Larry A. Sonna

Intensive communication: four-year follow-up from a clinical practice study.

PurposeTo determine the durability of the effects of a change in practice designed to promote the use of advanced supportive technology when it is of benefit but to limit its burdens when it is ineffective. We have reported that institution of a process of intensive communication reduced length of intensive care unit stay for dying patients and reduced mortality in a before-and-after study in a cohort of patients admitted to an adult intensive care unit. We now report the results of a 4-yr extension of this intervention. Materials and MethodsThe number of counseling sessions, intensive care unit length of stay, and mortality were measured for 2,361 adult medical patients consecutively admitted to a university tertiary care hospital. To determine the durability of the effects of our intervention, we compared our experience during the subsequent 4 yrs with that of the 134 consecutive patients before and 396 patients after our intensive communication intervention. ResultsWe conducted an equivalent number of intensive communication sessions in our subsequent practice as during the intervention (1.5 vs. 1.6 sessions per patient admitted to the intensive care unit). However, sessions tended to be of shorter duration, and direct participation by social workers, chaplains, and care coordinators was less frequent in our subsequent experience. Intensive communication produced a significant and durable reduction in length of stay (median length of stay, 4 days [2–11 days, interquartile range] before; 3 days [2–6 days, interquartile range] during the study; 3 days [2–6 days, interquartile range] subsequently). Our intervention was associated with a significant and durable reduction in intensive care unit mortality (31.3% before, 22.7% during the intervention, 18% subsequently;p < .001). ConclusionsIntensive communication is associated with durable reductions in intensive care unit length of stay and reduced mortality in critically ill adult medical patients. Intensive communication was applied more efficiently subsequent to the intervention, and its effectiveness does not seem to be dependent on nondirect caregivers’ participation in the sessions. This process encourages the continuation of advanced supportive technology to patients with the potential to survive and allows the earlier withdrawal of advanced supportive technology when it is ineffective.

Monocyte Chemotactic Protein‐4 (MCP‐4; CCL‐13): A Biomarker of Asthma

Airway expression of monocyte chemotactic protein‐4 (MCP‐4; CCL‐13) is known to be increased in asthmatic airways where it is induced by proallergic cytokines, but the relationship of its systemic expression to asthma and naturally occurring exacerbations is unknown. We determined plasma levels of MCP‐4 in 356 individuals with chronic‐stable asthma and 240 normal subjects and compared plasma levels of MCP‐4 in 30 patients who presented for emergent treatment of asthma with levels in 90 subjects with chronic‐stable asthma matched for age, gender, and ethnicity. Median plasma MCP‐4 levels were higher in patients with chronic‐stable asthma than in normal subjects (399 vs. 307 pg/mL) (p < 0.001). In our entire cohort (n=596), subjects with an MCP‐4 ≥ 218 pg/mL were at increased risk of asthma (p < 0.001 odds ratio, 3.26; 95% CI, 2.22–4.79). Logistic regression identified MCP‐4 as an independent predictor of asthma diagnosis. The MCP‐4 levels are higher in individuals with an acute asthma exacerbation than in subjects with chronic‐stable asthma (513 vs. 355 pg/mL) (p = 0.002). The MCP‐4 is a systemically expressed biomarker that independently predicts susceptibility to asthma and is directly associated with exacerbations. Elevated MCP‐4 levels identify a group of asthmatics with systemic evidence of allergic inflammation who may be at risk for exacerbations or may benefit from abrogation of MCP‐4.

Nitric oxide synthase-2 down-regulates surfactant protein-B expression and enhances endotoxin-induced lung injury in mice

Acute respiratory distress syndrome (ARDS) is a life‐threatening ailment characterized by severe lung injury involving inflammatory cell recruitment to the lung, cytokine production, surfactant dysfunction, and up‐regulation of nitric oxide synthase 2 (NOS2) resulting in nitric oxide (NO) production. We hypothesized that NO production from NOS2 expressed in lung parenchymal cells in a murine model of ARDS would correlate with abnormal surfactant function and reduced surfactant protein‐B (SP‐B) expression. Pulmonary responses to nebulized endotoxin (lipopolysaccharide, LPS) were evaluated in wild‐type (WT) mice, NOS2 null (‒/‒) mice, and NOS2‐chimeric animals derived from bone marrow transplantation. NOS2‒/‒ animals exhibited significantly less physiologic lung dysfunction and loss of SP‐B expression than did WT animals. However, lung neutrophil recruitment and bronchoalveolar lavage cytokine levels did not significantly differ between NOS2‒/‒ and WT animals. Chimeric animals for NOS2 exhibited the phenotype of the recipient and therefore demonstrated that parenchymal production of NOS2 is critical for the development of LPS‐induced lung injury. Furthermore, administration of NO donors, independent of cytokine stimulation, decreased SP‐B promoter activity and mRNA expression in mouse lung epithelial cells. This study demonstrates that expression of NOS2 in lung epithelial cells is critical for the development of lung injury and mediates surfactant dysfunction independent of NOS2 inflammatory cell expression and cytokine production.

Heat shock protein 90β: A novel mediator of vitamin D action

We investigated the role of Heat shock protein 90 (Hsp90) in vitamin D action in Caco-2 cells using geldanamycin (GA) to block Hsp90 function and RNA interference to reduce Hsp90beta expression. When cells were exposed to GA, vitamin D-mediated gene expression and transcriptional activity were inhibited by 69% and 54%, respectively. Gel shift analysis indicated that GA reduced vitamin D-mediated DNA binding activity of the vitamin D receptor (VDR). We tested the specific role of Hsp90beta by knocking down its expression with stably expressed short hairpin RNA. Vitamin D-induced gene expression and transcriptional activity were reduced by 90% and 80%, respectively, in Hsp90beta-deficient cells. Nuclear protein for VDR and RXRalpha, its heterodimer partner, were not reduced in Hsp90beta-deficient cells. These findings indicate that Hsp90beta is needed for optimal vitamin D responsiveness in the enterocyte and demonstrate a specific role for Hsp90beta in VDR signaling.

Exertional heat illness and human gene expression

Microarray analysis of gene expression at the level of RNA has generated new insights into the relationship between cellular responses to acute heat shock in vitro, exercise, and exertional heat illness. Here we discuss the systemic physiology of exertional hyperthermia and exertional heat illness, and compare the results of several recent microarray studies performed in vitro on human cells subjected to heat shock and in vivo on samples obtained from subjects performing exercise or suffering from exertional heat injury. From these comparisons, a concept of overlapping component responses emerges. Namely, some of the gene expression changes observed in peripheral blood mononuclear cells during exertional heat injury can be accounted for by normal cellular responses to heat, exercise, or both; others appear to be specific to the disease state itself. If confirmed in future studies, these component responses might provide a better understanding of adaptive and pathological responses to exercise and exercise-induced hyperthermia, help find new ways of identifying individuals at risk for exertional heat illness, and perhaps even help find rational molecular targets for therapeutic intervention.