Ventilation following established ARDS: a preclinical model framework to improve predictive power.

BACKGROUND: Despite advances in understanding the pathophysiology of acute respiratory distress syndrome, effective pharmacological interventions have proven elusive. We believe this is a consequence of existing preclinical models being designed primarily to explore biological pathways, rather than predict treatment effects. Here, we describe a mouse model in which both therapeutic intervention and ventilation were superimposed onto existing injury and explored the impact of ß-agonist treatment, which is effective in simple models but not clinically. METHODS: Mice had lung injury induced by intranasal lipopolysaccharide (LPS), which peaked at 48 hours post-LPS based on clinically relevant parameters including hypoxaemia and impaired mechanics. At this peak of injury, mice were treated intratracheally with either terbutaline or tumour necrosis factor (TNF) receptor 1-targeting domain antibody, and ventilated with moderate tidal volume (20 mL/kg) to induce secondary ventilator-induced lung injury (VILI). RESULTS: Ventilation of LPS-injured mice at 20 mL/kg exacerbated injury compared with low tidal volume (8 mL/kg). While terbutaline attenuated VILI within non-LPS-treated animals, it was ineffective to reduce VILI in pre-injured mice, mimicking its lack of clinical efficacy. In contrast, anti-TNF receptor 1 antibody attenuated secondary VILI within pre-injured lungs, indicating that the model was treatable. CONCLUSIONS: We propose adoption of a practical framework like that described here to reduce the number of ultimately ineffective drugs reaching clinical trials. Novel targets should be evaluated alongside interventions which have been previously tested clinically, using models that recapitulate the (lack of) clinical efficacy. Within such a framework, outperforming a failed pharmacologic should be a prerequisite for drugs entering trials.

Longitudinal changes in bone parameters in young girls with anorexia nervosa.

BACKGROUND: Anorexia nervosa (AN) during childhood and adolescence has been reported to adversely affect bone health, but few studies have investigated longitudinal changes. METHOD: DXA-derived bone parameters and body composition were retrospectively assessed in 111 young girls with AN with a median age of 15.4 years (10.9, 19.8). In 68 (61%) vertebral fracture assessment (VFA) was performed and in 31 (28%), a follow-up DXA was performed. Correlations with growth, changes in body composition and effects of illness duration and menstruation were examined. Size adjusted DXA standard deviation scores were calculated for total body (TB) less head bone mineral content (TBLH-BMC) and lumbar spine bone mineral apparent density (LS-BMAD). RESULTS: Mean (range) bone area (BA) for height centile was 27.1 (0-97), and mean lean mass for height centile was 28.8 (0-95) at baseline. Mean (range) LS BMAD was -1.0 (-2.6, 0.8) SDS at first and - 1.2 (-3.0, -0.2) at second DXA (p = 0.023). On follow up, lean mass for height increased from 27th centile (0, 75) to 40th centile (0, 70) (p = 0.006), and fat mass for height increased from 55 g/cm to 67 g/cm (11.3, 124.2) (p < 0.001). Duration of illness was the only negative predictor of LS BMAD (p < 0.0001). Change in height SDS was the only positive predictor of change in TBLH-BMC (r = 0.384, p = 0.037), and change in LS BMAD (r-0.934, p < 0.0001). Of 68 patients who had VFA, 4 (5.9%) had a mild vertebral fracture. CONCLUSION: Bones are smaller and less dense in childhood/adolescent AN compared to healthy adolescents. Although there are significant gains in lean mass and fat mass, over time, BMAD SDS decreases slightly. Improvement in BMAD SDS is related to improvement in height SDS.

High-Fat Feeding Protects Mice From Ventilator-Induced Lung Injury, Via Neutrophil-Independent Mechanisms.

OBJECTIVE: Obesity has a complex impact on acute respiratory distress syndrome patients, being associated with increased likelihood of developing the syndrome but reduced likelihood of dying. We propose that such observations are potentially explained by a model in which obesity influences the iatrogenic injury that occurs subsequent to intensive care admission. This study therefore investigated whether fat feeding protected mice from ventilator-induced lung injury. DESIGN: In vivo study. SETTING: University research laboratory. SUBJECTS: Wild-type C57Bl/6 mice or tumor necrosis factor receptor 2 knockout mice, either fed a high-fat diet for 12-14 weeks, or age-matched lean controls. INTERVENTIONS: Anesthetized mice were ventilated with injurious high tidal volume ventilation for periods up to 180 minutes. MEASUREMENTS AND MAIN RESULTS: Fat-fed mice showed clear attenuation of ventilator-induced lung injury in terms of respiratory mechanics, blood gases, and pulmonary edema. Leukocyte recruitment and activation within the lungs were not significantly attenuated nor were a host of circulating or intra-alveolar inflammatory cytokines. However, intra-alveolar matrix metalloproteinase activity and levels of the matrix metalloproteinase cleavage product soluble receptor for advanced glycation end products were significantly attenuated in fat-fed mice. This was associated with reduced stretch-induced CD147 expression on lung epithelial cells. CONCLUSIONS: Consumption of a high-fat diet protects mice from ventilator-induced lung injury in a manner independent of neutrophil recruitment, which we postulate instead arises through blunted up-regulation of CD147 expression and subsequent activation of intra-alveolar matrix metalloproteinases. These findings may open avenues for therapeutic manipulation in acute respiratory distress syndrome and could have implications for understanding the pathogenesis of lung disease in obese patients.

Inhibition of TNF Receptor p55 By a Domain Antibody Attenuates the Initial Phase of Acid-Induced Lung Injury in Mice.

BACKGROUND: Tumor necrosis factor-α (TNF) is strongly implicated in the development of acute respiratory distress syndrome (ARDS), but its potential as a therapeutic target has been hampered by its complex biology. TNF signals through two receptors, p55 and p75, which play differential roles in pulmonary edema formation during ARDS. We have recently shown that inhibition of p55 by a novel domain antibody (dAb™) attenuated ventilator-induced lung injury. In the current study, we explored the efficacy of this antibody in mouse models of acid-induced lung injury to investigate the longer consequences of treatment. METHODS: We employed two acid-induced injury models, an acute ventilated model and a resolving spontaneously breathing model. C57BL/6 mice were pretreated intratracheally or intranasally with p55-targeting dAb or non-targeting "dummy" dAb, 1 or 4 h before acid instillation. RESULTS: Acid instillation in the dummy dAb group caused hypoxemia, increased respiratory system elastance, pulmonary inflammation, and edema in both the ventilated and resolving models. Pretreatment with p55-targeting dAb significantly attenuated physiological markers of ARDS in both models. p55-targeting dAb also attenuated pulmonary inflammation in the ventilated model, with signs that altered cytokine production and leukocyte recruitment persisted beyond the very acute phase. CONCLUSION: These results demonstrate that the p55-targeting dAb attenuates lung injury and edema formation in models of ARDS induced by acid aspiration, with protection from a single dose lasting up to 24 h. Together with our previous data, the current study lends support toward the clinical targeting of p55 for patients with, or at risk of ARDS.

Emergency preparedness needs assessment of centralized school foodservice and warehousing operations.

Managers of onsite retail foodservice operations, particularly those in centralized school foodservice operations, are called on to provide meals during emergencies, yet there is a paucity of research on their readiness to handle emergencies. Qualitative research and a cross-sectional survey design were used to conduct a needs assessment for emergency preparedness (emergency readiness, food recalls, and food defense) in centralized school foodservice operations, including warehousing. An open-ended written questionnaire was mailed to eight foodservice directors, and responses were used to develop a written questionnaire that was mailed to school foodservice directors in 200 districts identified as having centralized food production and warehousing. Directors from 78 districts responded (39% response rate). Most districts (n=72) had an emergency response team, and foodservice was included as part of 63 of those teams. Not all districts had written procedures for food recalls (47 of 73), natural disasters (37 of 74), or food defense (30 of 74). Barriers to implementing emergency preparedness policies and procedures included limited money, emergency equipment, and time. Most current training related to food safety with little training related to emergency preparedness. Training on the emergency preparedness plan was done in 61 of 78 districts. Training on emergency procedures was done by less than half of the districts during the previous year. This study identified best practices related to emergency preparedness that can be implemented in onsite retail foodservice operations. Results indicate a need to emphasize emergency preparedness, develop written standard operating procedures, and train employees to be prepared to respond to emergencies.