Abstract Objective The purpose of this study was to establish a reliable, chronic model of abdominal aortic aneurysm (AAA). Methods Wild-type 8-week-old C56BL/6 male mice (n = 120) were equally ...divided into three groups: (1) BAPN group: 0.2% 3-aminopropionitrile fumarate salt (BAPN) drinking water was provided to mice 2 days before surgery until the end of study. Sham aneurysm induction surgery was performed using 5 μL of heat deactivated elastase. (2) Elastase group: mice were given regular drinking water without BAPN. During aneurysm induction surgery, 5 μL of the active form of elastase (10.3 mg protein/mL, 5.9 U/mg protein) was applied on top of the infrarenal abdominal aorta adventitia for 5 minutes. (3) BAPN+elastase group: mice were given BAPN drinking water and the active form of elastase application, as above. On postoperative days 7, 14, 21, 28, and 100, aortic samples were collected for histology, cytokine array, and gelatin zymography after aortic diameter measurement. Results Compared with the elastase group, the BAPN+elastase group had a higher AAA formation rate (93% vs 65%; P < .01) with more advanced AAAs (25 of 42 vs 1 of 40 for stage II and III; P < .001). Aneurysms from the BAPN+elastase group demonstrated persistent long-term growth (221.5% ± 36.6%, 285.8% ± 78.6%, and 801% ± 160% on days 21, 28, and 100, respectively; P < .001), with considerable thrombus formation (54%) and rupture (31%) at the advanced stages of AAA development. Cytokine levels (pro-matrix metalloproteinase 9, interleukin-1β, interleukin-6, chemokine C-C motif ligand 5, triggering receptor expressed on myeloid cells 1, monocyte chemotactic protein 1, and tissue inhibitor of metalloproteinase 1) in the BAPN+elastase group were higher than in the elastase group on day 7. After day 7, cytokine levels returned to baseline, with the exception of elevated matrix metalloproteinase 2 activity. By histology, CD3-positive T cells in the BAPN+elastase group were elevated on days 28 and 100. Conclusions A combination of oral BAPN administration and periaortic elastase application induced a chronic, advanced-stage AAA with characteristics of persistent aneurysm growth, thrombus formation, and spontaneous rupture. Future studies should use this model, especially for examining tissue remodeling during the late stages of aneurysm development.
This report aims to characterize the kinetics of serum albumin in critically ill patients with coronavirus disease 2019 compared with critically ill patients with sepsis-induced acute respiratory ...distress syndrome.
Retrospective analysis.
We analyzed two critically ill cohorts, one with coronavirus disease 2019 and another with sepsis-induced acute respiratory distress syndrome, treated in the New York Presbyterian Hospital-Weill Cornell Medical Center.
Adult patients in the coronavirus disease 2019 cohort, diagnosed through reverse transcriptase-polymerase chain reaction assays performed on nasopharyngeal swabs, were admitted from March 3, 2020, to July 10, 2020. Adult patients in the sepsis-induced acute respiratory distress syndrome cohort, defined by Sepsis III criteria receipt of invasive mechanical ventilation and a Pao
/Fio
ratio less than 300 were admitted from December 12, 2006, to February 26, 2019.
None.
We evaluated serial serum albumin levels within 30 days after ICU admission in each cohort. We then examined the albumin progression trajectories, aligned at ICU admission time to test the relationship at a similar point in disease progression, in survivors and nonsurvivors. Albumin trajectory in all critically ill coronavirus disease 2019 patients show two distinct phases: phase I (deterioration) showing rapid albumin loss and phase II (recovery) showing albumin stabilization or improvement. Meanwhile, albumin recovery predicted clinical improvement in critical coronavirus disease 2019. In addition, we found a deterioration and recovery trends in survivors in the sepsis-induced acute respiratory distress syndrome cohort but did not find such two-phase trend in nonsurvivors.
The changes in albumin associated with coronavirus disease 2019 associated respiratory failure are transient compared with sepsis-associated acute respiratory distress syndrome and highlight the potential for recovery following a protracted course of severe coronavirus disease 2019.
Summary Background Iodine deficiency is the most common cause of preventable mental impairment worldwide. It is defined by WHO as mild if the population median urinary iodine excretion is 50–99 μg/L, ...moderate if 20–49 μg/L, and severe if less than 20 μg/L. No contemporary data are available for the UK, which has no programme of food or salt iodination. We aimed to assess the current iodine status of the UK population. Methods In this cross-sectional survey, we systematically assessed iodine status in schoolgirls aged 14–15 years attending secondary school in nine UK centres. Urinary iodine concentrations and tap water iodine concentrations were measured in June–July, 2009, and November–December, 2009. Ethnic origin, postcode, and a validated diet questionnaire assessing sources of iodine were recorded. Findings 810 participants provided 737 urine samples. Data for dietary habits and iodine status were available for 664 participants. Median urinary iodine excretion was 80·1 μg/L (IQR 56·9–109·0). Urinary iodine measurements indicative of mild iodine deficiency were present in 51% (n=379) of participants, moderate deficiency in 16% (n=120), and severe deficiency in 1% (n=8). Prevalence of iodine deficiency was highest in Belfast (85%, n=135). Tap water iodine concentrations were low or undetectable and were not positively associated with urinary iodine concentrations. Multivariable general linear model analysis confirmed independent associations between low urinary iodine excretion and sampling in summer (p<0·0001), UK geographical location (p<0·0001), low intake of milk (p=0·03), and high intake of eggs (p=0·02). Interpretation Our findings suggest that the UK is iodine deficient. Since developing fetuses are the most susceptible to adverse effects of iodine deficiency and even mild perturbations of maternal and fetal thyroid function have an effect on neurodevelopment, these findings are of potential major public health importance. This study has drawn attention to an urgent need for a comprehensive investigation of UK iodine status and implementation of evidence-based recommendations for iodine supplementation. Funding Clinical Endocrinology Trust.
Background Dedicator of cytokinesis 8 (DOCK8) deficiency is a combined immunodeficiency caused by autosomal recessive loss-of-function mutations in DOCK8 . This disorder is characterized by recurrent ...cutaneous infections, increased serum IgE levels, and severe atopic disease, including food-induced anaphylaxis. However, the contribution of defects in CD4+ T cells to disease pathogenesis in these patients has not been thoroughly investigated. Objective We sought to investigate the phenotype and function of DOCK8-deficient CD4+ T cells to determine (1) intrinsic and extrinsic CD4+ T-cell defects and (2) how defects account for the clinical features of DOCK8 deficiency. Methods We performed in-depth analysis of the CD4+ T-cell compartment of DOCK8-deficient patients. We enumerated subsets of CD4+ T helper cells and assessed cytokine production and transcription factor expression. Finally, we determined the levels of IgE specific for staple foods and house dust mite allergens in DOCK8-deficient patients and healthy control subjects. Results DOCK8-deficient memory CD4+ T cells were biased toward a TH 2 type, and this was at the expense of TH 1 and TH 17 cells. In vitro polarization of DOCK8-deficient naive CD4+ T cells revealed the TH 2 bias and TH 17 defect to be T-cell intrinsic. Examination of allergen-specific IgE revealed plasma IgE from DOCK8-deficient patients is directed against staple food antigens but not house dust mites. Conclusion Investigations into the DOCK8-deficient CD4+ T cells provided an explanation for some of the clinical features of this disorder: the TH 2 bias is likely to contribute to atopic disease, whereas defects in TH 1 and TH 17 cells compromise antiviral and antifungal immunity, respectively, explaining the infectious susceptibility of DOCK8-deficient patients.
Background Testosterone is theorized to play a major role in the pathophysiology of abdominal aortic aneurysms (AAAs) because this disease occurs primarily in men. The role of the androgen receptor ...(AR) in the formation of AAAs has not been well elucidated, and therefore, it is hypothesized that androgen blockade will attenuate experimental aortic aneurysm formation. Methods Aortas of 8- to 12-week-old male C57Bl/6 wild-type (WT) mice or male AR knockout (AR−/− ) mice were perfused with purified porcine pancreatic elastase (0.35 U/mL) to induce AAA formation. Two groups of WT male mice were treated with the AR blockers flutamide (50 mg/kg) or ketoconazole (150 mg/kg) twice daily by intraperitoneal injection. Aortas were harvested on day 14 after video micrometry was used to measure AAA diameter. Cytokine arrays and histologic analysis were performed on aortic tissue. Groups were compared using an analysis of variance and a Tukey post hoc test. Results Flutamide and ketoconazole treatment (mean ± standard error of the mean) attenuated AAA formation in WT mice (84.2% ± 22.8% P = .009 and 91.5% ± 18.2% P = .037) compared with WT elastase (121% ± 5.23%). In addition, AR−/− mice showed attenuation of AAA growth (64.4% ± 22.7%; P < .0001) compared with WT elastase. Cytokine arrays of aortic tissue revealed decreased levels of proinflammatory cytokines interleukin (IL)-α, IL-6, and IL-17 in flutamide-treated and AR−/− groups compared with controls. Conclusions Pharmacologic and genetic AR blockade cause attenuation of AAA formation. Therapies for AR blockade used in prostate cancer may provide medical treatment to halt progression of AAAs in humans.
Objective Patients presenting with acute coronary syndrome (ACS) are treated with dual antiplatelet agents, including aspirin and clopidogrel, to prevent mortality and recurrent ischemia. However, ...those who require coronary artery bypass grafting (CABG) could have increased postoperative bleeding and bleeding-related adverse outcomes. The current guidelines on clinical management differ significantly. The present meta-analysis examined the evidence for clopidogrel in the treatment of patients presenting with ACS requiring CABG, with a focus on the timing of medication cessation before surgery. Methods A systematic review of 9 electronic databases was performed to identify all relevant studies with comparable outcomes for patients with ACS treated with clopidogrel before CABG. The endpoints included reoperation, major bleeding, mortality, and a composite endpoint of mortality and recurrent myocardial infarction. Results Five relevant studies were identified according to the predefined selection criteria. Patients who had received clopidogrel had a significantly lower incidence of composite endpoints than those who had not. However, patients who underwent CABG < 5 days after the last dose of clopidogrel had a significantly greater incidence of reoperation, major bleeding, and combined adverse outcomes than those who had had a washout period >5 days. Conclusions The results from the present meta-analysis suggest that patients who present with ACS should be treated with dual antiplatelet therapy, including clopidogrel. However, for patients subsequently referred for CABG, a minimum washout period of 5 days should be observed to minimize perioperative bleeding and bleeding-related complications, unless emergency indications exist. These results differ from those of previous studies and guidelines.
Background There is a lack of validated standardized outcome measures for epidermolysis bullosa (EB) that can separate activity from damage. Objective We sought to develop and validate an instrument ...for inherited EB of all ages and subtypes, the EB Disease Activity and Scarring Index (EBDASI), which scores activity responsive to therapy separately from scarring. Methods The EBDASI was validated by comparing its reliability and validity against the Birmingham EB Severity (BEBS) score (partially validated with activity mixed with scarring), using the Physician Global Assessment (PGA) scale as a reference measurement. Sixteen patients with EB (7 EB simplex, 5 dominant dystrophic EB DDEB, 2 junctional EB, and 2 recessive dystrophic EB) were assessed by 5 EB experts using the EBDASI, BEBS, and PGA, and data from 9 additional patients assessed on an ad hoc basis during routine patient clinic were also included. Results For interrater reliability, the overall total score intraclass correlation coefficients (95% confidence intervals) were: EBDASI 0.964 (0.929-0.986), BEBS 0.852 (0.730-0.937), and PGA 0.873 (0.765-0.946). For intrarater reliability, the intraclass correlation coefficients were: EBDASI 0.994 (0.976-0.998), BEBS 0.926 (0.748-0.981), and PGA 0.932 (0.764-0.982). The EBDASI had a higher correlation with PGA (ρ = 0.871) than BEBS with PGA (ρ = 0.852). Intraclass correlation coefficients scatterplots showed the EBDASI was better at distinguishing milder forms of EB, with better correlations at higher severity scores than the BEBS. Limitations A limited number of patients were recruited for this study. An independent study will be required to demonstrate the responsiveness of the EBDASI. Conclusion The EBDASI demonstrated excellent reliability and validity, as compared with 2 other outcome measures.
Abstract Background We previously showed in heart failure (HF) patients that obstructive respiratory events during sleep and generation of negative intrathoracic pressure during Mueller manoeuvres, ...mimicking obstructive apneas, acutely reduced stroke volume (SV). We also showed that treating obstructive sleep apnea (OSA) with continuous positive airway pressure (CPAP) increased left ventricular ejection fraction over a 1-month period. We therefore hypothesized that, in HF patients, those with OSA would have greater overnight declines in SV and cardiac output (CO) than in those without sleep apnea, and that therapy of OSA using CPAP would prevent these declines. Methods We examined overnight percent change in SV and CO in 32 HF patients with and 28 without OSA using digital photoplethysmography. Among patients with OSA, we also examined changes in SV and CO during a CPAP titration study. Results During the baseline polysomnogram SV and CO decreased more overnight in those with OSA than in those without sleep apnea (−12.6 ± 7.7% vs −3.2 ± 6.8%; P < 0.001 and −16.2 ± 9.9% vs −3.7 ± 8.3%; P < 0.001, respectively). Overnight changes in SV and CO correlated inversely with total apnea-hypopnea index ( r = −0.551; P < 0.001 and r = −0.522; P < 0.001, respectively). In 21 patients with OSA, CPAP reduced the total apnea-hypopnea index from 37.7 ± 21.4 to 15.0 ± 16.0 ( P < 0.001) in association with attenuation of the overnight reduction of SV (from −14.0 ± 7.9% to −3.4 ± 9.8%; P = 0.002) and CO (from −17.2 ± 9.0% to −9.7 ± 10.7%; P = 0.042). Conclusions In patients with HF, coexisting OSA causes overnight declines in SV and CO that are prevented through reversal of OSA by CPAP.
Severe cutaneous adverse reactions (SCAR) are a group of delayed presumed T-cell mediated hypersensitivities associated with significant morbidity and mortality. Despite their shared global ...healthcare burden and impact, the clinical phenotypes, genomic predisposition, drug causality, and treatment outcomes may vary. We describe the establishment and results from the first Australasian registry for SCAR (AUS-SCAR), that via a collaborative network advances strategies for the prevention, diagnosis and treatment of SCAR.
Prospective multi-center registry of SCAR in Australian adult and adolescents, with planned regional expansion. The registry collects externally verified phenotypic data drug causality, therapeutics and long-term patient outcomes. In addition, biorepository specimens and DNA are collected at participating sites.
we report on the first 100 patients enrolled in the AUS-SCAR database. DRESS (50%) is the most predominant phenotype followed by SJS/TEN (39%) and AGEP (10%), with median age of 52 years old (IQR 37.5, 66) with 1:1 male-to-female ratio. The median latency for all implicated drugs is highly variable but similar for DRESS (median 15 days IQR 5,25) and SJS/TEN (median 21 days, IQR 7,27), while lowest for AGEP (median 2.5 days, IQR 1,8). Antibiotics (54.5%) are more commonly listed as primary implicated drug compare with non-antibiotics agent (45.5%). Mortality rate at 90 days was highest in SJS/TEN at 23.1%, followed by DRESS (4%) and AGEP (0%).
In the first prospective national phenotypic and biorepository of SCAR in the southern hemisphere we demonstrate notable differences to other reported registries; including DRESS-predominant phenotype, varied antibiotic causality and low overall mortality rate. This study also highlights the lack of standardised preventative pharmacogenomic measures and in vitro/in vivo diagnostic strategies to ascertain drug causality.
ANZCTR ACTRN12619000241134. Registered 19 February 2019.
Abstract Background No medical therapies are yet available to slow abdominal aortic aneurysm (AAA) growth. This study sought to investigate the effect of different genders of bone marrow-derived ...mesenchymal stem cells (MSC) on AAA growth in a murine AAA model. Given the decreased rate of AAA in women, it is hypothesized that female MSC would attenuate AAA growth more so than male MSC. Materials and methods Aortas of 8–10-wk-old male C57Bl/6 mice were perfused with purified porcine pancreatic elastase to induce AAA formation. Bone marrow-derived MSC from male and female mice were dosed via tail vein injection (3 million cells per dose, 500 μL of volume per injection) on postaortic perfusion days 1, 3, and 5. Aortas were harvested after 14 d. Results Mean aortic dilation in the elastase group was 121 ± 5.2% (mean ± standard error of the mean), while male MSC inhibited AAA growth (87.8 ± 6.9%, P = 0.008) compared with that of elastase. Female MSC showed the most marked attenuation of AAA growth (75.2 ± 8.3% P = 0.0004). Proinflammatory cytokines tumor necrosis factor α, interleukin 1β, and monocyte chemotactic protein-1 (MCP-1) were only decreased in tissues treated with female MSC ( P = 0.017, P = 0.001, and P < 0.0001, respectively, when compared with elastase). Conclusions These data exhibit that female MSC more strongly attenuate AAA growth in the murine model. Furthermore, female MSC and male MSC inhibit proinflammatory cytokines at varying levels. The effects of MSC on aortic tissue offer a promising insight into biologic therapies for future medical treatment of AAAs in humans.
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