Phenotype of the Cyp1a1/1a2/1b1-/- triple-knockout mouse

Crossing the Cyp1a1/1a2(-/-) double-knockout mouse with the Cyp1b1(-/-) single-knockout mouse, we generated the Cyp1a1/1a2/1b1(-/-) triple-knockout mouse. In this triple-knockout mouse, statistically significant phenotypes (with incomplete penetrance) included slower weight gain and greater risk of embryolethality before gestational day 11, hydrocephalus, hermaphroditism, and cystic ovaries. Oral benzo[a]pyrene (BaP) daily for 18 days in the Cyp1a1/1a2(-/-) produced the same degree of marked immunosuppression as seen in the Cyp1a1(-/-) mouse; we believe this reflects the absence of intestinal CYP1A1. Oral BaP-treated Cyp1a1/1a2/1b1(-/-) mice showed the same "rescued" response as that seen in the Cyp1a1/1b1(-/-) mouse; we believe this reflects the absence of CYP1B1 in immune tissues. Urinary metabolite profiles were dramatically different between untreated triple-knockout and wild-type; principal components analysis showed that the shifts in urinary metabolite patterns in oral BaP-treated triple-knockout and wild-type mice were also strikingly different. Liver microarray cDNA differential expression (comparing triple-knockout with wild-type) revealed at least 89 genes up- and 62 genes down-regulated (P-value < or = 0.00086). Gene Ontology "classes of genes" most perturbed in the untreated triple-knockout (compared with wild-type) include lipid, steroid, and cholesterol biosynthesis and metabolism; nucleosome and chromatin assembly; carboxylic and organic acid metabolism; metal-ion binding; and ion homeostasis. In the triple-knockout compared with the wild-type mice, response to zymosan-induced peritonitis was strikingly exaggerated, which may well reflect down-regulation of Socs2 expression. If a single common molecular pathway is responsible for all of these phenotypes, we suggest that functional effects of the loss of all three Cyp1 genes could be explained by perturbations in CYP1-mediated eicosanoid production, catabolism and activities.     

Clinical and electrocardiographic correlates of normal coronary angiography in patients referred for primary percutaneous coronary intervention

This study sought to determine the prevalence as well as clinical and electrocardiographic correlates of patients referred for primary percutaneous coronary intervention (PCI) who had angiographically normal coronary arteries. Data for 690 consecutive patients with ST-elevation myocardial infarction (STEMI) referred for primary PCI within a metropolitan area health service were reviewed. Characteristics of patients with angiographically normal coronary arteries (n = 87; 13%) were compared with patients with angiographically shown culprit lesions (control group; n = 594). Nine patients with significant coronary disease, but no identifiable culprit lesion, were excluded. Electrocardiograms (ECGs) from both groups were reviewed by 2 cardiologists blinded to angiographic findings. Patients in the normal coronaries group were younger and had fewer risk factors. On expert review of ECGs, 55% of patients in the normal coronaries group had ST-elevation criteria for STEMI (vs 93% in the control group; p <0.001), but the ECG was considered consistent with a diagnosis of STEMI by both observers in only 33% (vs 92% in the control group; p <0.001). Left branch bundle block independently correlated with normal coronary arteries on multivariate analysis (odds ratio for STEMI 0.016, 95% confidence interval 0.004 to 0.064, p <0.001). The discharge diagnosis in the normal coronaries group was predominantly pericarditis (n = 72; 83%). In conclusion, the prevalence of angiographically normal coronary arteries in patients referred for primary PCI was 13%. Electrocardiographic correlation suggested that this can be reduced by adherence to conventional electrocardiographic criteria for STEMI diagnosis and review of ECGs by experienced clinicians.     

Statins and Anti-Inflammatory Therapies for Subarachnoid Hemorrhage

Aneurysmal subarachnoid hemorrhage (SAH) induces a potent inflammatory cascade that contributes to endothelial dysfunction, imbalance of vasoactive substances (excess endothelin, depletion of nitric oxide), and arterial vasospasm. This process results in delayed cerebral ischemia, a major cause of neurologic disability in those surviving the initial hemorrhage. The only therapy shown to be effective in improving neurologic outcomes after SAH is a calcium-channel antagonist, nimodipine (although it achieved this result without reducing vasospasm). A number of novel therapies have been explored to inhibit the development of vasospasm and reduce the burden of ischemia and cerebral infarction. Statins are promising candidates, as they block multiple aspects of the inflammatory pathway that contributes to ischemic brain injury. Early clinical trials have produced conflicting results, however, and the adoption of statins in clinical practice should await the results of larger, more definitive studies. Though endothelin-receptor antagonists showed promise in significantly reducing vasospasm in preliminary trials, their failure to improve clinical outcomes in phase 3 studies has been disappointing, highlighting the complex link between vasospasm and ischemia. Future directions in the quest to improve outcomes of patients with SAH may need to approach ischemia as a multifactorial process with inflammatory, vasoactive, and ionic/metabolic components.     

Satisfaction with joint replacement in public versus private hospitals: a cohort study

Introduction: In Australia, the majority of total knee and hip replacement surgeries occur in the private sector. Outcome-based research needs to be inclusive of this sector if the findings are intended to reflect the broader picture. This study compares outcomes up to 1 year post knee and hip replacement between patients treated in the public and private sectors. Methods: A prospective, observational study was performed in four high-volume joint replacement centres: two public, two private. Experienced orthopaedic surgeons contributed via their public and private practices. Knee and hip patients were recruited preoperatively. Self-reported questionnaires were completed preoperatively and at 6 and 12 months post-operatively. The primary outcome was satisfaction with surgery. Secondary outcomes included Oxford score, and SF-36 physical and mental component summary scores. Regression modelling was performed to adjust for potential confounders. Results: Three hundred and thirty-one patients (184 public, 147 private; 215 knees, 116 hips) were recruited, with 6- and 12-month follow-up rates of 95% and 89%, respectively. Satisfaction rates were high in both public and private patients (approximately 90%) at 6 and 12 months, but private patients were less likely to be satisfied after adjusting for the strong effect of patient expectation. For both hip and knee cohorts, no between-sector differences were found in either the magnitude or rate of improvement in Oxford score or quality of life post-operatively. Discussion: Joint replacement outcomes are similar for patients treated in public and private hospitals. Surgeons should manage patient expectation prior to surgery, particularly in private patients.     

Geographic Variation in Cardiovascular Health Among American Adults

ObjectiveTo evaluate the contemporary geographic trends in cardiovascular health in the United States and its relationship with geographic distribution of cardiovascular mortality.MethodsBy use of a retrospective cross-sectional design, the 2011-2017 Behavioral Risk Factor Surveillance System (BRFSS) was queried to determine the age-adjusted prevalence of cardiovascular health index (CVHI) metrics (sum of ideal blood pressure, blood glucose concentration, lipid levels, body mass index, smoking, physical activity, and diet). Cardiovascular health was estimated as both continuous (0 to 7 points) and categorical (ideal, intermediate, poor) variables from the BRFSS. Age-adjusted cardiovascular mortality for 2017 was obtained from the Centers for Disease Control and Prevention WONDER database.ResultsAmong 1,362,529 American adult participants of the BRFSS 2011-2017 and all American residents in 2017, the CVHI score increased from 3.89±0.004 in 2011 to 3.96±0.005 in 2017 (P_trend<.001) nationally, with modest improvement across all regions (P_trend<.05 for all). Ideal cardiovascular health prevalence improved in the northeastern (P_trend=.03) and southern regions (P_trend=.002). In 2017, the prevalence of coronary heart disease (6.8%; 95% CI, 6.5% to 7.1%) and stroke (3.7%; 95% CI, 3.4% to 3.9%) was highest in the southern region. The CVHI score (3.81±0.01) and the prevalence of ideal cardiovascular health (12.2%; 95% CI, 11.7% to 12.7%) were lowest in the southern United States. This corresponded to the higher cardiovascular mortality in the southern region (233.0 [95% CI, 232.2- to 33.8] per 100,000 persons).ConclusionDespite a modest improvement in CVHI, only 1 in 6 Americans has ideal cardiovascular health with significant geographic differences. These differences correlate with the geographic distribution of cardiovascular mortality. An urgent unmet need exists to mitigate the geographic disparities in cardiovascular morbidity and mortality.     

Pneumothorax as a Complication of Apnea Testing for Brain Death

Background

Pneumothorax is an under-recognized complication of apnea testing performed as part of the neurological determination of death. It may result in hemodynamic instability or even cardiac arrest, compromising ability to declare brain death (BD) and viability of organs for transplantation. We report three cases of pneumothorax with apnea testing (PAT) and review the available literature of this phenomenon.

Methods

Series of three cases supplemented with a systematic review of literature (including discussion of apnea testing in major brain death guidelines).

Results

Two patients were diagnosed with PAT due to immediate hemodynamic compromise, while the third was diagnosed many hours after BD. An additional nine cases of PAT were found in the literature. Information regarding oxygen cannula diameter was available for nine patients (range 2.3–5.3 mm), and flow rate was available for ten patients (mean 11 L/min). Pneumothorax was treated to resolution in the majority of patients (n = 8), although only six completed apnea testing following diagnosis/treatment of pneumothorax and only three patients became organ donors afterward. Review of major BD guidelines showed that although use of low oxygen flow rate (usually ≤ 6 L/min) during apnea testing is suggested, the risk of PAT was explicitly mentioned in just one.

Conclusion

Development of PAT may adversely affect the process of BD determination and could limit the opportunity for organ donation. Each institution should have preventive measures in place.

     

Geographic Inequalities in Cardiovascular Mortality in the United States: 1999 to 2018

ObjectiveTo evaluate the trends in cardiovascular, ischemic heart disease (IHD), stroke, and heart failure mortality in the stroke belt in comparison with the rest of the United States.Patients and MethodsWe evaluated the nationwide mortality data of all Americans from the Centers for Disease Control and Prevention Wide-Ranging Online Data for Epidemiologic Research database from 1999 to 2018. Cause-specific deaths were identified in the stroke belt and nonstroke belt populations using International Statistical Classification of Diseases and Related Health Problems, Tenth Revision codes. The relative percentage gap was estimated as the absolute difference computed relative to nonstroke belt mortality. Piecewise linear regression and age-period-cohort modeling were used to assess, respectively, the trends and to forecast mortality across the 2 regions.ResultsThe cardiovascular mortality rate (per 100,000 persons) was 288.3 (95% CI, 288.0 to 288.6; 3,684,273 deaths) in the stroke belt region and 251.2 (95% CI, 251.0 to 251.3; 13,296,164 deaths) in the nonstroke belt region. In the stroke belt region, age-adjusted mortality rates due to all cardiovascular causes (average annual percentage change [AAPC] in mortality rates, ?2.4; 95% CI, ?2.8 to ?2.0), IHD (AAPC, ?3.8; 95% CI, ?4.2 to ?3.5), and stroke (AAPC, ?2.8; 95% CI, ?3.4 to ?2.1) declined from 1999 to 2018. A similar decline in cardiovascular (AAPC, ?2.5; 95% CI, ?3.0 to ?2.0), IHD (AAPC, ?4.0; 95% CI, ?4.3 to ?3.7), and stroke (AAPC, ?2.9; 95% CI, ?3.2 to ?2.2) mortality was seen in the nonstroke belt region. There was no overall change in heart failure mortality in both regions (P_AAPC>.05). The cardiovascular mortality gap was 11.8% in 1999 and 15.9% in 2018, with a modest reduction in absolute mortality rate difference (~7 deaths per 100,000 persons). These patterns were consistent across subgroups of age, sex, race, and urbanization status. An estimated 101,953 additional cardiovascular deaths need to be prevented from 2020 to 2025 in the stroke belt to ameliorate the gap between the 2 regions.ConclusionDespite the overall decline, substantial geographic disparities in cardiovascular mortality persist. Novel approaches are needed to attenuate the long-standing geographic inequalities in cardiovascular mortality in the United States, which are projected to increase.