BACKGROUND

We investigated the hypothesis that postconditioning by FTY720 (FTY) in isolated perfused mouse hearts is independent of the sphingosine 1-phosphate (S1P) pathway.

MATERIAL AND METHODS

Ex vivo hearts were exposed to postconditioning (POST) by either ischemia or FTY720. Protection against ischemia/reperfusion (IR) injury was measured by recovery of left ventricular developed pressure (LVDP) and infarct size.

RESULTS

FTY effectively postconditioned (POST) ex vivo hearts against ischemia/reperfusion (IR) injury as measured by recovery of LVDP and a low infarct size. FTY protection, unlike S1P but like sphingosine (Sph), was insensitive to inhibition of S1P G-Protein Coupled Receptors (GPCRs) or inhibition of PI3 kinase. Protection by FTY and Sph was however blocked by inhibitors of PKA and PKG. Thus, FTY follows the same cardioprotective pathway as Sph. This was further supported by studies of FTY POST in knockout (KO) mice lacking the SphK2 form of Sph kinase that is needed for phosphorylation of FTY to an S1P analog. In the absence of SphK2, FTY (and Sph) POST was still cardioprotective. This differed from the effect of SphK2 KO on protection by ischemic POST (IPOST). IPOST was not effective in KO hearts. To see if the GPCR signaling pathway to protection is normal in KO hearts, we looked at POST by GPCR agonists S1P and adenosine. Both provided effective protection even in KO hearts suggesting that the problem with IPOST in KO hearts is a low level of S1P available for release during IPOST. Thus, pharmacologic POST with FTY or Sph, like adenosine and S1P, is unaffected in the KO.

CONCLUSIONS

FTY720 administered in vivo might behave in a dual manner showing both S1P-like effects and sphingosine-like effects. It appears that the latter may have been overlooked and may be the more important in aging hearts.

Readmissions to the hospital are common and costly, often resulting from poor care coordination. Despite increased attention given to improving the quality and safety of care transitions, little is known about patient and provider perspectives of the transitional care needs of rehospitalized Veterans. As part of a larger quality improvement initiative to reduce hospital readmissions, the authors conducted semi-structured interviews with 25 patients and 14 of their interdisciplinary health care providers to better understand their perspectives of the transitional care needs and challenges faced by rehospitalized Veterans. Patients identified 3 common themes that led to rehospitalization: (1) knowledge gaps and deferred power; (2) difficulties navigating the health care system; and (3) complex psychiatric and social needs. Providers identified different themes that led to rehospitalization: (1) substance abuse and mental illness; (2) lack of social or financial support and homelessness; (3) premature discharge and poor communication; and (4) nonadherence with follow-up. Results underscore that rehospitalized Veterans have a complex overlapping profile of real and perceived physical, mental, and social needs. A paradigm of disempowerment and deferred responsibility appears to exist between patients and providers that contributes to ineffective care transitions, resulting in readmissions. These results highlight the cultural constraints on systems of care and suggest that process improvements should focus on increasing the sense of partnership between patients and providers, while simultaneously creating a culture of empowerment, ownership, and engagement, to achieve success in reducing hospital readmissions.

OBJECTIVES

The purpose of this study was to investigate the associations of traditional risk factors and longitudinal measures of human immunodeficiency virus (HIV) disease severity with risk of incident atrial fibrillation (AF) in a contemporary cohort of HIV-infected individuals.

BACKGROUND

Cardiovascular disease is common in HIV-infected persons; however, the most common cardiac arrhythmia, AF, has not been adequately studied in this population.

METHODS

We studied a national sample of 30,533 HIV-infected veterans followed in the Veterans Affairs HIV Clinical Case Registry from 1996 to 2011. We examined the independent associations of demographic characteristics, time-updated comorbidities, and time-updated clinical measurements including CD4(+) cell count and viral load with the outcome of incident AF using proportional hazards regression for multivariable analysis.

RESULTS

Over a median follow-up of 6.8 years, 780 (2.6%) patients developed AF. After multivariable adjustment for traditional risk factors, a lower CD4(+) cell count (<200 compared with >350 cells/mm(3); hazard ratio [HR]: 1.4; 95% confidence interval [CI]: 1.1 to 1.8; p = 0.018) and higher viral load (>100,000 compared with <500 copies/ml; HR: 1.7; 95% CI: 1.2 to 2.4; p = 0.002) were independently associated with increased risk of incident AF. Additional risk factors independently associated with risk of AF included older age, White race, coronary artery disease, congestive heart failure, alcoholism, proteinuria, reduced kidney function, and hypothyroidism.

CONCLUSIONS

In a large HIV-infected cohort, markers of HIV disease severity represented by low CD4(+) cell count and high viral load, assessed by multiple time-updated measures, were independently associated with development of AF.

IMPORTANCE

Predominantly neutrophilic infiltrates are seen in a subset of patients with urticaria. The lesions tend to be less itchy and poorly responsive to standard therapy, including antihistamines. We describe 2 patients having neutrophilic urticaria with systemic inflammation (NUSI) without known connective tissue disorder or malignancy. We propose the term NUSI to help classify a previously undefined multisystemic inflammatory entity likely mediated by interleukin 1 (IL-1).

OBSERVATIONS

Patient 1, a 47-year-old woman, was seen with urticaria and associated night sweats, fevers, and polyarticular arthritis. Acute-phase reactants were elevated with worsening of symptoms. Initial treatment with a combination of topical and systemic corticosteroids, antihistamines, and immunosuppressants was unsuccessful. A 100% clinical resolution was achieved with anakinra, an IL-1 receptor antagonist. Patient 2, a 24-year-old woman, was seen with urticaria and associated joint pain and swelling. Initial treatment included a combination of antihistamines, colchicine, and dapsone. Only colchicine provided moderate benefit but was stopped because of significant gastrointestinal tract discomfort. Anakinra was initiated; the patient achieved 100% control while receiving daily therapy.

CONCLUSIONS AND RELEVANCE

The diagnosis of NUSI is important to consider in patients who are seen with antihistamine-resistant urticaria in combination with systemic inflammatory symptoms. Interleukin 1 blockade is a viable option for therapy.