James M. Cross

The relationship of blood product ratio to mortality: survival benefit or survival bias?

BACKGROUND Recent studies show an apparent survival advantage associated with the administration of higher cumulative ratios of fresh frozen plasma (FFP) to packed red blood cells (PRBC). It remains unclear how temporal factors and survival bias may influence these results. The objective of this study was to evaluate the temporal relationship between blood product ratios and mortality in massively transfused trauma patients. METHODS Patients requiring massive transfusion (>10 units of PRBC within 24 hours of admission) between 2005 and 2007 were identified (n = 134). In-hospital mortality was compared between patients receiving high (>1:2) versus low (<1:2) FFP:PRBC ratios with a regression model, using the FFP:PRBC ratio as a fixed value at 24 hours (method I) and as a time-varying covariate (method II). RESULTS The FFP:PRBC ratio for all patients was low early and increased over time. Sixty-eight percent of total blood products were given and 54% of deaths occurred during the first 6 hours. Using method I, patients receiving a high FFP:PRBC ratio (mean, 1:1.3) by 24 hours had a 63% lower risk of death (RR, 0.37; 95% CI, 0.22-0.64) compared with those receiving a low ratio (mean, 1:3.7). However, this association was no longer statistically significant (RR, 0.84; 95% CI, 0.47-1.50) when the timing of component product transfusion was taken into account (method II). CONCLUSIONS Similar to previous studies, an association between higher FFP:PRBC ratios at 24 hours and improved survival was observed. However, after adjustment for survival bias in the analysis, the association was no longer statistically significant. Prospective trials are necessary to evaluate whether hemostatic resuscitation is clinically beneficial.

Potent myofiber hypertrophy during resistance training in humans is associated with satellite cell-mediated myonuclear addition: a cluster analysis.

A present debate in muscle biology is whether myonuclear addition is required during skeletal muscle hypertrophy. We utilized K-means cluster analysis to classify 66 humans after 16 wk of knee extensor resistance training as extreme (Xtr, n = 17), modest (Mod, n = 32), or nonresponders (Non, n = 17) based on myofiber hypertrophy, which averaged 58, 28, and 0%, respectively (Bamman MM, Petrella JK, Kim JS, Mayhew DL, Cross JM. J Appl Physiol 102: 2232-2239, 2007). We hypothesized that robust hypertrophy seen in Xtr was driven by superior satellite cell (SC) activation and myonuclear addition. Vastus lateralis biopsies were obtained at baseline and week 16. SCs were identified immunohistochemically by surface expression of neural cell adhesion molecule. At baseline, myofiber size did not differ among clusters; however, the SC population was greater in Xtr (P < 0.01) than both Mod and Non, suggesting superior basal myogenic potential. SC number increased robustly during training in Xtr only (117%; P < 0.001). Myonuclear addition occurred in Mod (9%; P < 0.05) and was most effectively accomplished in Xtr (26%; P < 0.001). After training, Xtr had more myonuclei per fiber than Non (23%; P < 0.05) and tended to have more than Mod (19%; P = 0.056). Both Xtr and Mod expanded the myonuclear domain to meet (Mod) or exceed (Xtr) 2,000 mum(2) per nucleus, possibly driving demand for myonuclear addition to support myofiber expansion. These findings strongly suggest myonuclear addition via SC recruitment may be required to achieve substantial myofiber hypertrophy in humans. Individuals with a greater basal presence of SCs demonstrated, with training, a remarkable ability to expand the SC pool, incorporate new nuclei, and achieve robust growth.

Translational signaling responses preceding resistance training-mediated myofiber hypertrophy in young and old humans.

While skeletal muscle protein accretion during resistance training (RT)-mediated myofiber hypertrophy is thought to result from upregulated translation initiation signaling, this concept is based on responses to a single bout of unaccustomed resistance exercise (RE) with no measure of hypertrophy across RT. Further, aging appears to affect acute responses to RE, but whether age differences in responsiveness persist during RT leading to impaired RT adaptation is unclear. We therefore tested whether muscle protein fractional synthesis rate (FSR) and Akt/mammalian target of rapamycin (mTOR) signaling in response to unaccustomed RE differed in old vs. young adults, and whether age differences in acute responsiveness were associated with differences in muscle hypertrophy after 16 wk of RT. Fifteen old and 21 young adult subjects completed the 16-wk study. The phosphorylation states of Akt, S6K1, ribosomal protein S6 (RPS6), eukaryotic initiation factor 4E (eIF4E) binding protein (4EBP1), eIF4E, and eIF4G were all elevated (23-199%) 24 h after a bout of unaccustomed RE. A concomitant 62% increase in FSR was found in a subset (6 old, 8 young). Age x time interaction was found only for RPS6 phosphorylation (+335% in old subjects only), while there was an interaction trend (P = 0.084) for FSR (+96% in young subjects only). After 16 wk of RT, gains in muscle mass, type II myofiber size, and voluntary strength were similar in young and old subjects. In conclusion, at the level of translational signaling, we found no evidence of impaired responsiveness among older adults, and for the first time, we show that changes in translational signaling after unaccustomed RE were associated with substantial muscle protein accretion (hypertrophy) during continued RT.

Effects of oxandrolone on outcome measures in the severely burned: a multicenter prospective randomized double-blind trial.

Severe burns induce pathophysiologic problems, among them catabolism of lean mass, leading to protracted hospitalization and prolonged recovery. Oxandrolone is an anabolic agent shown to decrease lean mass catabolism and improve wound healing in the severely burned patients. We enrolled 81 adult subjects with burns 20% to 60% TBSA in a multicenter trial testing the effects of oxandrolone on length of hospital stay. Subjects were randomized between oxandrolone 10 mg every 12 hours or placebo. The study was stopped halfway through projected enrollment because of a significant difference between groups found on planned interim analysis. We found that length of stay was shorter in the oxandrolone group (31.6 ± 3.1 days) than placebo (43.3 ± 5.3 days; P < .05). This difference strengthened when deaths were excluded and hospital stay was indexed to burn size (1.24 ± 0.15 days/% TBSA burned vs 0.87 ± 0.05 days/% TBSA burned, P < .05). We conclude that treatment using oxandrolone should be considered for use in the severely burned while hepatic transaminases are monitored.

Gender differences in mortality following burn injury.

Clinical and experimental studies have demonstrated higher mortality following nonthermal trauma among males compared with females. To date, few clinical retrospective studies have focused on gender differences in outcome following burn injury with respect to age. All patients admitted to the University of Alabama at Birmingham (UAB) Burn Center between January 1994 and December 2000 were selected for inclusion in the study. Gender differences in demographic, clinical, and outcome characteristics were compared. Unadjusted and adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were calculated for the association between mortality and gender, both overall and stratified by age. Over the 7-year study period, 1229 males and 382 females were admitted to the UAB Burn Center, and mortality rates were 7.2% and 13.4%, respectively (P = 0.0002). Female patients were more likely to be older, of the black race, and in poorer health. In addition, females were more likely to suffer flame and scald burns. The association between mortality and gender was modified by age. Up to age 60, mortality rates among females were over twice that of males (OR 2.3, 95% CI 1.4–3.8); however, no difference was noted among those 60 and older (OR 0.9, 95% CI 0.5–1.6). These associations persisted following adjustment for potentially confounding variables. Causes and timing of death were similar for males and females. Women less than 60 years of age who sustain burn injuries have an increased risk of death compared with males. Differences in the natural history of nonthermal trauma and burn injury may provide insight regarding these divergent findings.

Exercise Dosing to Retain Resistance Training Adaptations in Young and Older Adults

UNLABELLED Resistance training (RT) is a proven sarcopenia countermeasure with a high degree of potency. However, sustainability remains a major issue that could limit the appeal of RT as a therapeutic approach without well-defined dosing requirements to maintain gains. PURPOSE To test the efficacy of two maintenance prescriptions on muscle mass, myofiber size and type distribution, and strength. We hypothesized the minimum dose required to maintain RT-induced adaptations would be greater in the old (60-75 yr) versus young (20-35 yr). METHODS Seventy adults participated in a two-phase exercise trial that consisted of RT 3 d·wk for 16 wk (phase 1) followed by a 32-wk period (phase 2) with random assignment to detraining or one of two maintenance prescriptions (reducing the dose to one-third or one-ninth of that during phase 1). RESULTS Phase 1 resulted in expected gains in strength, myofiber size, and muscle mass along with the typical IIx-to-IIa shift in myofiber-type distribution. Both maintenance prescriptions preserved phase 1 muscle hypertrophy in the young but not the old. In fact, the one-third maintenance dose led to additional myofiber hypertrophy in the young. In both age groups, detraining reversed the phase 1 IIx-to-IIa myofiber-type shift, whereas a dose response was evident during maintenance training with the one-third dose better maintaining the shift. Strength gained during phase 1 was largely retained throughout detraining with only a slight reduction at the final time point. CONCLUSIONS We conclude that older adults require a higher dose of weekly loading than the young to maintain myofiber hypertrophy attained during a progressive RT program, yet gains in specific strength among older adults were well preserved and remained at or above levels of the untrained young.

Differential genomic responses in old vs. young humans despite similar levels of modest muscle damage after resistance loading

Across numerous model systems, aging skeletal muscle demonstrates an impaired regenerative response when exposed to the same stimulus as young muscle. To better understand the impact of aging in a human model, we compared changes to the skeletal muscle transcriptome induced by unaccustomed high-intensity resistance loading (RL) sufficient to cause moderate muscle damage in young (37 yr) vs. older (73 yr) adults. Serum creatine kinase was elevated 46% 24 h after RL in all subjects with no age differences, indicating similar degrees of myofiber membrane wounding by age. Despite this similarity, from genomic microarrays 318 unique transcripts were differentially expressed after RL in old vs. only 87 in young subjects. Follow-up pathways analysis and functional annotation revealed among old subjects upregulation of transcripts related to stress and cellular compromise, inflammation and immune responses, necrosis, and protein degradation and changes in expression (up- and downregulation) of transcripts related to skeletal and muscular development, cell growth and proliferation, protein synthesis, fibrosis and connective tissue function, myoblast-myotube fusion and cell-cell adhesion, and structural integrity. Overall the transcript-level changes indicative of undue inflammatory and stress responses in these older adults were not mirrored in young subjects. Follow-up immunoblotting revealed higher protein expression among old subjects for NF-kappaB, heat shock protein (HSP)70, and IL-6 signaling [total and phosphorylated signal transducer and activator of transcription (STAT)3 at Tyr705]. Together, these novel findings suggest that young and old adults are equally susceptible to RL-mediated damage, yet the muscles of older adults are much more sensitive to this modest degree of damage-launching a robust transcriptome-level response that may begin to reveal key differences in the regenerative capacity of skeletal muscle with advancing age.

Heightened muscle inflammation susceptibility may impair regenerative capacity in aging humans

The regenerative response of skeletal muscle to mechanically induced damage is impaired with age. Previous work in our laboratory suggests this may result from higher proinflammatory signaling in aging muscle at rest and/or a greater inflammatory response to damage. We, therefore, assessed skeletal muscle proinflammatory signaling at rest and 24 h after unaccustomed, loaded knee extension contractions that induced modest muscle damage (72% increase in serum creatine kinase) in a cohort of 87 adults across three age groups (AGE40, AGE61, and AGE76). Vastus lateralis muscle gene expression and protein cell signaling of the IL-6 and TNF-α pathways were determined by quantitative PCR and immunoblot analysis. For in vitro studies, cell signaling and fusion capacities were compared among primary myoblasts from young (AGE28) and old (AGE64) donors treated with TNF-α. Muscle expression was higher (1.5- to 2.1-fold) in AGE76 and AGE61 relative to AGE40 for several genes involved in IL-6, TNF-α, and TNF-like weak inducer of apoptosis signaling. Indexes of activation for the proinflammatory transcription factors signal transducer and activator of transcription-3 and NF-κB were highest in AGE76. Resistance loading reduced gene expression of IL-6 receptor, muscle RING finger 1, and atrogin-1, and increased TNF-like weak inducer of apoptosis receptor expression. Donor myoblasts from AGE64 showed impaired differentiation and fusion in standard media and greater NF-κB activation in response to TNF-α treatment (compared with AGE28). We show for the first time that human aging is associated with muscle inflammation susceptibility (i.e., higher basal state of proinflammatory signaling) that is present in both tissue and isolated myogenic cells and likely contributes to the impaired regenerative capacity of skeletal muscle in the older population.

The Association Between Blood Alcohol Level and Infectious Complications Among Burn Patients

Approximately 50% of fatal and 15% of nonfatal burn-injured patients have detectable blood alcohol content (BAC) at the time of admission, and it is hypothesized that alcohol exacerbates burn-related immunosuppression. The purpose of this study was to evaluate the association between BAC and infectious complications in burn patients. The study population consisted of 1161 burn patients admitted to a large academic burn center between January 1998 and June 2007. Patients were categorized into no BAC (0.0 g/100 ml), low/moderate BAC (>0.0 and <0.1 g/100 ml) and high BAC (≥0.1 g/100 ml) groups based on BAC at time of admission. Risk ratios (RRs) and 95% confidence intervals (CIs) were calculated for associations between pneumonia, sepsis, urinary tract infection, line infection, and wound infection and BAC, adjusted for total burn surface area and inhalation injury. Relative to no BAC patients, both low/moderate and high BAC patients had nonsignificantly increased risk for most infectious complications. High BAC patients were at significantly increased risk for any infectious complication (RR 2.06, CI 1.25–3.41) and pneumonia (RR 2.06, CI 1.04–4.09) and a nonsignificantly increased risk of urinary tract infection (RR 2.12, CI 0.0.94–4.78). Results suggest that preinjury alcohol consumption places patients at an increased risk for infectious complications, most notably pneumonia. Further studies examining the relationship between alcohol and pneumonia among burn patients will help elucidate the reason for the increased risk observed in the current study and suggest ways to prevent infection for this particular subgroup of burn patients.

Bombesin Prevents Gastric Injury in the Rat: Role of Gastrin

Bombesin or gastrin-releasing peptide preventsgastric injury by an unknown mechanism. Since exogenousgastrin is a gastroprotective agent, this study wasundertaken to test the hypothesis that gastroprotection by bombesin involves release of endogenousgastrin. Subcutaneous bombesin (10-100 μg/kg) dosedependently reduced macroscopic injury to theacid-secreting portion of the stomach caused by 1 ml oforogastric acidified ethanol (150 mM hydrochloric acid-50%ethanol). Blockade of type A cholecystokinin receptorswith intraperitoneal MK-329 (1 mg/kg) reversedintravenous cholecystokinin (5 nmol/kg)-inducedgastroprotection, but not that of bombesin. In contrast,intraperitoneal type B cholecystokinin (gastrin)receptor blockade with L-365,260 (25 mg/kg) diminishedthe protective actions of both subcutaneous bombesin(100 mug/kg) and intravenous gastrin (25 pmol/kg). Inadditional studies, subcutaneous bombesin (10-100μg/kg) dose dependently increased serum gastrinlevels (radioimmunoassay). Both the gastroprotectiveactions of bombesin and bombesininduced gastrin releasewere enhanced following immunoneutralization ofendogenous somatostatin with intraperitonealsomatostatin antibody (2 mg). These data indicate thatbombesin prevents gastric injury primarily by release ofendogenous gastrin and both effects are modified byendogenous somatostatin.