Mechanisms of Injury Leading to Concussions in Collegiate Soccer Players: A CARE Consortium Study.

BACKGROUND: Few previous studies have investigated how different injury mechanisms leading to sport-related concussion (SRC) in soccer may affect outcomes. PURPOSE: To describe injury mechanisms and evaluate injury mechanisms as predictors of symptom severity, return to play (RTP) initiation, and unrestricted RTP (URTP) in a cohort of collegiate soccer players. STUDY DESIGN: Cohort study; Level of evidence, 2. METHODS: The Concussion Assessment, Research and Education (CARE) Consortium database was used. The mechanism of injury was categorized into head-to-ball, head-to-head, head-to-body, and head-to-ground/equipment. Baseline/acute injury characteristics-including Sports Concussion Assessment Tool-3 total symptom severity (TSS), loss of consciousness (LOC), and altered mental status (AMS); descriptive data; and recovery (RTP and URTP)-were compared. Multivariable regression and Weibull models were used to assess the predictive value of the mechanism of injury on TSS and RTP/URTP, respectively. RESULTS: Among 391 soccer SRCs, 32.7% were attributed to a head-to-ball mechanism, 27.9% to a head-to-body mechanism, 21.7% to a head-to-head mechanism, and 17.6% to a head-to-ground/equipment mechanism. Event type was significantly associated with injury mechanism [χ2(3) = 63; P < .001), such that more head-to-ball concussions occurred in practice sessions (n = 92 [51.1%] vs n = 36 [17.1%]) and more head-to-head (n = 65 [30.8%] vs n = 20 [11.1]) and head-to-body (n = 76 [36%] vs n = 33 [18.3%]) concussions occurred in competition. The primary position was significantly associated with injury mechanism [χ2(3) = 24; P < .004], with goalkeepers having no SRCs from the head-to-head mechanism (n = 0 [0%]) and forward players having the least head-to-body mechanism (n = 15 [19.2%]). LOC was also associated with injury mechanism (P = .034), with LOC being most prevalent in head-to-ground/equipment. Finally, AMS was most prevalent in head-to-ball (n = 54 [34.2%]) and head-to-body (n = 48 [30.4%]) mechanisms [χ2(3) = 9; P = .029]. In our multivariable models, the mechanism was not a predictor of TSS or RTP; however, it was associated with URTP (P = .044), with head-to-equipment/ground injuries resulting in the shortest mean number of days (14 ± 9.1 days) to URTP and the head-to-ball mechanism the longest (18.6 ± 21.6 days). CONCLUSION: The mechanism of injury differed by event type and primary position, and LOC and AMS were different across mechanisms. Even though the mechanism of injury was not a significant predictor of acute symptom burden or time until RTP initiation, those with head-to-equipment/ground injuries spent the shortest time until URTP, and those with head-to-ball injuries had the longest time until URTP.

Recovery After Sport-Related Concussion in Collegiate Athletes With Self-Reported Pre-Injury Migraines.

Pre-injury migraines might be a risk factor for prolonged recovery after sport-related concussion (SRC). We sought to examine whether a pre-injury history of migraines is associated with worse recovery following SRC in collegiate athletes. Data were collected through a prospective concussion surveillance system in 11 National Collegiate Athletic Association (NCAA) Division III college athletic programs between September 2014 and March 2020. Our primary independent variable, pre-injury migraines, were self-reported by the athletes. Between those with and without migraines, the outcomes of days to return-to-learn (RTL) without academic accommodations and return-to-play (RTP) were compared using Mann-Whitney U tests. Each athlete's RTL and RTP status was dichotomized (i.e., returned vs. not returned) at various time points for RTL (i.e., 7/14/21/28 days) and RTP (i.e., 14/21/28/56 days). Chi-squared tests were performed to compare the proportions of RTL and RTP status between groups. Multivariable regressions analyzed potential predictors of RTL and RTP adjusting for age, gender, prior concussions, other health conditions, and symptom severity. Of 1409 athletes with an SRC, 111 (7.9%) had a pre-injury history of migraines. Compared with those without migraines, those with migraines had longer median (interquartile range [IQR]) days to RTL (migraines = 7.0 [3.0-12.3] vs. no migraines = 5.0 [2.0-10.0], U = 53,590.5, p = 0.022). No differences were found in RTP between the two groups (migraines = 16.0 [10.0-33.0] vs. nχo migraines 15.0 [11.0-23.0], U = 38,545.0, p = 0.408). Regarding RTL, significantly lower proportions of athletes in the migraine group had fully RTL, without accommodations, at ≤14 days (77.5% vs. 85.2%, χ2 = 4.33, p = 0.037), ≤21 days (85.3% vs. 93.0%, χ2 = 7.99, p = 0.005), and ≤28 days (88.2% vs. 95.6%, χ2 = 10.60, p = 0.001). Regarding RTP, a significantly lower proportion of athletes in the migraine group RTP at ≤28 days (72.0% vs. 82.7%, χ2 = 5.40, p = 0.020) and ≤56 days (84.0% vs. 93.0%, χ2 = 8.19, p = 0.004). In a multivariable model predicting RTL that was adjusted for age, gender, acute concussion symptoms, and other health variables (e.g., attention-deficit/hyperactivity disorder [ADHD], history of mental health difficulties), pre-injury history of migraine was associated with longer RTL (ß = 0.06, p = 0.030). In a multivariable model predicting RTP, pre-injury history of migraine was not associated with RTP (ß = 0.04, p = 0.192). In collegiate athletes, pre-injury migraine history was independently associated with longer RTL but not RTP. When comparing the proportions of those with successful RTP by days, significantly lower proportions of those with migraines showed successful RTP at ≤28 days and ≤56 days. Futures studies should study the generalizability of our findings in other school levels.

Symptom resolution following a repeat concussion within the same athlete.

INTRODUCTION: Repeat sport-related concussion (SRC) is anecdotally associated with prolonged recovery. Few studies have examined repeat concussion within the same athlete. We sought to explore differences in symptom burden and recovery outcomes in an individual athlete's initial and repeat SRC. METHODS: A retrospective within-subject cohort study of athletes aged 12-23 years diagnosed with two separate SRCs from 11/2017-10/2020 was conducted. Primary outcomes were initial symptom severity and time-to-symptom-resolution. Secondary outcomes included return-to-learn (RTL) and return-to-play (RTP) duration. RESULTS: Of 868 athletes seen, 47 athletes presented with repeat concussions. Median time between concussions was 244 days (IQR 136-395). Comparing initial to repeat concussion, no differences were observed in time-to-clinic (4.3 ± 7.3vs.3.7 ± 4.6 days, p = 0.56) or initial PCSS (26.2 ± 25.3 vs. 30.5 ± 24.1, p = 0.32). While a difference was observed in time-to-symptom resolution between initial/repeat concussion (21.2 ± 16.3 vs. 41.7 ± 86.0 days, p = 0.30), this did not reach statistical significance. No significant differences were observed in time-to-RTL (17.8 ± 60.6 vs. 6.0 ± 8.3 days, p = 0.26) and RTP (33.2 ± 44.1 vs. 29.4 ± 39.1 days, p = 0.75). Repeat concussion was not associated with symptom resolution on univariate (HR 1.64, 95% CI 0.96-2.78, p = 0.07) and multivariable (HR 0.85, 95% CI 0.49-1.46, p = 0.55) Cox regression. CONCLUSION: No significant differences in symptom duration and RTP/RTL were seen between initial/repeat concussion.

Acute psychological symptom profiles in high school football players following sport-related concussion.

OBJECTIVE: In a cohort of high school football athletes, the authors sought to 1) describe the proportion of those with acute psychological symptoms postconcussion, 2) determine predictors of more acute psychological symptoms postconcussion, and 3) determine if acute psychological symptoms impact recovery. METHODS: A retrospective cohort study of high school football athletes (14-18 years of age) who sustained a sport-related concussion between November 2017 and April 2022 and presented to a multidisciplinary concussion center was performed. Based on their Post-Concussion Symptom Scale (PCSS) scores at the initial clinic visit, their total psychological symptom cluster score was calculated by summing their scores for the four affective symptoms (irritability, sadness, nervousness, and feeling more emotional). The psychological symptom ratio was defined as the ratio of the psychological symptom cluster score to the total initial PCSS score. Primary outcomes included time to return to learn (RTL), symptom resolution, and return to play (RTP). Uni- and multivariable regression analyses were performed controlling for demographic factors, learning disabilities, attention-deficit/hyperactivity disorder, and personal and/or family history of psychological diagnoses and migraine. RESULTS: A total of 195 male football players (mean age 16.2 ± 1.2 years) were included in the study. About one-third of the sample (n = 70, 35.9%) reported at least one psychological symptom. Of these 70 athletes, their psychological symptom scores were 1 (10.3%), 2 (7.7%), and ≥ 3 (17.9%). Irritability was the most endorsed psychological symptom (25.1%), followed by nervousness (15.9%), feeling more emotional (12.8%), and sadness (11.8%). The multivariable regression model showed that a positive psychological history (B = 2.66, 95% CI 0.74-4.58, p = 0.007) and family psychological history (B = 2.43, 95% CI 0.98-3.88, p = 0.001) were significant predictors of a higher psychological symptom cluster score. Multivariable linear regression analysis showed that a higher psychological symptom cluster score was associated with a longer time to RTP (B = 1.22, 95% CI 0.17-2.264, p = 0.023) but not with time to symptom resolution or RTL. The psychological symptom ratio was not a significant predictor. CONCLUSIONS: In a cohort of male football players, 36% reported at least one psychological symptom, with irritability being most commonly reported. Athletes with a personal and/or family history of psychological disorders experienced more acute psychological symptoms following a sport-related concussion. A higher psychological symptom cluster score was associated with delayed time to RTP but not time to RTL or symptom resolution.

Do academic accommodations help students recover following sport-related concussion? A retrospective study of 96 youth athletes.

OBJECTIVE: Many schools utilize academic accommodations to help athletes return-to-learn after sport-related concussion, yet little is known about the impact of accommodations on recovery. In a cohort of adolescent athletes with sport-related concussion, the authors sought to 1) describe academic accommodations, 2) determine predictors of receiving accommodations, and 3) determine how accommodations influenced recovery, as defined by days to return-to-learn, symptom resolution, and return-to-play. METHODS: A retrospective survey study was undertaken that included all athletes between the ages of 12 and 24 years who were seen at a regional sport-related concussion center from April 1, 2020, to April 1, 2022. Demographic characteristics, past medical history, injury characteristics, school-related factors, and recovery were collected via a telephone-based survey and from medical charts. The independent variable was the use of academic accommodations by students. The outcome variables included days to return-to-learn, symptom resolution, and return-to-play. Univariable and multivariable logistic regression analyses were performed. RESULTS: Of 300 athletes contacted, 96 consented to participate in this study (mean age ± SD 16.6 ± 2.6 years, 60.4% male). The mean return-to-learn was 9.0 ± 13.2 days. In total, 63.5% of athletes received some kind of school accommodation. The most common accommodations included extra time on tests (46/96 [47.9%] athletes) and extra time for assignments (43/96 [44.8%]), whereas preferential seating in class (0/96 [0.0%]) and reduced workloads (4/96 [4.2%]) were the least commonly used accommodations. Multivariable logistic regression revealed that White race (OR 0.17, 95% CI 0.02-0.71, p = 0.03) and higher initial Post-Concussion Symptom Scale (PCSS) score (OR 1.04, 95% CI 1.01-1.07, p = 0.02) were predictive of receiving accommodations. Univariable models showed that receiving accommodations was not predictive of return-to-learn (ß = 4.67, 95% CI -0.92 to 10.25, p = 0.10), symptom resolution (ß = 24.71, 95% CI -17.41 to 66.83, p = 0.26), or return-to-play (ß = 13.35, 95% CI -14.56 to 41.27, p = 0.35). Regarding other predictors of each outcome, several factors emerged irrespective of accommodations. Multivariable analysis revealed that longer time to return-to-learn was associated with a history of psychiatric illness (ß = 8.00, 95% CI 1.71-14.29, p = 0.02) and initial PCSS score (ß = 0.14, 95% CI 0.06-0.23, p < 0.01). Finally, predictors of days to return-to-play included school personnel who were knowledgeable of concussion (ß = -5.07, 95% CI -9.93 to -0.21, p = 0.04) and higher initial PCSS score (ß = 0.67, 95% CI 0.04-1.29, p = 0.03). CONCLUSIONS: The most common accommodation was extra time on tests/assignments, whereas reduced workload was the least common. White race and greater initial PCSS score were associated with receiving accommodations. Receiving accommodations did not significantly impact days to return-to-learn, symptom resolution, or return-to-play.

Do Sport-Related Concussions Later in the Season Take Longer to Recover From?

OBJECTIVE: In a cohort of high-school football athletes with sport-related concussion (SRC), we sought to investigate the role of seasonality, defined as time of injury during a season, on recovery. DESIGN: Retrospective cohort study. SETTING: Regional sport concussion center. PARTICIPANTS: High-school football athletes ages 14 to 19 -years old who sustained an SRC from 11, 2017 to 04, 2022. INTERVENTION: Athletes were divided into 3 groups based on seasonality: early, middle, and late season. MAIN OUTCOME MEASURES: The primary outcomes were initial Post-Concussion Symptom Scale score and recovery, as defined by time to return-to-learn (RTL), symptom resolution, and return-to-play (RTP). Descriptive statistics, analysis-of-variance, t tests, and multivariable regressions were performed. RESULTS: Of our cohort of 273 high-school football players who sustained an SRC, 97 (35.5%) sustained an SRC during early season, 107 (39.2%) during middle season, and 69 (25.3%) during late season. Compared with late-season concussions, early-season concussions took less days to symptom resolution (early = 11.5 ± 12.9 vs late = 25.5 ± 27.0, P = 0.03), but no differences were found in days to RTL (early = 5.3 ± 4.8 vs late = 7.2 ± 15.8, P = 0.51) and RTP (early = 13.5 ± 11.8 vs late = 23.0 ± 22.8, P = 0.08). Seasonality was not a significant predictor for any recovery metric in multivariable regressions. CONCLUSION: Sport-related concussions occurring in the early third of the season took significantly less time to symptom resolution than those occurring in the later third of the season; however, this was not statistically significant in multivariable analyses. No association was observed between seasonality and time to RTL and RTP. A trend of worse recovery with concussions later in the season may be present.

Does recovery after sport-related concussion vary by time point in a season? A multi-sport investigation.

OBJECTIVE: Seasonality, or the specific point in time within a season in which the injury occurs, may have an impact on the recovery following sport-related concussions (SRCs). In a cohort of high school athletes across multiple sports, the authors sought to investigate the impact of seasonality on 1) concussion frequency, 2) acute symptom presentation (initial Post-Concussion Symptom Scale [PCSS] score), and 3) recovery outcomes, including the time to return to learn (RTL), symptom resolution (SR), and return to play (RTP). METHODS: A retrospective, single-institution, cohort study was conducted with adolescent athletes aged 14-19 years who sustained an SRC between November 2017 and April 2022 and presented to a multidisciplinary specialty concussion clinic. The time from first practice to the end of the regular season was evenly trichotomized into early, middle, and late season. Teams that participated in the playoffs were included in a subanalysis. One-way ANOVA and independent t-tests were used to compare PCSS scores, RTL, SR, and RTP across seasonality. Univariable and multivariable regressions were used to determine predictors for recovery, defined as total days from initial visit to each outcome. RESULTS: Of the 1504 eligible athletes, 620 high school athletes met inclusion criteria; 491 (79.2%) sustained a concussion during the regular season with 73 (14.9%), 136 (27.7%), and 282 (57.4%) concussions occurring in the early, middle, and late seasons, respectively. No differences were seen for initial PCSS score, RTL, SR, or RTP across early-, middle-, and late-season concussions. The initial PCSS score was significantly higher for playoff compared with regular-season concussions (playoffs: 33.4 ± 27.5; regular season: 23.3 ± 22.8; t = -1.979, p = 0.048). A subanalysis of playoff concussions (n = 24) compared with regular-season concussions showed that concussion in the playoffs was associated with a higher initial PCSS score in univariable (ß = 0.093, p = 0.048) and multivariable (ß = 0.112, p = 0.014) analyses. CONCLUSIONS: The majority of concussions occurred during the late-season period. No difference in acute symptoms or recovery outcomes was seen when comparing the three regular season time points. Playoff concussions were associated with significantly increased symptom scores compared with nonplayoff concussions.

Systematic Review Examining the Reporting of Race and Ethnicity in Sport-Related Concussion Studies.

OBJECTIVE: Sport-related concussion (SRC) is an evolving public health concern among youth athletes. Despite emerging evidence that race/ethnicity are important factors in determining concussion outcomes, studies examining race/ethnicity are limited. We conducted a systematic review to: 1) determine the prevalence of SRC studies that report race/ethnicity of their participants, 2) describe how race/ethnicity are used within each study, and 3) assess predictive factors for reporting of race/ethnicity. DATA SOURCES: PubMed/Embase/PsycINFO/CINAHL databases. STUDY SELECTION: Study inclusion criteria were: 1) primary/peer-reviewed research 2) related to the diagnosis/treatment/recovery of SRC 3) involving school-aged athletes (ages 5-25) 4) with ≥ 25 participants. The search was performed 03/2021 and included only studies published after 03/2013. DATA EXTRACTION: For each article, we looked at whether race/ethnicity were reported, and if so, which races/ethnicities were mentioned. For each race/ethnicity mentioned, we extracted the corresponding sample size and how they were used as variables in the study. DATA SYNTHESIS: Of 4,583 studies screened, 854 articles met inclusion criteria. Of the included articles, 132 (15.5%) reported race of their sample and 65 (7.6%) reported ethnicity, whereas 721 (84.4%) reported neither. When examining the demographic characteristics of the 132 studies that reported race, 69.8% of athletes were reported to be White. Additionally, 79.5% of these studies solely used race as a demographic descriptor as opposed to as a main exposure or covariate of interest. Studies published more recently were more likely to report race. Further, specific study/journal topics and geographic location of the authors were more likely to report race. CONCLUSIONS: Reporting of race/ethnicity is limited in current SRC literature. Future studies should improve the reporting of race/ethnicity, diversify study samples by focusing on enrolling athletes from underrepresented groups, and consider the potential impact of race/ethnicity as social determinants of health on risk factors, recovery, and long-term sequelae after SRC.

Return-to-learn after sport-related concussion: does school level matter?

OBJECTIVE: Return-to-learn (RTL) after sport-related concussion (SRC) is an important yet understudied topic. The authors sought to do the following: 1) describe patterns of RTL among athletes by school level (i.e., middle school, high school, college); and 2) evaluate the predictive value of school level on RTL duration. METHODS: A retrospective, single-institution cohort study of adolescent and young adult athletes 12-23 years old who sustained an SRC between November 2017 and April 2022 and who presented to a multidisciplinary specialty concussion clinic was conducted. The independent variable was school level, trichotomized into middle school, high school, and college. Time to RTL was the primary outcome and was defined as days from SRC to return to any academic activities. ANOVA was used to compare RTL duration across school levels. A multivariable linear regression was performed to evaluate for predictive value of school level on RTL duration. Covariates included the following: sex, race/ethnicity, learning disorder, psychiatric conditions, migraines, family history of psychiatric conditions/migraines, initial Post-Concussion Symptom Scale score, and number of prior concussions. RESULTS: Of 1007 total athletes, 116 (11.5%) were in middle school, 835 (83.0%) were in high school, and 56 (5.6%) were in college. The mean RTL times (in days) were as follows: 8.0 ± 13.1 (middle school), 8.5 ± 13.7 (high school), and 15.6 ± 22.3 (college). One-way ANOVA showed a statistically significant difference between groups (F[2, 1007] = 6.93, p = 0.001). A Tukey post hoc test revealed a longer RTL duration in collegiate athletes when compared to middle school (p = 0.003) and high school (p < 0.001) athletes. Collegiate athletes had longer RTL duration compared to other school levels (ß = 0.14, p < 0.001). There was no difference between middle school and high school athletes (p = 0.935). The subanalysis revealed a longer RTL duration in high school freshmen/sophomores (9.5 ± 14.9 days) when compared to juniors/seniors (7.6 ± 12.6 days; t = 2.05, p = 0.041), and being an older (junior/senior) high school athlete was predictive of shorter RTL duration (ß = -0.11, p = 0.011). CONCLUSIONS: When examining patients who presented to a multidisciplinary sport concussion center, RTL duration was longer in collegiate athletes when compared to middle and high school athletes. Younger high school athletes had longer time to RTL compared to their older counterparts. This study provides insight into how varying scholastic environments may contribute to RTL.

Positive Head Computed Tomography Findings in the Setting of Sport Head Injuries: Can These Athletes Return-to-Play?

BACKGROUND: The literature on athletes with positive head computed tomography (HCT) findings in the setting of sport head injuries remains sparse. OBJECTIVE: To report the proportions of athletes with a positive HCT and compare acute injury characteristics and recovery between those with and without a positive HCT. METHODS: A retrospective, single-institution, cohort study was performed with all athletes aged 12 to 23 years seen at a regional concussion center from 11/2017 to 04/2022. The cohort was dichotomized into positive vs negative HCT (controls). Acute injury characteristics (ie, loss of consciousness and amnesia) and recovery, as measured by days to return-to-learn (RTL), symptom resolution, and return-to-play (RTP) were compared. χ 2 and Mann-Whitney U tests were performed. RESULTS: Of 2061 athletes, 226 (11.0%) received an HCT and 9 (4.0%) had positive findings. HCT findings included 4 (44.4%) subdural hematomas, 1 (11.1%) epidural hematoma, 2 (22.2%) facial fractures, 1 (11.1%) soft tissue contusion, and 1 (11.1%) cavernous malformation. All 9 (100.0%) athletes were treated nonoperatively and successfully returned-to-play at a median (IQR) of 73.0 (55.0-82.0) days. No differences in loss of consciousness or amnesia were seen between positive HCT group and controls. The Mann-Whitney U test showed differences in RTL (17.0 vs 4.0 days; U = 45.0, P = .016) and RTP (73.0 vs 27.0 days; U = 47.5, P = .007) but not in symptom resolution. Our subanalysis showed no differences across all recovery metrics between acute hemorrhages and controls. CONCLUSION: Among athletes seen at a regional concussion center who underwent an acute HCT, positive findings were seen in 4%. Although athletes with a positive HCT had longer RTL and RTP, symptom resolution was similar between those with a positive and negative HCT. All athletes with a positive HCT successfully returned to play. Despite a more conservative approach to athletes with a positive HCT, clinical outcomes are similar between those with and without a positive HCT.

Use of acute cognitive symptom cluster to predict return-to-learn duration following a sport-related concussion.

OBJECTIVE: Adolescents sustaining sport-related concussion often experience difficulties with the return-to-learn (RTL) process. Whereas the initial symptom burden has predicted prolonged RTL, no studies have established a relationship between acute cognitive symptoms and RTL duration. The authors sought to evaluate the relationship between initial cognitive symptoms and RTL duration. METHODS: A retrospective single-institution cohort study of adolescent athletes aged 12-23 years who were evaluated within 5 days of a diagnosed sport-related concussion between November 2017 and October 2020 was conducted. Athletes missing cognitive symptom ratings and RTL data were excluded. The primary exposure variable was the Cognitive Symptom Ratio (CSR), defined as total cognitive symptom cluster score divided by total Post-Concussion Symptom Scale (PCSS) score from the initial clinic visit. Primary and secondary outcomes were time to RTL and total length of care, respectively. Multivariable Cox proportional hazards modeling was used to assess the effect of CSR on RTL duration. RESULTS: Of 653 athletes evaluated within 5 days of injury, 346 patients were included in the final cohort. Athletes reported a median initial PCSS score of 21 (interquartile range [IQR] 6-37) and a median cognitive symptom score of 4 (IQR 0-9). Most patients endorsed some degree of difficulty concentrating (n = 212, 61.3%). The median CSR was 0.18 (IQR 0.00-0.27). On multivariable regression analysis, a higher CSR was associated with prolonged RTL duration (HR 0.30, 95% CI 0.13-0.69, p = 0.004). When initial PCSS score was added to the model, the previously significant association between CSR and RTL was no longer significant (HR 0.67, 95% CI 0.29-1.59, p = 0.367). When dichotomized based on frequency distribution, a higher proportion of patients with low CSR achieved RTL by 7 days postinjury (82.2% vs 69.9%, p = 0.007), a difference not seen at 14 days (92.2% vs 87.3%, p = 0.133). CONCLUSIONS: An acute ratio of cognitive symptoms may predict patients at increased risk for prolonged RTL and those with normal PCSS scores who may experience difficulties once resuming school activities.

Mesenchymal IGF-I overexpression: paracrine effects in the intestine, distinct from endocrine actions.

Local IGF-I expression is frequently increased in intestinal mesenchyme during adaptive growth of intestinal epithelium, but paracrine growth effects of IGF-I in vivo are not defined. We tested whether overexpression of IGF-I in intestinal mesenchyme increases epithelial growth and if effects are distinct from known effects of circulating IGF-I. SMP8-IGF-I-transgenic (TG) mice overexpress IGF-I driven by an alpha-smooth muscle actin promoter. Mucosal and muscularis growth were assessed in the jejunum, ileum, and colon of SMP8-IGF-I-TG mice and wild-type littermates. Abundance of the SMP8-IGF-I transgene and IGF binding protein (IGFBP)-3 and -5 mRNAs was determined. Mucosal growth was increased in SMP8-IGF-I-TG ileum but not jejunum or colon; muscularis growth was increased throughout the bowel. IGFBP-5 mRNA was increased in SMP8-IGF-I-TG jejunum and ileum and was specifically upregulated in ileal lamina propria. Overexpression of IGF-I in intestinal mesenchymal cells has preferential paracrine effects on the ileal mucosal epithelium and autocrine effects on the muscularis throughout the bowel. Locally expressed IGF-I has distinct actions on IGFBP expression compared with circulating IGF-I.

Reduction of spontaneous and irradiation-induced apoptosis in small intestine of IGF-I transgenic mice.

Insulin-like growth factor I (IGF-I) may promote survival of putative stem cells in the small intestinal epithelium. Mitosis and apoptosis were quantified in crypts of nonirradiated and irradiated IGF-I transgenic (TG) and wild-type (WT) littermates. The mean apoptotic index was significantly greater in WT vs. TG littermates. After irradiation, apoptotic indexes increased, and WT mice showed a more dramatic increase in apoptosis than TG mice at the location of putative stem cells. After irradiation, no mitotic figures were observed in WT crypts, whereas mitosis was maintained within the jejunal epithelium of TG mice. The abundance and localization of Bax mRNA did not differ between nonirradiated littermates. However, there was more Bax mRNA in TG vs. WT mice after irradiation. Bax mRNA was located along the entire length of the irradiated crypt epithelium, but there was less Bax protein observed in the bottom third of TG mouse crypts compared with WT littermates. IGF-I regulates cell number by stimulating crypt cell proliferation and decreasing apoptosis preferentially within the stem cell compartment.