Insulin Concentration Modulates Hepatic Lipid Accumulation in Mice in Part via Transcriptional Regulation of Fatty Acid Transport Proteins

Fatty liver disease (FLD) is commonly associated with insulin resistance and obesity, but interestingly it is also observed at low insulin states, such as prolonged fasting. Thus, we asked whether insulin is an independent modulator of hepatic lipid accumulation.In mice we induced, hypo- and hyperinsulinemia associated FLD by diet induced obesity and streptozotocin treatment, respectively. The mechanism of free fatty acid induced steatosis was studied in cell culture with mouse liver cells under different insulin concentrations, pharmacological phosphoinositol-3-kinase (PI3K) inhibition and siRNA targeted gene knock-down. We found with in vivo and in vitro models that lipid storage is increased, as expected, in both hypo- and hyperinsulinemic states, and that it is mediated by signaling through either insulin receptor substrate (IRS) 1 or 2. As previously reported, IRS-1 was up-regulated at high insulin concentrations, while IRS-2 was increased at low levels of insulin concentration. Relative increase in either of these insulin substrates, was associated with an increase in liver-specific fatty acid transport proteins (FATP) 2&5, and increased lipid storage. Furthermore, utilizing pharmacological PI3K inhibition we found that the IRS-PI3K pathway was necessary for lipogenesis, while FATP responses were mediated via IRS signaling. Data from additional siRNA experiments showed that knock-down of IRSs impacted FATP levels.States of perturbed insulin signaling (low-insulin or high-insulin) both lead to increased hepatic lipid storage via FATP and IRS signaling. These novel findings offer a common mechanism of FLD pathogenesis in states of both inadequate (prolonged fasting) and ineffective (obesity) insulin signaling

Prediction of mortality in pediatric trauma patients: New injury severity score outperforms injury severity score in the severely injured

Background: The Injury Severity Score (ISS) is a widely accepted method of measuring severity of traumatic injury. A modification has been proposed--the New Injury Severity Score (NISS). This has been shown to predict mortality better in adult trauma patients, but it had no predictive benefit in pediatric patients. The aim of this study was to determine whether the NISS outperforms the ISS in a large pediatric trauma population. Methods: Admissions in the National Pediatric Trauma Registry between April 1996 and September 1999 were included. The ISS and NISS were calculated for each patient. The study endpoints were mortality at hospital discharge, functional outcome in three domains (expression, locomotion, and feeding), and discharge disposition for the survivors. Predictive ability of each score was assessed by area under the receiver operating characteristic curve. Results: The NISS and ISS performed equally well at predicting mortality in patients with lower injury severity (ISS \u3c 25), but the NISS was significantly better at predicting mortality in the more severely injured patients. Both scores performed equally well at predicting expression and feeding ability. The NISS was superior to the ISS in predicting locomotion ability at discharge. Thirty-seven percent of patients had an NISS that was higher than their ISS. These patients had a significantly higher mortality and suffered worse functional outcomes. Conclusion: The NISS performs as well as the ISS in pediatric patients with lower injury severity and outperforms the ISS in those with higher injury severit

Black children experience worse clinical and functional outcomes after traumatic brain injury: An analysis of the national pediatric trauma registry

Background: Recent studies suggest racial disparities in the treatment and outcomes of children with traumatic brain injury (TBI). This study aims to identify race-based clinical and functional outcome differences among pediatric TBI patients in a national database. Methods: A total of 41,122 patients (ages 2-16 years) who were included in the National Pediatric Trauma Registry (from 1996-2001) were studied. TBI was categorized by Relative Head Injury Severity Score (RHISS) and patients with moderate to severe TBI were included. Individual race groups were compared with white as the majority group. Differences between races in functional outcomes at discharge in three domains-speech, locomotion, and feeding-were determined using multiple logistic regression. Cases were adjusted for age, sex, severity of head injury (using RHISS), severity of injury (using New Injury Severity Score and Pediatric Trauma Score), premorbidities, mechanism, and injury intent. Results: A total of 7,778 children had moderate or severe TBI with or without associated injuries. All races had similar demographics. Hispanics (n=1,041) had outcomes comparable to whites (n=4,762). Black children (n=1,238) had significantly increased premorbidities, penetrating trauma, and violent intent. They also had higher unadjusted mortality and longer mean intensive care unit and floor stays. After adjustment, there was no difference in the odds of death between black and white children. However, black patients were more likely to be discharged to an inpatient rehabilitation facility and had increased odds of possessing a functional deficit at discharge for all three domains studied. Conclusion: Black children with traumatic brain injury have worse clinical and functional outcomes at discharge when compared with equivalently injured white childre

Traumatic brain injury in the elderly: Increased mortality and worse functional outcome at discharge despite lower injury severity

Objective: The purpose of this study was to compare data obtained from a statewide data set for elderly patients (age \u3e 64 years) that presented with traumatic brain injury with data from nonelderly patients (age \u3e 15 and \u3c 65 years) with similar injuries. Methods: The New York State Trauma Registry from January 1994 through December 1995, from trauma centers and community hospitals excluding New York City (45,982 patients), was examined. Head-injured patients were identified by International Classification of Diseases, Ninth Revision diagnosis codes. A relative head injury severity scale (RHISS) was constructed on the basis of groups of these codes (range, 0 = none to 3 = severe). Comparisons were made with nonelderly patients for mortality, Glasgow Coma Scale (GCS) score at admission and discharge, Injury Severity Score, New Injury Severity Score, and RHISS. Outcome was assessed by a Functional Independence Measure score in three major domains: expression, locomotion, and feeding. Data were analyzed by the chi2 test and Mann-Whitney U test, with p \u3c 0.05 considered significant. Results: There were 11,772 patients with International Classification of Diseases, Ninth Revision diagnosis of head injury, of which 3,244 (27%) were elderly. There were more male subjects in the nonelderly population (78% male subjects) compared with the elderly population (50% men). Mortality was 24.0% in the elderly population compared with 12.8% in the nonelderly population (risk ratio, 2.2; 95% confidence interval, 1.99-2.43). The elderly nonsurvivors were statistically older, and mortality rate increased with age. Stratified by GCS score, there was a higher percentage of nonsurvivors in the elderly population, even in the group with only moderately depressed GCS score (GCS score of 13-15; risk ratio, 7.8; 95% confidence interval, 6.1-9.9 for elderly vs. nonelderly). Functional outcome in all three domains was significantly worse in the elderly survivors compared with the nonelderly survivors. Conclusion: Elderly traumatic brain injury patients have a worse mortality and functional outcome than nonelderly patients who present with head injury even though their head injury and overall injuries are seemingly less sever

Injury prevention priority score: A new method for trauma centers to prioritize injury prevention initiatives

Background: Trauma centers are expected to develop injury prevention programs that address needs of the local population. A relatively simple, objective, and quantitative method is needed for prioritizing local injury prevention initiatives based on both injury frequency and severity. Study design: Pediatric trauma patients (16 years or younger; n= 7,958) admitted to two Level I regional trauma centers (Johns Hopkins Children Center and Westchester Medical Center) from 1993 to 1999 were grouped by injury causal mechanism according to ICD-9 external cause codes. An Injury Prevention Priority Score (IPPS), balancing the influences of severity (based on the Injury Severity Score) and frequency, was calculated for each mechanism and mechanisms were ranked accordingly. Results: IPPS-based rank lists differed across centers. The highest ranked mechanism of injury among children presenting to Johns Hopkins Children Center was pedestrian struck by motor vehicle, and at Westchester Medical Center it was motor vehicle crash. Different age groups also had specific injury prevention priorities, eg, child abuse was ranked second highest among infants at both centers. IPPS was found to be stable (r = 0.82 to 0.93, p \u3c 0.05) across alternate measures of injury severity. Conclusions: IPPS is a relatively simple and objective tool that uses data available in trauma center registries to rank injury causes according to both frequency and severity. Differences between two centers and across age groups suggest IPPS may be useful in tailoring injury prevention programs to local population need