Liver injury is associated with mortality in sickle cell disease.

BACKGROUND: Increased life expectancy in sickle cell disease (SCD) has resulted in greater recognition of the consequences of repeated intravascular vaso-occlusion and chronic haemolysis to multiple organ systems. AIM: To report the long-term consequences of liver dysfunction in SCD. METHODS: A cohort of SCD patients was prospectively evaluated at the National Institutes of Health (NIH) Clinical Center. The association of mortality with liver enzymes, parameters of liver synthetic function and iron overload was evaluated using Cox regression. RESULTS: Exactly, 247 SCD patients were followed up for 30 months of whom 22 (9%) died. After controlling for predictors, increased direct bilirubin (DB), ferritin, alkaline phosphatase and decreased albumin were independently associated with mortality. In a multivariable model, only high DB and ferritin remained significant. Ferritin correlated with hepatic iron content and total blood transfusions but not haemolysis markers. Forty patients underwent liver biopsies and 11 (28%) had fibrosis. Twelve of 26 patients (48%) had portal hypertension by hepatic venous pressure gradient (HVPG) measurements. All patients with advanced liver fibrosis had iron overload; however, most patients (69%) with iron overload were without significant hepatic fibrosis. Ferritin did not correlate with left ventricular dysfunction by echocardiography. DB correlated with bile acid levels suggesting liver pathology. Platelet count and soluble CD14 correlated with HVPG indicating portal hypertension. CONCLUSIONS: Ferritin and direct bilirubin are independently associated with mortality in sickle cell disease. Ferritin likely relates to transfusional iron overload, while direct bilirubin suggests impairment of hepatic function, possibly impairing patients' ability to tolerate systemic insults.

Evaluating the impact of physical renovation, computerization, and use of an inquiry approach in an undergraduate, allied health human anatomy and physiology lab.

This paper describes and evaluates a major renovation of a human anatomy and physiology lab for allied health students. A Howard Hughes Medical Institute award funded an extensive collaboration between faculty involved in teaching the course and faculty with expertise in industrial and furniture design. The resulting physical lab has unique features designed to improve work in groups, student movement, and integration of computers with wet laboratories. The anatomy curriculum was switched from fetal pig dissections to the use of human cadavers, computer animations, and plastic models. An inquiry approach was integrated into the physiology curriculum. Student attitude surveys suggest that the physical and curricular changes resulted in a significant increase in student learning. An experiment designed to specifically test the effect of new vs. old equipment did not support a benefit to new equipment independent of changes in the lab physical environment and curriculum. Because the improvements in student attitude surveys occurred in the physiology but not the anatomy labs, we suggest that at least a portion of the increase is due to the institution of the inquiry approach.

Relative role of heme nitrosylation and beta-cysteine 93 nitrosation in the transport and metabolism of nitric oxide by hemoglobin in the human circulation.

To quantify the reactions of nitric oxide (NO) with hemoglobin under physiological conditions and to test models of NO transport on hemoglobin, we have developed an assay to measure NO-hemoglobin reaction products in normal volunteers, under basal conditions and during NO inhalation. NO inhalation markedly raised total nitrosylated hemoglobin levels, with a significant arterial-venous gradient, supporting a role for hemoglobin in the transport and delivery of NO. The predominant species accounting for this arterial-venous gradient is nitrosyl(heme)hemoglobin. NO breathing increases S-nitrosation of hemoglobin beta-chain cysteine 93, however only to a fraction of the level of nitrosyl(heme)hemoglobin and without a detectable arterial-venous gradient. A strong correlation between methemoglobin and plasma nitrate formation was observed, suggesting that NO metabolism is a primary physiological cause of hemoglobin oxidation. Our results demonstrate that NO-heme reaction pathways predominate in vivo, NO binding to heme groups is a rapidly reversible process, and S-nitrosohemoglobin formation is probably not a primary transport mechanism for NO but may facilitate NO release from heme.

Inhaled nitric oxide augments nitric oxide transport on sickle cell hemoglobin without affecting oxygen affinity.

Nitric oxide (NO) inhalation has been reported to increase the oxygen affinity of sickle cell erythrocytes. Also, proposed allosteric mechanisms for hemoglobin, based on S-nitrosation of beta-chain cysteine 93, raise the possibility of altering the pathophysiology of sickle cell disease by inhibiting polymerization or by increasing NO delivery to the tissue. We studied the effects of a 2-hour treatment, using varying concentrations of inhaled NO. Oxygen affinity, as measured by P(50), did not respond to inhaled NO, either in controls or in individuals with sickle cell disease. At baseline, the arterial and venous levels of nitrosylated hemoglobin were not significantly different, but NO inhalation led to a dose-dependent increase in mean nitrosylated hemoglobin, and at the highest dosage, a significant arterial-venous difference emerged. The levels of nitrosylated hemoglobin are too low to affect overall hemoglobin oxygen affinity, but augmented NO transport to the microvasculature seems a promising strategy for improving microvascular perfusion.

Primary end points in phase III clinical trials of severe head trauma: DRS versus GOS. The American Brain Injury Consortium Study Group.

The most commonly used primary end point in phase III clinical trials of severe head trauma is the Glasgow Outcome Scale (GOS), usually dichotomized to favorable (good) and unfavorable (poor) outcomes. The alternative endpoints include the Disability Rating Scale (DRS) with a 31-point scale. The purpose of this study was to compare DRS and GOS using the data collected from two completed clinical trials organized by the American Brain Injury Consortium and two pharmaceutical companies. The two outcome scales were examined and compared in terms of the correlation between the two scales, sensitivity, and p values between the differences between two arms of the trials. There was no indication that the DRS was more sensitive or advantageous relative to the dichotomized or four-category GOS. In addition, the highly significant correlation between the two outcome scales (r = 0.95; p < 0.0001) could not justify the DRS as an end point. The other problems with the DRS include the difficulty of determining the clinically meaningful difference in designing trials. The study suggested that the GOS is a better primary end point than DRS.

Effects of a potent melanocortin agonist on the diabetic/obese phenotype in yellow mice.

OBJECTIVE: To test the hypothesis that a melanocortin agonist can reverse obesity and insulin resistance in mice overexpressing the agouti protein. EXPERIMENTAL MODEL: Mice overexpressing the agouti protein either by transgene introduction (beta-actin promotor) or by mutation (Ay). DESIGN: NDPMSH was tested for pharmacokinetic suitability. NDPMSH at various doses was administered subcutaneously twice a day for 2-3 weeks. MEASUREMENTS: Fur pigmentation, various fatness parameters (core temperature, fat pad weight and body weight), blood glucose and hormones, fatty acid synthase measurement. RESULTS: NDPMSH caused fur pigmentation and core temperature changes, but failed to affect any metabolic parameters in agouti-dependent manner. CONCLUSION: NDPMSH, as a representation melanocortin agonist, does not compete with agouti in reversing agouti-dependent metabolic effects. This suggests that 1) agouti works via a receptor other than a melanocortin receptor to mediate its metabolic effects, 2) agouti-dependent metabolic effects are mediated through melanocortin receptors but not via antagonism of these receptors, or 3) NDPMSH is pharmacodynamically an inappropriate molecule for these types of studies.

Development of a scintillation proximity assay for peroxisome proliferator-activated receptor gamma ligand binding domain.

A scintillation proximity assay for peroxisome proliferator-activated receptor gamma ligand binding domain is described. Scintillation proximity offers an equilibrium method for detecting ligands that is both cost effective and fully automatable. The method described here is the first reported scintillation proximity assay for a peroxisome proliferator-activated receptor. The design of this system is generic in nature, allowing it to be adapted for other ligand binding proteins.

Magnetic resonance imaging: utilization in the management of central nervous system trauma.

OBJECTIVE: To determine the availability, use, and perceived value of magnetic resonance imaging (MR) in the management of acute central nervous system (CNS) trauma in United States Level I (or equivalent) trauma centers (TCs). DESIGN, MATERIALS, AND METHODS: One hundred sixty-nine American College of Surgeons, state or locally designated Level I (or equivalent) TCs were identified using compiled lists and telephone contacts. Surveys about MR use in CNS trauma were mailed to each institution. Follow-up telephone calls were made to nonresponding institutions. Data were analyzed using frequency distribution. MEASUREMENTS: Using returned questionnaires from trauma directors and follow-up telephone contacts, data on the physical location, technologist availability, and patient monitoring capabilities were accrued. The questionnaire addressed the perceived value and cost-effectiveness of MR for acute CNS trauma in general, distinguishing between spinal cord and traumatic brain injury, using a Likert-type rating scale. MAIN RESULTS: One hundred nine (65%) of identified TCs responded by mail. Sixty (33%) required contact by telephone. One hundred fifty-two (93%) reported MR scanners "on site." Five of seven TCs without on-site MR had facilities within 5 miles. No TC reported the inability to obtain MR scans. Seventy-four percent of TCs reported MR angiography capabilities. Ninety-seven percent of MR facilities were staffed 24 hours per day, 83% by on-call, out-of-hospital technologists at night and on weekends. TCs reported patient monitoring capabilities including cardiac monitoring (83%) and pulse oximetry (91%). Seventy-one percent reported the ability to scan intubated patients. Forty-five percent of TCs "rarely" use MR, 51% report "occasional" use, and 4% "frequently" use MR for acute trauma. Ninety-four percent of trauma directors agreed or strongly agreed that MR directed management and was cost-effective for spinal cord trauma. Fifty-four percent agreed or strongly agreed that MR directed management and was cost-effective for traumatic brain injury. No correlation existed between perceptions of MR applicability in CNS trauma and the number of trauma admissions or on-site availability. CONCLUSIONS: Most trauma directors consider MR important in the acute evaluation of spinal trauma and, to a lesser extent, for traumatic brain injury. Despite these opinions, the vast majority of these centers reported only "rare" to "occasional" use of MR in the setting of acute CNS trauma. Our results show that most TCs have on-site and continuously available MR facilities capable of cardiac and pulmonary monitoring. Other factors such as the higher relative cost of MR may be responsible for the discrepancy between the perceived value and the actual utilization of MR imaging in the setting of CNS trauma.

Mutations in the carboxyl terminus of the agouti protein decrease agouti inhibition of ligand binding to the melanocortin receptors.

Several mutations that cause ectopic expression of the agouti gene result in obesity, hyperinsulinemia, and yellow coat color. A candidate pathway for agouti induced obesity and hyperinsulinemia is through altered signaling by melanocortin receptors, as agouti normally regulates coat coloration through antagonism of melanocortin receptor 1. Furthermore, melanocortin peptides mediate functions including steroidogenesis, lipolysis, and thermoregulation. We report apparent inhibition dissociation constants for mouse and human agouti protein inhibition of ligand binding to the melanocortin receptors, to determine which of these receptors might be involved in agouti induced diabetes. The similarity in the apparent K(I) values for agouti inhibition of ligand binding to the brain melanocortin receptors 3 and 4 (mouse: K(I) app = 190 +/- 74 and 54 +/- 18 nM; human: K(I) app = 140 +/- 56 and 70 +/- 18 nM, respectively) suggests that the MC3-R is a potential candidate for a receptor mediating the effects of agouti protein overexpression. Agouti residues important for melanocortin receptor inhibition were identified through the analysis of deletion constructs and site-specific variants. Val83 is important for inhibition of binding to MC1-R (K(I) app for Val83Ala agouti increased 13-fold relative to wild-type protein). Arg85, Pro86, and Pro89 are important for selective inhibition of binding between MC1-R and MC3-R and MC4-R as their apparent K(I) values are essentially unchanged at MC1-R, while they have increased 6-10-fold relative to wild-type protein at MC3-R and MC4-R.

Mild traumatic brain injuries in low-risk trauma patients.

BACKGROUND: Moderate or severe traumatic brain injury (TBI) resulting from cranial trauma is usually easily recognizable. Mild TBI (MTBI), however, may escape detection at presentation because of delayed symptoms and the absence of radiographic abnormalities. Despite its subtle or delayed presentation, the spectrum of symptoms often experienced after MTBI, collectively referred to as "postconcussive syndrome," may cause serious psychosocial dysfunction. METHODS/RESULTS: To assess the sensitivity of emergency department screening for MTBI, a prospective follow-up study was conducted on a group of patients (N = 129) who had been evaluated at a regional trauma center after blunt trauma. None had symptoms or signs of TBI at presentation, nor any history of direct cranial trauma. All were discharged to home from the emergency department without a diagnosis of TBI. At 1 month after injury, 41 of 129 (32%) patients described an increase in symptoms consistent with MTBI. The most common symptoms were insomnia (62%), headaches (58%), irritability (56%) and fatigue (56%). At 2 months, most symptoms had decreased significantly, and none had increased in severity. Despite improvement in their symptoms over that time period, 11% of those with persistent symptoms remained unable to resume their premorbid daily activities. CONCLUSIONS: These data, obtained from a population of patients considered to be at extremely low risk for TBI, indicate that MTBI occurs more often among blunt trauma patients than is commonly appreciated, even in busy trauma centers. Because early recognition of MTBI may expedite referral of these patients for appropriate outpatient follow-up care, thereby avoiding potentially serious social and financial repercussions, emergency department personnel should have a high index of suspicion for MTBI in any patient sustaining blunt systemic trauma. Current measures that screen for MTBI appear to be inadequate; follow-up protocols may prove to be more sensitive screening tools.

Detection of impaired cerebral autoregulation using spectral analysis of intracranial pressure waves.

Successful resuscitation following severe traumatic brain injury (TBI) requires rapid evaluation of intracranial pressure (ICP), cerebrovascular reactivity (autoregulation), and cerebral metabolism. During impaired autoregulation, inadequate cerebral blood flow (CBF) can lead to ischemia while excessive CBF can result in elevated ICP. Without information regarding the state of autoregulation, treatment of either situation may ameliorate one problem but exacerbate the other. It has been hypothesized that fast Fourier transform (FFT) analysis of arterial blood pressure (BP) and ICP waves can differentiate states of intact and impaired autoregulation. BP and ICP waves were recorded in canines before and after ischemic injury during arterial normotension, hypertension, and hypotension induced with dopamine or nitroprusside infusion. Transfer functions (TFn) were calculated from FFT spectra as ratios of ICP and BP harmonic peak amplitudes to distinguish states of vasoreactivity. During normotension and hypertension, autoregulation was intact and TF1 averaged 0.05. During hypotension, TF1 averaged 0.22 (8 x baseline, p < 0.010). During impaired autoregulation following ischemic injury, TF1 averaged 0.50 (18 x baseline, p < 0.010; 2 x nitroprusside levels, p < 0.01). This large difference in TF relative to baseline extended over a large range of BP (60 < BP < 180 mm Hg). Based on these data and previous results, it was estimated that TF can differentiate impaired autoregulation from effects solely related to elevated ICP or active vasodilation for ICP < 30-40 mm Hg. This suggests that for specific, but widely applicable physiologic conditions, spectral analysis can identify states of impaired autoregulation and, as an adjunct to traditional monitoring techniques, aid in acute resuscitation and prevention of secondary injury in TBI.

Agouti structure and function: characterization of a potent alpha-melanocyte stimulating hormone receptor antagonist.

The murine agouti gene encodes for a novel 131 amino acid protein. The sequence includes a 22 residue putative secretion signal, an internal basic region, and a C-terminal domain containing 10 cysteines. Agouti has been found to antagonize the binding of certain pro-opiomelanocortin peptides, such as alpha-melanocyte stimulating hormone (alpha-MSH), to the murine melanocortin-1 receptor (MC1-R). We report the purification of a secreted murine agouti to homogeneity by a two-step procedure from baculovirus-infected Trichoplusia ni (T. ni). The protein is glycosylated and exhibits competitive, high-affinity antagonism (Ki = 0.8 nM) versus alpha-MSH in cell-based assays employing B16F10 cells. Association state analysis by analytical ultracentrifugation reveals that agouti exists in a monomer--dimer plus aggregate equilibrium at low micromolar concentrations. Data from secondary structure studies indicate that the protein is highly stable to thermal denaturation. Enzymatic digestion to probe disulfide bond arrangement yielded a discrete C-terminal (Val 83-Cys 131) domain. The isolated highly cysteine-rich C-terminal domain retains alpha-MSH antagonism equipotent with mature agouti. This bioactive domain contains all 10 cysteines which exhibit sequence homology when aligned with several conotoxins.

Agouti antagonism of melanocortin binding and action in the B16F10 murine melanoma cell line.

Several dominant mutations at the murine agouti locus result in the expression of a number of phenotypic changes, including a predominantly yellow coat color, obesity, and hyperinsulinemia. The mutants exhibit ectopic overexpression of normal agouti protein, suggesting that agouti regulates coat coloration by direct antagonism of the alpha-melanocyte-stimulating hormone receptor. We have tested this hypothesis by examining agouti inhibition of both melanocortin-stimulated cyclic adenosine monophosphate production and the binding of a radioactive melanocortin analog in the murine B16F10 melanoma cell line. Inhibition of melanocortin-induced cyclic nucleotide accumulation did not require preincubation of the cells with agouti and was independent of the agonist used. Furthermore, inhibition of both agonist binding to and activation of melanocortin receptor could be described by a simple competitive model with similar inhibition constants of 1.9 and 0.9 nM, respectively. The mutually exclusive binding of agouti and melanocortin was verified by cross-linking experiments using a radiolabeled alpha-melanocyte-stimulating hormone analog. Competitive inhibition of alpha-melanocyte-stimulating hormone binding can account for the effects of agouti on coat coloration and suggests the possibility that the other phenotypic changes observed on agouti overexpression may be due to direct action of agouti at a novel melanocortin receptor(s).

Elevated intracranial pressure masks hemorrhagic hypotension in a canine model.

Previous clinical studies of blunt trauma patients with severe brain injuries have demonstrated that emergency department vital signs failed to consistently identify life-threatening abdominal injury. One hypothesis to explain this is that bradycardia and systemic hypertension from brainstem injury (the Cushing response) may mask the tachycardia and hypotension ordinarily manifested by hemorrhagic hypovolemia. This would result in inappropriately normal or near-normal emergency department vital signs for otherwise clinically apparent hypovolemia. To test this hypothesis, splenectomized dogs (n = 9) were phlebotomized to a systolic blood pressure (SBP) of 60 mm Hg. Subsequently, intracranial pressure (ICP) was artificially elevated in a controlled, incremental fashion. From a mean SBP of 58.4 +/- 3.9 mm Hg at a baseline ICP of 8.1 +/- 4.2 mm Hg, increases in ICP of only 20 mm Hg significantly raised SBP (in some animals). When ICP reached 70 mm Hg, mean SBP reached 95.1 +/- 8.7 mm Hg (p < 0.001) in spite of profound hemorrhagic hypovolemia. In all subjects, the tachycardia that accompanied hypovolemia tended towards normal with incremental increases in ICP. However, this did not reach statistical significance. In response to elevations in ICP, this hypovolemic canine model displayed normalization of SBP with variable changes in heart rate. These changes could mask hemorrhagic hypotension in humans sustaining multiple system trauma. These experimental data support clinical studies advocating immediate definitive abdominal evaluation in unconscious blunt trauma patients, regardless of vital signs.

Early definitive abdominal evaluation in the triage of unconscious normotensive blunt trauma patients.

The need for simultaneous diagnosis and treatment of life-threatening intracranial mass lesions and intra-abdominal injury results in controversy over the appropriate triage of unconscious blunt trauma patients with stable vital signs. To aid in early decisions for these patients, a retrospective analysis of 290 patients with Glasgow Coma Scale (GCS) scores < or = 8 and systolic blood pressures (SBP) > 90 mm Hg was undertaken. The hypothesis of this study was that life-threatening abdominal injury frequently occurs in these patients and injuries cannot be consistently identified from vital signs alone. Data were analyzed for injury mechanism, SBP, heart rate (HR), Injury Severity Score (ISS), Revised Trauma Score (RTS), Abbreviated Injury Scale score for the abdomen and brain (A-AIS, CNS-AIS), and the need for emergent laparotomy. Patients with concurrent injuries were more likely to come from motor vehicle crashes than falls (p < 0.001). Although severe abdominal injuries (A-AIS > or = 3) were frequently identified based on SBP and HR, the use of clinical signs alone resulted in more missed injuries than did using the results diagnostic peritoneal lavage (DPL). This study suggests that all unconscious normotensive blunt trauma patients undergo immediate DPL to prevent missing life-threatening injuries.

Determination of endothelin by an immobilized receptor assay utilizing a 96-well format.

Bovine cerebellar membranes immobilized on 96-well microtiter plates provide receptors for 125I-labeled endothelin-1 as the basis for a competitive binding assay. Adsorption of the membranes to a surface does not significantly alter the ligand-receptor interaction and reduces non-specific binding to 3-7% of total binding compared to 10-20% for a filtration technique. Considerable savings in reagents are realized since assays can be performed in 100 microliter volumes with only 10-20 micrograms of membrane protein. The 96-well format allows the rapid quantitation of large numbers of samples, and the assay is especially attractive in that it utilizes readily available reagents and equipment without the need for specific antibodies. The endothelin-receptor-based assay may be used to measure conversion of big endothelin-1 to endothelin-1 in aqueous assays. Since the presence of serum does not affect this method, tissue culture medium may be directly analyzed for endothelin production by cultured cells. All three isoforms of endothelin are detected, and the specificity of the receptor is retained since fragments and precursor forms of endothelin are not recognized. In cases where multiple endothelin isoforms may be present or where specificity of binding is in question, this assay may be used in conjunction with high pressure liquid chromatography to distinguish active peptides.

Metabolism of 11-deoxycorticosterone by hamster adrenal mitochondria.

Metabolism of 11-deoxycorticosterone (DOC) by hamster adrenal mitochondria gives 19-hydroxy-DOC and corticosterone (via 11-hydroxylation) in approximately equal yields. The ratio of 19- to 11-hydroxylation was invariant with changes in concentration of substrate or a competitive inhibitor. It is most likely, therefore, that a single 11,19-hydroxylase catalyzes both oxidations. Both primary products are further oxidized to the corresponding carbonyl analogs, 19-oxo-DOC and 11-dehydrocorticosterone, at rates that are approx. 20% of their rates of formation. The oxidation of 11-dehydrocorticosterone is catalyzed by a dehydrogenase utilizing either NAD or NADP while the oxidation of 19-hydroxy-DOC is catalyzed by an oxidase requiring NADPH. The 11-dehydrocorticosterone is stable in this enzyme preparation while 19-oxo-DOC is metabolized to two additional products, which are tentatively identified as 19-oic-DOC and 19-norcorticosterone. 19-nor-DOC was found to be hydroxylated at a rate that is 20% faster than the rate for DOC under the same conditions. It is therefore possible that 19-norcorticosterone can arise from 19-oic-DOC via decarboxylation to 19-nor-DOC and subsequent 11-hydroxylation, but the kinetics of its formation suggest that it may actually be formed directly from 19-oxo-DOC without free intermediates. 4-Androstene-3,17-dione and 17-hydroxy-DOC were also substrates for this 11,19-hydroxylase, but 18-hydroxy-DOC was not. Maintenance of hamsters on a low sodium diet had no effect on the metabolism of DOC by the isolated adrenal mitochondria.

Role of mast cell chymase in the extracellular processing of big-endothelin-1 to endothelin-1 in the perfused rat lung.

Previous studies of endothelin-1 (ET) synthesis have shown that some cultured endothelial cells secrete an intermediate product, big-endothelin-1 (bigET), suggesting that the processing of secreted bigET to ET may be physiologically significant. In this study, two pertinent ET converting enzyme activities, mast cell chymase I (EC 3.4.21.39) and a phosphoramidon-sensitive, neutral metalloprotease, were identified in a rat lung particulate fraction. We perfused rat lungs with bigET and chymostatin or phosphoramidon to study the relevance of these two proteases to the processing of extracellular bigET in vivo. Addition of compound 48/80 (a compound which activates mast cells, causing degranulation and release of chymase) to the perfusion buffer greatly increased hydrolysis of exogenously added bigET to ET. ET formation was inhibited completely by 32 microM chymostatin, whereas inhibition by 50 microM phosphoramidon was incomplete and variable. Perfusate histamine levels were used to monitor the extent of mast cell degranulation, and inhibition of ET production by phosphoramidon was attributed to inhibition of degranulation, per se. There was a direct correlation between perfusate ET and histamine levels in both control and phosphoramidon-treated (but not chymostatin-treated) lungs. Our results suggest that chymase from lung mast cells is capable of physiologically relevant extracellular processing by bigET to ET in the perfused rat lung.

Concussion in sports. Guidelines for the prevention of catastrophic outcome.

Concussion (defined as a traumatically induced alteration in mental status, not necessarily with loss of consciousness) is a common form of sports-related injury too often dismissed as trivial by physicians, athletic trainers, coaches, sports reporters, and athletes themselves. While head injuries can occur in virtually any form of athletic activity, they occur most frequently in contact sports, such as football, boxing, and martial arts competition, or from high-velocity collisions or falls in basketball, soccer, and ice hockey. The pathophysiology of concussion is less well understood than that of severe head injury, and it has received less attention as a result. We describe a high school football player who died of diffuse brain swelling after repeated concussions without loss of consciousness. Guidelines have been developed to reduce the risk of such serious catastrophic outcomes after concussion in sports.