Publications

It is unclear where within tissues subsets of effector and memory CD8 T cells persist during viral infection and whether their localization affects function and long-term survival. Following lymphocytic choriomeningitis virus infection, we found most killer cell lectin-like receptor G1 (KLRG1)(lo)IL-7R(hi) effector and memory cells, which are long-lived and high proliferative capacity, in the T cell zone of the spleen. In contrast, KLRG1(hi)IL-7R(lo) cells, which appear terminally differentiated and have shorter life spans, were exclusively localized to the red pulp. KLRG1(lo)IL-7R(hi) T cells homed to the T cell zone using pertussis toxin-sensitive chemokine receptors and appeared to contact gp38(+) stromal cells, which produce the chemokines CCL19 and CCL21 and the T cell survival cytokine IL-7. The transcription factors T-bet and B lymphocyte-induced maturation protein-1 controlled effector CD8 T cell splenic migration. Effector CD8 T cells overexpressing T-bet homed to the red pulp, whereas those lacking B lymphocyte-induced maturation protein-1 homed to the T cell zone. Upon memory formation, CD62L(+) memory T cells were predominantly found in the T cell zone, whereas CD62L(-) cells were found in the red pulp. Thus, effector and memory CD8 T cell subset localization within tissues is linked to their differentiation states, and this may identify anatomical niches that regulate their longevity and homeostasis.

Heme oxygenase-1 (HO-1) and its catabolic by-products have potent anti-inflammatory activity in many models of disease. It is not known, however, if HO-1 also plays a role in the homeostatic control of T cell activation and proliferation. We demonstrate here that the HO-1 inhibitor tin mesoporphyrin (SnMP) induces activation, proliferation, and maturation of naive CD4(+) and CD8(+) T cells via interactions with CD14(+) monocytes in vitro. This response is dependent upon interactions of T cells with MHC class I and II on the surface of CD14(+) monocytes. Furthermore, CD4(+)CD25(+)FoxP3(+) regulatory T cells were able to suppress this proliferation, even though their suppressive activity was itself impaired by SnMP. Given the magnitude of the Ag-independent T cell response induced by SnMP, we speculate that HO-1 plays an important role in dampening nonspecific T cell activation. Based on these findings, we propose a potential role for HO-1 in the control of naive T cell homeostatic proliferation.

BACKGROUND

Recently, there has been a surge of interest by clinicians, industry, and the government in the development and use of ventricular assist devices (VAD) in children. Despite this rapidly expanding interest, the incidence of VAD use in children across the United States is unknown. The Healthcare Cost and Utilization Project (H-CUP) Kids' Inpatients Database (KID) was analyzed to characterize the current utilization of VADs in children nationwide.

METHODS

The most recent HCUP-KID (2006) was analyzed (n = 7.5 million). This database is a nationwide sampling of hospital discharges of patients less than 20 years old weighted to provide national estimates.

RESULTS

In 2006, 187 children had a VAD implanted in the United States. Mean age was 13 ± 7 years. Forty patients (21%) were bridged to VAD by extracorporeal membrane oxygenation. Forty-nine patients (26%) were bridged to heart transplant. Fifty-six patients (30%) died in hospital. Eighty-six patients (46%) were discharged or transferred. Length of stay was 29 days (range, 0 to 285). Total cost was $174,743 (range, $4,230 to $1,911,588). Sixty-seven hospitals placed VADs; 66% of VADs (124) were implanted at large teaching hospitals (more than 500 beds), and 46% (85) were at high-volume hospitals (more than 5 VADs per year). High-volume, large teaching hospitals (10) had better survival (89% versus 61%; p < 0.001) and lower hospital cost ($236,000 ± $184,000 versus $300,000 ± $355,000; p = 0.002) compared with all other hospitals. On multivariate analysis, acute renal failure and extracorporeal membrane oxygenation were risk factors for mortality, whereas transplant and being at a high-volume large teaching hospital were protective factors from death.

CONCLUSIONS

Preliminary data suggest that the growing use of VADs in children may be better served in regard to resource utilization and outcomes if centralized to high-volume large teaching hospitals.

RATIONALE

Pulmonary hypertension (PH) is a progressive disease with unclear etiology. The significance of autophagy in PH remains unknown.

OBJECTIVES

To determine the mechanisms by which autophagic proteins regulate tissue responses during PH.

METHODS

Lungs from patients with PH, lungs from mice exposed to chronic hypoxia, and human pulmonary vascular cells were examined for autophagy using electron microscopy and Western analysis. Mice deficient in microtubule-associated protein-1 light chain-3B (LC3B(-/-)), or early growth response-1 (Egr-1(-/-)), were evaluated for vascular morphology and hemodynamics.

MEASUREMENTS AND MAIN RESULTS

Human PH lungs displayed elevated lipid-conjugated LC3B, and autophagosomes relative to normal lungs. These autophagic markers increased in hypoxic mice, and in human pulmonary vascular cells exposed to hypoxia. Egr-1, which regulates LC3B expression, was elevated in PH, and increased by hypoxia in vivo and in vitro. LC3B(-/-) or Egr-1(-/-), but not Beclin 1(+/-), mice displayed exaggerated PH during hypoxia. In vitro, LC3B knockdown increased reactive oxygen species production, hypoxia-inducible factor-1α stabilization, and hypoxic cell proliferation. LC3B and Egr-1 localized to caveolae, associated with caveolin-1, and trafficked to the cytosol during hypoxia.

CONCLUSIONS

The results demonstrate elevated LC3B in the lungs of humans with PH, and of mice with hypoxic PH. The increased susceptibility of LC3B(-/-) and Egr-1(-/-) mice to hypoxia-induced PH and increased hypoxic proliferation of LC3B knockdown cells suggest adaptive functions of these proteins during hypoxic vascular remodeling. The results suggest that autophagic protein LC3B exerts a protective function during the pathogenesis of PH, through the regulation of hypoxic cell proliferation.

BACKGROUND

Practice parameters for the treatment of obstructive sleep apnea syndrome (OSAS) in adults by surgical modification of the upper airway were first published in 1996 by the American Academy of Sleep Medicine (formerly ASDA). The following practice parameters update the previous practice parameters. These recommendations were reviewed and approved by the Board of Directors of the American Academy of Sleep Medicine.

METHODS

A systematic review of the literature was performed, and the GRADE system was used to assess the quality of evidence. The findings from this evaluation are provided in the accompanying review paper, and the subsequent recommendations have been developed from this review. The following procedures have been included: tracheostomy, maxillo-mandibular advancement (MMA), laser assisted uvulopalatoplasty (LAUP), uvulopalatopharyngoplasty (UPPP), radiofrequency ablation (RFA), and palatal implants.

RECOMMENDATIONS

The presence and severity of obstructive sleep apnea must be determined before initiating surgical therapy (Standard). The patient should be advised about potential surgical success rates and complications, the availability of alternative treatment options such as nasal positive airway pressure and oral appliances, and the levels of effectiveness and success rates of these alternative treatments (Standard). The desired outcomes of treatment include resolution of the clinical signs and symptoms of obstructive sleep apnea and the normalization of sleep quality, the apnea-hypopnea index, and oxyhemoglobin saturation levels (Standard). Tracheostomy has been shown to be an effective single intervention to treat obstructive sleep apnea. This operation should be considered only when other options do not exist, have failed, are refused, or when this operation is deemed necessary by clinical urgency (Option). MMA is indicated for surgical treatment of severe OSA in patients who cannot tolerate or who are unwilling to adhere to positive airway pressure therapy, or in whom oral appliances, which are more often appropriate in mild and moderate OSA patients, have been considered and found ineffective or undesirable (Option). UPPP as a sole procedure, with or without tonsillectomy, does not reliably normalize the AHI when treating moderate to severe obstructive sleep apnea syndrome. Therefore, patients with severe OSA should initially be offered positive airway pressure therapy, while those with moderate OSA should initially be offered either PAP therapy or oral appliances (Option). Use of multi-level or stepwise surgery (MLS), as a combined procedure or as stepwise multiple operations, is acceptable in patients with narrowing of multiple sites in the upper airway, particularly if they have failed UPPP as a sole treatment (Option). LAUP is not routinely recommended as a treatment for obstructive sleep apnea syndrome (Standard). RFA can be considered as a treatment in patients with mild to moderate obstructive sleep apnea who cannot tolerate or who are unwilling to adhere to positive airway pressure therapy, or in whom oral appliances have been considered and found ineffective or undesirable (Option). Palatal implants may be effective in some patients with mild obstructive sleep apnea who cannot tolerate or who are unwilling to adhere to positive airway pressure therapy, or in whom oral appliances have been considered and found ineffective or undesirable (Option). Postoperatively, after an appropriate period of healing, patients should undergo follow-up evaluation including an objective measure of the presence and severity of sleep-disordered breathing and oxygen saturation, as well as clinical assessment for residual symptoms. Additionally, patients should be followed over time to detect the recurrence of disease (Standard).

CONCLUSIONS

While there has been significant progress made in surgical techniques for the treatment of OSA, there is a lack of rigorous data evaluating surgical modifications of the upper airway. Systematic and methodical investigations are needed to improve the quality of evidence, assess additional outcome measures, determine which populations are most likely to benefit from a particular procedure or procedures, and optimize perioperative care.