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We designed a study to determine whether chronic encephalopathy occurs in elite, active soccer players resulting from repetitive heading of the soccer ball. Studies have suggested that the cumulative effects of heading a ball can cause a chronic brain syndrome similar to dementia pugilistica, which is seen in professional boxers. Twenty of 25 members of the U.S. Men's National Soccer Team training camp (average age, 24.9; average years of soccer, 17.7), who completed a questionnaire on head injury symptoms and had magnetic resonance imaging of the brain, were compared with 20 age-matched male elite track athletes. The soccer players were surveyed about playing position, teams, number of headers, acute head injuries, and years of playing experience. An exposure index to headers was developed to assess a dose-response effect of chronic heading. The soccer and track groups were questioned regarding alcohol use and history of acute head traumas. Questionnaire analysis and magnetic resonance imaging demonstrated no statistical differences between the two groups. Among the soccer players, symptoms and magnetic resonance imaging findings did not correlate with age, years of play, exposure index results, or number of headers. However, reported head injury symptoms, especially in soccer players, correlated with histories of prior acute head injuries (r = 0.63). These findings suggest that any evidence of encephalopathy in soccer players relates more to acute head injuries received playing soccer than from repetitive heading. [ABSTRACT FROM AUTHOR]

Aggressive marketing has led millions of recreational and elite athletes to use nutrition supplements in hopes of improving performance. Unfortunately, these aids can be costly and potentially harmful, and the advertised ergogenic gains are often based on little or no scientific evidence. No benefits have been convincingly demonstrated for amino acids, L-carnitine, L-tryptophan, or chromium picolinate. Creatine, beta-hydroxy-beta-methylbutyrate, and dehydroepiandrosterone (DHEA) may confer ergogenic or anabolic effects. Chromium picolinate and DHEA have adverse side effects, and the safety of the other products remains in question. [ABSTRACT FROM AUTHOR]

Abstract Background Although training and education have long been accepted as integral to disaster preparedness, many currently taught practices are neither evidence-based nor standardized. The need for effective evidence-based disaster training of healthcare staff at all levels, including the development of standards and guidelines for training in the multi-disciplinary health response to major events, has been designated by the disaster response community as a high priority. We describe the application of systematic evidence-based consensus building methods to derive educational competencies and objectives in criteria-based preparedness and response relevant to all hospital healthcare workers. Methods The conceptual development of cross-cutting competencies incorporated current evidence through a systematic consensus building process with the following steps: (1) review of peer-reviewed literature on relevant content areas and educational theory; (2) structured review of existing competencies, national level courses and published training objectives; (3) synthesis of new cross-cutting competencies; (4) expert panel review; (5) refinement of new competencies and; (6) development of testable terminal objectives for each competency using similar processes covering requisite knowledge, attitudes, and skills. Results Seven cross-cutting competencies were developed: (1) Recognize a potential critical event and implement initial actions; (2) Apply the principles of critical event management; (3) Demonstrate critical event safety principles; (4) Understand the institutional emergency operations plan; (5) Demonstrate effective critical event communications; (6) Understand the incident command system and your role in it; (7) Demonstrate the knowledge and skills needed to fulfill your role during a critical event. For each of the cross-cutting competencies, comprehensive terminal objectives are described. Conclusion Cross-cutting competencies and objectives developed through a systematic evidence-based consensus building approach may serve as a foundation for future hospital healthcare worker training and education in disaster preparedness and response.

As anthropogenic disturbances continue to drive habitat loss and range contractions, the maintenance of evolutionary processes will increasingly require targeting measures to the population level, even for common and widespread species. Doing so requires detailed knowledge of population genetic structure, both to identify populations of conservation need and value, as well as to evaluate suitability of potential donor populations. We conducted a range-wide analysis of the genetic structure of red foxes in the contiguous western U.S., including a federally endangered distinct population segment of the Sierra Nevada subspecies, with the objectives of contextualizing field observations of relative scarcity in the Pacific mountains and increasing abundance in the cold desert basins of the Intermountain West. Using 31 autosomal microsatellites, along with mitochondrial and Y-chromosome markers, we found that populations of the Pacific mountains were isolated from one another and genetically depauperate (e.g., estimated Ne range = 3-9). In contrast, red foxes in the Intermountain regions showed relatively high connectivity and genetic diversity. Although most Intermountain red foxes carried indigenous western matrilines (78%) and patrilines (85%), the presence of nonindigenous haplotypes at lower elevations indicated admixture with fur-farm foxes and possibly expanding midcontinent populations as well. Our findings suggest that some Pacific mountain populations could likely benefit from increased connectivity (i.e., genetic rescue) but that nonnative admixture makes expanding populations in the Intermountain basins a non-ideal source. However, our results also suggest contact between Pacific mountain and Intermountain basin populations is likely to increase regardless, warranting consideration of risks and benefits of proactive measures to mitigate against unwanted effects of Intermountain gene flow., (© 2022. The Author(s).)

Background: Frailty in older adults is a rapidly growing unmet medical need. It is an aging-related syndrome characterized by physical decline leading to higher risk of adverse health outcomes., Objectives: To evaluate the efficacy of Lomecel-B, an allogeneic medicinal signaling cell (MSC) formulation, in older adults with frailty., Design: This multicenter, randomized, parallel-arm, double-blinded, and placebo-controlled phase 2b trial is designed to evaluate dose-range effects of Lomecel-B for frailty on physical functioning, patient-reported outcomes (PROs), frailty status, and biomarkers., Setting: Eight enrolling clinical research centers, including the Miami Veterans Affairs Medical Center., Participants: Target enrollment is 150 subjects aged 70-85 years of any race, ethnicity, or gender. Enrollment criteria include a Clinical Frailty Score of 5 ("mild") or 6 ("moderate"), a 6MWT of 200-400 m, and serum tumor necrosis factor-alpha (TNF-α) ≥2.5 pg/mL., Intervention: A single intravenous infusion of Lomecel-B (25, 50, 100, or 200 million cells) or placebo (N=30/arm). Patients are followed for 365 days for safety, and the efficacy assessments performed at 90, 180, and 270 days., Measurements: The primary endpoint is change in 6MWT in the Lomecel-B-treated arms versus placebo at 180 days post-infusion. Secondary and exploratory endpoints include change in: 6MWT and other physical function measures at all time points; PROs; frailty status; cognitive status; and an inflammatory biomarkers panel. A pre-specified sub-study examines vascular/endothelial biomarkers. Safety is evaluated throughout the trial., Results: The trial is conducted under a Food and Drug Administration Investigational New Drug (IND), with Institutional Review Board approval, and monitoring by an NIH-appointed independent Data Safety Monitoring Board., Conclusion: This clinical trial investigates the use of a regenerative medicine strategy for frailty in older adults. The results will further the understanding of the potential for Lomecel-B in the geriatric condition of frailty., Competing Interests: AAO, BH, LM-M, KNR, KY, LD, GAG and JMH are affiliated with Longeveron Inc. JMH is a co-founder, board member and paid consultant of Longeveron Inc. JMH is also inventor of technology licensed to Longeveron Inc. This relationship is reported to the University of Miami, and a management plan is in place. EV and JW are members of Longeveron’s Science Advisory Board, for which they receive personal fees (honoraria). The University of Miami is an equity owner in Longeveron, which has licensed intellectual property from the University of Miami.

Objective: To understand catchers' preferences for mask type and perceptions regarding safety, comfort, and fit, and determine whether mask type is correlated with self-reported concussion and related symptoms after impacts from foul tips or backswings., Design: Cross-sectional study., Setting: Survey of active baseball catchers., Participants: Professional baseball catchers., Intervention: From May 1, 2015, to June 30, 2015, an online survey was administered in English and Spanish to all Major and Minor League catchers (n = 836)., Main Outcome Measures: Survey items addressed the type of mask routinely and previously used (conventional or hockey style); brand and material (steel or titanium); perceptions regarding safety, comfort, and fit; and experiences with concussions., Results: The sample consisted of 596 catchers of which 26% reported being diagnosed with a concussion. Some concussions occurred from non-baseball activities, such as car accidents or off the field incidents. For those that occurred playing baseball, 35% resulted from a foul tip. Once catchers entered professional baseball, the use of a conventional mask rose significantly: 71% of catchers reported wearing conventional-style masks, and 30% hockey-style masks at the time the survey was conducted (P < 0.05). Both conventional and hockey-style mask wearers significantly selected hockey-style masks as providing better overall safety and protection than conventional masks (P < 0.05)., Conclusions: This research supports foul tips as an important cause of concussion in catchers and provides important information about preferences among catchers for masks that are not perceived as the safest and strongest. Future research should supplement these data by conducting laboratory testing to determine which masks are stronger and by collecting qualitative data to explore why some players are more likely to wear a mask type that they perceive as offering less safety or protection.

The Berlin statement on sport-related concussion was published in 2017 using evidence-based recommendations. We aimed to examine (1) the implementation of, distribution and education based on the Berlin recommendations, and the development of sport-specific protocols/guidelines among professional and elite sports, (2) the implementation of guidelines at the community level, (3) translation of guidelines into different languages, and (4) research activities. Senior medical advisers and chief medical officers from Australian Football League, All Japan Judo Federation, British Horseracing Authority, Cricket Australia, Fédération Equestre Internationale, Football Association, Gaelic Athletic Association, International Boxing Association, Irish Horseracing Regulatory Board, Major League Baseball, National Football League, National Hockey League, National Rugby League, and World Rugby completed a questionnaire. The results demonstrated that all 14 sporting organizations have published concussion protocols/guidelines based on the Berlin recommendations, including Recognize, Removal from play, Re-evaluation, Rest, Recovery, and Return to play. There is variable inclusion of Prolonged symptoms. Prevention and Risk reduction and Long-term effects are addressed in the guidelines, rules and regulations, and/or sport-specific research. There is variability in education programs, monitoring compliance with guidelines, and publication in other languages. All sporting bodies are actively involved in concussion research. We conclude that the Berlin recommendations have been included in concussion protocols/guidelines by all the sporting bodies, with consistency in the essential components of the recommendations, whilst also allowing for sport- and regional-specific variations. Education at the elite, community, and junior levels remains an ongoing challenge, and future iterations of guidelines may consider multiple language versions, and community- and junior-level guidelines., (Copyright © 2020 by the Congress of Neurological Surgeons.)

Patients pursue wilderness experiences throughout the entire life cycle, and while outdoor pursuits are relatively safe, injuries do occur. Many of these adverse events can be anticipated, identified, and prevented through a wilderness preparticipation examination (PPE). To accomplish this, it is incumbent on the physician to assess the extrinsic and intrinsic factors faced by the patient and attempt to correct them to ensure an enjoyable experience in the outdoors. This article outlines the goals of the PPE along with identification of various risk factors that can influence a trip. Most injuries and rescues occur from underestimating the risks from extrinsic, environmental factors, and/or overestimating one's intrinsic skills. By matching the patient's fitness and skill level to the environment, the physician can help reduce the risk of serious injury., (Copyright © 2015. Published by Elsevier Inc.)

Background: Although mild traumatic brain injury (MTBI) is not as common in professional baseball as in collision sports, it does occur and frequently results in significant loss of time away from the sport. To date, no study has investigated MTBI among an entire cohort of professional baseball players., Purpose: To investigate MTBIs in major and minor league baseball players to determine the most common mechanisms of injury, activity at time of injury, position, level of play, and time lost, as well as ultimately inform prevention efforts. A secondary objective was to document the association between MTBI and return to play using several different measures., Study Design: Descriptive epidemiologic study., Methods: Data were captured from a newly implemented league-wide injury surveillance system that records injuries among all professional baseball players as entered by certified athletic trainers and physicians. The MTBIs were identified with respect to level of play, activity, field location, and mechanism of injury. Time loss was assessed by 3 measures of return to play, and MTBI game rates were reported as injuries per 1000 athlete-exposures. Data were combined over the 2011-2012 seasons for analysis, and results were presented separately for minor and major league players. Chi-square tests were used to test the hypothesis of equal proportions between the various categories of MTBI injury characteristics., Results: There were 41 reported MTBIs in the major leagues and 266 in the minor leagues over the 2-year period under study. The overall MTBI game rate across both major and minor league ball clubs was 0.42 per 1000 athlete-exposures. The median time lost was 9 days. Mild traumatic brain injury accounted for 1% of all injuries resulting in time lost from play. For MTBIs that occurred while fielding, catchers were significantly overrepresented. No differences were noted among the 3 measures of time lost., Conclusion: Mild traumatic brain injury is an important problem in professional baseball players, especially for catchers. This study provides a foundation for future inquiry to reduce the incidence of MTBI in those positions at greatest risk and to provide a baseline as rules and equipment evolve., (© 2015 The Author(s).)

Background: Uveal melanoma (UM) is the most common primary intraocular malignancy in adults. Early treatment may improve any chances of preventing metastatic disease, but diagnosis of small UM is challenging. Up to 95 % of all UMs carry somatic mutations in the G-coupled proteins GNAQ and GNA11 promoting anchorage-independent growth and proliferation. About 50 % of UMs are fatal. Once metastatic, patients have limited options for successful therapy., Methods: We have developed functionalized gold nanoparticles (AuNPs) to visualize transcripts of mutant GNAQ mRNA in living cells. In addition to their suitability as a specific tool for GNAQ mutation detection, we have developed a novel linker that enables conjugation of siRNAs to AuNPs allowing for greater and more rapid intracellular release of siRNAs compared to previously described approaches., Results: Binding of modified AuNPs to matching target mRNA leads to conformational changes, resulting in a detectable fluorescent signal that can be used for mutation detection in living cells. Knockdown of GNAQ with siRNA-AuNPs effectively reduced downstream signals and decreased cell viability in GNAQ mutant uveal melanoma cells., Conclusion: AuNPs may in future be developed to serve as sensors for mutations of vital importance. The new release system for siRNA-AuNP improves previous systems, which conceivably will be useful for future therapeutic gene regulatory approaches.

To help clinicians understand the risks associated with performance-enhancing drugs, this overview covers prohibited lists of substances and methods, therapeutic use exemptions, the legitimate indications and adverse effects, including for megadose and polypharmacy doping of stimulants, anabolic steroids, erythropoiesis-stimulating agents, and growth hormone and ways in which physicians or patients risk committing anti-doping rule violations inadvertently., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Context: The therascreen KRAS RGQ polymerase chain reaction kit is being developed as a companion diagnostic to aid clinicians, through detection of KRAS mutations, in the identification of patients with metastatic colorectal cancer (mCRC) who are more likely to benefit from cetuximab., Objectives: To assess whether KRAS mutation status, determined by using the therascreen KRAS kit, is a predictive marker of cetuximab efficacy., Design: Tissue samples were obtained from patients with mCRC treated on the National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) CO.17 phase 3 study of cetuximab plus best supportive care (BSC) versus BSC alone. Tumor DNA samples were assessed for the presence of KRAS mutations by using the therascreen KRAS kit. Efficacy and safety were assessed to determine whether mutation status was predictive of outcomes. Results.-Evaluable samples were available from 453 patients (79.2%) enrolled in the NCIC CTG CO.17 trial. The KRAS wild-type subset represented 54.1% (245 of 453) of the evaluated population. Median overall survival of patients with KRAS wild-type tumors was 8.6 months among those who received cetuximab plus BSC and 5.0 months among patients who received BSC alone (hazard ratio [HR], 0.63; P = .002). Among patients with KRAS mutant mCRC, no meaningful difference in overall survival was observed between arms (HR, 0.91; P = .55). These results are consistent with a previous report that analyzed patient tumor samples by using bidirectional sequencing., Conclusions: These data support the utility of the therascreen KRAS kit as a means of selecting patients who may benefit from cetuximab therapy.

Activating mutations in the neuroblastoma rat sarcoma viral oncogene homolog (NRAS) gene are common genetic events in malignant melanoma being found in 15-25% of cases. NRAS is thought to activate both mitogen activated protein kinase (MAPK) and PI3K signaling in melanoma cells. We studied the influence of different components on the MAP/extracellular signal-regulated (ERK) kinase (MEK) and PI3K/mammalian target of rapamycin (mTOR)-signaling cascade in NRAS mutant melanoma cells. In general, these cells were more sensitive to MEK inhibition compared with inhibition in the PI3K/mTOR cascade. Combined targeting of MEK and PI3K was superior to MEK and mTOR1,2 inhibition in all NRAS mutant melanoma cell lines tested, suggesting that PI3K signaling is more important for cell survival in NRAS mutant melanoma when MEK is inhibited. However, targeting of PI3K/mTOR1,2 in combination with MEK inhibitors is necessary to effectively abolish growth of NRAS mutant melanoma cells in vitro and regress xenografted NRAS mutant melanoma. Furthermore, we showed that MEK and PI3K/mTOR1,2 inhibition is synergistic. Expression analysis confirms that combined MEK and PI3K/mTOR1,2 inhibition predominantly influences genes in the rat sarcoma (RAS) pathway and growth factor receptor pathways, which signal through MEK/ERK and PI3K/mTOR, respectively. Our results suggest that combined targeting of the MEK/ERK and PI3K/mTOR pathways has antitumor activity and might serve as a therapeutic option in the treatment of NRAS mutant melanoma, for which there are currently no effective therapies.

According to Gary Green, MD, everyone who deals with athletes is a "stakeholder" in the issue of performance-enhancing drugs and can influence athletes in a positive or negative role. In this issue of ORTHOPEDICS, Dr Green shares his thoughts on testing, prevention, and education of performance-enhancing drug use.

Drug testing is now ubiquitous in sport, and it often falls to the team physician to perform a variety of roles including interpreting test results, designing drug-testing programs, acting as medical review officer, and providing therapeutic use exemptions, education, and counseling. Proper understanding of current testing methods for drugs such as anabolic-androgenic steroids, erythropoietin, and growth hormone is essential if the team physician is going to assume these positions. This article outlines the basics of athletic drug testing from the collection process through the interpretation of results to assist the team physician in this field.

Background: Doping with erythropoietic proteins such as recombinant human erythropoietin (rHuEPO) and darbepoetin alfa is a serious issue in sport. There is little information on the time course of detection of rHuEPO in urine and on methods to evaluate electrophoresis-based data., Methods: We used a recently described isoelectric focusing method for detecting rHuEPO and endogenous EPO in urine obtained from individuals treated with placebo or epoetin alfa. The latter was administered subcutaneously at 50 IU/kg on days 0, 2, 4, 7, 9, 11, 14, 16, and 18. Blood and urine samples were collected during the morning of study days -3, 0, 2, 4, 7, 9, 11, 14, 16, and 18 and on days 2, 3, 4, and 7 postadministration. We developed visual and numerical (two-band ratio) techniques to evaluate the electropherograms for the presence of rHuEPO., Results: Compared with the placebo group, the epoetin alfa-treated group responded with increases in hematocrit, reticulocytes, macrocytes, serum EPO, and serum soluble transferrin receptor. The electropherograms showed that the pattern of bands arising from urinary rHuEPO is different from that of endogenous urinary EPO. Both the two-band ratio and the visual technique detected rHuEPO in all 14 epoetin alfa-treated individuals 3 days after the last dose. On the 7th day after the last dose, both techniques detected rHuEPO in approximately one-half of the participants. rHuEPO was not detected in the placebo-treated individuals., Conclusions: The isoelectric focusing method detects rHuEPO in most urine samples collected 3 days after nine doses of epoetin alfa. The numerical two-band ratio was equivalent to a visual method for detecting rHuEPO in urine.

Premature very-low-birth-weight infants with posthemorrhagic hydrocephalus are often managed with intermittent cerebrospinal fluid drainage from a ventricular reservoir. There are little data regarding intracranial pressure changes during intermittent drainage to determine the amount and frequency of cerebrospinal fluid removal or to determine the correct resistance of future programmable shunts. The objective of this study was to determine the feasibility of using a commercially available intracranial pressure transducer to measure changes in pressure associated with this procedure. Continuous intracranial pressure was measured in three infants with a transducer placed at the time of ventricular reservoir insertion. Daily reservoir taps began 48 hours after placement and intracranial pressure was monitored for 7 days. Intracranial pressure before the initial tap was comparable to levels previously reported as normal. The daily removal of 10 cc/kg of cerebrospinal fluid was sufficient to lower intracranial pressure below baseline, however it was associated with wide swings in pressure and, in one patient, sustained negative pressure. The use of direct intracranial pressure monitoring may be useful in determining the optimal amount and frequency of cerebrospinal drainage from infants with posthemorrhagic hydrocephalus managed with a ventricular reservoir, as well as determining resistance settings of subsequent programmable shunts.

Objective: To determine if steroids containing over-the-counter (OTC) dietary supplements conform to the labeling requirements of the 1994 Dietary Supplement Health and Education Act (DSHEA)., Design: 12 brands of OTC supplements containing 8 different steroids were randomly selected for purchase in stores that cater to athletes. There are two androstenediones (4- and 5-androstene-3,17-dione), two androstenediols (4- and 5-androstene-3beta, 17beta-diol), and 4 more are 19-nor cogeners (19-nor-4- and 5-androstene-3,17-dione and 19-nor-4- and 5-androstene-3beta, 17beta-diol)., Main Outcome Measures: 12 brands of OTC anabolic-androgenic supplements were analyzed by high-pressure liquid chromatography., Results: We found that 11 of 12 brands tested did not meet the labeling requirements set out in the 1994 Dietary Supplement Health and Education Act. One brand contained 10 mg of testosterone, a controlled steroid, another contained 77% more than the label stated, and 11 of 12 contained less than the amount stated on the label., Conclusions: These mislabeling problems show that the labels of the dietary steroid supplements studied herein cannot be trusted for content and purity information. In addition, many sport organizations prohibit OTC steroids; thus, athletes who use them are at risk for positive urine test results. In this article we provide the details of the analyses, a summary of the steroids by name and structure, and information on the nature of the positive test results. Athletes and their physicians need this information because of the potential medical consequences and positive urine test results.

Nonsteroidal anti-inflammatory drugs (NSAIDs) annually account for 70 million prescriptions and 30 billion over-the-counter (OTC) medications sold in the United States alone. Despite our familiarity with these drugs, NSAIDs are full of paradoxes that pose significant challenges for the medical community. Although NSAIDs are among the oldest of drugs, new formulations continue to come to market. Some formulas are safe enough to be sold OTC for use in infants with fever, while others are available only as a prescription medication and are a leading cause of iatrogenic reactions, hospitalizations, and death. Physicians face the choice of prescribing lower cost, older NSAIDs versus the more expensive but potentially safer ones. The use of NSAIDs is clearly increasing. Factors contributing to this increase are the availability of OTC preparations and the aging of the population with a concomitant increase in osteoarthritis. One indication of the popularity of NSAIDs is that following the introduction of 2 new cyclooxygenase-2 (COX-2) selective inhibitors in 1999, these drugs immediately became the most frequently prescribed new drugs in the United States. This article will familiarize the practitioner with the various types of NSAIDs, including the newer COX-2 formulations, their mechanism of action, and potential adverse reactions and efficacy. Although most practitioners are aware of the indications for NSAIDs, research is continuing to explore nontraditional applications. A new framework is being created that will allow new additions to the NSAID class of medications.

Objective: To determine the substance-use patterns of National Collegiate Athletic Association (NCAA) student-athletes for alcohol, amphetamines, anabolic steroids, cocaine/crack, ephedrine, marijuana/hashish, psychedelics/hallucinogens, and smokeless tobacco., Design: Self-reported, anonymous, retrospective survey., Participants: Male and female student-athletes from 30 sports competing at 991 NCAA Division I, II, and III institutions., Main Outcome Measures: Respondents were queried about their use of eight categories of substances in the previous 12-month period. In addition, data were collected regarding substance use according to team, ethnicity, NCAA Division, reasons for use, and the sources for drugs., Results: The overall response rate was 64.3% with 637 of 991 schools reporting with usable data on 13,914 student-athletes. For the eight categories of substance use, alcohol was the most widely used drug in the past year at 80.5%, followed by marijuana at 28.4%, and smokeless tobacco at 22.5%. Although anabolic steroid use was reported at 1.1% overall, some sports demonstrated higher use, and 32.1% obtained their anabolic steroids from a physician other than the institution's team physician. There were wide variations in the pattern of substance abuse according to sport. The results were also analyzed according to division, and it was found that the likelihood of alcohol, amphetamines, marijuana, and psychedelics use is highest in Division III. In addition, the probability of ephedrine use is highest in both Division II and III, while Division II had the highest likelihood of cocaine use. Finally, the results were analyzed according to ethnicity and we found that the likelihood of use of smokeless tobacco, alcohol, ephedrine, amphetamines, marijuana, and psychedelics is highest for Caucasian student-athletes., Conclusion: The study demonstrates a wide variation of use across NCAA divisions and sports, as well as among ethnic groups. The majority of student-athletes engage in substance use, especially alcohol. According to the survey, substance use is highest among Division III student-athletes and also among Caucasians. By examining reasons for use, the study will assist professionals in designing specific interventions for various substances. This study provides a methodology for surveying a large number of NCAA student-athletes, which will be repeated every 4 years to identify trends in substance abuse.

Context: Several anabolic steroids are sold over-the-counter (OTC) in the United States, and their production is not regulated by the US Food and Drug Administration. Reports have suggested that use of these supplements can cause positive urine test results for metabolites of the prohibited steroid nandrolone., Objectives: To assess the content and purity of OTC androstenedione and to determine if androstenedione and 19-norandrostenedione administration causes positive urine test results for 19-norandrosterone, a nandrolone metabolite., Design: Randomized controlled trial of androstenedione, open-label trial of 19-norandrostenedione, and mass spectrometry of androstenedione preparations, conducted between October 1998 and April 2000., Setting: Outpatient facility of a university hospital., Participants: A total of 41 healthy men aged 20 to 44 years., Intervention: Participants were randomly assigned to receive oral androstenedione, 100 mg/d (n = 13) or 300 mg/d (n = 11) for 7 days, or no androstenedione (n = 13); in addition, 4 patients received 10 microg of 19-norandrostenedione., Main Outcome Measures: Content of OTC androstenedione preparations; level of 19-norandrosterone in urine samples, determined by mass spectrometry, compared among the 3 randomized groups at day 1 and day 7, and among the participants who received 19-norandrostenedione from October 1998 to April 2000., Results: All urine samples from participants treated with androstenedione contained 19-norandrosterone, while no samples from the no-androstenedione group did. Urinary concentrations were averaged for day 1 vs day 7 measurements; mean (SD) 19-norandrosterone concentrations in the 100-mg/d and 300-mg/d groups were 3.8 (2.5) ng/mL and 10.2 (6.9) ng/mL, respectively (P =. 006). The 19-norandrosterone content exceeded the cutoff for reporting positive cases (>2.0 ng/mL) in 20 of 24. The androstenedione preparation used was pure at a sensitivity of 0.1%, but at 0.001% 19-norandrostenedione was found. For the 4 participants to whom 10 microg of 19-norandrostenedione was administered, 19-norandrosterone was found in all urine samples. Of 7 brands of androstenedione analyzed at the 1% level, 1 contained no androstenedione, 1 contained 10 mg of testosterone, and 4 more contained 90% or less of the amount stated on the label., Conclusion: Our study suggests that trace contamination of androstenedione with 19-norandrostenedione is sufficient to cause urine test results positive for 19-norandrosterone, the standard marker for nandrolone use. Oral steroid doses as small as 10 microg are absorbed and excreted in urine. Some brands of androstenedione are grossly mislabeled. Careful analysis of androstenedione preparations is recommended in all studies of its biological effects. JAMA. 2000;284:2618-2621.

While the crucial role of haemoglobin in aerobic exercise has been well accepted, there is still a great deal of controversy about the optimal haematological parameters in the athletic population. The initial part of this review will examine the question of anaemia in athletes. The most common finding in athletes is a dilutional pseudoanaemia that is caused by a plasma volume expansion, rather than an actual blood loss. It is not a pathological state and normalises with training cessation in 3 to 5 days. This entity should be distinguished from conditions associated with lowered blood counts, such as intravascular haemolysis or iron deficiency anaemia. The evaluation of true anaemia states in the athlete must take into account not only blood losses secondary to exercise, such as foot strike haemolysis or iron losses through sweat, but non-athletic causes as well. Depending on the age and sex of the athlete, consideration must be given to evaluation of the gastrointestinal or genitourinary systems for blood loss. Finally, a comprehensive nutritional history must be taken, as athletes, especially women, are frequently not consuming adequate dietary iron. The second section of the paper will deal with the very contentious issue of sickle cell trait. While there have been studies demonstrating an increased risk of sudden death in people with sickle cell trait, it is still quite rare and should not be used as a restriction to activity. Further, studies have demonstrated that patients with sickle cell trait have an exercise capacity that is probably normal or near normal. However, in the cases of sudden death, it has been secondary to rhabdomyolysis occurring among sickle cell trait athletes performing at intense exertion under hot conditions, soon after arriving at altitude. The recommendations are that athletes with sickle cell trait adhere to compliance with the general guidelines for fluid replacement and acclimatisation to hot conditions and altitude. The final section of the paper examines the issue of haematological manipulation for the purposes of ergogenic improvement. Although experiments with blood doping revealed improvements in running time to exhaustion and maximal oxygen uptake, the introduction of recombinant erythropoietin has rendered blood doping little more than a historical footnote. However, the improvements in performance are not without risk, and the use of exogenous erythropoietin has the potential for increased viscosity of the blood and thrombosis with potentially fatal results. Until a definitive test is developed for detection of exogenous erythropoietin, it will continue to be a part of elite athletics.

A premature infant exposed to carbamazepine in utero had a markedly undersized brain on cranial ultrasonogram. Postmortem examination of the brain revealed no evidence of hypoxic-ischemic injury, hemorrhage, infarction, congenital infection, or calcification. The normal cortical gyral pattern, normal residual germinal matrix, and normal cortical lamination suggested the diagnosis of a radial microbrain form of micrencephaly.

This article examines the types of forces that the brain is subjected to in soccer, secondary to both acute brain injury and repetitive heading of the ball. The incidence of acute brain injury is reviewed, as well as studies documenting the effects of heading the ball. Finally, 10 actions are proposed that would make soccer a safer sport with respect to brain injuries and provide avenues for further study in this area.

Background: In most reported surgical series, prostate carcinoma patients with a Gleason score of 7 have had worse outcomes than those with other moderately differentiated cancers. Because of variations in reporting grade and grouping Gleason scores, radiation series have conflicting results., Methods: Five hundred sixty-three men with clinical Stage T1-T3, N0 or Nx, M0 adenocarcinoma of the prostate and known pretreatment prostate specific (PSA) levels received external beam radiation only. The median pretreatment PSA was 10.3 ng/mL (range, 0.2-191 ng/mL). The median duration of follow-up was 42 months (range, 2-114 months). Survival without biochemical failure (bNED) was defined as PSA < or = 1.5 ng/mL and not rising when measured on two consecutive occasions., Results: The 5-year rate of bNED control for all 563 patients was 62%. Increasing Gleason score predicted for decreased bNED control (78% for 2-4, 63% for 5-6, 37% for 7, and 33% for 8-10 at 5 years; P = 0.0001 for overall comparison). The bNED control rate for patients with a Gleason score of 7 was significantly less than the rate for those with Gleason 5-6 in both univariate (P = 0.0008) and multivariate (P = 0.0068) analysis. T classification by palpation, pretreatment PSA, and dose were also shown to be independent predictors of bNED control in multivariate analysis., Conclusions: Even after adjustment for other known prognostic factors, a Gleason score of 7 was associated with worse bNED control than Gleason scores of 2-4 and 5-6 among patients treated with external beam radiotherapy only for clinically localized prostate carcinoma. Patients with a Gleason score of 7 should not be lumped together with those who have a Gleason score of 5-6; they may instead benefit from more aggressive treatment strategies.

Background: The purpose of this study was to describe the levels of health-related fitness and quality of life in a group of organ transplant recipients who participated in the 1996 U.S. Transplant Games., Methods: A total of 128 transplant recipients were selected on a first reply basis for testing. Subjects with the following organ types were tested: kidney (n=76), liver (n=16), heart (n=19), lung (n=6), pancreas/kidney (n=7), and bone marrow (n=4). Cardiorespiratory fitness (peak oxygen uptake) was measured using symptom-limited treadmill exercise tests with expired gas analysis. The percentage of body fat was measured using skinfold measurements, and the Medical Outcomes Short Form questionnaire (SF-36) was used to evaluate health-related quality of life., Results: Participants achieved near age-predicted cardiorespiratory fitness (94.7+/-32.5% of age-predicted levels). Scores on the SF-36 were near normal. The active subjects (76% of total sample) had significantly higher levels of peak VO2 and quality of life and a lower percentage of body fat compared with inactive subjects (P<0.01)., Conclusions: Although this is a highly select group which is not representative of the general transplant population, the data suggest that near-normal levels of physical functioning and quality of life are possible after transplantation and that those who participate in regular physical activity may achieve even higher levels.

Objective: To determine whether college athletes are at greater risk for maladaptive lifestyle and health-risk behaviors than their nonathletic peers and to identify high risk taking groups by gender, sport, and other identifiers., Design: Multicenter, cross-sectional study., Setting: Seven major geographically represented collegiate institutions in the United States., Participants: A total of 2,298 college athletes and 683 randomized nonathlete controls completed a confidential survey questionnaire between the summer of 1993 and winter of 1994, assessing lifestyle and health-risk behaviors over the previous 12 months., Main Outcome Measures: Self-reports of lifestyle behaviors and health risks in the following areas: motor-vehicle safety, substance abuse, sexually transmitted diseases and contraception, mental health, cancer prevention, nutrition, exercise and general preventive health issues., Results: Athletes demonstrated significantly higher risk-taking behaviors (p < 0.05) than their nonathlete peers in the following areas: less likely always to use seatbelts; less likely always to use helmets with motorcycles, mopeds, and bicycles; more often drive as a passenger with a driver under the influence of alcohol or drugs; greater quantity and frequency of alcoholic beverages; greater frequency of smokeless tobacco and anabolic steroid use; less-safe sex; greater number of sexual partners; less contraceptive use; and more involvement in physical fights. Female athletes reported a higher prevalence of irregular menses, amenorrhea, and stress fractures compared with female nonathletes. Male athletes had more risk-taking behaviors than did female athletes (p < 0.05), and athletes in contact sports demonstrated more risk-taking behaviors than did athletes in noncontact sports (p < 0.05). Athletes with one risk-taking behavior were likely to have multiple risk-taking behaviors (p < 0.05)., Conclusions: College athletes appear to be at higher risk than their nonathletic peers for certain maladaptive lifestyle behaviors. Athlete subgroups at highest risk include male athletes and athletes participating in contact sports. Athletes at risk for one high-risk behavior demonstrated an increased risk for multiple risk-taking behaviors. Preventive health interventions deserve further study to determine strategies for risk reduction in high-risk groups.

An assay for hepatitis B surface antigen (HBsAg) should reliably detect 0.2 microgram/L, the lowest reported concentration in an asymptomatic blood donor. The difference between this concentration and the assay cutoff defines the analytical quality requirement in a total error format. The design of a statistical QC procedure is critically dependent on the precision of the assay. The precision of a developmental ELISA of HBsAg under study ranged from 17.5% to 9.6% for controls containing 0.07 to 1.50 micrograms/L, respectively. Use of one positive control with the 1(3s), QC rule provided an 85% chance of detecting a critical loss of assay sensitivity; use of two positive controls increased the chance of detecting critical loss of assay sensitivity to nearly 100%. These rules are based on the precision of this developmental assay, and must be developed individually for other assays. The development of the proposed QC procedures illustrates how quantitative QC can be provided for qualitative assays.

The CD23 antigen is a low-affinity immunoglubulin E receptor that is expressed during B-cell activation. Recently, it has been shown to be of diagnostic utility in distinguishing between small lymphocytic lymphoma (SLL) and mantle cell lymphoma (MCL), two entities that can have similar morphologic and immunophenotypic features. Such studies, however, generally required viable cells in cell suspension or cryostat sections for detection of CD23. We evaluated staining for the CD23 antigen in paraffin sections, using BU38, an antibody that detects a fixation-resistant epitope of the antigen. We analyzed 44 SLLs, 3 lymphoplasmacytoid lymphomas, and 39 MCLs. Staining was performed on formalin- or B5-fixed paraffin-embedded tissue sections using L26 (CD20), CD3, Leu22 (CD43), and BU38 (CD23) antibodies. All of the cases were of B-cell phenotype (CD20+), and 42/44 SLLs, 3/3 lymphoplasmacytoid lymphomas, and 33/39 MCLs coexpressed the CD43 antigen. CD23 was positive in 41 (93%) of 44 SLLs. The majority of neoplastic cells (75% or more) stained positively, with a membranous pattern of staining. The staining was moderate in intensity and easily interpreted. Only 1/39 MCLs and 1/3 lymphoplasmacytoid lymphomas were CD23 positive. CD23-positive follicular dendritic cells were, however, present in all of the MCLs, either in residual follicles or in large, disordered meshworks. These results demonstrate that the BU38 antibody can detect CD23 on the cells of SLLs in paraffin sections and that this antibody can have diagnostic utility in routine diagnosis.

The lethal toxin (LT) from Clostridium sordellii belongs to the family of large clostridial cytotoxins causing morphological alterations in cultured cell lines accompanied by destruction of the actin cytoskeleton. C. sordellii LT exhibits 90% homology to Clostridium difficile toxin B, which has been recently identified as a monoglucosyltransferase (Just, I., Selzer, J., Wilm, M., von Eichel-Streiber, C., Mann, M., and Aktories, K. (1995) Nature 375, 500-503). We report here that LT too is a glucosyltransferase, which uses UDP-glucose as cosubstrate to modify low molecular mass GTPases. LT selectively modifies Rac and Ras, whereas the substrate specificity of toxin B is confined to the Rho subfamily proteins Rho, Rac, and Cdc42, which participate in the regulation of the actin cytoskeleton. In Rac, both toxin B and LT share the same acceptor amino acid, threonine 35. Glucosylation of Ras by LT results in inhibition of the epidermal growth factor-stimulated p42/p44 MAP-kinase signal pathway. LT is the first bacterial toxin to inactivate Ras in intact cells.

In ileal loop assay, ELISA and anion-exchange column chromatography, Clostridium sordellii strain 6018 was shown to produce a cytotoxin, but no detectable enterotoxin. DNA sequence and polymerase chain reaction analyses indicated that the lack of enterotoxin activity is not due to a lack of gene transcription, but to lack of a major portion of the enterotoxin gene. This is the first characterisation of such a strain.

Hybridization of an oligodeoxyribonucleotide (oligo) probe, designed from a repeated sequence ('oligo rep') at the C terminus of the Clostridium difficile (Cd) cytotoxin (Cyt), revealed that homologies exist between the Cd cyt gene and the genomes of several other clostridia, including Clostridium sordellii (Cs), suggesting a common ancestral cyt amongst the Clostridium genus. This Cd 'oligo rep' probe was used to clone the Cs (strain 6018) cyt. The sequenced (7095 bp) region encodes 2364 amino acids (aa) and corresponds to a protein of 270,614 Da. Cs Cyt has 76% identity with the Cd Cyt and 47% identity with the Cd enterotoxin (Ent). The latter third of the protein consists of repeated units, similar to those found for Cd Cyt. A highly conserved hydrophobic domain can be delineated. Few structural differences are evident between Cd and Cs Cyt to explain their different cellular and sub-cellular effects. A small open reading frame (ORF) encoding a protein of 16,484 Da is located 210 bp downstream from cyt. No homology was evident with any known sequence. The first 30 aa of this ORF may correspond to a signal peptide.

The most common acute knee injuries are collateral ligament sprains, meniscal damage, cruciate ligament sprains and patellar dislocation or subluxation events. Initial treatment for these soft tissue injuries includes rest, ice application, compression and elevation for the first 24 to 72 hours, as well as anti-inflammatory medication. Accurate assessment, utilizing a thorough history and physical examination and judicious use of radiographic studies, facilitates proper management and return to activity. Athletic patients should be offered the option of surgical reconstruction.

A thorough history and physical examination are helpful in the diagnosis of meniscal damage, cruciate and collateral ligament sprains and patellar instability, the four major acute knee injuries. When performing a physical examination in a patient with a knee injury, the uninjured knee should always be assessed first and used for comparison. Examination includes passive and active range-of-motion testing, palpation of the joint line spaces, and a variety of maneuvers to evaluate knee stability. Valgus and varus testing provides assessment of the collateral ligaments. The Lachman and pivot shift tests are useful in the evaluation of the anterior cruciate ligament. The posterior drawer and tibial sag tests are used to evaluate the posterior cruciate ligament. The bounce test, McMurray's test and Apley's grind test can aid in the diagnosis of meniscal injury.