we hypothesized that increased CTGF contributes to TGF attenuation, which in turn increases PGC in ZOR. We performed a renal micropuncture experiment and measured stop-flow pressure (PSF), which is an indirect measurement of PGC in ZOR. Maximal TGF response at 40 nl/min was attenuated in ZOR (4.47 ± 0.60 mmHg) in comparison to the Zucker lean rats (ZLR; 8.54 ± 0.73 mmHg, P < 0.05), and CTGF was elevated in ZOR (5.34 ± 0.87 mmHg) compared with ZLR (1.12 ± 1.28 mmHg, P < 0.05). CTGF inhibition with epithelial sodium channel blocker normalized the maximum PSF change in ZOR indicating that CTGF plays a significant role in TGF attenuation (ZOR, 10.67 ± 1.07 mmHg vs. ZLR, 9.5 ± 1.53 mmHg). We conclude that enhanced CTGF contributes to TGF attenuation in ZOR and potentially contribute to progressive renal damage.

Noninvasive measurement of renal blood flow by magnetic resonance imaging in rats.

Renal blood flow (RBF) provides important information regarding renal physiology and nephropathies. Arterial spin labeling-magnetic resonance imaging (ASL-MRI) is a noninvasive method of measuring blood flow without exogenous contrast media. However, low signal-to-noise ratio and respiratory motion artifacts are challenges for RBF measurements in small animals. Our objective was to evaluate the feasibility and reproducibility of RBF measurements by ASL-MRI using respiratory-gating and navigator correction methods to reduce motion artifacts. ASL-MRI images were obtained from the kidneys of Sprague-Dawley (SD) rats on a 7-Tesla Varian MRI system with a spin-echo imaging sequence. After 4 days, the study was repeated to evaluate its reproducibility. RBF was also measured in animals under unilateral nephrectomy and in renal artery stenosis (RST) to evaluate the sensitivity in high and low RBF models, respectively. RBF was also evaluated in Dahl salt-sensitive (SS) rats and spontaneous hypertensive rats (SHR). In SD rats, the cortical RBFs (cRBF) were 305 ± 59 and 271.8 ± 39 ml·min-1·100 g tissue-1 in the right and left kidneys, respectively. Retest analysis revealed no differences ( P = 0.2). The test-retest reliability coefficient was 92 ± 5%. The cRBFs before and after the nephrectomy were 296.8 ± 30 and 428.2 ± 45 ml·min-1·100 g tissue-1 ( P = 0.02), respectively. The kidneys with RST exhibited a cRBF decrease compared with sham animals (86 ± 17.6 vs. 198 ± 33.7 ml·min-1·100 g tissue-1; P < 0.01). The cRBFs in SD, Dahl-SS, and SHR rats were not different ( P = 0.35). We conclude that ASL-MRI performed with navigator correction and respiratory gating is a feasible and reliable noninvasive method for measuring RBF in rats.

Connecting tubule glomerular feedback mediates tubuloglomerular feedback resetting after unilateral nephrectomy.

Unilaterally nephrectomized rats (UNx) have higher glomerular capillary pressure (PGC) that can cause significant glomerular injury in the remnant kidney. PGC is controlled by the ratio of afferent (Af-Art) and efferent arteriole resistance. Af-Art resistance in turn is regulated by two intrinsic feedback mechanisms: 1) tubuloglomerular feedback (TGF) that causes Af-Art constriction in response to increased NaCl in the macula densa; and 2) connecting tubule glomerular feedback (CTGF) that causes Af-Art dilatation in response to an increase in NaCl transport in the connecting tubule via the epithelial sodium channel (ENaC). Resetting of TGF post-UNx can allow systemic pressure to be transmitted to the glomerulus and cause renal damage, but the mechanism behind this resetting is unclear. Since CTGF is an Af-Art dilatory mechanism, we hypothesized that CTGF is increased after UNx and contributes to TGF resetting. To test this hypothesis, we performed UNx in Sprague-Dawley (8) rats. Twenty-four hours after surgery, we performed micropuncture of individual nephrons and measured stop-flow pressure (PSF). PSF is an indirect measurement of PGC. Maximal TGF response at 40 nl/min was 8.9 ± 1.24 mmHg in sham-UNx rats and 1.39 ± 1.02 mmHg in UNx rats, indicating TGF resetting after UNx. When CTGF was inhibited with the ENaC blocker benzamil (1 µM/l), the TGF response was 12.29 ± 2.01 mmHg in UNx rats and 13.03 ± 1.25 mmHg in sham-UNx rats, indicating restoration of the TGF responses in UNx. We conclude that enhanced CTGF contributes to TGF resetting after UNx.

Screening and follow-up for depression among Arab Americans.

BACKGROUND: The authors compared proportions and associations of depression screening, major depression, and follow-up care of Arab Americans compared to non-Hispanic whites, non-Hispanic blacks, Asians, and Hispanics. METHODS: Administrative data was electronically abstracted from a large health system in metropolitan Detroit among 97,918 adult patients in 2014 and 2015. A valid and reliable surname list was used to identify Arab Americans. Using chi-squares, we examined the relationship between race/ethnicity and depression screening, major depression, and follow-up care. We calculated odds ratios (OR) and 95% confidence intervals (CI) to examine the relationship between the main independent variable of race/ethnicity and the dependent variables of depression screening and major depression while controlling for confounders. RESULTS: Arab American women were 23% less likely to be screened for depression compared to non-Hispanic white women (OR = 0.77; 95% CI = 0.70, 0.86). The age- and sex-adjusted proportions of major depression were 5.5% for Arab Americans compared to 7.0% for Hispanics, 6.0% for non-Hispanic blacks, 5.9% for non-Hispanic whites, and 1.5% for Asians. Arab Americans with major depression were less likely to follow up with a behavioral specialist and more likely to follow up with a primary care physician compared to other racial and ethnic groups. CONCLUSIONS: Our study adds to the discourse on depression care among Arab Americans by highlighting the existing disparities related to adequate screening and appropriate management of depression. Future studies should include information about the influences of acculturation, culture, stigma, family, and religion on depression care.

Dermatologic Conditions and Risk of Suicide: A Case-Control Study.

BACKGROUND: Patients diagnosed with skin conditions have a higher risk of comorbid psychiatric conditions and suicide-related outcomes such as suicidal ideations and behaviors. There is paucity of evidence in the US general population about the risk of suicide death in patients with dermatologic conditions. METHODS: We conducted a retrospective case-control study to investigate the risk of suicide death in patients receiving care for dermatologic conditions. This study involved 8 US health systems. A total of 2674 individuals who died by suicide (cases) were matched with 267,400 general population control individuals. RESULTS: After adjusting for age, sex, and any mental health or substance use condition, we did not find an association between death by suicide and any skin condition including conditions where clinicians are generally concerned about the risk such as acne (adjusted odds ratio [aOR] = 1.04, p = 0.814), atopic dermatitis (aOR = 0.77, p = 0.28), and psoriasis (aOR = 0.91, p = 0.64). CONCLUSION: This case-control study provides no evidence of increased risk of death by suicide in individuals with major skin disorders in the US general population.

Effect of salt intake on afferent arteriolar dilatation: role of connecting tubule glomerular feedback (CTGF).

Afferent arteriole (Af-Art) resistance is modulated by two intrinsic nephron feedbacks: 1) the vasoconstrictor tubuloglomerular feedback (TGF) mediated by Na+-K+-2Cl- cotransporters (NKCC2) in the macula densa and blocked by furosemide and 2) the vasodilator connecting tubule glomerular feedback (CTGF), mediated by epithelial Na+ channels (ENaC) in the connecting tubule and blocked by benzamil. High salt intake reduces Af-Art vasoconstrictor ability in Dahl salt-sensitive rats (Dahl SS). Previously, we measured CTGF indirectly, by differences between TGF responses with and without CTGF inhibition. We recently developed a new method to measure CTGF more directly by simultaneously inhibiting NKCC2 and the Na+/H+ exchanger (NHE). We hypothesize that in vivo during simultaneous inhibition of NKCC2 and NHE, CTGF causes an Af-Art dilatation revealed by an increase in stop-flow pressure (PSF) in Dahl SS and that is enhanced with a high salt intake. In the presence of furosemide alone, increasing nephron perfusion did not change the PSF in either Dahl salt-resistant rats (Dahl SR) or Dahl SS. When furosemide and an NHE inhibitor, dimethylamiloride, were perfused simultaneously, an increase in tubular flow caused Af-Art dilatation that was demonstrated by an increase in PSF. This increase was greater in Dahl SS [4.5 ± 0.4 (SE) mmHg] than in Dahl SR (2.5 ± 0.3 mmHg; P < 0.01). We confirmed that CTGF causes this vasodilation, since benzamil completely blocked this effect. However, a high salt intake did not augment the Af-Art dilatation. We conclude that during simultaneous inhibition of NKCC2 and NHE in the nephron, CTGF induces Af-Art dilatation and a high salt intake failed to enhance this effect.

Assessing differences in inhaled corticosteroid response by self-reported race-ethnicity and genetic ancestry among asthmatic subjects.

BACKGROUND: Inhaled corticosteroids (ICSs) are the preferred treatment for achieving asthma control. However, little is known regarding the factors contributing to treatment response and whether treatment response differs by population group. OBJECTIVE: We sought to assess behavioral, sociodemographic, and genetic factors related to ICS response among African American and European American subjects with asthma. METHODS: Study participants were part of the Study of Asthma Phenotypes and Pharmacogenomic Interactions by Race-ethnicity (SAPPHIRE). The analytic sample included asthmatic subjects aged 12 to 56 years with greater than 12% bronchodilator reversibility and percent predicted FEV1 of between 40% and 90%. Participants received 6 weeks of inhaled beclomethasone dipropionate. The primary measure of ICS response was a change in Asthma Control Test (ACT) score; the secondary measure was a change in prebronchodilator FEV1. Adherence was measured with electronic monitors. Genetic ancestry was estimated for African American participants by using genome-wide genotype data. RESULTS: There were 339 study participants; 242 self-identified as African American and 97 as European American. Baseline ACT score, percent predicted FEV1, degree of bronchodilator response, and ICS adherence were significantly associated with ICS response. A baseline ACT score of 19 or less was useful in identifying those who would respond, as evidenced by the significant dose-response relationship with ICS adherence. Neither self-reported race-ethnicity among all participants nor proportion of African ancestry among African American participants was associated with ICS responsiveness. CONCLUSIONS: Our findings suggest that baseline lung function measures and self-reported asthma control predict ICS response, whereas self-reported race-ethnicity and genetic ancestry do not.

Mechanisms of connecting tubule glomerular feedback enhancement by aldosterone.

Connecting tubule glomerular feedback (CTGF) is a mechanism where an increase in sodium (Na) concentration in the connecting tubule (CNT) causes the afferent arteriole (Af-Art) to dilate. We recently reported that aldosterone within the CNT lumen enhances CTGF via a nongenomic effect involving GPR30 receptors and sodium/hydrogen exchanger (NHE), but the signaling pathways of this mechanism are unknown. We hypothesize that aldosterone enhances CTGF via cAMP/protein kinase A (PKA) pathway that activates protein kinase C (PKC) and stimulates superoxide (O2-) production. Rabbit Af-Arts and their adherent CNTs were microdissected and simultaneously perfused. Two consecutive CTGF curves were elicited by increasing the CNT luminal NaCl. We found that the main effect of aldosterone was to sensitize CTGF and we analyzed data by comparing NaCl concentration in the CNT perfusate needed to achieve half of the maximal response (EC50). During the control period, the NaCl concentration that elicited a half-maximal response (EC50) was 37.0 ± 2.0 mmol/l; addition of aldosterone (10-8 mol/l) to the CNT lumen decreased EC50 to 19.3 ± 1.3 mmol/l (P ≤ 0.001 vs. Control). The specific adenylyl cyclase inhibitor 2',3'-dideoxyadenosine (ddA; 2 × 10-4 mol/l) and the PKA inhibitor H-89 dihydrochloride hydrate (H-89; 2 × 10-6 mol/l) prevented the aldosterone effect. The selective PKC inhibitor GF109203X (10-8 mol/l) also prevented EC50 reduction caused by aldosterone. CNT intraluminal addition of O2- scavenger tempol (10-4 mol/l) blocked the aldosterone effect. We conclude that aldosterone inside the CNT lumen enhances CTGF via a cAMP/PKA/PKC pathway and stimulates O2- generation and this process may contribute to renal damage by increasing glomerular capillary pressure.

The anti-inflammatory peptide Ac-SDKP is released from thymosin-ß4 by renal meprin-α and prolyl oligopeptidase.

N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) is a natural tetrapeptide with anti-inflammatory and antifibrotic properties. Previously, we have shown that prolyl oligopeptidase (POP) is involved in the Ac-SDKP release from thymosin-ß4 (Tß4). However, POP can only hydrolyze peptides shorter than 30 amino acids, and Tß4 is 43 amino acids long. This indicates that before POP hydrolysis takes place, Tß4 is hydrolyzed by another peptidase that releases NH2-terminal intermediate peptide(s) with fewer than 30 amino acids. Our peptidase database search pointed out meprin-α metalloprotease as a potential candidate. Therefore, we hypothesized that, prior to POP hydrolysis, Tß4 is hydrolyzed by meprin-α. In vitro, we found that the incubation of Tß4 with both meprin-α and POP released Ac-SDKP, whereas no Ac-SDKP was released when Tß4 was incubated with either meprin-α or POP alone. Incubation of Tß4 with rat kidney homogenates significantly released Ac-SDKP, which was blocked by the meprin-α inhibitor actinonin. In addition, kidneys from meprin-α knockout (KO) mice showed significantly lower basal Ac-SDKP amount, compared with wild-type mice. Kidney homogenates from meprin-α KO mice failed to release Ac-SDKP from Tß4. In vivo, we observed that rats treated with the ACE inhibitor captopril increased plasma concentrations of Ac-SDKP, which was inhibited by the coadministration of actinonin (vehicle, 3.1 ± 0.2 nmol/l; captopril, 15.1 ± 0.7 nmol/l; captopril + actinonin, 6.1 ± 0.3 nmol/l; P < 0.005). Similar results were obtained with urinary Ac-SDKP after actinonin treatment. We conclude that release of Ac-SDKP from Tß4 is mediated by successive hydrolysis involving meprin-α and POP.

Ac-SDKP suppresses TNF-α-induced ICAM-1 expression in endothelial cells via inhibition of IκB kinase and NF-κB activation.

N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) is a naturally occurring tetrapeptide that prevents inflammation and fibrosis in hypertension and other cardiovascular diseases. We previously showed that, in angiotensin II-induced hypertension, Ac-SDKP decreased the activation of nuclear transcription factor NF-κB, whereas, in experimental autoimmune myocarditis and hypertension animal models, it also reduced the expression of endothelial leukocyte adhesion molecule ICAM-1. However, the mechanisms by which Ac-SDKP downregulated ICAM-1 expression are still unclear. TNF-α is a proinflammatory cytokine that induces ICAM-1 expression in various cell types via TNF receptor 1 and activation of the classical NF-κB pathway. We hypothesized that in endothelial cells Ac-SDKP suppresses TNF-α-induced ICAM-1 expression by decreasing IKK phosphorylation that as a consequence leads to a decrease of IκB phosphorylation and NF-κB activation. To test this hypothesis, human coronary artery endothelial cells were treated with Ac-SDKP and then stimulated with TNF-α. We found that TNF-α-induced ICAM-1 expression was significantly decreased by Ac-SDKP in a dose-dependent manner. Ac-SDKP also decreased TNF-α-induced NF-κB translocation from cytosol to nucleus, as assessed by electrophoretic mobility shift assay, which correlated with a decrease in IκB phosphorylation. In addition, we found that Ac-SDKP decreased TNF-α-induced IKK phosphorylation and IKK-ß expression. However, Ac-SDKP had no effect on TNF-α-induced phosphorylation of p38 MAP kinase or ERK. Thus we conclude that Ac-SDKP inhibition of TNF-α activation of canonical, i.e., IKK-ß-dependent, NF-κB pathway and subsequent decrease in ICAM-1 expression is achieved via inhibition of IKK-ß.

Cardiac-deleterious role of galectin-3 in chronic angiotensin II-induced hypertension.

Galectin-3 (Gal-3), a member of the ß-galactoside lectin family, has an important role in immune regulation. In hypertensive rats and heart failure patients, Gal-3 is considered a marker for an unfavorable prognosis. Nevertheless, the role and mechanism of Gal-3 action in hypertension-induced target organ damage are unknown. We hypothesized that, in angiotensin II (ANG II)-induced hypertension, genetic deletion of Gal-3 prevents left ventricular (LV) adverse remodeling and LV dysfunction by reducing the innate immune responses and myocardial fibrosis. To induce hypertension, male C57BL/6J and Gal-3 knockout (KO) mice were infused with ANG II (3 µg·min-1·kg-1 sc) for 8 wk. We assessed: 1) systolic blood pressure by plethysmography, 2) LV function and remodeling by echocardiography, 3) myocardial fibrosis by histology, 4) cardiac CD68+ macrophage infiltration by histology, 5) ICAM-1 and VCAM-1 expression by Western blotting, 6) plasma cytokines, including interleukin-6 (IL-6), by enzyme-linked immunosorbent assay, and 7) regulatory T (Treg) cells by flow cytometry as detected by their combined expression of CD4, CD25, and FOXP3. Systolic blood pressure and cardiac hypertrophy increased similarly in both mouse strains when infused with ANG II. However, hypertensive C57BL/6J mice suffered impaired ejection and shortening fractions. In these mice, the extent of myocardial fibrosis and macrophage infiltration was greater in histological sections, and cardiac ICAM-1, as well as plasma IL-6, expression was higher as assessed by Western blotting. However, all these parameters were blunted in Gal-3 KO mice. Hypertensive Gal-3 KO mice also had a higher number of splenic Treg lymphocytes. In conclusion, in ANG II-induced hypertension, genetic deletion of Gal-3 prevented LV dysfunction without affecting blood pressure or LV hypertrophy. This study indicates that the ANG II effects are, in part, mediated or triggered by Gal-3 together with the related intercellular signaling (ICAM-1 and IL-6), leading to cardiac inflammation and fibrosis.

Clinical utility of carotid duplex ultrasound prior to cardiac surgery.

OBJECTIVE: Clinical utility and cost-effectiveness of carotid duplex examination prior to cardiac surgery have been questioned by the multidisciplinary committee creating the 2012 Appropriate Use Criteria for Peripheral Vascular Laboratory Testing. We report the clinical outcomes and postoperative neurologic symptoms in patients who underwent carotid duplex ultrasound prior to open heart surgery at a tertiary institution. METHODS: Using the combined databases from our clinical vascular laboratory and the Society of Thoracic Surgery, a retrospective analysis of all patients who underwent carotid duplex ultrasound within 13 months prior to open heart surgery from March 2005 to March 2013 was performed. The outcomes between those who underwent carotid duplex scanning (group A) and those who did not (group B) were compared. RESULTS: Among 3233 patients in the cohort who underwent cardiac surgery, 515 (15.9%) patients underwent a carotid duplex ultrasound preoperatively, and 2718 patients did not (84.1%). Among the patients who underwent carotid screening vs no screening, there was no statistically significant difference in the risk factors of cerebrovascular disease (10.9% vs 12.7%; P = .26), prior stroke (8.2% vs 7.2%; P = .41), and prior transient ischemic attack (2.9% vs 3.3%; P = .24). For those undergoing isolated coronary artery bypass grafting (CABG), 306 (17.8%) of 1723 patients underwent preoperative carotid duplex ultrasound. Among patients who had carotid screening prior to CABG, the incidence of carotid disease was low: 249 (81.4%) had minimal or mild stenosis (<50%); 25 (8.2%) had unilateral moderate stenosis (50%-69%); 10 (3.3%) had bilateral moderate stenosis; 9 (2.9%) had unilateral severe stenosis (70%-99%); 5 (1.6%) had contralateral moderate stenosis; 2 (0.7%) had bilateral severe stenosis; 4 (1.3%) had unilateral occluded with contralateral less than 50% stenosis, 1 (0.3%) had unilateral occluded with contralateral (70%-99%) stenosis; and 1 had bilateral occluded carotid arteries. Primary outcomes of patients who underwent isolated CABG showed no difference in the perioperative mortality (2.9% vs 4.3%; P = .27) and stroke (2.9% vs 2.6%; P = .70) between patients undergoing preoperative duplex scanning and those who did not. Primary outcomes of patients who underwent open heart surgery also showed no difference in the perioperative mortality (5.1% vs 6.9%; P = .14) and stroke (2.6% vs 2.4%; P = .85) between patients undergoing preoperative duplex scanning and those who did not. Operative intervention of severe carotid stenosis prior to isolated CABG occurred in 2 of the 17 patients (11.8%) identified who underwent carotid endarterectomy with CABG. CONCLUSIONS: In this study, the correlation between preoperative duplex-documented high-grade carotid stenosis and postoperative stroke was low. Prudent use of preoperative carotid duplex ultrasound should be based on the presence of cerebrovascular symptoms and the type of open heart surgery.

Examining health literacy among urban African-American adolescents with asthma.

OBJECTIVE: This exploratory study assessed health literacy among urban African-American high school students to improve understanding of the association between adolescent health literacy and asthma. METHODS: We conducted a secondary data analysis of the control group (n = 181) of the Puff City randomized controlled trial (2006-2010), a web-based intervention to promote asthma management among students, grades 9 through 12. A validated self-report 3-item health literacy screening instrument was completed at final online follow-up survey. Logistic regression was used to explore the association between health literacy, demographic characteristics, quality of life, asthma management, and health care utilization. RESULTS: Multivariate analysis revealed that an overall inadequate health literacy score was associated with students who were more likely to be younger (OR 0.61; 95% CI 0.44-0.84), not on Medicaid (OR 0.36; 95% CI 0.17-0.76), have at least one hospitalization (OR 1.29; 95% CI 1.07-1.56); and a lower overall quality of life (OR 0.75; 95% CI 0.59-0.95). Those lacking confidence in filling out medical forms, needing help reading hospital materials, and having difficulty understanding written information were more likely to not have a rescue inhaler (OR 0.49; 95% CI 0.25-0.94), have one or more emergency visits (OR 1.21 95% CI 1.02-1.43), and one or more hospitalizations (OR 1.19; 95% CI 1.01-1.41), respectively. CONCLUSIONS: The findings indicate a significant association between inadequate health literary and suboptimal asthma management. It is important to advance understanding of adolescent health literacy, especially those at-risk, as they assume asthma self-management tasks and move toward independent adult self-care.