Skeletal consequences of preterm birth in pigs as a model for preterm infants.

Preterm birth affects about 10% of all live births with many resultant health challenges, including metabolic bone disease of prematurity (MBDP) which is characterized by elevated alkaline phosphatase, suppressed phosphate, and deficient skeletal development. Because of the lack of an animal model, very little is known about bone structure, strength, and quality after preterm birth. This study investigated the utility of a pig model to replicate clinical features of preterm birth, including MBDP, and sought to determine if early postnatal administration of insulin-like growth factor (IGF)-1 was an effective treatment. Preterm pigs, born by caesarean section at 90% gestation, were reared in intensive care facilities (respiratory, thermoregulatory and nutritional support) and compared with sow-reared term pigs born vaginally. Preterm pigs were systemically treated with vehicle or IGF-1 (recombinant human IGF-1/BP-3, 2.25 mg/kg/day). Tissues were collected at postnatal days 1, 5, and 19 (the normal weaning period in pigs). Most bone-related outcomes were affected by preterm birth throughout the study period whereas IGF-1 supplementation had almost no effect. By day 19, alkaline phosphatase was elevated, phosphate and calcium were reduced, and the bone resorption marker CTX-1 was elevated in preterm pigs compared to term pigs. Preterm pigs also had decrements in femoral cortical cross-sectional properties, consistent with reduced whole-bone strength. Thus, the preterm pig model replicates many features of preterm bone development in infants, including features of MBDP, and allows for direct interrogation of skeletal tissues, enhancing the field's ability to examine underlying mechanisms.

Premature birth interrupts a critical period of skeletal development as the majority of fetal bone mineral accumulation occurs during the last gestational trimester, leaving preterm infants at increased risk for low bone mineral density and fractures. While there are some data on growth in bone mass in preterm infants, very little is known about bone structural properties, quality, and strength during development after preterm birth. In this study we sought to evaluate the pig as a model for postnatal skeletal development after premature birth. Preterm pigs born after approximately 90% of the full gestation period were compared to full-term control pigs through day 19 of life. Levels of two blood markers used to diagnose osteoporosis of prematurity were replicated in the pig model. Bone properties related to strength were reduced even when accounting for their smaller body size, possibly suggesting elevated fracture risk in preterm infants. Based on the similarities between the preterm pig model and preterm human infants, the pig model may prove to be useful to study factors and interventions affecting postnatal bone development after preterm birth.

An Evaluation of Diagnostic Tests for Aerodigestive Injuries in Penetrating Neck Trauma.

Assessment of aerodigestive injuries in penetrating neck trauma (PNT) is currently left up to the discretion of physicians which can result in a lot of confusion and unnecessary testing. This study was performed at a level 1 trauma center to assess the role of computed tomography arteriogram (CTA) in evaluating for aerodigestive injury in PNT. A total of 242 patients met criteria, with ages ranging from 7 to 86 years. Computed tomography arteriogram, EGD, esophagography, and bronchoscopy were classified into positive, negative, and indeterminate results. Computed tomography arteriogram was then further analyzed for violation of the carotid sheath, investing, pretracheal, and deep cervical fascias. Results showed a high sensitivity and NPV (100%) of CTA in assessing aerodigestive injury. Computed tomography arteriogram is a reliable first-line screening tool for aerodigestive injury. EGD appears more useful than esophagography at identifying esophageal injuries. Esophagography and bronchoscopy should be reserved to aid in injury management decision-making rather than as screening studies.

Colon epithelial cell-specific Bmal1 deletion impairs bone formation in mice.

The circadian clock system regulates multiple metabolic processes, including bone metabolism. Previous studies have demonstrated that both central and peripheral circadian signaling regulate skeletal growth and homeostasis in mice. Disruption in central circadian rhythms has been associated with a decline in bone mineral density in humans and the global and osteoblast-specific disruption of clock genes in bone tissue leads to lower bone mass in mice. Gut physiology is highly sensitive to circadian disruption. Since the gut is also known to affect bone remodeling, we sought to test the hypothesis that circadian signaling disruption in colon epithelial cells affects bone. We therefore assessed structural, functional, and cellular properties of bone in 8 week old Ts4-Cre and Ts4-Cre;Bmal1fl/fl (cBmalKO) mice, where the clock gene Bmal1 is deleted in colon epithelial cells. Axial and appendicular trabecular bone volume was significantly lower in cBmalKO compared to Ts4-Cre 8-week old mice in a sex-dependent fashion, with male but not female mice showing the phenotype. Similarly, the whole bone mechanical properties were deteriorated in cBmalKO male mice. The tissue level mechanisms involved suppressed bone formation with normal resorption, as evidenced by serum markers and dynamic histomorphometry. Our studies demonstrate that colon epithelial cell-specific deletion of Bmal1 leads to failure to acquire trabecular and cortical bone in male mice.

The American Association for the Surgery of Trauma (AAST) Liver Injury Grade Does Not Equally Predict Interventions in Blunt and Penetrating Trauma.

INTRODUCTION: The AAST liver injury grade has a validated association with mortality and need for operation. AAST liver injury grade is the same regardless of the mechanism of trauma. METHODS: A 5-year retrospective review of all liver injuries at an urban, level-one trauma center was performed. RESULTS: Totally, 315 patients were included (29% blunt, 71% penetrating). In blunt trauma, AAST grade was associated with need for laparotomy (0%, 7%, 5%, 33%, 29%, Grade 1-5, p = 0.01), angiography (0%, 7%, 25%, 40%, 57%, p < 0.001), embolization (0%, 7%, 15%, 33%, 43%, p = 0.01), and percutaneous drainage procedures (13% use in Grade 4, otherwise 0%, p = 0.04), but not ERCP (0% for all grades). In penetrating trauma, AAST grade was associated with need for angiography (7%, 4%, 15%, 24%, 30%, p < 0.01) and percutaneous drainage (7%, 2%, 14%, 18%, 26%, p = 0.03) and had a marginal association with embolization (0%, 4%, 11%, 13%, 22%, p = 0.06). Laparotomy, ERCP, sphincterotomy, and stenting rates increased with AAST grade, but this was not statistically significant. CONCLUSION: AAST grade is associated with the need for surgical hemostasis, angioembolization, and percutaneous drainage in both penetrating and blunt trauma. Operative, endoscopic, and percutaneous procedures are utilized more in penetrating trauma. Angioembolization was used more in blunt trauma. Mechanism should be considered when using AAST grade to guide management of liver injuries.

Longer-term liraglutide administration at the highest dose approved for obesity increases reward-related orbitofrontal cortex activation in response to food cues: Implications for plateauing weight loss in response to anti-obesity therapies.

AIMS: GLP-1 analogs have recently risen to the forefront as effective medications for lowering weight through actions in the central nervous system (CNS). However, their actions in the CNS have not yet been studied in the human brain after longer-term administration at the highest dose approved for obesity (liraglutide 3.0 mg). MATERIALS AND METHODS: A total of 20 participants with obesity were treated with placebo and liraglutide (3.0 mg) in the context of a randomized, placebo-controlled, double-blind, cross-over trial after 5 weeks of dose escalation. Neurocognitive and neuroimaging (fMRI) responses to food cues were examined at the clinical research center of Beth Israel Deaconess Medical Center. RESULTS: While using liraglutide, patients lost more weight (placebo-subtracted -2.7%; P < .001), had decreased fasting glucose (P < .001) and showed improved cholesterol levels. In an uncontrolled analysis, brain activation in response to food images was not altered by liraglutide vs placebo. When controlled for BMI/weight, liraglutide increased activation of the right orbitofrontal cortex (OFC) in response to food cues (P < .016, corrected for multiple comparisons). CONCLUSIONS: In contrast to prior studies, we demonstrate for the first time that liraglutide treatment, administered over a longer period at the highest doses approved for obesity, does not alter brain activation in response to food cues. A counter-regulatory increase in reward-related OFC activation in response to food cues can be observed when neuroimaging data are controlled for BMI changes, indicating changes in CNS that could lead to later plateaus of weight loss. These data point to a promising focus for additional interventions which, by contributing to the CNS reward system, could provide tangible benefits in reversing the plateauing phenomenon and promoting further weight loss.